TY - JOUR T1 - The distribution of coagulation factors VII and VIII and fibrinogen in adults over 65 years. Results from the Cardiovascular Health Study. JF - Ann Epidemiol Y1 - 1992 A1 - Tracy, R P A1 - Bovill, E G A1 - Fried, L P A1 - Heiss, G A1 - Lee, M H A1 - Polak, J F A1 - Psaty, B M A1 - Savage, P J KW - African Continental Ancestry Group KW - Age Factors KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Factor VII KW - Factor VIII KW - Female KW - Fibrinogen KW - Humans KW - Male KW - Middle Aged KW - Risk Factors AB -

The Cardiovascular Health Study (CHS) was designed to examine cardiovascular disease and its risk factors in older adults. We report here the distributions of the coagulation factors fibrinogen, factor VII, and factor VIII in a population-based cohort of men and women 65 years or older. In other studies of middle-aged individuals, these factors were shown to be associated with cardiovascular risk. In the CHS cohort, all three factors were elevated, compared to levels reported in middle-aged individuals, and fibrinogen and factor VIII values were higher in each successive age group; factor VII values, in contrast, declined slightly with age in the CHS cohort. Compared to white subjects, blacks had higher values for fibrinogen and factor VIII and lower values for factor VII. While women had markedly higher values for factor VII and factor VIII than men at all ages in the CHS, mean fibrinogen values were not different between men and women.

VL - 2 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/1342301?dopt=Abstract ER - TY - JOUR T1 - Assessment of cerebrovascular disease in the Cardiovascular Health Study. JF - Ann Epidemiol Y1 - 1993 A1 - Price, T R A1 - Psaty, B A1 - O'Leary, D A1 - Burke, G A1 - Gardin, J KW - Aged KW - Aged, 80 and over KW - Cerebrovascular Disorders KW - Cohort Studies KW - Coronary Disease KW - Female KW - Humans KW - Ischemic Attack, Transient KW - Longitudinal Studies KW - Male KW - Prevalence AB -

The Cardiovascular Health Study (CHS) is a longitudinal population-based study of coronary heart disease and stroke in men and women 65 years and older. The initial CHS cohort consisted of 5201 men and women recruited from a random sample of the Health Care Financing Administration (HCFA) Medicare eligibility lists in four communities in the United States. Extensive historical, physical, and laboratory evaluations were performed at the baseline examination in 1989 to 1990 to identify risk factors and subclinical disease. Periodic contacts are carried out to ascertain and verify incident cardiac and stroke events and their sequelae. Since only a short time has passed since entry of all the patients into the study, data are not available on time trends in the mortality rate of stroke, but we expect to contribute in this area in the years ahead. This article then is a description of the CHS, of methods of assessing stroke in the CHS cohort, and of prevalence of stroke and transient ischemic attacks at the initial examination.

VL - 3 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8167827?dopt=Abstract ER - TY - JOUR T1 - Properties of the random zero sphygmomanometer. JF - Hypertension Y1 - 1993 A1 - Kronmal, R A A1 - Rutan, G H A1 - Manolio, T A A1 - Borhani, N O KW - Aged KW - Blood Pressure KW - Blood Pressure Determination KW - Cohort Studies KW - Diastole KW - Humans KW - Regression Analysis KW - Systole AB -

The random zero sphygmomanometer is widely used in studies involving blood pressure measurement because it is believed to eliminate digit preference and reduce measurement error. We performed blood pressure measurements sequentially using random zero and standard sphygmomanometers in random order in 1,356 participants in the Cardiovascular Health Study. Despite adherence to the manufacturer's instructions, we observed a substantially nonuniform distribution of zero levels generated by the random zero sphygmomanometer and a disturbing correlation between the zero level and blood pressures taken with the standard sphygmomanometer. With the random zero device, the pooled estimated slopes for the regression of standard systolic and diastolic pressures on the zero level were -0.71 and -0.17, respectively (both p < 0.0001). The only plausible explanation for this relation between the random zero device and the standard device is that by some unknown mechanism the subject's blood pressure is influencing the zero level. Systolic and diastolic blood pressures measured with the random zero device were, respectively, 1.65 and 1.84 mm Hg lower (both p < 0.0001) than standard blood pressures. Digit preference was detectable in the uncorrected blood pressure and zero level measured with the random zero device but was eliminated after calculation of the corrected blood pressure. For most epidemiological studies, the random zero sphygmomanometer offers no significant advantage over the standard sphygmomanometer. It may still be useful in those epidemiological studies and clinical trials where blinding is important.

VL - 21 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8491498?dopt=Abstract ER - TY - JOUR T1 - Recruitment of adults 65 years and older as participants in the Cardiovascular Health Study. JF - Ann Epidemiol Y1 - 1993 A1 - Tell, G S A1 - Fried, L P A1 - Hermanson, B A1 - Manolio, T A A1 - Newman, A B A1 - Borhani, N O KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - Epidemiologic Methods KW - Female KW - Humans KW - Male AB -

Few large-scale epidemiologic studies have enrolled older adults; hence, little is known about the feasibility of recruiting this group for long-term population-based studies. In this article we present the recruitment experience of the Cardiovascular Health Study (CHS), a population-based, longitudinal study of cardiovascular diseases in adults 65 years and older. Participants were sampled from the Health Care Financing Administration's (HCFA) Medicare eligibility lists in four US communities. Letters were mailed to 11,955 sampled individuals. Persons recruited were required to complete an extensive home interview and then a 4-hour in-clinic examination. Excluded were persons who were expected to be able to complete the baseline examination and who were not expected to return for the 3-year follow-up. Some 3654 participants were recruited from those randomly selected from the Medicare sampling frame. In addition, 1547 other age-eligible persons living in the household with the sampled individuals also participated, yielding a total of 5201 participants. Of those who were contacted, 9.6% were ineligible and 34.9% refused participation. Among those eligible, 38.6% refused and 57.3% were enrolled (the remaining did not refuse but were not enrolled before the recruitment ended). Data from a subsample indicate that compared to those who were ineligible or who refused, enrolled participants were younger, more highly educated, more likely to be married, and less likely to report limitations in activity. Compared to those who were eligible but refused, enrolled participants were less likely to have high blood pressure and stroke and more likely to have quit smoking and to perceive their health status as very good or excellent.(ABSTRACT TRUNCATED AT 250 WORDS)

VL - 3 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8275211?dopt=Abstract ER - TY - JOUR T1 - Temporal patterns of antihypertensive medication use among elderly patients. The Cardiovascular Health Study. JF - JAMA Y1 - 1993 A1 - Psaty, B M A1 - Savage, P J A1 - Tell, G S A1 - Polak, J F A1 - Hirsch, C H A1 - Gardin, J M A1 - McDonald, R H KW - Adrenergic beta-Antagonists KW - Aged KW - Analysis of Variance KW - Angiotensin-Converting Enzyme Inhibitors KW - Antihypertensive Agents KW - Calcium Channel Blockers KW - Cohort Studies KW - Diuretics KW - Drug Utilization KW - Female KW - Follow-Up Studies KW - Humans KW - Hypertension KW - Linear Models KW - Logistic Models KW - Male KW - Medicare KW - Practice Patterns, Physicians' KW - Recurrence KW - United States KW - Vasodilator Agents AB -

OBJECTIVES: To estimate the incidence of newly treated hypertension and to describe the patterns of antihypertensive medication use among those aged 65 years and older.

DESIGN: Medicare eligibility lists from four US communities (Forsyth County, North Carolina; Washington County, Maryland; Sacramento County, California; and Pittsburgh, Pa) were used to obtain a representative sample of 5201 community-dwelling elderly for the Cardiovascular Health Study, a prospective cohort study of risk factors for coronary heart disease and stroke. Participants were examined at baseline and again 1 year later. The two examinations included standardized questionnaires, blood pressure measurements, and the assessment of medication use by medication inventory. In this cohort analysis, we excluded 231 subjects (4.4%) who did not return for follow-up, 69 (1.3%) who had missing data for medications, and another 495 (9.5%) who were taking "antihypertensive" medications for an indication other than high blood pressure.

INTERVENTIONS: None.

RESULTS: Among the 4406 participants, 1613 used antihypertensive medications at both visits. Between the two visits, 144 started and 115 stopped antihypertensive therapy. Among nonusers at baseline, the annual incidence of newly treated hypertension was 5.2% in women and 5.6% in men. Due to the number of participants who stopped therapy, the overall prevalence of antihypertensive treatment increased only slightly, from 40.7% to 41.1% in women and from 37.1% to 38.2% in men, during 1 year of follow-up. After adjustment for age, systolic blood pressure, number of antihypertensive drugs, diabetes, and cardiovascular disease, the newly treated hypertensives were about half as likely as the previously treated hypertensives to receive diuretics (odds ratio [OR], 0.59; P = .008) or beta-blockers (OR, 0.52; P = .01); and they were about twice as likely to receive calcium channel blockers (OR, 1.88; P < .004) or angiotensin converting enzyme inhibitors (OR, 2.40; P < .001). A similar pattern of within-person changes over time was apparent among the continuous users.

CONCLUSIONS: Between June 1990 and June 1991, physicians were increasingly prescribing angiotensin converting enzyme inhibitors and calcium channel blockers in place of diuretics and beta-blockers for the treatment of hypertension in elderly patients, especially for those just starting therapy.

VL - 270 IS - 15 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8105112?dopt=Abstract ER - TY - JOUR T1 - Correlates of blood pressure in community-dwelling older adults. The Cardiovascular Health Study. Cardiovascular Health Study (CHS) Collaborative Research Group. JF - Hypertension Y1 - 1994 A1 - Tell, G S A1 - Rutan, G H A1 - Kronmal, R A A1 - Bild, D E A1 - Polak, J F A1 - Wong, N D A1 - Borhani, N O KW - Aged KW - Aged, 80 and over KW - Aging KW - Blood Pressure KW - Cohort Studies KW - Coronary Disease KW - Female KW - Health Surveys KW - Humans KW - Hypertrophy, Left Ventricular KW - Male KW - Regression Analysis KW - United States AB -

Although elevated blood pressure is an important predictor of cardiovascular disease and stroke in the elderly, little information exists on the distribution and risk factor correlates of blood pressure in this group. As part of the Cardiovascular Health Study, a population-based cohort study of 5201 men and women aged 65 to 101 years, we investigated correlates of systolic and diastolic blood pressure. Multiple regression analyses were conducted for all participants and a subgroup of 2482 without coronary heart disease and not on antihypertensive therapy (the "healthier" subgroup). In the total group, independent predictors of diastolic blood pressure included heart rate, aortic root dimension, creatinine, hematocrit, alcohol use, and black race (positive associations) and internal carotid artery wall thickness, mitral early/late peak flow velocity, white blood cell count, cigarette smoking, and age (negative associations). Positive predictors of systolic blood pressure included mitral late peak flow velocity, left ventricular mass, common carotid artery wall thickness, serum albumin, factor VII, diabetes, alcohol use, and age; negative predictors were coronary heart disease, uric acid, height, and smoking. In the healthier subgroup, positive predictors of diastolic blood pressure included heart rate, hematocrit, serum albumin, creatinine, and body weight, whereas mitral early/late peak flow velocity, serum potassium, smoking, and age inversely related to diastolic pressure. For the same group, common carotid artery wall thickness, left ventricular mass, serum albumin, factor VII, high-density lipoprotein cholesterol, and age were directly related to systolic blood pressure, whereas serum potassium was inversely related. Both systolic and diastolic pressures varied considerably by geographic site.(ABSTRACT TRUNCATED AT 250 WORDS)

VL - 23 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8282331?dopt=Abstract ER - TY - JOUR T1 - High density lipoprotein cholesterol subfractions in older people. JF - J Gerontol Y1 - 1994 A1 - Ettinger, W H A1 - Verdery, R B A1 - Wahl, P W A1 - Fried, L P KW - Aged KW - Aged, 80 and over KW - Alcohol Drinking KW - Body Weight KW - Carotid Stenosis KW - Cholesterol KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Coronary Disease KW - Cross-Sectional Studies KW - Drug Therapy KW - Female KW - Humans KW - Insulin KW - Lipoproteins, HDL KW - Lipoproteins, HDL2 KW - Lipoproteins, HDL3 KW - Male KW - Sex Factors KW - Socioeconomic Factors AB -

BACKGROUND: High density lipoprotein (HDL) may be an important risk factor for cardiovascular disease in older people. HDL is heterogeneous with several subfractions. This article describes the distribution and correlates of HDL2 cholesterol (C) and HDL3-C in older people.

METHODS: HDL subfraction cholesterols were measured in 1,127 females and 825 males > or = 65 years old who participated in the Cardiovascular Health Study. Distributions of HDL subfraction cholesterols and bivariate and multivariate relationships were determined in cross-sectional analyses.

RESULTS: Mean (+/- SD) concentrations of HDL subfractions were: HDL3-C (M .98 +/- .25, F 1.2 +/- .29 mmol/l), HDL2-C (M .09 +/- .08, F .13 +/- .09 mmol/l). HDL2-C, but not HDL3-C, was slightly higher with age. Using multivariate analysis, both HDL2-C and HDL3-C (in females) were inversely correlated with triglyceride, body weight, and fasting insulin; HDL3-C was inversely correlated with central fat distribution in women. Both HDL2-C and HDL3-C were lower in participants with prevalent cardiovascular disease. However, only HDL3-C was significantly inversely related to carotid stenosis, as measured by ultrasound.

CONCLUSIONS: The slight increase in HDL-C with age appears to be due to an increase in the HDL2-C subfraction. HDL-C subfractions are independently related to triglyceride levels, body weight, and insulin concentrations in older people, all potentially modifiable risk factors. Both HDL2-C and HDL3-C are lower in older people with prevalent cardiovascular disease, although only HDL3-C was correlated with carotid atherosclerosis. These findings are consistent with the hypothesis that HDL subfractions are important risk factors for atherosclerotic cardiovascular disease in the elderly.

VL - 49 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8169333?dopt=Abstract ER - TY - JOUR T1 - A method for using MR to evaluate the effects of cardiovascular disease on the brain: the cardiovascular health study. JF - AJNR Am J Neuroradiol Y1 - 1994 A1 - Bryan, R N A1 - Manolio, T A A1 - Schertz, L D A1 - Jungreis, C A1 - Poirier, V C A1 - Elster, A D A1 - Kronmal, R A KW - Aged KW - Brain KW - Cerebral Infarction KW - Cerebral Ventricles KW - Cerebrovascular Disorders KW - Cohort Studies KW - Coronary Disease KW - Cross-Sectional Studies KW - Diagnosis, Differential KW - Feasibility Studies KW - Female KW - Humans KW - Image Interpretation, Computer-Assisted KW - Incidence KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Mass Screening KW - Observer Variation KW - Pilot Projects KW - Prospective Studies KW - Risk Factors KW - United States AB -

PURPOSE: To do a pilot study for the Cardiovascular Health Study (a population-based, longitudinal study of coronary heart disease and stroke in adults 65 years of age and older designed to identify risk factors related to cerebrovascular disease, particularly stroke): (a) to determine the feasibility of adding brain MR to the full-scale study; (b) to evaluate the reliability of standardized MR image interpretation in a multicenter study; and (c) to compare the prevalence of stroke determined by MR with that by clinical history.

METHODS: Protocol-defined MR studies were performed in 100 subjects with clinical histories of stroke and 203 subjects without reported histories of stroke. MR scans were independently evaluated by two trained neuroradiologists for the presence of small (< or = 3 mm) and large (> 3 mm) "infarctlike" lesions. The sizes of the cerebral sulci and lateral ventricles and the extent of white matter disease were graded on a scale of 0 to 9.

RESULTS: Eighty percent of the Cardiovascular Health Study participants who were invited to undergo MR studies agreed to do so; 95% of those agreeing to the procedure successfully completed the exams. Intrareader and interreader reliability of infarctlike lesion identification was high for large lesions (kappa, 0.71 and 0.78, respectively) but not for small lesions (kappa, 0.71 and 0.32, respectively). Relaxed intrareader and interreader kappa scores for sulcal and ventricular sizes and extent of white matter disease were greater than 0.8 MR evidence of infarctlike lesions was present in 77% of the participants with histories of stroke but was also present in 23% of the participants without clinical histories of stroke. Seventy-nine percent of the infarctlike lesions were larger than 3 mm.

CONCLUSIONS: This preliminary study indicates that a large, prospective, epidemiologic study of elderly subjects using MR scans of the brain for identification of cerebrovascular disease is feasible and that the interpretative results are reproducible, and suggests that MR evidence of stroke is more prevalent than reported clinical history of stroke.

VL - 15 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7847205?dopt=Abstract ER - TY - JOUR T1 - Prevalence and correlates of respiratory symptoms and disease in the elderly. Cardiovascular Health Study. JF - Chest Y1 - 1994 A1 - Enright, P L A1 - Kronmal, R A A1 - Higgins, M W A1 - Schenker, M B A1 - Haponik, E F KW - Aged KW - Aged, 80 and over KW - California KW - Cohort Studies KW - Female KW - Humans KW - Lung Diseases KW - Male KW - Maryland KW - Multivariate Analysis KW - North Carolina KW - Pennsylvania KW - Prevalence KW - Prognosis KW - Respiratory Tract Diseases KW - Spirometry KW - Surveys and Questionnaires AB -

Spirometry was performed by 5,201 elderly participants of the Cardiovascular Health Study during their baseline examination and a subset of the ATS/DLD-78 respiratory questionnaire was administered by trained interviewers. In never smokers (46 percent of the cohort), the overall prevalence of chronic cough was 9 percent, chronic phlegm was 13 percent, attacks of wheezing with dyspnea were 8 percent, and grade 3 dyspnea on exertion was 10 percent. The prevalence of lung disease in current smokers (12 percent of the cohort) was 8/7 percent (men/women) with chronic bronchitis and 14/5 percent with emphysema. Overall, 6 percent reported asthma (a physician-confirmed history) and 12 percent reported hay fever. Using a logistic regression model, attacks of wheezing with dyspnea were strongly associated with a lower FEV1, coronary heart disease, heart failure, and a large waist size (in participants without a diagnosis of asthma, chronic bronchitis, or emphysema). Undiagnosed airways obstruction was twice as likely in women and those with lower income, and was associated with current and former smoking, pack-years of smoking, and chronic cough. Dyspnea on exertion (DOE) was three times or more likely if a participant reported heart failure, coronary heart disease, or emphysema; and much more likely if their FEV1 or FVC was substantially reduced. Dyspnea on exertion was also positively associated with older age, chronic bronchitis or asthma, a larger waist or hip size, pack-years of smoking, and less education. We conclude that DOE and attacks of wheezing with dyspnea are commonly associated with cardiovascular disease and a low FEV1 in those over 65 years and that airways obstruction frequently remains undiagnosed in the elderly.

VL - 106 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8082366?dopt=Abstract ER - TY - JOUR T1 - Relation of smoking with carotid artery wall thickness and stenosis in older adults. The Cardiovascular Health Study. The Cardiovascular Health Study (CHS) Collaborative Research Group. JF - Circulation Y1 - 1994 A1 - Tell, G S A1 - Polak, J F A1 - Ward, B J A1 - Kittner, S J A1 - Savage, P J A1 - Robbins, J KW - Aged KW - Aged, 80 and over KW - Carotid Arteries KW - Carotid Stenosis KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Smoking KW - Ultrasonography AB -

BACKGROUND: Cigarette smoking has been associated with increased risk of atherosclerotic diseases in hospital-based studies and in studies of middle-aged populations but not in population-based studies of older adults with and without clinical cardiovascular disease.

METHODS AND RESULTS: We investigated the relation of smoking to carotid artery atherosclerotic disease, expressed as intimal-medial wall thickness and arterial lumen narrowing (stenosis) measured by ultrasound. Subjects were 5116 older adults participating in the baseline examination of the Cardiovascular Health Study, a community-based study of cardiovascular diseases in older age. With increased smoking there was significantly greater internal and common carotid wall thickening and internal carotid stenosis: current smokers > former smokers > never-smokers; for instance, the unadjusted percent stenosis was 24%, 20%, and 16%, respectively (P < .0001). A significant dose-response relation was seen with pack-years of smoking. These findings persisted after adjusting for other cardiovascular risk factors and were also confirmed when analyses were restricted to those without prevalent cardiovascular disease. The difference in internal carotid wall thickness between current smokers and nonsmokers was greater than the difference associated with 10 years of age among never-smoking participants (0.39 mm versus 0.31 mm). Among all participants, the prevalence of clinically significant (> or = 50%) internal carotid stenosis increased from 4.4% in never-smokers to 7.3% in former smokers to 9.5% in current smokers (P < .0001).

CONCLUSIONS: These findings extend previous reports of a positive relation between smoking and carotid artery disease to a population-based sample of older adults using several different indicators of atherosclerotic disease.

VL - 90 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7994837?dopt=Abstract ER - TY - JOUR T1 - Self-reported causes of physical disability in older people: the Cardiovascular Health Study. CHS Collaborative Research Group. JF - J Am Geriatr Soc Y1 - 1994 A1 - Ettinger, W H A1 - Fried, L P A1 - Harris, T A1 - Shemanski, L A1 - Schulz, R A1 - Robbins, J KW - Activities of Daily Living KW - Aged KW - Aged, 80 and over KW - Arthritis KW - Cardiovascular Diseases KW - Chronic Disease KW - Cohort Studies KW - Cross-Sectional Studies KW - Disabled Persons KW - Female KW - Health Status KW - Health Surveys KW - Heart Diseases KW - Humans KW - Lung Diseases KW - Male KW - Observer Variation KW - Reproducibility of Results KW - Risk Factors KW - Sex Factors KW - United States AB -

OBJECTIVE: To determine the major conditions and symptoms reported to cause difficulty in 17 physical tasks of daily life and the criterion validity of self-report of diseases given as the causes of the difficulty in functioning, in community-dwelling older people.

DESIGN: Cross sectional analyses of data obtained in an observational cohort study.

SETTING: Research clinics in four US communities: Winston-Salem, NC, Hagerstown, MD, Pittsburgh, PA, and Sacramento, CA.

PARTICIPANTS: 5201 community-dwelling people > or = 65 years old.

RESULTS: Arthritis and other musculoskeletal diseases were given as the primary causes of difficulty in performing physical tasks by 49.0% of the participants reporting difficulty in any task, followed by heart disease (13.7%), injury (12.0%), old age (11.7%), lung disease (6.0%), and stroke (2.9%). The self-reports of diseases that caused disability varied by task. Whereas arthritis was given as a cause of difficulty in most of the 17 different tasks, heart and lung disease were more likely to be reported as causing difficulty with activities requiring high aerobic work capacity such as walking one-half mile or doing heavy housework. Stroke was more likely to be reported as causing difficulty with use of the upper extremities and in performing basic activities of daily living. There was a high degree of consistency (91%) between the diseases and symptoms reported to cause disabilities. The percentage of people who reported a disease as the cause of their difficulty performing a task and had independent confirmation of the diagnosis was 85% in men and 71% in women, and varied according to type of disease and the individual's cognitive status and health status.

CONCLUSION: These data suggest that age-related chronic diseases are important causes of disability in older people but that the type of disability is dependent on the underlying disease that causes the disability. Also, self-report of the cause of disability appears to be generally accurate but is influenced by gender, health status, and type of disease.

VL - 42 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7930326?dopt=Abstract ER - TY - JOUR T1 - Fibrinogen and factor VIII, but not factor VII, are associated with measures of subclinical cardiovascular disease in the elderly. Results from The Cardiovascular Health Study. JF - Arterioscler Thromb Vasc Biol Y1 - 1995 A1 - Tracy, R P A1 - Bovill, E G A1 - Yanez, D A1 - Psaty, B M A1 - Fried, L P A1 - Heiss, G A1 - Lee, M A1 - Polak, J F A1 - Savage, P J KW - Aged KW - Aged, 80 and over KW - Blood Pressure KW - Cardiovascular Diseases KW - Carotid Stenosis KW - Cohort Studies KW - Factor VII KW - Factor VIII KW - Fibrinogen KW - Humans KW - Multivariate Analysis KW - Prospective Studies KW - Regression Analysis KW - Risk Factors AB -

No studies have examined the associations of coagulation factor levels with measures of subclinical cardiovascular disease (CVD) in the elderly. The Cardiovascular Health Study (CHS) is a prospective, population-based cohort study of CVD in persons older than 65 years. At the baseline examination, we measured fibrinogen, factor VII, and factor VIII levels in 5024 of the 5201 participants of the CHS and examined the associations of these coagulation factors with measures of subclinical CVD in a cross-sectional analysis. Subclinical CVD measures were based on electrocardiography, carotid ultrasonography, echocardiography, and ankle-arm blood pressure measurements (AAI). For analyses, we used the full cohort as well as two mutually exclusive subgroups: those with prevalent clinical CVD at baseline and those without. Fibrinogen and to a lesser extent factor VIII showed positive associations with a variety of subclinical CVD measures. In age-adjusted analyses, fibrinogen and factor VIII were significantly associated with 8 of 10 measures. In multivariate analyses, fibrinogen was significantly associated with carotid artery stenosis, internal (but not common) carotid artery wall thickness, and AAI. Factor VIII was associated with abnormal wall motion and AAI in the full cohort only. Factor VII was not consistently associated with subclinical disease measures. In bivariate analyses that included data from all three groups, there were 5 positive subclinical disease associations and 5 negative associations for factor VII. In multivariate analyses, there were no significant associations between factor VII and subclinical CVD in the full cohort or in either subgroup. We conclude that in these cross-sectional analyses, fibrinogen and to a lesser extent factor VIII are associated with subclinical CVD in the elderly, even in those without symptoms or a history of clinical CVD. Factor VII, however, was not associated with subclinical CVD in the elderly.

VL - 15 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7670938?dopt=Abstract ER - TY - JOUR T1 - Hematological and biochemical laboratory values in older Cardiovascular Health Study participants. JF - J Am Geriatr Soc Y1 - 1995 A1 - Robbins, J A1 - Wahl, P A1 - Savage, P A1 - Enright, P A1 - Powe, N A1 - Lyles, M KW - Age Factors KW - Aged KW - Analysis of Variance KW - California KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Health Status KW - Humans KW - Male KW - Maryland KW - Middle Aged KW - North Carolina KW - Pennsylvania KW - Reference Values KW - Risk Factors KW - Sex Characteristics AB -

OBJECTIVE: To define reference hematologic and biochemical lab values in older individuals.

DESIGN: Randomly selected, age- and gender-stratified participants.

SETTING: Visits by participants to four research clinics.

PATIENTS: A total of 5201 participants in the Cardiovascular Health Study, an observational study of older Medicare-eligible individuals living at home.

MEASUREMENT: Information about health status, previous illness, and medication use was obtained from participants and/or their MDs. This information was used to define a healthy subset of the population. Blood samples were obtained for Cholesterol, HDL and LDL cholesterol, fasting and 2-hour postload glucose and insulin, fibrinogen, factors VII and VIII, potassium, creatinine, albumin, uric acid, white blood count, hematocrit, hemoglobin, and platelet count.

RESULTS: Significant differences were found for age group and/or gender for all mean values. Many tests were significantly different from the generally accepted reference ranges used in clinical laboratories.

CONCLUSIONS: In some situations accepted laboratory norms for the general population can not be extrapolated to older adults. There are implications for both research and clinical practice.

VL - 43 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7636091?dopt=Abstract ER - TY - JOUR T1 - Methods of assessing prevalent cardiovascular disease in the Cardiovascular Health Study. JF - Ann Epidemiol Y1 - 1995 A1 - Psaty, B M A1 - Kuller, L H A1 - Bild, D A1 - Burke, G L A1 - Kittner, S J A1 - Mittelmark, M A1 - Price, T R A1 - Rautaharju, P M A1 - Robbins, J KW - Aged KW - Cerebrovascular Disorders KW - Cohort Studies KW - Coronary Disease KW - Electrocardiography KW - Epidemiologic Methods KW - False Negative Reactions KW - Female KW - Humans KW - Male KW - Population Surveillance KW - Prevalence KW - Prospective Studies KW - Reproducibility of Results KW - Risk Factors KW - Self Disclosure KW - United States AB -

The objective of this article is to describe the methods of assessing cardiovascular conditions among older adults recruited to the Cardiovascular Health Study (CHS), a cohort study of risk factors for coronary disease and stroke. Medicare eligibility lists from four US communities were used to obtain a representative sample of 5201 community-dwelling elderly, who answered standardized questionnaires and underwent an extensive clinic examination at baseline. For each cardiovascular condition, self-reports were confirmed by components of the baseline examination or, if necessary, by a validation protocol that included either the review of medical records or surveys of treating physicians. Potential underreporting of a condition was detected either by the review of medical records at baseline for other self-reported conditions or, during prospective follow-up, by the investigation of potential incident events. For myocardial infarction, 75.5% of the self-reports in men and 60.6% in women were confirmed. Self-reported congestive heart failure was confirmed in 73.3% of men and 76.6% of women; stroke, in 59.6% of men and 53.8% of women; and transient ischemic attack, in 41.5% of men and 37.0% of women. Underreporting was also common. During prospective follow-up of an average of about 3 years per person, approximately 50% of men and 38% of women were hospitalized or investigated for at least one potential incident event; for each cardiovascular condition, about 1 to 4% of those investigated during prospective follow-up were found to have had the cardiovascular condition prior to entry into the cohort.(ABSTRACT TRUNCATED AT 250 WORDS)

VL - 5 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8520708?dopt=Abstract ER - TY - JOUR T1 - Sex, age, and disease affect echocardiographic left ventricular mass and systolic function in the free-living elderly. The Cardiovascular Health Study. JF - Circulation Y1 - 1995 A1 - Gardin, J M A1 - Siscovick, D A1 - Anton-Culver, H A1 - Lynch, J C A1 - Smith, V E A1 - Klopfenstein, H S A1 - Bommer, W J A1 - Fried, L A1 - O'Leary, D A1 - Manolio, T A KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Cohort Studies KW - Coronary Disease KW - Echocardiography KW - Female KW - Humans KW - Hypertrophy, Left Ventricular KW - Male KW - Sex Factors KW - Systole AB -

BACKGROUND: Left ventricular (LV) hypertrophy, as measured by M-mode echocardiography, is an independent predictor of mortality and/or morbidity from coronary heart disease (CHD). LV global and segmental systolic dysfunction also have been associated with myocardial ischemia and cardiovascular morbidity and mortality. Echocardiographic data, especially two-dimensional, have not been available previously from multicenter-based studies of the elderly. This report describes the distribution and relation at baseline of echocardiographic LV mass and global and segmental LV wall motion to age, sex, and clinical disease category in the Cardiovascular Health Study (CHS), a cohort of 5201 men and women (4850 white) 65 years of age and older.

METHODS AND RESULTS: M-mode LV mass adjusted for body weight increased modestly with age (P < .0001), increasing less than one gram per year increase in age for both men and women. After adjustment for weight, LV mass was significantly greater in men than in women and in participants with clinical CHD compared with participants with neither clinical heart disease nor hypertension (both P < .001). Across all CHS age subgroups, the difference in weight-adjusted LV mass by sex was greater in magnitude than the difference related to clinical CHD. M-mode measurements of LV mass could not be made in 34% of CHS participants, and this was highly related to age (29% in the 65 to 69 year versus 50% in the 85+ year age group, P < .001) and other risk factors. In participants with clinical CHD and with neither clinical heart disease nor hypertension, LV ejection fraction and segmental wall motion abnormalities were more prevalent in men than women (all P < .001). Of interest, 0.5% of men and 0.4% of women with neither clinical heart disease nor hypertension had LV segmental wall motion abnormalities, suggesting silent disease, compared with 26% of men and 10% of women in the clinical CHD group (P < .0001). Multivariate analyses revealed male sex and presence of clinical CHD (both P < .001) to be independent predictors of LV akinesis or dyskinesis.

CONCLUSIONS: Significant baseline relations were detected between differences in sex, prevalent disease status, and echocardiographic measurements of LV mass and systolic function in the CHS cohort. Age was weakly associated with LV mass measurements and LV ejection fraction abnormalities. These relations should be considered in evaluating the preclinical and clinical effects of CHD risk factors in the elderly.

VL - 91 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7882482?dopt=Abstract ER - TY - JOUR T1 - Subclinical disease as an independent risk factor for cardiovascular disease. JF - Circulation Y1 - 1995 A1 - Kuller, L H A1 - Shemanski, L A1 - Psaty, B M A1 - Borhani, N O A1 - Gardin, J A1 - Haan, M N A1 - O'Leary, D H A1 - Savage, P J A1 - Tell, G S A1 - Tracy, R KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Coronary Disease KW - Female KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Myocardial Infarction KW - Odds Ratio KW - Reference Values KW - Risk Factors AB -

BACKGROUND: The primary aim of the present study was to determine the relation between measures of subclinical cardiovascular disease and the incidence of clinical cardiovascular disease among 5201 adults 65 years of age or older who were participating in the Cardiovascular Health Study.

METHODS AND RESULTS: A new method of classifying subclinical disease at baseline examination in the Cardiovascular Health Study included measures of ankle-brachial blood pressure, carotid artery stenosis and wall thickness, ECG and echocardiographic abnormalities, and positive response to the Rose Angina and Claudication Questionnaire. Participants were followed for an average of 2.39 years (maximum, 3 years). For participants without evidence of clinical cardiovascular disease at baseline, the presence of subclinical disease compared with no subclinical disease was associated with a significant increased risk of incident total coronary heart disease including CHD deaths and nonfatal MI and angina pectoris for both men and women. For individuals with subclinical disease, the increased risk of total coronary heart disease was 2.0 for men and 2.5 for women, and the increased risk of total mortality was 2.9 for men and 1.7 for women. The increased risk changed little after adjustment for other risk factors, including lipoprotein levels, blood pressure, smoking, and diabetes.

CONCLUSIONS: The measurement of subclinical disease provides an approach for identifying high-risk older individuals who may be candidates for more active intervention to prevent clinical disease.

VL - 92 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/7641349?dopt=Abstract ER - TY - JOUR T1 - Association of fibrinogen and coagulation factors VII and VIII with cardiovascular risk factors in the elderly: the Cardiovascular Health Study. Cardiovascular Health Study Investigators. JF - Am J Epidemiol Y1 - 1996 A1 - Cushman, M A1 - Yanez, D A1 - Psaty, B M A1 - Fried, L P A1 - Heiss, G A1 - Lee, M A1 - Polak, J F A1 - Savage, P J A1 - Tracy, R P KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Analysis of Variance KW - Cardiovascular Diseases KW - Cohort Studies KW - Factor VII KW - Factor VIII KW - Female KW - Fibrinogen KW - Humans KW - Linear Models KW - Logistic Models KW - Male KW - Prevalence KW - Risk Factors KW - Sex Distribution KW - United States AB -

The cross-sectional correlates of three hemostatic factors--fibrinogen, factor VII, and factor VIII--were examined in the Cardiovascular Health Study, a population-based cohort study of 5,201 subjects over age 65 years. Subjects were recruited in 1989-1990 in Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Pittsburgh, Pennsylvania. In multivariate linear regression models, cardiac risk factors significantly associated with fibrinogen were current smoking, race, lipids, and white blood count. In women, alcohol use, obesity, physical activity, and insulin level were also significant, while in men hypertension was correlated. The significant correlates of factor VII were lipids and white blood count in men and estrogen use, alcohol use, race, lipids, insulin level, white blood count, and obesity in women. The independent correlates of factor VIII were insulin, glucose, and race in both sexes; low density lipoprotein cholesterol, white blood count, and diuretic use in men; and alcohol use in women. In multivariate models, factors known to be modifiable risk factors for cardiovascular disease accounted for more of the population variance of these hemostatic factors in women than in men, especially for factor VII. The hemostatic factors may mediate some effects of risk factors on disease, and this should be considered in longitudinal studies.

VL - 143 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8651228?dopt=Abstract ER - TY - JOUR T1 - Asthma and its association with cardiovascular disease in the elderly. The Cardiovascular Health Study Research Group. JF - J Asthma Y1 - 1996 A1 - Enright, P L A1 - Ward, B J A1 - Tracy, R P A1 - Lasser, E C KW - Aged KW - Aged, 80 and over KW - Asthma KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Humans KW - Lung KW - Male KW - Multivariate Analysis KW - Prevalence KW - Risk Factors KW - Sex Distribution KW - Smoking AB -

Cardiovascular disease (CVD) is more prevalent in elderly than in middle-aged patients. Symptoms such as intermittent wheezing with dyspnea may then be due to either CVD or asthma. The objective of this study was to determine the prevalence and correlates of asthma in the elderly and their associations with CVD and CVD risk factors. A community sample of 5201 elderly persons from the Cardiovascular Health Study was asked if they had a physician diagnosis of asthma, and multiple cardiovascular risk and disease variables were measured. Six percent of the participants (309) recalled a history of asthma, and half of these were never smokers. Thirty percent of those with asthma were currently taking a bronchodilator, 14% inhaled steroids, and 10% oral prednisone. Men and women with asthma who were cigarette smokers were more likely to report a concurrent diagnosis of congestive heart failure than smokers without asthma (p = .04). However, when we determined the independent CVD correlates of asthma in this cohort, controlling for smoking status, age, gender, and diagnoses of chronic bronchitis and emphysema, only higher levels of high-density lipoprotein cholesterol (HDL-C) and higher plasma fibrinogen levels were significantly associated with asthma. It was concluded that asthma is as prevalent in the elderly as in middle-aged persons and is associated with higher HDL-C and higher fibrinogen levels, but not with prevalent cardiovascular disease.

VL - 33 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8621370?dopt=Abstract ER - TY - JOUR T1 - Carotid artery measures are strongly associated with left ventricular mass in older adults (a report from the Cardiovascular Health Study). JF - Am J Cardiol Y1 - 1996 A1 - Kronmal, R A A1 - Smith, V E A1 - O'Leary, D H A1 - Polak, J F A1 - Gardin, J M A1 - Manolio, T A KW - Aged KW - Carotid Arteries KW - Cohort Studies KW - Female KW - Heart Ventricles KW - Humans KW - Hypertrophy, Left Ventricular KW - Male KW - Regression Analysis KW - Risk Factors KW - Ultrasonography AB -

Associations of carotid artery diameter and intimal-medial thickness by ultrasound with echocardiographic left ventricular (LV) structure were examined in 3,409 participants in the Cardiovascular Health Study, a population-based study of risk factors for coronary heart disease and stroke in men and women aged > or = 65 years. At baseline, sector-guided M-mode echocardiography and B-mode ultrasound were used to evaluate the left ventricle and carotid arteries, respectively. Common carotid artery diameter and intimal-medial thickness were significantly related to LV mass in correlational analysis (r=0.40 and 0.20, respectively, p<0.01), and each was independently associated with LV mass after adjustment for age, gender, weight, systolic and diastolic blood pressure, antihypertensive medication use, prior coronary heart disease, electrocardiographic abnormalities, high-density lipoprotein, and factor VII. We speculate that changes in the arterial wall affect impedance to LV ejection leading to increases in LV mass. Further follow-up of this cohort is in progress and will help to determine whether such carotid artery measures could, by exacerbating LV hypertrophy, constitute another important risk factor for adverse cardiovascular outcomes.

VL - 77 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8610615?dopt=Abstract ER - TY - JOUR T1 - Clinical correlates of white matter findings on cranial magnetic resonance imaging of 3301 elderly people. The Cardiovascular Health Study. JF - Stroke Y1 - 1996 A1 - Longstreth, W T A1 - Manolio, T A A1 - Arnold, A A1 - Burke, G L A1 - Bryan, N A1 - Jungreis, C A A1 - Enright, P L A1 - O'Leary, D A1 - Fried, L KW - Age Factors KW - Aged KW - Aging KW - Blood Pressure KW - Brain KW - Cardiovascular Diseases KW - Cerebrovascular Disorders KW - Cohort Studies KW - Female KW - Humans KW - Ischemic Attack, Transient KW - Magnetic Resonance Imaging KW - Male KW - Multivariate Analysis KW - Risk Factors KW - Sex Factors AB -

BACKGROUND AND PURPOSE: Our aim was to identify potential risk factors for and clinical manifestations of white matter findings on cranial MRI in elderly people.

METHODS: Medicare eligibility lists were used to obtain a representative sample of 5888 community-dwelling people aged 65 years or older. Correlates of white matter findings were sought among 3301 participants who underwent MRI scanning and denied a history of stroke or transient ischemic attack. Participants underwent extensive standardized evaluations at baseline and on follow-up, including standard questionnaires, physical examination, multiple blood tests, electrocardiogram, pulmonary function tests, carotid sonography, and M-mode echocardiography. Neuroradiologists graded white matter findings from 0 (none) to 9 (maximal) without clinical information.

RESULTS: Many potential risk factors were related to the white matter grade, but in the multivariate model the factors significantly (all P < .01) and independently associated with increased grade were greater age, clinically silent stroke on MRI, higher systolic blood pressure, lower forced expiratory volume in 1 second (FEV1), and income less than $50,000 per year. If excluded, FEV1 was replaced in the model by female sex, history of smoking, and history of physician-diagnosed hypertension at the baseline examination. Many clinical features were correlated with the white matter grade, especially those indicating impaired cognitive and lower extremity function.

CONCLUSIONS: White matter findings were significantly associated with age, silent stroke, hypertension, FEV1, and income. The white matter findings may not be considered benign because they are associated with impaired cognitive and lower extremity function.

VL - 27 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8711786?dopt=Abstract ER - TY - JOUR T1 - Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease. JF - Arterioscler Thromb Vasc Biol Y1 - 1996 A1 - Cushman, M A1 - Psaty, B M A1 - Macy, E A1 - Bovill, E G A1 - Cornell, E S A1 - Kuller, L H A1 - Tracy, R P KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Hemostasis KW - Humans KW - Male KW - Risk Factors KW - Thrombin AB -

Studies suggest that thrombosis is important in the progression of atherosclerotic lesions. The biochemical markers prothrombin fragment 1-2 and fibrinopeptide A reflect in vivo thrombin generation and activity, respectively. As such, they are markers that might be associated with cardiovascular risk. From the Cardiovascular Health Study, a cohort study of 5201 persons over 65 years of age, 399 persons free of clinical cardiovascular disease (CVD) at the baseline examination were selected for study of specialized markers of hemostasis. We report the cross-sectional relationships of the thrombin markers to CVD risk factors and measures of subclinical CVD. The range of fragment 1-2 2 was 0.12 to 0.85 nmol/L. The range of fibrinopeptide A was 0.9 to 44.1 micrograms/L. High levels of fragment 1-2 and fibrinopeptide A were associated with age, with levels higher in women than men. Fragment 1-2 was associated with smoking; high levels of triglyceride, creatinine, and C-reactive protein; and low levels of glucose. Fibrinopeptide A was associated with high C-reactive protein and apolipoprotein(a) and lower ankle-brachial index. There were no significant associations of the thrombin markers with race, fibrinogen, alcohol consumption, diabetes, or most measures of subclinical CVD. Study findings support a hypothesis that there are physiological interrelationships between cardiac risk factors, hemostasis, inflammation, and progression of atherosclerosis.

VL - 16 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8792770?dopt=Abstract ER - TY - JOUR T1 - Current estrogen-progestin and estrogen replacement therapy in elderly women: association with carotid atherosclerosis. CHS Collaborative Research Group. Cardiovascular Health Study. JF - Ann Epidemiol Y1 - 1996 A1 - Jonas, H A A1 - Kronmal, R A A1 - Psaty, B M A1 - Manolio, T A A1 - Meilahn, E N A1 - Tell, G S A1 - Tracy, R P A1 - Robbins, J A A1 - Anton-Culver, H KW - Aged KW - Arteriosclerosis KW - Carotid Arteries KW - Carotid Stenosis KW - Cohort Studies KW - Confidence Intervals KW - Cross-Sectional Studies KW - Databases, Factual KW - Drug Therapy, Combination KW - Estrogen Replacement Therapy KW - Estrogens KW - Female KW - Health Status Indicators KW - Humans KW - Odds Ratio KW - Progestins KW - Reproductive History KW - Ultrasonography KW - United States KW - Women's Health AB -

The cardioprotective effects of combined estrogen/progestin replacement therapy have been questioned. Therefore, we have compared carotid arterial wall thickening and the prevalence of carotid stenosis in elderly women (> or = 65 years old) currently using replacement estrogen/progestins (E + P) with arterial pathology and its prevalence in women using unopposed estrogens (E). This cross-sectional study used baseline data from all 2962 women participating in the Cardiovascular Health Study, a population-based study of coronary heart disease and stroke in elderly adults. Users of hormone replacement therapy (HRT) were categorized as never (n = 1726), past (n = 787), current E (n = 280), or current E + P (n = 73). Maximal intimal-medial thicknesses of the internal and common carotid arteries and stenosis of the internal carotid arteries were measured by ultrasonography. Current E + P users resembled current E users in most respects, although some lifestyle factors were more favorable among E + P users. Current E + P use and current E use (as compared with no use) were associated with smaller internal carotid wall thicknesses (-0.22 mm; P = 0.003; and -0.09 mm; P = 0.05, respectively) and smaller common carotid wall thicknesses (-0.05 mm; P = 0.03; and -0.02 mm; P = 0.1, respectively) and lower odds ratios (OR) for carotid stenosis (> or = 1% vs. 0%); OR = 0.61; 95% confidence interval [CI]: 0.36 to 1.01; and OR = 0.91, 95% CI: 0.67 to 1.24, respectively), after adjustment for current lifestyle and risk factors. When both groups of current HRT users were compared, there were no significant differences in carotid wall thicknesses or prevalence of carotid stenosis. For this sample of elderly women, both current E + P therapy and current E therapy were associated with decreased measures of carotid atherosclerosis. These measures did not differ significantly between the two groups of HRT users.

VL - 6 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8876842?dopt=Abstract ER - TY - JOUR T1 - Risk factors for abdominal aortic aneurysms in older adults enrolled in The Cardiovascular Health Study. JF - Arterioscler Thromb Vasc Biol Y1 - 1996 A1 - Alcorn, H G A1 - Wolfson, S K A1 - Sutton-Tyrrell, K A1 - Kuller, L H A1 - O'Leary, D KW - Aged KW - Anthropometry KW - Aortic Aneurysm, Abdominal KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Comorbidity KW - Female KW - Humans KW - Male KW - Middle Aged KW - Pilot Projects KW - Prevalence KW - Reproducibility of Results KW - Risk Factors KW - Smoking KW - Ultrasonography KW - United States AB -

B-mode ultrasound examinations of the abdominal aorta were performed from 1990 to 1992 to evaluate the prevalence of abdominal aortic aneurysm (AAA) in a subgroup of the Pittsburgh cohort (656 participants, aged 65 to 90 years) of the Cardiovascular Health Study (CHS). In this pilot study, we evaluated various definitions of aneurysm and the reproducibility of the measurements. In year 5 (1992 to 1993) of the CHS, the entire cohort (4741 participants) was examined. AAA was defined as an infrarenal aortic diameter of > or= 3.0 cm, or a ratio of infrarenal to suprarenal diameter of > or= 1.2, or a history of AAA repair. For the entire CHS cohort, prevalence of aneurysms was 9.5% (451/4741) overall, with a prevalence among men of 14.2% (278/1956) and prevalence among women of 6.2% (173/2785). Variables significantly related to AAA were older age; male sex; history of angina, coronary heart disease, and myocardial infarction; lower ankle-arm blood pressure ratio; higher maximum carotid stenosis; greater intima-media thickness of the internal carotid artery; higher creatinine; lower HDL levels and higher LDL levels; and cigarette smoking. The study has documented the strong association of cardiovascular risk factors and measures of clinical and subclinical atherosclerosis and cardiovascular disease and prevalence of aneurysms. We used a definition that is more sensitive than previously reported (diameter or ratio), which allowed the detection of smaller aneurysms and possibly those at an earlier stage of development. Follow-up of this cohort may lead to new criteria for determining the risk factors for progression of aneurysms.

VL - 16 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8696960?dopt=Abstract ER - TY - JOUR T1 - Short-term predictors of incident stroke in older adults. The Cardiovascular Health Study. JF - Stroke Y1 - 1996 A1 - Manolio, T A A1 - Kronmal, R A A1 - Burke, G L A1 - O'Leary, D H A1 - Price, T R KW - Age Factors KW - Aged KW - Cardiovascular Physiological Phenomena KW - Cerebrovascular Disorders KW - Cohort Studies KW - Female KW - Health Status KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Multivariate Analysis KW - Prognosis KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Sex Factors KW - Time Factors AB -

BACKGROUND AND PURPOSE: Risk factors for incident stroke have been examined in middle-aged persons, but less is known about stroke precursors in the elderly, who suffer the highest rates of stroke. Short-term risk factors for incident stroke were examined in a longitudinal, population-based study including extensive measures of subclinical disease.

METHODS: Prospective study of 5201 women and men aged 65 years and older was undertaken in the multicenter Cardiovascular Health Study.

RESULTS: During an average 3.31-year follow-up, 188 incident strokes occurred. Stroke incidence increased significantly with age and was similar in women and men. Factors associated with increased stroke risk in multivariate analysis included age, aspirin use, diabetes, impaired glucose tolerance, higher systolic blood pressure, increased time needed to walk 15 ft. frequent falls, elevated creatinine level, abnormal left ventricular (LV) wall motion and increased LV mass on echocardiography, ultrasound-defined carotid stenosis, and atrial fibrillation. Increased LV mass and carotid stenosis were associated with twofold and threefold increases in incidences of stroke, respectively (P < .001). Aspirin users had a 52% higher risk of stroke (relative risk, 1.52; 95% confidence interval, 1.1 to 2.0; P < .007) after adjustment for other factors. This association was present only among aspirin users without prior coronary disease, atrial fibrillation, claudication, or transient ischemic attack, who had an 84% higher risk (relative risk, 1.84; 95% confidence interval, 1.2 to 2.8).

CONCLUSIONS: Short-term risk of stroke has a complex relationship with aspirin use and is strongly related to subclinical disease in this sample of older adults. These relationships should be considered in assessing stroke risk in the elderly, in whom recognized and subclinical cardiovascular disease is highly prevalent.

VL - 27 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8784116?dopt=Abstract ER - TY - JOUR T1 - Thickening of the carotid wall. A marker for atherosclerosis in the elderly? Cardiovascular Health Study Collaborative Research Group. JF - Stroke Y1 - 1996 A1 - O'Leary, D H A1 - Polak, J F A1 - Kronmal, R A A1 - Savage, P J A1 - Borhani, N O A1 - Kittner, S J A1 - Tracy, R A1 - Gardin, J M A1 - Price, T R A1 - Furberg, C D KW - Adult KW - Aged KW - Arteriosclerosis KW - Blood Pressure KW - Carotid Artery, Common KW - Carotid Artery, Internal KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Coronary Disease KW - Diabetes Mellitus KW - Diabetic Angiopathies KW - Electrocardiography KW - Female KW - Humans KW - Male KW - Medical History Taking KW - Physical Examination KW - Prospective Studies KW - Regression Analysis KW - Risk Factors KW - Sex Characteristics KW - Smoking KW - Tunica Intima KW - Tunica Media KW - Ultrasonography AB -

BACKGROUND AND PURPOSE: We investigated the relationships between prevalent coronary heart disease (CHD), clinically manifest atherosclerotic disease (ASD), and major established risk factors for atherosclerosis and intima-media thickness (IMT) in the common carotid arteries (CCA) and internal carotid arteries (ICA) separately and in combination in older adults. We wished to determine whether a noninvasive measurement can serve as an indicator of clinically manifest atherosclerotic disease and to determine which of the two variables, CCA IMT or ICA IMT, is a better correlate.

METHODS: IMT of the CCA and ICA was measured with duplex ultrasound in 5117 of 5201 individuals enrolled in the Cardiovascular Health Study, a study of the risk factors and the natural history of cardiovascular disease in adults aged 65 years or more. Histories of CHD, peripheral arterial disease, and cerebrovascular disease were obtained during baseline examination. Risk factors included cholesterol levels, cigarette smoking, elevated blood pressure, diabetes, age, and sex. Relationships between risk factors and IMT were studied by multiple regression analysis and canonical variate analysis. Prediction of prevalent CHD and ASD by IMT measurements in CCAs and ICAs were made by logistic regression, adjusting for age and sex.

RESULTS: IMT measurements of the CCAs and ICAs were greater in persons with CHD and ASD than those without, even after controlling for sex (P < .001). IMT measurements in the ICA were greater than those in the CCA. Risk factors for ASD accounted for 17% and 18% of the variability in IMT in the CCA and ICA, respectively. These same risk factors accounted for 25% of the variability of a composite measurement consisting of the sum of the ICA IMT and CCA IMT. The ability to predict CHD and ASD was greater for ICA IMT (odds ratio [confidence interval]: 1.36 [1.31 to 1.41] and 1.35 [1.25 to 1.44], respectively) than for CCA IMT (1.09 [1.05 to 1.13] and 1.17 [1.09 to 1.25]).

CONCLUSIONS: Whereas CCA IMT is associated with major risk factors for atherosclerosis and existing CHD and ASD in older adults, this association is not as strong as that for ICA IMT. The combination of these measures relates more strongly to existing CHD and ASD and cerebrovascular disease risk factors than either taken alone.

VL - 27 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8571414?dopt=Abstract ER - TY - JOUR T1 - The association of antihypertensive agents with MRI white matter findings and with Modified Mini-Mental State Examination in older adults. JF - J Am Geriatr Soc Y1 - 1997 A1 - Heckbert, S R A1 - Longstreth, W T A1 - Psaty, B M A1 - Murros, K E A1 - Smith, N L A1 - Newman, A B A1 - Williamson, J D A1 - Bernick, C A1 - Furberg, C D KW - Adrenergic beta-Antagonists KW - Aged KW - Aged, 80 and over KW - Antihypertensive Agents KW - Brain KW - Calcium Channel Blockers KW - Cognition KW - Cohort Studies KW - Cross-Sectional Studies KW - Diuretics KW - Female KW - Geriatric Assessment KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Risk Factors AB -

OBJECTIVES: To examine the association of antihypertensive regimen with magnetic resonance imaging (MRI) white matter hyperintensity and with cognitive impairment in older adults.

DESIGN: Cross-sectional study.

SETTING: The Cardiovascular Health study, an observational prospective cohort study of risk factors for coronary heart disease and stroke in men and women 65 years of age and older.

PARTICIPANTS: 1268 men and women with pharmacologically treated hypertension.

MEASUREMENTS: Information on medication use, medical history, and health habits was collected at clinic examinations. Participants completed the Modified Mini-Mental State Examination (3MS) and underwent MRI examination. Without clinical information, study neuroradiologists assigned an overall grade of white matter signal intensity on MRI on a scale from 0 (no findings) to 9 (extensive findings).

RESULTS: Adjusted mean white matter grade was higher for users of calcium channel blockers (2.59, P = .007) and users of loop diuretics (2.60, P = .015) than for users of beta blockers (2.12). The association was present for both dihydropyridine and non-dihydropyridine calcium channel blockers. Adjusted mean 3MS scores were lower for users of calcium channel blockers (89.6, P < .002), especially dihydropyridines, and users of loop diuretics (89.7, P < .006) than for users of beta blockers (92.3). No statistically significant association could be shown for users of other drug regimens, including thiazides and ACE inhibitors.

CONCLUSION: In this study, users of antihypertensive regimens which included calcium channel blockers or loop diuretics had more severe white matter hyperintensity on MRI and worse performance on 3MS than users of beta blockers.

VL - 45 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9400550?dopt=Abstract ER - TY - JOUR T1 - The association of antihypertensive medication with serum creatinine changes in older adults. JF - Am J Hypertens Y1 - 1997 A1 - Smith, N L A1 - Psaty, B M A1 - Heckbert, S R A1 - Lemaitre, R N A1 - Kates, D M A1 - Rutan, G H A1 - Bleyer, A KW - Aged KW - Antihypertensive Agents KW - Cohort Studies KW - Creatinine KW - Female KW - Humans KW - Male AB -

Many of the potential effects of antihypertensive therapy, including renal function, have been inadequately investigated in clinical trials in older adults. In an observational study, we examined the association between treatment with various classes of antihypertensive agents and 3-year changes in serum creatinine in 1296 older adults with treated hypertension and without prior renal disease (mean age 72.2 years; 60% female; 30% diabetic; 42% with cardiovascular disease (CVD)) from the Cardiovascular Health Study. Baseline antihypertensive medications included thiazides (HCT), beta-adrenergic blockers, angiotensin converting enzyme inhibitors (ACE-I), calcium channel blockers (CCB), vasodilators (VAS), HCT + BB, HCT + ACE-I, HCT + CCB, HCT + VAS, loop diuretics (LOOP), and other combinations. Unadjusted results indicated that minimal changes in mean serum creatinine occurred over time for all therapies and only a few changes were statistically significant (HCT: +0.02 mg/dL, ACE-I: +0.04, CCB: +0.04; all P < .05; LOOP: +0.06 mg/dL; P < .001). In multivariate analyses with HCT users as the reference group and adjusting for baseline serum creatinine, age, sex, smoking, diabetes mellitus, CVD, height, weight, common carotid intima-media thickness, and use of allopurinol, phenytoin, cimetidine, and nonsteroidal antiinflammatory drugs, all of the relative changes were small and statistically nonsignificant except for HCT + VAS users (+0.07 mg/dL; P < .05). When users of the same therapy at baseline and follow-up were restricted, only LOOP users had significant albeit small changes in serum creatinine (+0.05 mg/dL; P < .05). Although results from clinical trials are needed to confirm these findings, these observational data suggest no major differences between specific antihypertensive therapies in 3-year serum creatinine changes in older adults without prior renal disease.

VL - 10 IS - 12 Pt 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9443772?dopt=Abstract ER - TY - JOUR T1 - Clinically serious abnormalities found incidentally at MR imaging of the brain: data from the Cardiovascular Health Study. JF - Radiology Y1 - 1997 A1 - Yue, N C A1 - Longstreth, W T A1 - Elster, A D A1 - Jungreis, C A A1 - O'Leary, D H A1 - Poirier, V C KW - Aged KW - Aged, 80 and over KW - Brain KW - Brain Diseases KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Humans KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male AB -

PURPOSE: To determine the prevalence of clinically serious findings unrelated to stroke on cranial magnetic resonance (MR) images in a population of community-dwelling elderly people.

MATERIALS AND METHODS: Neuroradiologists reviewed MR images of 3,672 people aged 65 years and older who were enrolled in a longitudinal, population-based study of cardiovascular and cerebrovascular disease. The neuroradiologists alerted MR imaging field centers about potentially serious abnormalities. Clinical information was obtained from clinical examinations performed before MR imaging, hospital discharge summaries, and the field centers at which MR imaging was performed.

RESULTS: On 3,672 image sets, 64 (1.74%) clinically serious abnormalities were found. Among the presumptive diagnoses were 19 meningiomas (0.52%), six pituitary adenomas (0.16%), five cavernous malformations (0.14%), eight vascular stenoses (0.22%), four aneurysms (0.11%), two intraventricular masses (0.05%), two subdural fluid collections (0.05%), and two other tumors (0.05%). Only nine participants with these abnormalities required surgery. All but one of the meningiomas were in women, and the prevalence of the tumor decreased with increasing age.

CONCLUSION: Physicians should be alert to the possible presence of clinically serious conditions in otherwise asymptomatic elderly individuals.

VL - 202 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8988190?dopt=Abstract ER - TY - JOUR T1 - Does the association of risk factors and atherosclerosis change with age? An analysis of the combined ARIC and CHS cohorts. The Atherosclerosis Risk in Communities (ARIC) and Cardiovascular Health Study (CHS) investigators. JF - Stroke Y1 - 1997 A1 - Howard, G A1 - Manolio, T A A1 - Burke, G L A1 - Wolfson, S K A1 - O'Leary, D H KW - African Americans KW - African Continental Ancestry Group KW - Aged KW - Aging KW - Arteriosclerosis KW - Body Mass Index KW - Cardiovascular Physiological Phenomena KW - Cardiovascular System KW - Carotid Arteries KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Health Status KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Regression Analysis KW - Risk Factors KW - Sex Factors KW - Smoking KW - Tunica Intima KW - Tunica Media KW - Ultrasonography AB -

INTRODUCTION: A decrease in the estimated relative risk of cerebrovascular and cardiovascular diseases associated with known disease risk factors has been observed among elderly cohorts, perhaps suggesting that continued risk factor management in the elderly may not be as efficacious as with younger age groups. In this paper, the differential magnitude of the association of risk factors with atherosclerosis across the age spectrum from 45 years to older than 75 years is presented.

METHODS: Subclinical atherosclerosis as measured by carotid ultrasonography and risk factor prevalence were assessed using similar methods among participants aged 45 to 64 years in the Atherosclerosis Risk in Communities (ARIC) study and among participants 65 years and older in the Cardiovascular Health Study (CHS). Pooling these two cohorts provided data on the relationship of risk factors and atherosclerosis on nearly 19,000 participants over a broad age range. Regression analyses were used to assess the consistency of the magnitude of the association of risk factors with atherosclerosis across the age spectrum separately for black and white participants in cross-sectional analyses.

RESULTS: As expected, each of the risk factors was globally (across all ages) associated with increased atherosclerosis. However, the magnitude of the association did not differ across the age spectrum for hypertension, low density lipoprotein cholesterol (LDL-c), fibrinogen, or body mass index (BMI). For whites, there was a significantly greater impact of smoking and HDL-C among older age strata but a smaller impact of diabetes. For black women, the impact of HDL-C decreased among the older age strata.

CONCLUSIONS: These data suggest that most risk factors continue to be associated with increased atherosclerosis at older ages, possibly suggesting a continued value in investigation of strategies to reduce atherosclerosis by controlling risk factors at older ages.

VL - 28 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9303011?dopt=Abstract ER - TY - JOUR T1 - Incidence of and risk factors for atrial fibrillation in older adults. JF - Circulation Y1 - 1997 A1 - Psaty, B M A1 - Manolio, T A A1 - Kuller, L H A1 - Kronmal, R A A1 - Cushman, M A1 - Fried, L P A1 - White, R A1 - Furberg, C D A1 - Rautaharju, P M KW - Adult KW - Aged KW - Atrial Fibrillation KW - Blood Glucose KW - Blood Pressure KW - Cerebrovascular Disorders KW - Cohort Studies KW - Coronary Disease KW - Electrocardiography KW - Female KW - Follow-Up Studies KW - Hospital Records KW - Humans KW - Incidence KW - Male KW - Prospective Studies KW - Risk Factors KW - United States AB -

BACKGROUND: This study aimed to describe the incidence of atrial fibrillation (AF) among older adults during 3 years of follow-up.

METHODS AND RESULTS: In this cohort study, 5201 adults > or = 65 years old were examined annually on four occasions between June 1989 and May 1993. At baseline, participants answered questionnaires and underwent a detailed examination that included carotid ultrasound, pulmonary function tests, ECG, and echocardiography. Subjects with a pacemaker or AF at baseline (n=357) were excluded. New cases of AF were identified from three sources: (1) annual self-reports, (2) annual ECGs, and (3) hospital discharge diagnoses. Cox proportional-hazards models were used to assess baseline risk factors as predictors of incident AF. Among 4844 participants, 304 developed a first episode of AF during an average follow-up of 3.28 years, for an incidence of 19.2 per 1000 person-years. The onset was strongly associated with age, male sex, and the presence of clinical cardiovascular disease. For men 65 to 74 and 75 to 84 years old, the incidences were 17.6 and 42.7, respectively, and for women, 10.1 and 21.6 events per 1000 person-years. In stepwise models, the use of diuretics, a history of valvular heart disease, coronary disease, advancing age, higher levels of systolic blood pressure, height, glucose, and left atrial size were all associated with an increased risk of AF. The use of beta-blockers and high levels of alcohol use, cholesterol, and forced expiratory volume in 1 second were associated with a reduced risk of AF.

CONCLUSIONS: The incidence of AF in older adults may be higher than estimated by previous population studies. Left atrial size appears to be an important risk factor, and the control of blood pressure and glucose may be important in preventing the development of AF.

VL - 96 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9337224?dopt=Abstract ER - TY - JOUR T1 - Infarctlike lesions in the brain: prevalence and anatomic characteristics at MR imaging of the elderly--data from the Cardiovascular Health Study. JF - Radiology Y1 - 1997 A1 - Bryan, R N A1 - Wells, S W A1 - Miller, T J A1 - Elster, A D A1 - Jungreis, C A A1 - Poirier, V C A1 - Lind, B K A1 - Manolio, T A KW - Aged KW - Brain KW - Cardiovascular Diseases KW - Cerebral Infarction KW - Cohort Studies KW - Female KW - Humans KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Prevalence AB -

PURPOSE: To determine the prevalence and anatomic characteristics of infarctlike lesions seen on cranial magnetic resonance (MR) images.

MATERIALS AND METHODS: The study cohort consisted of 5,888 community-living individuals aged 65 years and older enrolled in a longitudinal, population-based study of cardiovascular disease. MR images were obtained from 3,658 participants and evaluated by trained readers. Lesion size, anatomic location, and signal intensity were recorded. Infarctlike lesion was defined as a nonmass, hyperintense region on spin-density- and T2-weighted images and, in cerebral white matter and brain stem, a hypointense region on T1-weighted images.

RESULTS: Infarctlike lesions were depicted on MR images of 1,323 (36%) participants. Eighty-five percent (1,128 participants) had lesions 3 mm or larger in maximum dimension, although 70.9% (1,320 of 1,861) of these lesions were 10 mm or less. Lesion prevalence increased with age, especially with lesions 3 mm or larger, which increased from 22.1% (86 of 389) in the 65-69-year age group to 42.9% (88 of 205) in the over-85-year age group (P < .0001). Lesion prevalence was slightly greater in men (497 of 1,527 [32.5%]) than in women (631 of 2,131 [29.6%]), but did not differ between blacks and non-blacks. The deep nuclei were the most commonly affected anatomic sites, with 78.2% (1,451 of 1,856) of lesions. Lesions that involved the cerebrum and posterior fossa accounted for 11.7% (218 of 1,856) and 10.1% (187 of 1,856) of lesions, respectively.

CONCLUSION: If the lesions reported in this study indicate cerebrovascular disease, subclinical disease may be more prevalent than clinical disease, and the prevalence of disease may rise with age. Also, infarctlike lesions have a distinctive anatomic profile.

VL - 202 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8988191?dopt=Abstract ER - TY - JOUR T1 - Left ventricular mass in the elderly. The Cardiovascular Health Study. JF - Hypertension Y1 - 1997 A1 - Gardin, J M A1 - Arnold, A A1 - Gottdiener, J S A1 - Wong, N D A1 - Fried, L P A1 - Klopfenstein, H S A1 - O'Leary, D H A1 - Tracy, R A1 - Kronmal, R KW - Aged KW - Aged, 80 and over KW - Blood Pressure KW - Body Weight KW - Cardiovascular Diseases KW - Cohort Studies KW - Echocardiography KW - Female KW - Humans KW - Hypertrophy, Left Ventricular KW - Male KW - Prospective Studies KW - Risk Factors KW - Ventricular Function, Left AB -

Left ventricular (LV) mass, as estimated from M-mode echocardiography (echo), has previously been shown to be an independent predictor of incident cardiovascular disease morbidity and mortality. We evaluated the relationship at baseline of echo LV mass to relevant cardiovascular disease risk factors and other potential covariates in the Cardiovascular Health Study, multicenter study sponsored by the National Heart, Lung, and Blood Institute of 5201 men and women aged 65 years or older (mean, 73). Two-dimensionally directed M-mode echo LV mass measurements could be obtained in 1357 men and 2053 women (66% of this elderly cohort). Stepwise linear regression analyses of the relationship of echo LV mass to demographic and risk factor, physical activity, electrocardiographic, and prevalent disease variables resulted in a model that explained 37% of the variance for the entire cohort. In order of decreasing importance, factors positively associated with echo LV mass were body weight, male sex, systolic pressure, presence of congestive heart failure, present smoking, major and minor electrocardiographic abnormalities, treatment for hypertension, valvular heart disease, aortic regurgitation by color Doppler, and mitral regurgitation by color Doppler (in men) whereas diastolic pressure, bioresistance (a measure of adiposity), and high-density lipoprotein cholesterol were inversely related to echo LV mass. Although height and weight were both related to LV mass, height added nothing once weight was entered in multiple linear regression analyses. Furthermore, in the multiple regression models, diastolic pressure was inversely and systolic BP positively related to LV mass, with similar magnitudes for their coefficients. In consonance with these findings, pulse pressure was positively related to LV mass in bivariate analyses. Multiple linear regression analyses explained less of the variance for ventricular septal thickness (R2 = .13) and LV posterior wall thickness (R2 = .14) than for LV mass (R2 = .37) and LV diastolic dimension (R2 = .27). Intriguing findings in the elderly Cardiovascular Health Study cohort included the presence of pulse pressure as a positive correlate, and high-density lipoprotein cholesterol as an inverse correlate, of LV mass. Longitudinal studies in the Cardiovascular Health Study cohort will help to clarify the importance of demographic, risk factor, and other variables, and changes in these variables, in predicting changes in echo LV mass and its components as well as the prognostic significance of LV mass in the elderly.

VL - 29 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9149672?dopt=Abstract ER - TY - JOUR T1 - The Sleep Heart Health Study: design, rationale, and methods. JF - Sleep Y1 - 1997 A1 - Quan, S F A1 - Howard, B V A1 - Iber, C A1 - Kiley, J P A1 - Nieto, F J A1 - O'Connor, G T A1 - Rapoport, D M A1 - Redline, S A1 - Robbins, J A1 - Samet, J M A1 - Wahl, P W KW - Adult KW - Aged KW - Aged, 80 and over KW - Arteriosclerosis KW - Cohort Studies KW - Coronary Disease KW - Female KW - Humans KW - Hypertension KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Polysomnography KW - Positive-Pressure Respiration KW - Prospective Studies KW - Research Design KW - Sleep Apnea Syndromes AB -

The Sleep Heart Health Study (SHHS) is a prospective cohort study designed to investigate obstructive sleep apnea (OSA) and other sleep-disordered breathing (SDB) as risk factors for the development of cardiovascular disease. The study is designed to enroll 6,600 adult participants aged 40 years and older who will undergo a home polysomnogram to assess the presence of OSA and other SDB. Participants in SHHS have been recruited from cohort studies in progress. Therefore, SHHS adds the assessment of OSA to the protocols of these studies and will use already collected data on the principal risk factors for cardiovascular disease as well as follow-up and outcome information pertaining to cardiovascular disease. Parent cohort studies and recruitment targets for these cohorts are the following: Atherosclerosis Risk in Communities Study (1,750 participants), Cardiovascular Health Study (1,350 participants), Framingham Heart Study (1,000 participants), Strong Heart Study (600 participants), New York Hypertension Cohorts (1,000 participants), and Tucson Epidemiologic Study of Airways Obstructive Diseases and the Health and Environment Study (900 participants). As part of the parent study follow-up procedures, participants will be surveyed at periodic intervals for the incidence and recurrence of cardiovascular disease events. The study provides sufficient statistical power for assessing OSA and other SDB as risk factors for major cardiovascular events, including myocardial infarction and stroke.

VL - 20 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9493915?dopt=Abstract ER - TY - JOUR T1 - Sulcal, ventricular, and white matter changes at MR imaging in the aging brain: data from the cardiovascular health study. JF - Radiology Y1 - 1997 A1 - Yue, N C A1 - Arnold, A M A1 - Longstreth, W T A1 - Elster, A D A1 - Jungreis, C A A1 - O'Leary, D H A1 - Poirier, V C A1 - Bryan, R N KW - Aged KW - Aged, 80 and over KW - Aging KW - Brain KW - Cardiovascular Diseases KW - Cerebral Ventricles KW - Cohort Studies KW - Continental Population Groups KW - Female KW - Humans KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Reproducibility of Results KW - Sex Factors AB -

PURPOSE: To determine the distribution of changes in sulcal size, ventricular size, and white matter signal intensity depicted on cranial magnetic resonance (MR) images, with stratification according to age, race, and sex.

MATERIALS AND METHODS: Ventricular size, sulcal size, and white matter signal intensity changes were graded on cranial MR images of 3,660 community-living, elderly participants in the Cardiovascular Health Study. A healthier subgroup was also defined. Summary statistics for both groups were generated for age, race, and sex.

RESULTS: Regression models of the entire imaged cohort showed higher grades of all variables with increasing age, and higher ventricular and sulcal grades in men and in nonblack individuals. White matter grade was greater in women and in black individuals. Regression models of the healthier subgroup showed similar associations, except for a lack of association of sulcal and ventricular size with race.

CONCLUSION: Sulcal width, ventricular size, and white matter signal intensity change with age, sex, and race. Knowledge of these changes is important in appropriate interpretation of MR images of the elderly.

VL - 202 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/8988189?dopt=Abstract ER - TY - JOUR T1 - Use of calcium channel blockers and breast carcinoma risk in postmenopausal women. JF - Cancer Y1 - 1997 A1 - Fitzpatrick, A L A1 - Daling, J R A1 - Furberg, C D A1 - Kronmal, R A A1 - Weissfeld, J L KW - Age Factors KW - Aged KW - Breast Neoplasms KW - Calcium Channel Blockers KW - Cohort Studies KW - Estrogens KW - Female KW - Humans KW - Postmenopause KW - Proportional Hazards Models KW - Risk Factors AB -

BACKGROUND: The use of calcium channel blockers in an elderly population recently was reported to be associated with the incidence of cancer. The Cardiovascular Health Study, a multisite observational cohort study, provided the opportunity to investigate the epidemiologic association between the use of calcium channel blockers and breast carcinoma risk in 3198 women age > or = 65 years.

METHODS: Standard questionnaires and clinical procedures were administered at four study sites annually from 1989-1990 to 1993-1994. Drug usage was assessed by a medication inventory and hospitalizations for 75 incident invasive breast carcinoma cases were identified using International Classification of Diseases-9 Clinical Modification codes. Time-dependent Cox proportional hazards regression models were used to assess associations between incident breast carcinoma and the use of specific antihypertensive medication including calcium channel blockers.

RESULTS: In adjusted Cox proportional hazards models, an elevated risk of breast carcinoma was associated with use of calcium channel blockers (hazard ratio [HR]: 2.57; 95% confidence interval [CI], 1.47-4.49). This association persisted when the comparison group was users of other antihypertensive medication. No associations between the use of other antihypertensive medication with incident breast carcinoma were found. Associations were enhanced by assessment of high dose at baseline (HR: 4.42; 95% CI, 1.37-14.27) and when calcium channel blockers were combined with estrogen use (HR: 4.48; 95% CI, 1.58-12.75). The association was found to be strongest for the use of estrogens with immediate release calcium channel blockers (HR: 8.48; 95% CI, 2.99-24.08).

CONCLUSIONS: Although the number of cases was limited in this observational study, associations found between the use of calcium channel blockers and incident invasive breast carcinoma warrant further investigation. Site specific carcinomas should be included as an outcome of ongoing and planned long term clinical trials using calcium channel blockers.

VL - 80 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9338468?dopt=Abstract ER - TY - JOUR T1 - Aspirin use and incident stroke in the cardiovascular health study. CHS Collaborative Research Group. JF - Stroke Y1 - 1998 A1 - Kronmal, R A A1 - Hart, R G A1 - Manolio, T A A1 - Talbert, R L A1 - Beauchamp, N J A1 - Newman, A KW - Aged KW - Aspirin KW - Brain Ischemia KW - Cardiovascular Diseases KW - Cerebral Hemorrhage KW - Cerebrovascular Disorders KW - Cohort Studies KW - Cyclooxygenase Inhibitors KW - Dose-Response Relationship, Drug KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Male KW - Regression Analysis KW - Risk Factors KW - Sex Factors KW - Time Factors AB -

BACKGROUND AND PURPOSE: Randomized clinical trials testing aspirin in relatively low-risk, middle-aged people have consistently shown small increases in stroke associated with aspirin use. We analyzed the relationship between the regular use of aspirin and incident ischemic and hemorrhagic stroke among people aged 65 years or older participating in the Cardiovascular Health Study.

METHODS: We conducted a multivariate analysis of incident stroke rates in a prospectively assessed, observational cohort of 5011 elderly people followed for a mean of 4.2 years.

RESULTS: Participants had a mean age of 72 years, and 58% were women. Twenty-three percent used aspirin frequently, and 17% used aspirin infrequently at study entry. Frequent aspirin use was associated with an increased rate of ischemic stroke compared with nonusers (relative risk= 1.6; 95% confidence interval [CI], 1.2 to 2.2; P=0.001). After adjustment for other stroke risk factors, women who used aspirin frequently or infrequently at study entry had a 1.8-fold (95% CI, 1.2 to 2.8) and 1.6-fold (95% CI, 0.9 to 3.0) increased risk of ischemic stroke, respectively (P<0.01, test for trend), compared with nonusers. In men, aspirin use was not statistically significantly associated with stroke risk. Findings were similar when aspirin use in the years before the incident stroke was used in the modeling. Aspirin use at entry was also associated with a 4-fold (95% CI, 1.6 to 10.0) increase in risk of hemorrhagic stroke for both infrequent and frequent users of aspirin (P=0.003).

CONCLUSIONS: Aspirin use was associated with increased risks of ischemic stroke in women and hemorrhagic stroke overall in this elderly cohort, after adjustment for other stroke predictors. The possibility exists of confounding by reasons for aspirin use rather than cause and effect. Whether regular aspirin use increases stroke risk for elderly people without cardiovascular disease can only be determined by randomized clinical trials.

VL - 29 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9596230?dopt=Abstract ER - TY - JOUR T1 - Asymptomatic internal carotid artery stenosis defined by ultrasound and the risk of subsequent stroke in the elderly. The Cardiovascular Health Study. JF - Stroke Y1 - 1998 A1 - Longstreth, W T A1 - Shemanski, L A1 - Lefkowitz, D A1 - O'Leary, D H A1 - Polak, J F A1 - Wolfson, S K KW - Aged KW - Blood Flow Velocity KW - Carotid Artery, Internal KW - Carotid Stenosis KW - Cerebrovascular Disorders KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Prevalence KW - Risk Factors KW - Systole KW - Ultrasonography, Doppler AB -

BACKGROUND AND PURPOSE: We sought in this study to relate carotid ultrasound findings in asymptomatic older adults to the 5-year risk of various cerebrovascular outcomes used in the Asymptomatic Carotid Atherosclerosis Study (ACAS).

METHODS: The Cardiovascular Health Study (CHS) is a longitudinal study of people 65 years and older. Analyses of internal carotid artery stenosis defined by multiple different cutoffs of peak systolic velocity, rather than one particular cutoff, were performed in the 5441 participants who underwent carotid ultrasound and lacked a history of transient ischemic attack or stroke. The 5-year risks of 7 cerebrovascular disease outcomes used in ACAS were estimated for each cutoff.

RESULTS: Associations with the 5-year risk of outcomes were substantially elevated only at cutoffs with high peak systolic velocities. In this population, the number of people with such high velocities was small. For example, with a cutoff of approximately 2.5 m/s, suggesting a stenosis of >70%, the 5-year risk of an ipsilateral fatal or nonfatal stroke was 5%, and only 0.5% of the group had velocities at least this high.

CONCLUSIONS: In a group of older adults likely to participate in a screening program, as evidenced by willingness to participate in CHS, high peak systolic velocities consistent with high-grade carotid stenosis were uncommon and risk of subsequent cerebrovascular disease outcomes was relatively low. These findings do not suggest that similar populations of older adults would benefit from a program using ultrasound to screen for asymptomatic carotid stenosis.

VL - 29 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9804651?dopt=Abstract ER - TY - JOUR T1 - Body mass index and mortality in nonsmoking older adults: the Cardiovascular Health Study. JF - Am J Public Health Y1 - 1998 A1 - Diehr, P A1 - Bild, D E A1 - Harris, T B A1 - Duxbury, A A1 - Siscovick, D A1 - Rossi, M KW - Age Distribution KW - Aged KW - Body Mass Index KW - Cardiovascular Diseases KW - Cause of Death KW - Cohort Studies KW - Female KW - Humans KW - Logistic Models KW - Male KW - Mortality KW - Predictive Value of Tests KW - Risk Factors KW - Sex Distribution KW - Smoking KW - Survival Analysis KW - United States KW - Weight Loss AB -

OBJECTIVES: This study assesses the relationship of body mass index to 5-year mortality in a cohort of 4317 nonsmoking men and women aged 65 to 100 years.

METHODS: Logistic regression analyses were conducted to predict mortality as a function of baseline body mass index, adjusting for demographic, clinical, and laboratory covariates.

RESULTS: There was an inverse relationship between body mass index and mortality; death rates were higher for those who weighed the least. Inclusion of covariates had trivial effects on these results. People who had lost 10% or more of their body weight since age 50 had a relatively high death rate. When that group was excluded, there was no remaining relationship between body mass index and mortality.

CONCLUSIONS: The association between higher body mass index and mortality often found in middle-aged populations was not observed in this large cohort of older adults. Over-weight does not seem to be a risk factor for 5-year mortality in this age group. Rather, the risks associated with significant weight loss should be the primary concern.

VL - 88 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9551005?dopt=Abstract ER - TY - JOUR T1 - Correlates of daytime sleepiness in 4578 elderly persons: the Cardiovascular Health Study. JF - Sleep Y1 - 1998 A1 - Whitney, C W A1 - Enright, P L A1 - Newman, A B A1 - Bonekat, W A1 - Foley, D A1 - Quan, S F KW - Activities of Daily Living KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Brain KW - Cardiovascular Diseases KW - Circadian Rhythm KW - Cognition Disorders KW - Cohort Studies KW - Continental Population Groups KW - Cross-Sectional Studies KW - Disorders of Excessive Somnolence KW - Electrocardiography KW - Female KW - Health Status KW - Health Surveys KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Neuropsychological Tests KW - Prevalence KW - Sex Distribution AB -

OBJECTIVES: To describe the prevalence of self-reported daytime sleepiness in older men and women and to describe their relationships with demographic factors, nocturnal complaints, health status, and cardiovascular diseases (CVD).

DESIGN: Cross-sectional survey and clinical exam.

SETTING: Participants in the Cardiovascular Health Study, 4578 adults aged 65 and older, recruited from a random sample of non-institutionalized Medicare enrollees in four U.S. communities.

MEASURES: Daytime sleepiness measured by the Epworth Sleepiness Scale (ESS), magnetic resonance imaging of the brain (MRI), cognitive function tests, and standardized questionnaires for cardiopulmonary symptoms and diseases, depressive symptoms, social support, activities of daily living, physical activity, and current medications.

RESULTS: Approximately 20% of the participants reported that they were "usually sleepy in the daytime". Although elderly black men were less likely to report frequent awakenings than those in the other three race and gender groups, they had significantly higher mean ESS scores. The following were independently associated with higher ESS scores in gender-specific models: non-white race, depression, loud snoring, awakening with dyspnea or snorting, frequent nocturnal awakenings, medications used to treat congestive heart failure, non-use of sleeping pills, a sedentary lifestyle, and limitation of activities of daily living in both men and women; additional correlates included hip circumference and current smoking in men, and hayfever in women. The following were not independently associated with ESS in the models: age, education, use of wine or beer to aid sleep, use of tricyclic antidepressants, long- or short-acting benzodiazepines, asthma, angina, myocardial infarction, congestive heart failure itself, forced vital capacity, social support, cognitive function, or MRI evidence of global brain atrophy or white matter abnormality.

CONCLUSIONS: Daytime sleepiness is common in the elderly, probably due to nocturnal disturbances such as frequent awakenings and snoring. The occasional use of sleeping pills for insomnia is associated with reduced daytime sleepiness in the elderly, while the use of medications for congestive heart failure is associated with daytime sleepiness. Surprisingly, anatomic abnormalities such as evidence of previous strokes and brain atrophy (as seen on brain MRI scans) were not associated with daytime sleepiness in these non-institutionalized elderly persons.

VL - 21 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9485530?dopt=Abstract ER - TY - JOUR T1 - Diabetes in older adults: comparison of 1997 American Diabetes Association classification of diabetes mellitus with 1985 WHO classification. JF - Lancet Y1 - 1998 A1 - Wahl, P W A1 - Savage, P J A1 - Psaty, B M A1 - Orchard, T J A1 - Robbins, J A A1 - Tracy, R P KW - African Americans KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Diabetes Mellitus KW - Female KW - Glucose Tolerance Test KW - Humans KW - Male KW - Prevalence KW - Societies, Medical KW - World Health Organization AB -

BACKGROUND: We aimed to compare the prevalence of abnormal glucose tolerance identified by the 1985 WHO and the 1997 American Diabetes Association (ADA) diagnostic categories based on information collected in the Cardiovascular Health Study, an epidemiological study of elderly people.

METHODS: We measured glucose concentrations during fasting and 2 h after a 75 g oral glucose-tolerance test in participants aged 65-100 years in the Cardiovascular Health Study. From a 1989 cohort, we analysed the glucose measurements of 4515 individuals without a previous diagnosis of diabetes and of 262 additional measurements from an African-American cohort recruited in 1992-93.

FINDINGS: In the 1989 cohort, the prevalence of untreated diabetes with ADA diagnostic fasting criteria was 7.7% versus a prevalence of 14.8% by the WHO criteria. In the African-American cohort, the prevalence of untreated diabetes was 2.7% with ADA criteria and 11.8% with WHO criteria. 3509 (77.7%) of the 4515 participants in the 1989 cohort had normal glucose concentrations according to ADA fasting criteria, compared with 2401 (53.2%) according to WHO criteria. In the African-American cohort, the corresponding numbers were 239 (91.2%) versus 153 (58.4%). All differences in prevalence of abnormal glucose tolerance between ADA and WHO classifications were significant (p<0.0001).

INTERPRETATION: Among elderly individuals, there was a significant difference in the prevalence of diabetes identified by the WHO diagnostic criteria based on oral glucose-tolerance test and the ADA fasting criteria. Consequently, many individuals currently classified as non-diabetic according to ADA criteria would previously have had a diagnosis of diabetes according to WHO criteria. Longitudinal studies are needed to assess the value of the criteria in the identification of individuals at increased risk of diabetes-associated chronic complications.

VL - 352 IS - 9133 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9759743?dopt=Abstract ER - TY - JOUR T1 - Differences in prevalence of and risk factors for subclinical vascular disease among black and white participants in the Cardiovascular Health Study. JF - Arterioscler Thromb Vasc Biol Y1 - 1998 A1 - Kuller, L A1 - Fisher, L A1 - McClelland, R A1 - Fried, L A1 - Cushman, M A1 - Jackson, S A1 - Manolio, T KW - African Americans KW - Aged KW - Cardiovascular Physiological Phenomena KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Health Status KW - Humans KW - Male KW - Multivariate Analysis KW - Prevalence KW - Regression Analysis KW - Risk Factors KW - Vascular Diseases AB -

A composite measure of subclinical vascular disease has been developed in the Cardiovascular Health Study (CHS). In previous reports, we measured the prevalence of subclinical disease among the original 5201 participants in the CHS, the relationship of risk factors to subclinical disease, and the association of subclinical disease to clinical coronary heart disease. In 1992 to 1993 (year 4 of the study), a larger cohort of 424 black women and 248 black men was added to the study. In this study, we have compared the prevalence of subclinical disease among blacks and whites in the CHS and the association with cardiovascular risk factors. The prevalence of subclinical disease for all participants (aged > or =65 years) was 41.3% for white women, 39.7% for black women, 41.9% for white men, and 43.7% for black men. The prevalence increased with age. The risk factor associations for subclinical disease were similar among blacks and whites. In multivariate analysis, age, systolic blood pressure, LDL cholesterol, smoking, and family history of myocardial infarction were independently associated with subclinical disease among both black and white women, while for white men, systolic blood pressure, use of antihypertensive medication, smoking, body mass index, and diastolic blood pressure (inverse) were related to subclinical disease. In black men, blood triglyceride level, use of antihypertensive medications, and family history of myocardial infarction (inverse) were associated with subclinical disease.

VL - 18 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9484995?dopt=Abstract ER - TY - JOUR T1 - Hypoechoic plaque at US of the carotid artery: an independent risk factor for incident stroke in adults aged 65 years or older. Cardiovascular Health Study. JF - Radiology Y1 - 1998 A1 - Polak, J F A1 - Shemanski, L A1 - O'Leary, D H A1 - Lefkowitz, D A1 - Price, T R A1 - Savage, P J A1 - Brant, W E A1 - Reid, C KW - Aged KW - Aged, 80 and over KW - Carotid Artery, Internal KW - Carotid Stenosis KW - Cerebrovascular Disorders KW - Cohort Studies KW - Female KW - Humans KW - Intracranial Arteriosclerosis KW - Male KW - Proportional Hazards Models KW - Risk KW - Ultrasonography, Doppler, Duplex KW - Ultrasonography, Doppler, Transcranial AB -

PURPOSE: To investigate the association between incident (first) stroke and the echogenicity of internal carotid arterial plaque at ultrasonography (US).

MATERIALS AND METHODS: A cohort of 4, 886 individuals who, at baseline, were 65 years of age or older and without symptoms of cerebrovascular disease was followed up for an average of 3.3 years. Baseline clinical findings were from color Doppler and duplex US studies of the carotid arteries and a record of traditional risk factors: age, sex, presence of diabetes mellitus, pack-years of cigarette smoking, presence of hypertension, elevated systolic and diastolic blood pressure, elevated low-density lipoprotein cholesterol level.

RESULTS: Incident strokes, excluding hemorrhagic strokes and strokes of cardiac origin, were seen in 104 individuals (2.1%) at risk. Age- and sex-adjusted odds ratios for incident stroke were significant for hypoechoic plaque (odds ratio, 2.53; 95% CI, 1,42,4.53). After controlling for risk factors in a Cox proportional hazards model, the relative risk (RR) of incident stroke was 1.72 (p = .015) for hypoechoic plaque and 2.32 (P = .004) for internal carotid arterial narrowing of at least 50%. In addition, hypoechoic plaque (RR, 2.78; CI, 1.36,5.69) and 50%-100% stenosis (RR, 3.08; CI, 1.28, 7.41) were associated with ipsilateral, nonfatal stroke.

CONCLUSION: In asymptomatic adults aged 65 years or older, that risk of incident stroke was associated with two US features: hypoechoic internal carotid arterial plaque and an estimated internal carotid arterial stenosis of 50%-100%.

VL - 208 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9722841?dopt=Abstract ER - TY - JOUR T1 - Left ventricular diastolic filling in the elderly: the cardiovascular health study. JF - Am J Cardiol Y1 - 1998 A1 - Gardin, J M A1 - Arnold, A M A1 - Bild, D E A1 - Smith, V E A1 - Lima, J A A1 - Klopfenstein, H S A1 - Kitzman, D W KW - Aged KW - Aged, 80 and over KW - Analysis of Variance KW - Blood Flow Velocity KW - Cardiovascular Diseases KW - Cohort Studies KW - Diastole KW - Echocardiography, Doppler KW - Electrocardiography KW - Female KW - Health Status KW - Heart Ventricles KW - Humans KW - Male KW - Ventricular Function, Left AB -

Changes in left ventricular (LV) diastolic function (e.g., as measured by transmitral flow velocity) are known to occur with aging. In addition, impaired LV diastolic function plays an important role in such cardiovascular disorders common in the elderly as hypertension, ischemic heart disease, and congestive heart failure (CHF). Participants in the Cardiovascular Health Study, a multicenter study of community-dwelling men (n=2,239) and women (n=2,962) > or = 65 years of age, underwent an extensive baseline evaluation, including echocardiography. Early diastolic LV Doppler (transmitral) peak filling velocity decreased, and peak late diastolic (atrial) velocity increased with age in multivariate analyses (all p <0.001). Early and late diastolic peak filling velocities were both significantly higher in women than in men, even after adjustment for body surface area (or height and weight). In multivariate models in the entire cohort and a healthy subgroup (n=703), gender, age, heart rate, and blood pressure (BP) were most strongly related to early and late diastolic transmitral peak velocities. Early and late diastolic peak velocities both increased with increases in systolic BP and decreased with increases in diastolic BP (p <0.001). Doppler transmitral velocities were compared among health status subgroups. In multiple regression models adjusted for other covariates, and in analysis of variance models examining differences across subgroups adjusted only for age, the subgroup with CHF had the highest early diastolic peak velocities. All clinical disease subgroups had higher late diastolic peak velocities than the healthy subgroup, with the subgroups with either CHF or hypertension having the highest age-adjusted means. The subgroup with hypertension had the lowest ratio of early-to-late diastolic peak velocity, and men with CHF had the highest ratio. These findings are consistent with previous reports that hypertensive subjects exhibit an abnormal relaxation pattern, whereas patients with CHF develop a pattern suggestive of an increased early diastolic left atrial-LV pressure gradient.

VL - 82 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9708665?dopt=Abstract ER - TY - JOUR T1 - Risk factors for 5-year mortality in older adults: the Cardiovascular Health Study. JF - JAMA Y1 - 1998 A1 - Fried, L P A1 - Kronmal, R A A1 - Newman, A B A1 - Bild, D E A1 - Mittelmark, M B A1 - Polak, J F A1 - Robbins, J A A1 - Gardin, J M KW - African Americans KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Follow-Up Studies KW - Health Surveys KW - Humans KW - Male KW - Mortality KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - United States AB -

CONTEXT: Multiple factors contribute to mortality in older adults, but the extent to which subclinical disease and other factors contribute independently to mortality risk is not known.

OBJECTIVE: To determine the disease, functional, and personal characteristics that jointly predict mortality in community-dwelling men and women aged 65 years or older.

DESIGN: Prospective population-based cohort study with 5 years of follow-up and a validation cohort of African Americans with 4.25-year follow-up.

SETTING: Four US communities.

PARTICIPANTS: A total of 5201 and 685 men and women aged 65 years or older in the original and African American cohorts, respectively.

MAIN OUTCOME MEASURES: Five-year mortality.

RESULTS: In the main cohort, 646 deaths (12%) occurred within 5 years. Using Cox proportional hazards models, 20 characteristics (of 78 assessed) were each significantly (P<.05) and independently associated with mortality: increasing age, male sex, income less than $50000 per year, low weight, lack of moderate or vigorous exercise, smoking for more than 50 pack-years, high brachial (>169 mm Hg) and low tibial (< or = 127 mm Hg) systolic blood pressure, diuretic use by those without hypertension or congestive heart failure, elevated fasting glucose level (>7.2 mmol/L [130 mg/dL]), low albumin level (< or = 37 g/L), elevated creatinine level (> or = 106 micromol/L [1.2 mg/dL]), low forced vital capacity (< or = 2.06 mL), aortic stenosis (moderate or severe) and abnormal left ventricular ejection fraction (by echocardiography), major electrocardiographic abnormality, stenosis of internal carotid artery (by ultrasound), congestive heart failure, difficulty in any instrumental activity of daily living, and low cognitive function by Digit Symbol Substitution test score. Neither high-density lipoprotein cholesterol nor low-density lipoprotein cholesterol was associated with mortality. After adjustment for other factors, the association between age and mortality diminished, but the reduction in mortality with female sex persisted. Finally, the risk of mortality was validated in the second cohort; quintiles of risk ranged from 2% to 39% and 0% to 26% for the 2 cohorts.

CONCLUSIONS: Objective measures of subclinical disease and disease severity were independent and joint predictors of 5-year mortality in older adults, along with male sex, relative poverty, physical activity, smoking, indicators of frailty, and disability. Except for history of congestive heart failure, objective, quantitative measures of disease were better predictors of mortality than was clinical history of disease.

VL - 279 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9486752?dopt=Abstract ER - TY - JOUR T1 - Time trends in the use of cholesterol-lowering agents in older adults: the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 1998 A1 - Lemaitre, R N A1 - Furberg, C D A1 - Newman, A B A1 - Hulley, S B A1 - Gordon, D J A1 - Gottdiener, J S A1 - McDonald, R H A1 - Psaty, B M KW - Aged KW - Anticholesteremic Agents KW - Cholesterol, LDL KW - Cohort Studies KW - Female KW - Humans KW - Hypercholesterolemia KW - Male KW - Prevalence KW - Risk Factors KW - United States AB -

OBJECTIVES: To describe recent temporal patterns of cholesterol-lowering medication use and the characteristics that may have influenced the initiation of cholesterol-lowering therapy among those aged 65 years or older.

SUBJECTS AND METHODS: A cohort of 5201 adults 65 years or older were examined annually between June 1989 and May 1996. We added 687 African American adults to the cohort in 1992-1993. We measured blood lipid levels at baseline and for the original cohort in the third year of follow-up. We assessed the use of cholesterol-lowering drugs at each visit.

RESULTS: The prevalence of cholesterol-lowering drug use in 1989-1990 was 4.5% among the men and 5.9% among the women; these figures increased over the next 6 years to 8.1% and 10.0%, respectively, in 1995-1996. There was a 4-fold increase in the use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors during the 6 years of follow-up, from 1.9% of all participants in 1989-1990 to 7.5% in 1995-1996. The use of bile acid sequestrants, nicotinic acid, and probucol declined from initial levels of less than 1% each. Among the participants who were untreated in 1989-1990, but eligible for cholesterol-lowering therapy after a trial of dietary therapy according to the 1993 guidelines of the National Cholesterol Education Panel, less than 20% initiated drug therapy in the 6 years of follow-up, even among subjects with a history of coronary heart disease. Among participants untreated at baseline but eligible for either cholesterol-lowering therapy or dietary therapy, initiation of cholesterol-lowering drug therapy was directly associated with total cholesterol levels, hypertension, and a history of coronary heart disease, and was inversely related to age, high-density lipoprotein cholesterol levels, and difficulties with activities of daily living. Other characteristics that form the basis of the 1993 National Cholesterol Education Panel guidelines-diabetes, smoking, family history of premature coronary heart disease, and total number of risk factors-were not associated with the initiation of cholesterol-lowering drug therapy.

CONCLUSIONS: Given the clinical trial evidence for benefit, those aged 65 to 75 years and with prior coronary heart disease appeared undertreated with cholesterol-lowering drug therapy.

VL - 158 IS - 16 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9738605?dopt=Abstract ER - TY - JOUR T1 - Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group. JF - Arterioscler Thromb Vasc Biol Y1 - 1999 A1 - Newman, A B A1 - Shemanski, L A1 - Manolio, T A A1 - Cushman, M A1 - Mittelmark, M A1 - Polak, J F A1 - Powe, N R A1 - Siscovick, D KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Ankle KW - Arm KW - Blood Pressure Determination KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Humans KW - Hypertension KW - Male KW - Predictive Value of Tests KW - Risk Factors KW - Sex Distribution KW - Survival Analysis AB -

Peripheral arterial disease (PAD) in the legs, measured noninvasively by the ankle-arm index (AAI) is associated with clinically manifest cardiovascular disease (CVD) and its risk factors. To determine risk of total mortality, coronary heart disease, or stroke mortality and incident versus recurrent CVD associated with a low AAI, we examined the relationship of the AAI to subsequent CVD events in 5888 older adults with and without CVD. The AAI was measured in 5888 participants >/=65 years old at the baseline examination of the Cardiovascular Health Study. All participants had a detailed assessment of prevalent CVD and were contacted every 6 months for total mortality and CVD events (including CVD mortality, fatal and nonfatal myocardial infarction, congestive heart failure, angina, stroke, and hospitalized PAD). The crude mortality rate at 6 years was highest (32.3%) in those participants with prevalent CVD and a low AAI (P<0.9), and it was lowest in those with neither of these findings (8.7%, P<0.01). Similar patterns emerged from analysis of recurrent CVD and incident CVD. The risk for incident congestive heart failure (relative risk [RR]=1.61) and for total mortality (RR=1.62) in those without CVD at baseline but with a low AAI remained significantly elevated after adjustment for cardiovascular risk factors. Hospitalized PAD events occurred months to years after the AAI was measured, with an adjusted RR of 5.55 (95% CI, 3.08 to 9.98) in those at risk for incident events. A statistically significant decline in survival was seen at each 0.1 decrement in the AAI. An AAI of <0.9 is an independent risk factor for incident CVD, recurrent CVD, and mortality in this group of older adults in the Cardiovascular Health Study.

VL - 19 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10073955?dopt=Abstract ER - TY - JOUR T1 - Antidiabetic treatment trends in a cohort of elderly people with diabetes. The cardiovascular health study, 1989-1997. JF - Diabetes Care Y1 - 1999 A1 - Smith, N L A1 - Heckbert, S R A1 - Bittner, V A A1 - Savage, P J A1 - Barzilay, J I A1 - Dobs, A S A1 - Psaty, B M KW - Aged KW - Blood Glucose KW - Cardiovascular Diseases KW - Cohort Studies KW - Diabetes Mellitus KW - Drug Therapy KW - Female KW - Follow-Up Studies KW - Humans KW - Hypoglycemic Agents KW - Insulin KW - Male KW - Prospective Studies KW - Risk Factors KW - Time Factors KW - United States AB -

OBJECTIVE: This study characterizes the pharmaceutical treatment of type 2 diabetes from 1989-1990 to 1996-1997 in an elderly cohort.

RESEARCH DESIGN AND METHODS: A total of 5,888 adults aged > or = 65 years were recruited and attended a baseline clinic visit in 1989-1990 (n = 5,201, original cohort) or 1992-1993 (n = 687. African-American [new] cohort) as participants of the Cardiovascular Health Study. Fasting serum glucose (FSG) was measured at baseline. Medication use was ascertained by drug inventory at all annual clinic visits. Diabetes was defined at baseline as insulin or oral hypoglycemic agent (OHA) use or as having an FSG > or = 7.0 mmol/l (126 mg/dl), the current consensus definition of diabetes.

RESULTS: A total of 387 (7%) original (FSG = 9.8 mmol/l [177 mg/dl]) and 115 (17%) new (FSG = 10.6 mmol/l [191 mg/dl]) cohort members had pharmacologically treated diabetes at baseline. Among those in the original and in the new cohorts who survived follow-up, respectively, OHA use decreased from 80 to 48% (P < 0.001) and from 67 to 50% (P < 0.003) and insulin use increased from 20 to 33% (P = 0.001) and from 33 to 37% (P = 0.603). There were 396 (8%) original (FSG = 8.8 mmol/l [159 mg/dl]) and 45 (7%) new (FSG = 10.0 mmol/l [181 mg/dl]) cohort members with diabetes untreated at baseline. Among them, respectively, OHA use reached 38 and 30% and insulin use reached 6 and 16% in 1996-1997.

CONCLUSIONS: Diabetes was common in this elderly cohort, and > 80% of treated patients with diabetes at baseline were not achieving fasting glucose goals of < or = 6.7 mmol/l (120 mg/dl). Many untreated at baseline remained untreated after 7 years of follow-up.

VL - 22 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10332674?dopt=Abstract ER - TY - JOUR T1 - Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women. JF - Arterioscler Thromb Vasc Biol Y1 - 1999 A1 - Sakkinen, P A A1 - Cushman, M A1 - Psaty, B M A1 - Rodriguez, B A1 - Boineau, R A1 - Kuller, L H A1 - Tracy, R P KW - Aged KW - Aged, 80 and over KW - alpha-2-Antiplasmin KW - Antifibrinolytic Agents KW - Asian Continental Ancestry Group KW - Cohort Studies KW - Coronary Disease KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Fibrinolysin KW - Fibrinolysis KW - Humans KW - Insulin Resistance KW - Male KW - Multivariate Analysis KW - Myocardial Infarction KW - Plasminogen Activator Inhibitor 1 KW - Risk Factors AB -

Plasmin-alpha2-antiplasmin complex (PAP) marks plasmin generation and fibrinolytic balance. We recently observed that elevated levels of PAP predict acute myocardial infarction in the elderly, yet little is known about the correlates of PAP. We measured PAP in 800 elderly subjects who were free of clinical cardiovascular disease in 2 cohort studies: the Cardiovascular Health Study and the Honolulu Heart Program. Median PAP levels did not differ between the Cardiovascular Health Study (6.05+/-1.46 nmol/L) and the Honolulu Heart Program (6.11+/-1.44 nmol/L), and correlates of PAP were similar in both cohorts. In CHS, PAP levels increased with age (r=0. 30), procoagulant factors (eg, factor VIIc, r=0.15), thrombin activity (prothrombin fragment F1+2, r=0.29), and inflammation-sensitive proteins (eg, fibrinogen, r=0.44; factor VIIIc, r=0.37). PAP was associated with increased atherosclerosis as measured by the ankle-arm index (AAI) (P for trend, VL - 19 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10073949?dopt=Abstract ER - TY - JOUR T1 - Relationships of cerebral MRI findings to ultrasonographic carotid atherosclerosis in older adults : the Cardiovascular Health Study. CHS Collaborative Research Group. JF - Arterioscler Thromb Vasc Biol Y1 - 1999 A1 - Manolio, T A A1 - Burke, G L A1 - O'Leary, D H A1 - Evans, G A1 - Beauchamp, N A1 - Knepper, L A1 - Ward, B KW - Aged KW - Arteriosclerosis KW - Brain KW - Cardiovascular System KW - Carotid Artery Diseases KW - Cerebral Infarction KW - Cohort Studies KW - Cross-Sectional Studies KW - Echoencephalography KW - Female KW - Health Status KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Prevalence AB -

Cerebral magnetic resonance imaging (MRI) has demonstrated a high prevalence of infarct-like lesions, white matter hyperintensities, and evidence of cerebral atrophy in older adults. While these findings are generally believed to be related to ischemia and atherosclerosis, their relationship to atherosclerosis in the carotid arteries remains to be explored. Study subjects were part of the multicenter Cardiovascular Health Study, a cross-sectional study of 3502 women and men >/=65 years of age undergoing cranial MRI and carotid ultrasonography. MRI infarcts were detected in 1068 participants (29.3%) and measurable carotid plaque in 2745 (75.3%). MRI infarcts, ventricular and sulcal widening, and white matter score were strongly associated with carotid intimal-medial thickness (IMT) and stenosis degree after adjustment for age and sex (all P<0. 01). Associations with plaque characteristics were less strong and less consistent; MRI infarcts were weakly associated only with surface irregularity, and ventricular size was weakly associated only with lesion density (both P<0.04). In contrast, sulcal widening was strongly related to plaque characteristics, with scores being higher in those with heterogeneous and irregular plaque (both P<0. 009). Adjustment for other risk factors, and for carotid IMT/stenosis, removed associations of MRI findings with plaque characteristics except for weak relationships remaining between MRI infarcts and surface irregularity and between sulcal score and heterogeneous plaque (both P<0.03). MRI abnormalities show strong and consistent relationships with increasing carotid IMT and stenosis degree but less strong associations with plaque characteristics, especially after adjusting for IMT and stenosis.

VL - 19 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9974419?dopt=Abstract ER - TY - JOUR T1 - The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons. JF - JAMA Y1 - 1999 A1 - Haan, M N A1 - Shemanski, L A1 - Jagust, W J A1 - Manolio, T A A1 - Kuller, L KW - Aged KW - Aging KW - Alleles KW - Apolipoproteins E KW - Cardiovascular Diseases KW - Cognition Disorders KW - Cohort Studies KW - Diabetes Mellitus KW - Genotype KW - Humans KW - Mental Status Schedule KW - Prospective Studies KW - Risk Factors AB -

CONTEXT: Cognitive decline in elderly persons is often an early predictor of dementia. Subclinical cardiovascular disease (CVD) and diabetes mellitus may contribute to substantial decline in cognitive function in the elderly. These risks may be modified by gene-environment interactions between apolipoprotein E (APOE) genotype and CVD risk factors or subclinical CVD.

OBJECTIVES: To examine the association between subclinical CVD and decline in cognitive functioning in the elderly and to examine effect modification by the APOE genotype of the association between subclinical disease and cognitive decline.

DESIGN: The Cardiovascular Health Study, a population-based, prospective cohort study.

SETTING AND POPULATION: A total of 5888 randomly selected Medicare-eligible participants from Sacramento County, California; Forsyth County, North Carolina; Washington County, Maryland; and Pittsburgh, Pa, aged 65 years or older, who were recruited in 1989-1990 (n = 5201) and in 1992-1993 (n = 687) and who were followed up for 7 and 5 years, respectively.

MAIN OUTCOME MEASURES: Change over time in scores on the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test as a function of APOE genotype, subclinical CVD, and diabetes mellitus.

RESULTS: Seventy percent of participants had no significant decline on the Modified Mini-Mental State Examination. Systolic blood pressure, the ankle-arm brachial index, atherosclerosis of the internal carotid artery, diabetes mellitus, and several diagnoses of prevalent CVD were significantly associated with declines in scores on the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test. The rate of cognitive decline associated with peripheral vascular disease, atherosclerosis of the common and internal carotid arteries, or diabetes mellitus was increased by the presence of any APOE epsilon4 allele.

CONCLUSIONS: Most healthy elderly people did not experience cognitive decline. Measures of subclinical CVD were modest predictors of cognitive decline. Those with any APOE epsilon4 allele in combination with atherosclerosis, peripheral vascular disease, or diabetes mellitus were at substantially higher risk of cognitive decline than those without the APOE epsilon4 allele or subclinical CVD. High levels of atherosclerosis increased cognitive decline independently of APOE genotype.

VL - 282 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10404910?dopt=Abstract ER - TY - JOUR T1 - Stroke risk in an elderly population with atrial fibrillation. JF - J Gen Intern Med Y1 - 1999 A1 - Feinberg, W M A1 - Kronmal, R A A1 - Newman, A B A1 - Kraut, M A A1 - Bovill, E G A1 - Cooper, L A1 - Hart, R G KW - Aged KW - Atrial Fibrillation KW - Cerebrovascular Disorders KW - Cohort Studies KW - Humans KW - Male KW - Poisson Distribution KW - Proportional Hazards Models KW - Risk Factors AB -

Patients with nonvalvular atrial fibrillation (AF) have an increased risk of stroke, but the absolute rate of stroke varies widely depending on coexistent vascular disease. We assessed the stroke rate and predictive value of two published schemes for stroke risk stratification in a population-derived cohort of 259 elderly people with nonvalvular AF followed for a median of 5.3 years. The rate of ischemic stroke was 2.8% per year (95% confidence interval [CI] 1.9, 3.9). Thirty-one percent were predicted to be at low risk, and their stroke rate was 1.7% per year (95% CI 0.6, 3.8). Many people with AF in this population-derived cohort had relatively low rates of stroke. Further studies to reliably stratify stroke risk in patients with AF are needed.

VL - 14 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/9893092?dopt=Abstract ER - TY - JOUR T1 - Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. Sleep Heart Health Study. JF - JAMA Y1 - 2000 A1 - Nieto, F J A1 - Young, T B A1 - Lind, B K A1 - Shahar, E A1 - Samet, J M A1 - Redline, S A1 - D'Agostino, R B A1 - Newman, A B A1 - Lebowitz, M D A1 - Pickering, T G KW - Adult KW - Aged KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Humans KW - Hypertension KW - Logistic Models KW - Male KW - Middle Aged KW - Obesity KW - Polysomnography KW - Sleep Apnea Syndromes KW - Snoring AB -

CONTEXT: Sleep-disordered breathing (SDB) and sleep apnea have been linked to hypertension in previous studies, but most of these studies used surrogate information to define SDB (eg, snoring) and were based on small clinic populations, or both.

OBJECTIVE: To assess the association between SDB and hypertension in a large cohort of middle-aged and older persons.

DESIGN AND SETTING: Cross-sectional analyses of participants in the Sleep Heart Health Study, a community-based multicenter study conducted between November 1995 and January 1998.

PARTICIPANTS: A total of 6132 subjects recruited from ongoing population-based studies (aged > or = 40 years; 52.8% female).

MAIN OUTCOME MEASURES: Apnea-hypopnea index (AHI, the average number of apneas plus hypopneas per hour of sleep, with apnea defined as a cessation of airflow and hypopnea defined as a > or = 30% reduction in airflow or thoracoabdominal excursion both of which are accompanied by a > or = 4% drop in oxyhemoglobin saturation) [corrected], obtained by unattended home polysomnography. Other measures include arousal index; percentage of sleep time below 90% oxygen saturation; history of snoring; and presence of hypertension, defined as resting blood pressure of at least 140/90 mm Hg or use of antihypertensive medication.

RESULTS: Mean systolic and diastolic blood pressure and prevalence of hypertension increased significantly with increasing SDB measures, although some of this association was explained by body mass index (BMI). After adjusting for demographics and anthropometric variables (including BMI, neck circumference, and waist-to-hip ratio), as well as for alcohol intake and smoking, the odds ratio for hypertension, comparing the highest category of AHI (> or = 30 per hour) with the lowest category (< 1.5 per hour), was 1.37 (95% confidence interval [CI], 1.03-1.83; P for trend = .005). The corresponding estimate comparing the highest and lowest categories of percentage of sleep time below 90% oxygen saturation (> or = 12% vs < 0.05%) was 1.46 (95% CI, 1.12-1.88; P for trend <.001). In stratified analyses, associations of hypertension with either measure of SDB were seen in both sexes, older and younger ages, all ethnic groups, and among normal-weight and overweight individuals. Weaker and nonsignificant associations were observed for the arousal index or self-reported history of habitual snoring.

CONCLUSION: Our findings from the largest cross-sectional study to date indicate that SDB is associated with systemic hypertension in middle-aged and older individuals of different sexes and ethnic backgrounds.

VL - 283 IS - 14 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10770144?dopt=Abstract ER - TY - JOUR T1 - Daytime sleepiness predicts mortality and cardiovascular disease in older adults. The Cardiovascular Health Study Research Group. JF - J Am Geriatr Soc Y1 - 2000 A1 - Newman, A B A1 - Spiekerman, C F A1 - Enright, P A1 - Lefkowitz, D A1 - Manolio, T A1 - Reynolds, C F A1 - Robbins, J KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Health Status KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Multivariate Analysis KW - Myocardial Infarction KW - Odds Ratio KW - Risk Factors KW - Sex Factors KW - Sleep Apnea Syndromes KW - Sleep Stages KW - Sleep Wake Disorders KW - Snoring KW - Surveys and Questionnaires KW - United States AB -

INTRODUCTION: As part of the baseline examination in the Cardiovascular Health Study, sleep disturbance symptoms including snoring and daytime sleepiness, were assessed as potential risk factors or precipitants of cardiovascular disease (CVD). Because of the association of sleep disturbance with poorer health and the possible associations of sleep apnea with CVD, we hypothesized that those with poorer sleep or daytime sleepiness may be at increased risk of mortality or incident CVD.

SETTING: Participants (n = 5888) were recruited in 1989, with an additional minority cohort recruited in 1993, in four US communities for a cohort study designed to evaluate risk factors for cardiovascular disease.

METHODS: An interview-administered questionnaire regarding health and sleep habits with ongoing ascertainment of total mortality and cardiovascular disease morbidity and mortality, including total CVD morbidity and mortality, incident myocardial infarction, and congestive heart failure.

RESULTS: Daytime sleepiness was the only sleep symptom that was significantly associated with mortality in both men and women. The unadjusted hazard ratio was 2.12 (1.66, 2.72) in women and 1.40 (1.12, 1.73) in men. Men who reported difficulty falling asleep also had an increased mortality rate (HR = 1.43 (1.14, 1.80)) which was not seen in women. The risks were attenuated with adjustment for age but remained significant for daytime sleepiness in women (HR = 1.82 (1.42, 2.34)) and for difficulty falling asleep in men. (HR = 1.29 (1.03, 1.63)). Frequent awakenings, early morning awakening, and snoring were not associated with a significantly increased risk of mortality in these older men and women. Crude event rates were evaluated for total incident cardiovascular morbidity and mortality, incident myocardial infarction, and incident congestive heart failure (CHF). Incident CVD rates were higher in both men and women with daytime sleepiness. The aged adjusted HR was 1.35 (95% CI = 1.03, 1.76) in men and was 1.66 (95% CI = 1.28, 2.16) in women. Incident CVD was not higher in those with any other sleep disturbance including snoring. The risk of CVD events associated with daytime sleepiness was attenuated but remained significant in women after adjustment for age. Incident myocardial infarction (MI) rates were also higher in women with daytime sleepiness but were not significantly higher in men. Incident CHF rates were increased in both men and women with daytime sleepiness. In men, the age adjusted HR was 1.49 (95% CI, 1.12- 1.98) and in women, was 2.21 (95% CI, 1.64-2.98). Women reporting both daytime sleepiness and frequent awakening had a hazard ratio of 2.34 (95% CI, 1.66-3.29) for incident CHF compared with those with daytime sleepiness but without frequent awakening. This interaction was not found in men.

CONCLUSIONS: In this study, daytime sleepiness was the only sleep disturbance symptom that was associated with mortality, incident CVD morbidity and mortality, MI, and CHF. These findings were stronger in women than men, i.e., the associations persisted for mortality, CVD, and CHF in women after adjustment for age and other factors. Thus, a report of daytime sleepiness identifies older adults at increased risk for total and cardiovascular mortality, and is an independent risk factor in women.

VL - 48 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10682939?dopt=Abstract ER - TY - JOUR T1 - Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Cardiovascular Health Study Collaborative Research Group. JF - Circulation Y1 - 2000 A1 - Ariyo, A A A1 - Haan, M A1 - Tangen, C M A1 - Rutledge, J C A1 - Cushman, M A1 - Dobs, A A1 - Furberg, C D KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Coronary Disease KW - Depression KW - Female KW - Humans KW - Male KW - Prospective Studies KW - Risk Factors KW - United States AB -

BACKGROUND: Several epidemiological studies have associated depressive symptoms with cardiovascular disease. We investigated whether depressive symptoms constituted a risk for coronary heart disease (CHD) and total mortality among an apparently healthy elderly cohort.

METHODS AND RESULTS: In a prospective cohort of 5888 elderly Americans (>/=65 years) who were enrolled in the Cardiovascular Health Study, 4493 participants who were free of cardiovascular disease at baseline provided annual information on their depressive status, which was assessed using the Depression Scale of the Center for Epidemiological Studies. These 4493 subjects were followed for 6 years for the development of CHD and mortality. The cumulative mean depression score was assessed for each participant up to the time of event (maximum 6-year follow-up). Using time-dependent, proportional-hazards models, the unadjusted hazard ratio associated with every 5-unit increase in mean depression score for the development of CHD was 1.15 (P:=0.006); the ratio for all-cause mortality was 1.29 (P:<0.0001). In multivariate analyses adjusted for age, race, sex, education, diabetes, hypertension, cigarette smoking, total cholesterol, triglyceride level, congestive heart failure, and physical inactivity, the hazard ratio for CHD was 1.15 (P:=0.006) and that for all-cause mortality was 1.16 (P:=0.006). Among participants with the highest cumulative mean depression scores, the risk of CHD increased by 40% and risk of death by 60% compared with those who had the lowest mean scores.

CONCLUSIONS: Among elderly Americans, depressive symptoms constitute an independent risk factor for the development of CHD and total mortality.

VL - 102 IS - 15 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11023931?dopt=Abstract ER - TY - JOUR T1 - Does snoring predict sleepiness independently of apnea and hypopnea frequency? JF - Am J Respir Crit Care Med Y1 - 2000 A1 - Gottlieb, D J A1 - Yao, Q A1 - Redline, S A1 - Ali, T A1 - Mahowald, M W KW - Adult KW - Aged KW - Arousal KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Polysomnography KW - Risk Factors KW - Sleep Apnea, Obstructive KW - Snoring KW - Wakefulness AB -

Obstructive apneas and hypopneas during sleep are a well recognized cause of excessive daytime sleepiness. Snoring is also associated with excess sleepiness, although it is not known whether this reflects an independent effect of snoring or whether snoring is simply a marker for obstructive sleep apnea. To further explore the relation of snoring to sleepiness, we conducted a cross-sectional cohort study of community-dwelling adults participating in the Sleep Heart Health Study. The study sample comprises 2,737 men and 3,040 women with a mean age of 64 (SD 11) yr. Sleepiness was quantified using the Epworth Sleepiness Scale (ESS). Snoring history was obtained via a self-completion questionnaire. The respiratory disturbance index (RDI), defined as the number of apneas plus hypopneas per hour of sleep, was measured during in-home polysomnography. The ESS score increased progressively with increasing RDI, from a mean of 7.1 (4.2) in subjects with RDI < 1.5 to 8.8 (4.8) in subjects with RDI >/= 15 (p < 0.001). A progressive increase in ESS score was also seen across five categories of snoring frequency, from 6.4 (4.2) in current nonsnorers to 9.3 (4.8) in subjects who snored six to seven nights per week (p < 0.001). The prevalence of excessive daytime sleepiness, defined as an ESS score >/= 11, increased from 15% in never-snorers to 39% in those who snored six to seven nights per week. The relation of snoring to sleepiness was seen at all levels of RDI, with no significant change in the relation of snoring to ESS score after adjustment for RDI in multivariate models. The effects of snoring and RDI on sleepiness were little affected by adjustment for age, sex, race, body mass index, or questionnaire evidence of insufficient sleep time or nocturnal leg jerks or cramps. We conclude that both snoring and RDI are independently associated with excess sleepiness in community-dwelling, middle-aged and older adults.

VL - 162 IS - 4 Pt 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11029370?dopt=Abstract ER - TY - JOUR T1 - Tobacco, hypertension, and vascular disease: risk factors for renal functional decline in an older population. JF - Kidney Int Y1 - 2000 A1 - Bleyer, A J A1 - Shemanski, L R A1 - Burke, G L A1 - Hansen, K J A1 - Appel, R G KW - African Continental Ancestry Group KW - Aged KW - Aging KW - Cohort Studies KW - Creatinine KW - European Continental Ancestry Group KW - Female KW - Humans KW - Hypertension KW - Kidney KW - Male KW - Regression Analysis KW - Retrospective Studies KW - Risk Factors KW - Smoking KW - Vascular Diseases AB -

BACKGROUND: A decline in renal function with age has been noted in some but not all individuals. The purpose of this study was to identify risk factors associated with a clinically significant increase in serum creatinine (of at least 0.3 mg/dL) in an older nondiabetic population.

METHODS: A retrospective case-control study was performed analyzing data obtained from 4142 nondiabetic participants of the Cardiovascular Health Study Cohort, all at least 65 years of age, who had two measurements of serum creatinine performed at least three years apart. Cases were identified as participants who developed an increase in serum creatinine of at least 0.3 mg/dL, with controls including participants who did not sustain such an increase.

RESULTS: There was an increase in the serum creatinine of at least 0.3 mg/dL in 2.8% of the population. In a multivariate "best-fit" model adjusted for gender, weight, black race, baseline serum creatinine, and age, the following factors were associated with an increase in serum creatinine: number of cigarettes smoked per day, systolic blood pressure, and maximum internal carotid artery intimal thickness.

CONCLUSIONS: These data suggest that three very preventable or treatable conditions-hypertension, smoking, and prevalent vascular disease, which are associated with large and small vessel disease-are highly associated with clinically important changes in renal function in an older population.

VL - 57 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/10792626?dopt=Abstract ER - TY - JOUR T1 - Associations of subclinical cardiovascular disease with frailty. JF - J Gerontol A Biol Sci Med Sci Y1 - 2001 A1 - Newman, A B A1 - Gottdiener, J S A1 - McBurnie, M A A1 - Hirsch, C H A1 - Kop, W J A1 - Tracy, R A1 - Walston, J D A1 - Fried, L P KW - Aged KW - Ankle KW - Arm KW - Black or African American KW - Blood Pressure KW - Brain KW - Cardiovascular Diseases KW - Carotid Artery Diseases KW - Cerebral Infarction KW - Cerebrovascular Disorders KW - Cohort Studies KW - Echocardiography KW - Electrocardiography KW - Frail Elderly KW - Health Status KW - Heart Failure KW - Humans KW - Magnetic Resonance Imaging KW - United States KW - Vascular Diseases AB -

BACKGROUND: Frail health in old age has been conceptualized as a loss of physiologic reserve associated with loss of lean mass, neuroendocrine dysregulation, and immune dysfunction. Little work has been done to define frailty and describe the underlying pathophysiology.

METHODS: Frailty status was defined in participants of the Cardiovascular Health Study (CHS), a cohort of 5,201 community-dwelling older adults, based on the presence of three out of five clinical criteria. The five criteria included self-reported weight loss, low grip strength, low energy, slow gait speed, and low physical activity. We examined the spectrum of clinical and subclinical cardiovascular disease in those who were frail (3/5 criteria) or of intermediate frailty status (1 or 2/5 criteria), compared to those who were not frail (0/5). We hypothesized that the severity of frailty would be related to a higher prevalence of reported cardiovascular disease (CVD), as well as to a greater extent of CVD, measured by noninvasive testing.

RESULTS: Of 4,735 eligible participants, 2,289 (48%) were not frail, 299 (6%) were frail, and 2.147 (45%) were of intermediate frailty status. Those who were frail were older (77.2 yrs) compared to those who were not frail (71.5 yrs) or intermediate (73.4 yrs) (p < .001). Frailty status was associated with clinical CVD and most strongly with congestive heart failure (odds ratio [OR] = 7.51 (95% confidence interval [CI] = 4.66-12.12). In those without a history of a CVD event (n = 1.259), frailty was associated with many noninvasive measures of CVD. Those with carotid stenosis >75% (adjusted OR = 3.41), ankle-arm index <0.8 (adjusted OR = 3.17) or 0.8-0.9 (adjusted OR = 2.01), major electrocardiography (ECG) abnormalities (adjusted OR = 1.58), greater left ventricular (LV) mass by echocardiography (adjusted OR = 1.16), and higher degree of infarct-like lesions in the brain (adjusted OR = 1.71), were more likely to be frail compared to those who were not frail. The overall associations of each of these noninvasive measures of CVD with frailty level were significant (all p < .05).

CONCLUSIONS: Cardiovascular disease was associated with an increased likelihood of frail health. In those with no history of CVD, the extent of underlying cardiovascular disease measured by carotid ultrasound and ankle-arm index, LV hypertrophy by ECG and echocardiography, was related to frailty. Infarct-like lesions in the brain on magnet resonance imaging were related to frailty as well.

VL - 56 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11253157?dopt=Abstract ER - TY - JOUR T1 - Cluster analysis and patterns of findings on cranial magnetic resonance imaging of the elderly: the Cardiovascular Health Study. JF - Arch Neurol Y1 - 2001 A1 - Longstreth, W T A1 - Diehr, P A1 - Manolio, T A A1 - Beauchamp, N J A1 - Jungreis, C A A1 - Lefkowitz, D KW - Aged KW - Brain KW - Cerebral Infarction KW - Cerebrovascular Disorders KW - Cluster Analysis KW - Cohort Studies KW - Discriminant Analysis KW - Female KW - Humans KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Risk Factors AB -

OBJECTIVE: To characterize patterns of findings on cranial magnetic resonance imaging (MRI) of the elderly using a statistical technique called cluster analysis.

SUBJECTS AND METHODS: The Cardiovascular Health Study is a population-based, longitudinal study of 5888 people 65 years and older. Of these, 3230 underwent cranial MRI scans, which were coded for presence of infarcts and grades for white matter, ventricles, and sulci. Cluster analysis separated participants into 5 clusters based solely on patterns of MRI findings. Participants comprising each cluster were contrasted with respect to cardiovascular risk factors and clinical manifestations.

RESULTS: One cluster was low on all the MRI findings (normal) and another was high on all of them (complex infarcts). Another cluster had evidence for infarcts alone (simple infarcts), whereas the last 2 clusters lacked infarcts, one having enlarged ventricles and sulci (atrophy) and the other having prominent white matter changes and enlarged ventricles (leukoaraiosis). Factors that distinguished these clusters in a discriminant analysis were age, sex, several measures of hypertension, internal carotid artery wall thickness, smoking, and prevalent claudication before the MRI. The atrophy group had the highest percentage of men and the normal group had the lowest. Cognitive and motor performance also differed across clusters, with the atrophy cluster performing better than may have been expected.

CONCLUSIONS: These MRI patterns identified participants with different vascular disease risk factors and clinical manifestations. Results of these exploratory analyses warrant consideration in other populations of elderly people. Such patterns may provide clues about the pathophysiology of structural brain changes in the elderly.

VL - 58 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11295995?dopt=Abstract ER - TY - JOUR T1 - Coronary artery calcification in older adults to age 99: prevalence and risk factors. JF - Circulation Y1 - 2001 A1 - Newman, A B A1 - Naydeck, B L A1 - Sutton-Tyrrell, K A1 - Feldman, A A1 - Edmundowicz, D A1 - Kuller, L H KW - Age Distribution KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Black People KW - Calcinosis KW - Calcium KW - Cohort Studies KW - Comorbidity KW - Coronary Angiography KW - Coronary Artery Disease KW - Coronary Vessels KW - Demography KW - Female KW - Humans KW - Logistic Models KW - Male KW - Predictive Value of Tests KW - Prevalence KW - Risk Factors KW - Sex Distribution KW - Sex Factors KW - Tomography, X-Ray Computed KW - White People AB -

BACKGROUND: Coronary artery calcification has been proposed as a noninvasive method to assess cardiovascular disease (CVD) risk. However, the prevalence and risk factors for coronary artery calcification in populations >65 years have not been well studied.

METHODS AND RESULTS: Electron beam tomography was performed to assess coronary artery calcium (CAC) in 614 older adults aged, on average, 80 years (range, 67 to 99 years); 367 (60%) were women, and 143 (23%) were black. Calcium scores ranged from 0 to 5459. Median scores were 622 for men and 205 for women. Scores increased by age and were lower in blacks than in whites. Nine percent of subjects (n=57) had no CAC, and 31% (n=190) had a score lower than 100. A history of CVD was associated with calcium score. Age, male sex, white race, CVD, triglyceride level, pack-years of smoking, and asthma, emphysema, or bronchitis (chronic obstructive pulmonary disease) were independently associated with CAC score in the fourth quartile.

CONCLUSIONS: A wide range of CAC scores was observed, suggesting adaptation with aging. CAC may have potential to predict CVD in older adults, but this remains to be determined.

VL - 104 IS - 22 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11723018?dopt=Abstract ER - TY - JOUR T1 - Echocardiographic features of the right heart in sleep-disordered breathing: the Framingham Heart Study. JF - Am J Respir Crit Care Med Y1 - 2001 A1 - Guidry, U C A1 - Mendes, L A A1 - Evans, J C A1 - Levy, D A1 - O'Connor, G T A1 - Larson, M G A1 - Gottlieb, D J A1 - Benjamin, E J KW - Adult KW - Age Factors KW - Aged KW - Cohort Studies KW - Cross-Sectional Studies KW - Data Interpretation, Statistical KW - Echocardiography KW - Female KW - Forced Expiratory Volume KW - Humans KW - Hypertrophy, Right Ventricular KW - Linear Models KW - Male KW - Middle Aged KW - Obesity KW - Observer Variation KW - Polysomnography KW - Prospective Studies KW - Sex Factors KW - Sleep Apnea Syndromes KW - Ventricular Function, Right KW - Vital Capacity AB -

The effect of sleep-disordered breathing (SDB) on right heart structure and function is controversial. Studies of patients referred for evaluation of possible sleep apnea have yielded conflicting results, and the impact of SDB on the right heart has not been investigated in the general population. We examined the echocardiographic features of subjects with SDB at the Framingham Heart Study site of the Sleep Heart Health Study. Of 1,001 polysomnography subjects, 90 with SDB defined as a respiratory disturbance index (RDI) score > 90th percentile (mean RDI = 42) were compared with 90 low-RDI subjects (mean RDI = 5) matched for age, sex, and body mass index. Right heart measurements, made without knowledge of clinical status, were compared between groups. The majority of the subjects were male (74%). After multivariable adjustment, right ventricle (RV) wall thickness was significantly greater (p = 0.005) in subjects with SDB (0.78 +/- 0.02 cm) than in the low-RDI subjects (0.68 +/- 0.02 cm). Right atrial dimensions, RV dimensions, and RV systolic function were not found to be significantly different between subjects with SDB and the low-RDI subjects. We conclude that in this community-based study of SDB and right heart echocardiographic features, RV wall thickness was increased in subjects with SDB. Whether the RV hypertrophy observed in persons with SDB is associated with increased morbidity and mortality remains unknown.

VL - 164 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11587973?dopt=Abstract ER - TY - JOUR T1 - Factors associated with healthy aging: the cardiovascular health study. JF - J Am Geriatr Soc Y1 - 2001 A1 - Burke, G L A1 - Arnold, A M A1 - Bild, D E A1 - Cushman, M A1 - Fried, L P A1 - Newman, A A1 - Nunn, C A1 - Robbins, J KW - Aged KW - Aged, 80 and over KW - Aging KW - Cardiovascular Diseases KW - Cohort Studies KW - Diet KW - Exercise KW - Female KW - Health Status KW - Humans KW - Incidence KW - Life Style KW - Longitudinal Studies KW - Lung Diseases, Obstructive KW - Male KW - Neoplasms KW - Probability KW - Reference Values KW - Risk Factors KW - Sex Distribution KW - Socioeconomic Factors KW - Survival Rate KW - United States AB -

OBJECTIVES: To identify factors associated with remaining healthy in older adults.

DESIGN: Longitudinal cohort study.

SETTING: Data were collected at the four Cardiovascular Health Study field centers.

PARTICIPANTS: 5,888 participants age 65 years and older in the Cardiovascular Health Study.

MEASUREMENTS: Presence of chronic disease was assessed at baseline and over a maximum 7-year follow-up period. Participants who were free of chronic disease (no cardiovascular disease (CVD), chronic obstructive pulmonary disease, or self-reported cancer, except nonmelanoma skin cancer) at the baseline examination were then monitored for the onset of incident cancer, cardiovascular disease, and fatal outcomes.

RESULTS: A high proportion of these older adults was healthy at the initial examination and remained healthy over the follow-up period. Numerous behavioral factors were associated with continued health, including physical activity, refraining from cigarette smoking, wine consumption (women), higher educational status, and lower waist circumference. A number of CVD risk factors and subclinical disease measures were associated with continued health, including higher high-density lipoprotein (HDL) cholesterol, lack of diabetes, thinner common carotid intimal nmedial thickness, lower blood pressure, lower C-reactive protein, and higher ankle-arm blood pressure ratio. Among the behavioral factors, exercise, not smoking, and not taking aspirin remained significant predictors of health even after controlling for CVD risk factors and subclinical disease in older adults.

CONCLUSIONS: These data suggest that a number of modifiable behavioral factors (physical activity, smoking, and obesity) and cardiovascular risk factors (diabetes, HDL cholesterol, and blood pressure) are associated with maintenance of good health in older adults.

VL - 49 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11300235?dopt=Abstract ER - TY - JOUR T1 - Frailty in older adults: evidence for a phenotype. JF - J Gerontol A Biol Sci Med Sci Y1 - 2001 A1 - Fried, L P A1 - Tangen, C M A1 - Walston, J A1 - Newman, A B A1 - Hirsch, C A1 - Gottdiener, J A1 - Seeman, T A1 - Tracy, R A1 - Kop, W J A1 - Burke, G A1 - McBurnie, M A KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Disabled Persons KW - Fatigue KW - Female KW - Frail Elderly KW - Humans KW - Incidence KW - Male KW - Muscle Weakness KW - Phenotype KW - Prevalence KW - Sex Distribution KW - United States KW - Weight Loss AB -

BACKGROUND: Frailty is considered highly prevalent in old age and to confer high risk for falls, disability, hospitalization, and mortality. Frailty has been considered synonymous with disability, comorbidity, and other characteristics, but it is recognized that it may have a biologic basis and be a distinct clinical syndrome. A standardized definition has not yet been established.

METHODS: To develop and operationalize a phenotype of frailty in older adults and assess concurrent and predictive validity, the study used data from the Cardiovascular Health Study. Participants were 5,317 men and women 65 years and older (4,735 from an original cohort recruited in 1989-90 and 582 from an African American cohort recruited in 1992-93). Both cohorts received almost identical baseline evaluations and 7 and 4 years of follow-up, respectively, with annual examinations and surveillance for outcomes including incident disease, hospitalization, falls, disability, and mortality.

RESULTS: Frailty was defined as a clinical syndrome in which three or more of the following criteria were present: unintentional weight loss (10 lbs in past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity. The overall prevalence of frailty in this community-dwelling population was 6.9%; it increased with age and was greater in women than men. Four-year incidence was 7.2%. Frailty was associated with being African American, having lower education and income, poorer health, and having higher rates of comorbid chronic diseases and disability. There was overlap, but not concordance, in the cooccurrence of frailty, comorbidity, and disability. This frailty phenotype was independently predictive (over 3 years) of incident falls, worsening mobility or ADL disability, hospitalization, and death, with hazard ratios ranging from 1.82 to 4.46, unadjusted, and 1.29-2.24, adjusted for a number of health, disease, and social characteristics predictive of 5-year mortality. Intermediate frailty status, as indicated by the presence of one or two criteria, showed intermediate risk of these outcomes as well as increased risk of becoming frail over 3-4 years of follow-up (odds ratios for incident frailty = 4.51 unadjusted and 2.63 adjusted for covariates, compared to those with no frailty criteria at baseline).

CONCLUSIONS: This study provides a potential standardized definition for frailty in community-dwelling older adults and offers concurrent and predictive validity for the definition. It also finds that there is an intermediate stage identifying those at high risk of frailty. Finally, it provides evidence that frailty is not synonymous with either comorbidity or disability, but comorbidity is an etiologic risk factor for, and disability is an outcome of, frailty. This provides a potential basis for clinical assessment for those who are frail or at risk, and for future research to develop interventions for frailty based on a standardized ascertainment of frailty.

VL - 56 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11253156?dopt=Abstract ER - TY - JOUR T1 - Hormone replacement therapy is associated with higher FEV1 in elderly women. JF - Am J Respir Crit Care Med Y1 - 2001 A1 - Carlson, C L A1 - Cushman, M A1 - Enright, P L A1 - Cauley, J A A1 - Newman, A B KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Estrogen Replacement Therapy KW - Female KW - Forced Expiratory Volume KW - Humans KW - Longitudinal Studies KW - Spirometry KW - Vital Capacity AB -

Estrogen and progesterone use have been associated with improved pulmonary function in premenopausal women. However, little research has examined the relationship between hormone replacement therapy (HRT) and pulmonary function in postmenopausal women. We examined the relationship of HRT with spirometry in 2,353 women aged 65 yr and older participating in the Cardiovascular Health Study in 1993/1994. Current use of HRT was hypothesized to be associated with higher FEV1, higher FVC, and less pulmonary obstruction (FEV1/FVC < 65%). FEV1 was higher among current HRT users compared to noncurrent users in the following groups: overall (1.82 L versus 1.66 L, p < 0.0001), among women without asthma (1.85 L versus 1.69 L, p < 0.0001), among former smokers (1.76 L versus 1.60 L, p = 0.013), and among never smokers (1.90 L versus 1.72 L, p < 0.0001). Overall, HRT use was associated with a lower prevalence of pulmonary obstruction (OR 0.75 [95% CI 0.55, 0.99]). After controlling for potential confounders, HRT use was significantly associated with higher FEV(1) (p = 0.031) and with a lower prevalence of obstruction (OR 0.67 [95% CI 0.48, 0.95]). We conclude that postmenopausal women who use HRT have higher levels of FEV1 and less obstruction, which could not be explained by their lower rates of smoking and other health factors associated with HRT use.

VL - 163 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11179117?dopt=Abstract ER - TY - JOUR T1 - Hypertension, heart rate, use of antihypertensives, and incident prostate cancer. JF - Ann Epidemiol Y1 - 2001 A1 - Fitzpatrick, A L A1 - Daling, J R A1 - Furberg, C D A1 - Kronmal, R A A1 - Weissfeld, J L KW - Aged KW - Antihypertensive Agents KW - Cohort Studies KW - Heart Rate KW - Humans KW - Hypertension KW - Incidence KW - Male KW - Proportional Hazards Models KW - Prostatic Neoplasms KW - Risk KW - United States AB -

PURPOSE: Recent studies have reported conflicting results on a possible relationship between hypertension, heart rate, and prostate cancer. A model has been developed suggesting that high blood pressure and high heart rate may both be markers for increased central sympathetic nervous activity, which may result in androgen-mediated stimulation of prostate cancer growth.

METHODS: In this study we examined the associations between hypertension, heart rate, use of antihypertensive medications, and incident prostate cancer in a cohort of 2442 men. Data from the Cardiovascular Health Study (CHS), an NHLBI-sponsored observational study of adults age 65 or older in four U.S. communities, were analyzed using Cox proportional hazards regression. Seated systolic and diastolic blood pressures were measured using a standardized protocol at the initial clinical examination and annually at follow-up visits. Medications data were transcribed by trained interviewers from prescription medication containers brought into the clinic by participants.

RESULTS: A total of 209 cases of incident prostate cancer were identified from either an ICD-9 code of 185 in hospital medical records (n = 130) or by self-report from annual surveillance interviews (n = 79). An average of 5.6 years of follow-up was available for analyses. No associations between blood pressure measures at entry into the study and prostate cancer were found, although these results may have been affected by subsequent treatment of hypertension. An association between resting heart rate (HR) equal to or greater than 80 beats per minute and incident prostate cancer was found compared to men with a rate of less than 60 beats per minute (HR: 1.6, 95% confidence interval [CI]: 1.03-2.5). An inverse association was found between risk of incident prostate cancer and use of any antihypertensive medication (HR: 0.7, 95% CI: 0.5-0.9). A test of heterogeneity found no difference between use of the specific classes of antihypertensive medication and the association with prostate cancer risk.

CONCLUSIONS: These data tend to support the hypothesized causal pathway between vascular disease markers and prostate cancer.

VL - 11 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11709272?dopt=Abstract ER - TY - JOUR T1 - Patterns of self-rated health in older adults before and after sentinel health events. JF - J Am Geriatr Soc Y1 - 2001 A1 - Diehr, P A1 - Williamson, J A1 - Patrick, D L A1 - Bild, D E A1 - Burke, G L KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Death KW - Female KW - Follow-Up Studies KW - Health Status KW - Health Status Indicators KW - Hip Fractures KW - Hospitalization KW - Humans KW - Linear Models KW - Longitudinal Studies KW - Male KW - Random Allocation KW - Time Factors AB -

OBJECTIVES: To describe and compare patterns of change in self-rated health for older adults before death and before and after stroke, myocardial infarction, congestive heart failure, cardiac procedure, hospital admission for cancer, and hip fracture.

DESIGN: "Event cohort," measuring time in months before and after the event.

SETTING: Four U.S. communities.

PARTICIPANTS: 5888 participants in the Cardiovascular Health Study (CHS), sampled from Medicare rolls and followed up to 8 years. Mean age at baseline was 73.

MEASUREMENTS: Self-rated health, including a category for death, assessed at 6-month intervals, and ascertainment of events.

METHODS: We examined the percentage that was healthy each month in the 5 years before death and in the 2 years before and after the other events, and compared the patterns to a "no event" group and to one another, using graphs and linear regression.

RESULTS: For people who died, health status declined slowly until about 9 months before death, when it dropped steeply. Comparing persons equally far from death, health was unrelated to age, but men and whites were healthier than women and blacks. Health for other events declined before the event, dropped steeply at the event, showed some recovery, and then declined further after the event. About 65% to 80% of the subjects were healthy 2 years before their event, but only 35% to 65% were healthy two years afterwards. Patterns were similar although less extreme for the "no event" group.

CONCLUSION: Visualizing trajectories of health helps us understand how serious health events changes health. Conclusions about change must be drawn with care because of a variety of possible biases. We have described the trajectories in detail. Work is now needed to explain, predict, and possibly prevent such changes in health.

VL - 49 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11207840?dopt=Abstract ER - TY - JOUR T1 - Prevalence of clinical and isolated subclinical cardiovascular disease in older adults with glucose disorders: the Cardiovascular Health Study. JF - Diabetes Care Y1 - 2001 A1 - Barzilay, J I A1 - Spiekerman, C F A1 - Kuller, L H A1 - Burke, G L A1 - Bittner, V A1 - Gottdiener, J S A1 - Brancati, F L A1 - Orchard, T J A1 - O'Leary, D H A1 - Savage, P J KW - Aged KW - Angina Pectoris KW - Cardiovascular Diseases KW - Cerebrovascular Disorders KW - Cohort Studies KW - Diabetes Mellitus KW - Diabetes Mellitus, Type 1 KW - Diabetes Mellitus, Type 2 KW - Electrocardiography KW - Female KW - Glucose Intolerance KW - Heart Diseases KW - Humans KW - Male KW - Peripheral Vascular Diseases KW - Prevalence KW - United States AB -

OBJECTIVE: Clinical cardiovascular disease (CVD) is highly prevalent among people with diabetes. However, there is little information regarding the prevalence of subclinical CVD and its relation to clinical CVD in diabetes and in the glucose disorders that precede diabetes.

RESEARCH DESIGN AND METHODS: Participants in the Cardiovascular Health Study, aged > or = 65 years (n = 5,888), underwent vascular and metabolic testing. Individuals with known disease in the coronary, cerebral, or peripheral circulations were considered to have clinical disease. Those without any clinical disease in whom CVD was detected by ultrasonography, electrocardiography, or ankle arm index in any of the three vascular beds were considered to have isolated subclinical disease.

RESULTS: Approximately 30% of the cohort had clinical disease, and approximately 60% of the remainder had isolated subclinical disease. In those with normal glucose status, isolated subclinical disease made up most of the total CVD. With increasing glucose severity, the proportion of total CVD that was clinical disease increased; 75% of men and 66% of women with normal fasting glucose status had either clinical or subclinical CVD. Among those with known diabetes, the prevalence was approximately 88% (odds ratio [OR] 2.46 for men and 4.22 for women, P < 0.0001). There were intermediate prevalences and ORs for those with impaired fasting glucose status and newly diagnosed diabetes.

CONCLUSIONS: Isolated subclinical CVD is common among older adults. Glucose disorders are associated with an increased prevalence of total CVD and an increased proportion of clinical disease relative to subclinical disease.

VL - 24 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11423508?dopt=Abstract ER - TY - JOUR T1 - The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. JF - Diabetes Y1 - 2001 A1 - Barzilay, J I A1 - Abraham, L A1 - Heckbert, S R A1 - Cushman, M A1 - Kuller, L H A1 - Resnick, H E A1 - Tracy, R P KW - Aged KW - Biomarkers KW - Blood Glucose KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cohort Studies KW - Diabetes Mellitus KW - Female KW - Humans KW - Hypoglycemia KW - Inflammation KW - Longitudinal Studies KW - Male KW - Reference Values KW - Risk Factors AB -

Several studies suggest that inflammation plays a role in the pathogenesis of some glucose disorders in adults. We tested this hypothesis in a longitudinal cohort study of older individuals who had normal fasting glucose (FG) values at baseline. We compared the baseline levels of six inflammatory markers in participants who had developed glucose disorders at follow-up with those of participants whose FG remained normal at follow-up. Participants were members of the Cardiovascular Health Study, a prospective study of risk factors for cardiovascular disease in adults > or =65 years. All 5,888 participants had baseline testing, including FG and markers of inflammation: white blood cell and platelet counts and albumin, fibrinogen, C-reactive protein (CRP), and factor VIIIc levels. At 3-4 years of follow-up, 4,481 (84.5%) of those who were alive had FG levels retested. Participants who developed diabetes (n = 45) had higher median levels of CRP at baseline than those who remained normoglycemic. On multivariate analysis, those with elevated CRP levels (75th percentile [2.86 mg/l] vs. 25th percentile [0.82 mg/l]) were 2.03 times (95% confidence intervals, 1.44-2.86) more likely to have diabetes on follow-up. Adjustment for confounders and other inflammatory markers did not appreciably change this finding. There was no relationship between the development of diabetes and other markers of inflammation. Inflammation, as measured by CRP levels, is associated with the development of diabetes in the elderly. Understanding the role of inflammation in the pathogenesis of glucose disorders in this age-group may lead to better classification and treatment of glucose disorders among them.

VL - 50 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11574423?dopt=Abstract ER - TY - JOUR T1 - The role of comorbidity in the assessment of intermittent claudication in older adults. JF - J Clin Epidemiol Y1 - 2001 A1 - Newman, A B A1 - Naydeck, B L A1 - Sutton-Tyrrell, K A1 - Polak, J F A1 - Kuller, L H KW - Aged KW - Angina Pectoris KW - Arterial Occlusive Diseases KW - Cerebrovascular Disorders KW - Cohort Studies KW - Comorbidity KW - Diabetes Mellitus KW - Female KW - Humans KW - Intermittent Claudication KW - Leg KW - Male KW - Prevalence KW - Sensitivity and Specificity KW - Surveys and Questionnaires AB -

The prevalence of intermittent claudication (IC) in older adults by questionnaire is less than 5% while the prevalence of peripheral arterial disease (PAD) by non-invasive testing is 2-4-fold higher. Comorbid conditions may result in under-reporting intermittent claudication (IC) as assessed by the Rose Questionnaire. We examined characteristics of those who report leg pain in relationship to other comorbid conditions and disability in 5888 participants of the Cardiovascular Health Study (CHS). Older adults with exertional leg pain, not meeting criteria for IC, had a higher prevalence of PAD on non-invasive testing with the ankle-arm index than those without pain, as well as a higher prevalence of arthritis. The pattern of responses suggested that pain for both conditions was reported together. The Rose Questionnaire for IC is specific for PAD, but a negative questionnaire does not indicate a lack of symptoms, rather the presence of PAD along with other conditions that can cause pain.

VL - 54 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11223327?dopt=Abstract ER - TY - JOUR T1 - Silent MRI infarcts and the risk of future stroke: the cardiovascular health study. JF - Neurology Y1 - 2001 A1 - Bernick, C A1 - Kuller, L A1 - Dulberg, C A1 - Longstreth, W T A1 - Manolio, T A1 - Beauchamp, N A1 - Price, T KW - Aged KW - Cerebral Infarction KW - Cohort Studies KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Magnetic Resonance Imaging KW - Male KW - Predictive Value of Tests KW - Risk Factors KW - Stroke AB -

BACKGROUND: Silent infarcts are commonly discovered on cranial MRI in the elderly.

OBJECTIVE: To examine the association between risk of stroke and presence of silent infarcts, alone and in combination with other stroke risk factors.

METHODS: Participants (3,324) in the Cardiovascular Health Study (CHS) without a history of stroke underwent cranial MRI scans between 1992 and 1994. Silent infarcts were defined as focal lesions greater than 3 mm that were hyperintense on T2 images and, if subcortical, hypointense on T1 images. Incident strokes were identified and classified over an average follow-up of 4 years. The authors evaluated the risk of subsequent symptomatic stroke and how it was modified by other potential stroke risk factors among those with silent infarcts.

RESULTS: Approximately 28% of CHS participants had evidence of silent infarcts (n = 923). The incidence of stroke was 18.7 per 1,000 person-years in those with silent infarcts (n = 67) compared with 9.5 per 1,000 person-years in the absence of silent infarcts. The adjusted relative risk of incident stroke increased with multiple (more than one) silent infarcts (hazard ratio 1.9 [1.2 to 2.8]). Higher values of diastolic and systolic blood pressure, common and internal carotid wall thickness, and the presence of atrial fibrillation were associated with an increased risk of strokes in those with silent infarcts (n = 53 strokes).

CONCLUSION: The presence of silent cerebral infarcts on MRI is an independent predictor of the risk of symptomatic stroke over a 4-year follow- up in older individuals without a clinical history of stroke.

VL - 57 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11591840?dopt=Abstract ER - TY - JOUR T1 - Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. JF - Am J Respir Crit Care Med Y1 - 2001 A1 - Shahar, E A1 - Whitney, C W A1 - Redline, S A1 - Lee, E T A1 - Newman, A B A1 - Nieto, F J A1 - O'Connor, G T A1 - Boland, L L A1 - Schwartz, J E A1 - Samet, J M KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Sleep Apnea Syndromes AB -

Disordered breathing during sleep is associated with acute, unfavorable effects on cardiovascular physiology, but few studies have examined its postulated association with cardiovascular disease (CVD). We examined the cross-sectional association between sleep- disordered breathing and self-reported CVD in 6,424 free-living individuals who underwent overnight, unattended polysomnography at home. Sleep-disordered breathing was quantified by the apnea-hypopnea index (AHI)-the average number of apneas and hypopneas per hour of sleep. Mild to moderate disordered breathing during sleep was highly prevalent in the sample (median AHI: 4.4; interquartile range: 1.3 to 11.0). A total of 1,023 participants (16%) reported at least one manifestation of CVD (myocardial infarction, angina, coronary revascularization procedure, heart failure, or stroke). The multivariable-adjusted relative odds (95% CI) of prevalent CVD for the second, third, and fourth quartiles of the AHI (versus the first) were 0.98 (0.77-1.24), 1.28 (1.02-1.61), and 1.42 (1.13-1.78), respectively. Sleep-disordered breathing was associated more strongly with self-reported heart failure and stroke than with self-reported coronary heart disease: the relative odds (95% CI) of heart failure, stroke, and coronary heart disease (upper versus lower AHI quartile) were 2.38 (1.22-4.62), 1.58 (1.02- 2.46), and 1.27 (0.99-1.62), respectively. These findings are compatible with modest to moderate effects of sleep-disordered breathing on heterogeneous manifestations of CVD within a range of AHI values that are considered normal or only mildly elevated.

VL - 163 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11208620?dopt=Abstract ER - TY - JOUR T1 - Usefulness of T-axis deviation as an independent risk indicator for incident cardiac events in older men and women free from coronary heart disease (the Cardiovascular Health Study). JF - Am J Cardiol Y1 - 2001 A1 - Rautaharju, P M A1 - Nelson, J C A1 - Kronmal, R A A1 - Zhang, Z M A1 - Robbins, J A1 - Gottdiener, J S A1 - Furberg, C D A1 - Manolio, T A1 - Fried, L KW - Aged KW - Algorithms KW - Cohort Studies KW - Coronary Disease KW - Electrocardiography KW - Female KW - Follow-Up Studies KW - Humans KW - Male KW - Prevalence KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Stroke KW - Survival Analysis AB -

T-axis shift has been reported to be an indicator of increased mortality risk. We evaluated the association of spatial T-axis deviation with incident coronary heart disease (CHD) events in older men and women free from clinically overt CHD. Spatial T-axis deviation was measured from the standard 12-lead electrocardiogram of a subgroup of 4,173 subjects considered free of CHD at baseline in the Cardiovascular Health Study, a prospective cohort study of risk factors for CHD and stroke in older men and women. Cox regression analysis was used to evaluate the association of altered repolarization with the risk of incident CHD events. The prevalence of marked T-axis deviation (> or =45 degrees ) was 12%. During the median follow-up of 7.4 years, there were 161 CHD deaths, 743 deaths from all causes, and 679 incident CHD events. Adjusting for demographic and clinical risk factors, including other electrocardiographic abnormalities, there was a nearly twofold excess risk of CHD death, and approximately a 50% excess risk of incident CHD and all-cause mortality for those with marked T-axis deviation. From other electrocardiographic abnormalities, only QT prolongation was associated with excess risk for incident CHD comparable to that for abnormal T-axis deviation. These results suggest that T-axis deviation is an easily quantified marker for subclinical disease and an independent indicator for the risk of incident CHD events in older men and women free of CHD.

VL - 88 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11448406?dopt=Abstract ER - TY - JOUR T1 - Cerebrovascular disease and evolution of depressive symptoms in the cardiovascular health study. JF - Stroke Y1 - 2002 A1 - Steffens, David C A1 - Krishnan, K Ranga Rama A1 - Crump, Casey A1 - Burke, Gregory L KW - Aged KW - Aged, 80 and over KW - Basal Ganglia Cerebrovascular Disease KW - Brain KW - Cerebrovascular Disorders KW - Cohort Studies KW - Comorbidity KW - Depression KW - Disease Progression KW - Female KW - Health Surveys KW - Humans KW - Incidence KW - Logistic Models KW - Magnetic Resonance Imaging KW - Male KW - Neuropsychological Tests KW - Odds Ratio KW - United States AB -

BACKGROUND AND PURPOSE: Previous studies have reported an association between cerebrovascular disease and depressive symptoms. The Cardiovascular Health Study (CHS) provides an opportunity to examine the relationship between vascular brain pathology seen on neuroimaging and changes in depressive symptoms.

METHODS: The sample included 3236 CHS participants who had an MRI brain scan. Demographic variables, medical history, functional status, and apolipoprotein E genotype were obtained at baseline. Annual scores on a modified version of the Centers for Epidemiologic Studies Depression (CES-D) scale were obtained initially and up to 7 years subsequently.

RESULTS: After controlling for important covariates, occurrence of depressive symptoms (defined as modified CES-D score of >7) was associated with small lesions in the basal ganglia, large cortical white-matter lesions, and severe subcortical white-matter grade. Neuroimaging variables did not predict incident depression among those who were nondepressive at the time of MRI. Persistence of depressive symptoms across 2 consecutive time points was associated with small basal ganglia lesions and large cerebral cortical white-matter lesions. Worsening of depression (increase in CES-D score of > or =5) was associated with subcortical white-matter lesions.

CONCLUSIONS: These findings suggest that cerebrovascular disease at baseline is related to depression symptoms over time. Further studies are needed to investigate the differential effects of subcortical white- versus gray-matter lesions on mood.

VL - 33 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12053004?dopt=Abstract ER - TY - JOUR T1 - Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). JF - Am J Med Y1 - 2002 A1 - Tsai, Albert W A1 - Cushman, Mary A1 - Rosamond, Wayne D A1 - Heckbert, Susan R A1 - Tracy, Russell P A1 - Aleksic, Nena A1 - Folsom, Aaron R KW - Aged KW - Biomarkers KW - Blood Coagulation Factors KW - C-Reactive Protein KW - Cohort Studies KW - Confidence Intervals KW - Factor VII KW - Female KW - Fibrinogen KW - Humans KW - Inflammation Mediators KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Multivariate Analysis KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Sensitivity and Specificity KW - Thromboembolism KW - Venous Thrombosis KW - von Willebrand Factor AB -

PURPOSE: We sought to assess prospectively whether higher levels of blood coagulation factors and inflammation markers are risk factors for venous thromboembolism.

SUBJECTS AND METHODS: In two pooled population-based cohort studies, we measured levels of factor VII, factor VIII, von Willebrand factor, fibrinogen, and C-reactive protein, and white blood cell count, in samples obtained from 19,237 adults with no baseline history of venous thromboembolism, cancer, or warfarin use. The endpoint was validated venous thromboembolism during follow-up (median, 7.8 years).

RESULTS: A total of 159 venous thromboembolism events occurred. Factor VIII and von Willebrand factor were linearly associated with increased risk of venous thromboembolism (P for trend <0.0001). As compared with those in the lowest quartile, the multivariate-adjusted hazard ratio (HR) of venous thromboembolism was 2.6 (95% confidence interval [CI]: 1.6 to 4.3) for factor VIII levels in the highest quartile and 3.8 (95% CI: 2.0 to 7.2) for the highest fifth percentile. For von Willebrand factor, the hazard ratios in middle-aged subjects were 4.6 (95% CI: 2.2 to 9.2) for the highest quartile and 7.6 (95% CI: 3.1 to 18) for the highest fifth percentile. Factor VII levels above the 95th percentile, as compared with the lowest quartile, also conveyed a higher risk of venous thromboembolism (HR = 2.4; 95% CI: 1.2 to 4.8). In contrast, there was no association of venous thromboembolism with fibrinogen or C-reactive protein levels, or white cell count.

CONCLUSIONS: In this prospective study, elevated factor VIII and von Willebrand factor levels were common, independent, and dose-dependent risk factors for venous thromboembolism, and an elevated factor VII level was a possible risk factor. Venous thromboembolism, unlike arterial disease, was not related to inflammatory markers.

VL - 113 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12505113?dopt=Abstract ER - TY - JOUR T1 - Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 2002 A1 - Walston, Jeremy A1 - McBurnie, Mary Ann A1 - Newman, Anne A1 - Tracy, Russell P A1 - Kop, Willem J A1 - Hirsch, Calvin H A1 - Gottdiener, John A1 - Fried, Linda P KW - Aged KW - Aged, 80 and over KW - Blood Coagulation Disorders KW - Cardiovascular Diseases KW - Cohort Studies KW - Diabetes Complications KW - Diabetes Mellitus KW - Female KW - Frail Elderly KW - Geriatric Assessment KW - Humans KW - Inflammation KW - Longitudinal Studies KW - Male AB -

BACKGROUND: The biological basis of frailty has been difficult to establish owing to the lack of a standard definition, its complexity, and its frequent coexistence with illness.

OBJECTIVE: To establish the biological correlates of frailty in the presence and absence of concurrent cardiovascular disease and diabetes mellitus.

METHODS: Participants were 4735 community-dwelling adults 65 years and older. Frail, intermediate, and nonfrail subjects were identified by a validated screening tool and exclusion criteria. Bivariate relationships between frailty level and physiological measures were evaluated by Pearson chi2 tests for categorical variables and analysis of variance F tests for continuous variables. Multinomial logistic regression was performed to evaluate multivariable relationships between frailty status and physiological measures.

RESULTS: Of 4735 Cardiovascular Health Study participants, 299 (6.3%) were identified as frail, 2147 (45.3%) as intermediate, and 2289 (48.3%) as not frail. Frail vs nonfrail participants had increased mean +/- SD levels of C-reactive protein (5.5 +/- 9.8 vs 2.7 +/- 4.0 mg/L), factor VIII (13 790 +/- 4480 vs 11 860 +/- 3460 mg/dL), and, in a smaller subset, D dimer (647 +/- 1033 vs 224 +/- 258 ng/mL) (P< or =.001 for all, chi2 test for trend). These differences persisted when individuals with cardiovascular disease and diabetes were excluded and after adjustment for age, sex, and race.

CONCLUSIONS: These findings support the hypothesis that there is a specific physiological basis to the geriatric syndrome of frailty that is characterized in part by increased inflammation and elevated markers of blood clotting and that these physiological differences persist when those with diabetes and cardiovascular disease are excluded.

VL - 162 IS - 20 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12418947?dopt=Abstract ER - TY - JOUR T1 - Incidence, manifestations, and predictors of brain infarcts defined by serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. JF - Stroke Y1 - 2002 A1 - Longstreth, W T A1 - Dulberg, Corinne A1 - Manolio, Teri A A1 - Lewis, Michael R A1 - Beauchamp, Norman J A1 - O'Leary, Daniel A1 - Carr, Jeff A1 - Furberg, Curt D KW - Aged KW - Brain Infarction KW - California KW - Cohort Studies KW - Creatinine KW - Follow-Up Studies KW - Humans KW - Incidence KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Maryland KW - Multivariate Analysis KW - Neuropsychological Tests KW - North Carolina KW - Odds Ratio KW - Pennsylvania KW - Predictive Value of Tests KW - Risk Factors AB -

BACKGROUND AND PURPOSE: MRI-defined infarcts are common in the elderly. We sought to explore incidence, manifestations, and predictors of such infarcts.

METHODS: The Cardiovascular Health Study (CHS) is a population-based, longitudinal study of 5888 people aged > or =65 years. Participants have had extensive baseline and follow-up evaluations; 1433 participants underwent 2 MRI scans separated by 5 years and had no infarcts on initial MRI.

RESULTS: On follow-up MRI, 254 participants (17.7%) had 1 or more infarcts. Most were single (75.6%), subcortical (79.9%), and small (3 to 20 mm in 87.0%). Only 11.4% of those with infarcts experienced a documented transient ischemic attack or stroke between the scans. Although participants were similar at initial MRI, those with MRI-defined infarcts on follow-up experienced greater decline than those without infarcts on the Modified Mini-Mental State Examination and Digit-Symbol Substitution test (both P<0.01). Severity of white matter changes on initial MRI was the strongest predictor of incident infarcts. When it was excluded from stepwise multivariable models, predictors were serum creatinine, age, and ankle-arm index.

CONCLUSIONS: Incident MRI-defined infarcts commonly affect the elderly. Most are small, subcortical, and not associated with acute symptoms recognized as a transient ischemic attack or stroke. Nonetheless, they cannot be considered silent because of their association with subtle cognitive deficits. These covert infarcts are associated with white matter changes, which may share a common pathophysiology. Whether control of vascular risk factors, such as blood pressure, would reduce the risk of developing these infarcts and associated cognitive decline deserves further investigation.

VL - 33 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12364724?dopt=Abstract ER - TY - JOUR T1 - Measures of cognitive function in persons with varying degrees of sleep-disordered breathing: the Sleep Heart Health Study. JF - J Sleep Res Y1 - 2002 A1 - Boland, Lori L A1 - Shahar, Eyal A1 - Iber, Conrad A1 - Knopman, David S A1 - Kuo, Tracy F A1 - Nieto, F Javier KW - Aged KW - Body Mass Index KW - Brain KW - Cognition Disorders KW - Cohort Studies KW - Female KW - Humans KW - Hypoxia KW - Male KW - Middle Aged KW - Neuropsychological Tests KW - Oxygen KW - Polysomnography KW - Severity of Illness Index KW - Sleep Apnea, Central AB -

Epidemiologic literature suggests that persons with clinically diagnosed sleep apnoea frequently have impaired cognitive function, but whether milder degrees of sleep-disordered breathing (SDB) are associated with cognitive dysfunction in the general population is largely unknown. Approximately 1700 subjects free of clinically diagnosed SDB underwent at-home polysomnography (PSG) as part of the Sleep Heart Health Study (SHHS) and completed three cognitive function tests within 1-2 years of their PSG: the Delayed Word Recall Test (DWR), the WAIS-R Digit Symbol Subtest (DSS), and the Word Fluency test (WF). A respiratory disturbance index (RDI) was calculated as the number of apnoeas and hypopnoeas per hour of sleep. After adjustment for age, education, occupation, field centre, diabetes, hypertension, body-mass index, use of CNS medications, and alcohol drinking status, there was no consistent association between the RDI and any of the three cognitive function measures. There was no evidence of a dose-response relation between the RDI and cognitive function scores and the adjusted mean scores by quartiles of RDI never differed from one another by more than 5% for any of the tests. In this sample of free-living individuals with mostly mild to moderate levels of SDB, the degree of SDB appeared to be unrelated to three measures of cognitive performance.

VL - 11 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12220323?dopt=Abstract ER - TY - JOUR T1 - Nuclear magnetic resonance spectroscopy of lipoproteins and risk of coronary heart disease in the cardiovascular health study. JF - Arterioscler Thromb Vasc Biol Y1 - 2002 A1 - Kuller, Lewis A1 - Arnold, Alice A1 - Tracy, Russell A1 - Otvos, James A1 - Burke, Greg A1 - Psaty, Bruce A1 - Siscovick, David A1 - Freedman, David S A1 - Kronmal, Richard KW - Aged KW - Aging KW - Cardiovascular System KW - Case-Control Studies KW - Cohort Studies KW - Coronary Disease KW - Female KW - Health Status KW - Humans KW - Lipoproteins, HDL KW - Lipoproteins, LDL KW - Lipoproteins, VLDL KW - Magnetic Resonance Spectroscopy KW - Male KW - Nuclear Magnetic Resonance, Biomolecular KW - Risk Factors KW - Sex Factors AB -

OBJECTIVES: Relationships between incident cardiovascular disease and lipoprotein subclass measurements by nuclear magnetic resonance spectroscopy were evaluated in the Cardiovascular Health Study (CHS) in a nested case-cohort analysis.

METHODS AND RESULTS: The case group consisted of 434 participants with incident myocardial infarction (MI) and angina diagnosed after entry to the study (1990 to 1995) and the comparison group, 249 "healthy" participants with no prevalent clinical or subclinical disease. By univariate analysis, the median levels for healthy participants versus participants with incident MI and angina were 0 versus 7 mg% for small low density lipoprotein (LDL), 1501 versus 1680 nmol/L for the number of LDL particles, and 21.6 versus 21.3 for LDL size, and these values were significantly different between "healthy" participants and those with incident MI and angina for women but not men. The levels of less dense LDL, which is most of the total LDL cholesterol among women, was not related to incident MI and angina. For women, large high density lipoprotein cholesterol (HDLc), but not small HDLc, levels were significantly higher for healthy participants compared with levels for participants with MI and angina. For men and women, levels of total and very low density lipoprotein triglycerides were higher for the case group than for the healthy group. In multivariate models for women that included triglycerides and HDLc, the number of LDL particles (but not LDL size) remained significantly related to MI and angina.

CONCLUSIONS: Small LDL, the size of LDL particles, and the greater number of LDL particles are related to incident coronary heart disease among older women.

VL - 22 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12117734?dopt=Abstract ER - TY - JOUR T1 - Predictors of sleep-disordered breathing in community-dwelling adults: the Sleep Heart Health Study. JF - Arch Intern Med Y1 - 2002 A1 - Young, Terry A1 - Shahar, Eyal A1 - Nieto, F Javier A1 - Redline, Susan A1 - Newman, Anne B A1 - Gottlieb, Daniel J A1 - Walsleben, Joyce A A1 - Finn, Laurel A1 - Enright, Paul A1 - Samet, Jonathan M KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Continental Population Groups KW - Female KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Predictive Value of Tests KW - Residence Characteristics KW - Risk Factors KW - Sex Factors KW - Sleep Apnea Syndromes KW - Snoring AB -

BACKGROUND: Sleep-disordered breathing (SDB) is common, but largely undiagnosed in the general population. Information on demographic patterns of SDB occurrence and its predictive factors in the general population is needed to target high-risk groups that may benefit from diagnosis.

METHODS: The sample comprised 5615 community-dwelling men and women aged between 40 and 98 years who were enrolled in the Sleep Heart Health Study. Data were collected by questionnaire, clinical examinations, and in-home polysomnography. Sleep-disordered breathing status was based on the average number of apnea and hypopnea episodes per hour of sleep (apnea-hypopnea index [AHI]). We used multiple logistic regression modeling to estimate cross-sectional associations of selected participant characteristics with SDB defined by an AHI of 15 or greater.

RESULTS: Male sex, age, body mass index, neck girth, snoring, and repeated breathing pause frequency were independent, significant correlates of an AHI of 15 or greater. People reporting habitual snoring, loud snoring, and frequent breathing pauses were 3 to 4 times more likely to have an AHI of 15 or greater vs an AHI less than 15, but there were weaker associations for other factors with an AHI of 15 or greater. The odds ratios (95% confidence interval) for an AHI of 15 or greater vs an AHI less than 15 were 1.6 and 1.5, respectively, for 1-SD increments in body mass index and neck girth. As age increased, the magnitude of associations for SDB and body habitus, snoring, and breathing pauses decreased.

CONCLUSIONS: A significant proportion of occult SDB in the general population would be missed if screening or case finding were based solely on increased body habitus or male sex. Breathing pauses and obesity may be particularly insensitive for identifying SDB in older people. A better understanding of predictive factors for SDB, particularly in older adults, is needed.

VL - 162 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11966340?dopt=Abstract ER - TY - JOUR T1 - Prevalence of renovascular disease in the elderly: a population-based study. JF - J Vasc Surg Y1 - 2002 A1 - Hansen, Kimberley J A1 - Edwards, Matthew S A1 - Craven, Timothy E A1 - Cherr, Gregory S A1 - Jackson, Sharon A A1 - Appel, Richard G A1 - Burke, Gregory L A1 - Dean, Richard H KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Ethnic Groups KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Prevalence KW - Prospective Studies KW - Renal Artery KW - Renal Artery Obstruction KW - Risk Factors KW - Sex Factors KW - Ultrasonography, Doppler, Duplex AB -

PURPOSE: The purpose of this investigation was to estimate the population-based prevalence of renovascular disease (RVD), defined as > or = 60% diameter-reducing renal artery stenosis or occlusion, and to define its associations with age, gender, race, and other potential risk factors among participants in the Cardiovascular Health Study (CHS).

METHODS: The CHS is a multicenter, longitudinal cohort study of cardiovascular disease risk factors, morbidity, and mortality among free-living adults of more than 65 years of age. As part of an ancillary investigation, participants in the Forsyth County cohort of the CHS were invited to undergo renal duplex sonography (RDS) to define the presence or absence of RVD. RVD was defined as stenosis with a focal renal artery peak systolic velocity exceeding 1.8 m/s in the main renal artery and defined as occlusion when an imaged renal artery lacked a Doppler signal. Demographic and atherosclerotic risk factor data were gathered as part of the baseline CHS examination. Univariable tests of association were performed with chi(2) and Student t tests and logistic regression analysis. Multivariate associations were examined with logistic regression analysis.

RESULTS: Eight hundred seventy CHS participants underwent RDS. Of these examinations, 834 (96%) were technically adequate to define the presence or absence of RVD. The RDS study cohort had a mean age of 77.2 +/- 4.9 years and consisted of 63% women and 37% men. Participant race was 76% white and 23% African American. The overall prevalence rate of RVD was 6.8%. Among the 57 patients with RVD, 50 (88%) had unilateral disease and seven (12%) had bilateral disease. Seven cases were seen of renal artery occlusion, including one case with contralateral renal artery stenosis. The mean ages of patients with and without RVD were 78.7 +/- 5.7 years and 77.1 +/- 4.9 years (P =.018). RVD was present in 5.5% of women and 9.1% of men (P =.053). RVD was present in 6.9% of white participants and 6.7% of African American participants (P =.933). Multivariate analysis revealed increasing participant age (P =.028; odds ratio, 1.34; 95% CI, 1.03, 1.73), high-density lipoprotein cholesterol levels of less than 40 mg/dL (P =.003; odds ratio, 2.63; 95% CI, 1.40, 4.93), and increasing systolic blood pressure (P =.007; odds ratio, 1.44; 95% CI, 1.10, 1.87) to be significantly and independently associated with the presence of RVD.

CONCLUSION: This investigation provides the first population-based estimate of the prevalence of RVD among free-living, elderly black and white Americans. RVD was present in 6.8% of the study cohort. RVD showed no association with ethnicity. However, its presence was significantly and independently associated with increasing age, low high-density lipoprotein cholesterol levels, and increasing systolic blood pressure.

VL - 36 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12218965?dopt=Abstract ER - TY - JOUR T1 - A prospective study of venous thromboembolism in relation to factor V Leiden and related factors. JF - Blood Y1 - 2002 A1 - Folsom, Aaron R A1 - Cushman, Mary A1 - Tsai, Michael Y A1 - Aleksic, Nena A1 - Heckbert, Susan R A1 - Boland, Lori L A1 - Tsai, Albert W A1 - Yanez, N David A1 - Rosamond, Wayne D KW - Activated Protein C Resistance KW - Aged KW - Cohort Studies KW - Continental Population Groups KW - Factor V KW - Genotype KW - Haplotypes KW - Humans KW - Incidence KW - Longitudinal Studies KW - Middle Aged KW - Odds Ratio KW - Prospective Studies KW - Risk Factors KW - Thromboembolism KW - Venous Thrombosis AB -

The aim of this study was to examine the occurrence of venous thromboembolism (VTE) in relation to factor V-related risk factors. Using a nested case-control design combining 2 population-based prospective studies, we measured factor V Leiden, HR2 haplotype, activated protein C (APC) resistance, and plasma factor V antigen in 335 participants who developed VTE during 8 years of follow-up and 688 controls. The overall odds ratio (OR) of VTE was 3.67 (95% CI, 2.20-6.12) in participants carrying factor V Leiden compared with noncarriers. APC resistance measured after predilution with factor V-deficient plasma conferred an OR of 2.58 (95% CI, 1.62-4.10). All 3 participants homozygous for the HR2 haplotype had a VTE, and the OR of VTE for homozygosity was estimated to be 5.5 (95% CI, 2.45-12.5). Carriers of the HR2 haplotype otherwise were not at increased risk of VTE overall (OR = 1.05; 95% CI, 0.64-1.72), but double heterozygotes for HR2 and factor V Leiden carried an OR of idiopathic VTE of 16.3 (95% CI, 1.7-159) compared with noncarriers. Factor V antigen also was not associated with VTE overall, but for participants with the combination of high factor V antigen plus factor V Leiden the OR of idiopathic VTE was 11.5 (95% CI, 4.2-31.4). In the general population, APC resistance and factor V Leiden were important VTE risk factors; homozygosity for the HR2 haplotype may be a risk factor but was rare; otherwise, HR2 haplotype and factor V antigen were not risk factors except in carriers of factor V Leiden.

VL - 99 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11929758?dopt=Abstract ER - TY - JOUR T1 - Protein C, antithrombin, and venous thromboembolism incidence: a prospective population-based study. JF - Arterioscler Thromb Vasc Biol Y1 - 2002 A1 - Folsom, Aaron R A1 - Aleksic, Nena A1 - Wang, Lu A1 - Cushman, Mary A1 - Wu, Kenneth K A1 - White, Richard H KW - Adult KW - Aged KW - Aged, 80 and over KW - Antithrombins KW - Arteriosclerosis KW - Cohort Studies KW - Humans KW - Incidence KW - Longitudinal Studies KW - Middle Aged KW - Odds Ratio KW - Population Surveillance KW - Prospective Studies KW - Protein C KW - Protein C Deficiency KW - Pulmonary Embolism KW - Thromboembolism KW - Venous Thrombosis AB -

Although deficiencies of protein C and antithrombin, 2 natural plasma anticoagulants, are known risk factors for venous thrombosis, population-based prospective incidence data on these associations are lacking. Venous thromboembolic events have been identified in adults in 2 longitudinal cohort studies, the Atherosclerosis Risk in Communities (ARIC) Study and the Cardiovascular Health Study (CHS). Incidence was examined in relation to prediagnostic plasma levels of protein C (ARIC Study only) and antithrombin. Over a mean of 8.1 years of follow-up, there were 130 incident venous thromboembolic events that were not due to cancer in the ARIC Study. The age-adjusted incidence was elevated 3.36-fold (95% CI 1.24 to 9.11) in the 1.1% of subjects with protein C values <2.0 mg/L compared with subjects with higher values. In contrast, in the ARIC Study and the CHS, there was no association between low plasma antithrombin and venous thromboembolism. In conclusion, in this population-based study, a low protein C, but not antithrombin, level has been determined to be associated with an increased incidence of venous thromboembolism. Attributable risk estimates suggest that low protein C levels account for approximately 2.5% of venous thromboembolic events in the ARIC population.

VL - 22 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12067914?dopt=Abstract ER - TY - JOUR T1 - Racial differences in coronary artery calcification in older adults. JF - Arterioscler Thromb Vasc Biol Y1 - 2002 A1 - Newman, Anne B A1 - Naydeck, Barbara L A1 - Whittle, Jeff A1 - Sutton-Tyrrell, Kim A1 - Edmundowicz, Daniel A1 - Kuller, Lewis H KW - Age Factors KW - Aged KW - Calcinosis KW - Cohort Studies KW - Coronary Artery Disease KW - Female KW - Humans KW - Logistic Models KW - Male KW - Risk Factors KW - Sex Factors KW - Tomography, X-Ray Computed AB -

Reports on race-related differences in coronary artery calcium (CAC) are just beginning to emerge and have not been well studied in the elderly. This study was undertaken to assess whether such differences exist and the relationship between CAC and cardiovascular risk factors in a cohort of elderly community-dwelling adults. CAC was measured by using electron-beam tomography in 614 adults (aged 67 to 99 years), of whom 59% were women and 23% were black. The median CAC score was lower in blacks than in whites for men (159 versus 787, respectively; P<0.001) and for women (134 versus 233, respectively; P=0.02) after adjustment for age, cardiovascular disease, and risk factors for cardiovascular disease, although this difference was stronger and remained significant among men only. Lower CAC scores were also observed in the subgroup of blacks with a history of myocardial infarction. The lower CAC scores in blacks compared with whites observed in this study is consistent with either a lower prevalence of coronary artery disease or a lower extent of calcification of coronary artery disease.

VL - 22 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11884285?dopt=Abstract ER - TY - JOUR T1 - The relation of atherosclerotic cardiovascular disease to retinopathy in people with diabetes in the Cardiovascular Health Study. JF - Br J Ophthalmol Y1 - 2002 A1 - Klein, Ronald A1 - Marino, Emily K A1 - Kuller, Lewis H A1 - Polak, Joseph F A1 - Tracy, Russell P A1 - Gottdiener, John S A1 - Burke, Gregory L A1 - Hubbard, Larry D A1 - Boineau, Robin KW - Age of Onset KW - Aged KW - Aged, 80 and over KW - Arteriosclerosis KW - Black People KW - Blood Pressure KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Diabetic Retinopathy KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Odds Ratio KW - Prospective Studies KW - Regression Analysis KW - Risk Factors KW - Time Factors KW - White People AB -

AIMS: To describe the association of retinopathy with atherosclerosis and atherosclerotic risk factors in people with diabetes.

METHODS: 296 of the 558 people classified as having diabetes by the American Diabetes Association criteria, from a population based cohort of adults (ranging in age from 69 to 102 years) living in four United States communities (Allegheny County, Pennsylvania; Forsyth County, North Carolina; Sacramento County, California; and Washington County, Maryland) were studied from 1997 to 1998. Lesions typical of diabetic retinopathy were determined by grading a 45 degrees colour fundus photograph of one eye of each participant, using a modification of the Airlie House classification system.

RESULTS: Retinopathy was present in 20% of the diabetic cohort, with the lowest prevalence (16%), in those 80 years of age or older. Retinopathy was detected in 20.3% of the 296 people with diabetes; 2.7% of the 296 had signs of proliferative retinopathy and 2.1% had signs of macular oedema. The prevalence of diabetic retinopathy was higher in black people (35.4%) than white (16.0%). Controlling for age, sex, and blood glucose, retinopathy was more frequent in black people than white (odds ratio (OR) 2.26, 95% confidence interval (CI) 1.01, 5.05), in those with longer duration of diabetes (OR (per 5 years of diabetes) 1.42, 95% CI 1.18, 1.70), in those with subclinical cardiovascular disease (OR 1.49, 95% CI 0.51, 4.31), or coronary heart disease or stroke (OR 3.23, 95% CI 1.09, 9.56) than those without those diseases, in those with higher plasma low density lipoprotein (LDL) cholesterol (OR (per 10 mg/dl of LDL cholesterol) 1.12, 95% CI 1.02, 1.23), and in those with gross proteinuria (OR 4.76, 95% CI 1.53, 14.86).

CONCLUSION: Data from this population based study suggest a higher prevalence of retinopathy in black people than white people with diabetes and the association of cardiovascular disease, elevated plasma LDL cholesterol, and gross proteinuria with diabetic retinopathy. However, any conclusions or explanations regarding associations described here must be made with caution because only about one half of those with diabetes mellitus were evaluated.

VL - 86 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/11801510?dopt=Abstract ER - TY - JOUR T1 - The relationship between chronically disrupted sleep and healthcare use. JF - Sleep Y1 - 2002 A1 - Kapur, Vishesh K A1 - Redline, Susan A1 - Nieto, F Javier A1 - Young, Terry B A1 - Newman, Anne B A1 - Henderson, Jeffrey A KW - Adult KW - Chronic Disease KW - Cohort Studies KW - Community Health Services KW - Cross-Sectional Studies KW - Disorders of Excessive Somnolence KW - Female KW - Health Status KW - Humans KW - Male KW - Middle Aged KW - Patient Acceptance of Health Care KW - Polysomnography KW - Prevalence KW - Severity of Illness Index KW - Sleep Apnea, Obstructive KW - Sleep Deprivation AB -

STUDY OBJECTIVES: To determine whether chronic sleep deprivation, sleep disruption, sleepiness, insomnia, and OSA are associated with increased healthcare use in a community-based population.

DESIGN: Cross-sectional study.

SETTING/PARTICIPANTS: 6440 Sleep Heart Health Study (SHHS) participants recruited from ongoing cohort studies.

INTERVENTIONS: N/A.

MEASUREMENTS: Polysomnography results (Apnea Hypopnea Index (AHI), percent of sleep time with oxyhemoglobin saturation below 90% (CT90), arousal index) as well as data on sleep related symptoms, medication use, and chronic illness. The indirect measure of predicted healthcare utilization was the modified Chronic Disease Score (CDS) calculated from medication data.

RESULTS: After adjustment for age, gender, BMI and study site, subjects in the highest quartiles of AHI, CT90 and Epworth score had CDS that were 6%-9% higher than the lowest quartiles. The adjusted mean CDS for subjects with sleep apnea was similar to that for subjects with hypertension, chronic bronchitis or asthma and 18% greater than the mean CDS for subjects without sleep apnea. Among subjects who did not have significant sleep-disordered breathing, complaints of insomnia, sleepiness, fatigue, and not getting enough sleep were associated with increased CDS.

CONCLUSIONS: This study demonstrated an association between subjective complaints of daytime sleepiness, inadequate sleep time, insomnia as well as objective measures of severity of SDB, and an indirect measure of healthcare utilization in a community-based sample. Though the percent increases in healthcare utilization observed were modest, the prevalence of these factors in the general population is high, and may therefore be associated with a substantial cost burden to the healthcare system.

VL - 25 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12003159?dopt=Abstract ER - TY - JOUR T1 - Relationship between coronary artery calcification and other measures of subclinical cardiovascular disease in older adults. JF - Arterioscler Thromb Vasc Biol Y1 - 2002 A1 - Newman, Anne B A1 - Naydeck, Barbara L A1 - Sutton-Tyrrell, Kim A1 - Edmundowicz, Daniel A1 - O'Leary, Daniel A1 - Kronmal, Richard A1 - Burke, Gregory L A1 - Kuller, Lewis H KW - Aged KW - Aged, 80 and over KW - Calcinosis KW - Cardiovascular Diseases KW - Carotid Stenosis KW - Cohort Studies KW - Coronary Artery Disease KW - Demography KW - Female KW - Humans KW - Male KW - Prevalence KW - Risk Factors KW - Sensitivity and Specificity KW - Sex Factors KW - Tomography, X-Ray Computed KW - Tunica Intima KW - Tunica Media AB -

BACKGROUND: In the Cardiovascular Health Study, subclinical cardiovascular disease (CVD) predicted CVD events in older adults. The extent to which this measure or its components reflect calcified coronary disease is unknown.

METHODS AND RESULTS: Coronary artery calcium (CAC) was assessed with electron beam tomography in 414 participants without clinical CVD and examined using cut points (CAC> or =400 and CAC> or =800) and the log(CAC); 274 had subclinical CVD by ankle-arm index, ECG, or carotid ultrasound. Cut points for subclinical disease as previously defined in the Cardiovascular Health Study were examined as well as continuous measures to produce receiver operating characteristic curve curves. A low ankle-arm index was highly specific for a high CAC score. The internal carotid artery intima-media thickness was most strongly correlated with CAC (r=0.30) and was significantly related to both CAC cut points and to the log(CAC) score independently of all other measures.

CONCLUSIONS: In these community-dwelling older adults without clinical CVD, internal carotid artery intima-media thickness was most closely related to CAC. However, 17.5% of those with a CAC> or =400 would be missed in the ascertainment of subclinical atherosclerosis using the previously published composite of subclinical atherosclerosis. Prospective follow-up will determine whether the CAC score improves prediction of CVD events over other noninvasive measures.

VL - 22 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12377748?dopt=Abstract ER - TY - JOUR T1 - Retinal microvascular abnormalities and blood pressure in older people: the Cardiovascular Health Study. JF - Br J Ophthalmol Y1 - 2002 A1 - Wong, T Y A1 - Hubbard, L D A1 - Klein, R A1 - Marino, E K A1 - Kronmal, R A1 - Sharrett, A R A1 - Siscovick, D S A1 - Burke, G A1 - Tielsch, J M KW - Aged KW - Aged, 80 and over KW - Blood Pressure KW - Cohort Studies KW - Diabetic Retinopathy KW - Eye KW - Female KW - Humans KW - Male KW - Microcirculation KW - Prospective Studies KW - Retina KW - Retinal Diseases AB -

AIM: To examine the relation between blood pressure and retinal microvascular abnormalities in older people.

METHODS: The Cardiovascular Health Study is a prospective cohort study conducted in four US communities initiated in 1989 to 1990. Blood pressure was measured according to standardised protocols at each examination. During the 1997-8 examination, retinal photographs were taken of 2405 people aged 69-97 years (2056 without diabetes and 349 with diabetes). Signs of focal microvascular abnormalities (focal arteriolar narrowing, arteriovenous nicking, and retinopathy) were evaluated from photographs according to standardised methods. To quantify generalised arteriolar narrowing, the photographs were digitised and diameters of individual arterioles were measured and summarised.

RESULTS: In non-diabetic people, elevated concurrent blood pressure taken at the time of retinal photography was strongly associated with presence of all retinal microvascular lesions. The multivariable adjusted odds ratios, comparing the highest to lowest quintile of concurrent systolic blood pressure, were 4.0 (95% confidence intervals (CI): 2.4 to 6.9, p test of trend<0.001) for focal arteriolar narrowing, 2.9 (95% CI: 1.6 to 5.3, p<0.001) for arteriovenous nicking, 2.8 (95% CI: 1.5 to 5.2, p<0.001) for retinopathy, and 2.1 (95% CI: 1.4 to 3.1, p<0.001) for generalised arteriolar narrowing. Generalised arteriolar narrowing and possibly arteriovenous nicking were also significantly associated with past blood pressure measured up to 8 years before retinal photography, even after adjustment for concurrent blood pressure. These associations were somewhat weaker in people with diabetes.

CONCLUSIONS: Retinal microvascular abnormalities are related to elevated concurrent blood pressure in older people. Additionally, generalised retinal arteriolar narrowing and possibly arteriovenous nicking are related to previously elevated blood pressure, independent of concurrent blood pressure. These data suggest that retinal microvascular changes reflect severity and duration of hypertension.

VL - 86 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12185128?dopt=Abstract ER - TY - JOUR T1 - Serum potassium level and dietary potassium intake as risk factors for stroke. JF - Neurology Y1 - 2002 A1 - Green, D M A1 - Ropper, A H A1 - Kronmal, R A A1 - Psaty, B M A1 - Burke, G L KW - Aged KW - Cohort Studies KW - Confidence Intervals KW - Diuretics KW - Humans KW - Linear Models KW - Male KW - Potassium KW - Potassium, Dietary KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Stroke AB -

BACKGROUND: Numerous studies have found that low potassium intake and low serum potassium are associated with increased stroke mortality, but data regarding stroke incidence have been limited. Serum potassium levels, dietary potassium intake, and diuretic use in relation to risk for stroke in a prospectively studied cohort were investigated.

METHODS: The study comprised 5,600 men and women older than 65 years who were free of stroke at enrollment. Baseline data included serum potassium level, dietary potassium intake, and diuretic use. Participants were followed for 4 to 8 years, and the incidence and types of strokes were recorded. Low serum potassium was defined as less than 4.1 mEq/L, and low potassium intake as less than 2.4 g/d.

RESULTS: Among diuretic users, there was an increased risk for stroke associated with lower serum potassium (relative risk [RR]: 2.5, p < 0.0001). Among individuals not taking diuretics, there was an increased risk for stroke associated with low dietary potassium intake (RR: 1.5, p < 0.005). The small number of diuretic users with lower serum potassium and atrial fibrillation had a 10-fold greater risk for stroke compared with those with higher serum potassium and normal sinus rhythm.

CONCLUSIONS: A lower serum potassium level in diuretic users, and low potassium intake in those not taking diuretics were associated with increased stroke incidence among older individuals. Lower serum potassium was associated with a particularly high risk for stroke in the small number of diuretic users with atrial fibrillation. Further study is required to determine if modification of these factors would prevent strokes.

VL - 59 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12177362?dopt=Abstract ER - TY - JOUR T1 - Time trends in high blood pressure control and the use of antihypertensive medications in older adults: the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 2002 A1 - Psaty, Bruce M A1 - Manolio, Teri A A1 - Smith, Nicholas L A1 - Heckbert, Susan R A1 - Gottdiener, John S A1 - Burke, Gregory L A1 - Weissfeld, Joel A1 - Enright, Paul A1 - Lumley, Thomas A1 - Powe, Neil A1 - Furberg, Curt D KW - Age Factors KW - Aged KW - Antihypertensive Agents KW - Awareness KW - Cohort Studies KW - Drug Therapy KW - Female KW - Health Knowledge, Attitudes, Practice KW - Humans KW - Hypertension KW - Male KW - Prospective Studies KW - Time Factors AB -

BACKGROUND: Control of high blood pressure (BP) in older adults is an important part of public health efforts at prevention.

OBJECTIVE: To assess recent time trends in the awareness, treatment, and control of high BP and in the use of medications to treat high BP.

METHODS: In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline, participants underwent an extensive examination that included the measurement of BP, use of medications, and other risk factors. Participants were followed up with annual visits that assessed BP and medication use from baseline in 1989-1990 through the examination in 1998-1999. The primary outcome measures were control of BP to levels lower than than 140/90 mm Hg and the prevalence of use of various classes of antihypertensive medications.

RESULTS: The awareness, treatment, and control of high BP improved during the 1990s. The proportions aware and treated were higher among blacks than whites, though control prevalences were similar. For both groups combined, the control of high BP to lower than 140/90 mm Hg increased from 37% at baseline to 49% in 1999. The 51% whose BP was not controlled generally had isolated mild to moderate elevations in systolic BP. Among treated persons, the improvement in control was achieved in part by a mean increase of 0.2 antihypertensive medications per person over the course of 9 years. Improved control was also achieved by increasing the proportion of the entire Cardiovascular Health Study population that was treated for hypertension, from 34.5% in 1990 to 51.1% in 1999. Time trends in antihypertensive drug use were pronounced. Among those without coronary disease, the use of low-dose diuretics and beta-blockers decreased, while the use of newer agents, such as calcium channel blockers, angiotensin-converting enzyme inhibitors, and alpha-blockers increased.

CONCLUSIONS: While control of high BP improved in the 1990s, about half the participants with hypertension had uncontrolled BP, primarily mild to moderate elevations in systolic BP. Low-dose diuretics and beta-blockers--the preferred agents since 1993 according to the recommendations of the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure--remained underused. More widespread use of these agents will be an important intervention to prevent the devastating complications of hypertension, including stroke, myocardial infarction, and heart failure.

VL - 162 IS - 20 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12418946?dopt=Abstract ER - TY - JOUR T1 - The 6-min walk test: a quick measure of functional status in elderly adults. JF - Chest Y1 - 2003 A1 - Enright, Paul L A1 - McBurnie, Mary Ann A1 - Bittner, Vera A1 - Tracy, Russell P A1 - McNamara, Robert A1 - Arnold, Alice A1 - Newman, Anne B KW - Activities of Daily Living KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - Coronary Disease KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Exercise Test KW - Female KW - Humans KW - Ischemic Attack, Transient KW - Linear Models KW - Male KW - Mass Screening KW - Sensitivity and Specificity KW - Stroke KW - United States KW - Walking AB -

OBJECTIVES: To determine the correlates of the total 6-min walk distance (6MWD) in a population sample of adults > or = 68 years old.

METHODS: The standardized 6-min walk test (6MWT) was administered to the Cardiovascular Health Study cohort during their seventh annual examination.

RESULTS: Of the 3,333 participants with a clinic visit, 2,281 subjects (68%) performed the 6MWT. There were no untoward events. The mean 6MWD was 344 m (SD, 88 m). Independent general correlates of a shorter 6MWD in linear regression models in women and men included the following: older age, higher weight, larger waist, weaker grip strength, symptoms of depression, and decreased mental status. Independent disease or risk factor correlates of a shorter 6MWD included the following: a low ankle BP, use of angiotensin-converting enzyme inhibitors, and arthritis in men and women; higher C-reactive protein, diastolic hypertension, and lower FEV(1) in women; and the use of digitalis in men. Approximately 30% of the variance in 6MWD was explained by the linear regression models. Newly described bivariate associations of a shorter 6MWD included impaired activities of daily living; self-reported poor health; less education; nonwhite race; a history of coronary heart disease, transient ischemic attacks, stroke, or diabetes; and higher levels of C-reactive protein, fibrinogen, or WBC count.

CONCLUSIONS: Most community-dwelling elderly persons can quickly and safely perform this functional status test in the outpatient clinic setting. The test may be used clinically to measure the impact of multiple comorbidities, including cardiovascular disease, lung disease, arthritis, diabetes, and cognitive dysfunction and depression, on exercise capacity and endurance in older adults. Expected values should be adjusted for the patient's age, gender, height, and weight.

VL - 123 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12576356?dopt=Abstract ER - TY - JOUR T1 - The association between time since last meal and blood pressure in older adults: the cardiovascular health study. JF - J Am Geriatr Soc Y1 - 2003 A1 - Smith, Nicholas L A1 - Psaty, Bruce M A1 - Rutan, Gale H A1 - Lumley, Thomas A1 - Yanez, David A1 - Chaves, Paulo H M A1 - Kronmal, Richard A KW - Aged KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Eating KW - Female KW - Humans KW - Hypotension KW - Male KW - Postprandial Period KW - Prospective Studies KW - Risk Factors KW - Time Factors AB -

OBJECTIVES: To demonstrate a postprandial hypotensive (PPH) phenomenon in older adults.

DESIGN: Observational, prospective cohort study composed of baseline and nine follow-up visits.

SETTING: Cardiovascular Health Study, an epidemiological study of risk factors for cardiovascular disease in older adults.

PARTICIPANTS: Five thousand eight hundred eighty-eight community-dwelling adults aged 65 and older.

MEASUREMENTS: Blood pressure and time since last meal were recorded synchronously at baseline and at follow-up clinic visits. Generalized estimating equations were used to estimate associations between time since last meal and blood pressure and to adjust variance estimates to account for repeated blood pressure measures within subjects across fasting times.

RESULTS: Mean systolic and diastolic blood pressures were lower in the first hour after the last meal and were progressively higher through the fourth hour after the last meal than blood pressures measured immediately after the last meal (0 hour: 133.7/68.8 mmHg; 1st hour: 130.1/66.6 mmHg; 4th hour: 136.5/71.1 mmHg). Changes were significant for systolic and diastolic measures (P <.001 for both). Exploratory analyses suggested that the systolic PPH association was more pronounced in women. Little evidence was found that the degree of systolic or diastolic PPH varied by age, race, prevalent cardiovascular disease, heart rate, ejection fraction, treated hypertension or diabetes mellitus, or body mass index.

CONCLUSION: These data support previous observations that there is a significant drop in blood pressure within 1 hour after a meal in older adults. Time since last meal may be an important factor to consider when measuring blood pressure in older adults, and perhaps national standards need to be set.

VL - 51 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12757570?dopt=Abstract ER - TY - JOUR T1 - Beta2-adrenergic receptor polymorphisms and risk of incident cardiovascular events in the elderly. JF - Circulation Y1 - 2003 A1 - Heckbert, Susan R A1 - Hindorff, Lucia A A1 - Edwards, Karen L A1 - Psaty, Bruce M A1 - Lumley, Thomas A1 - Siscovick, David S A1 - Tang, Zhonghua A1 - Durda, J Peter A1 - Kronmal, Richard A A1 - Tracy, Russell P KW - African Continental Ancestry Group KW - Aged KW - Alleles KW - Brain Ischemia KW - Cardiovascular Diseases KW - Cohort Studies KW - Comorbidity KW - Coronary Disease KW - European Continental Ancestry Group KW - Follow-Up Studies KW - Gene Frequency KW - Humans KW - Incidence KW - Linkage Disequilibrium KW - Polymorphism, Genetic KW - Receptors, Adrenergic, beta-2 KW - Risk Assessment KW - Stroke KW - United States AB -

BACKGROUND: Genetic polymorphisms at codons 16 and 27 of the beta2-adrenergic receptor have been associated with altered response to sympathetic stimulation. We examined these polymorphisms in relation to cardiovascular event risk in the Cardiovascular Health Study.

METHODS AND RESULTS: A total of 808 black and 4441 white participants (mean age, 73 years) were genotyped for the Arg16Gly and Gln27Glu polymorphisms of the beta2-adrenergic receptor. There were 702 incident coronary events, 438 ischemic strokes, and 1136 combined cardiovascular events during 7 to 10 years of follow-up. Allele frequencies differed by race but not by age or hypertension status. Glu27 carriers had a lower risk of coronary events than Gln27 homozygotes (hazard ratio, 0.82; 95% CI, 0.70 to 0.95), and there was a suggestion of decreased risk among Gly16 carriers compared with Arg16 homozygotes (hazard ratio, 0.88; 95% CI, 0.72 to 1.07). There was no association of beta2-adrenergic receptor genotype with ischemic stroke or combined cardiovascular events.

CONCLUSIONS: The Glu27 allele of the beta2-adrenergic receptor was associated with a lower risk of incident coronary events in this elderly population.

VL - 107 IS - 15 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12682000?dopt=Abstract ER - TY - JOUR T1 - Body composition in the elderly: the influence of nutritional factors and physical activity. JF - J Nutr Health Aging Y1 - 2003 A1 - Mitchell, D A1 - Haan, M N A1 - Steinberg, F M A1 - Visser, M KW - Absorptiometry, Photon KW - Aged KW - Aged, 80 and over KW - Aging KW - Body Composition KW - Cohort Studies KW - Cross-Sectional Studies KW - Diet KW - Dietary Carbohydrates KW - Dietary Fats KW - Dietary Proteins KW - Energy Intake KW - Exercise KW - Female KW - Humans KW - Male KW - Walking AB -

BACKGROUND: Controversy exists regarding the relative contribution of diet and exercise to body composition. Few studies have examined these associations in the elderly, where changes occur in the body fat to muscle ratio.

OBJECTIVE: The primary objective of this paper is to determine whether energy intake or physical activity are associated with body composition. Secondly, to investigate whether specific macronutrients are associated with fat or lean tissue.

DESIGN: Data (n= 1404) for this cross-sectional analysis were collected from a population-based sub-sample of elderly enrollees in the Cardiovascular Health Study (CHS). Dietary intake and physical activity were assessed by questionnaires. Body composition was measured by Dual Energy X-ray Absorptiometry (DEXA). Linear regression models were used to assess the associations of diet and activity with body composition.

RESULTS: Total energy intake was not associated with any of the body composition measures. Higher dietary saturated fat was associated with higher percent body mass as fat and trunk fat in both sexes (p<0.01), and in men other dietary fats were associated with body fat. In women, distance walked was inversely associated with fat masses even after adjustment for pace of walking. In both sexes, faster pace of walking was associated with lower body and fat mass (p<0.01). Lean muscle mass was not associated with physical activity or dietary intakes.

CONCLUSION: Physical activity and dietary fat intake in this the elderly population were more closely associated with body fat mass than was total energy intake.

VL - 7 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12766789?dopt=Abstract ER - TY - JOUR T1 - C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study. JF - Circulation Y1 - 2003 A1 - Cao, Jie J A1 - Thach, Chau A1 - Manolio, Teri A A1 - Psaty, Bruce M A1 - Kuller, Lewis H A1 - Chaves, Paulo H M A1 - Polak, Joseph F A1 - Sutton-Tyrrell, Kim A1 - Herrington, David M A1 - Price, Thomas R A1 - Cushman, Mary KW - Aged KW - Brain Ischemia KW - C-Reactive Protein KW - California KW - Carotid Arteries KW - Cohort Studies KW - Comorbidity KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Maryland KW - North Carolina KW - Odds Ratio KW - Pennsylvania KW - Proportional Hazards Models KW - Risk Assessment KW - Risk Factors KW - Stroke KW - Tunica Intima KW - Tunica Media KW - Ultrasonography AB -

BACKGROUND: Increased carotid artery intima-media thickness (IMT) and elevated C-reactive protein (CRP) are both associated with the occurrence of stroke. We investigated whether elevated CRP is a risk factor for ischemic stroke independent of carotid IMT and studied the interaction between CRP and IMT.

METHODS AND RESULTS: We studied 5417 participants aged 65 years or older without preexisting stroke or chronic atrial fibrillation who were participants in the Cardiovascular Health Study. The hazard ratio of incident ischemic stroke was estimated by Cox proportional hazards regression. During 10.2 years of follow-up, 469 incident ischemic strokes occurred. The adjusted hazard ratios for ischemic stroke in the 2nd to 4th quartiles of baseline CRP, relative to the 1st quartile, were 1.19 (95% CI 0.92 to 1.53), 1.05 (95% CI 0.81 to 1.37), and 1.60 (95% CI 1.23 to 2.08), respectively. With additional adjustment for carotid IMT, there was little confounding. The association of CRP with stroke was significantly different depending on IMT (P<0.02), with no association of CRP with stroke among those in the lowest IMT tertile and a significant association among those with higher levels of IMT.

CONCLUSIONS: We conclude that elevated CRP is a risk factor for ischemic stroke, independent of atherosclerosis severity as measured by carotid IMT. The association of CRP with stroke is more apparent in the presence of a higher carotid IMT. CRP and carotid IMT may each be independent integrals in determining the risk of ischemic stroke.

VL - 108 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12821545?dopt=Abstract ER - TY - JOUR T1 - Early age-related maculopathy in the cardiovascular health study. JF - Ophthalmology Y1 - 2003 A1 - Klein, Ronald A1 - Klein, Barbara E K A1 - Marino, Emily K A1 - Kuller, Lewis H A1 - Furberg, Curt A1 - Burke, Gregory L A1 - Hubbard, Larry D KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Arteriosclerosis KW - Blood Pressure KW - C-Reactive Protein KW - California KW - Cohort Studies KW - Diet KW - European Continental Ancestry Group KW - Female KW - Humans KW - Hypertension KW - Leukocyte Count KW - Longitudinal Studies KW - Macular Degeneration KW - Male KW - Mid-Atlantic Region KW - North Carolina KW - Prevalence KW - Prospective Studies KW - Risk Factors KW - Serum Albumin AB -

OBJECTIVE: To describe the prevalence of early age-related maculopathy (ARM) and its relation to atherosclerosis, lipids, hypertension, and inflammatory factors in a population studied for cardiovascular disease risk factors and outcomes.

DESIGN: Population-based cohort study.

PARTICIPANTS: A biracial population of 2361 adults (ranging from 69-97 years of age; 1998 whites and 363 blacks) living in four US counties (Allegheny County, Pennsylvania; Forsyth County, North Carolina; Sacramento County, California; and Washington County, Maryland) were examined during the interval from 1997 to 1998.

METHODS: Drusen and other lesions typical of ARM were identified by examining a 45 degrees color fundus photograph of one eye of each participant and classified by means of a modification of the Wisconsin Age-Related Maculopathy Grading System.

MAIN OUTCOME MEASURES: Early ARM.

RESULTS: Early ARM was present in 15.5% and late ARM in 1.3% of the cohort. The overall prevalence of any ARM was lower in blacks (9.1%) compared with whites (18.2%). While controlling for age, race, gender, and total calories consumed in the diet, factors associated with ARM were cerebral white matter disease as detected by magnetic resonance imaging (odds ratio [OR], 1.50; 95% confidence interval [CI], 1.05, 2.16, P = 0.027), and lower serum total cholesterol (OR, per 10 mg/dl increase 0.95; 95% CI, 0.91, 0.98, P = 0.02). There were no associations between hypertension, blood pressure, common carotid artery plaque, or any systemic inflammatory factors studied and early ARM.

CONCLUSIONS: This population-based study documents the higher prevalence of ARM in whites compared with blacks. Although an association was found between signs of white matter disease and early ARM, there was no evidence of an association of ARM with either hypertension or inflammatory factors.

VL - 110 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12511342?dopt=Abstract ER - TY - JOUR T1 - Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. JF - Circulation Y1 - 2003 A1 - Shlipak, Michael G A1 - Fried, Linda F A1 - Crump, Casey A1 - Bleyer, Anthony J A1 - Manolio, Teri A A1 - Tracy, Russell P A1 - Furberg, Curt D A1 - Psaty, Bruce M KW - Aged KW - alpha-2-Antiplasmin KW - Biomarkers KW - Blood Coagulation Factors KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cohort Studies KW - Creatinine KW - Cross-Sectional Studies KW - Female KW - Fibrin Fibrinogen Degradation Products KW - Fibrinogen KW - Fibrinolysin KW - Humans KW - Inflammation KW - Interleukin-6 KW - Male KW - Prospective Studies KW - Renal Insufficiency KW - Risk Factors AB -

BACKGROUND: Renal insufficiency has been associated with cardiovascular disease events and mortality in several prospective studies, but the mechanisms for the elevated risk are not clear. Little is known about the association of renal insufficiency with inflammatory and procoagulant markers, which are potential mediators for the cardiovascular risk of kidney disease.

METHODS AND RESULTS: The cross-sectional association of renal insufficiency with 8 inflammatory and procoagulant factors was evaluated using baseline data from the Cardiovascular Health Study, a population-based cohort study of 5888 subjects aged > or =65 years. C-reactive protein, fibrinogen, factor VIIc, and factor VIIIc levels were measured in nearly all participants; interleukin-6, intercellular adhesion molecule-1, plasmin-antiplasmin complex, and D-dimer levels were measured in nearly half of participants. Renal insufficiency was defined as a serum creatinine level > or =1.3 mg/dL in women and > or =1.5 mg/dL in men. Multivariate linear regression was used to compare adjusted mean levels of each biomarker in persons with and without renal insufficiency after adjustment for other baseline characteristics. Renal insufficiency was present in 647 (11%) of Cardiovascular Health Study participants. After adjustment for baseline differences, levels of C-reactive protein, fibrinogen, interleukin-6, factor VIIc, factor VIIIc, plasmin-antiplasmin complex, and D-dimer were significantly greater among persons with renal insufficiency (P<0.001). In participants with clinical, subclinical, and no cardiovascular disease at baseline, the positive associations of renal insufficiency with these inflammatory and procoagulant markers were similar.

CONCLUSION: Renal insufficiency was independently associated with elevations in inflammatory and procoagulant biomarkers. These pathways may be important mediators leading to the increased cardiovascular risk of persons with kidney disease.

VL - 107 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12515748?dopt=Abstract ER - TY - JOUR T1 - Evaluation of dementia in the cardiovascular health cognition study. JF - Neuroepidemiology Y1 - 2003 A1 - Lopez, Oscar L A1 - Kuller, Lewis H A1 - Fitzpatrick, Annette A1 - Ives, Diane A1 - Becker, James T A1 - Beauchamp, Norman KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cognition Disorders KW - Cohort Studies KW - Cross-Sectional Studies KW - Dementia KW - Female KW - Humans KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Prevalence KW - Risk Factors KW - Sex Distribution AB -

OBJECTIVE: To describe a methodology to evaluate dementia and frequency of different types of dementia and prevalence of the Cardiovascular Health Study (CHS).

METHODS: The CHS is a longitudinal study of cardiovascular disease among community-dwelling individuals over the age of 65. Of the 5,888 participants in the original study, 3,608 had a magnetic resonance imaging (MRI) of the brain in 1991, and formed the cohort for the dementia study. The CHS included yearly measures of cognitive function and, from 1998 to 2000, participants were evaluated for dementia by detailed neurological, and neuropsychological examinations. The possible cases of dementia and mild cognitive impairment (MCI) were adjudicated by a review committee of neurologists and psychiatrists.

RESULTS: There were 480 cases of (13.3%) incident dementia in the total sample, 227 (6.3%) prevalent dementia, 577 (16.0%) MCI, and 2,318 (64.4%) normal. The adjudication committee classified 69% of the incident dementia as Alzheimer's disease (AD), 11% as vascular dementia (VaD), 16% as both, and 4% as other types. There was a substantial agreement between pre- and postMRI diagnosis of types of dementia. The frequency of dementia within the CHS cohort which survived to the end of the study in 1998-1999, was 13.5% for white men, 14.5% for white women, 22.2% for black men and 23.4% for black women.

CONCLUSION: The CHS has developed a methodology for longitudinal studies of dementia in large cohorts and represents the largest study of dementia including cognitive testing, MRI and genetic markers.

VL - 22 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12566948?dopt=Abstract ER - TY - JOUR T1 - Fibrin fragment D-dimer and the risk of future venous thrombosis. JF - Blood Y1 - 2003 A1 - Cushman, Mary A1 - Folsom, Aaron R A1 - Wang, Lu A1 - Aleksic, Nena A1 - Rosamond, Wayne D A1 - Tracy, Russell P A1 - Heckbert, Susan R KW - Aged KW - Body Mass Index KW - Cohort Studies KW - Continental Population Groups KW - Factor V KW - Factor VIII KW - Female KW - Fibrin Fibrinogen Degradation Products KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Odds Ratio KW - Prospective Studies KW - Prothrombin KW - Risk Factors KW - Venous Thrombosis AB -

Plasma D-dimer concentration rises more than 100-fold during acute deep vein thrombosis, but there are no prospective data concerning D-dimer as a risk factor for incident venous thrombosis in a general population. Incident venous thrombosis was ascertained in 2 prospective observational studies, the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Of 21 690 participants enrolled between 1987 and 1993, after 8 years of follow-up, D-dimer was measured using baseline stored plasma of 307 participants who developed venous thrombosis and 616 who did not. Relative to the first quintile of the distribution of D-dimer, the age-adjusted odds ratios for future venous thrombosis for the second to fifth quintiles of D-dimer were 1.6, 2.3, 2.3, and 4.2, respectively (P for trend <.0001). Following added adjustment for sex, race, body mass index, factor V Leiden, prothrombin 20210A, and elevated factor VIII coagulant activity (factor VIII:c), these odds ratios were 1.5, 2.1, 1.9, and 3.0, respectively (P for trend <.0001). Among those with idiopathic thrombosis or secondary thrombosis unrelated to cancer, the adjusted fifth quintile odds ratios were 3.5 and 4.8, respectively. By contrast, D-dimer in the fifth versus first quintile was not related to occurrence of cancer-associated thrombosis (odds ratio, 1.1). Odds ratios for elevated D-dimer were consistently elevated in subgroups defined by age, sex, race, duration of follow-up, and thrombosis type (deep vein thrombosis or pulmonary embolus). D-dimer is strongly and positively related to the occurrence of future venous thrombosis.

VL - 101 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12393393?dopt=Abstract ER - TY - JOUR T1 - Hormone replacement therapy and sleep-disordered breathing. JF - Am J Respir Crit Care Med Y1 - 2003 A1 - Shahar, Eyal A1 - Redline, Susan A1 - Young, Terry A1 - Boland, Lori L A1 - Baldwin, Carol M A1 - Nieto, F Javier A1 - O'Connor, George T A1 - Rapoport, David M A1 - Robbins, John A KW - Age Distribution KW - Aged KW - Body Mass Index KW - Causality KW - Cohort Studies KW - Confidence Intervals KW - Estrogen Replacement Therapy KW - Female KW - Humans KW - Logistic Models KW - Middle Aged KW - Multivariate Analysis KW - Odds Ratio KW - Polysomnography KW - Postmenopause KW - Prevalence KW - Sensitivity and Specificity KW - Severity of Illness Index KW - Sleep Apnea Syndromes KW - Sleep Stages KW - United States AB -

Disordered breathing during sleep is more common among postmenopausal women than among their premenopausal counterparts, possibly because of declining levels of estrogen and progesterone. We examined the relationship between the use of replacement hormones and sleep-disordered breathing in a sample of 2,852 noninstitutionalized women, 50 years of age or older, who participated in the Sleep Heart Health Study. The frequency of apneas and hypopneas per hour of sleep (apnea-hypopnea index) was determined by unattended, single-night polysomnography at the participant's home. The prevalence of sleep-disordered breathing (apnea-hypopnea index of 15 or more) among hormone users (61 of 907) was approximately half the prevalence among nonusers (286 of 1,945). Multivariable adjustment for known determinants of the disorder, including age, body mass index, and neck circumference, has attenuated the association, but only moderately (adjusted odds ratio, 0.55; 95% confidence interval, 0.41 to 0.75). The inverse association between hormone use and sleep-disordered breathing was evident in various subgroups and was particularly strong among women 50 to 59 years old (adjusted odds ratio, 0.36; 95% confidence interval, 0.21 to 0.60). If the observed associations are causal, hormone replacement therapy could have a role in preventing or alleviating sleep-disordered breathing.

VL - 167 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12531779?dopt=Abstract ER - TY - JOUR T1 - Hormone replacement therapy and the risk of incident congestive heart failure: the Cardiovascular Health Study. JF - J Womens Health (Larchmt) Y1 - 2003 A1 - Rea, Thomas D A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Cushman, Mary A1 - Meilahn, Elaine A1 - Olson, Jean L A1 - Lemaitre, Rozenn N A1 - Smith, Nicholas L A1 - Sotoodehnia, Nona A1 - Chaves, Paulo H M KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Cohort Studies KW - Estrogen Replacement Therapy KW - Female KW - Heart Failure KW - Humans KW - Incidence KW - Life Style KW - Middle Aged KW - Multivariate Analysis KW - Obesity KW - Osteoporosis, Postmenopausal KW - Proportional Hazards Models KW - Prospective Studies KW - Risk KW - Risk Factors KW - United States KW - Women's Health AB -

BACKGROUND: The development of congestive heart failure (CHF) in older persons is related to a variety of mechanisms. Hormone replacement therapy (HRT) affects several of the pathways that may be important in the development of CHF. We hypothesized that HRT would be associated with a decreased risk of incident CHF.

METHODS: Using Cox proportional-hazards regression, we assessed the risk of incident CHF (n = 304) associated with time-dependent past and current use of HRT compared to never use. The Cardiovascular Health Study is a prospective cohort study of community-dwelling adults aged 65 years and older. This analysis included female participants without a history of CHF at baseline (n = 3223).

RESULTS: At baseline, 62% were never users, 26% were past users, and 12% were current users of HRT. Compared with never users, the multivariable relative risk (RR) of CHF was 1.01 (95% confidence interval [95% CI] 0.76,1.34) for past users and 1.34 (0.93,1.94) for current users. Results were similar among most treatment and clinical subgroups, except that the association of current HRT with CHF appeared to depend on body mass index (BMI) or osteoporosis status. The RR was 0.82 (0.43,1.60) for normal weight women, 1.65 (0.95,2.88) for overweight women, and 2.22 (1.06,4.67) for obese women (p = 0.01 for interaction). Similarly, the RR was 0.15 (0.04,0.65) for women with osteoporosis and 1.82 (1.25,2.65) for women without osteoporosis (p = 0.001 for interaction).

CONCLUSIONS: Overall, HRT was not associated with the risk of incident CHF, although BMI and osteoporosis appeared to modify the association of HRT with CHF. The risk of CHF was lower in patients with lower BMI or osteoporosis.

VL - 12 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12804341?dopt=Abstract ER - TY - JOUR T1 - Lack of association of the plasminogen activator inhibitor-1 4G/5G promoter polymorphism with cardiovascular disease in the elderly. JF - J Thromb Haemost Y1 - 2003 A1 - Crainich, P A1 - Jenny, N S A1 - Tang, Z A1 - Arnold, A M A1 - Kuller, L H A1 - Manolio, T A1 - Sharrett, A R A1 - Tracy, R P KW - African Continental Ancestry Group KW - Aged KW - Alleles KW - Cardiovascular Diseases KW - Case-Control Studies KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genotype KW - Homozygote KW - Humans KW - Male KW - Myocardial Infarction KW - Plasminogen Activator Inhibitor 1 KW - Polymorphism, Genetic KW - Promoter Regions, Genetic KW - Risk AB -

Elevated circulating plasminogen activator inhibitor-1 (PAI-1) may increase risk of cardiovascular disease (CVD). The 4G allele of the 4G/5G PAI-1 promoter polymorphism is associated with higher levels of PAI-1. We examined the association of PAI-1 4G/5G genotype and CVD events in the elderly participants of the Cardiovascular Health Study (CHS). We measured 4G/5G genotype in a nested case-control study within the CHS. Cases included incident angina, myocardial infarction (MI), and stroke. 4G/5G genotype was not found to be associated with markers of fibrinolysis or CVD risk in the selected elderly cohort. There were no differences in genotype frequencies by case-control status (5G/5G frequency 16-22%; chi2P= 0.07). The 5G allele was not associated with incident CVD events when individuals with at least one 5G allele were compared to 4G/4G homozygotes. The presence of at least one 4G allele was likewise not associated with incident CVD when those with 4G/4G and 4G/5G genotypes were compared to 5G/5G homozygotes. Our results suggest that the PAI-1 4G/5G promoter polymorphism is not associated CVD risk factors or incident CVD events in the elderly.

VL - 1 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12911596?dopt=Abstract ER - TY - JOUR T1 - Multiple imputation of baseline data in the cardiovascular health study. JF - Am J Epidemiol Y1 - 2003 A1 - Arnold, Alice M A1 - Kronmal, Richard A KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Analysis of Variance KW - Cardiovascular Diseases KW - Cause of Death KW - Cohort Studies KW - Data Collection KW - Data Interpretation, Statistical KW - Epidemiologic Studies KW - Female KW - Humans KW - Linear Models KW - Male KW - Mathematical Computing KW - Models, Statistical KW - Predictive Value of Tests KW - Proportional Hazards Models KW - Risk Factors KW - Software KW - Survival Analysis KW - United States KW - Ventricular Remodeling AB -

Most epidemiologic studies will encounter missing covariate data. Software packages typically used for analyzing data delete any cases with a missing covariate to perform a complete case analysis. The deletion of cases complicates variable selection when different variables are missing on different cases, reduces power, and creates the potential for bias in the resulting estimates. Recently, software has become available for producing multiple imputations of missing data that account for the between-imputation variability. The implementation of the software to impute missing baseline data in the setting of the Cardiovascular Health Study, a large, observational study, is described. Results of exploratory analyses using the imputed data were largely consistent with results using only complete cases, even in a situation where one third of the cases were excluded from the complete case analysis. There were few differences in the exploratory results across three imputations, and the combined results from the multiple imputations were very similar to results from a single imputation. An increase in power was evident and variable selection simplified when using the imputed data sets.

VL - 157 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12505893?dopt=Abstract ER - TY - JOUR T1 - n-3 Polyunsaturated fatty acids, fatal ischemic heart disease, and nonfatal myocardial infarction in older adults: the Cardiovascular Health Study. JF - Am J Clin Nutr Y1 - 2003 A1 - Lemaitre, Rozenn N A1 - King, Irena B A1 - Mozaffarian, Dariush A1 - Kuller, Lewis H A1 - Tracy, Russell P A1 - Siscovick, David S KW - Aged KW - alpha-Linolenic Acid KW - Biomarkers KW - Case-Control Studies KW - Cohort Studies KW - Coronary Disease KW - Dietary Supplements KW - Docosahexaenoic Acids KW - Eicosapentaenoic Acid KW - Fatty Acids, Omega-3 KW - Female KW - Fish Oils KW - Humans KW - Incidence KW - Male KW - Myocardial Infarction KW - Odds Ratio KW - Phospholipids KW - Prevalence KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: Little is known about the relation of the dietary intake of n-3 polyunsaturated fatty acids, ie, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) from fatty fish and alpha-linolenic acid from vegetable oils, with ischemic heart disease among older adults.

OBJECTIVE: We investigated the associations of plasma phospholipid concentrations of DHA, EPA, and alpha-linolenic acid as biomarkers of intake with the risk of incident fatal ischemic heart disease and incident nonfatal myocardial infarction in older adults.

DESIGN: We conducted a case-control study nested in the Cardiovascular Health Study, a cohort study of adults aged > or = 65 y. Cases experienced incident fatal myocardial infarction and other ischemic heart disease death (n = 54) and incident nonfatal myocardial infarction (n = 125). Matched controls were randomly selected (n = 179). We measured plasma phospholipid concentrations of n-3 polyunsaturated fatty acids in blood samples drawn approximately 2 y before the event.

RESULTS: A higher concentration of combined DHA and EPA was associated with a lower risk of fatal ischemic heart disease, and a higher concentration of alpha-linolenic acid with a tendency to lower risk, after adjustment for risk factors [odds ratio: 0.32 (95% CI: 0.13, 0.78; P = 0.01) and 0.52 (0.24, 1.15; P = 0.1), respectively]. In contrast, n-3 polyunsaturated fatty acids were not associated with nonfatal myocardial infarction.

CONCLUSIONS: Higher combined dietary intake of DHA and EPA, and possibly alpha-linolenic acid, may lower the risk of fatal ischemic heart disease in older adults. The association of n-3 polyunsaturated fatty acids with fatal ischemic heart disease, but not with nonfatal myocardial infarction, is consistent with possible antiarrhythmic effects of these fatty acids.

VL - 77 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12540389?dopt=Abstract ER - TY - JOUR T1 - Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 1. JF - Arch Neurol Y1 - 2003 A1 - Lopez, Oscar L A1 - Jagust, William J A1 - DeKosky, Steven T A1 - Becker, James T A1 - Fitzpatrick, Annette A1 - Dulberg, Corinne A1 - Breitner, John A1 - Lyketsos, Constantine A1 - Jones, Beverly A1 - Kawas, Claudia A1 - Carlson, Michelle A1 - Kuller, Lewis H KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cognition Disorders KW - Cohort Studies KW - Dementia KW - Female KW - Humans KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Memory Disorders KW - Neuropsychological Tests KW - Pennsylvania KW - Population KW - Psychiatric Status Rating Scales AB -

OBJECTIVE: To examine the prevalence of mild cognitive impairment (MCI) and its diagnostic classification in the Cardiovascular Health Study (CHS) Cognition Study.

DESIGN: The CHS Cognition Study is an ancillary study of the CHS that was conducted to determine the presence of MCI and dementia in the CHS cohort.

SETTING: Multicenter population study.

PATIENTS: We examined 3608 participants in the CHS who had undergone detailed neurological, neuropsychological, neuroradiological, and psychiatric testing to identify dementia and MCI.

MAIN OUTCOME MEASURES: The prevalence of MCI was determined for the whole cohort, and specific subtypes of MCI were examined in detail only at the Pittsburgh, Pa, center (n = 927). Mild cognitive impairment was classified as either MCI amnestic-type or MCI multiple cognitive deficits-type.

RESULTS: The overall prevalence of MCI was 19% (465 of 2470 participants); prevalence increased with age from 19% in participants younger than 75 years to 29% in those older than 85 years. The overall prevalence of MCI at the Pittsburgh center was 22% (130 of 599 participants); prevalence of the MCI amnesic-type was 6% and of the MCI multiple cognitive deficits-type was 16%.

CONCLUSIONS: Twenty-two percent of the participants aged 75 years or older had MCI. Mild cognitive impairment is a heterogeneous syndrome, where the MCI amnestic-type is less frequent than the MCI multiple cognitive deficits-type. Most of the participants with MCI had comorbid conditions that may affect their cognitive functions.

VL - 60 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/14568808?dopt=Abstract ER - TY - JOUR T1 - Recruitment of healthy adults into a study of overnight sleep monitoring in the home: experience of the Sleep Heart Health Study. JF - Sleep Breath Y1 - 2003 A1 - Lind, Bonnie K A1 - Goodwin, James L A1 - Hill, Joel G A1 - Ali, Tauqeer A1 - Redline, Susan A1 - Quan, Stuart F KW - Adult KW - Body Mass Index KW - Cardiovascular Diseases KW - Catchment Area, Health KW - Circadian Rhythm KW - Cohort Studies KW - Disorders of Excessive Somnolence KW - Health Status KW - Home Care Services KW - Humans KW - Hypertension KW - Patient Selection KW - Polysomnography KW - Prospective Studies KW - Severity of Illness Index KW - Sleep Apnea Syndromes KW - Surveys and Questionnaires KW - United States AB -

The Sleep Heart Health Study (SHHS) is a prospective cohort study using participants from several ongoing cardiovascular and respiratory disease research projects to investigate the relationship between sleep-disordered breathing and cardiovascular disease. This study design required unusual and different recruiting techniques to meet the study's enrollment goal of between 6000 and 6600 participants. Individuals were recruited to undergo an overnight home polysomnogram, completion of several questionnaires, and collection of a small amount of physical examination data. This article describes the methods used to recruit these participants and how these procedures influenced the final participation rate and the representativeness of SHHS to its parent cohorts. Of 30,773 people eligible for recruitment into SHHS, attempts were made to enroll 11,145 (36%). Of those contacted, 6441 ultimately agreed to participate (58%). Recruitment rates (38 to 91%) varied among sites. SHHS participants were slightly younger (63.0 vs. 65.0 years, p < 0.001), had more years of education (14.1 vs. 13.7, p < 0.001), more likely to snore (34% vs. 23%, p < 0.001), had higher Epworth sleepiness scores (7.7 vs. 6.5, p < 0.001), slightly higher higher systolic and diastolic blood pressures (127.6/73.9 vs. 127.2/72.1, p < 0.001 for diastolic only), and a slightly higher body mass index (BMI) (28.5 vs. 27.5, p < 0.001). We conclude that it is feasible to recruit existing participants from one large-scale epidemiologic study into another with a high degree of success. However, the characteristics of the new cohort may vary in several respects from their original cohorts and therefore interpretation of study results will have to consider these differences.

VL - 7 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12712393?dopt=Abstract ER - TY - JOUR T1 - Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. JF - Arch Neurol Y1 - 2003 A1 - Lopez, Oscar L A1 - Jagust, William J A1 - Dulberg, Corinne A1 - Becker, James T A1 - DeKosky, Steven T A1 - Fitzpatrick, Annette A1 - Breitner, John A1 - Lyketsos, Constantine A1 - Jones, Beverly A1 - Kawas, Claudia A1 - Carlson, Michelle A1 - Kuller, Lewis H KW - Aged KW - Apolipoprotein E4 KW - Apolipoproteins E KW - Brain KW - Cardiovascular Diseases KW - Cognition Disorders KW - Cohort Studies KW - Depressive Disorder KW - Female KW - Humans KW - Logistic Models KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Mood Disorders KW - Pennsylvania KW - Population KW - Risk Factors AB -

OBJECTIVE: To examine the risk factors for mild cognitive impairment (MCI) in a longitudinal population study-the Cardiovascular Health Study Cognition Study.

DESIGN: We examined the factors that in the period 1991 through 1994 predicted the development of MCI in all participants of the Cardiovascular Health Study Cognition Study. Further examination was conducted in the Pittsburgh, Pa, cohort (n = 927), where participants with MCI were classified as having either the MCI amnestic-type or the MCI multiple cognitive deficits-type.

SETTING: Multicenter population study.

PATIENTS: This study includes all participants of the Cardiovascular Health Study Cognition Study (n = 3608) who had a magnetic resonance imaging (MRI) scan of the brain between 1991 and 1994, and detailed neuropsychological, neurological, and medical evaluations to identify the presence of MCI or dementia in the period 1998 to 1999. The mean time between the closest clinical examination to the MRI and the diagnostic evaluation for cognitive disorders was 5.8 years for the Cardiovascular Health Study Cognition Study cohort and 6.0 years for the Pittsburgh cohort.

MAIN OUTCOME MEASURES: Risk factors for MCI at the time of the MRI were identified using logistic regression, controlling for age, race, educational level, baseline Modified Mini-Mental State Examination and Digit Symbol Test scores, measurements of depression, MRI findings (atrophy, ventricular volume, white matter lesions, and infarcts), the presence of the apolipoprotein E (APOE) epsilon4 allele, hypertension, diabetes mellitus, and heart disease.

RESULTS: Mild cognitive impairment (n = 577) was associated with race (African American), low educational level, low Modified Mini-Mental State Examination and Digit Symbol Test scores, cortical atrophy, MRI-identified infarcts, and measurements of depression. The MCI amnestic-type was associated with MRI-identified infarcts, the presence of the APOE epsilon4 allele, and low Modified Mini-Mental State Examination scores. The MCI multiple cognitive deficits-type was associated with low Modified Mini-Mental State Examination and Digit Symbol Test scores.

CONCLUSIONS: The development of MCI is associated with measurements of cognition and depression, racial and constitutional factors, and cerebrovascular disease. Early cognitive deficits seem to be a common denominator for the 2 forms of MCI; the presence of cerebrovascular disease and the APOE epsilon4 allele is associated with the amnestic type of MCI.

VL - 60 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/14568809?dopt=Abstract ER - TY - JOUR T1 - Serum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE). JF - Am J Hematol Y1 - 2003 A1 - Tsai, Albert W A1 - Cushman, Mary A1 - Tsai, Michael Y A1 - Heckbert, Susan R A1 - Rosamond, Wayne D A1 - Aleksic, Nena A1 - Yanez, N David A1 - Psaty, Bruce M A1 - Folsom, Aaron R KW - Aged KW - Aging KW - Animals KW - Case-Control Studies KW - Cohort Studies KW - Factor V KW - Female KW - Genotype KW - Homocysteine KW - Humans KW - Longitudinal Studies KW - Male KW - Methylenetetrahydrofolate Reductase (NADPH2) KW - Middle Aged KW - Odds Ratio KW - Oxidoreductases Acting on CH-NH Group Donors KW - Polymorphism, Genetic KW - Prospective Studies KW - Risk Factors KW - Venous Thrombosis AB -

We sought to examine prospectively the association of serum homocysteine and the methylene tetrahydrofolate reductase (MTHFR) C677T gene polymorphism with risk of venous thromboembolism (VTE). We studied these relationships in a nested case-control study of 303 VTE cases and 635 matched controls from a population-based cohort of 21,680 adults from six U.S. communities. The highest quintile of serum homocysteine carried a non-statistically significant adjusted odds ratio of 1.55 (95% CI, 0.93-2.58) compared to the lowest quintile in the overall cohort but a significant association among adults aged 45-64 years (OR = 2.05, 95% CI, 1.10-3.83) and an inverse association in those > or = 65 years of age. Carriers of the MTHFR C677T polymorphism were not at higher risk for VTE than those with normal genotype (OR = 0.74, 95% CI = 0.56-0.98). Our prospective data showed, at most, a weak relationship between homocysteine and VTE risk, with associations larger among younger participants. MTHFR C677T was not a risk factor for VTE.

VL - 72 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12605391?dopt=Abstract ER - TY - JOUR T1 - Sleep and sleep-disordered breathing in adults with predominantly mild obstructive airway disease. JF - Am J Respir Crit Care Med Y1 - 2003 A1 - Sanders, Mark H A1 - Newman, Anne B A1 - Haggerty, Catherine L A1 - Redline, Susan A1 - Lebowitz, Michael A1 - Samet, Jonathan A1 - O'Connor, George T A1 - Punjabi, Naresh M A1 - Shahar, Eyal KW - Aged KW - Cohort Studies KW - Female KW - Forced Expiratory Volume KW - Humans KW - Male KW - Middle Aged KW - Oxyhemoglobins KW - Polysomnography KW - Prospective Studies KW - Pulmonary Disease, Chronic Obstructive KW - Sleep KW - Sleep Apnea, Obstructive KW - Spirometry KW - Vital Capacity AB -

Neither the association between obstructive airways disease (OAD) and sleep apnea-hypopnea (SAH) nor the sleep consequences of each disorder alone and together have been characterized in an adult community setting. Our primary aims were (1) to determine if there is an association between OAD and SAH and (2) identify predictors of oxyhemoglobin desaturation during sleep in persons having OAD with and without SAH. Polysomnography and spirometry results from 5,954 participants in the Sleep Heart Health Study were analyzed. OAD was defined by a FEV1/FVC value less than 70%. Assessment of SAH prevalence in OAD was performed using thresholds of respiratory disturbance index (RDI) greater than 10 and greater than 15. A total of 1,132 participants had OAD that was predominantly mild (FEV1/FVC 63.81 +/- 6.56%, mean +/- SD). SAH was not more prevalent in participants with OAD than in those without OAD (22.32 versus 28.86%, with and without OAD, respectively, at RDI threshold values greater than 10; and 13.97 versus 18.63%, with and without OAD, respectively, at RDI threshold value greater than 15). In the absence of SAH, the adjusted odds ratio for sleep desaturation (> 5% total sleep time with saturation < 90%) was greater than 1.9 when FEV1/FVC was less than 65%. Participants with both OAD and SAH had greater sleep perturbation and desaturation than those with one disorder. Generally mild OAD alone was associated with minimally altered sleep quality. We conclude that (1) there is no association between generally mild OAD and SAH; (2) exclusive of SAH and after adjusting for demographic factors and awake oxyhemoglobin saturation, an FEV1/FVC value less than 65% is associated with increased risk of sleep desaturation; (3) desaturation is greater in persons with both OAD and SAH compared with each of these alone; and (4) individuals with generally mild OAD and without SAH in the community have minimally perturbed sleep.

VL - 167 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/12502472?dopt=Abstract ER - TY - JOUR T1 - APOE epsilon4 is associated with obstructive sleep apnea/hypopnea: the Sleep Heart Health Study. JF - Neurology Y1 - 2004 A1 - Gottlieb, D J A1 - DeStefano, A L A1 - Foley, D J A1 - Mignot, E A1 - Redline, S A1 - Givelber, R J A1 - Young, T KW - Adult KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Alleles KW - Apolipoprotein E4 KW - Apolipoproteins E KW - Cardiovascular Diseases KW - Cohort Studies KW - Comorbidity KW - Female KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Hyperlipidemias KW - Hypertension KW - Male KW - Middle Aged KW - Obesity KW - Polysomnography KW - Sleep Apnea, Obstructive KW - Smoking AB -

BACKGROUND: Obstructive sleep apnea/hypopnea (OSAH) has a strong heritable component, although its genetic basis remains largely unknown. One epidemiologic study found a significant association between the APOE epsilon4 allele and OSAH in middle-aged adults, a finding that was not replicated in a cohort of elderly adults. The objective of this study was to further examine the association of the APOE epsilon4 allele with OSAH in a community-dwelling cohort, exploring age dependency of the association.

METHODS: A genetic association study was performed, nested within a prospective cohort study of the cardiovascular consequences of OSAH. Unattended, in-home nocturnal polysomnography was used to measure apnea-hypopnea index (AHI) in 1,775 participants age 40 to 100 years. OSAH was defined as an AHI > or = 15. The relation of APOE genotype to prevalent OSAH was analyzed using generalized estimating equations to account for non-independent observations of individuals from the same sibship.

RESULTS: At least one APOE epsilon4 allele was present in 25% of subjects, with 1.3% epsilon4/epsilon4 homozygotes. The prevalence of OSAH was 19%. After adjustment for age, sex, and BMI, the presence of any APOE epsilon4 allele was associated with increased odds of OSAH (OR 1.41, 95% CI 1.06 to 1.87, p = 0.02). The effect was approximately twice as great in subjects <75 (OR 1.61, CI 1.02 to 2.54) as in those > or =75 years old (OR 1.32, CI 0.91 to 1.90). Exploratory analyses revealed that the strongest effect of APOE epsilon4 was in subjects age <65 (OR 3.08, CI 1.43 to 6.64), and was stronger in those with hypertension or cardiovascular disease than in those without.

CONCLUSION: The APOE epsilon4 allele is associated with increased risk of OSAH, particularly in individuals under age 65. The mechanisms underlying this association are uncertain. Age-dependency of the APOE-OSAH association may explain previous conflicting results.

VL - 63 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15326239?dopt=Abstract ER - TY - JOUR T1 - The association of personal and neighborhood socioeconomic indicators with subclinical cardiovascular disease in an elderly cohort. The cardiovascular health study. JF - Soc Sci Med Y1 - 2004 A1 - Nordstrom, Cheryl K A1 - Diez Roux, Ana V A1 - Jackson, Sharon A A1 - Gardin, Julius M KW - Aged KW - California KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Geography KW - Humans KW - Male KW - Maryland KW - Medicare KW - North Carolina KW - Pennsylvania KW - Residence Characteristics KW - Risk Factors KW - Social Class KW - Socioeconomic Factors KW - Surveys and Questionnaires AB -

There has been recent interest in determining whether neighborhood characteristics are related to the cardiovascular health of residents. However, there are no data regarding the relationship between neighborhood socioeconomic status (SES) and prevalence of subclinical cardiovascular disease (CVD) in the elderly. We related personal SES (education, income, and occupation type) and neighborhood socioeconomic characteristics (a block-group score summing six variables reflecting neighborhood income and wealth, education, and occupation) to the prevalence of subclinical CVD (asymptomatic peripheral vascular disease or carotid atherosclerosis, electrocardiogram or echocardiogram abnormalities, and/or positive responses to Rose Questionnaire claudication or angina pectoris) among 3545 persons aged 65 and over, without prevalent CVD, in the Cardiovascular Health Study. Sixty percent of participants had at least one indicator of subclinical disease. Compared to those without, those with subclinical disease had significantly lower education, income, and neighborhood scores and were more likely to have blue-collar jobs. After adjustment for age, gender, and race, those in the lowest SES groups had increased prevalence of subclinical disease compared with those in the highest SES groups (OR = 1.50; 95% CI 1.21, 1.86 for income; OR = 1.41; 95% CI 1.18, 1.69 for education; OR = 1.39; 95% CI 1.16, 1.67 for block-group score). Those reporting a blue-collar lifetime occupation had greater prevalence of subclinical disease relative to those reporting a white-collar occupation (OR = 1.29; 95% CI 1.02-1.59). After adjustment for behavioral and biomedical risk factors, all of these associations were reduced. Neighborhood score tended to remain inversely associated with subclinical disease after adjustment for personal socioeconomic indicators but associations were not statistically significant. Personal income and blue-collar occupation remained significantly associated with subclinical disease after simultaneous adjustment for neighborhood score and education. Personal and neighborhood socioeconomic indicators were associated with subclinical disease prevalence in this elderly cohort. These relationships were reduced after controlling for traditional CVD risk factors.

VL - 59 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15351479?dopt=Abstract ER - TY - JOUR T1 - Associations between gender and measures of daytime somnolence in the Sleep Heart Health Study. JF - Sleep Y1 - 2004 A1 - Baldwin, Carol M A1 - Kapur, Vishesh K A1 - Holberg, Catharine J A1 - Rosen, Carol A1 - Nieto, F Javier KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Cross-Sectional Studies KW - Disorders of Excessive Somnolence KW - Female KW - Health Status KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Polysomnography KW - Severity of Illness Index KW - Sex Factors AB -

STUDY OBJECTIVES: To examine the relationship of gender to subjective measures of sleepiness, including the Epworth Sleepiness Scale (ESS), in a community-based population.

DESIGN: A cross-sectional study.

SETTING/PARTICIPANTS: Multicenter Sleep Heart Health Study participants (N = 6.440, 52% women) recruited from ongoing cohort studies.

INTERVENTIONS: N/A.

MEASUREMENTS: Scores from the ESS, Sleep Heart Health Study daytime sleepiness and feeling unrested questions, polysomnography results (respiratory disturbance index at 4% desaturation), as well as data on difficulty initiating and maintaining sleep, insufficient sleep, sedative use, alcohol use, cardiovascular or respiratory disease, frequent awakening due to leg cramps.

RESULTS: Women reported feeling sleepy as often as men did (odds ratio [OR] = 1.06; confidence interval [CI], 0.86-1.32), but women were less likely to have an ESS score > 10 (adjusted OR = 0.77; CI, 0.66-0.90) and more likely to report feeling unrested (adjusted OR = 1.39; CI, 1.14-1.69) than men. In men, the ESS score was more strongly correlated with reports of feeling unrested or sleepy compared to women.

CONCLUSIONS: Men and women answer questions on sleepiness differently. Findings indicate that using the ESS to detect subjective sleepiness is more likely to identify men with sleepiness. Since the ESS is more strongly related to other subjective measures in men, the ESS may be a more sensitive measure of subjective sleepiness in men than in women.

VL - 27 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15124727?dopt=Abstract ER - TY - JOUR T1 - Associations between renovascular disease and prevalent cardiovascular disease in the elderly: a population-based study. JF - Vasc Endovascular Surg Y1 - 2004 A1 - Edwards, Matthew S A1 - Hansen, Kimberley J A1 - Craven, Timothy E A1 - Bleyer, Anthony J A1 - Burke, Gregory L A1 - Levy, Pavel J A1 - Dean, Richard H KW - Aged KW - Arteriosclerosis KW - Cardiovascular Diseases KW - Cohort Studies KW - Humans KW - Hypertension, Renovascular KW - Longitudinal Studies KW - Male KW - Multivariate Analysis KW - Prevalence KW - Prospective Studies KW - Renal Artery Obstruction KW - Ultrasonography KW - United States AB -

Atherosclerotic renovascular disease (RVD) is a suspected contributor to the morbidity and mortality of cardiovascular disease (CVD) through its potential effects on blood pressure and excretory renal function as well as through its associations with other forms of CVD. However, population-based data regarding the associations between the presence of RVD and prevalent CVD are lacking. The Cardiovascular Health Study (CHS) is a prospective, multicenter cohort study of CVD among elderly Americans. As part of an ancillary study, participants in the Forsyth County, North Carolina, cohort of the CHS were invited to undergo renal duplex sonography (RDS) to establish the presence or absence of RVD (defined as any focal peak systolic velocity >/= 1.8 m/second or the absence of a Doppler-shifted signal from an imaged artery). Demographic, risk factor, and prevalent CVD data were obtained from the CHS coordinating center and matched with ancillary study participants. Eight hundred thirty-four CHS participants (including 525 women [63%], 309 men [37%], 194 African-Americans [23%], and 635 Caucasians [76%]) with a mean age of 77.2 +/-4.9 years underwent RDS examination. RVD was present in 57 participants (6.8%). Overall, clinical and/or subclinical manifestations of CVD were present in 603 participants (72.3%) at the time of RDS. Participants with RVD demonstrated a significantly greater prevalence of angina (p = 0.002), previous myocardial infarction (p < 0.001), >/= 25% diameter-reducing internal carotid artery stenosis (p = 0.010), increased carotid intimal medial thickness (p = 0.003), and major electrocardiographic abnormalities (p = 0.013). Following adjustment for demographics and cardiovascular risk factors, the presence of RVD demonstrated a significant and independent association with prevalent coronary artery disease but not with prevalent cerebrovascular or lower extremity vascular disease. These results suggest important population-based associations between RVD and both clinical and subclinical manifestations of CVD, especially coronary artery disease.

VL - 38 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/14760474?dopt=Abstract ER - TY - JOUR T1 - Cognitive impairment and decline are associated with carotid artery disease in patients without clinically evident cerebrovascular disease. JF - Ann Intern Med Y1 - 2004 A1 - Johnston, S Claiborne A1 - O'Meara, Ellen S A1 - Manolio, Teri A A1 - Lefkowitz, David A1 - O'Leary, Daniel H A1 - Goldstein, Steven A1 - Carlson, Michelle C A1 - Fried, Linda P A1 - Longstreth, W T KW - Aged KW - Carotid Stenosis KW - Cognition Disorders KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Humans KW - Male KW - Neuropsychological Tests KW - Odds Ratio KW - Risk Factors KW - Tunica Intima AB -

BACKGROUND: Whether carotid artery disease is a cause of cognitive impairment in persons who have not had stroke is unknown. If this is the case, diminished performance on the Modified Mini-Mental State Examination should be more common in persons with left carotid artery disease than in those with right carotid artery disease.

OBJECTIVE: To determine whether left carotid artery disease is associated with cognitive impairment.

DESIGN: Cross-sectional and cohort study.

SETTING: Four U.S. communities participating in the Cardiovascular Health Study.

PATIENTS: 4006 right-handed men and women 65 years of age or older without history of stroke, transient ischemic attack, or carotid endarterectomy.

MEASUREMENTS: Internal carotid artery stenosis and intima-media thickness of the common carotid artery were assessed by using duplex ultrasonography. Cognitive impairment was defined as a score less than 80 on the Modified Mini-Mental State Examination, and cognitive decline was defined as an average decrease of more than 1 point annually in Modified Mini-Mental State Examination score during up to 5 years of follow-up. Multivariate logistic regression models were used to estimate the risk for cognitive impairment and decline associated with left internal carotid artery stenosis and intima-media thickness, after adjustment for measures of right-sided disease and risk factors for vascular disease.

RESULTS: After adjustment for right-sided stenosis, high-grade (> or =75% narrowing of diameter) stenosis of the left internal carotid artery (32 patients) was associated with cognitive impairment (odds ratio, 6.7 [95% CI, 2.4 to 18.1] compared with no stenosis) and cognitive decline (odds ratio, 2.6 [CI, 1.1 to 6.3]). Intima-media thickness of the left common carotid artery was associated with cognitive impairment and decline in univariate analysis, but this effect did not persist after adjustment.

CONCLUSIONS: Cognitive impairment and decline are associated with asymptomatic high-grade stenosis of the left internal carotid artery. The persistence of the association after adjustment for right-sided stenosis indicates that the association is not due to underlying vascular risk factors or atherosclerosis in general.

VL - 140 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/14970146?dopt=Abstract ER - TY - JOUR T1 - Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. JF - Am J Med Y1 - 2004 A1 - Cushman, Mary A1 - Tsai, Albert W A1 - White, Richard H A1 - Heckbert, Susan R A1 - Rosamond, Wayne D A1 - Enright, Paul A1 - Folsom, Aaron R KW - Aged KW - Case-Control Studies KW - Cohort Studies KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Neoplasms KW - Population Surveillance KW - Pulmonary Embolism KW - Recurrence KW - Risk Factors KW - Survival Rate KW - Venous Thrombosis AB -

PURPOSE: To determine the incidence of deep vein thrombosis and pulmonary embolism in two cohorts representing regions of the United States.

METHODS: The sample comprised 21,680 participants of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study. Subjects were aged >/=45 years, resided in six communities, and were followed for 7.6 years. All hospitalizations were identified and thromboses were validated by chart review.

RESULTS: The age-standardized incidence of first-time venous thromboembolism was 1.92 per 1000 person-years. Rates were higher in men than women, and increased with age in both sexes. There was no antecedent trauma, surgery, immobilization, or diagnosis of cancer for 48% (175/366) of events. The 28-day case-fatality rate was 11% (29/265) after a first venous thromboembolism and 25% (17/67) for cancer-associated thrombosis. The recurrence rate 2 years after a first venous thromboembolism was 7.7% per year (95% confidence interval [CI]: 4.5% to 10.9% per year). Cancer was the only factor independently associated with 28-day fatality (relative risk [RR] = 5.2; 95% CI: 1.4 to 19.9) or recurrent thrombosis (RR = 9.2; 95% CI: 2.0 to 41.7).

CONCLUSION: The incidence of venous thromboembolism in this cohort of middle- and older-aged subjects was similar to that observed in more geographically homogeneous samples. Half of cases were idiopathic. Short-term mortality and 2-year recurrence rates were appreciable, especially among subjects with cancer. Based on this study we estimate that 187,000 cases of first-time venous thromboembolism are diagnosed yearly in the United States among those aged 45 years or older.

VL - 117 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15210384?dopt=Abstract ER - TY - JOUR T1 - Fish intake and risk of incident atrial fibrillation. JF - Circulation Y1 - 2004 A1 - Mozaffarian, Dariush A1 - Psaty, Bruce M A1 - Rimm, Eric B A1 - Lemaitre, Rozenn N A1 - Burke, Gregory L A1 - Lyles, Mary F A1 - Lefkowitz, David A1 - Siscovick, David S KW - Aged KW - Animals KW - Atrial Fibrillation KW - Cardiotonic Agents KW - Cohort Studies KW - Cooking KW - Diet KW - Dietary Fats KW - Fatty Acids, Omega-3 KW - Fish Oils KW - Fishes KW - Follow-Up Studies KW - Humans KW - Incidence KW - Massachusetts KW - Proportional Hazards Models KW - Prospective Studies KW - Risk KW - Seafood KW - Tuna AB -

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is particularly common in the elderly. Although effects of fish intake, including potential antiarrhythmic effects, may favorably influence risk of AF, relationships between fish intake and AF incidence have not been evaluated.

METHODS AND RESULTS: In a prospective, population-based cohort of 4815 adults > or =age 65 years, usual dietary intake was assessed at baseline in 1989 and 1990. Consumption of tuna and other broiled or baked fish correlated with plasma phospholipid long-chain n-3 fatty acids, whereas consumption of fried fish or fish sandwiches (fish burgers) did not. AF incidence was prospectively ascertained on the basis of hospital discharge records and annual electrocardiograms. During 12 years' follow-up, 980 cases of incident AF were diagnosed. In multivariate analyses, consumption of tuna or other broiled or baked fish was inversely associated with incidence of AF, with 28% lower risk with intake 1 to 4 times per week (HR=0.72, 95% CI=0.58 to 0.91, P=0.005), and 31% lower risk with intake > or =5 times per week (HR=0.69, 95% CI=0.52 to 0.91, P=0.008), compared with <1 time per month (P trend=0.004). Results were not materially different after adjustment for preceding myocardial infarction or congestive heart failure. In similar analyses, fried fish/fish sandwich consumption was not associated with lower risk of AF.

CONCLUSIONS: Among elderly adults, consumption of tuna or other broiled or baked fish, but not fried fish or fish sandwiches, is associated with lower incidence of AF. Fish intake may influence risk of this common cardiac arrhythmia.

VL - 110 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15262826?dopt=Abstract ER - TY - JOUR T1 - Mesenteric artery disease in the elderly. JF - J Vasc Surg Y1 - 2004 A1 - Hansen, Kimberley J A1 - Wilson, David B A1 - Craven, Timothy E A1 - Pearce, Jeffrey D A1 - English, William P A1 - Edwards, Matthew S A1 - Ayerdi, Juan A1 - Burke, Gregory L KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Arteriosclerosis KW - Celiac Artery KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Mesenteric Arteries KW - Mesenteric Artery, Superior KW - Mesenteric Vascular Occlusion KW - Prevalence KW - Ultrasonography, Doppler, Duplex KW - Weight Loss AB -

PURPOSE: The purpose of this study was to estimate the population-based prevalence of mesenteric artery stenosis (MAS) and occlusion among independent elderly Americans.

METHOD: As part of an ancillary investigation to the Cardiovascular Health Study (CHS), participants in the Forsyth County, NC cohort had visceral duplex sonography of the celiac arteries and superior mesenteric arteries (SMAs). Critical MAS was defined by celiac peak systolic velocity >or=2.0 m/s and/or SMA peak systolic velocity >or=2.7 m/s. Occlusion of either vessel was defined by lack of a Doppler-shifted signal within the imaged artery. Demographic data, blood pressures, and blood lipid levels were collected as part of the baseline CHS examination. Participants' weights were measured at baseline and before the duplex exam. Univariate tests of association were performed with two-way contingency tables, Student t tests, and Fisher exact tests. Multivariate associations were examined with logistic regression analysis.

RESULTS: A total of 553 CHS participants had visceral duplex sonography technically adequate to define the presence or absence of MAS. The study group had a mean age of 77.2 +/- 4.9 years and comprised 63% women and 37% men. Participant race was 76% white and 23% African-American. Ninety-seven participants (17.5%) had MAS. There was no significant difference in age, race, gender, body mass index, blood pressure, cholesterol, or low-density lipoproteins for participants with or without MAS. Forward stepwise variable selection found renal artery stenosis (P =.008; odds ratio [OR], 2.85; 95% confidence interval [CI], 1.31, 6.21) and high-density lipoprotein >40 (P =.02; OR, 3.03; 95% CI, 1.17, 7.81) significantly associated with MAS in a multivariate logistic regression model. Eighty-three of the 97 participants with MAS (15.0% of the cohort) had isolated celiac stenosis. Seven participants (1.3% of the cohort) had combined celiac and SMA stenosis. Five participants (0.9% of the cohort) had isolated SMA stenosis. Two participants (0.4% of the cohort) had celiac occlusion. Considering all participants with MAS, there was no association with weight change. However, SMA stenosis and celiac occlusion demonstrated an independent association with annualized weight loss (P =.028; OR, 1.54; 95% CI, 1.05, 2.26) and with renal artery stenosis (P =.001; OR, 9.48; 95% CI, 2.62, 34.47).

CONCLUSION: This investigation provides the first population-based estimate of the prevalence of MAS among independent elderly Americans. MAS existed in 17.5% of the study cohort. The majority had isolated celiac disease. SMA stenosis and celiac artery occlusion demonstrated a significant and independent association with weight loss and concurrent renal artery disease.

VL - 40 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15218461?dopt=Abstract ER - TY - JOUR T1 - Polysomnography performed in the unattended home versus the attended laboratory setting--Sleep Heart Health Study methodology. JF - Sleep Y1 - 2004 A1 - Iber, Conrad A1 - Redline, Susan A1 - Kaplan Gilpin, Adele M A1 - Quan, Stuart F A1 - Zhang, Lin A1 - Gottlieb, Daniel J A1 - Rapoport, David A1 - Resnick, Helaine E A1 - Sanders, Mark A1 - Smith, Philip KW - Adult KW - Aged KW - Body Mass Index KW - Clinical Laboratory Techniques KW - Cohort Studies KW - Health Status KW - Home Care Services KW - Humans KW - Middle Aged KW - Polysomnography KW - Sleep Apnea Syndromes KW - Sleep, REM AB -

STUDY OBJECTIVE: To compare polysomnographic recordings obtained in the home and laboratory setting.

DESIGN AND SETTING: Multicenter study comparing unsupervised polysomnography performed in the participant's home with polysomnography supervised at an academic sleep disorders center, using a randomized sequence of study setting. Sleep Heart Health Study (SHHS) standardized polysomnographic recording and scoring techniques were used for both settings.

PARTICIPANTS: 64 of 76 non-SHHS participants recruited from 7 SHHS field sites who had both a laboratory and home polysomnogram meeting acceptable quality criteria.

MEASUREMENTS AND RESULTS: Median sleep duration was greater in the home than in the laboratory (375 vs 318 minutes, respectively, P < .0001) as was sleep efficiency (86% vs 82%, respectively, P < .0024). Very small, but significant increases in percentage of rapid eye movement sleep and decreases in stage 1 sleep were noted in the laboratory. Employing multiple definitions of respiratory disturbance index (RDI), median RDI was similar in both settings (for example, RDI with 3% desaturation: home 12.4, range 0.6-67; laboratory 9.5, range 0.1-93.4, P = .41). Quartile analysis of laboratory RDI showed moderate agreement with home RDI measurements. Based on the mean of laboratory and home RDI and using a cutpoint of 20, there was a biphasic distribution, with the RDI 3% above 20 being more common in the recordings performed in the laboratory than in the home and below 20 being more common in the recordings performed in the home than in the laboratory. These differences could not be attributed to quality of recording, age, sex, or body mass index.

CONCLUSIONS: Using SHHS methodology, median RDI was similar in the unattended home and attended laboratory setting with differences of small magnitude in some sleep parameters. Differences in RDI between settings resulted in a rate of disease misclassification that is similar to repeated studies in the same setting.

VL - 27 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15164911?dopt=Abstract ER - TY - JOUR T1 - Preclinical Alzheimer disease: neuropsychological test performance 1.5 to 8 years prior to onset. JF - Neurology Y1 - 2004 A1 - Saxton, J A1 - Lopez, O L A1 - Ratcliff, G A1 - Dulberg, C A1 - Fried, L P A1 - Carlson, M C A1 - Newman, A B A1 - Kuller, L KW - Age of Onset KW - Alzheimer Disease KW - Cardiovascular Diseases KW - Cognition Disorders KW - Cohort Studies KW - Confounding Factors, Epidemiologic KW - Disease Progression KW - Early Diagnosis KW - Educational Status KW - Female KW - Follow-Up Studies KW - Humans KW - Male KW - Memory Disorders KW - Neuropsychological Tests KW - Predictive Value of Tests KW - Proportional Hazards Models KW - Risk KW - Sensitivity and Specificity KW - Time Factors AB -

OBJECTIVE: To determine if individuals ultimately diagnosed with Alzheimer disease (AD) exhibited evidence of cognitive impairment on neuropsychological tests administered between 1.5 years and 8.1 years before dementia onset.

METHODS: A total of 693 community-dwelling individuals, part of the Cardiovascular Health Study, completed a neuropsychological test battery in 1991/92. Subjects were followed annually over the next 8 years (median follow-up = 7.4 years). Seventy-two individuals were ultimately diagnosed with AD (median follow-up = 4.5 years): 24 with AD onset 1.5 to 3.4 years after baseline neuropsychological testing, 20 with AD onset 3.5 to 5.0 years after testing, and 28 with onset 5.1 to 8.1 years after testing. A total of 621 individuals remained nondemented throughout the 8 years of follow-up (median follow-up = 7.5 years).

RESULTS: Subjects ultimately diagnosed with AD had poorer scores on baseline neuropsychological measures than subjects who remained nondemented. Although individuals closest to AD onset (i.e., 1.5 to 3.4 years) performed the most poorly, cognitive impairment was detected in individuals who did not develop AD until 5 to 8 years later.

CONCLUSIONS: Cognitive changes can be detected well before onset of Alzheimer disease.

VL - 63 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15623697?dopt=Abstract ER - TY - JOUR T1 - Racial differences in endothelial function in postmenopausal women. JF - Am Heart J Y1 - 2004 A1 - Loehr, Laura R A1 - Espeland, Mark A A1 - Sutton-Tyrrell, Kim A1 - Burke, Gregory L A1 - Crouse, John R A1 - Herrington, David M KW - African Continental Ancestry Group KW - Aged KW - Brachial Artery KW - Cohort Studies KW - Endothelium, Vascular KW - European Continental Ancestry Group KW - Female KW - Humans KW - Multivariate Analysis KW - Postmenopause KW - Risk Factors KW - Vasodilation AB -

OBJECTIVE: Racial differences in cardiovascular mortality among women remain largely unexplained. Preliminary data suggest that African American and Caucasian differences in endothelial function may parallel differential cardiovascular disease (CVD) risk in women. To further study differences in endothelial function between African American and Caucasian women, we analyzed measures of brachial artery flow-mediated dilation (FMD) in women enrolled in the Cardiovascular Health Study (CHS).

METHODS AND RESULTS: Brachial artery FMD was measured in the fasting state using established ultrasound techniques in 1330 Caucasian and 297 African American female participants in CHS (mean age 78.4 +/- 4.4 years). General linear models were used to compare FMD between African American and Caucasian women after adjusting for baseline brachial diameter, hypertension, diabetes, smoking, cholesterol, systolic blood pressure, body mass index, waist/hip ratio, age, education, income level; use of angiotensin-converting enzyme inhibitors, beta-blockers, nitroglycerin, estrogens and lipid-lowering drugs; and presence of clinical or subclinical disease. Adjusted absolute change and percent change in brachial artery diameter was significantly reduced in African American women compared with Caucasian women (P <.0001 and P =.0002, respectively). Similar results were found when the women were stratified by history of CVD (- CVD, P =.02; + CVD, P =.001) and CVD or subclinical vascular disease (- disease, P =.01, + disease, P =.03).

CONCLUSIONS: In this cohort, brachial artery FMD was lower in African American women compared to Caucasian women, and this difference persisted after adjustment by multivariable analysis. The increased CVD risk in African American women may be related to impaired endothelial function. It remains to be determined whether African American women may uniquely benefit by interventions designed to improve endothelial health.

VL - 148 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15459590?dopt=Abstract ER - TY - JOUR T1 - The relationship of fasting serum radioimmune insulin levels to incident coronary heart disease in an insulin-treated diabetic cohort. JF - J Clin Endocrinol Metab Y1 - 2004 A1 - Kronmal, Richard A A1 - Barzilay, Joshua I A1 - Tracy, Russell P A1 - Savage, Peter J A1 - Orchard, Trevor J A1 - Burke, Gregory L KW - Aged KW - Cohort Studies KW - Coronary Disease KW - Diabetes Mellitus, Type 1 KW - Fasting KW - Female KW - Follow-Up Studies KW - Humans KW - Hypoglycemic Agents KW - Incidence KW - Insulin KW - Male KW - Radioimmunoassay KW - Risk Factors AB -

It is not known whether insulin levels, in the setting of insulin treatment, are an independent risk factor for coronary heart disease (CHD). We studied a cohort of 116 insulin-treated individuals, 65 yr or older, who were followed for 5.6-9 yr. All were free of CHD at baseline. There were 47 incident CHD events. In Cox proportional hazards modeling, with fasting immune-reactive insulin levels as a continuous variable, the hazard ratio for CHD was statistically significant (P < 0.0001). When insulin levels were divided into intervals, those in the third interval [43-150 microU/ml (258-900 pmol/liter)] had an adjusted 30% increased relative risk (95% confidence interval, 0.57, 2.98) compared with those in the first interval [<20 microU/ml (<120 pmol/liter)]. Those in the fourth interval [151-400 microU/ml (906-2400 pmol/liter)] had an adjusted 5.6-fold increased risk (2.3-13.1; P < 0.0001). Approximately 15% of the cohort had such elevated insulin levels. Immune-reactive insulin levels were strongly correlated with specific insulin, proinsulin, and insulin antibody levels. Markedly elevated fasting immune-reactive insulin levels were an independent risk factor for CHD in this study of insulin-treated older adults. These observational findings should be confirmed through larger prospective studies, given their implications for insulin therapy.

VL - 89 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15181068?dopt=Abstract ER - TY - JOUR T1 - Risk of congestive heart failure in an elderly population treated with peripheral alpha-1 antagonists. JF - J Am Geriatr Soc Y1 - 2004 A1 - Bryson, Chris L A1 - Smith, Nicholas L A1 - Kuller, Lewis H A1 - Chaves, Paulo H M A1 - Manolio, Teri A A1 - Lewis, William A1 - Boyko, Edward J A1 - Furberg, Curt D A1 - Psaty, Bruce M KW - Adrenergic alpha-Antagonists KW - Aged KW - Antihypertensive Agents KW - Benzothiadiazines KW - Blood Pressure KW - Cohort Studies KW - Diuretics KW - Female KW - Heart Failure KW - Humans KW - Hypertension KW - Male KW - Risk Factors KW - Sodium Chloride Symporter Inhibitors KW - United States AB -

OBJECTIVES: To compare the risk of congestive heart failure (CHF) in elderly individuals treated with any peripheral alpha-1 antagonist for hypertension with any thiazide, test whether the risk persists in subjects without cardiovascular disease (CVD) at baseline, and examine CHF risk in normotensive men with prostatism treated with alpha antagonists.

DESIGN: Prospective cohort study.

SETTING: Four U.S. sites: Washington County, Maryland; Allegheny County, Pennsylvania; Sacramento County, California; and Forsyth County, North Carolina.

PARTICIPANTS: A total of 5,888 community-dwelling subjects aged 65 and older.

MEASUREMENTS: Adjudicated incident CHF.

RESULTS: The 3,105 participants with treated hypertension were at risk for CHF; 22% of men and 8% of women took alpha antagonists during follow-up. The age-adjusted risk of CHF in those receiving monotherapy treated with alpha antagonists was 1.90 (95% confidence interval=1.03-3.50) compared with thiazides. In subjects without CVD at baseline receiving monotherapy, women taking an alpha antagonist had a 3.6 times greater age-adjusted risk of CHF, whereas men had no difference in risk. Adjustment for systolic blood pressure attenuated statistical differences in risk. There were 930 men without hypertension at risk for CHF; 5% used alpha antagonists during follow-up, with no observed increase in CHF risk.

CONCLUSION: Subjects receiving alpha antagonist monotherapy for hypertension had a two to three times greater risk of incident CHF, also seen in lower-risk subjects, but differences in blood pressure control partly explained this.

VL - 52 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15450040?dopt=Abstract ER - TY - JOUR T1 - Sleep and reported daytime sleepiness in normal subjects: the Sleep Heart Health Study. JF - Sleep Y1 - 2004 A1 - Walsleben, Joyce A A1 - Kapur, Vishesh K A1 - Newman, Anne B A1 - Shahar, Eyal A1 - Bootzin, Richard R A1 - Rosenberg, Carl E A1 - O'Connor, George A1 - Nieto, F Javier KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Circadian Rhythm KW - Cohort Studies KW - Disorders of Excessive Somnolence KW - Female KW - Health Status KW - Humans KW - Male KW - Middle Aged KW - Polysomnography KW - Sleep KW - Sleep Stages KW - Surveys and Questionnaires AB -

STUDY OBJECTIVES: To describe the distribution of nocturnal sleep characteristics and reports of daytime sleepiness in a large well-defined group of healthy adults.

DESIGN: The Sleep Heart Health Study is a multicenter study examining sleep and cardiopulmonary parameters through nocturnal polysomnography in adults enrolled in geographically distinct cardiovascular cohorts.

SETTING: Community setting.

PARTICIPANTS: 470 subjects enrolled in the Sleep Heart Health Study (n = 6440) were selected as a 'normative' group based on screening of health conditions and daily habits that could interfere with sleep.

MEASUREMENTS AND RESULTS: Home-based nocturnal polysomnography was obtained on all participants and centrally scored for sleep and respiratory parameters. Demographic and health-related data were obtained and updated at the time of the home visit. Sleep efficiency decreased by 1.6% for each 10 years of increased age. Sleep time decreased by 0.1 hours (6.0 minutes) for each 10-year age increase and was longer in women. The arousal index increased by 0.8 for each 10-year increase in age and was lower by 1.4 in women. Women had a lower mean percentage of stage 1 and stage 2 sleep. Mean percentage of slow-wave sleep was higher in women (by 6.7%). Percentage of slow-wave sleep decreased with increased age for men only (by 1.9% for each 10-year age change).

CONCLUSIONS: Data suggest a clear lessening in the quantity and quality of sleep with age that appears to be more rapid in males compared to females.

VL - 27 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15124725?dopt=Abstract ER - TY - JOUR T1 - Sleep apnea and markers of vascular endothelial function in a large community sample of older adults. JF - Am J Respir Crit Care Med Y1 - 2004 A1 - Nieto, F Javier A1 - Herrington, David M A1 - Redline, Susan A1 - Benjamin, Emelia J A1 - Robbins, John A KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Body Mass Index KW - Brachial Artery KW - Cardiovascular Diseases KW - Cohort Studies KW - Comorbidity KW - Endothelium, Vascular KW - Female KW - Humans KW - Hypertension KW - Linear Models KW - Male KW - Polysomnography KW - Prevalence KW - Probability KW - Residence Characteristics KW - Risk Assessment KW - Sampling Studies KW - Severity of Illness Index KW - Sleep Apnea Syndromes KW - Ultrasonography, Doppler AB -

Clinical studies have suggested that sleep apnea is associated with impaired brachial artery flow-mediated dilation, a surrogate of endothelial dysfunction. We examined this question among older participants in the baseline examination of the Sleep Heart Health/Cardiovascular Health Study cohort (n = 1,037, age 68 years or older, 56% female). Indices of sleep apnea, derived from 12-channel home polysomnography, were the apnea-hypopnea index (average number of apneas/hypopneas per hour) and the hypoxemia index (percentage of time below 90% O2 saturation). Baseline arterial diameter and percentage of flow-mediated dilation were measured by ultrasound. Sleep apnea measures were associated with baseline diameter and the percentage of flow-mediated dilation, although these associations were weakened after adjustment for other cardiovascular risk factors, particularly body mass index. However, a statistically significant linear association between the hypoxemia index and baseline diameter was observed even after adjustment for body mass index and other confounders (p < 0.01). The associations were stronger among participants who were younger than 80 years and among those who with hypertension. This study adds to the growing body of evidence linking sleep apnea with vascular dysfunction in older subjects. Whether these relationships are entirely independent of obesity is unclear. This association might be one of the mechanisms explaining the relationship between sleep apnea, hypertension, and cardiovascular disease.

VL - 169 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/14551166?dopt=Abstract ER - TY - JOUR T1 - Sleep-disordered breathing, glucose intolerance, and insulin resistance: the Sleep Heart Health Study. JF - Am J Epidemiol Y1 - 2004 A1 - Punjabi, Naresh M A1 - Shahar, Eyal A1 - Redline, Susan A1 - Gottlieb, Daniel J A1 - Givelber, Rachel A1 - Resnick, Helaine E KW - Aged KW - Blood Gas Analysis KW - Body Constitution KW - Body Mass Index KW - Cohort Studies KW - Confounding Factors, Epidemiologic KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Glucose Intolerance KW - Glucose Tolerance Test KW - Humans KW - Insulin Resistance KW - Linear Models KW - Male KW - Middle Aged KW - Multivariate Analysis KW - Oxyhemoglobins KW - Polysomnography KW - Research Design KW - Risk Factors KW - Severity of Illness Index KW - Sleep Apnea Syndromes AB -

Clinic-based studies suggest that sleep-disordered breathing (SDB) is associated with glucose intolerance and insulin resistance. However, in the available studies, researchers have not rigorously controlled for confounding variables to assess the independent relation between SDB and impaired glucose metabolism. The objective of this study was to determine whether SDB was associated with glucose intolerance and insulin resistance among community-dwelling subjects (n=2,656) participating in the Sleep Heart Health Study (1994-1999). SDB was characterized with the respiratory disturbance index and measurements of oxygen saturation during sleep. Fasting and 2-hour glucose levels measured during an oral glucose tolerance test were used to assess glycemic status. Relative to subjects with a respiratory disturbance index of less than 5.0 events/hour (the reference category), subjects with mild SDB (5.0-14.9 events/hour) and moderate to severe SDB (> or =15 events/hour) had adjusted odds ratios of 1.27 (95% confidence interval: 0.98, 1.64) and 1.46 (95% confidence interval: 1.09, 1.97), respectively, for fasting glucose intolerance (p for trend < 0.01). Sleep-related hypoxemia was also associated with glucose intolerance independently of age, gender, body mass index, and waist circumference. The results of this study suggest that SDB is independently associated with glucose intolerance and insulin resistance and may lead to type 2 diabetes mellitus.

VL - 160 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15353412?dopt=Abstract ER - TY - JOUR T1 - Stroke risk factors and loss of high cognitive function. JF - Neurology Y1 - 2004 A1 - Elkins, J S A1 - O'Meara, E S A1 - Longstreth, W T A1 - Carlson, M C A1 - Manolio, T A A1 - Johnston, S C KW - Aged KW - Aged, 80 and over KW - Aging KW - Cognition Disorders KW - Cohort Studies KW - Comorbidity KW - Female KW - Follow-Up Studies KW - Higher Nervous Activity KW - Humans KW - Incidence KW - Male KW - Risk Assessment KW - Risk Factors KW - Sampling Studies KW - Sensitivity and Specificity KW - Severity of Illness Index KW - Stroke KW - United States AB -

BACKGROUND: Modifiable stroke risk factors may contribute to age-associated declines in cognitive function. Individuals with high levels of cognitive function after midlife may have less exposure to these stroke risk factors or may be less susceptible to their effects on cognition.

METHODS: The Cardiovascular Health Study (CHS)* is a population-based, longitudinal cohort study of 5,888 people age 65 years and older. Participants (n = 4,129) who were free of dementia, stroke, or TIA at the time of baseline cranial MRI were selected for analysis. High cognitive function at baseline was defined by performance at or above midlife norms on the Modified Mini-Mental State Examination (3MS).

RESULTS: The odds of having high cognitive function at baseline decreased by quartile of stroke risk (highest vs lowest risk quartile, adjusted odds ratio [OR] 0.68; 95% CI 0.52 to 0.88; p for trend = 0.005). Stroke risk was a predictor of decline on the 3MS in those with typical levels of cognitive function at baseline, even in the absence of incident stroke or TIA (highest vs lowest risk quartile for 3MS decline, adjusted OR 2.11; 95% CI 1.42 to 3.13; p for trend < 0.001). In contrast, stroke risk was not associated with decline on the 3MS in those with high cognitive function at baseline (p = 0.03 for interaction).

CONCLUSIONS: In a cohort of older adults without stroke, TIA, or dementia, cognitive function and incident cognitive decline were associated with risk for stroke. Additional studies are needed to determine whether modification of stroke risk factors can reduce the cognitive decline that is often attributed to normal aging.

VL - 63 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15365125?dopt=Abstract ER - TY - JOUR T1 - Survival associated with two sets of diagnostic criteria for congestive heart failure. JF - Am J Epidemiol Y1 - 2004 A1 - Schellenbaum, Gina D A1 - Rea, Thomas D A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Lumley, Thomas A1 - Roger, Veronique L A1 - Kitzman, Dalane W A1 - Taylor, Herman A A1 - Levy, Daniel A1 - Psaty, Bruce M KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Diagnosis, Differential KW - Female KW - Follow-Up Studies KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Prognosis KW - Severity of Illness Index KW - Survival Analysis AB -

Congestive heart failure (CHF) definitions vary across epidemiologic studies. The Framingham Heart Study criteria include CHF signs and symptoms assessed by a physician panel. In the Cardiovascular Health Study, a committee of physicians adjudicated CHF diagnoses, confirmed by signs, symptoms, clinical tests, and/or medical therapy. The authors used data from the Cardiovascular Health Study, a population-based cohort study of 5,888 elderly US adults, to compare CHF incidence and survival patterns following onset of CHF as defined by Framingham and/or Cardiovascular Health Study criteria. They constructed an inception cohort of nonfatal, hospitalized CHF patients. Of 875 participants who had qualifying CHF hospitalizations between 1989 and 2000, 54% experienced a first CHF event that fulfilled both sets of diagnostic criteria (concordant), 31% fulfilled only the Framingham criteria (Framingham only), and 15% fulfilled only the Cardiovascular Health Study criteria (Cardiovascular Health Study only). No significant survival difference was found between the Framingham-only group (hazard ratio = 0.87, 95% confidence interval: 0.71, 1.07) or the Cardiovascular Health Study-only group (hazard ratio = 0.89, 95% confidence interval: 0.68, 1.15) and the concordant group (referent). Compared with Cardiovascular Health Study central adjudication, Framingham criteria for CHF identified a larger group of participants with incident CHF, but all-cause mortality rates were similar across these diagnostic classifications.

VL - 160 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15383406?dopt=Abstract ER - TY - JOUR T1 - Time trends in the use of beta-blockers and other pharmacotherapies in older adults with congestive heart failure. JF - Am Heart J Y1 - 2004 A1 - Smith, Nicholas L A1 - Chan, Jeannie D A1 - Rea, Thomas D A1 - Wiggins, Kerri L A1 - Gottdiener, John S A1 - Lumley, Thomas A1 - Psaty, Bruce M KW - Adrenergic beta-Antagonists KW - Aged KW - Angiotensin II Type 1 Receptor Blockers KW - Angiotensin-Converting Enzyme Inhibitors KW - Cohort Studies KW - Drug Therapy KW - Drug Therapy, Combination KW - Female KW - Heart Failure KW - Humans KW - Male KW - Multivariate Analysis KW - Prevalence AB -

BACKGROUND: Evidence supporting pharmacotherapy of congestive heart failure (CHF) has grown substantially over the past decade and includes large, placebo-controlled trials with mortality end points. We describe beta-blocker and other medication temporal treatment trends of CHF in the Cardiovascular Health Study, a community-based cohort study of 5888 adults > or =65 years of age.

METHODS: Prescription medication data were collected from hospital discharge summaries for incident CHF events and at in-study annual clinic visits for prevalent CHF cases from 1989 to 2000. Change in use of agents over time was estimated by using generalized estimating equations while adjusting for potential confounding factors of age, sex, race, and cardiovascular and pulmonary comorbidities.

RESULTS: Among 1033 incident CHF events, beta-blocker use after diagnosis increased an average of 2.4 percentage points annually (95% CI, 1.5 to 3.4 points) from 1989 to 2000. The increasing trend was consistent throughout follow-up. Among participants with coronary disease and/or hypertension and among those with low ejection fractions (<45%), beta-blocker use remained flat from 1989 to 1994 and increased 4.7 points annually (2.5 to 6.9) and 10.0 points annually (6.1 to 13.8), respectively, from 1995 to 2000. Among participants without coronary disease or hypertension, there was no overall increase in use. Use of renin-angiotensin system inhibitors increased 2.3 points annually (1.0 to 3.5), digoxin use decreased 2.4 points annually (-3.6 to -1.1), and loop diuretic use remained flat between 1989 and 2000. In general, treatment trends were similar for prevalent CHF.

CONCLUSIONS: Treatment of CHF has changed gradually in the 1990s and may in part reflect the influence of CHF clinical trial evidence.

VL - 148 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15459605?dopt=Abstract ER - TY - JOUR T1 - Traditional and novel risk factors in older adults: cardiovascular risk assessment late in life. JF - Am J Geriatr Cardiol Y1 - 2004 A1 - Mukamal, Kenneth J A1 - Kronmal, Richard A A1 - Tracy, Russell P A1 - Cushman, Mary A1 - Siscovick, David S KW - Aged KW - Blood Coagulation Factors KW - Cardiovascular Diseases KW - Cohort Studies KW - Diabetes Complications KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Hypertension KW - Infections KW - Inflammation KW - Lipids KW - Longitudinal Studies KW - Male KW - Obesity KW - Predictive Value of Tests KW - Risk Factors KW - Smoking KW - United States AB -

As a population-based, longitudinal study of nearly 6000 older American adults, the Cardiovascular Health Study provides an excellent opportunity to assess the roles of traditional and novel cardiovascular risk factors in the development of coronary heart disease. Cardiovascular Health Study investigators have analyzed both traditional risk factors, such as diabetes, hypertension, and smoking, and new risk factors, such as hemostatic factors, inflammatory markers, exposure to infectious agents, and genetic determinants. These analyses have led to several important conclusions. First, older adults without previous cardiovascular events have a tremendous burden of subclinical vascular disease, which may change how physicians view risk factor modification in this age group. Second, some traditional cardiovascular risk factors lose importance as predictors of cardiovascular disease among older adults. Third, even modest elevations in fasting blood glucose or systolic blood pressure-below the levels used to define diabetes or hypertension-may have prognostic implications. Fourth, novel cardiovascular risk factors may add further information about cardiovascular disease risk in older adults. Promising potential candidates identified in the Cardiovascular Health Study include markers of hemostatic activation, fibrinogen, factor VIII coagulant activity, C-reactive protein, and exposure to herpes simplex virus-1 and possibly chlamydia. Future Cardiovascular Health Study investigations will help to clarify which combination of traditional and newer risk factors provides the best estimate of cardiovascular risk for older adults.

VL - 13 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15010653?dopt=Abstract ER - TY - JOUR T1 - Alcohol use and risk of ischemic stroke among older adults: the cardiovascular health study. JF - Stroke Y1 - 2005 A1 - Mukamal, Kenneth J A1 - Chung, Hyoju A1 - Jenny, Nancy S A1 - Kuller, Lewis H A1 - Longstreth, W T A1 - Mittleman, Murray A A1 - Burke, Gregory L A1 - Cushman, Mary A1 - Beauchamp, Norman J A1 - Siscovick, David S KW - Aged KW - Alcohol Drinking KW - Apolipoproteins E KW - Brain Infarction KW - Brain Ischemia KW - Cohort Studies KW - Female KW - Follow-Up Studies KW - Genetic Predisposition to Disease KW - Genotype KW - Humans KW - Hypertension KW - Inflammation KW - Ischemia KW - Lipids KW - Male KW - Middle Aged KW - Multivariate Analysis KW - Myocardial Infarction KW - Prospective Studies KW - Risk KW - Risk Factors KW - Stroke KW - Substance-Related Disorders KW - Thrombosis KW - Time Factors KW - Vascular Diseases AB -

BACKGROUND AND PURPOSE: The association of light to moderate alcohol consumption with risk of ischemic stroke remains uncertain, as are the roles of potentially mediating factors and modification by apolipoprotein E (apoE) genotype.

METHODS: We studied the prospective association of alcohol consumption and risk of ischemic stroke among 4410 participants free of cardiovascular disease at baseline in the Cardiovascular Health Study, a population-based cohort study of older adults from 4 US communities. Participants reported their consumption of alcoholic beverages yearly.

RESULTS: During an average follow-up period of 9.2 years, 434 cases of incident ischemic stroke occurred. Compared with long-term abstainers, the multivariate relative risks of ischemic stroke were 0.85 (95% CI, 0.63 to 1.13), 0.75 (95% CI, 0.53 to 1.06), 0.82 (95% CI, 0.51 to 1.30), and 1.03 (95% CI, 0.68 to 1.57) among consumers of <1, 1 to 6, 7 to 13, and > or =14 drinks per week (P quadratic trend 0.06). ApoE genotype appeared to modify the alcohol-ischemic stroke relationship (P interaction 0.08), with generally lower risks among drinkers than abstainers in apoE4-negative participants but higher risks among drinkers than abstainers among apoE4-positive participants. We could not identify candidate mediators among lipid, inflammatory, and prothrombotic factors.

CONCLUSIONS: In this study of older adults, the association of alcohol use and risk of ischemic stroke was U-shaped, with modestly lower risk among consumers of 1 to 6 drinks per week. However, apoE genotype may modify this association, and even moderate alcohol intake may be associated with an increased risk of ischemic stroke among apoE4-positive older adults.

VL - 36 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16081863?dopt=Abstract ER - TY - JOUR T1 - Association between screening for osteoporosis and the incidence of hip fracture. JF - Ann Intern Med Y1 - 2005 A1 - Kern, Lisa M A1 - Powe, Neil R A1 - Levine, Michael A A1 - Fitzpatrick, Annette L A1 - Harris, Tamara B A1 - Robbins, John A1 - Fried, Linda P KW - Absorptiometry, Photon KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Female KW - Hip Fractures KW - Humans KW - Incidence KW - Male KW - Mass Screening KW - Osteoporosis KW - Risk Factors KW - Sensitivity and Specificity AB -

BACKGROUND: Because direct evidence for the effectiveness of screening is lacking, guidelines disagree on whether people should be screened for osteoporosis.

OBJECTIVE: To determine whether population-based screening for osteoporosis in older adults is associated with fewer incident hip fractures than usual medical care.

DESIGN: Nonconcurrent cohort study.

SETTING: Population-based cohort enrolled in the Cardiovascular Health Study (CHS) from 4 states (California, Pennsylvania, Maryland, and North Carolina).

PATIENTS: 3107 adults 65 years of age and older who attended their CHS study visits in 1994-1995.

MEASUREMENTS: 31 participant characteristics (including demographic characteristics, medical histories, medications, and physical examination findings) and incident hip fractures over 6 years of follow-up.

INTERVENTION: Bone density scans (dual-energy x-ray absorptiometry [DEXA] at the hip) for participants in California and Pennsylvania (n = 1422) and usual care for participants in Maryland and North Carolina (n = 1685).

RESULTS: The incidence of hip fractures per 1000 person-years was 4.8 in the screened group and 8.2 in the usual care group. Screening was associated with a statistically significant lower hazard of hip fracture than usual care after adjustment for sex and propensity to be screened (Cox proportional hazard ratio, 0.64 [95% CI, 0.41 to 0.99]).

LIMITATIONS: The mechanism of the association was unclear. A small unmeasured confounder that decreased the hazard of hip fracture could diminish or erase the observed association.

CONCLUSIONS: Use of hip DEXA scans to screen for osteoporosis in older adults was associated with 36% fewer incident hip fractures over 6 years compared with usual medical care. Further research is needed to explore the mechanism of this association.

VL - 142 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15684205?dopt=Abstract ER - TY - JOUR T1 - Associations between retinal microvascular abnormalities and declining renal function in the elderly population: the Cardiovascular Health Study. JF - Am J Kidney Dis Y1 - 2005 A1 - Edwards, Matthew S A1 - Wilson, David B A1 - Craven, Timothy E A1 - Stafford, Jeanette A1 - Fried, Linda F A1 - Wong, Tien Y A1 - Klein, Ronald A1 - Burke, Gregory L A1 - Hansen, Kimberley J KW - African Americans KW - Aged KW - Aged, 80 and over KW - Aging KW - Antihypertensive Agents KW - Capillaries KW - Cohort Studies KW - Comorbidity KW - Creatinine KW - Diabetes Mellitus KW - Disease Progression KW - European Continental Ancestry Group KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Hypertension KW - Kidney KW - Male KW - Photography KW - Prospective Studies KW - Proteinuria KW - Retina KW - Retinal Diseases KW - Retinal Vessels AB -

BACKGROUND: Microvascular abnormalities in the kidney are common histopathologic findings in individuals with chronic kidney disease or renal failure. These abnormalities may represent one manifestation of ongoing systemic microvascular damage. We hypothesized that retinal microvascular abnormalities, when present, would be associated with progressive renal dysfunction in elderly individuals.

METHODS: The Cardiovascular Health Study (CHS) is a prospective, multicenter, cohort study initiated in 1989 designed to examine cardiovascular risk factors, morbidity, and mortality in elderly Americans. As part of an ancillary study, CHS participants underwent retinal photography in 1997 and 1998. Retinal microvascular abnormalities were assessed and graded by using standardized measures. Retinal microvascular abnormalities were defined as retinopathy (hard and soft exudates, hemorrhages, or microaneurysms) and/or retinal arteriolar abnormalities (arteriovenous nicking, focal arteriolar narrowing, or lowest quartile arteriole-venule ratio). Associations between these abnormalities and observed 4-year changes in serum creatinine levels and estimated glomerular filtration rates (eGFRs) from study years 5 to 9 (encompassing years 1994 to 2001) were examined by using regression modeling.

RESULTS: A total of 1,394 CHS participants had retinal and serum creatinine data. After adjustments for age, race, sex, weight, diabetes, hypertension, angiotensin-converting enzyme inhibitor use, and proteinuria, participants with retinopathy showed a significant increase in serum creatinine level and decline in eGFR compared with those without retinopathy during the 4-year study period (+0.24 mg/dL [+21 micromol/L] versus -0.21 mg/dL [-19 micromol/L] and -0.48 mL/min/1.73 m2 [-0.01 mL/s/1.73 m2] versus +1.74 mL/min/1.73 m2 [+0.03 mL/s/1.73 m2], respectively). Participants with retinopathy also were significantly more likely to have an observed significant deterioration in renal function, defined as a 0.3-mg/dL (27-micromol/L) increase in serum creatinine level or 20% or greater decline in eGFR (odds ratio, 3.20; 95% confidence interval, 1.58 to 6.50; and odds ratio, 2.84; 95% confidence interval, 1.56 to 5.16, respectively). These associations remained in separate stratified analyses of patients with and without diabetes. The presence of retinal arteriolar abnormalities was not associated with deteriorating renal function.

CONCLUSION: Retinal microvascular abnormalities defined as retinopathy were significantly associated with renal function deterioration. The observed findings were independent of effects of any associated diabetes or hypertension. These findings suggest that systemic microvascular disease may be associated with progressive renal dysfunction in the elderly population.

VL - 46 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16112039?dopt=Abstract ER - TY - JOUR T1 - Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4. JF - Neurology Y1 - 2005 A1 - Huang, T L A1 - Zandi, P P A1 - Tucker, K L A1 - Fitzpatrick, A L A1 - Kuller, L H A1 - Fried, L P A1 - Burke, G L A1 - Carlson, M C KW - Aged KW - Alzheimer Disease KW - Apolipoprotein E4 KW - Apolipoproteins E KW - Cohort Studies KW - Dementia KW - Dietary Fats, Unsaturated KW - Fatty Acids, Omega-3 KW - Feeding Behavior KW - Female KW - Fish Oils KW - Fish Products KW - Food, Formulated KW - Genetic Predisposition to Disease KW - Humans KW - Incidence KW - Male KW - Risk Factors KW - Socioeconomic Factors KW - Surveys and Questionnaires AB -

OBJECTIVE: To compare associations of lean fish vs fatty fish (tuna or other fish) intake with dementia, Alzheimer disease (AD), and vascular dementia (VaD) and in relation to APOE epsilon4 status in the Cardiovascular Health Cognition Study (CHCS).

METHODS: Fish intake was assessed by food frequency questionnaires. Incident dementia, AD, and VaD were determined through a series of cognitive tests, physician's assessment, and committee consensus. We used Cox proportional hazards regression to calculate hazard ratios of dementia, AD, and VaD with lean fried fish, fatty fish, or total fish intake, which were then stratified by the presence of APOE epsilon4.

RESULTS: Although consumption of lean fried fish had no protective effect, consumption of fatty fish more than twice per week was associated with a reduction in risk of dementia by 28% (95% CI: 0.51 to 1.02), and AD by 41% (95% CI: 0.36 to 0.95) in comparison to those who ate fish less than once per month. Stratification by APOE epsilon4 showed this effect to be selective to those without the epsilon4 allele. Adjustment by education and income attenuated the effect.

CONCLUSION: In the Cardiovascular Health Cognition Study, consumption of fatty fish was associated with a reduced risk of dementia and Alzheimer disease for those without the APOE epsilon4 allele.

VL - 65 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16275829?dopt=Abstract ER - TY - JOUR T1 - Classification of vascular dementia in the Cardiovascular Health Study Cognition Study. JF - Neurology Y1 - 2005 A1 - Lopez, O L A1 - Kuller, L H A1 - Becker, J T A1 - Jagust, W J A1 - DeKosky, S T A1 - Fitzpatrick, A A1 - Breitner, J A1 - Lyketsos, C A1 - Kawas, C A1 - Carlson, M KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Brain KW - Cerebral Arteries KW - Cohort Studies KW - Dementia, Vascular KW - Diagnosis, Differential KW - Disease Progression KW - Female KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Predictive Value of Tests KW - Stroke KW - United States AB -

OBJECTIVE: To describe the diagnostic classification of subjects with incident vascular dementia (VaD) participating in the Cardiovascular Health Study (CHS) Cognition Study.

METHODS: The CHS classified 480 incident cases between 1994 and 1999 among 3,608 CHS participants who had brain MRI in 1992 through 1994 and in 1997 through 1998. The patients were diagnosed before and after reviewing the brain MRI.

RESULTS: The pre-MRI classification showed that 52 participants had VaD and 76 had both Alzheimer disease (AD) and VaD. The post-MRI classification showed that the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) criteria classified 61 subjects as having VaD, the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria classified 43 subjects as having probable VaD and 10 as possible VaD, and the State of California Alzheimer's Disease Diagnostic and Treatment Center (ADDTC) criteria classified 117 as having probable VaD and 96 as possible. The combination of the ADDTC and National Institute of Neurological and Communication Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria was used to examine the spectrum of vascular disease in dementia. The dementia was attributable to only vascular factors in 56 cases (probable VaD); VaD coexisted with AD in 61 cases, although the VaD component was the leading cause of dementia (probable VaD with AD); AD was the leading cause of dementia in 61 cases (possible VaD and probable AD); and in 29 cases, it was not clear that either AD or VaD was the primary diagnosis (possible AD and possible VaD).

CONCLUSIONS: None of the clinical criteria for VaD identified the same group of subjects. The diagnosis of vascular dementia is difficult in epidemiologic studies because poststroke dementia can be due to Alzheimer disease (AD) and evidence of vascular disease can be found in the MRI of dementia cases without clinical strokes. Whether the clinical progression is related to AD pathology or vascular disease is difficult to establish.

VL - 64 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15883314?dopt=Abstract ER - TY - JOUR T1 - Common promoter polymorphisms of inflammation and thrombosis genes and longevity in older adults: the cardiovascular health study. JF - Atherosclerosis Y1 - 2005 A1 - Reiner, Alexander P A1 - Diehr, Paula A1 - Browner, Warren S A1 - Humphries, Stephen E A1 - Jenny, Nancy S A1 - Cushman, Mary A1 - Tracy, Russell P A1 - Walston, Jeremy A1 - Lumley, Thomas A1 - Newman, Anne B A1 - Kuller, Lewis H A1 - Psaty, Bruce M KW - Aged KW - Aging KW - Carboxypeptidase B2 KW - Cause of Death KW - Cohort Studies KW - Female KW - Genotype KW - Health Status KW - Humans KW - Inflammation KW - Longevity KW - Male KW - Middle Aged KW - Plasminogen Activator Inhibitor 1 KW - Polymorphism, Genetic KW - Promoter Regions, Genetic KW - Prospective Studies KW - Risk Factors KW - Thrombosis AB -

Inflammatory response genes may influence life span or quality at advanced ages. Using data from the population-based cardiovascular health study (CHS) cohort, we examined the associations between promoter polymorphisms of several inflammation and thrombosis genes with longevity. We ascertained genotypes for interleukin (IL)-6 -174 G/C, beta-fibrinogen -455 G/A, plasminogen activator inhibitor (PAI)-1 -675 4G/5G, and thrombin-activatable fibrinolysis inhibitor (TAFI) -438 G/A in 2224 men and women > or = 65 years old at baseline. During 10 years of follow-up, men with the TAFI -438 A/A genotype had decreased mortality due to all causes, and lived, on average, 0.9 more years of life, or 1.1 more years of healthy life, than men with the -438 G allele. The effects of TAFI -438 G/A in women were smaller and not statistically significant. PAI-1 4G/4G genotype appeared to be associated with lower non-cardiovascular mortality in men, but with greater cardiovascular mortality in women. In exploratory analyses, we observed a possible interaction among anti-inflammatory drugs, interleukin-6 -174 C/C genotype, and longevity. These findings suggest that modulators of fibrinolytic activity may have a generalized influence on aging, and merit further investigation in studies of genetic determinants of human longevity.

VL - 181 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15939070?dopt=Abstract ER - TY - JOUR T1 - Cystatin C and incident peripheral arterial disease events in the elderly: results from the Cardiovascular Health Study. JF - Arch Intern Med Y1 - 2005 A1 - O'Hare, Ann M A1 - Newman, Anne B A1 - Katz, Ronit A1 - Fried, Linda F A1 - Stehman-Breen, Catherine O A1 - Seliger, Stephen L A1 - Siscovick, David S A1 - Shlipak, Michael G KW - Aged KW - Cohort Studies KW - Cystatin C KW - Cystatins KW - Female KW - Health Surveys KW - Humans KW - Longitudinal Studies KW - Male KW - Peripheral Vascular Diseases KW - Predictive Value of Tests KW - Risk Factors KW - ROC Curve KW - United States AB -

BACKGROUND: The association of cystatin C, a novel marker of renal function, with risk for developing complications related to peripheral arterial disease (PAD) has not been examined.

METHODS: We evaluated the hypothesis that a high cystatin C concentration is independently associated with future PAD events among 4025 participants in the Cardiovascular Health Study who underwent serum cystatin C measurement at the 1992-1993 visit and who did not have PAD at baseline. The association of cystatin C quintiles with time to first lower-extremity PAD procedure (bypass surgery, angioplasty, or amputation) was evaluated using multivariable proportional hazards models. Secondary analyses were conducted using quintiles of serum creatinine level and estimated glomerular filtration rate (eGFR).

RESULTS: The annualized risk of undergoing a procedure for PAD was 0.43% per year among participants in the highest cystatin C quintile (>1.27 mg/L) compared with 0.21% per year or less in all other quintiles. After multivariable adjustment for known risk factors for PAD, elevated cystatin C levels remained associated with the outcome (hazard ratio, 2.5 for highest vs lowest quintile of cystatin C, 95% confidence interval, 1.2-5.1). The highest quintiles of serum creatinine level and eGFR were not associated with future PAD events in either unadjusted or adjusted analyses.

CONCLUSION: Elevated concentrations of cystatin C were independently predictive of incident PAD events among community-dwelling elderly patients.

VL - 165 IS - 22 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16344426?dopt=Abstract ER - TY - JOUR T1 - Dementia and Alzheimer's disease incidence in relationship to cardiovascular disease in the Cardiovascular Health Study cohort. JF - J Am Geriatr Soc Y1 - 2005 A1 - Newman, Anne B A1 - Fitzpatrick, Annette L A1 - Lopez, Oscar A1 - Jackson, Sharon A1 - Lyketsos, Constantine A1 - Jagust, William A1 - Ives, Diane A1 - DeKosky, Steven T A1 - Kuller, Lewis H KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Cardiovascular Diseases KW - Cohort Studies KW - Coronary Disease KW - Dementia KW - Female KW - Humans KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Peripheral Vascular Diseases KW - Risk Factors AB -

OBJECTIVES: To determine whether coronary artery disease, peripheral arterial disease (PAD), or noninvasive markers of cardiovascular disease (CVD) predict the onset of dementia and Alzheimer's disease (AD).

DESIGN: Longitudinal cohort study.

SETTING: Four U.S. communities.

PARTICIPANTS: Men and women (N=3,602) with a brain magnetic resonance imaging (MRI) scan but no dementia were followed for 5.4 years. Participants with stroke were excluded.

MEASUREMENTS: Neurologists and psychiatrists classified incident cases of dementia and subtype using neuropsychological tests, examination, medical records and informant interviews. CVD was defined at the time of the MRI scan. Noninvasive tests of CVD were assessed within 1 year of the MRI. Apolipoprotein E allele status, age, race, sex, education, Mini-Mental State Examination score, and income were assessed as potential confounders.

RESULTS: The incidence of dementia was higher in those with prevalent CVD, particularly in the subgroup with PAD. The rate of AD was 34.4 per 1,000 person-years for those with a history of CVD, versus 22.2 per 1,000 person-years without a history of CVD (adjusted hazard ratio (HR)=1.3, 95% confidence interval (CI)=1.0-1.7). Rates of AD were highest in those with PAD (57.4 vs 23.7 per 100 person-years, adjusted HR=2.4, 95% CI=1.4-4.2). Results were similar with further exclusion of those with vascular dementia from the AD group. A gradient of increasing risk was noted with the extent of vascular disease.

CONCLUSION: Older adults with CVD other than stroke had a higher risk of dementia and AD than did those without CVD. The risk was highest in people with PAD, suggesting that extensive peripheral atherosclerosis is a risk factor for AD.

VL - 53 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16108925?dopt=Abstract ER - TY - JOUR T1 - Determinants of vascular dementia in the Cardiovascular Health Cognition Study. JF - Neurology Y1 - 2005 A1 - Kuller, L H A1 - Lopez, O L A1 - Jagust, W J A1 - Becker, J T A1 - DeKosky, S T A1 - Lyketsos, C A1 - Kawas, C A1 - Breitner, J C S A1 - Fitzpatrick, A A1 - Dulberg, C KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Atrophy KW - Brain KW - Cardiovascular Diseases KW - Cerebral Arteries KW - Cerebral Infarction KW - Cohort Studies KW - Comorbidity KW - Continental Population Groups KW - Dementia, Vascular KW - Female KW - Humans KW - Lateral Ventricles KW - Magnetic Resonance Imaging KW - Male KW - Nerve Fibers, Myelinated KW - Neuropsychological Tests KW - Risk Factors KW - Sex Factors AB -

OBJECTIVE: The authors evaluated 3,375 participants without dementia at the time of MRI in 1991 to 1994 over 5.7 years for incident dementia and type of dementia.

METHODS: Incidence of and risk factors for vascular dementia (VaD) were measured using both pre-MRI and modified State of California Alzheimer's Disease Diagnostic and Treatment Centers (ADDTC) post-MRI review and further classified Alzheimer disease (AD) by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association (NINCDS-ADRDA) criteria.

RESULTS: Approximately 44% (213) of 480 incident dementia cases were classified as possible or probable VaD by ADDTC. The incidence of VaD increased with age and was greater in blacks than whites. Risk factors for VaD included age, Modified Mini-Mental State Examination, high white matter grade, number of MRI infarcts, ventricular size, and history of stroke.

CONCLUSIONS: Vascular disease in the brain is prevalent among incident dementia cases. There is a substantial overlap between cases classified as Alzheimer disease by Neurological and Communicative Disorders and Stroke and the Alzheimer's Disease and Related Disorders Association and vascular dementia (VaD) by modified State of California Alzheimer's Disease Diagnostic and Treatment Centers criteria. The substantial contribution of vascular disease would be missed without inclusion of MRI. Treatment of risk factors for VaD could have an important impact on incidence of dementia.

VL - 64 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15883315?dopt=Abstract ER - TY - JOUR T1 - Factors associated with incidence and persistence of symptoms of disturbed sleep in an elderly cohort: the Cardiovascular Health Study. JF - Am J Med Sci Y1 - 2005 A1 - Quan, Stuart F A1 - Katz, Ronit A1 - Olson, Jean A1 - Bonekat, William A1 - Enright, Paul L A1 - Young, Terry A1 - Newman, Anne KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Depression KW - Female KW - Health Status KW - Humans KW - Incidence KW - Logistic Models KW - Male KW - Odds Ratio KW - Prevalence KW - Risk Factors KW - Sex Factors KW - Sleep Initiation and Maintenance Disorders KW - Surveys and Questionnaires AB -

BACKGROUND: There are limited data pertaining to the factors influencing the incidence and persistence of sleep symptoms in the elderly. The purpose of this study was to determine the incidence and nonremission rates of the following sleep symptoms: trouble falling asleep (TFA), frequent awakenings (FA), and excessive daytime sleepiness (EDS) in the Cardiovascular Health Study (CHS), a prospective multicenter study of cardiovascular disease in a large cohort of elderly adults. Factors influencing these rates were assessed as well.

METHODS: 4467 participants in CHS were surveyed for the presence of TFA, FA, and EDS as well as other health problems at their baseline examination and at a follow-up examination 1 to 4 years later.

RESULTS: Annualized incidence and nonremission rates were the following: TFA (2.8% and 15.4%), FA (12.3% and 22.7%), and EDS (4.4% and 13.4%). Women were more likely to have incident and persistent TFA. Depression was the primary factor predicting the incidence of all three sleep symptoms. However, other health conditions, including respiratory symptoms and cardiovascular disease, and limitation in activities of daily living were important as well. Depression also was the most important factor associated with persistence of these sleep symptoms. The role of other health conditions in determining nonremission was much more limited.

CONCLUSIONS: Incidence of sleep disturbances in the elderly is related to depression, health conditions, and physical functioning. However, persistence of sleep disturbances is best predicted by the presence of depression.

VL - 329 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15832098?dopt=Abstract ER - TY - JOUR T1 - Fish consumption and stroke risk in elderly individuals: the cardiovascular health study. JF - Arch Intern Med Y1 - 2005 A1 - Mozaffarian, Dariush A1 - Longstreth, W T A1 - Lemaitre, Rozenn N A1 - Manolio, Teri A A1 - Kuller, Lewis H A1 - Burke, Gregory L A1 - Siscovick, David S KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Animals KW - Cohort Studies KW - Confidence Intervals KW - Diet KW - Fatty Acids, Omega-3 KW - Female KW - Fish Oils KW - Fishes KW - Humans KW - Incidence KW - Male KW - Multivariate Analysis KW - Probability KW - Proportional Hazards Models KW - Risk Assessment KW - Seafood KW - Sensitivity and Specificity KW - Sex Distribution KW - Stroke KW - Surveys and Questionnaires KW - Survival Rate KW - United States AB -

BACKGROUND: Associations between fish consumption and stroke risk have been inconsistent, possibly because of the differences in types of fish meals consumed. Additionally, such relationships have not been specifically evaluated in the elderly, in whom disease burden may be high and diet less influential.

METHODS: Among 4775 adults 65 years or older (range, 65-98 years) and free of known cerebrovascular disease at baseline in 1989-1990, usual dietary intake was assessed using a food frequency questionnaire. In a subset, consumption of tuna or other broiled or baked fish, but not fried fish or fish sandwiches (fish burgers), correlated with plasma phospholipid long-chain n-3 fatty acid levels. Incident strokes were prospectively ascertained.

RESULTS: During 12 years of follow-up, participants experienced 626 incident strokes, including 529 ischemic strokes. In multivariate analyses, tuna/other fish consumption was inversely associated with total stroke (P = .04) and ischemic stroke (P = .02), with 27% lower risk of ischemic stroke with an intake of 1 to 4 times per week (hazard ratio [HR], 0.73; 95% confidence interval [CI], 0.55-0.98) and 30% lower risk with intake of 5 or more times per week (HR, 0.70; 95% CI, 0.50-0.99) compared with an intake of less than once per month. In contrast, fried fish/fish sandwich consumption was positively associated with total stroke (P = .006) and ischemic stroke (P = .003), with a 44% higher risk of ischemic stroke with consumption of more than once per week (HR, 1.44; 95% CI, 1.12-1.85) compared with consumption of less than once per month. Fish consumption was not associated with hemorrhagic stroke.

CONCLUSIONS: Among elderly individuals, consumption of tuna or other broiled or baked fish is associated with lower risk of ischemic stroke, while intake of fried fish or fish sandwiches is associated with higher risk. These results suggest that fish consumption may influence stroke risk late in life; potential mechanisms and alternate explanations warrant further study.

VL - 165 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15668367?dopt=Abstract ER - TY - JOUR T1 - Fish intake and risk of incident heart failure. JF - J Am Coll Cardiol Y1 - 2005 A1 - Mozaffarian, Dariush A1 - Bryson, Chris L A1 - Lemaitre, Rozenn N A1 - Burke, Gregory L A1 - Siscovick, David S KW - Aged KW - Animals KW - Cohort Studies KW - Cooking KW - Diet KW - Diet Surveys KW - Disease-Free Survival KW - Female KW - Fishes KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Risk Factors KW - United States AB -

OBJECTIVES: Our aim was to investigate the relation between fish consumption and incidence of congestive heart failure (CHF).

BACKGROUND: The incidence and health burden of CHF are rising, particularly in older persons. Although n-3 fatty acids have effects that could favorably influence risk of CHF, the relation between fish intake and CHF incidence is unknown.

METHODS: Among 4,738 adults age > or =65 years and free of CHF at baseline in 1989-90, usual dietary intake was assessed using a food frequency questionnaire. In a participant subsample, consumption of tuna or other broiled or baked fish, but not fried fish, correlated with plasma phospholipid n-3 fatty acids. Incidence of CHF was prospectively adjudicated.

RESULTS: During 12 years' follow-up, 955 participants developed CHF. In multivariate-adjusted analyses, tuna/other fish consumption was inversely associated with incident CHF, with 20% lower risk with intake 1 to 2 times/week (hazard ratio [HR] = 0.80, 95% confidence interval [CI] = 0.64 to 0.99), 31% lower risk with intake 3 to 4 times/week (HR = 0.69, 95% CI = 0.52 to 0.91), and 32% lower risk with intake > or =5 times/week (HR = 0.68, 95% CI = 0.45 to 1.03), compared with intake <1 time/month (p trend = 0.009). In similar analyses, fried fish consumption was positively associated with incident CHF (p trend = 0.01). Dietary long-chain n-3 fatty acid intake was also inversely associated with CHF (p trend = 0.009), with 37% lower risk in the highest quintile of intake (HR = 0.73, 95% CI = 0.57 to 0.94) compared with the lowest.

CONCLUSIONS: Among older adults, consumption of tuna or other broiled or baked fish, but not fried fish, is associated with lower incidence of CHF. Confirmation in additional studies and evaluation of potential mechanisms is warranted.

VL - 45 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15963403?dopt=Abstract ER - TY - JOUR T1 - Kidney function as a predictor of noncardiovascular mortality. JF - J Am Soc Nephrol Y1 - 2005 A1 - Fried, Linda F A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Chaves, Paulo H M A1 - Jenny, Nancy Swords A1 - Stehman-Breen, Catherine A1 - Gillen, Dan A1 - Bleyer, Anthony J A1 - Hirsch, Calvin A1 - Siscovick, David A1 - Newman, Anne B KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cause of Death KW - Cohort Studies KW - Confidence Intervals KW - Creatinine KW - Cystatin C KW - Cystatins KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Failure, Chronic KW - Kidney Function Tests KW - Longitudinal Studies KW - Male KW - Probability KW - Proportional Hazards Models KW - Risk Assessment KW - Severity of Illness Index KW - Survival Analysis KW - United States AB -

Chronic kidney disease is associated with a higher risk for cardiovascular mortality, as well as all-cause mortality. Whether chronic kidney disease is a predictor of noncardiovascular mortality is less clear. To further explore the latter, the association of kidney function with total noncardiovascular mortality and cause-specific mortality was assessed in the Cardiovascular Health Study, a community-based cohort of older individuals. Kidney disease was assessed using cystatin C and estimated GFR in 4637 participants in 1992 to 1993. Participants were followed until June 30, 2001. Deaths were adjudicated as cardiovascular or noncardiovascular disease by committee, and an underlying cause of death was assigned. The associations of kidney function with total noncardiovascular mortality and cause-specific mortality were analyzed by proportional hazards regression. Noncardiovascular mortality rates increased with higher cystatin C quartiles (16.8, 17.1, 21.6, and 50.0 per 1000 person-years). The association of cystatin C with noncardiovascular mortality persisted after adjustment for demographic factors; the presence of diabetes, C-reactive protein, hemoglobin, and prevalent cardiovascular disease; and measures of atherosclerosis (hazard ratio 1.69; 95% confidence interval 1.33 to 2.15, for the fourth quartile versus the first quartile). Results for estimated GFR were similar. The risk for noncardiac deaths attributed to pulmonary disease, infection, cancer, and other causes was similarly associated with cystatin C levels. Kidney function predicts noncardiovascular mortality from multiple causes in the elderly. Further research is needed to understand the mechanisms and evaluate interventions to reduce the high mortality rate in chronic kidney disease.

VL - 16 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16251239?dopt=Abstract ER - TY - JOUR T1 - Population structure, admixture, and aging-related phenotypes in African American adults: the Cardiovascular Health Study. JF - Am J Hum Genet Y1 - 2005 A1 - Reiner, Alexander P A1 - Ziv, Elad A1 - Lind, Denise L A1 - Nievergelt, Caroline M A1 - Schork, Nicholas J A1 - Cummings, Steven R A1 - Phong, Angie A1 - Burchard, Esteban González A1 - Harris, Tamara B A1 - Psaty, Bruce M A1 - Kwok, Pui-Yan KW - African Americans KW - Aged KW - Aging KW - Algorithms KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Genetics, Population KW - Genotype KW - Humans KW - Male KW - Models, Genetic KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Risk Factors KW - Socioeconomic Factors AB -

U.S. populations are genetically admixed, but surprisingly little empirical data exists documenting the impact of such heterogeneity on type I and type II error in genetic-association studies of unrelated individuals. By applying several complementary analytical techniques, we characterize genetic background heterogeneity among 810 self-identified African American subjects sampled as part of a multisite cohort study of cardiovascular disease in older adults. On the basis of the typing of 24 ancestry-informative biallelic single-nucleotide-polymorphism markers, there was evidence of substantial population substructure and admixture. We used an allele-sharing-based clustering algorithm to infer evidence for four genetically distinct subpopulations. Using multivariable regression models, we demonstrate the complex interplay of genetic and socioeconomic factors on quantitative phenotypes related to cardiovascular disease and aging. Blood glucose level correlated with individual African ancestry, whereas body mass index was associated more strongly with genetic similarity. Blood pressure, HDL cholesterol level, C-reactive protein level, and carotid wall thickness were not associated with genetic background. Blood pressure and HDL cholesterol level varied by geographic site, whereas C-reactive protein level differed by occupation. Both ancestry and genetic similarity predicted the number and quality of years lived during follow-up, but socioeconomic factors largely accounted for these associations. When the 24 genetic markers were tested individually, there were an excess number of marker-trait associations, most of which were attenuated by adjustment for genetic ancestry. We conclude that the genetic demography underlying older individuals who self identify as African American is complex, and that controlling for both genetic admixture and socioeconomic characteristics will be required in assessing genetic associations with chronic-disease-related traits in African Americans. Complementary methods that identify discrete subgroups on the basis of genetic similarity may help to further characterize the complex biodemographic structure of human populations.

VL - 76 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15660291?dopt=Abstract ER - TY - JOUR T1 - Predictors of heartburn during sleep in a large prospective cohort study. JF - Chest Y1 - 2005 A1 - Fass, Ronnie A1 - Quan, Stuart F A1 - O'Connor, George T A1 - Ervin, Ann A1 - Iber, Conrad KW - Aged KW - Body Mass Index KW - Carbonated Beverages KW - Cohort Studies KW - Educational Status KW - Female KW - Gastroesophageal Reflux KW - Heartburn KW - Humans KW - Male KW - Middle Aged KW - Multivariate Analysis KW - Prospective Studies KW - Sleep KW - Surveys and Questionnaires AB -

BACKGROUND AND AIMS: Nocturnal gastroesophageal reflux, which may result in nocturnal heartburn, has been demonstrated to be associated with a more severe form of gastroesophageal reflux disease (GERD). The aim of this study was to determine the clinical predictors of heartburn during sleep in a large prospective cohort study.

METHODS: Study subjects were members of the parent cohorts from which the Sleep Heart Health Study (SHHS) recruited participants. SHHS is a multicenter, longitudinal, cohort study of the cardiovascular consequences of sleep-disordered breathing. As part of the recruitment process, parent cohort members completed a questionnaire that permitted an assessment of the relationships between heartburn during sleep, and patient demographics, sleep abnormalities, medical history, and social habits in nine community-based parent cohorts across the United States. All variables, significant at the p < 0.05 level, were included as independent variables in multivariate logistic regression models with heartburn during sleep status included as the dependent variable

RESULTS: A total of 15,314 subjects completed the questions about heartburn during sleep, and of these, 3,806 subjects (24.9%) reported having this symptom. In four increasingly comprehensive multivariate models, increased body mass index (BMI), carbonated soft drink consumption, snoring and daytime sleepiness (Epworth sleepiness scale score), insomnia, hypertension, asthma, and usage of benzodiazepines were strong predictors of heartburn during sleep. In contrast, college education decreased the risk of reporting heartburn during sleep.

CONCLUSIONS: Heartburn during sleep is very common in the general population. Reports of this type of symptom of GERD are strongly associated with increased BMI, carbonated soft drink consumption, snoring and daytime sleepiness, insomnia, hypertension, asthma, and usage of benzodiazepines. Overall, heartburn during sleep may be associated with sleep complaints and excessive daytime sleepiness.

VL - 127 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15888843?dopt=Abstract ER - TY - JOUR T1 - Progression and regression of sleep-disordered breathing with changes in weight: the Sleep Heart Health Study. JF - Arch Intern Med Y1 - 2005 A1 - Newman, Anne B A1 - Foster, Greg A1 - Givelber, Rachel A1 - Nieto, F Javier A1 - Redline, Susan A1 - Young, Terry KW - Body Weights and Measures KW - Causality KW - Cohort Studies KW - Comorbidity KW - Female KW - Follow-Up Studies KW - Humans KW - Linear Models KW - Male KW - Middle Aged KW - Obesity KW - Odds Ratio KW - Sex Distribution KW - Sleep Apnea Syndromes KW - United States KW - Weight Gain KW - Weight Loss AB -

BACKGROUND: The relationship of weight changes to the incidence, progression, and remission of sleep-disordered breathing (SDB) is not well defined. This study aims to determine the relationship between change in weight and progression or remission of SDB by polysomnography.

METHODS: We performed a longitudinal cohort study of the cardiovascular consequences of sleep apnea in diverse US communities. Sleep apnea and polysomnographic indicators of SDB were assessed 5 years apart.

RESULTS: A total of 2968 men and women (mean age, 62 years) participated in the study. Men were more likely to have an increase in Respiratory Disturbance Index (RDI) with a given increase in weight than were women, and this was not explained by differences in starting weight, waist circumference, age, or ethnicity. In a linear regression analysis, both men and women had a greater increase in RDI with weight gain than a decrease in RDI with weight loss. In a categorical analysis of larger degrees of change, this sex difference was also evident. Associations were similar in diverse ethnic groups. However, SDB progressed over time, even in those with stable weight.

CONCLUSION: Modest changes in weight were related to an increase or decrease in SDB, and this association was stronger in men than in women.

VL - 165 IS - 20 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16287771?dopt=Abstract ER - TY - JOUR T1 - Renal duplex parameters, blood pressure, and renal function in elderly people. JF - Am J Kidney Dis Y1 - 2005 A1 - Pearce, Jeffrey D A1 - Edwards, Matthew S A1 - Craven, Timothy E A1 - English, William P A1 - Mondi, Matthew M A1 - Reavis, Scott W A1 - Hansen, Kimberley J KW - African Americans KW - Aged KW - Aging KW - Arteriosclerosis KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Creatinine KW - Cross-Sectional Studies KW - Diastole KW - Disease Progression KW - European Continental Ancestry Group KW - Female KW - Humans KW - Hypertension, Renovascular KW - Kidney KW - Kidney Diseases KW - Kidney Function Tests KW - Male KW - Renal Artery KW - Renal Artery Obstruction KW - Renal Circulation KW - Risk Factors KW - Sampling Studies KW - Systole KW - Ultrasonography, Doppler, Duplex KW - United States AB -

BACKGROUND: Changes in renal artery and renal parenchyma perfusion are believed to correlate with severity of hypertension and worsened renal function, but population-based studies of these associations are not available. This study examines relationships between parameters derived from renal duplex sonography (RDS), blood pressure (BP), and excretory renal function in a population-based cohort of elderly Americans.

METHODS: Through an ancillary study to the Cardiovascular Health Study, 758 participants (37% men; mean age, 77 years) underwent RDS in which flow velocities and frequency shifts were determined from spectral analysis of Doppler-shifted signals obtained from the renal artery and parenchyma. Associations of these duplex parameters with BP and inverse serum creatinine were examined by using multivariate regression techniques.

RESULTS: Main renal artery peak systolic flow velocity (PSV) showed independent associations with BP, with an SD increase in PSV (0.53 m/s) associated with a 3.3-mm Hg increase in systolic BP (SBP) and a 2.4-mm Hg decrease in diastolic BP (DBP). An SD decrease in end-diastolic frequency shift (EDF; 131 kHz) was associated with a 6.0-mm Hg increase in SBP, a 4.2-mm Hg decrease in DBP, and a significant 3.7% decrease in inverse serum creatinine.

CONCLUSION: Increases in renal artery PSV and decreases in parenchymal EDF are associated with increased SBP and decreased DBP. Moreover, decreased parenchymal EDF showed significant associations with impaired excretory renal function. These results suggest that renal duplex parameters are associated with renal parenchymal changes caused by hypertension and progressive renal dysfunction in elderly people.

VL - 45 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15861349?dopt=Abstract ER - TY - JOUR T1 - Renovascular disease and the risk of adverse coronary events in the elderly: a prospective, population-based study. JF - Arch Intern Med Y1 - 2005 A1 - Edwards, Matthew S A1 - Craven, Timothy E A1 - Burke, Gregory L A1 - Dean, Richard H A1 - Hansen, Kimberley J KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Analysis of Variance KW - Cohort Studies KW - Comorbidity KW - Coronary Disease KW - Female KW - Geriatric Assessment KW - Heart Function Tests KW - Humans KW - Hypertension, Renovascular KW - Incidence KW - Kidney Function Tests KW - Male KW - Multivariate Analysis KW - Probability KW - Prognosis KW - Prospective Studies KW - Risk Assessment KW - Severity of Illness Index KW - Sex Distribution KW - Survival Rate KW - Ultrasonography, Doppler KW - United States AB -

BACKGROUND: Renovascular disease is a cause of secondary hypertension and renal insufficiency and is suspected to contribute to morbidity and mortality of coronary heart disease. This investigation prospectively examined associations between renovascular disease and adverse coronary events among a population-based sample of elderly Americans.

METHODS: The Cardiovascular Health Study is a prospective, multicenter cohort study of cardiovascular disease risk factors, morbidity, and mortality among Americans older than 65 years. Renal duplex sonography was performed on 870 individuals between January 1995 and February 1997. Renovascular disease was defined as any focal peak systolic velocity of 1.8 m/s or greater (renal artery stenosis) or the absence of a Doppler-shifted signal from an imaged artery (renal artery occlusion). Adverse coronary events were defined as hospitalized angina, fatal or nonfatal myocardial infarction, and coronary revascularization.

RESULTS: During a mean follow-up of 14 months, 68 participants experienced incident or recurrent adverse coronary events. The presence of renovascular disease demonstrated a significant relationship with adverse coronary events (hazard ratio, 1.96; 95% confidence interval, 1.00-3.83; P = .05) that remained after controlling for the effects of coexisting atherosclerotic risk factors and prevalent cardiovascular disease. The relationship between renovascular disease and adverse coronary events was not dependent on the effects of increased blood pressure.

CONCLUSIONS: The presence of renovascular disease was associated with an increase in the risk of adverse coronary events in this sample. The increment in risk was not dependent on the effects of associated atherosclerotic risk factors, other prevalent cardiovascular disease, or increased blood pressure.

VL - 165 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15668368?dopt=Abstract ER - TY - JOUR T1 - Sleepiness in patients with moderate to severe sleep-disordered breathing. JF - Sleep Y1 - 2005 A1 - Kapur, Vishesh K A1 - Baldwin, Carol M A1 - Resnick, Helaine E A1 - Gottlieb, Daniel J A1 - Nieto, F Javier KW - Aged KW - Body Mass Index KW - Cohort Studies KW - Cross-Sectional Studies KW - Disorders of Excessive Somnolence KW - Female KW - Humans KW - Male KW - Middle Aged KW - Oxygen KW - Polysomnography KW - Prevalence KW - Risk Factors KW - Severity of Illness Index KW - Sleep Apnea Syndromes KW - Sleep Arousal Disorders KW - Sleep Stages KW - Surveys and Questionnaires AB -

BACKGROUND: Population-based studies suggest that complaints of sleepiness are absent in many individuals with sleep-disordered breathing. We investigated the prevalence of sleepiness as well as factors associated with sleepiness in individuals with moderate to severe sleep-disordered breathing (apnea-hypopnea index > or = 15).

DESIGN: Cross-sectional study.

SETTING: The Sleep Heart Health Study.

PARTICIPANTS: Sleep Heart Health Study participants (N = 6440).

MEASUREMENTS AND RESULTS: Sleepiness was defined as an Epworth Sleepiness Scale score >10 or a report of at least frequently feeling unrested or sleepy. Forty-six percent of participants with moderate to severe sleep-disordered breathing (n = 1149) reported sleepiness. Characteristics associated with sleepiness after adjustment for confounders included presence of respiratory disease, shorter self-reported weekday and weekend sleep, sleep durations, complaints of insufficient sleep, complaints of sleep maintenance insomnia, early morning awakening, habitual snoring, and complaints of awakening with leg cramps or leg jerks. Some respiratory polysomnography measures were associated with sleepiness, but sleep-stage percentages and measures of sleep disruption were not.

CONCLUSIONS: In this community-based cohort, subjective sleepiness is absent in many individuals with significant sleep-disordered breathing. Comorbid conditions, including respiratory disease, sleep restriction, insomnia, and nocturnal leg complaints, are important risk factors for sleepiness in individuals with moderate to severe sleep-disordered breathing.

VL - 28 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16171292?dopt=Abstract ER - TY - JOUR T1 - Sometimes higher heart rate variability is not better heart rate variability: results of graphical and nonlinear analyses. JF - J Cardiovasc Electrophysiol Y1 - 2005 A1 - Stein, Phyllis K A1 - Domitrovich, Peter P A1 - Hui, Nelson A1 - Rautaharju, Pentti A1 - Gottdiener, John KW - Aged KW - Aged, 80 and over KW - Algorithms KW - Arrhythmia, Sinus KW - Cohort Studies KW - Diagnosis, Computer-Assisted KW - Electrocardiography KW - Female KW - Heart Rate KW - Humans KW - Male KW - Models, Cardiovascular KW - Nonlinear Dynamics KW - Numerical Analysis, Computer-Assisted KW - Prevalence KW - Proportional Hazards Models KW - Reproducibility of Results KW - Risk Assessment KW - Risk Factors KW - Sensitivity and Specificity KW - United States AB -

OBJECTIVE: To determine the prevalence and effect on traditional heart rate variability (HRV) indices of abnormal HRV patterns in the elderly.

METHODS: Hourly Poincaré plots and plots of spectral HRV from normal-to-normal interbeat intervals and hourly nonlinear HRV values were examined in a subset of 290 consecutive participants in the Cardiovascular Health Study. Only subjects in normal sinus rhythm with > or = 18 hours of usable data were included. Eligible subjects were 71 +/- 5 years. During 7 years of follow-up, 21.7% had died. Hours were scored as normal (0), borderline (0.5), or abnormal (1) from a combination of plot appearance and HRV. Summed scores were normalized to 100% to create an abnormality score (ABN). Short-term HRV versus each 5th percentile of ABN was plotted and a cutpoint for markedly increased HRV identified. The t-tests compared HRV for subjects above and below this cutpoint. Cox regression evaluated the association of ABN and mortality.

RESULTS: Of 5,815 eligible hourly plots, 64.4% were normal, 14.5% borderline, and 21.1% abnormal. HR, SDNN, SDNNIDX, ln VLF and LF power, and power law slope did not differ by the cutpoint for increased short-term HRV, while SDANN and ln ULF power were significantly lower for those above the cutpoint. However, many HRV indices including LF/HF ratio and normalized LF and HF power were significantly different between groups (P < 0.001). Increased ABN was significantly associated with mortality (P = 0.019). Despite similar values for many HRV indices, being in the group above the cutpoint was significantly associated with mortality (P = 0.04).

CONCLUSIONS: Abnormal HR patterns that elevate many HRV indices are prevalent among the elderly and associated with higher risk of mortality. Consideration of abnormal HRV may improve HRV-based risk stratification.

VL - 16 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16174015?dopt=Abstract ER - TY - JOUR T1 - Statin use and the risk of incident dementia: the Cardiovascular Health Study. JF - Arch Neurol Y1 - 2005 A1 - Rea, Thomas D A1 - Breitner, John C A1 - Psaty, Bruce M A1 - Fitzpatrick, Annette L A1 - Lopez, Oscar L A1 - Newman, Anne B A1 - Hazzard, William R A1 - Zandi, Peter P A1 - Burke, Gregory L A1 - Lyketsos, Constantine G A1 - Bernick, Charles A1 - Kuller, Lewis H KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - Dementia KW - Female KW - Humans KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors KW - Hyperlipidemias KW - Male AB -

BACKGROUND: Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) reduce cardiovascular risk through mechanisms that might affect the development of dementia.

OBJECTIVE: To evaluate whether statin use is associated with a lower risk of dementia compared with never use of lipid-lowering agents (LLAs).

DESIGN: Cohort study of community-dwelling adults 65 years and older. The analysis included 2798 participants free of dementia at baseline.

MAIN OUTCOME MEASURES: Using Cox proportional hazards regression analysis, we estimated the risk of incident all-cause and type-specific dementia associated with time-dependent statin therapy compared with never use of LLAs. The primary analyses incorporated a 1-year lag between exposure and outcome. Secondary analyses included the final year of exposure and modeled statin use as current use vs nonuse to simulate a case-control approach.

RESULTS: Compared with never use of LLAs, ever use of statins was not associated with the risk of all-cause dementia (multivariable-adjusted hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.77-1.52), Alzheimer disease alone (HR, 1.21; 95% CI, 0.76-1.91), mixed Alzheimer disease and vascular dementia (HR, 0.87; 95% CI, 0.44-1.72), or vascular dementia alone (HR, 1.36; 95% CI, 0.61-3.06). In contrast, in secondary analyses, current use of statins compared with nonuse of LLAs was associated with HRs of 0.69 (95% CI, 0.46-1.02) for all-cause dementia and 0.56 (95% CI, 0.35-0.92) for any Alzheimer disease.

CONCLUSIONS: In this cohort study, statin therapy was not associated with a decreased risk of dementia. Methodological differences may explain why results of this cohort investigation differ from those of prior case-control studies. Additional investigation is needed to determine whether and for whom statin use may affect dementia risk.

VL - 62 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16009757?dopt=Abstract ER - TY - JOUR T1 - Statins and cognitive function in the elderly: the Cardiovascular Health Study. JF - Neurology Y1 - 2005 A1 - Bernick, C A1 - Katz, R A1 - Smith, N L A1 - Rapp, S A1 - Bhadelia, R A1 - Carlson, M A1 - Kuller, L KW - Aged KW - Aged, 80 and over KW - Aging KW - Anticholesteremic Agents KW - Atrophy KW - Brain KW - Cholesterol KW - Cognition Disorders KW - Cohort Studies KW - Dementia KW - Female KW - Humans KW - Hydroxymethylglutaryl-CoA Reductase Inhibitors KW - Longitudinal Studies KW - Male KW - Memory Disorders KW - Nootropic Agents KW - Treatment Outcome AB -

OBJECTIVE: To examine the association of statin drug use on cognitive and MRI change in older adults.

METHODS: Participants in the Cardiovascular Health Study, a longitudinal study of people age 65 or older, were classified into three groups determined by whether they were taking statin drugs on a continuous basis, intermittently, or not at all. The untreated group was further divided into categories based on National Cholesterol Education Program recommendations for lipid-lowering treatment. Participants with prevalent or incident clinical TIA or stroke or with baseline Modified Mini-Mental State Examination (3MS) scores at or below 80 were excluded. Outcomes examined included rate of change on the 3MS over an average observational period of 7 years, along with changes in MRI white matter grade and measures of atrophy.

RESULTS: Three thousand three hundred thirty-four participants had adequate data for analysis. At baseline, the untreated group in which lipid-lowering drug treatment was recommended were slightly older, less likely to be on estrogen replacement, and had higher serum cholesterol and lower 3MS scores than the statin-treated group. The rate of decline on the 3MS was 0.48 point/year less in those taking statins compared with the untreated group for which treatment was recommended (p = 0.069) and 0.49 point/year less in statin users compared with the group in which lipid-lowering treatment was not recommended (p = 0.009). This effect remained after controlling for serum cholesterol levels. One thousand seven hundred thirty participants with baseline 3MS scores of > 80 underwent cranial MRI scans on two occasions separated by 5 years. There was no significant difference in white matter grade change or atrophy measures between groups.

CONCLUSION: Statin drug use was associated with a slight reduction in cognitive decline in an elderly population. This relationship could not be completely explained by the effect of statins on lowering of serum cholesterol.

VL - 65 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16275825?dopt=Abstract ER - TY - JOUR T1 - Vascular events, mortality, and preventive therapy following ischemic stroke in the elderly. JF - Neurology Y1 - 2005 A1 - Kaplan, R C A1 - Tirschwell, D L A1 - Longstreth, W T A1 - Manolio, T A A1 - Heckbert, S R A1 - Lefkowitz, D A1 - El-Saed, A A1 - Psaty, B M KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Anticoagulants KW - Antihypertensive Agents KW - Brain Ischemia KW - Cohort Studies KW - Comorbidity KW - Coronary Artery Disease KW - Drug Utilization KW - Female KW - Humans KW - Hyperlipidemias KW - Hypertension KW - Hypolipidemic Agents KW - Male KW - Mortality KW - Prospective Studies KW - Recurrence KW - Sex Factors KW - Stroke KW - Treatment Outcome AB -

BACKGROUND: The authors studied mortality, vascular events, and preventive therapies following ischemic stroke among adults aged > or =65 years.

METHODS: The authors identified 546 subjects with first ischemic stroke during 1989 to 2001 among Cardiovascular Health Study participants. Deaths, recurrent strokes, and coronary heart disease (CHD) events were identified over 3.2 years (median) follow-up.

RESULTS: During the first year of follow-up, rates were 105.4/1,000 for recurrent stroke and 59.3/1,000 for CHD. After the first year, the stroke rate was 52.0/1,000 and the CHD rate was 46.5/1,000. Cardioembolic strokes had the highest mortality (185.4/1,000) and recurrence rates (86.6/1,000). Lacunar strokes had the lowest mortality (119.3/1,000) and recurrence rates (43.0/1,000). Age and male sex predicted death and CHD, but not recurrence. Outcomes did not differ by race. Following stroke, 47.8% used aspirin and 13.5% used other antiplatelet agents; 52.6% of patients with atrial fibrillation used warfarin; 31.3% of hyperlipidemic subjects, 57.0% of diabetic patients, and 81.5% of hypertensive patients were drug-treated; and 40.0% of hypertensive patients had blood pressure (BP) <140/90 mm Hg. Older subjects were less likely to use lipid-lowering therapy, women were less likely to have BP <140/90 mm Hg, and low-income subjects were less likely to use diabetes medications.

CONCLUSIONS: Recurrent strokes were nearly twice as frequent as coronary heart disease (CHD) events during the first year after initial stroke, but stroke and CHD rates were similar after the first year. Preventive drug therapies were underused, which may reflect clinical uncertainty due to the lack of clinical trials among the elderly. Utilization was lower among the oldest patients, women, and low-income individuals.

VL - 65 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16186519?dopt=Abstract ER - TY - JOUR T1 - Adjusted mortality after hip fracture: From the cardiovascular health study. JF - J Am Geriatr Soc Y1 - 2006 A1 - Robbins, John A A1 - Biggs, Mary L A1 - Cauley, Jane KW - Aged KW - Cohort Studies KW - Female KW - Health Status KW - Health Surveys KW - Hip Fractures KW - Humans KW - Male KW - Mortality KW - Multicenter Studies as Topic KW - Proportional Hazards Models KW - Sex Distribution KW - Time Factors KW - United States AB -

OBJECTIVES: To estimate the risk of death associated with hip fracture (HFx), stratifying by sex and time since fracture.

DESIGN: Prospective cohort study compared participants with and without hip fracture, matched on sex, age, race, recruitment period, and time since enrollment.

SETTING: The Cardiovascular Health Study, a more-than-15-year longitudinal study of 5,888 older individuals from four U.S. sites.

PARTICIPANTS: Three hundred seventy-nine individuals with HFx were compared with 1,134 without HFx.

MEASUREMENTS: Extended Cox models were used to estimate mortality hazard ratios (HRs) for different periods after fracture, adjusting for prefracture health.

RESULTS: Age- and race-adjusted excess mortality was 9% in women and 24% in men 1 year after fracture, and 24% in women and 26% men 5 years postfracture. Multivariable-adjusted HRs of mortality associated with HFx in women were 7.1 (95% confidence interval (CI) = 2.3-21.5), 2.1 (95% CI = 1.0-4.1), 1.4 (95% CI = 1.1-2.0), and 1.0 (95% CI = 0.6-1.5) for 0 to 1 months, 2 to 6 months, 7 months to 4 years, and 5 to 8 years, respectively, after index date. In men, respective HRs for the same time periods were 39.9 (95% CI = 5.2-308.7), 3.8 (95% CI = 1.4-10.3), 1.1 (95% CI = 0.7-1.8), and 1.0 (95% CI = 0.3-2.7). HRs adjusted for age and race were 20% to 40% higher.

CONCLUSION: The risk of mortality was highest in the first 6 months after HFx. In men, the risk of death approximated that of men without HFx after 6 months; in women, a moderately greater risk persisted through the fourth year. Although the mortality pattern was different in women and men, excess mortality 5 years postfracture was similar for both sexes.

VL - 54 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17198494?dopt=Abstract ER - TY - JOUR T1 - Alcohol consumption and risk of coronary heart disease in older adults: the Cardiovascular Health Study. JF - J Am Geriatr Soc Y1 - 2006 A1 - Mukamal, Kenneth J A1 - Chung, Hyoju A1 - Jenny, Nancy S A1 - Kuller, Lewis H A1 - Longstreth, W T A1 - Mittleman, Murray A A1 - Burke, Gregory L A1 - Cushman, Mary A1 - Psaty, Bruce M A1 - Siscovick, David S KW - Aged KW - Alcohol Drinking KW - Apolipoproteins E KW - Beer KW - Cohort Studies KW - Coronary Disease KW - Female KW - Genotype KW - Health Behavior KW - Humans KW - Incidence KW - Male KW - Residence Characteristics KW - Risk Assessment KW - Socioeconomic Factors KW - United States KW - Wine AB -

OBJECTIVES: To evaluate several aspects of the relationship between alcohol use and coronary heart disease in older adults, including beverage type, mediating factors, and type of outcome.

DESIGN: Prospective cohort study.

SETTING: Four U.S. communities.

PARTICIPANTS: Four thousand four hundred ten adults aged 65 and older free of cardiovascular disease at baseline.

MEASUREMENTS: Risk of incident myocardial infarction or coronary death according to self-reported consumption of beer, wine, and spirits ascertained yearly.

RESULTS: During an average follow-up period of 9.2 years, 675 cases of incident myocardial infarction or coronary death occurred. Compared with long-term abstainers, multivariate relative risks of 0.90 (95% confidence interval (CI)=0.71-1.14), 0.93 (95% CI=0.73-1.20), 0.76 (95% CI=0.53-1.10), and 0.58 (95% CI=0.39-0.86) were found in consumers of less than one, one to six, seven to 13, and 14 or more drinks per week, respectively (P for trend=.007). Associations were similar for secondary coronary outcomes, including nonfatal and fatal events. No strong mediators of the association were identified, although fibrinogen appeared to account for 9% to 10% of the relationship. The associations were statistically similar for intake of wine, beer, and liquor and generally similar in subgroups, including those with and without an apolipoprotein E4 allele.

CONCLUSION: In this population, consumption of 14 or more drinks per week was associated with the lowest risk of coronary heart disease, although clinicians should not recommend moderate drinking to prevent coronary heart disease based on this evidence alone, because current National Institute on Alcohol Abuse and Alcoholism guidelines suggest that older adults limit alcohol intake to one drink per day.

VL - 54 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16420195?dopt=Abstract ER - TY - JOUR T1 - The association of race with frailty: the cardiovascular health study. JF - Ann Epidemiol Y1 - 2006 A1 - Hirsch, Calvin A1 - Anderson, Melissa L A1 - Newman, Anne A1 - Kop, Willem A1 - Jackson, Sharon A1 - Gottdiener, John A1 - Tracy, Russell A1 - Fried, Linda P KW - African Americans KW - Aged KW - Asthenia KW - Cardiovascular Diseases KW - Cohort Studies KW - Cross-Sectional Studies KW - European Continental Ancestry Group KW - Female KW - Frail Elderly KW - Health Status KW - Humans KW - Male KW - Middle Aged KW - Motor Activity KW - Odds Ratio KW - United States KW - Weight Loss AB -

PURPOSE: Frailty, which has been conceptualized as a state of decreased physiologic reserve contributing to functional decline, has a prevalence among older African Americans that is twice that in older whites. This study assesses the independent contribution of race to frailty.

METHODS: We evaluated 786 African-American and 4491 white participants of the Cardiovascular Health Study (CHS). Frailty is defined as meeting three or more of five criteria derived from CHS measures: lowest quintile for grip strength, self-reported exhaustion, unintentional weight loss of 10 lbs or greater in 1 year, slowest quintile for gait speed, and lowest quintile for physical activity. Controlling for age, sex, comorbidity, socioeconomic factors, and race, multinomial logistic regression estimated the odds ratio (OR) of prefrail (one or two criteria) to not frail and frail to not frail.

RESULTS: Among African Americans, 8.7% of men and 15.0% of women were frail compared with 4.6% and 6.8% of white men and women, respectively. In adjusted models, nonobese African Americans had a fourfold greater odds of frailty compared with whites. The increased OR of frailty associated with African-American race was less pronounced among those who were obese or disabled.

CONCLUSION: African-American race is associated independently with frailty.

VL - 16 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16388967?dopt=Abstract ER - TY - JOUR T1 - Association of usual sleep duration with hypertension: the Sleep Heart Health Study. JF - Sleep Y1 - 2006 A1 - Gottlieb, Daniel J A1 - Redline, Susan A1 - Nieto, F Javier A1 - Baldwin, Carol M A1 - Newman, Anne B A1 - Resnick, Helaine E A1 - Punjabi, Naresh M KW - Adult KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Cohort Studies KW - Comorbidity KW - Cross-Sectional Studies KW - Female KW - Health Surveys KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Odds Ratio KW - Prospective Studies KW - Sleep KW - Sleep Apnea, Obstructive KW - Sleep Deprivation KW - Statistics as Topic AB -

STUDY OBJECTIVES: Limited experimental data suggest that sleep restriction acutely elevates blood pressure; however, little is known about the relationship between usual sleep duration and hypertension. This study assesses the relationship between usual sleep duration and hypertension in a community-based cohort.

DESIGN: Cross-sectional observational study.

SETTING: The Sleep Heart Health Study, a community-based prospective study of the cardiovascular consequences of sleep-disordered breathing.

PARTICIPANTS: Two thousand eight hundred thirteen men and 3097 women, aged 40 to 100 years.

INTERVENTIONS: None.

MEASUREMENTS AND RESULTS: Usual weekday and weekend sleep durations were obtained by questionnaire, and their weighted average were categorized as less than 6, 6 to less than 7, 7 to less than 8, 8 to less than 9, and 9 or more hours per night. Hypertension was defined as a systolic blood pressure of 140 mm Hg or greater, a diastolic blood pressure of 90 mm Hg or greater, or use of medication to treat hypertension. The relationship between sleep duration and hypertension was examined using categorical logistic regression with adjustment for age, sex, race, apnea-hypopnea index, and body mass index. Compared to subjects sleeping 7 to less than 8 hours per night, those sleeping less than 6 and between 6 and 7 hours per night had adjusted odds ratios for hypertension of 1.66 (95% confidence interval 1.35-2.04) and 1.19 (1.02-1.39), respectively, whereas those sleeping between 8 and 9 and 9 or more hours per night had adjusted odds ratios for hypertension of 1.19 (1.04-1.37) and 1.30 (1.04-1.62), respectively (p < .0001 for association of sleep duration with hypertension). These associations persisted when analyses were further adjusted for caffeine and alcohol consumption, current smoking, insomnia symptoms, depression symptoms, sleep efficiency, and prevalent diabetes mellitus or cardiovascular disease.

CONCLUSIONS: Usual sleep duration above or below the median of 7 to less than 8 hours per night is associated with an increased prevalence of hypertension, particularly at the extreme of less than 6 hours per night.

VL - 29 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16944668?dopt=Abstract ER - TY - JOUR T1 - CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses. JF - Hum Mol Genet Y1 - 2006 A1 - Conley, Yvette P A1 - Jakobsdottir, Johanna A1 - Mah, Tammy A1 - Weeks, Daniel E A1 - Klein, Ronald A1 - Kuller, Lewis A1 - Ferrell, Robert E A1 - Gorin, Michael B KW - Aged KW - Aged, 80 and over KW - Case-Control Studies KW - Cohort Studies KW - Complement Factor H KW - Eye Proteins KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Intracellular Signaling Peptides and Proteins KW - Macular Degeneration KW - Male KW - Membrane Proteins KW - Proteins AB -

Age-related maculopathy (ARM) is an important cause of visual impairment in the elderly population. It is of crucial importance to identify genetic factors and their interactions with environmental exposures for this disorder. This study was aimed at investigating the CFH, ELOVL4, PLEKHA1 and LOC387715 genes in independent cohorts collected using different ascertainment schemes. The study used a case-control design with subjects originally recruited through the Cardiovascular Health Study (CHS) and the Age-Related Eye Disease Study (AREDS). CFH was significantly associated with ARM in both cohorts (P VL - 15 IS - 21 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17000705?dopt=Abstract ER - TY - JOUR T1 - Characteristics and baseline clinical predictors of future fatal versus nonfatal coronary heart disease events in older adults: the Cardiovascular Health Study. JF - Circulation Y1 - 2006 A1 - Pearte, Camille A A1 - Furberg, Curt D A1 - O'Meara, Ellen S A1 - Psaty, Bruce M A1 - Kuller, Lewis A1 - Powe, Neil R A1 - Manolio, Teri KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Carotid Artery, Common KW - Cohort Studies KW - Comorbidity KW - Coronary Disease KW - Diabetes Mellitus KW - Electrocardiography KW - Female KW - Follow-Up Studies KW - Forecasting KW - Heart Failure KW - Heart Ventricles KW - Hospitalization KW - Humans KW - Hyperlipidemias KW - Hypertension KW - Male KW - Multivariate Analysis KW - Myocardial Infarction KW - Organ Size KW - Predictive Value of Tests KW - Risk Factors KW - Sampling Studies KW - Tunica Intima KW - Tunica Media KW - United States AB -

BACKGROUND: Although >80% of annual coronary heart disease (CHD) deaths occur in adults aged >65 years and the population is aging rapidly, CHD event fatality and its predictors in the elderly have not been well described.

METHODS AND RESULTS: The first myocardial infarction (MI) or CHD death among the 5888 adults aged > or =65 years occurring during enrollment in the Cardiovascular Health Study during 1989-2001 was identified and adjudicated. Characteristics measured at examinations before the event were examined for associations with case fatality (death before hospitalization or hospital discharge) and for differences in predictors by demographics or clinical history. During a median follow-up of 8.2 years, 985 CHD events occurred, of which 30% were fatal. Case fatality decreased slightly over time, ranging from 28% to 30% per year in the early 1990s versus 23% by 2000-2001; with adjustment for age at MI and gender, there was a 6% lower odds of fatality with each successive year (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.90 to 0.98). Case fatality was similar by race and gender but higher with age and prior CHD (MI, angina, or revascularization). When considered alone, many subclinical disease measures, such as common carotid intima-media thickness, ankle-arm index, left ventricular mass by ECG, and a major ECG abnormality, and traditional risk factors, such as diabetes and hypertension, were associated with fatality. In multivariable analysis, independent predictors of fatality were prior congestive heart failure (OR, 3.20; 95% CI, 2.32 to 4.41), prior CHD rather than only history of MI (OR, 2.51; 95% CI, 1.84 to 3.43), diabetes (OR, 1.66; 95% CI, 1.10 to 2.31), and age (OR, 1.21 per 5 years; 95% CI, 1.07 to 1.37), adjusted for gender and each other. Prior congestive heart failure, regardless of left ventricular systolic function, age, gender, or prior CHD, conferred a > or =3-fold increased risk of fatality in almost all subgroups.

CONCLUSIONS: Among community-dwelling older adults, CHD case fatality remains substantial, with easily identifiable risk factors that may be different from those that predict incident disease. In the elderly in whom the risk/benefit of therapies may be influenced by multiple competing comorbidities and care needs, risk stratification possibly may be improved further by focusing more aggressive care on specific patients, especially those with a history of congestive heart failure or prior CHD.

VL - 113 IS - 18 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16651468?dopt=Abstract ER - TY - JOUR T1 - Clinical course of mesenteric artery stenosis in elderly americans. JF - Arch Intern Med Y1 - 2006 A1 - Wilson, David B A1 - Mostafavi, Kian A1 - Craven, Timothy E A1 - Ayerdi, Juan A1 - Edwards, Matthew S A1 - Hansen, Kimberley J KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Comorbidity KW - Female KW - Humans KW - Male KW - Mesenteric Arteries KW - Mesenteric Vascular Occlusion KW - Proportional Hazards Models KW - Prospective Studies KW - Radiography KW - Risk Factors KW - Surveys and Questionnaires KW - Ultrasonography AB -

BACKGROUND: To examine prospectively the relationship between stenosis or occlusion of the celiac and superior mesenteric arteries and symptoms of chronic intestinal ischemia in free-living elderly patients in the United States.

METHODS: As part of an ancillary study to the Cardiovascular Health Study, participants in the Forsyth County (North Carolina) cohort underwent visceral duplex ultrasonography of the celiac and superior mesenteric arteries. Critical mesenteric artery stenosis (MAS) or occlusion was defined by Doppler flow ultrasound-derived criteria. Clinical outcomes were assessed at annual follow-up examinations and review of death certificates. Multivariate associations between the presence of MAS and all-cause mortality and adverse cardiovascular events were analyzed. Participants with MAS were contacted to determine the presence of symptoms consistent with chronic intestinal ischemia.

RESULTS: Of 553 participants who underwent visceral duplex ultrasonography, 97 (17.5%) had disease of the celiac or superior mesenteric artery. At a mean follow-up of 6(1/2) years, 20 participants with MAS (20.6%) and 93 without MAS (20.4%) had died (relative risk, 1.01; 95% confidence interval, 0.66-1.55). No deaths were attributed to intestinal infarction. No association existed between the presence of MAS and prevalent cardiovascular disease, all-cause mortality, or adverse cardiovascular events. A questionnaire was completed by 71% of the surviving participants with MAS. No participant reported symptoms or weight loss consistent with chronic intestinal ischemia.

CONCLUSIONS: Mesenteric artery stenosis was a common finding in free-living elderly patients. At long-term follow-up, the presence of asymptomatic MAS was not associated with death or adverse cardiovascular events. Participants with asymptomatic MAS by duplex ultrasonographic criteria did not experience intestinal infarction or develop chronic intestinal ischemia.

VL - 166 IS - 19 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17060539?dopt=Abstract ER - TY - JOUR T1 - Congestive heart failure incidence and prognosis: case identification using central adjudication versus hospital discharge diagnoses. JF - Ann Epidemiol Y1 - 2006 A1 - Schellenbaum, Gina D A1 - Heckbert, Susan R A1 - Smith, Nicholas L A1 - Rea, Thomas D A1 - Lumley, Thomas A1 - Kitzman, Dalane W A1 - Roger, Veronique L A1 - Taylor, Herman A A1 - Psaty, Bruce M KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Female KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Patient Discharge KW - Prognosis AB -

PURPOSE: We compared hospitalized congestive heart failure (CHF) incidence and prognosis estimates using hospital discharge diagnoses or central adjudication.

METHODS: We used the Cardiovascular Health Study (CHS), a population-based cohort study of 5888 elderly adults. A physician committee adjudicated potential CHF events, confirmed by signs, symptoms, clinical tests, and/or medical therapy. A CHF discharge diagnosis included any of these ICD-9 codes in any position: 428, 425, 398.91, 402.01, 402.11, 402.91, and 997.1. We constructed an inception cohort of 1209 hospitalized, nonfatal, incident CHF cases, identified by discharge diagnosis, adjudication, or both.

RESULTS: Incidence rates for hospitalized CHF were 24.6 per 1000 person-years using discharge diagnoses and 17.1 per 1000 person-years using central adjudication. Compared to the group identified as having CHF by both methods, the group with only a discharge diagnosis (hazard ratio=0.77, 95% confidence interval=0.65-0.91) and the group with central adjudication only (hazard ratio=0.72, 95% confidence interval=0.55-0.94) had lower mortality rates.

CONCLUSIONS: In the elderly, studies using only discharge diagnoses, as compared to central adjudication, may estimate higher rates of incident hospitalized CHF. Mortality following CHF onset may be similar for these methods and higher if both methods are used together.

VL - 16 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/15964203?dopt=Abstract ER - TY - JOUR T1 - Genetic Susceptibility to Prostate Cancer: Prostate-specific Antigen and its Interaction with the Androgen Receptor (United States). JF - Cancer Causes Control Y1 - 2006 A1 - Sieh, Weiva A1 - Edwards, Karen L A1 - Fitzpatrick, Annette L A1 - Srinouanprachanh, Sengkeo L A1 - Farin, Fred M A1 - Monks, Stephanie A A1 - Kronmal, Richard A A1 - Eaton, David L KW - Aged KW - Biomarkers, Tumor KW - Case-Control Studies KW - Cohort Studies KW - Genetic Predisposition to Disease KW - Genotype KW - Haplotypes KW - Humans KW - Male KW - Polymorphism, Genetic KW - Prostate-Specific Antigen KW - Prostatic Neoplasms KW - Receptors, Androgen KW - United States AB -

OBJECTIVE: To determine whether directly observed prostate-specific antigen (PSA) promoter diploid haplotype, either alone or in conjunction with androgen receptor (AR) genotype, is associated with prostate cancer risk.

METHODS: We conducted a case-control study nested within the US population-based Cardiovascular Health Study cohort. Incident prostate cancers were identified by linkage to cancer registry records for the years 1989-2000. We genotyped 193 cases and 391 controls for the PSA -252 G/A and -158 G/A SNPs and the AR CAG microsatellite, and developed methods to directly determine proximal PSA promoter haplotypes. Exact logistic regression was used to estimate odds ratios and significance levels.

RESULTS: No significant associations were observed between PSA diplotype and prostate cancer overall. Short (< 20) AR CAG repeat lengths were associated with modest increases in the risk of prostate cancer (OR, 1.46; 95% CI, 0.97-2.19; p = 0.071) that were significant for advanced disease (OR, 1.82; 95% CI, 1.02-3.26; p = 0.044). Men who possessed two copies of the PSA*2 (-252G/-158G) haplotype and short AR CAG repeat lengths had a 4-fold (95% CI, 1.05-20.75; exact p = 0.040) increased risk of prostate cancer, and a 7-fold (95% CI, 1.25-39.78; exact p = 0.026) increased risk of advanced disease.

CONCLUSIONS: We found evidence that the PSA*2*2 diplotype in combination with short AR CAG alleles increases a man's risk of developing prostate cancer. These findings support an etiologic role in prostate cancer of genetic interactions between polymorphisms that increase AR transactivation strength and those that alter the regulatory regions of target genes such as PSA that are responsive to androgen stimulation.

VL - 17 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16425097?dopt=Abstract ER - TY - JOUR T1 - Lipoprotein subclass and particle size differences in Afro-Caribbeans, African Americans, and white Americans: associations with hepatic lipase gene variation. JF - Metabolism Y1 - 2006 A1 - Miljkovic-Gacic, Iva A1 - Bunker, Clareann H A1 - Ferrell, Robert E A1 - Kammerer, Candace M A1 - Evans, Rhobert W A1 - Patrick, Alan L A1 - Kuller, Lewis H KW - Adult KW - African Americans KW - Age Factors KW - Aged KW - Alleles KW - Body Mass Index KW - Cardiovascular Diseases KW - Caribbean Region KW - Cohort Studies KW - DNA KW - European Continental Ancestry Group KW - Gene Frequency KW - Genetic Variation KW - Humans KW - Lipase KW - Lipoproteins KW - Lipoproteins, HDL KW - Lipoproteins, LDL KW - Liver KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Particle Size KW - Trinidad and Tobago KW - United States AB -

Despite a higher prevalence of coronary heart disease risk factors, men of African origin have less coronary atherosclerosis, as measured by coronary calcification, than whites. In part, this is thought to be because of the less atherogenic lipoprotein profile observed in men of African origin, characterized by lower triglycerides and higher high-density lipoprotein (HDL) cholesterol. We hypothesized that the -514C>T polymorphism in the hepatic lipase gene (LIPC) plays a significant role in determining a less atherogenic lipoprotein profile observed in men of African origin. Previously conducted studies of the LIPC -514C>T polymorphism in African Americans may have been confounded by a higher level of European admixture; in addition, the results from these studies do not necessarily apply to other African populations because gene-environment interactions may differ. Thus, we compared nuclear magnetic resonance spectroscopy-measured lipoprotein subclass patterns and LIPC -514C>T genotypes in population-based samples of older white American (n = 532) and African American (n = 97) men from the Cardiovascular Health Study to those among older, less admixed, Afro-Caribbean men (n = 205) from the Tobago Health Study. Men of African origin had a more favorable lipoprotein profile than whites. In addition, levels of low-density lipoprotein cholesterol, total cholesterol, and triglyceride, and large and small very low-density lipoprotein, small low-density lipoprotein, as well as very low-density lipoprotein particle size, were remarkably lower in Afro-Caribbean men than in either African American or white men. The frequency of the LIPC -514T allele was much higher in Afro-Caribbeans (0.57) and in African Americans (0.49) than in whites (0.20). The -514T allele in both populations of African origin, but not in whites, was associated with elevated large HDL and greater HDL size. Our findings indicate that the higher frequency of the LIPC -514T allele found in men of African origin living in different environments significantly contributes to the more favorable distribution of HDL subclasses compared with whites.

VL - 55 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16324926?dopt=Abstract ER - TY - JOUR T1 - Metabolic syndrome and cardiovascular disease in older people: The cardiovascular health study. JF - J Am Geriatr Soc Y1 - 2006 A1 - McNeill, Ann Marie A1 - Katz, Ronit A1 - Girman, Cynthia J A1 - Rosamond, Wayne D A1 - Wagenknecht, Lynne E A1 - Barzilay, Joshua I A1 - Tracy, Russell P A1 - Savage, Peter J A1 - Jackson, Sharon A KW - African Americans KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Blood Glucose KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Fasting KW - Female KW - Humans KW - Incidence KW - Male KW - Metabolic Syndrome KW - Risk Factors KW - Sex Factors AB -

OBJECTIVES: To assess the prospective association between metabolic syndrome (MetS) and cardiovascular disease (CVD) in older people and to evaluate the effect of lowering the threshold for impaired fasting glucose (IFG) on the prevalence of IFG and MetS and the risk of CVD.

DESIGN: Prospective cohort study.

SETTING: Four field centers in U.S. communities.

PARTICIPANTS: Three thousand five hundred eighty-five subjects in the Cardiovascular Health Study free of diabetes mellitus and CVD at baseline (mean age 72, 62% female, 14% black).

MEASUREMENTS: Baseline measures of MetS components and adjudicated incident CVD events. MetS (2001) was defined first using the original criteria from the Third Adult Treatment Panel Report of the National Cholesterol Education Program (> or =3 of the following: large waist circumference (women >88 cm, men >102 cm), elevated triglycerides (> or =1.70 mmol/L), low high-density lipoprotein cholesterol (men <1.04 mmol/L, women <1.30 mmol/L), elevated fasting glucose (6.1-6.9 mmol/L), and high blood pressure (> or =130/85 mmHg or self-reported use of medications for hypertension). Subjects were also classified according to the revised definition of the MetS (2005) that applies the lower threshold for fasting glucose (5.6-6.9 mmol/L).

RESULTS: During follow-up (median 11 years), 818 coronary heart disease (CHD), 401 stroke, and 554 congestive heart failure (CHF) events occurred. Age- and race-adjusted hazard ratios (HRs) for CHD, stroke, and CHF were 1.30 (95% confidence interval (CI) = 1.07-1.57), 0.94 (95% CI = 0.73-1.21), and 1.40 (95% CI = 1.12-1.76) for women and 1.35 (95% CI = 1.10-1.66), 1.51 (95% CI = 1.08-2.12), and 1.47 (95% CI = 1.14-1.90) for men, respectively. Overall, women and men with MetS (2005) were 20% to 30% more likely to experience any CVD event than subjects without MetS (2005). Using the lower cut-point for IFG resulted in a near tripling in IFG prevalence (16% to 46%) and an additional 9% classified with MetS (2005) but HRs similar to those estimated from the original MetS (2001) criteria. High blood pressure was the component most strongly associated with incident CHD.

CONCLUSION: Results from this study of an elderly, population-based cohort provide support for earlier investigations in primarily middle-aged populations that link the presence of MetS with the development of CVD and further underscore the importance of recognizing and treating its individual components, particularly high blood pressure.

VL - 54 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16970637?dopt=Abstract ER - TY - JOUR T1 - Obstructive sleep apnea and plasma natriuretic peptide levels in a community-based sample. JF - Sleep Y1 - 2006 A1 - Patwardhan, Anjali A A1 - Larson, Martin G A1 - Levy, Daniel A1 - Benjamin, Emelia J A1 - Leip, Eric P A1 - Keyes, Michelle J A1 - Wang, Thomas J A1 - Gottlieb, Daniel J A1 - Vasan, Ramachandran S KW - Atrial Fibrillation KW - Body Mass Index KW - Cohort Studies KW - Female KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Natriuretic Peptides KW - Obesity KW - Polysomnography KW - Prevalence KW - Residence Characteristics KW - Severity of Illness Index KW - Sleep Apnea, Obstructive AB -

STUDY OBJECTIVES: We hypothesized that alterations in cardiac hemodynamics associated with obstructive sleep apnea-hypopnea (OSAH) would be reflected in higher natriuretic peptide levels. We examined the association of OSAH with natriuretic peptides in a community-based sample.

DESIGN: Cross-sectional, retrospective, observational study.

SETTING: Framingham Heart Study Offspring Cohort and Sleep Heart Health Study.

PARTICIPANTS: Community-based sample of 623 individuals.

MEASUREMENTS: Full-montage home polysomnography was used to determine apnea-hypopnea index (AHI) and percentage of time with an oxyhemoglobin saturation < 90% (PctLt90). Sensitive immunoradiometric assays were used to measure plasma B-type (BNP) and N-terminal pro-atrial natriuretic peptide (NT-ANP). Multivariable regression was used to examine the relations between natriuretic peptides and indicators of OSAH, adjusting for age, sex, body mass index, and clinical covariates.

RESULTS: No statistically significant relations between OSAH indices and BNP were observed in the multivariable model. Compared with an AHI < 5, relative levels of 1.20, 0.88, and 0.91 were observed forAHI categories 5-15, 15-30, >30 events per hour, respectively. For NT-ANP, no significant relations were seen with AHI in the multivariable model (relative levels of 0.98, 0.91, and 0.90). An inverse association was observed between NT-ANP and PctLt90 in age- and sex-adjusted models (relative levels of 0.93, 0.87, and 0.80), although this association became statistically nonsignificant after adjusting for body mass index.

CONCLUSION: Lack of association of natriuretic peptides with OSAH indices suggests that undiagnosed OSAH may not be associated with major alterations in left ventricular function, as reflected in morning natriuretic peptide levels.

VL - 29 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17068983?dopt=Abstract ER - TY - JOUR T1 - The prevalence of the 65-kilodalton isoform of glutamic acid decarboxylase autoantibodies by glucose tolerance status in elderly patients from the cardiovascular health study. JF - J Clin Endocrinol Metab Y1 - 2006 A1 - Barinas-Mitchell, Emma A1 - Kuller, Lewis H A1 - Pietropaolo, Susan A1 - Zhang, Ying-Jian A1 - Henderson, Tyona A1 - Pietropaolo, Massimo KW - Aged KW - Aging KW - Autoantibodies KW - Blood Glucose KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Glucose Intolerance KW - Glutamate Decarboxylase KW - Humans KW - Insulin KW - Isoenzymes KW - Lipids KW - Logistic Models KW - Male KW - Nutrition Surveys AB -

CONTEXT: Autoantibodies (AA) to glutamic acid decarboxylase (GAD65), a determinant of risk for autoimmune diabetes, have been found in up to 10% of patients with type 2 diabetes. In older adults, this marker may also serve as a determinant of risk for autoimmune diabetes and enhance diabetes classification.

OBJECTIVE: The objective of this study was to evaluate the relationship between GAD65AA and glucose tolerance status, current diabetes treatment, and clinical measures in older adults.

DESIGN: GAD65AA were measured at baseline in 3318 participants from the Cardiovascular Health Study, a cohort study of 5888 individuals 65 or older.

SETTING: The population-based cohort was recruited from four U.S. sites.

PATIENTS: Patients included all Cardiovascular Health Study participants with known diabetes, newly diagnosed diabetes, impaired fasting glucose, impaired glucose tolerance, and a sample of normal glucose-tolerant participants.

MAIN OUTCOME MEASURES: GAD65AA, body mass index, fasting glucose and insulin levels, blood pressure, lipid levels, and diabetes treatment at baseline were measured.

RESULTS: The prevalence of GAD65AA increased with decreasing glucose tolerance in both Blacks (n = 560) and Whites (n = 2730), being more pronounced in known diabetic individuals. GAD65AA were found in 2.3, 5.8, 7.8, and 8.3% of diabetic participants, reporting use of no diabetes medication, oral hypoglycemic agents, insulin only, and both oral hypoglycemic agents and insulin, respectively (P = 0.02, linear trend). Among diabetic participants, GAD65AA positivity was associated with diabetes treatment, higher fasting glucose, and lower body mass index.

CONCLUSIONS: Even among older individuals with diabetes, GAD65AA may be a useful marker in identifying a subgroup of autoimmune diabetes, serve as a marker of insulin requirement, and remain stable over years.

VL - 91 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16720660?dopt=Abstract ER - TY - JOUR T1 - Quantitative measures of gait characteristics indicate prevalence of underlying subclinical structural brain abnormalities in high-functioning older adults. JF - Neuroepidemiology Y1 - 2006 A1 - Rosano, Caterina A1 - Brach, Jennifer A1 - Longstreth, William T A1 - Newman, Anne B KW - Aged KW - Brain KW - Cerebral Infarction KW - Cerebral Ventricles KW - Cerebrovascular Disorders KW - Cohort Studies KW - Dementia KW - Female KW - Gait KW - Gait Disorders, Neurologic KW - Humans KW - Hypertension KW - Magnetic Resonance Imaging KW - Male KW - Neuropsychological Tests KW - Stroke KW - United States AB -

Abnormal gait in high-functioning older adults may indicate underlying subtle structural brain abnormalities. We tested the hypothesis that temporal and spatial parameters of gait, including speed, stride length and double support time, are cross-sectionally associated with white matter hyperintensity, subcortical infarcts or brain atrophy on brain MRI. We examined 321 men and women (mean age = 78.3) participating to the Cardiovascular Health Study who were free of dementia or stroke at the time of the gait assessment. Analyses were set with gait as independent variable and brain MRIs as dependent variables. Gait measures were determined from the footfalls recorded on a 4-meter-long instrumented walking surface, the GaitMat II. Brain MRIs were examined for the presence of white matter hyperintensity (WMG, graded from 0 to 9), brain infarcts (predominantly subcortical) and ventricular enlargement (graded from 0 to 9). Slower gait, shorter stride length and longer double support times were associated with greater prevalence of white matter grade > or =3 (p = 0.02), and at least 1 brain infarct (p = 0.04) independent of age. In multivariate logistic regression models adjusted for demographics and clinical cardiovascular diseases, those with gait speed <1.02 m/s were more likely to have WMG > or =3 and at least 1 brain infarct, compared with those with faster gait - odds ratio (OR): 2.85, 95% confidence interval (95% CI): 1.35, 6.02, and OR: 2.09, 95% CI: 1.04, 4.19. Shorter stride length was also associated with greater probability of having at least 1 brain infarct (gait stride <0.88 vs. >1.10 m: OR: 3.20, 95% CI: 1.49, 6.88), while longer double support times were associated with a greater probability of having WMG > or =3 (double support time >0.19 vs. <0.14 s: OR: 2.3, 95% CI: 1.1, 4.7) independent of demographics and clinical cardiovascular diseases. Gait parameters were not significantly associated with ventricular grade. In summary, in this group of high-functioning older adults, poorer gait speed, shorter stride and longer double support time are associated with high white matter disease and subclinical strokes.

VL - 26 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16254454?dopt=Abstract ER - TY - JOUR T1 - Quantitative retinal venular caliber and risk of cardiovascular disease in older persons: the cardiovascular health study. JF - Arch Intern Med Y1 - 2006 A1 - Wong, Tien Yin A1 - Kamineni, Aruna A1 - Klein, Ronald A1 - Sharrett, A Richey A1 - Klein, Barbara E A1 - Siscovick, David S A1 - Cushman, Mary A1 - Duncan, Bruce B KW - Aged KW - Aged, 80 and over KW - Algorithms KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Humans KW - Image Processing, Computer-Assisted KW - Incidence KW - Male KW - Photography KW - Prospective Studies KW - Retinal Diseases KW - Retinal Vein KW - Retinal Vessels KW - Risk Factors KW - Stroke KW - United States AB -

BACKGROUND: Small vessel disease may contribute to the risk of cardiovascular disease in older persons. We describe the relation of retinal vascular caliber to incident coronary heart disease (CHD) and stroke in elderly persons.

METHODS: Prospective population-based cohort study composed of 1992 men and women aged 69 to 97 years living in 4 US communities. Retinal arteriolar and venular calibers were measured from retinal photographs using a computer-assisted method. Incident CHD and stroke events were ascertained using standardized methods.

RESULTS: After 5 years of follow-up, there were 115 incident CHD events and 113 incident stroke events. Participants with larger retinal venular caliber had a higher incidence of CHD (11.7%; 95% confidence interval [CI], 8.7%-15.8%, vs 8.1%; 95% CI, 5.7%-11.6%), comparing largest with smallest venular caliber quartiles, and stroke (8.4%; 95% CI, 6.0-11.7, vs 5.8%; 95% CI, 3.9-8.4). At multivariable analysis, controlling for age, sex, race, arteriolar caliber, systolic and diastolic blood pressure, diabetes, glucose concentration, cigarette smoking, pack-years of smoking, and high-density-lipoprotein and low-density lipoprotein cholesterol levels, larger retinal venular caliber was associated with incident CHD (rate ratio, 3.0; 95% CI, 1.6-5.7, comparing largest with smallest venular caliber quartiles; P(trend) = .001) and incident stroke (rate ratio, 2.2; 95% CI, 1.1-4.3; P(trend) = .02). Additional adjustment for C-reactive protein and common and internal carotid artery intimal-media thickness had minimal effect on these associations. At multivariable analysis, smaller retinal arteriolar caliber was associated with incident CHD (rate ratio, 2.0; 95% CI, 1.1-3.7, comparing largest with smallest arteriolar caliber quartiles; P = .03) but not stroke (rate ratio,1.1; 95% CI, 0.5-2.2; P = .73).

CONCLUSION: Larger retinal venular caliber is independently associated with risk of cardiovascular disease in elderly persons.

VL - 166 IS - 21 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17130394?dopt=Abstract ER - TY - JOUR T1 - Subclinical atherosclerosis and the risk of future venous thrombosis in the Cardiovascular Health Study. JF - J Thromb Haemost Y1 - 2006 A1 - van der Hagen, P B A1 - Folsom, A R A1 - Jenny, N S A1 - Heckbert, S R A1 - O'Meara, E S A1 - Reich, L M A1 - Rosendaal, F R A1 - Cushman, M KW - Aged KW - Aged, 80 and over KW - Atherosclerosis KW - Carotid Artery Thrombosis KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Proportional Hazards Models KW - Risk Factors KW - Ultrasonography KW - Venous Thrombosis AB -

BACKGROUND: Recent reports have suggested an association of atherosclerosis with risk of venous thrombosis.

OBJECTIVE: To confirm whether subclinical atherosclerosis is a risk factor for venous thrombosis (VT) among men and women age 65 and older.

METHODS: Participants of the Cardiovascular Health Study (n = 4,108) without baseline clinical cardiovascular disease, anticoagulant use or previous VT were followed for a median of 11.7 years after non-invasive assessment of subclinical atherosclerosis using carotid ultrasound (intima-media thickness and presence of plaques), ankle-brachial blood pressure index and electrocardiogram. Each event was classified as idiopathic or secondary. We used Cox proportional hazards regression to estimate the relative risk of overall and idiopathic VT for individuals with and without baseline subclinical atherosclerosis.

RESULTS: There were 133 first time VT events. No subclinical atherosclerosis measures were associated with increased risk of overall or idiopathic VT. The adjusted relative risks of overall and idiopathic VT for presence of any type of subclinical disease were 0.60 (95% confidence interval 0.39-0.91) and 0.32 (0.18-0.59), respectively. Most of this association was explained by an inverse association of high-risk carotid plaques (prevalent in 54% of those at risk) with VT.

CONCLUSION: Non-invasively measured subclinical atherosclerosis was not associated with increased risk of overall or idiopathic VT in this observational study. Carotid plaques and arterial events during follow up were inversely associated, a finding that requires further study.

VL - 4 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/16961598?dopt=Abstract ER - TY - JOUR T1 - Alcohol consumption, interleukin-6 and apolipoprotein E genotypes, and concentrations of interleukin-6 and serum amyloid P in older adults. JF - Am J Clin Nutr Y1 - 2007 A1 - Mukamal, Kenneth J A1 - Jenny, Nancy S A1 - Tracy, Russell P A1 - Siscovick, David S KW - Aged KW - Alcohol Drinking KW - Apolipoprotein E4 KW - Apolipoproteins E KW - Blood Glucose KW - C-Reactive Protein KW - Cohort Studies KW - Female KW - Genotype KW - Humans KW - Interleukin-6 KW - Male KW - Promoter Regions, Genetic KW - Serum Amyloid P-Component AB -

BACKGROUND: Whether alcohol intake is associated with concentrations of interleukin-6 (IL-6) and serum amyloid P (SAP) is uncertain.

OBJECTIVE: We determined how alcohol intake and apolipoprotein E (apo E) and IL-6 promoter (IL-6 -174G-->C) polymorphisms interact for concentrations of IL-6 and SAP.

DESIGN: In the Cardiovascular Health Study, 2454 older adults reported their intake of beer, wine, and liquor and underwent measurements of circulating IL-6 and SAP.

RESULTS: Alcohol intake was not associated with IL-6 concentrations among apo E4-negative or IL-6C-positive participants but was positively associated among both apo E4-positive and IL-6C-negative participants (P for trend = 0.02 for both). The corresponding interactions on SAP were not significant for alcohol overall but were similar for liquor intake.

CONCLUSIONS: Among older adults free of clinical cardiovascular disease, specific IL-6 promoter and apo E alleles appeared to confer positive associations of alcohol consumption with IL-6 concentrations. Genetic heterogeneity should be considered in understanding the cardiovascular effects of alcohol intake.

VL - 86 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17684217?dopt=Abstract ER - TY - JOUR T1 - Are microvascular abnormalities in the retina associated with depression symptoms? The Cardiovascular Health Study. JF - Am J Geriatr Psychiatry Y1 - 2007 A1 - Sun, Cong A1 - Tikellis, Gabriella A1 - Klein, Ronald A1 - Steffens, David C A1 - Larsen, Emily K Marino A1 - Siscovick, David S A1 - Klein, Barbara E K A1 - Wong, Tien Y KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Cardiovascular Diseases KW - Cohort Studies KW - Comorbidity KW - Cross-Sectional Studies KW - Depression KW - Female KW - Fluorescein Angiography KW - Humans KW - Male KW - Microcirculation KW - Personality Inventory KW - Retinal Artery Occlusion KW - Retinal Diseases KW - Retinal Vein Occlusion KW - Risk Factors KW - Statistics as Topic KW - United States AB -

OBJECTIVE: Depression has been linked with vascular risk factors and stroke. The authors examined the relationship between retinal microvascular abnormalities and depression symptoms in an elderly population.

METHODS: The Cardiovascular Health Study is a population-based study conducted in four U.S. communities initiated in 1989-1990. A total of 2,420 persons aged 65 years and older were included in the current analyses. During the 1997-1998 examination, retinal photographs were performed and assessed for retinal microvascular abnormalities (retinopathy, focal arteriolar narrowing, arteriovenous nicking, generalized retinal arteriolar narrowing, and generalized retinal venular dilation) according to standardized methods. Depression symptoms were assessed by a modified version of the Centers for Epidemiologic Studies Depression (CES-D) scale annually from 1989 through 1997-1998 and was defined as a CES-D score of >9.

RESULTS: Participants with retinal microvascular abnormalities were not more likely to have depression symptoms, with adjusted odds ratio (OR) (95% confidence intervals) of 1.08 (0.71-1.65) for retinopathy, OR 1.09 (0.71-1.68) for focal arteriolar narrowing, OR 0.85 (0.52-1.40) for arteriovenous nicking, OR 0.97 (0.70-1.34) for generalized arteriolar narrowing, and OR 0.79 (0.56-1.12) for generalized venular dilation. Retinal microvascular abnormalities were not related to depression symptoms in multinomial logistic regression comparing the three top quartiles of the depression CES-D scores with the lowest quartile.

CONCLUSIONS: Our study did not find an association between retinal microvascular abnormalities and depression symptoms in older people.

VL - 15 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17384316?dopt=Abstract ER - TY - JOUR T1 - Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: the Cardiovascular Health Study. JF - Circulation Y1 - 2007 A1 - Cao, Jie J A1 - Arnold, Alice M A1 - Manolio, Teri A A1 - Polak, Joseph F A1 - Psaty, Bruce M A1 - Hirsch, Calvin H A1 - Kuller, Lewis H A1 - Cushman, Mary KW - African Americans KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Carotid Artery Diseases KW - Cohort Studies KW - Comorbidity KW - Diabetes Mellitus KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Hyperlipidemias KW - Hypertension KW - Incidence KW - Inflammation KW - Kaplan-Meier Estimate KW - Male KW - Mass Screening KW - Mortality KW - Myocardial Infarction KW - Obesity KW - Predictive Value of Tests KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - ROC Curve KW - Smoking KW - Stroke KW - Survival Analysis KW - Tunica Intima KW - Tunica Media KW - Ultrasonography KW - United States AB -

BACKGROUND: Carotid atherosclerosis, measured as carotid intima-media thickness or as characteristics of plaques, has been linked to cardiovascular disease (CVD) and to C-reactive protein (CRP) levels. We investigated the relationship between carotid atherosclerosis and CRP and their joint roles in CVD prediction.

METHODS AND RESULTS: Of 5888 participants in the Cardiovascular Health Study, an observational study of adults aged > or = 65 years, 5020 without baseline CVD were included in the analysis. They were followed up for as long as 12 years for CVD incidence and all-cause mortality after baseline ultrasound and CRP measurement. When CRP was elevated (> 3 mg/L) among those with detectable atherosclerosis on ultrasound, there was a 72% (95% CI, 1.46 to 2.01) increased risk for CVD death and a 52% (95% CI, 1.37 to 1.68) increased risk for all-cause mortality. Elevated CRP in the absence of atherosclerosis did not increase CVD or all-cause mortality risk. The proportion of excess risk attributable to the interaction of high CRP and atherosclerosis was 54% for CVD death and 79% for all-cause mortality. Addition of CRP or carotid atherosclerosis to conventional risk factors modestly increased in the ability to predict CVD, as measured by the c statistic.

CONCLUSIONS: In older adults, elevated CRP was associated with increased risk for CVD and all-cause mortality only in those with detectable atherosclerosis based on carotid ultrasound. Despite the significant associations of CRP and carotid atherosclerosis with CVD, these measures modestly improve the prediction of CVD outcomes after one accounts for the conventional risk factors.

VL - 116 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17576871?dopt=Abstract ER - TY - JOUR T1 - Association of physical activity with sleep-disordered breathing. JF - Sleep Breath Y1 - 2007 A1 - Quan, Stuart F A1 - O'Connor, George T A1 - Quan, Jason S A1 - Redline, Susan A1 - Resnick, Helaine E A1 - Shahar, Eyal A1 - Siscovick, David A1 - Sherrill, Duane L KW - Adult KW - Cardiac Rehabilitation KW - Cardiovascular Diseases KW - Cohort Studies KW - Exercise KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Obesity KW - Polysomnography KW - Pulmonary Disease, Chronic Obstructive KW - Pulmonary Ventilation KW - Risk Factors KW - Sex Factors KW - Sleep Apnea Syndromes KW - Sleep Apnea, Obstructive KW - Sleep Stages KW - Weight Loss AB -

This study was performed to determine whether there is a protective association between participation in vigorous or vigorous/moderately vigorous physical activity and the prevalence of sleep-disordered breathing (SDB). Polysomnographic and questionnaire data from the baseline examination of 4,275 participants in the Sleep Heart Health Study (SHHS) were analyzed in relation to information on amount of physical activity and other potentially relevant factors collected from five SHHS parent cohorts (Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Heart Study, Strong Heart Study, and Tucson Epidemiologic Study of Airways Obstructive Diseases). Logistic regression models were fitted to determine if amount and strenuousness of physical activity was associated with the presence of SDB. At least 3 h per week of vigorous physical activity reduced the odds of SDB, defined as a respiratory disturbance index (RDI) of at least 15 apneas/hypopneas per hour (Adjusted OR, 0.68; 95%CI, 0.51-0.91). A qualitatively similar but slightly weaker association was observed when SDB was defined as a RDI > or = 10 per hour (Adjusted OR, 0.81; 95%CI, 0.64-1.02). These findings remained after adjustment for sleepiness and restricting analyses to participants with good health. Three or more hours of moderately vigorous or vigorous physical activity also appeared to confer some protection against SDB, but these associations were weaker. Gender- and obesity-stratified analyses suggested that the protective association between physical activity and SDB occurred primarily in men and those who were obese. A program of regular vigorous physical activity of at least 3 h per week may be a useful adjunctive treatment modality for SDB, but this association needs confirmation with a prospective clinical trial.

VL - 11 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17221274?dopt=Abstract ER - TY - JOUR T1 - Association of total insulin-like growth factor-I, insulin-like growth factor binding protein-1 (IGFBP-1), and IGFBP-3 levels with incident coronary events and ischemic stroke. JF - J Clin Endocrinol Metab Y1 - 2007 A1 - Kaplan, Robert C A1 - McGinn, Aileen P A1 - Pollak, Michael N A1 - Kuller, Lewis H A1 - Strickler, Howard D A1 - Rohan, Tom E A1 - Cappola, Anne R A1 - Xue, XiaoNan A1 - Psaty, Bruce M KW - Aged KW - Cardiovascular Diseases KW - Case-Control Studies KW - Cohort Studies KW - Coronary Disease KW - Female KW - Humans KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Multivariate Analysis KW - Risk Factors KW - Stroke AB -

CONTEXT: Prior observational studies have demonstrated that the GH/IGF axis is associated with cardiovascular disease. However, this association has not been extensively studied among older adults.

OBJECTIVE: The objective of this study was to assess the association between levels of total IGF-I and IGF binding proteins (IGFBP-1, IGFBP-3) and risk of incident coronary events and ischemic stroke.

DESIGN AND PARTICIPANTS: A case-cohort analysis was conducted among adults 65 yr and older in the Cardiovascular Health Study.

MAIN OUTCOME MEASURES: A total of 534 coronary events [316 nonfatal myocardial infarctions (MIs), 48 fatal MIs, and 170 fatal coronary heart disease events] and 370 ischemic strokes were identified on follow-up. Comparison subjects were 1122 randomly selected participants from the Cardiovascular Health Study.

RESULTS: Mean follow-up time was 6.7 yr for coronary events, 5.6 yr for strokes, and 9.3 yr for comparison subjects. Hazard ratios (95% confidence intervals) associated with baseline levels of total IGF-I and IGFBPs were estimated using multivariate adjusted Cox proportional hazards models. Neither IGF-I nor IGFBP-1 levels predicted risk of incident coronary events or stroke. IGFBP-3 had an inverse association with risk of coronary events [adjusted hazard ratio per sd=0.88 (0.78-1.00), P=0.05] but was not associated with stroke. Exploratory analyses suggested that low IGF-I and low IGFBP-3 levels were significantly associated with higher risk of nonfatal MI (P<0.05) but not with risk of fatal MI or fatal coronary heart disease.

CONCLUSION: Circulating levels of total IGF-I or IGFBP-1 were not associated with risk of total coronary events or ischemic stroke among older adults, whereas low IGFBP-3 level was associated with increased risk of incident coronary events.

VL - 92 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17264182?dopt=Abstract ER - TY - JOUR T1 - Associations of plasma fibrinogen levels with established cardiovascular disease risk factors, inflammatory markers, and other characteristics: individual participant meta-analysis of 154,211 adults in 31 prospective studies: the fibrinogen studies collab JF - Am J Epidemiol Y1 - 2007 A1 - Kaptoge, S A1 - White, I R A1 - Thompson, S G A1 - Wood, A M A1 - Lewington, S A1 - Lowe, G D O A1 - Danesh, J KW - Adult KW - African Americans KW - Age Factors KW - Biomarkers KW - Body Mass Index KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Fibrinogen KW - Humans KW - Linear Models KW - Male KW - Prospective Studies KW - Risk Factors KW - Sex Factors KW - Smoking KW - Social Class KW - United States AB -

Long-term increases in plasma fibrinogen levels of 1 g/liter are associated with an approximate doubling of risk of major cardiovascular disease outcomes, but causality remains uncertain. To quantify cross-sectional associations of fibrinogen levels with established risk factors and other characteristics, the investigators combined individual data on 154,211 apparently healthy adults from 31 prospective studies conducted between 1967 and 2003, using a linear mixed model that included random effects at the cohort level. Fibrinogen levels increased with age and showed continuous, approximately linear relations with several risk markers and slightly curvilinear associations with log triglycerides, albumin, and tobacco and alcohol consumption. Female sex, Black ethnicity, lower socioeconomic status, and alcohol abstinence were each associated with modestly higher fibrinogen levels. Approximately one third of the variation in fibrinogen levels was explained by cohort, age, and sex. An additional 7% was explained by established risk factors (notably, positive associations with smoking and body mass index and an inverse association with high density lipoprotein cholesterol), and a further 10% was explained by inflammatory markers (notably, a positive association with C-reactive protein). The association with body mass index was twice as strong in women as in men, whereas the association with smoking was much stronger in men. These findings substantially advance understanding of the correlates and possible determinants of fibrinogen levels.

VL - 166 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17785713?dopt=Abstract ER - TY - JOUR T1 - Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study. JF - Circulation Y1 - 2007 A1 - Yeboah, Joseph A1 - Crouse, John R A1 - Hsu, Fang-Chi A1 - Burke, Gregory L A1 - Herrington, David M KW - Aged KW - Aged, 80 and over KW - Atherosclerosis KW - Biomarkers KW - Brachial Artery KW - Cardiovascular Diseases KW - Cohort Studies KW - Disease-Free Survival KW - Endothelium, Vascular KW - Female KW - Hemorheology KW - Humans KW - Hyperemia KW - Male KW - Predictive Value of Tests KW - Prognosis KW - Proportional Hazards Models KW - Prospective Studies KW - Reproducibility of Results KW - Risk Factors KW - Stress, Mechanical KW - Tourniquets KW - Ultrasonography KW - United States KW - Vasodilation AB -

BACKGROUND: The relationship between impaired brachial flow-mediated dilation (FMD) and subsequent clinical cardiovascular events is not well established, especially in older adults whose FMD is often diminished. We assessed the hypothesis that FMD predicts incident cardiovascular events in a population-based cohort of older adults.

METHODS AND RESULTS: FMD was measured at the 1997 to 1998 Cardiovascular Health Study clinic visit in 2792 adults aged 72 to 98 years (82.7% white, 58.6% women) recruited at 4 clinic sites in the United States. Log-rank test and Cox proportional hazard models were used to examine the association between FMD and adjudicated cardiovascular events. A total of 674 subjects (24.1%) had an adjudicated event over the 5-year follow-up period. Event-free survival rates for cardiovascular events were significantly higher in subjects with FMD greater than the sex-specific medians than in subjects with FMD less than or equal to the sex-specific medians (78.3% versus 73.6%, log-rank P=0.006). FMD remained a significant predictor of cardiovascular events after adjustment for age, gender, diabetes mellitus, cigarette smoking, systolic and diastolic blood pressure, baseline cardiovascular disease status, and total cholesterol (hazard ratio, 0.91 [95% CI, 0.83 to 0.99], P=0.02 per unit SD of FMD) but added only approximately 1% to the prognostic accuracy of the best Cox model. Brachial artery diameter was also predictive of CV events in the adjusted Cox proportional hazard model (hazard ratio, 1.12 [95% CI, 1.02 to 1.28], P=0.025) and also added approximately 1% to the accuracy of our best Cox model.

CONCLUSIONS: FMD is a predictor of future cardiovascular events but adds very little to the prognostic accuracy of traditional cardiovascular risk scores/factors in older adults. FMD and brachial artery diameter may have similar predictive values for cardiovascular events in older adults.

VL - 115 IS - 18 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17452608?dopt=Abstract ER - TY - JOUR T1 - Clinical factors, but not C-reactive protein, predict progression of calcific aortic-valve disease: the Cardiovascular Health Study. JF - J Am Coll Cardiol Y1 - 2007 A1 - Novaro, Gian M A1 - Katz, Ronit A1 - Aviles, Ronnier J A1 - Gottdiener, John S A1 - Cushman, Mary A1 - Psaty, Bruce M A1 - Otto, Catherine M A1 - Griffin, Brian P KW - Aged KW - Aged, 80 and over KW - Aortic Valve KW - Aortic Valve Stenosis KW - C-Reactive Protein KW - Calcinosis KW - Cardiovascular Diseases KW - Cohort Studies KW - Disease Progression KW - Female KW - Follow-Up Studies KW - Heart Valve Diseases KW - Humans KW - Male KW - Risk Factors AB -

OBJECTIVES: The purpose of this study was to examine the relationship between C-reactive protein (CRP) and calcific aortic valve disease in a large, randomly selected, population-based cohort.

BACKGROUND: The pathobiology of calcific aortic stenosis involves an active inflammatory, atheromatous, osteogenic process. Elevations in CRP, a measure of systemic inflammation, have been associated with aortic stenosis.

METHODS: Two-dimensional and Doppler echocardiography and CRP measurement were performed at baseline in 5,621 participants in the Cardiovascular Health Study. Multivariable analysis was used to identify CRP as a predictor of baseline and incident aortic stenosis.

RESULTS: At a mean echocardiographic follow-up of 5 years, 9% of subjects with aortic sclerosis progressed to some degree of aortic stenosis. Increasing age (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.09 to 1.16; p < 0.001) and male gender (OR 3.05, 95% CI 1.76 to 5.27; p < 0.001) were related to risk of incident aortic stenosis, whereas increasing height (OR 0.96, 95% CI 0.94 to 0.99; p = 0.013) and African-American ethnicity conveyed a lower risk (OR 0.49, 95% CI 0.25 to 0.95; p = 0.035). C-reactive protein, treated as a continuous variable, was not associated with baseline aortic stenosis, progression to aortic sclerosis (adjusted OR 0.93, 95% CI 0.85 to 1.02; p = 0.107), or progression to aortic stenosis (adjusted OR 0.85, 95% CI 0.70 to 1.03; p = 0.092).

CONCLUSIONS: In this large population-based cohort, approximately 9% of subjects with aortic sclerosis progressed to aortic stenosis over a 5-year follow-up period. There was no association between CRP levels and the presence of calcific aortic-valve disease or incident aortic stenosis. C-reactive protein appears to be a poor predictor of subclinical calcific aortic-valve disease.

VL - 50 IS - 20 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17996566?dopt=Abstract ER - TY - JOUR T1 - Depressive symptoms, inflammation, and ischemic stroke in older adults: a prospective analysis in the cardiovascular health study. JF - J Am Geriatr Soc Y1 - 2007 A1 - Arbelaez, Jose J A1 - Ariyo, Abraham A A1 - Crum, Rosa M A1 - Fried, Linda P A1 - Ford, Daniel E KW - Aged KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cerebral Infarction KW - Cohort Studies KW - Depression KW - Female KW - Geriatric Assessment KW - Humans KW - Inflammation KW - Kaplan-Meier Estimate KW - Longitudinal Studies KW - Male KW - Multivariate Analysis KW - Personality Assessment KW - Proportional Hazards Models KW - Prospective Studies KW - Psychoneuroimmunology KW - Risk Factors KW - Socioeconomic Factors KW - Statistics as Topic KW - United States AB -

OBJECTIVES: To investigate the mediator role of inflammation in any relationship between depressive symptoms and ischemic stroke.

DESIGN: Longitudinal prospective study.

SETTING: Review of medical records, death certificates, and the Medicare healthcare utilization database for hospitalizations.

PARTICIPANTS: Total of 5,525 elderly men and women aged 65 and older who were prospectively followed from 1989 to 2000 as participants in the Cardiovascular Health Study.

MEASUREMENTS: Depression symptom scores, inflammatory markers.

RESULTS: Greater depressive symptoms were associated with risk of ischemic stroke (unadjusted hazard ratio (HR)=1.32, 95% confidence interval (CI)=1.09-1.59; HR=1.26, 95% CI=1.03-1.54, adjusted for traditional risk factors). When a term for inflammation (C-reactive protein (CRP)) was introduced in the model, the HRs were not appreciably altered (unadjusted HR=1.31, 95% CI=1.08-1.58; adjusted HR=1.25, 95% CI=1.02-1.53), indicating that CRP at baseline was not a mediator in this relationship. In analyses stratified according to CRP levels, a J-shaped relationship between depressive symptoms and stroke was evident in the unadjusted analyses; in the fully adjusted model, only CRP in the highest tertile was associated with a higher risk for stroke in the presence of higher depressive symptoms scores.

CONCLUSION: The analyses from this prospective study provide evidence of a positive association between depressive symptoms and risk of incident stroke. Inflammation, as measured according to CRP at baseline, did not appear to mediate the relationship between depressive symptoms and stroke.

VL - 55 IS - 11 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17916124?dopt=Abstract ER - TY - JOUR T1 - Gait variability and the risk of incident mobility disability in community-dwelling older adults. JF - J Gerontol A Biol Sci Med Sci Y1 - 2007 A1 - Brach, Jennifer S A1 - Studenski, Stephanie A A1 - Perera, Subashan A1 - VanSwearingen, Jessie M A1 - Newman, Anne B KW - Aged KW - Aged, 80 and over KW - Aging KW - Cohort Studies KW - Female KW - Gait KW - Gait Disorders, Neurologic KW - Humans KW - Male KW - Mobility Limitation KW - Prospective Studies KW - Risk Factors KW - Walking AB -

BACKGROUND: Gait speed is a strong predictor of incident walking disability. The objective was to determine if gait variability adds to the prediction of incident mobility disability independent of gait speed.

METHODS: Participants included 379 older adults (mean age = 79 years; 78% Caucasian, and 40% men) in the Cardiovascular Health Study at the Pittsburgh site. All could ambulate independently and reported no difficulty walking a half mile. Gait characteristics were determined from a 4-meter computerized walkway. For each gait parameter, variability was defined as the standard deviation from the individual steps from two passes. Incident walking disability was obtained by phone interview every 6 months for 54 months and was defined as new difficulty walking a half mile or inability to walk a half mile.

RESULTS: Of the 379 participants, 222 (58.6%) developed incident mobility disability. In unadjusted Cox proportional hazards models gait speed, mean step length, mean stance time, and stance time variability were associated with incident mobility disability. After adjusting for gait speed, demographics, chronic conditions, prescription medications, health status, and physical activity level, only stance time variability remained an important indicator of disability. In the adjusted model, an increase in stance time variability of 0.01 seconds was associated with a 13% higher incidence of mobility disability (hazard ratio 1.13, 95% confidence interval, 1.01-1.27).

CONCLUSIONS: Stance time variability is an independent predictor of future mobility disability. Future efforts are needed to determine whether interventions that decrease stance time variability will also delay mobility disability.

VL - 62 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17895436?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association of sleep and circadian phenotypes. JF - BMC Med Genet Y1 - 2007 A1 - Gottlieb, Daniel J A1 - O'Connor, George T A1 - Wilk, Jemma B KW - Adult KW - Alleles KW - Cardiovascular Diseases KW - Circadian Rhythm KW - Cohort Studies KW - Female KW - Gene Frequency KW - Genetic Linkage KW - Genome, Human KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Sleep KW - Surveys and Questionnaires AB -

BACKGROUND: Numerous studies suggest genetic influences on sleepiness and circadian rhythms. The Sleep Heart Health Study collected questionnaire data on sleep habits and sleepiness from 2848 Framingham Heart Study Offspring Cohort participants. More than 700 participants were genotyped using the Affymetrix 100K SNP GeneChip, providing a unique opportunity to assess genetic linkage and association of these traits.

METHODS: Sleepiness (defined as the Epworth Sleepiness Scale score), usual bedtime and usual sleep duration were assessed by self-completion questionnaire. Standardized residual measures adjusted for age, sex and BMI were analyzed. Multipoint variance components linkage analysis was performed. Association of SNPs to sleep phenotypes was analyzed with both population-based and family-based association tests, with analysis limited to 70,987 autosomal SNPs with minor allele frequency > or =10%, call rate > or =80%, and no significant deviation from Hardy-Weinberg equilibrium (p > or = 0.001).

RESULTS: Heritability of sleepiness was 0.29, bedtime 0.22, and sleep duration 0.17. Both genotype and sleep phenotype data were available for 749 subjects. Linkage analysis revealed five linkage peaks of LOD >2: four to usual bedtime, one to sleep duration. These peaks include several candidate sleep-related genes, including CSNK2A2, encoding a known component of the circadian molecular clock, and PROK2, encoding a putative transmitter of the behavioral circadian rhythm from the suprachiasmatic nucleus. Association tests identified an association of usual bedtime with a non-synonymous coding SNP in NPSR1 that has been shown to encode a gain of function mutation of the neuropeptide S receptor, whose endogenous ligand is a potent promoter of wakefulness. Each copy of the minor allele of this SNP was associated with a 15 minute later mean bedtime. The lowest p value was for association of sleepiness with a SNP located in an intron of PDE4D, which encodes a cAMP-specific phosphodiesterase widely expressed in human brain. Full association results are posted at http://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?id=phs000007 webcite.

CONCLUSION: This analysis confirms prior reports of significant heritability of sleepiness, usual bedtime, and usual sleep duration. Several genetic loci with suggestive linkage to these traits are identified, including linkage peaks containing circadian clock-related genes. Association tests identify NPSR1 and PDE4D as possible mediators of bedtime and sleepiness.

VL - 8 Suppl 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17903308?dopt=Abstract ER - TY - JOUR T1 - IL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study. JF - Hum Genet Y1 - 2007 A1 - Walston, Jeremy D A1 - Fallin, M Daniele A1 - Cushman, Mary A1 - Lange, Leslie A1 - Psaty, Bruce A1 - Jenny, Nancy A1 - Browner, Warren A1 - Tracy, Russell A1 - Durda, Peter A1 - Reiner, Alex KW - African Americans KW - Aged KW - Alleles KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Humans KW - Interleukin-6 KW - Introns KW - Longitudinal Studies KW - Male KW - Polymorphism, Single Nucleotide KW - Promoter Regions, Genetic AB -

Interleukin-6 (IL-6) and C-reactive protein (CRP) levels increase with age and likely play a role in adverse health outcomes in older adults. The relationship between IL-6 gene tag single nucleotide polymorphisms (SNPs) and circulating IL-6 and CRP levels, cardiovascular disease (CVD) outcomes, and mortality in Caucasian (CA) and African American (AA) participants of the Cardiovascular Health Study (CHS) was evaluated using ANCOVA and Cox proportional hazards models. The minor allele of the promoter SNP 1510 and intronic SNP 3572 associates with significantly higher serum IL-6 and CRP levels in CA but not AA. The CRP association persisted after CA and AA populations were combined and after accounting for multiple comparisons. These associations did not carry through to cardiovascular disease outcomes. Decreased risk of stroke was identified in CA, with the minor allele of SNP 1111 (HRR 0.71, 95% CI 0.52, 0.95), P = 0.02, and increased risk of CVD and all-cause mortality (HRR 1.31, 95% CI 1.05-1.64) in AAs heterozygote for SNP 2989. While genetic variation in the IL-6 gene was associated with circulating IL-6 and especially with CRP concentrations in this study, there is little evidence for association between common IL-6 gene variation and adverse health outcomes in this population of older adults.

VL - 122 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17851695?dopt=Abstract ER - TY - JOUR T1 - Individual and neighborhood socioeconomic status and progressive chronic kidney disease in an elderly population: The Cardiovascular Health Study. JF - Soc Sci Med Y1 - 2007 A1 - Merkin, Sharon Stein A1 - Diez Roux, Ana V A1 - Coresh, Josef A1 - Fried, Linda F A1 - Jackson, Sharon A A1 - Powe, Neil R KW - Age Factors KW - Aged KW - Cohort Studies KW - Female KW - Humans KW - Incidence KW - Kidney Failure, Chronic KW - Male KW - Proportional Hazards Models KW - Residence Characteristics KW - Risk Factors KW - Sex Factors KW - Social Class KW - United States AB -

Few studies have focused on the association between socioeconomic status (SES) and progressive chronic kidney disease (pCKD) in an elderly population. We conducted a cohort study of 4735 Cardiovascular Health Study participants, ages 65 and older and living in 4 US communities, to examine the independent risk of pCKD associated with income, education and living in a low SES area. pCKD was defined as creatinine elevation 0.4 mg/dL (35 micromol/L) over a 4-7 year follow-up or CKD hospitalization. Area SES was characterized using measures of income, wealth, education and occupation for 1990 (corresponding to time of enrollment) US Census block groups of residence. Age and study site-adjusted incidence rates (per 1000 person years) of pCKD by quartiles of area-level SES score, income and education showed decreasing rates with increasing SES. Cox proportional hazards models showed that living in the lowest SES area quartile, as opposed to the highest, was associated with 50% greater risk of pCKD, after adjusting for age, gender, study site, baseline creatinine, and individual-level SES. This increased risk and trend persisted after adjusting for lifestyle risk factors, diabetes and hypertension. We found no significant independent associations between pCKD and individual-level income or education (after adjusting for all other SES factors). As such, living in a low SES area is associated with greater risk of pCKD in an elderly US population.

VL - 65 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17499411?dopt=Abstract ER - TY - JOUR T1 - Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study. JF - J Thromb Haemost Y1 - 2007 A1 - Zakai, N A A1 - Katz, R A1 - Jenny, N S A1 - Psaty, B M A1 - Reiner, A P A1 - Schwartz, S M A1 - Cushman, M KW - Aged KW - Aging KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cholesterol KW - Cohort Studies KW - Factor VIII KW - Female KW - Fibrinogen KW - Hemostasis KW - Homocysteine KW - Humans KW - Inflammation Mediators KW - Interleukin-6 KW - Leukocyte Count KW - Lipoprotein(a) KW - Male KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: There are few studies of inflammation and hemostasis biomarkers and cardiovascular disease risk (CVD) in older adults.

OBJECTIVES: To assess multiple biomarkers simultaneously and in combinations for CVD risk assessment in older individuals.

PATIENTS/METHODS: Thirteen biomarkers, interleukin-6 (IL-6), C-reactive protein (CRP), D-dimer, fibrinogen, factor VII, factor VIII, leukocyte count (WBC), platelet count, lipoprotein(a), soluble intercellular adhesion molecule-1 (sICAM-1), albumin, homocysteine and uric acid, were correlated with incident CVD in 4510 individuals in the Cardiovascular Health Study. Baseline biomarkers were analyzed as gender-specific SD increments and quintiles in proportional hazards models adjusted for demographics, CVD risk factors and medications.

RESULTS: Over 9 years with 1700 CVD events, seven biomarkers were associated with CVD. Adjusted hazard ratios (HRs, 95% CI) per SD increment were 1.16 (1.09, 1.23) for IL-6, 1.16 (1.09, 1.23) for CRP, 1.13 (1.05, 1.21) for D-dimer, 1.17 (1.09, 1.25) for homocysteine, 1.06 (1.00, 1.12) for WBC, 1.06 (1.00, 1.12) for factor VIII, and 1.07 (1.00, 1.13) for lipoprotein(a). Fibrinogen was associated with CVD in men only (HR 1.12, 95% CI 1.04, 1.22) and sICAM-1 in women only (HR 1.16, 95% CI 1.05, 1.27). IL-6 and CRP remained associated with CVD when modeled with WBC. Participants were classified by all combinations of two biomarkers being high or low (IL-6, CRP, WBC, factor VIII, cholesterol/HDL). All were associated with CVD when cholesterol/HDL was low and none when CRP was low.

CONCLUSIONS: Seven biomarkers were associated with CVD in older adults, with CRP having some advantages compared with others. Even larger studies are needed to better characterize these associations.

VL - 5 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17388967?dopt=Abstract ER - TY - JOUR T1 - Physical activity and white matter lesion progression: assessment using MRI. JF - Neurology Y1 - 2007 A1 - Podewils, L J A1 - Guallar, E A1 - Beauchamp, N A1 - Lyketsos, C G A1 - Kuller, L H A1 - Scheltens, P KW - Activities of Daily Living KW - Aged KW - Alzheimer Disease KW - Cognition Disorders KW - Cohort Studies KW - Demyelinating Diseases KW - Disease Progression KW - Female KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Motor Activity KW - United States AB -

We evaluated the association between physical activity and changes in white matter lesions (WMLs) on MRI in a sample of 179 older adults comprising 59 incident cases of Alzheimer disease, 60 persons with mild cognitive impairment, and 60 persons who remained cognitively stable over a median 5-year follow-up. Physical activity was not significantly associated with a decreased rate of periventricular or deep WML progression.

VL - 68 IS - 15 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17420407?dopt=Abstract ER - TY - JOUR T1 - Relationship of uric acid with progression of kidney disease. JF - Am J Kidney Dis Y1 - 2007 A1 - Chonchol, Michel A1 - Shlipak, Michael G A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Newman, Anne B A1 - Siscovick, David S A1 - Kestenbaum, Bryan A1 - Carney, Jan Kirk A1 - Fried, Linda F KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Cross-Sectional Studies KW - Disease Progression KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Diseases KW - Male KW - Prospective Studies KW - Uric Acid AB -

BACKGROUND: Uric acid levels are increased in patients with kidney dysfunction. We tested the hypothesis that uric acid may be associated with kidney disease progression.

STUDY DESIGN: Cohort study.

SETTING & PARTICIPANTS: 5,808 participants of the Cardiovascular Health Study.

PREDICTOR: Uric acid levels.

OUTCOMES & MEASUREMENTS: Kidney disease progression was defined as a decrease in estimated glomerular filtration rate (GFR) of 3 mL/min/1.73 m(2) per year or greater (>or=0.05 mL/s) and as incident chronic kidney disease (CKD). Measures of kidney function were estimated GFR using the Modification of Diet in Renal Disease Study equation.

RESULTS: Higher quintiles of uric acid levels were associated with greater prevalences of estimated GFR less than 60 mL/min/1.73 m(2) (<1.00 mL/s) of 7%, 14%, 12%, 25%, and 42% for quintiles 1 (6.90 mg/dL [>410 micromol/L]), respectively. In comparison, there was only a modest, but significant, association between quintiles of uric acid levels and progression of kidney function decrease, with adjusted odds ratios of 1.0, 0.88 (95% confidence interval [CI], 0.64 to 1.21), 1.23 (95% CI, 0.87 to 1.75), 1.47 (95% CI, 1.04 to 2.07), and 1.49 (95% CI, 1.00 to 2.22) for quintiles 1 through 5, respectively. No significant association was found between uric acid level and incident CKD (adjusted odds ratio, 1.00; 95% CI, 0.89 to 1.14).

LIMITATIONS: Measurements of albuminuria were not available.

CONCLUSIONS: Uric acid levels are associated strongly with prevalent CKD. In comparison, greater uric acid levels had a significant, but much weaker, association with progression of kidney disease.

VL - 50 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17660025?dopt=Abstract ER - TY - JOUR T1 - USF1 gene variants, cardiovascular risk, and mortality in European Americans: analysis of two US cohort studies. JF - Arterioscler Thromb Vasc Biol Y1 - 2007 A1 - Reiner, Alexander P A1 - Carlson, Christopher S A1 - Jenny, Nancy S A1 - Durda, J Peter A1 - Siscovick, David S A1 - Nickerson, Deborah A A1 - Tracy, Russell P KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Blood Glucose KW - C-Reactive Protein KW - Calcium KW - Cardiovascular Diseases KW - Carotid Artery, Common KW - Cohort Studies KW - Coronary Artery Disease KW - Coronary Vessels KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Genetic Predisposition to Disease KW - Humans KW - Hyperlipidemia, Familial Combined KW - Insulin KW - Interleukin-6 KW - Linkage Disequilibrium KW - Lipids KW - Male KW - Odds Ratio KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Time Factors KW - United States KW - Upstream Stimulatory Factors AB -

OBJECTIVE: A common haplotype of the upstream transcription factor 1 gene (USF1) has been associated with decreased susceptibility to familial combined hyperlipidemia (FCHL) and, paradoxically, with increased risk of cardiovascular disease (CVD) and all-cause mortality.

METHODS AND RESULTS: We assessed associations between USF1 tagSNPs, CVD risk factors, and aging-related phenotypes using data from 2 large population-based cohorts, Coronary Artery Risk Development in Young Adults (CARDIA) and the Cardiovascular Health Study (CHS), comprising younger and older adults, respectively. In CARDIA, each additional copy of the FCHL low-risk allele was associated with 2.4 mg/dL lower levels of LDL cholesterol (P=0.01) and decreased risk of subclinical atherosclerosis as assessed by coronary artery calcium (odds ratio 0.79; 95%CI 0.63 to 0.98). Whereas there was little association between USF1 genotype and metabolic or CVD traits in older adults from CHS, the USF1 low-risk dyslipidemia allele was associated with higher plasma C-reactive protein and interleukin (IL)-6 levels and with increased risk of mortality, particularly attributable to noncardiovascular causes.

CONCLUSIONS: There appears to be a complex and possibly age-dependent relationship between USF1 genotype, atherosclerosis phenotypes, and CVD risk. USF1 may influence mortality through pathways distinct from atherosclerosis. Alternatively, linkage disequilibrium with neighboring polymorphisms in other genes such as F11R may be responsible for the observed USF1 genotype-phenotype associations in older adults.

VL - 27 IS - 12 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17885212?dopt=Abstract ER - TY - JOUR T1 - Ventricular structure and function in hypertensive participants with heart failure and a normal ejection fraction: the Cardiovascular Health Study. JF - J Am Coll Cardiol Y1 - 2007 A1 - Maurer, Mathew S A1 - Burkhoff, Daniel A1 - Fried, Linda P A1 - Gottdiener, John A1 - King, Donald L A1 - Kitzman, Dalane W KW - Age Distribution KW - Aged KW - Body Size KW - Case-Control Studies KW - Cohort Studies KW - Comorbidity KW - Continental Population Groups KW - Echocardiography KW - Female KW - Heart Failure KW - Heart Ventricles KW - Humans KW - Hypertension KW - Longitudinal Studies KW - Male KW - Multivariate Analysis KW - Prevalence KW - Regression Analysis KW - Risk Factors KW - Sex Distribution KW - Stroke Volume KW - United States AB -

OBJECTIVES: The purpose of this study was to evaluate left ventricular (LV) size and structure in elderly subjects with hypertension (HTN) and heart failure who have a normal ejection fraction (HFNEF) in a large population-based sample.

BACKGROUND: The pathophysiology of HFNEF is incompletely understood but is generally attributed to LV diastolic dysfunction with normal or reduced LV diastolic chamber size despite greater than normal filling pressures.

METHODS: In the Cardiovascular Health Study (n = 5,888), demographic and clinical characteristics and ventricular structure and function were compared in healthy normal subjects (healthy; n = 499), subjects with HTN but not heart failure (HTN; n = 2,184), and subjects with HTN and HFNEF (HFNEF; n = 167).

RESULTS: Subjects with HFNEF were older, more obese, and more often African American than healthy and HTN subjects and had a higher prevalence of diabetes, coronary heart disease, and anemia than HTN subjects. Serum creatinine and cystatin-C were increased in HFNEF subjects. Average LV diastolic dimension was significantly increased in HFNEF subjects (5.2 +/- 0.8 cm) compared with healthy (4.8 +/- 0.6 cm) and HTN (4.9 +/- 0.6 cm) subjects. As a result, average calculated stroke volume (89 +/- 25 ml vs. 78 +/- 20 ml and 80 +/- 20 ml) and cardiac output (6.0 +/- 2.0 l/min vs. 4.8 +/- 1.3 l/min and 5.1 +/- 1.4 l/min) were increased in HFNEF compared with healthy and HTN subjects, respectively.

CONCLUSIONS: As a group, HFNEF subjects have increased LV diastolic diameter and increased calculated stroke volume. They also have increased prevalence of multiple comorbidities, including anemia, renal dysfunction, and obesity, that can cause volume overload. These data suggest that extracardiac factors, via volume overload, may contribute to the pathophysiology of HFNEF in the elderly.

VL - 49 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17336721?dopt=Abstract ER - TY - JOUR T1 - Adiponectin and risk of coronary heart disease in older men and women. JF - J Clin Endocrinol Metab Y1 - 2008 A1 - Kizer, Jorge R A1 - Barzilay, Joshua I A1 - Kuller, Lewis H A1 - Gottdiener, John S KW - Adiponectin KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Body Weight KW - Case-Control Studies KW - Cohort Studies KW - Coronary Disease KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Odds Ratio KW - Risk Factors AB -

CONTEXT: Despite established insulin-sensitizing and antiatherogenic preclinical effects, epidemiological investigations of adiponectin have yielded conflicting findings, and its relationship with coronary heart disease (CHD) remains uncertain.

OBJECTIVE: Our objective was to investigate the relationship between adiponectin and CHD in older adults.

DESIGN, SETTING, AND PARTICIPANTS: This was a case-control study (n = 1386) nested within the population-based Cardiovascular Health Study from 1992--2001. Controls were frequency-matched to cases by age, sex, race, subclinical cardiovascular disease, and center.

MAIN OUTCOME MEASURES: Incident CHD was defined as angina pectoris, percutaneous or surgical revascularization, nonfatal myocardial infarction (MI), or CHD death. A more restrictive CHD endpoint was limited to nonfatal MI and CHD death.

RESULTS: Adiponectin exhibited significant negative correlations with baseline adiposity, insulin resistance, dyslipidemia, inflammatory markers, and leptin. After controlling for matching factors, adjustment for waist to hip ratio, hypertension, smoking, alcohol, low-density lipoprotein cholesterol, creatinine, and leptin revealed a modestly increased risk of incident CHD with adiponectin concentrations at the upper end [odds ratio = 1.37 (quintile 5 vs. 1-4), 95% confidence interval 1.02-1.84]. This association was stronger when the outcome was limited to nonfatal MI and fatal CHD (odds ratio = 1.69, 95% confidence interval 1.23-2.32). The findings were not influenced by additional adjustment for weight change, health status, or cystatin C, nor were they abolished by adjustment for potential mediators.

CONCLUSIONS: This study shows an association between adiponectin and increased risk of first-ever CHD in older adults. Further research is needed to elucidate the basis for the concurrent beneficial and detrimental aspects of this relationship, and under what circumstances one or the other may predominate.

VL - 93 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18593765?dopt=Abstract ER - TY - JOUR T1 - Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. JF - JAMA Y1 - 2008 A1 - Fowkes, F G R A1 - Murray, G D A1 - Butcher, I A1 - Heald, C L A1 - Lee, R J A1 - Chambless, L E A1 - Folsom, A R A1 - Hirsch, A T A1 - Dramaix, M A1 - deBacker, G A1 - Wautrecht, J-C A1 - Kornitzer, M A1 - Newman, A B A1 - Cushman, M A1 - Sutton-Tyrrell, K A1 - Fowkes, F G R A1 - Lee, A J A1 - Price, J F A1 - D'Agostino, R B A1 - Murabito, J M A1 - Norman, P E A1 - Jamrozik, K A1 - Curb, J D A1 - Masaki, K H A1 - Rodríguez, B L A1 - Dekker, J M A1 - Bouter, L M A1 - Heine, R J A1 - Nijpels, G A1 - Stehouwer, C D A A1 - Ferrucci, L A1 - McDermott, M M A1 - Stoffers, H E A1 - Hooi, J D A1 - Knottnerus, J A A1 - Ogren, M A1 - Hedblad, B A1 - Witteman, J C A1 - Breteler, M M B A1 - Hunink, M G M A1 - Hofman, A A1 - Criqui, M H A1 - Langer, R D A1 - Fronek, A A1 - Hiatt, W R A1 - Hamman, R A1 - Resnick, H E A1 - Guralnik, J A1 - McDermott, M M KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Ankle KW - Atherosclerosis KW - Blood Pressure KW - Brachial Artery KW - Cardiovascular Diseases KW - Cohort Studies KW - Confidence Intervals KW - Female KW - Global Health KW - Humans KW - Male KW - Middle Aged KW - Odds Ratio KW - Predictive Value of Tests KW - Risk Assessment KW - Risk Factors KW - Severity of Illness Index AB -

CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction.

OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction.

DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies.

STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality.

DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease.

RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women.

CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

VL - 300 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18612117?dopt=Abstract ER - TY - JOUR T1 - Antidepressant treatment and worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. JF - Stroke Y1 - 2008 A1 - Steffens, David C A1 - Chung, Hyoju A1 - Krishnan, K Ranga R A1 - Longstreth, W T A1 - Carlson, Michelle A1 - Burke, Gregory L KW - Aged KW - Antidepressive Agents KW - Antidepressive Agents, Tricyclic KW - Cohort Studies KW - Disease Progression KW - Female KW - Follow-Up Studies KW - Humans KW - Leukoaraiosis KW - Magnetic Resonance Imaging KW - Male KW - Multivariate Analysis KW - Risk Assessment KW - Serotonin Uptake Inhibitors AB -

BACKGROUND AND PURPOSE: In some studies, late life depression is associated with white matter lesions on MRI. The effect of different classes of antidepressants on progression of white matter lesions is unknown. Selective serotonergic reuptake inhibitors (SSRIs) may decrease platelet aggregation. We hypothesized that Cardiovascular Health Study participants taking SSRIs would less often have worsening white matter on serial MRI than participants not on antidepressants.

METHODS: Among 1826 participants who were not using an antidepressant at initial MRI scan, we examined the association of worsening in white matter grade from initial to follow-up MRI scans, 5 years apart on average, and antidepressant use between the scans. Logistic regression models were used, controlling for a variety of potential confounding variables.

RESULTS: Use of any antidepressant during the period of study was associated with worsening white matter. In a multivariable model, risk was slightly increased, not reduced, with use of serotonergic agents (OR 1.36, 95% CI 0.87 to 2.12) and was significantly increased with the use of tricyclic antidepressants (OR 1.77, 95% CI 1.07 to 2.94).

CONCLUSIONS: The association between worsening white matter and use of tricyclic antidepressants was an unexpected finding that may relate to indications for use other than depression or to side effects such as hypotension. Protection against worsening was not seen with use of serotonergic agents.

VL - 39 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18239166?dopt=Abstract ER - TY - JOUR T1 - Association between brachial artery reactivity and cardiovascular disease status in an elderly cohort: the cardiovascular health study. JF - Atherosclerosis Y1 - 2008 A1 - Yeboah, Joseph A1 - Sutton-Tyrrell, Kim A1 - McBurnie, Mary Ann A1 - Burke, Gregory L A1 - Herrington, David M A1 - Crouse, John R KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Brachial Artery KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Hemorheology KW - Humans KW - Male KW - Peripheral Vascular Diseases KW - ROC Curve KW - Ultrasonography KW - Vasodilation AB -

BACKGROUND AND OBJECTIVES: The association of brachial flow-mediated dilation (FMD) and cardiovascular disease (CVD) status is unclear especially in older adults whose FMD is greatly diminished. We assessed the association of FMD and the presence or absence of subclinical and clinical CVD in a population based cohort of older adults.

METHODS AND RESULTS: FMD was measured in 2971 adults aged 72-98 years (mean age 78.6 years) who participated in the Cardiovascular Health Study. Multiple linear regression analysis was used to examine the association between FMD and CVD status (clinical, subclinical and free of CVD). Out of 2791 with complete data, 82.7% were Caucasians and 59% females. Seven hundred and forty-three were classified as having clinical CVD, 607 as subclinical CVD and 1441 as neither clinical CVD nor subclinical CVD (CVD free). FMD was higher in the CVD free group compared with either the clinical (3.13+/-0.05% vs 2.93+/-0.07%, p=0.025) or the subclinical CVD group (3.13+/-0.05% vs 2.95+/-0.08%, p=0.05) after adjusting for covariates. There was no significant difference between the FMD of subjects with clinical and subclinical CVD (2.93+/-0.07% vs 2.95+/-0.08%, p=0.84). Similar but inverted associations were observed between height adjusted brachial artery diameter (BAD) and CVD status. However, FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD.

CONCLUSION: Among older adults, those with either clinical or subclinical CVD have lower FMD than CVD free subjects. BAD showed similar but inverted associations with CVD status in this cohort. FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD.

VL - 197 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17714717?dopt=Abstract ER - TY - JOUR T1 - Association between lower digit symbol substitution test score and slower gait and greater risk of mortality and of developing incident disability in well-functioning older adults. JF - J Am Geriatr Soc Y1 - 2008 A1 - Rosano, Caterina A1 - Newman, Anne B A1 - Katz, Ronit A1 - Hirsch, Calvin H A1 - Kuller, Lewis H KW - Activities of Daily Living KW - Aged KW - Aged, 80 and over KW - Analysis of Variance KW - Atrophy KW - Brain KW - Brain Diseases KW - Cause of Death KW - Cohort Studies KW - Disability Evaluation KW - Discrimination Learning KW - Female KW - Gait KW - Humans KW - Male KW - Memory, Short-Term KW - Mobility Limitation KW - Neuropsychological Tests KW - Pattern Recognition, Visual KW - Psychometrics KW - Psychomotor Performance KW - Risk Factors AB -

OBJECTIVES: To determine whether, in well-functioning older adults, a lower score on the Digit Symbol Substitution Test (DSST) and slower gait are associated with greater risk of mortality and of developing incident disability independent of other risk factors, including brain structural abnormalities (white matter hyperintensities, brain infarcts, ventricular enlargement) and whether the combination of varying levels of DSST score and gait speed are associated with a greater risk of mortality and disability than low DSST or slow gait alone.

DESIGN: Observational cohort study.

SETTING: Community.

PARTICIPANTS: Three thousand one hundred fifty-six (43% men, 29% black, mean age 70.4) participants in the Cardiovascular Health Study (CHS), free from stroke and physical disability and with a modified Mini-Mental State Examination (3MS) score of 80 or higher.

MEASUREMENTS: Total mortality and incident disability (self-report of any difficulty performing one or more of the six activities of daily living) ascertained over a median follow-up time of 8.4 years.

RESULTS: By the end of follow-up, 704 participants had died and 1,096 had incident disability. In Cox proportional hazards models adjusted for age, sex, race, education, cardiovascular disease, and brain magnetic resonance imaging abnormalities, lower DSST score and slower gait remained significantly associated with greater risk of mortality and of incident disability. Mortality rates were higher in those who had both low DSST score (<27 points) and slow gait (speed <1.0 m/s) than in those who had only low DSST score, only slow gait, or neither (rates per 1,000 person years (p-y): 61.2, 42.8, 20.8, and 16.3, respectively). A similar risk gradient was observed for incident disability (82.0, 57.9, 47.9, and 36.0/1,000 p-y, respectively).

CONCLUSION: In well-functioning older adults, low DSST score and slow gait, alone or in combination, could be risk factors for mortality and for developing disability, independent of other risk factors, including measures of brain integrity.

VL - 56 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18691275?dopt=Abstract ER - TY - JOUR T1 - Biomarkers of Inflammation and MRI-Defined Small Vessel Disease of the Brain: The Cardiovascular Health Study. JF - Stroke Y1 - 2008 A1 - Fornage, Myriam A1 - Chiang, Y Aron A1 - O'Meara, Ellen S A1 - Psaty, Bruce M A1 - Reiner, Alexander P A1 - Siscovick, David S A1 - Tracy, Russell P A1 - Longstreth, W T KW - African Continental Ancestry Group KW - Aged KW - Biomarkers KW - Brain Infarction KW - C-Reactive Protein KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Haplotypes KW - Humans KW - Inflammation KW - Interleukin-6 KW - Magnetic Resonance Imaging KW - Male KW - Polymorphism, Single Nucleotide AB -

BACKGROUND AND PURPOSE: To clarify the role of inflammation in the pathogenesis of small vessel disease of the brain, we investigated the association between common variation in the C-reactive protein (CRP) and interleukin (IL)-6 genes, plasma CRP and IL6 levels, and presence of MRI-defined white matter lesions (WML) and brain infarcts (BI) in elderly participants of the Cardiovascular Health Study.

METHODS: Tag single nucleotide polymorphisms (SNPs) in the CRP and IL6 genes were selected from the SeattleSNPs database. In cross-sectional analyses, logistic regression models adjusting for known cardiovascular disease risk factors were constructed to assess the associations of plasma CRP and IL6 levels and common CRP and IL6 gene haplotypes with presence of WML or BI in Blacks (n=532) and Whites (n=2905).

RESULTS: Plasma IL6 and CRP levels were associated with presence of WML and BI in both races. In Whites, common haplotypes of the IL6 gene were significantly associated with WML and BI. The common haplotype tagged by the -174G/C promoter polymorphism was associated with an increased risk of WML (OR=1.14; 95% CI: [1.02; 1.28]). The common haplotype tagged by the -572G/C promoter polymorphism was associated with an increased risk of BI (OR=1.57; 95% CI: [1.15; 2.14]). Significant associations were lacking for WML or BI with IL6 gene variation in Blacks, or with CRP gene variation in either race.

CONCLUSIONS: This study provides evidence of a genetic basis underlying the relationship between plasma biomarkers of inflammation and small vessel disease of the brain. Further studies to elucidate the specific role of IL6 in disease pathogenesis are warranted.

VL - 39 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18436879?dopt=Abstract ER - TY - JOUR T1 - Cardiovascular and mortality risk prediction and stratification using urinary albumin excretion in older adults ages 68-102: the Cardiovascular Health Study. JF - Atherosclerosis Y1 - 2008 A1 - Cao, Jie J A1 - Biggs, Mary L A1 - Barzilay, Joshua A1 - Konen, Joseph A1 - Psaty, Bruce M A1 - Kuller, Lewis A1 - Bleyer, Anthony J A1 - Olson, Jean A1 - Wexler, Jason A1 - Summerson, John A1 - Cushman, Mary KW - Aged KW - Aged, 80 and over KW - Albuminuria KW - Biomarkers KW - Cohort Studies KW - Coronary Disease KW - Cross-Sectional Studies KW - Female KW - Health Surveys KW - Humans KW - Male KW - Predictive Value of Tests KW - Risk AB -

BACKGROUND: Elevated urinary albumin excretion (UAE) is associated with the risk of cardiovascular disease (CVD) and all-cause mortality. We tested the hypothesis that elevated UAE improves cardiovascular risk stratification in an elderly cohort aged 68-102 years.

METHODS: We evaluated UAE in 3112 participants of the Cardiovascular Health Study who attended the 1996-1997 examination and had median follow up of 5.4 years. Elevated UAE was defined as urinary albumin to creatinine ratio > or =30 microg/mg. Microalbuminuria and macroalbuminuria were defined as urinary albumin to creatinine ratio 30-300 microg/mg and >300 microg/mg, respectively. Outcomes included CVD (myocardial infarction, stroke, cardiovascular death) and all-cause mortality. Cox proportional hazards models were used to assess the risk of outcomes associated with elevated UAE.

RESULTS: The prevalence of elevated UAE was 14.3%, 17.1% and 26.9% in those aged 68-74, 75-84 and 85-102 years, respectively. CVD incidence and all-cause mortality were doubled (7.2% and 8.1% per year) in those with microalbuminuria and tripled (11.1% and 12.3% per year) in those with macroalbuminuria compared to those with normal UAE (3.3% and 3.8% per year). The increased CVD and mortality risks were observed in all age groups after adjustment for conventional risk factors. The adjusted population attributable risk percent of CVD and all-cause mortality for elevated UAE was 11% and 12%, respectively. When participants were cross-classified by UAE and Framingham Risk Score categories, the 5-year cumulative incidence of coronary heart disease among participants with elevated UAE and a 5-year predicted risk of 5-10% was 20%, substantially higher than 6.3% in those with UAE <30m microg/mg.

CONCLUSION: Elevated UAE was associated with an increased risk of CVD and all-cause mortality in all age groups from 68 to 102 years. Combining elevated UAE with the Framingham risk scores may improve risk stratification for CVD in the elderly.

VL - 197 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17875308?dopt=Abstract ER - TY - JOUR T1 - Common variants in the CRP gene in relation to longevity and cause-specific mortality in older adults: the Cardiovascular Health Study. JF - Atherosclerosis Y1 - 2008 A1 - Hindorff, Lucia A A1 - Rice, Kenneth M A1 - Lange, Leslie A A1 - Diehr, Paula A1 - Halder, Indrani A1 - Walston, Jeremy A1 - Kwok, Pui A1 - Ziv, Elad A1 - Nievergelt, Caroline A1 - Cummings, Steven R A1 - Newman, Anne B A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - Reiner, Alexander P KW - African Americans KW - Aged KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cause of Death KW - Cohort Studies KW - Female KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Linear Models KW - Longevity KW - Male KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - United States AB -

Common polymorphisms in the CRP gene are associated with plasma CRP levels in population-based studies, but associations with age-related events are uncertain. A previous study of CRP haplotypes in older adults was broadened to include longevity and cause-specific mortality (all-cause, noncardiovascular (non-CV), and cardiovascular (CV)). Common haplotypes were inferred from four tagSNPs in 4512 whites and five tagSNPs in 812 blacks from the Cardiovascular Health Study, a longitudinal cohort of adults over age 65. Exploratory analyses addressed early versus late mortality. CRP haplotypes were not associated with all-cause mortality or longevity overall in either population, but associations with all-cause mortality differed during early and late periods. In blacks, the haplotype tagged by 3872A (rs1205) was associated with increased risk of non-CV mortality, relative to other haplotypes (adjusted hazard ratio for each additional copy: 1.42, 95% CI: 1.07, 1.87). Relative to other haplotypes, this haplotype was associated with decreased risk of early but not decreased risk of late CV mortality in blacks; among whites, a haplotype tagged by 2667C (rs1800947) gave similar but nonsignificant findings. If confirmed, CRP genetic variants may be weakly associated with CV and non-CV mortality in older adults, particularly in self-identified blacks.

VL - 197 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17888441?dopt=Abstract ER - TY - JOUR T1 - Cystatin C concentration as a predictor of systolic and diastolic heart failure. JF - J Card Fail Y1 - 2008 A1 - Moran, Andrew A1 - Katz, Ronit A1 - Smith, Nicolas L A1 - Fried, Linda F A1 - Sarnak, Mark J A1 - Seliger, Stephen L A1 - Psaty, Bruce A1 - Siscovick, David S A1 - Gottdiener, John S A1 - Shlipak, Michael G KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Cohort Studies KW - Confidence Intervals KW - Cystatin C KW - Cystatins KW - Echocardiography KW - Female KW - Heart Failure, Diastolic KW - Heart Failure, Systolic KW - Humans KW - Longitudinal Studies KW - Male KW - Predictive Value of Tests KW - Probability KW - Proportional Hazards Models KW - Risk Assessment KW - Sensitivity and Specificity KW - Stroke Volume KW - Survival Analysis AB -

BACKGROUND: Risk factors for heart failure (HF) may differ according to ejection fraction (EF). Higher cystatin C, a marker of kidney dysfunction, is associated with incident HF, but previous studies did not determine EF at diagnosis. We hypothesized that kidney dysfunction would predict diastolic HF (DHF) better than systolic HF (SHF) in the Cardiovascular Health Study.

METHODS AND RESULTS: Cystatin C was measured in 4453 participants without HF at baseline. Incident HF was categorized as DHF (EF > or = 50%) or SHF (EF < 50%). We compared the association of cystatin C with the risk for DHF and SHF, after adjustment for age, sex, race, medications, and HF risk factors. During 8 years of follow-up, 167 participants developed DHF and 206 participants developed SHF. After adjustment, sequentially higher quartiles of cystatin C were associated with risk for SHF (competing risks hazard ratios 1.0 [reference], 1.99 [95% confidence interval 1.14-3.48], 2.32 [1.32-4.07], 3.17 [1.82-5.50], P for trend < .001). The risk for DHF was apparent only at the highest cystatin C quartile (hazard ratios 1.0 [reference], 1.09 [0.62-1.89], 1.08 [0.61-1.93], and 1.83 [1.07-3.11]).

CONCLUSIONS: Cystatin C levels are linearly associated with the incidence of systolic HF, whereas only the highest concentrations of cystatin C predict diastolic HF.

VL - 14 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18226769?dopt=Abstract ER - TY - JOUR T1 - Dietary fish and omega-3 fatty acid consumption and heart rate variability in US adults. JF - Circulation Y1 - 2008 A1 - Mozaffarian, Dariush A1 - Stein, Phyllis K A1 - Prineas, Ronald J A1 - Siscovick, David S KW - Aged KW - Aged, 80 and over KW - Animals KW - Cardiovascular Diseases KW - Cohort Studies KW - Cross-Sectional Studies KW - Electrocardiography KW - Fatty Acids, Omega-3 KW - Female KW - Fishes KW - Heart Rate KW - Humans KW - Male KW - Risk Factors KW - Seafood KW - Tuna KW - United States AB -

BACKGROUND: Fish and omega-3 fatty acid consumption reduce risk of cardiac death, but mechanisms are not well established. Heart rate variability (HRV) predicts cardiac death and reflects specific electrophysiological pathways and influences. We hypothesized that habitual consumption of fish and marine omega-3 fatty acids would be associated with more favorable HRV, elucidating electrophysiological influences and supporting effects on clinical risk.

METHODS AND RESULTS: In a population-based cohort of older US adults, we evaluated cross-sectional associations of usual dietary fish and omega-3 consumption during the prior year and ECG-derived (n=4263) and 24-hour Holter monitor-derived (n=1152) HRV. After multivariable adjustment, consumption of tuna or other broiled/baked fish was associated with specific HRV components, including indices suggesting greater vagal predominance and moderated baroreceptor responses (eg, higher root mean square successive differences of normal-to-normal intervals [P=0.001]; higher normalized high-frequency power [P=0.008]; and lower low-frequency/high-frequency ratio [P=0.03]) and less erratic sinoatrial node firing (eg, lower Poincaré ratio [P=0.02] and higher short-term fractal scaling exponent [P=0.005]) but not measures of circadian fluctuations (eg, 24-hour standard deviation of normal-to-normal intervals). Findings were similar for estimated dietary consumption of marine omega-3 fatty acids. For magnitudes of observed differences in HRV comparing the highest to lowest category of fish intake, differences in relative risk of cardiac death during 10.8 years of follow-up ranged from 1.1% (for difference in standard deviation of normal-to-normal intervals) to 5.9% and 8.4% (for differences in Poincaré ratio and short-term fractal scaling exponent) lower risk.

CONCLUSIONS: Habitual tuna/other fish and marine omega-3 consumption are associated with specific HRV components in older adults, particularly indices of vagal activity, baroreceptor responses, and sinoatrial node function. Cellular mechanisms and implications for clinical risk deserve further investigation.

VL - 117 IS - 9 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18285566?dopt=Abstract ER - TY - JOUR T1 - Distribution and correlates of lipoprotein-associated phospholipase A2 in an elderly cohort: the Cardiovascular Health Study. JF - J Am Geriatr Soc Y1 - 2008 A1 - Furberg, Curt D A1 - Nelson, Jeanenne J A1 - Solomon, Cam A1 - Cushman, Mary A1 - Jenny, Nancy Swords A1 - Psaty, Bruce M KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Aged KW - Atherosclerosis KW - Body Mass Index KW - Cardiac Output, Low KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Cross-Sectional Studies KW - Electrocardiography KW - Female KW - Heart Failure KW - Humans KW - Hypertrophy, Left Ventricular KW - Long QT Syndrome KW - Male KW - Reference Values KW - Renal Insufficiency KW - Risk Factors KW - Statistics as Topic KW - Triglycerides AB -

OBJECTIVES: To determine whether high levels of lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) are associated with prevalent cardiovascular disease (CVD) and to evaluate factors most influencing Lp-PLA(2) levels in a community-based cohort of older adults.

DESIGN: Cross-sectional.

SETTING: The Cardiovascular Health Study (CHS), a population-based cohort study of men and women aged 65 and older.

PARTICIPANTS: Five thousand five hundred thirty-one CHS participants.

MEASUREMENTS: Levels of Lp-PLA(2) activity were determined using stored blood samples from the baseline examination.

RESULTS: Mean Lp-PLA(2) was higher in participants with electrocardiographically determined ventricular conduction defect and major Q-wave abnormality and was positively correlated with left ventricular (LV) mass. It was high in those with echocardiographically determined abnormal LV ejection fraction, which persisted after adjustment. Mean Lp-PLA(2) was also higher in participants with mild renal insufficiency and kidney disease. After multivariable adjustment, there was a modest but significant 27% greater risk of prevalent CHF per standard deviation increment of Lp-PLA(2) and a modest but significant 12% greater risk of prevalent myocardial infarction. Lp-PLA(2) was weakly but mainly most strongly correlated with cholesterol and lipoproteins, but those correlations were not especially strong. Lp-PLA(2) was weakly positively correlated with soluble intercellular adhesion molecule-1 but not interleukin-6. In total, all factors considered could explain only 29% of Lp-PLA(2) activity.

CONCLUSION: Novel findings in the study are the associations, in those aged 65 and older, between Lp-PLA(2) activity and LV dysfunction, CHF, and renal disease. CVD risk factors only minimally explain levels of Lp-PLA(2).

VL - 56 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18363676?dopt=Abstract ER - TY - JOUR T1 - Effect of sleep disordered breathing on the sleep of bed partners in the Sleep Heart Health Study. JF - Sleep Y1 - 2008 A1 - Sharief, Imran A1 - Silva, Graciela E A1 - Goodwin, James L A1 - Quan, Stuart F KW - Aged KW - Arousal KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Polysomnography KW - Quality of Life KW - Sleep Apnea, Obstructive KW - Snoring KW - Spouses AB -

OBJECTIVE: To study the sleep quality of bed partners of persons with sleep disordered breathing in a non-clinical population based sample in a home environment.

DESIGN: Cross-sectional study in a community sample.

METHODS: 110 pairs of subjects living in the same household from the Tucson, Minnesota, and Pittsburgh sites of the Sleep Heart Health Study (SHHS) were included if both partners had an in-home, unattended polysomnogram (PSG) performed as a part of SHHS exam cycle 2. Sleep disordered breathing (SDB) was considered present if the respiratory disturbance index (RDI) was > or =10 events/h and no SDB if RDI was <5 events/h. Pairs were classified according to their SDB status and assigned to one of 3 groups: 1) NoSDB-NoSDB (n = 46), 2) NoSDB-SDB (n = 42), and 3) SDB-SDB (n = 22).

RESULTS: There were no differences between the NoSDB-NoSDB and the SDB-SDB partners in their demographic, PSG, or quality of life variables. However, within the NoSDB-SDB group, NoSDB in comparison to their SDB partners weighed less (mean BMI: 26 vs. 29 kg/m2, P < 0.0003), had decreased stage 2% (55 vs. 64, P < 0.0001), increased stage 3 and 4% (21 vs. 11, P <0.0005) and a lower arousal index (13.8 vs. 20 events/h, P < 0.0001). When comparing the NoSDB subjects from the NoSDB-SDB group to subjects in the NoSDB-NoSDB group and to subjects in the SDB-SDB group, significant differences were seen for RDI and BMI but not for any other parameter.

CONCLUSION: In a non-clinical population based sample, the sleep quality of bed partners of SDB subjects without SDB is better than their SDB bed partner. However, their sleep quality was not different in comparison to the sleep of those without SDB who also had a bed partner without SDB.

VL - 31 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18853943?dopt=Abstract ER - TY - JOUR T1 - Enhanced risk for Alzheimer disease in persons with type 2 diabetes and APOE epsilon4: the Cardiovascular Health Study Cognition Study. JF - Arch Neurol Y1 - 2008 A1 - Irie, Fumiko A1 - Fitzpatrick, Annette L A1 - Lopez, Oscar L A1 - Kuller, Lewis H A1 - Peila, Rita A1 - Newman, Anne B A1 - Launer, Lenore J KW - African Americans KW - Age Factors KW - Aged KW - Alzheimer Disease KW - Apolipoprotein E4 KW - Cognition KW - Cohort Studies KW - Confidence Intervals KW - Dementia, Vascular KW - Diabetes Mellitus, Type 2 KW - European Continental Ancestry Group KW - Female KW - Genotype KW - Humans KW - Longitudinal Studies KW - Male KW - Neuropsychological Tests KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Sex Factors AB -

BACKGROUND: Diabetes and the apolipoprotein E epsilon4 allele (APOE epsilon4) increase the risk for Alzheimer disease (AD). We hypothesize that APOE epsilon4 may modify the risk for AD in individuals with diabetes.

OBJECTIVE: To examine the joint effect of type 2 diabetes and APOE epsilon4 on the risk of AD, AD with vascular dementia (mixed AD), and vascular dementia without AD.

DESIGN: The Cardiovascular Health Study (CHS) Cognition Study (1992-2000) is a prospective study designed to identify all existing and new cases of dementia among study participants. Diagnoses were made according to international criteria for dementia and subtypes. There were 2547 dementia-free participants in the CHS Cognition Study cohort with complete information on APOE epsilon4 and type 2 diabetes status; among these, 411 new cases of dementia developed. Risk of dementia was estimated with a Cox proportional hazard model adjusted for age and other demographic and cardiovascular risk factors.

RESULTS: Compared with those who had neither type 2 diabetes nor APOE epsilon4, those with both factors had a significantly higher risk of AD (hazard ratio, 4.58; 95% confidence interval, 2.18-9.65) and mixed AD (hazard ratio, 3.89; 95% confidence interval, 1.46-10.40).

CONCLUSION: These data suggest that having both diabetes and APOE epsilon4 increases the risk of dementia, especially for AD and mixed AD.

VL - 65 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18195144?dopt=Abstract ER - TY - JOUR T1 - Fasting glycemia in sleep disordered breathing: lowering the threshold on oxyhemoglobin desaturation. JF - Sleep Y1 - 2008 A1 - Stamatakis, Katherine A1 - Sanders, Mark H A1 - Caffo, Brian A1 - Resnick, Helaine E A1 - Gottlieb, Dan J A1 - Mehra, Reena A1 - Punjabi, Naresh M KW - Aged KW - Blood Glucose KW - Body Mass Index KW - Cohort Studies KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Humans KW - Male KW - Middle Aged KW - Odds Ratio KW - Oxygen KW - Oxyhemoglobins KW - Polysomnography KW - Reference Values KW - Sleep Apnea, Obstructive AB -

STUDY OBJECTIVES: Commonly used definitions of sleep-disordered breathing (SDB) are based on identifying discrete events of breathing abnormalities during sleep that are accompanied by an oxyhemoglobin desaturation (delta SaO2) of at least 4%. However, it is not known whether disordered breathing events with oxyhemoglobin desaturation less than 4% are associated with clinical sequelae such as abnormalities in fasting glycemia.

DESIGN: Cross-sectional study.

SUBJECTS AND SETTING: Participants from the Sleep Heart Health Study (SHHS) with a fasting glucose measurement made within a year of the baseline polysomnogram.

MEASUREMENTS AND RESULTS: SDB severity was defined using the apnea-hypopnea index (AHI) and the hypopnea index (HI) by counting events with different levels of oxyhemoglobin desaturation (0.0%-1.9%, 2.0%-2.9%, 3.0%-3.9%, > or = 4.0%). Fasting glucose levels were used to classify individuals into normal (<100 mg/dL), impaired (100-125 mg/dL), and diabetic (> or = 126 mg/dL) groups. Ordinal logistic regression was used to determine the adjusted relative odds of an abnormal glucose value across quartiles of the hypopnea index, independent of factors such as age, body mass index, waist circumference, and usual sleep duration. The prevalence of impaired and diabetic fasting glucose in the analytical sample was 32.9% and 5.8%, respectively. The covariate-adjusted relative odds of impaired or diabetic fasting glucose in the highest versus the lowest AHI quartile was 1.35 (95% CI: 1.04-1.76) for events with a delta SaO2 > or = 4.0%, 1.72 (95% CI: 1.20-2.48) for events with a delta SaO2 between 3.0%-3.9%, 1.41 (95% CI: 1.07-1.86) for events with a delta SaO2 between 2.0%-2.9%, and 1.07 (95% CI: 0.84-1.37) for events with a delta SaO2 between 0.0%-1.9%. The corresponding odds ratios for the HI were 1.47 (95% CI: 1.13-1.92), 2.25 (95% CI: 1.59-3.19), 1.44 (95% CI: 1.09-1.90), and 1.15 (95% CI: 0.90-1.47), respectively.

CONCLUSIONS: The results of this study indicate that SDB events accompanied by oxyhemoglobin desaturation of between 2% to 4% are associated with fasting hyperglycemia. These findings suggest that milder degrees of SDB may predispose to adverse metabolic outcomes.

VL - 31 IS - 7 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18652097?dopt=Abstract ER - TY - JOUR T1 - Hemostatic and inflammatory risk factors for intracerebral hemorrhage in a pooled cohort. JF - Stroke Y1 - 2008 A1 - Sturgeon, Jared D A1 - Folsom, Aaron R A1 - Longstreth, W T A1 - Shahar, Eyal A1 - Rosamond, Wayne D A1 - Cushman, Mary KW - Age Distribution KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cerebral Hemorrhage KW - Cohort Studies KW - Factor VIII KW - Female KW - Fibrinogen KW - Follow-Up Studies KW - Humans KW - Leukocyte Count KW - Lipoprotein(a) KW - Male KW - Middle Aged KW - Multivariate Analysis KW - Prevalence KW - Risk Factors KW - Stroke KW - United States KW - Vasculitis KW - von Willebrand Factor AB -

BACKGROUND AND PURPOSE: The purpose of this study was to identify novel risk factors for intracerebral hemorrhagic stroke (ICH).

METHODS: Risk factors were assessed at baseline in a pooled cohort of the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) involving 21,680 adults aged 45 or over. Over 263,489 person-years of follow-up, we identified 135 incident ICH events.

RESULTS: In multivariable models, for each SD higher baseline level of fibrinogen, the relative rate of incident ICH increased 35% (95% CI, 17% to 55%). Fibrinogen was more strongly related to ICH in ARIC than in CHS. In multivariable models, those with von Willebrand factor levels above the median were 1.72 (95% CI, 0.97 to 3.03) times more likely to have an incident ICH as those below the median. Factor VIII was significantly positively related to ICH in ARIC (relative rate per standard deviation of 1.31; 95% CI, 1.07 to 1.62), but not in CHS. There was no relation in multivariable models between lipoprotein (a), Factor VII, white blood cell count, or C-reactive protein and ICH.

CONCLUSIONS: Greater plasma fibrinogen and, to some degree, von Willebrand factor were associated with increased rates of ICH in these prospective studies, whereas Factor VIII was related to ICH in younger ARIC study participants only.

VL - 39 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18535282?dopt=Abstract ER - TY - JOUR T1 - Incident physical disability in people with lower extremity peripheral arterial disease: the role of cardiovascular disease. JF - J Am Geriatr Soc Y1 - 2008 A1 - Brach, Jennifer S A1 - Solomon, Cam A1 - Naydeck, Barbara L A1 - Sutton-Tyrrell, Kim A1 - Enright, Paul L A1 - Jenny, Nancy Swords A1 - Chaves, Paulo M A1 - Newman, Anne B KW - Activities of Daily Living KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Comorbidity KW - Disability Evaluation KW - Female KW - Gait KW - Geriatric Assessment KW - Humans KW - Lower Extremity KW - Male KW - Mobility Limitation KW - Peripheral Vascular Diseases KW - Proportional Hazards Models KW - Risk Assessment KW - Risk Factors KW - United States AB -

OBJECTIVES: To evaluate the risk of incident physical disability and the decline in gait speed over a 6-year follow-up associated with a low ankle-arm index (AAI) in older adults.

DESIGN: Observational cohort study.

SETTING: Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania.

PARTICIPANTS: Four thousand seven hundred five older adults, 58% women and 17.6% black, participating in the Cardiovascular Health Study.

MEASUREMENTS: AAI was measured in 1992/93 (baseline). Self-reported mobility, activity of daily living (ADL), and instrumental activity of daily living (IADL) disability and gait speed were recorded at baseline and at 1-year intervals over 6 years of follow-up. Mobility disability was defined as any difficulty walking half a mile and ADL and IADL disability was defined as any difficulty with 11 specific ADL and IADL tasks. Individuals with mobility, ADL, or IADL disability at baseline were excluded from the respective incident disability analyses.

RESULTS: Lower baseline AAI values were associated with increased risk of mobility disability and ADL/IADL disability. Clinical cardiovascular disease (CVD), diabetes mellitus, and interim CVD events partially explained these associations for mobility disability and clinical CVD and diabetes mellitus partially explained these associations for ADL and IADL disability. Individuals with an AAI less than 0.9 had on average a mean decrease in gait speed of 0.02 m/s per year, or a decline of 0.12 m/s over the 6-year follow-up. Prevalent CVD partly explained this decrease but interim CVD events did not further attenuate it.

CONCLUSION: Low AAI serves as marker of future disability risk. Reduction of disability risk in patients with a low AAI should consider cardiovascular comorbidity and the prevention of additional disabling CVD events.

VL - 56 IS - 6 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18384579?dopt=Abstract ER - TY - JOUR T1 - Insulin-like growth factor-(IGF)-axis, inflammation, and glucose intolerance among older adults. JF - Growth Horm IGF Res Y1 - 2008 A1 - Rajpathak, Swapnil N A1 - McGinn, Aileen P A1 - Strickler, Howard D A1 - Rohan, Thomas E A1 - Pollak, Michael A1 - Cappola, Anne R A1 - Kuller, Lewis A1 - Xue, XiaoNan A1 - Newman, Anne B A1 - Strotmeyer, Elsa S A1 - Psaty, Bruce M A1 - Kaplan, Robert C KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Glucose Intolerance KW - Humans KW - Inflammation KW - Insulin-Like Growth Factor Binding Proteins KW - Male KW - Signal Transduction KW - Somatomedins AB -

Increasing evidence suggests that the insulin-like growth factor (IGF)-axis may play a role in glucose metabolism and may also be associated with systemic inflammation. The aim of this study was to evaluate the association of insulin-like growth factor-1 (IGF-I) and its binding proteins, IGFBP-1 and IGFBP-3, with glucose intolerance and inflammation among older adults. We conducted a cross-sectional analysis in a in a random subsample (n=922) of the Cardiovascular Health Study (CHS), a prospective cohort of men and women > or = 65 years. Mean IGFBP-1 levels were significantly lower in older adults with impaired glucose tolerance (IGT), impaired fasting glucose (IFG) and diabetes compared to those with normal fasting and post-load glucose. High IGFBP-1 was associated with a reduced prevalence of IGT and IFG; the multivariable OR between extreme quartiles of IGFBP-1 was 0.60 (95% CI: 0.37, 0.95; p-trend: 0.03) for IGT and 0.41 (95% CI: 0.26, 0.64; p-trend: <0.01) for IFG. We did not find any significant association between IGF-I and glucose intolerance in this study and the association for IGFBP-3 was less clear. However, low levels of IGF-I and IGFBP-3 were associated with increased levels of markers of inflammation including C-reactive protein and interleukin-6 levels. We conclude that among adults > or = 65 years, low IGFBP-1 levels are associated with increased prevalence of glucose intolerance. We did not confirm prior associations of low IGF-I with glucose intolerance in this cohort of older individuals.

VL - 18 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17904401?dopt=Abstract ER - TY - JOUR T1 - No advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies. JF - Neurology Y1 - 2008 A1 - Szekely, C A A1 - Green, R C A1 - Breitner, J C S A1 - Østbye, T A1 - Beiser, A S A1 - Corrada, M M A1 - Dodge, H H A1 - Ganguli, M A1 - Kawas, C H A1 - Kuller, L H A1 - Psaty, B M A1 - Resnick, S M A1 - Wolf, P A A1 - Zonderman, A B A1 - Welsh-Bohmer, K A A1 - Zandi, P P KW - Acetaminophen KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Amyloid beta-Peptides KW - Analgesics, Non-Narcotic KW - Anti-Inflammatory Agents, Non-Steroidal KW - Aspirin KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Neuroprotective Agents KW - Peptide Fragments KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors AB -

INTRODUCTION: Observational studies show reduced incidence of Alzheimer dementia (AD) in users of nonsteroidal anti-inflammatory drugs (NSAIDs). One hypothesis holds that the subset of NSAIDs known as selective A beta(42)-lowering agents (SALAs) is responsible for this apparent reduction in AD risk.

METHODS: We pooled individual-level data from six prospective studies to obtain a sufficient sample to examine AD risk in users of SALA vs non-SALA NSAIDs.

RESULTS: Of 13,499 initially dementia-free participants (70,863 person-years), 820 developed incident AD. Users of NSAIDs (29.6%) showed reduced risk of AD (adjusted hazard ratio [aHR] 0.77, 95% CI 0.65-0.91). The point estimates were similar for SALAs (aHR 0.87, CI 0.72-1.04) and non-SALAs (aHR 0.75, CI 0.56-1.01). Because 573 NSAID users (14.5%) reported taking both a SALA and non-SALA, we examined their use alone and in combination. Resulting aHRs were 0.82 (CI 0.67-0.99) for SALA only, 0.60 (CI 0.40-0.90) for non-SALA only, and 0.87 (CI 0.57-1.33) for both NSAIDs (Wald test for differences, p = 0.32). The 40.7% of participants who used aspirin also showed reduced risk of AD, even when they used no other NSAIDs (aHR 0.78, CI 0.66-0.92). By contrast, there was no association with use of acetaminophen (aHR 0.93, CI 0.76-1.13).

CONCLUSIONS: In this pooled dataset, nonsteroidal anti-inflammatory drug (NSAID) use reduced the risk of Alzheimer dementia (AD). However, there was no apparent advantage in AD risk reduction for the subset of NSAIDs shown to selectively lower A beta(42), suggesting that all conventional NSAIDs including aspirin have a similar protective effect in humans.

VL - 70 IS - 24 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18509093?dopt=Abstract ER - TY - JOUR T1 - Pancreatic beta-cell function as a predictor of cardiovascular outcomes and costs: findings from the Cardiovascular Health Study. JF - Curr Med Res Opin Y1 - 2008 A1 - Curtis, Lesley H A1 - Hammill, Bradley G A1 - Bethel, M Angelyn A1 - Anstrom, Kevin J A1 - Liao, Lawrence A1 - Gottdiener, John S A1 - Schulman, Kevin A KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - Coronary Disease KW - Female KW - Follow-Up Studies KW - Health Care Costs KW - Heart Failure KW - Humans KW - Insulin-Secreting Cells KW - Male KW - Myocardial Infarction KW - Outcome Assessment, Health Care KW - Prognosis KW - Prospective Studies KW - Stroke AB -

OBJECTIVE: To explore relationships between beta-cell function and incident cardiovascular events, death, and medical costs among elderly individuals.

RESEARCH DESIGN AND METHODS: In a prospective, population-based cohort of 4555 elderly individuals, we examined the effect of beta-cell function on incident cardiovascular events and mortality. We also examined costs for 3715 of these individuals. We used the computer-based homeostasis model assessment (HOMA) to calculate indices of beta-cell function (HOMA-%B) and insulin sensitivity (HOMA-%S) using baseline fasting glucose and insulin levels. All subjects were followed from 1992/1993 for 6 years or until death.

MAIN OUTCOME MEASURES: Discrete-time survival model of the effects of beta-cell function on incident cardiovascular events and all-cause mortality; and semiparametric estimators for calculations of mean 6-year costs.

RESULTS: Controlling for HOMA-%S, a 20% decrease in HOMA-%B was associated with increased odds of incident cardiovascular events (odds ratio [OR], 1.09; 95% confidence interval [CI], 1.05-1.14) and death (OR, 1.10; 95% CI, 1.07-1.14). The relationships persisted after controlling for clinical and sociodemographic confounders. A 20% decrease in HOMA-%B was also associated with increased costs (cost ratio, 1.03; 95% CI, 1.01-1.05). The significant association did not persist after controlling for confounders.

LIMITATIONS: The sample comprises relatively healthy elderly individuals and is based on data from 1992 through 1999, which may not reflect current experience. The measure of beta-cell function is an estimate generated from single measures of glucose and insulin.

CONCLUSIONS: Beta-cell function as measured by HOMA-%B is a significant predictor of incident cardiovascular events and mortality but not of costs, controlling for HOMA-%S and sociodemographic and clinical confounders.

VL - 24 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18021490?dopt=Abstract ER - TY - JOUR T1 - Prevalence, prognosis, and implications of isolated minor nonspecific ST-segment and T-wave abnormalities in older adults: Cardiovascular Health Study. JF - Circulation Y1 - 2008 A1 - Kumar, Anita A1 - Prineas, Ronald J A1 - Arnold, Alice M A1 - Psaty, Bruce M A1 - Furberg, Curt D A1 - Robbins, John A1 - Lloyd-Jones, Donald M KW - Age Factors KW - Aged KW - Arrhythmias, Cardiac KW - Cardiovascular Diseases KW - Cohort Studies KW - Electrocardiography KW - Female KW - Health Status KW - Humans KW - Male KW - Middle Aged KW - Prevalence KW - Prognosis KW - Prospective Studies AB -

BACKGROUND: The prevalence and prognostic significance of isolated minor nonspecific ST-segment and T-wave abnormalities (NSSTTAs) in older adults are poorly understood.

METHODS AND RESULTS: Cardiovascular Health Study participants free of both clinical cardiovascular disease and major ECG abnormalities were included. We examined the prospective association of isolated minor NSSTTAs (defined by Minnesota Codes 4-3, 4-4, 5-3, and 5-4) with total, cardiovascular, and coronary mortality and incident nonfatal myocardial infarction. Among 3224 participants (61.9% women; mean age, 72 years), 233 (7.2%) had isolated NSSTTAs at baseline. Covariates associated with isolated NSSTTAs included older age, nonwhite race (20.5% of blacks versus 4.8% of whites; P<0.001), diabetes, and higher blood pressure and body mass index but not the presence of subclinical cardiovascular disease. After 39 518 person-years of follow-up, the presence of isolated NSSTTAs was associated with significantly increased risk for coronary heart disease mortality (multivariable-adjusted hazards ratio, 1.76; 95% CI, 1.18 to 2.61) but not with incident nonfatal myocardial infarction (multivariable-adjusted hazards ratio, 0.71; 95% CI, 0.43 to 1.17). The association of isolated NSSTTAs with coronary death was independent of subclinical atherosclerosis and left ventricular mass measures. In secondary analyses, among those with cardiac death, there was a significantly higher rate of primary arrhythmic death (32.3% versus 15.4%; P=0.02) in participants with isolated NSSTTAs versus those without NSSTTAs.

CONCLUSIONS: Isolated NSSTTAs are common in older Americans and are associated with significantly increased risk for coronary death. However, isolated NSSTTAs are not associated with incident nonfatal myocardial infarction, suggesting that they are associated particularly with increased risk for primary arrhythmic death.

VL - 118 IS - 25 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19064684?dopt=Abstract ER - TY - JOUR T1 - Relationship between brachial flow-mediated dilation and carotid intima-media thickness in an elderly cohort: the Cardiovascular Health Study. JF - Atherosclerosis Y1 - 2008 A1 - Yeboah, Joseph A1 - Burke, Gregory L A1 - Crouse, John R A1 - Herrington, David M KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Brachial Artery KW - Carotid Arteries KW - Carotid Artery Diseases KW - Cohort Studies KW - Female KW - Hemorheology KW - Humans KW - Male KW - Tunica Intima KW - Tunica Media KW - Ultrasonography KW - Vasodilation AB -

OBJECTIVE: The aim of this study was to determine the relationship between brachial flow-mediated dilation (FMD) and carotid intima-media thickness (IMT) in a large multi-ethnic elderly cohort.

BACKGROUND: Brachial flow-mediated dilation (FMD) is a physiologic measure and carotid IMT is an anatomic structural measure of subclinical atherosclerosis. Both brachial FMD and carotid IMT have been associated with cardiovascular risk factors and cardiovascular events. The relationship between brachial FMD and carotid IMT is less clear especially in older adults.

METHODS: Brachial FMD, carotid IMT and traditional cardiovascular risk factors were measured in 2338 adults, age 72-98 years who were participants in the Cardiovascular Health Study. The relationship between FMD and IMT was assessed both unadjusted and also after adjusting for age, gender and race/ethnicity, BMI, HDL, LDL, systolic and diastolic blood pressure, serum creatinine, current smoking, diabetes mellitus, hormone therapy and prior CVD.

RESULTS: Both brachial FMD and carotid IMT correlated significantly with age, HDL levels, waist/hip ratio, serum cholesterol and number of CV risk factors. Brachial FMD was not associated with CCA IMT in this elderly cohort (Pearson partial correlation coefficient=-0.0252, p=0.222). In the adjusted linear regression model with CCA IMT as the dependent variable, brachial FMD was also not associated with CCA IMT (beta coefficient=-0.006, p=0.470).

CONCLUSION: Brachial FMD and CCA IMT are not related in population-based older adults. Brachial FMD and CCA IMT may be distinct and independent stages in the complex atherosclerotic process.

VL - 197 IS - 2 U1 - https://www.ncbi.nlm.nih.gov/pubmed/17804000?dopt=Abstract ER - TY - JOUR T1 - The relationship between exercise and risk of venous thrombosis in elderly people. JF - J Am Geriatr Soc Y1 - 2008 A1 - van Stralen, Karlijn J A1 - Doggen, Carine J M A1 - Lumley, Thomas A1 - Cushman, Mary A1 - Folsom, Aaron R A1 - Psaty, Bruce M A1 - Siscovick, David A1 - Rosendaal, Frits R A1 - Heckbert, Susan R KW - Aged KW - Aged, 80 and over KW - Case-Control Studies KW - Cohort Studies KW - Energy Metabolism KW - Exercise KW - Female KW - Humans KW - Male KW - Prevalence KW - Risk Factors KW - United States KW - Venous Thrombosis AB -

OBJECTIVES: To study whether exercise is associated with the risk of venous thrombosis in elderly people.

DESIGN: Observational study with a median follow-up of 11.6 years.

SETTING: The Cardiovascular Health Study in four U.S. communities.

PARTICIPANTS: People aged 65 and older without prior venous thrombosis (deep venous thrombosis or pulmonary embolism).

MEASUREMENTS: Self-reported exercise was measured two or three times during follow-up and was defined as expending more than 500 kcal/wk on exercise, including walking for exercise. Venous thrombosis cases were verified using medical record review.

RESULTS: Of 5,534 participants, 171 developed a first venous thrombosis. Self-reported exercise at baseline was not related to the risk of venous thrombosis after adjustment for sex, age, race, self-reported health, and body mass index (adjusted hazard ratio (HR(adj))=1.16, 95% confidence interval (CI)=0.84-1.61), although with exercise modeled as a time-varying exposure, overall results were in the direction of greater risk of venous thrombosis (HR(adj)=1.38, 95% CI=0.99-1.91). For mild-intensity exercise, such as walking, there was a nonsignificant finding in the direction of benefit (HR(adj)=0.75, 95% CI=0.49-1.16), but strenuous exercise, such as jogging, was associated with greater risk of venous thrombosis (HR(adj)=1.75, 95% CI=1.08-2.83) than no exercise at all.

CONCLUSION: In elderly people, strenuous exercise was associated with a higher risk of venous thrombosis than no exercise at all. Future studies are needed to explain this unexpected higher risk.

VL - 56 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18179500?dopt=Abstract ER - TY - JOUR T1 - Sleep-disordered breathing and cardiovascular disease: an outcome-based definition of hypopneas. JF - Am J Respir Crit Care Med Y1 - 2008 A1 - Punjabi, Naresh M A1 - Newman, Anne B A1 - Young, Terry B A1 - Resnick, Helaine E A1 - Sanders, Mark H KW - Aged KW - Apnea KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Odds Ratio KW - Oxyhemoglobins KW - Polysomnography KW - Sleep Apnea Syndromes KW - Terminology as Topic AB -

RATIONALE: Epidemiologic studies on the consequences of sleep-disordered breathing invariably use the apnea-hypopnea index as the primary measure of disease severity. Although hypopneas constitute a majority of disordered breathing events, significant controversy remains about the best criteria used to define these events.

OBJECTIVES: The current investigation sought to assess the most appropriate definition for hypopneas that would be best correlated with cardiovascular disease.

METHODS: A community sample of middle-aged and older adults was recruited as part of the Sleep Heart Health Study. Full-montage polysomnography was conducted and hypopneas were defined using different thresholds of oxyhemoglobin desaturation with and without arousals. Prevalent cardiovascular disease was assessed based on self-report. Logistic regression analysis was used to characterize the independent association between the hypopnea index and prevalent cardiovascular disease.

MEASUREMENTS AND MAIN RESULTS: Using a sample of 6,106 adults with complete data on cardiovascular disease status and polysomnography, the current study found that hypopneas associated with an oxyhemoglobin desaturation of 4% or more were associated with prevalent cardiovascular disease independent of confounding covariates. The adjusted prevalent odds ratios for quartiles of the hypopnea index using a 4% desaturation criterion were as follows: 1.00 (<1.10 events/h), 1.10 (1.01-3.20 events/h), 1.33 (3.21-7.69 events/h), and 1.41 (>7.69 events/h). Hypopnea measures based on less than 4% oxyhemoglobin desaturation or presence of arousals showed no association with cardiovascular disease.

CONCLUSIONS: Hypopneas comprise a significant component of sleep-disordered breathing in the general community. By varying the criteria for defining hypopneas, this study demonstrates that hypopneas with a desaturation of at least 4% are independently associated with cardiovascular disease. In contrast, no association was observed between cardiovascular disease and hypopneas associated with milder desaturations or arousals.

VL - 177 IS - 10 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18276938?dopt=Abstract ER - TY - JOUR T1 - Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The Cardiovascular Health study. JF - J Am Coll Cardiol Y1 - 2008 A1 - Rodondi, Nicolas A1 - Bauer, Douglas C A1 - Cappola, Anne R A1 - Cornuz, Jacques A1 - Robbins, John A1 - Fried, Linda P A1 - Ladenson, Paul W A1 - Vittinghoff, Eric A1 - Gottdiener, John S A1 - Newman, Anne B KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Echocardiography KW - Female KW - Heart KW - Heart Failure KW - Heart Function Tests KW - Humans KW - Hyperthyroidism KW - Hypertrophy, Left Ventricular KW - Hypothyroidism KW - Male KW - Risk Factors KW - Time Factors AB -

OBJECTIVES: The goal of this study was to determine whether subclinical thyroid dysfunction was associated with incident heart failure (HF) and echocardiogram abnormalities.

BACKGROUND: Subclinical hypothyroidism and hyperthyroidism have been associated with cardiac dysfunction. However, long-term data on the risk of HF are limited.

METHODS: We studied 3,044 adults>or=65 years of age who initially were free of HF in the Cardiovascular Health Study. We compared adjudicated HF events over a mean 12-year follow-up and changes in cardiac function over the course of 5 years among euthyroid participants, those with subclinical hypothyroidism (subdivided by thyroid-stimulating hormone [TSH] levels: 4.5 to 9.9, >or=10.0 mU/l), and those with subclinical hyperthyroidism.

RESULTS: Over the course of 12 years, 736 participants developed HF events. Participants with TSH>or=10.0 mU/l had a greater incidence of HF compared with euthyroid participants (41.7 vs. 22.9 per 1,000 person years, p=0.01; adjusted hazard ratio: 1.88; 95% confidence interval: 1.05 to 3.34). Baseline peak E velocity, which is an echocardiographic measurement of diastolic function associated with incident HF in the CHS cohort, was greater in those patients with TSH>or=10.0 mU/l compared with euthyroid participants (0.80 m/s vs. 0.72 m/s, p=0.002). Over the course of 5 years, left ventricular mass increased among those with TSH>or=10.0 mU/l, but other echocardiographic measurements were unchanged. Those patients with TSH 4.5 to 9.9 mU/l or with subclinical hyperthyroidism had no increase in risk of HF.

CONCLUSIONS: Compared with euthyroid older adults, those adults with TSH>or=10.0 mU/l have a moderately increased risk of HF and alterations in cardiac function but not older adults with TSH<10.0 mU/l. Clinical trials should assess whether the risk of HF might be ameliorated by thyroxine replacement in individuals with TSH>or=10.0 mU/l.

VL - 52 IS - 14 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18804743?dopt=Abstract ER - TY - JOUR T1 - Association of chronic kidney disease with the spectrum of ankle brachial index the CHS (Cardiovascular Health Study). JF - J Am Coll Cardiol Y1 - 2009 A1 - Ix, Joachim H A1 - Katz, Ronit A1 - de Boer, Ian H A1 - Kestenbaum, Brian R A1 - Allison, Matthew A A1 - Siscovick, David S A1 - Newman, Anne B A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Criqui, Michael H KW - Aged KW - Aged, 80 and over KW - Ankle Brachial Index KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Chronic Disease KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Diseases KW - Lipids KW - Male KW - Risk Factors AB -

OBJECTIVES: This study sought to determine the association of chronic kidney disease (CKD) with high ankle brachial index (ABI) measurement and to compare its strength with that of CKD with a low ABI.

BACKGROUND: CKD is an important risk factor for cardiovascular disease (CVD) events. A high ABI, a marker of lower extremity arterial stiffness, is associated with CVD events and mortality. The association between CKD and high ABI is unknown.

METHODS: The CHS (Cardiovascular Health Study) enrolled community-living people >65 years of age and measured kidney function and ABI. Glomerular filtration rate (GFR) was estimated using equations that incorporated either cystatin C or creatinine, and CKD was defined by estimated GFR <60 ml/min/1.73 m(2). The ABI was categorized as low (<0.90), low-normal (0.90 to 1.09), normal (1.10 to 1.40), and high (>1.40 or incompressible). Multinomial logistic regression was used to evaluate the associations of CKD with ABI categories.

RESULTS: Among 4,513 participants, 23% had CKD, 13% had a low ABI, and 3% had a high ABI. In models adjusted for age, sex, race, hypertension, diabetes, smoking, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and C-reactive protein, cystatin C-based CKD was associated with both low ABI (relative risk [RR]: 2.0; 95% confidence interval [CI]: 1.6 to 2.5; p <0.001) and high ABI (RR: 1.6; 95% CI: 1.0 to 2.3; p = 0.03). Results were similar when CKD was defined by creatinine.

CONCLUSIONS: CKD is associated with both the high and the low extremes of ABI in community-living older people. Future studies should evaluate whether arterial stiffness is an important mechanism leading to CVD in people with CKD.

VL - 54 IS - 13 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19761940?dopt=Abstract ER - TY - JOUR T1 - Association of novel genetic Loci with circulating fibrinogen levels: a genome-wide association study in 6 population-based cohorts. JF - Circ Cardiovasc Genet Y1 - 2009 A1 - Dehghan, Abbas A1 - Yang, Qiong A1 - Peters, Annette A1 - Basu, Saonli A1 - Bis, Joshua C A1 - Rudnicka, Alicja R A1 - Kavousi, Maryam A1 - Chen, Ming-Huei A1 - Baumert, Jens A1 - Lowe, Gordon D O A1 - McKnight, Barbara A1 - Tang, Weihong A1 - de Maat, Moniek A1 - Larson, Martin G A1 - Eyhermendy, Susana A1 - McArdle, Wendy L A1 - Lumley, Thomas A1 - Pankow, James S A1 - Hofman, Albert A1 - Massaro, Joseph M A1 - Rivadeneira, Fernando A1 - Kolz, Melanie A1 - Taylor, Kent D A1 - van Duijn, Cornelia M A1 - Kathiresan, Sekar A1 - Illig, Thomas A1 - Aulchenko, Yurii S A1 - Volcik, Kelly A A1 - Johnson, Andrew D A1 - Uitterlinden, André G A1 - Tofler, Geoffrey H A1 - Gieger, Christian A1 - Psaty, Bruce M A1 - Couper, David J A1 - Boerwinkle, Eric A1 - Koenig, Wolfgang A1 - O'Donnell, Christopher J A1 - Witteman, Jacqueline C A1 - Strachan, David P A1 - Smith, Nicholas L A1 - Folsom, Aaron R KW - Adult KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Pedigree KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

BACKGROUND: Fibrinogen is both central to blood coagulation and an acute-phase reactant. We aimed to identify common variants influencing circulation fibrinogen levels.

METHODS AND RESULTS: We conducted a genome-wide association analysis on 6 population-based studies, the Rotterdam Study, the Framingham Heart Study, the Cardiovascular Health Study, the Atherosclerosis Risk in Communities Study, the Monitoring of Trends and Determinants in Cardiovascular Disease/KORA Augsburg Study, and the British 1958 Birth Cohort Study, including 22 096 participants of European ancestry. Four loci were marked by 1 or more single-nucleotide polymorphisms that demonstrated genome-wide significance (P<5.0 x 10(-8)). These included a single-nucleotide polymorphism located in the fibrinogen beta chain (FGB) gene and 3 single-nucleotide polymorphisms representing newly identified loci. The high-signal single-nucleotide polymorphisms were rs1800789 in exon 7 of FGB (P=1.8 x 10(-30)), rs2522056 downstream from the interferon regulatory factor 1 (IRF1) gene (P=1.3 x 10(-15)), rs511154 within intron 1 of the propionyl coenzyme A carboxylase (PCCB) gene (P=5.9 x 10(-10)), and rs1539019 on the NLR family pyrin domain containing 3 isoforms (NLRP3) gene (P=1.04 x 10(-8)).

CONCLUSIONS: Our findings highlight biological pathways that may be important in regulation of inflammation underlying cardiovascular disease.

VL - 2 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20031576?dopt=Abstract ER - TY - JOUR T1 - Association of renal function with cardiac calcifications in older adults: the cardiovascular health study. JF - Nephrol Dial Transplant Y1 - 2009 A1 - Asselbergs, Folkert W A1 - Mozaffarian, Dariush A1 - Katz, Ronit A1 - Kestenbaum, Bryan A1 - Fried, Linda F A1 - Gottdiener, John S A1 - Shlipak, Michael G A1 - Siscovick, David S KW - Aged KW - Aortic Valve KW - Calcinosis KW - Case-Control Studies KW - Cohort Studies KW - Creatinine KW - Cystatin C KW - Female KW - Glomerular Filtration Rate KW - Heart Valve Diseases KW - Humans KW - Kidney Diseases KW - Male KW - Mitral Valve KW - Risk Factors AB -

BACKGROUND: Aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) are highly prevalent in patients with end-stage renal disease. It is less well established whether milder kidney disease is associated with cardiac calcifications. We evaluated the relationships between renal function and MAC, aortic annular calcification (AAC) and AVS in the elderly.

METHODS: From the Cardiovascular Health Study, a community-based cohort of ambulatory adults >or= age 65, a total of 3929 individuals (mean +/- SD age 74 +/- 5 years, 60% women) were evaluated with two-dimensional echocardiography. Renal function was assessed by means of creatinine-based estimated glomerular filtration rate (eGFR) and cystatin C.

RESULTS: The prevalences of MAC and AAC were significantly higher in individuals with an eGFR < 45 mL/ min/1.73 m(2) (P < 0.01 for each), and cystatin C levels were significantly higher in individuals with MAC or AAC compared to individuals without these cardiac calcifications (P < 0.001 for each). After multivariate-adjustment, an eGFR <45 mL/min/1.73 m(2) was significantly associated with MAC [odds ratio 1.54 (95% CI 1.16-2.06), P = 0.003] and not associated with AAC [1.30 (0.97-1.74), P = 0.085] and AVS [1.15 (0.86-1.53), P = 0.355]. In addition, cystatin C levels were independently associated with MAC [odds ratio per SD 1.12 (1.05-1.21), P = 0.001] and not associated with AAC [1.07 (1.00-1.15), P = 0.054] and AVS [0.99 (0.93-1.06), P = 0.82]. Furthermore, the prevalence of multiple cardiac calcifications was higher in subjects with an eGFR < 45 mL/ min/1.73 m(2) and increased per quartile of cystatin C (P-values < 0.001). In addition, a significant trend was observed between an eGFR < 45 mL/min/1.73 m(2), increasing levels of cystatin C and the number of cardiac calcifications (P < 0.05).

CONCLUSIONS: In a community-based cohort of the elderly, moderate kidney disease as defined by an eGFR <45 mL/min/1.73m(2) and elevated levels of cystatin C was associated with prevalent MAC. In addition, a significant trend was observed between an eGFR <45 mL/min/1.73m(2), increasing levels of cystatin C and the number of cardiac calcifications. No associations were found between renal function and AAC or AVS.

VL - 24 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/18840892?dopt=Abstract ER - TY - JOUR T1 - Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium: Design of prospective meta-analyses of genome-wide association studies from 5 cohorts. JF - Circ Cardiovasc Genet Y1 - 2009 A1 - Psaty, Bruce M A1 - O'Donnell, Christopher J A1 - Gudnason, Vilmundur A1 - Lunetta, Kathryn L A1 - Folsom, Aaron R A1 - Rotter, Jerome I A1 - Uitterlinden, André G A1 - Harris, Tamara B A1 - Witteman, Jacqueline C M A1 - Boerwinkle, Eric KW - Adult KW - Aged KW - Aging KW - Cohort Studies KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Heart Diseases KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Phenotype KW - Research Design KW - Risk Factors AB -

BACKGROUND: The primary aim of genome-wide association studies is to identify novel genetic loci associated with interindividual variation in the levels of risk factors, the degree of subclinical disease, or the risk of clinical disease. The requirement for large sample sizes and the importance of replication have served as powerful incentives for scientific collaboration. Methods- The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium was formed to facilitate genome-wide association studies meta-analyses and replication opportunities among multiple large population-based cohort studies, which collect data in a standardized fashion and represent the preferred method for estimating disease incidence. The design of the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium includes 5 prospective cohort studies from the United States and Europe: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study. With genome-wide data on a total of about 38 000 individuals, these cohort studies have a large number of health-related phenotypes measured in similar ways. For each harmonized trait, within-cohort genome-wide association study analyses are combined by meta-analysis. A prospective meta-analysis of data from all 5 cohorts, with a properly selected level of genome-wide statistical significance, is a powerful approach to finding genuine phenotypic associations with novel genetic loci.

CONCLUSIONS: The Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium and collaborating non-member studies or consortia provide an excellent framework for the identification of the genetic determinants of risk factors, subclinical-disease measures, and clinical events.

VL - 2 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20031568?dopt=Abstract ER - TY - JOUR T1 - Common coding variants of the HNF1A gene are associated with multiple cardiovascular risk phenotypes in community-based samples of younger and older European-American adults: the Coronary Artery Risk Development in Young Adults Study and The Cardiovascula JF - Circ Cardiovasc Genet Y1 - 2009 A1 - Reiner, Alexander P A1 - Gross, Myron D A1 - Carlson, Christopher S A1 - Bielinski, Suzette J A1 - Lange, Leslie A A1 - Fornage, Myriam A1 - Jenny, Nancy S A1 - Walston, Jeremy A1 - Tracy, Russell P A1 - Williams, O Dale A1 - Jacobs, David R A1 - Nickerson, Deborah A KW - Adolescent KW - Adult KW - African Americans KW - Aged KW - Aged, 80 and over KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cholesterol, LDL KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - gamma-Glutamyltransferase KW - Genetic Predisposition to Disease KW - Genotype KW - Hepatocyte Nuclear Factor 1-alpha KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

BACKGROUND: The transcription factor hepatocyte nuclear factor (HNF)-1 alpha regulates the activity of a number of genes involved in innate immunity, blood coagulation, lipid and glucose transport and metabolism, and cellular detoxification. Common polymorphisms of the HNF-1 alpha gene (HNF1A) were recently associated with plasma C-reactive protein and gamma-glutamyl transferase concentration in middle-aged to older European Americans (EA).

METHODS AND RESULTS: We assessed whether common variants of HNF1A are associated with C-reactive protein, gamma-glutamyl transferase, and other atherosclerotic and metabolic risk factors, in the large, population-based Coronary Artery Risk Development in Young Adults Study of healthy young EA (n=2154) and African American (AA; n=2083) adults. The minor alleles of Ile27Leu (rs1169288) and Ser486Asn (rs2464196) were associated with 0.10 to 0.15 standard deviation units lower C-reactive protein and gamma-glutamyl transferase levels in EA. The same HNF1A coding variants were associated with higher low-density lipoprotein cholesterol, apolipoprotein B, creatinine, and fibrinogen in EA. We replicated the associations between HNF1A coding variants and C-reactive protein, fibrinogen, low-density lipoprotein cholesterol, and renal function in a second population-based sample of EA adults 65 years and older from the Cardiovascular Health Study. The HNF1A Ser486Asn and/or Ile27Leu variants were also associated with increased risk of subclinical coronary atherosclerosis in Coronary Artery Risk Development in Young Adults and with incident coronary heart disease in Cardiovascular Health Study. The Ile27Leu and Ser486Asn variants were 3-fold less common in AA than in EA. There was little evidence of association between HNF1A genotype and atherosclerosis-related phenotypes in AA.

CONCLUSIONS: Common polymorphisms of HNF1A seem to influence multiple phenotypes related to cardiovascular risk in the general population of younger and older EA adults.

VL - 2 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20031592?dopt=Abstract ER - TY - JOUR T1 - External validity of the cardiovascular health study: a comparison with the Medicare population. JF - Med Care Y1 - 2009 A1 - DiMartino, Lisa D A1 - Hammill, Bradley G A1 - Curtis, Lesley H A1 - Gottdiener, John S A1 - Manolio, Teri A A1 - Powe, Neil R A1 - Schulman, Kevin A KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Comorbidity KW - Female KW - Humans KW - Male KW - Medicare KW - Randomized Controlled Trials as Topic KW - Reproducibility of Results KW - Socioeconomic Factors KW - United States AB -

BACKGROUND: The Cardiovascular Health Study (CHS), a population-based prospective cohort study, has been used to identify major risk factors associated with cardiovascular disease and stroke in the elderly.

OBJECTIVE: To assess the external validity of the CHS.

RESEARCH DESIGN: Comparison of the CHS cohort to a national cohort of Medicare beneficiaries and to Medicare beneficiaries residing in the CHS geographic regions.

SUBJECTS: CHS participants and a 5% sample of Medicare beneficiaries.

MEASURES: Demographic and administrative characteristics, comorbid conditions, resource use, and mortality.

RESULTS: Compared with both Medicare cohorts, the CHS cohort was older and included more men and African American participants. CHS participants were more likely to be enrolled in Medicare managed care than beneficiaries in the national Medicare cohort. Compared with the Medicare cohorts, mortality in the CHS was more than 40% lower at 1 year, approximately 25% lower at 5 years, and approximately 15% lower at 10 years. There were minimal differences in comorbid conditions and health care resource use.

CONCLUSION: The CHS cohort is comparable with the Medicare population, particularly with regard to comorbid conditions and resource use, but had lower mortality. The difference in mortality may reflect the CHS recruitment strategy or volunteer bias. These findings suggest it may not be appropriate to project absolute rates of disease and outcomes based on CHS data to the entire Medicare population. However, there is no reason to expect that the relative risks associated with physiologic processes identified by CHS data would differ for nonparticipants.

VL - 47 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19597373?dopt=Abstract ER - TY - JOUR T1 - Genomewide association studies of stroke. JF - N Engl J Med Y1 - 2009 A1 - Ikram, M Arfan A1 - Seshadri, Sudha A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - DeStefano, Anita L A1 - Aulchenko, Yurii S A1 - Debette, Stephanie A1 - Lumley, Thomas A1 - Folsom, Aaron R A1 - van den Herik, Evita G A1 - Bos, Michiel J A1 - Beiser, Alexa A1 - Cushman, Mary A1 - Launer, Lenore J A1 - Shahar, Eyal A1 - Struchalin, Maksim A1 - Du, Yangchun A1 - Glazer, Nicole L A1 - Rosamond, Wayne D A1 - Rivadeneira, Fernando A1 - Kelly-Hayes, Margaret A1 - Lopez, Oscar L A1 - Coresh, Josef A1 - Hofman, Albert A1 - DeCarli, Charles A1 - Heckbert, Susan R A1 - Koudstaal, Peter J A1 - Yang, Qiong A1 - Smith, Nicholas L A1 - Kase, Carlos S A1 - Rice, Kenneth A1 - Haritunians, Talin A1 - Roks, Gerwin A1 - de Kort, Paul L M A1 - Taylor, Kent D A1 - de Lau, Lonneke M A1 - Oostra, Ben A A1 - Uitterlinden, André G A1 - Rotter, Jerome I A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Mosley, Thomas H A1 - van Duijn, Cornelia M A1 - Breteler, Monique M B A1 - Longstreth, W T A1 - Wolf, Philip A KW - African Continental Ancestry Group KW - Aged KW - Chromosomes, Human, Pair 12 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Markers KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Risk Factors KW - Stroke AB -

BACKGROUND: The genes underlying the risk of stroke in the general population remain undetermined.

METHODS: We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons.

RESULTS: Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant.

CONCLUSIONS: A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.

VL - 360 IS - 17 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19369658?dopt=Abstract ER - TY - JOUR T1 - Insomnia did not predict incident hypertension in older adults in the cardiovascular health study. JF - Sleep Y1 - 2009 A1 - Phillips, Barbara A1 - Bůzková, Petra A1 - Enright, Paul KW - African Americans KW - Aged KW - Cohort Studies KW - Comorbidity KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Health Surveys KW - Humans KW - Hypertension KW - Male KW - Prospective Studies KW - Risk Factors KW - Sleep Initiation and Maintenance Disorders KW - United States AB -

STUDY OBJECTIVE: We hypothesized that the sleep complaints of insomnia predict incident hypertension, particularly in African Americans. The purpose of this study was to analyze insomnia complaints as predictors of incident hypertension in the Cardiovascular Health Study (CHS), stratifying by gender and allowing for race and sleep variable interaction.

DESIGN: This is a prospective cohort study over a 6-year period of follow-up.

SETTING: This is a community-based study of participants in Forsyth County, North Carolina; Pittsburgh, Pennsylvania; Sacramento County, California; and Washington County, Maryland.

PARTICIPANTS: The study analyzed data from 1419 older individuals (baseline mean age 73.4 +/- 4.4 years) from the Cardiovascular Health Study who were not hypertensive at baseline.

INTERVENTIONS: none.

MEASUREMENTS: We constructed relative risks of incident hypertension over a 6-year period for insomnia complaints singly and in combination.

RESULTS: Difficulty falling asleep, singly or in combination with other sleep complaints, predicted a statistically significant reduction of risk for incident hypertension for non-African American men in 6 years of follow-up. Insomnia complaints did not predict incident hypertension in 6 years of follow-up in women or in African Americans, although there may not have been enough power to show a significant association for African Americans.

CONCLUSIONS: Insomnia did not predict hypertension in this older cohort which was free of hypertension at baseline. Difficulty falling asleep was associated with reduced risk of hypertension in non-African American men.

VL - 32 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19189780?dopt=Abstract ER - TY - JOUR T1 - Longitudinal evaluation of sleep-disordered breathing and sleep symptoms with change in quality of life: the Sleep Heart Health Study (SHHS). JF - Sleep Y1 - 2009 A1 - Silva, Graciela E A1 - An, Ming-Wen A1 - Goodwin, James L A1 - Shahar, Eyal A1 - Redline, Susan A1 - Resnick, Helaine A1 - Baldwin, Carol M A1 - Quan, Stuart F KW - Aged KW - Attitude to Health KW - Cohort Studies KW - Comorbidity KW - Disease Progression KW - Disorders of Excessive Somnolence KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Polysomnography KW - Quality of Life KW - Sleep Apnea, Obstructive KW - Sleep Initiation and Maintenance Disorders AB -

STUDY OBJECTIVES: Findings from population studies evaluating the progression and incidence of sleep disordered breathing have shown evidence of a longitudinal increase in the severity of sleep disordered breathing. The present study evaluates the association among changes in sleep disordered breathing, sleep symptoms, and quality of life over time.

DESIGN: Prospective cohort study. Data were from the Sleep Heart Health Study.

SETTING: Multicenter study.

PARTICIPANTS: Three thousand seventy-eight subjects aged 40 years and older from the baseline and follow-up examination cycles were included.

MEASUREMENTS: The primary outcomes were changes in the Physical Component Summary and Mental Component Summary scales obtained from the Medical Outcomes Study Short-Form Health Survey. The primary exposure was change in the respiratory disturbance index obtained from unattended overnight polysomnograms performed approximately 5 years apart. Other covariates included measures of excessive daytime sleepiness and difficulty initiating and maintaining sleep.

RESULTS: Mean respiratory disturbance index increased from 8.1 +/- 11 SD at baseline to 10.9 +/- 14 (P < 0.0001) at follow-up. The mean Physical Component Summary and Mental Component Summary scores were 48.5 and 54.1 at baseline and 46.3 and 54.8 at follow-up. No associations between change in respiratory disturbance index and changes in Physical Component Summary or Mental Component Summary scores were seen. However, worsening of difficulty initiating and maintaining sleep and excessive daytime sleepiness were significantly associated with lower quality of life.

CONCLUSIONS: A slight increase in severity of sleep disordered breathing was seen over 5 years; this was not associated with worsening of quality of life. However, subjective symptoms of quality of sleep and daytime sleepiness were associated with declining quality of life.

VL - 32 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19725256?dopt=Abstract ER - TY - JOUR T1 - Long-term function in an older cohort--the cardiovascular health study all stars study. JF - J Am Geriatr Soc Y1 - 2009 A1 - Newman, Anne B A1 - Arnold, Alice M A1 - Sachs, Michael C A1 - Ives, Diane G A1 - Cushman, Mary A1 - Strotmeyer, Elsa S A1 - Ding, Jingzhong A1 - Kritchevsky, Stephen B A1 - Chaves, Paulo H M A1 - Fried, Linda P A1 - Robbins, John KW - Activities of Daily Living KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Attention KW - Cardiovascular Diseases KW - Chronic Disease KW - Cohort Studies KW - Comorbidity KW - Cross-Sectional Studies KW - Female KW - Follow-Up Studies KW - Gait KW - Geriatric Assessment KW - Hand Strength KW - Health Surveys KW - Humans KW - Male KW - Memory, Short-Term KW - Mental Status Schedule KW - Proportional Hazards Models KW - Psychometrics KW - Risk Factors KW - United States AB -

OBJECTIVES: To evaluate shared and unique risk factors for maintaining physical and cognitive function into the ninth decade and beyond.

DESIGN: Longitudinal cohort study.

SETTING: Four U.S. communities.

PARTICIPANTS: One thousand six hundred seventy-seven participants in the Cardiovascular Health Study All Stars Study, assessed in 2005/06. Median age was 85 (range 77-102), 66.5% were women, and 16.6% were black.

MEASUREMENTS: Intact function was defined as no difficulty with any activities of daily living and a score of 80 or higher on the Modified Mini-Mental State Examination. Baseline characteristics assessed in 1992/93 included demographics, behavioral health factors, chronic disease history, subclinical disease markers, cardiovascular risk factors, and inflammatory markers. Multinomial logistic regression was used to compare risk for physical disability, cognitive impairment,and combined impairments with no functional impairment.

RESULTS: Of the 1,677 participants evaluated in both domains, 891 (53%) were functionally intact. Continuous measures of function, including the Digit Symbol Substitution Test and gait speed, showed that all groups, including the most functional, had declined over time. The functional group had less decline but also tended to have higher starting values. Functional individuals had a higher baseline health profile than those with either or cognitive impairment or both impairments combined. Women and individuals with greater weight had higher rates of physical impairment but not cognitive impairment. Risk factors common to both types of impairment included cardiovascular disease and hypertension.

CONCLUSION: Intact function was found in only approximately half of these older adults in the ninth decade and beyond. High baseline function and low vascular disease risk characterized functional aging.

VL - 57 IS - 3 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19187412?dopt=Abstract ER - TY - JOUR T1 - Metabolic syndrome and risk of venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology. JF - J Thromb Haemost Y1 - 2009 A1 - Steffen, L M A1 - Cushman, M A1 - Peacock, J M A1 - Heckbert, S R A1 - Jacobs, D R A1 - Rosamond, W D A1 - Folsom, A R KW - Blood Coagulation Factors KW - Blood Glucose KW - Blood Pressure KW - Body Mass Index KW - Cohort Studies KW - Female KW - Fibrinogen KW - Humans KW - Lipids KW - Longitudinal Studies KW - Male KW - Metabolic Syndrome KW - Proportional Hazards Models KW - Risk Factors KW - Venous Thromboembolism AB -

SUMMARY BACKGROUND: In a recent case-control study, the odds of metabolic syndrome (MetSyn) among deep vein thrombosis cases were almost twice those among controls. We tested the hypothesis that the incidence of non-cancer-related venous thromboembolism (VTE) is higher among adults with MetSyn and further, that associations are stronger for idiopathic than secondary VTE.

METHODS: A total of 20 374 middle-aged and elderly adults were followed for over 12 years for incident VTE in the Longitudinal Investigation of Thromboembolism Etiology (LITE). All hospitalizations were identified and VTEs validated by chart review. Baseline MetSyn was defined using ATP III guidelines, including >or=3 of the following components: abdominal obesity, elevated blood pressure, low HDL-cholesterol, high triglycerides and high glucose. Because sex modified the relation between MetSyn and VTE (p(interaction) = 0.001), proportional hazards regression analyses were stratified by sex to assess the associations of MetSyn and its components with risk of incident non-cancer-related VTE, adjusting for potential confounders.

RESULTS: Incident VTE (n = 358) included 196 idiopathic events. Baseline MetSyn was associated with risk of total VTE (hazard ratio (HR) = 1.84, 95% CI = 1.30, 2.59) and idiopathic VTE (HR = 1.59, 95% CI = 1.02, 2.47) among men, but not women. The association was largely attributable to abdominal obesity (HR of VTE = 2.10, 95% CI = 1.51, 2.93, in men; HR of VTE = 1.70, 95% CI = 1.24, 2.34, in women), with no additional contribution by the other MetSyn components.

CONCLUSION: Although abdominal obesity was associated with increased risk of VTE in both men and women, MetSyn and its other components do not seem important in VTE etiology.

VL - 7 IS - 5 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19175496?dopt=Abstract ER - TY - JOUR T1 - Multiple loci associated with indices of renal function and chronic kidney disease. JF - Nat Genet Y1 - 2009 A1 - Köttgen, Anna A1 - Glazer, Nicole L A1 - Dehghan, Abbas A1 - Hwang, Shih-Jen A1 - Katz, Ronit A1 - Li, Man A1 - Yang, Qiong A1 - Gudnason, Vilmundur A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Smith, Albert V A1 - Arking, Dan E A1 - Astor, Brad C A1 - Boerwinkle, Eric A1 - Ehret, Georg B A1 - Ruczinski, Ingo A1 - Scharpf, Robert B A1 - Chen, Yii-Der Ida A1 - de Boer, Ian H A1 - Haritunians, Talin A1 - Lumley, Thomas A1 - Sarnak, Mark A1 - Siscovick, David A1 - Benjamin, Emelia J A1 - Levy, Daniel A1 - Upadhyay, Ashish A1 - Aulchenko, Yurii S A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Chasman, Daniel I A1 - Paré, Guillaume A1 - Ridker, Paul M A1 - Kao, W H Linda A1 - Witteman, Jacqueline C A1 - Coresh, Josef A1 - Shlipak, Michael G A1 - Fox, Caroline S KW - Chromosome Mapping KW - Cohort Studies KW - Genetic Variation KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Meta-Analysis as Topic KW - Mucoproteins KW - Netherlands KW - Polymorphism, Single Nucleotide KW - Prevalence KW - Uromodulin AB -

Chronic kidney disease (CKD) has a heritable component and is an important global public health problem because of its high prevalence and morbidity. We conducted genome-wide association studies (GWAS) to identify susceptibility loci for glomerular filtration rate, estimated by serum creatinine (eGFRcrea) and cystatin C (eGFRcys), and CKD (eGFRcrea < 60 ml/min/1.73 m(2)) in European-ancestry participants of four population-based cohorts (ARIC, CHS, FHS, RS; n = 19,877; 2,388 CKD cases), and tested for replication in 21,466 participants (1,932 CKD cases). We identified significant SNP associations (P < 5 × 10(-8)) with CKD at the UMOD locus, with eGFRcrea at UMOD, SHROOM3 and GATM-SPATA5L1, and with eGFRcys at CST and STC1. UMOD encodes the most common protein in human urine, Tamm-Horsfall protein, and rare mutations in UMOD cause mendelian forms of kidney disease. Our findings provide new insights into CKD pathogenesis and underscore the importance of common genetic variants influencing renal function and disease.

VL - 41 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19430482?dopt=Abstract ER - TY - JOUR T1 - Multiple loci influence erythrocyte phenotypes in the CHARGE Consortium. JF - Nat Genet Y1 - 2009 A1 - Ganesh, Santhi K A1 - Zakai, Neil A A1 - van Rooij, Frank J A A1 - Soranzo, Nicole A1 - Smith, Albert V A1 - Nalls, Michael A A1 - Chen, Ming-Huei A1 - Köttgen, Anna A1 - Glazer, Nicole L A1 - Dehghan, Abbas A1 - Kuhnel, Brigitte A1 - Aspelund, Thor A1 - Yang, Qiong A1 - Tanaka, Toshiko A1 - Jaffe, Andrew A1 - Bis, Joshua C M A1 - Verwoert, Germaine C A1 - Teumer, Alexander A1 - Fox, Caroline S A1 - Guralnik, Jack M A1 - Ehret, Georg B A1 - Rice, Kenneth A1 - Felix, Janine F A1 - Rendon, Augusto A1 - Eiriksdottir, Gudny A1 - Levy, Daniel A1 - Patel, Kushang V A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Hofman, Albert A1 - Sambrook, Jennifer G A1 - Hernandez, Dena G A1 - Zheng, Gang A1 - Bandinelli, Stefania A1 - Singleton, Andrew B A1 - Coresh, Josef A1 - Lumley, Thomas A1 - Uitterlinden, André G A1 - Vangils, Janine M A1 - Launer, Lenore J A1 - Cupples, L Adrienne A1 - Oostra, Ben A A1 - Zwaginga, Jaap-Jan A1 - Ouwehand, Willem H A1 - Thein, Swee-Lay A1 - Meisinger, Christa A1 - Deloukas, Panos A1 - Nauck, Matthias A1 - Spector, Tim D A1 - Gieger, Christian A1 - Gudnason, Vilmundur A1 - van Duijn, Cornelia M A1 - Psaty, Bruce M A1 - Ferrucci, Luigi A1 - Chakravarti, Aravinda A1 - Greinacher, Andreas A1 - O'Donnell, Christopher J A1 - Witteman, Jacqueline C M A1 - Furth, Susan A1 - Cushman, Mary A1 - Harris, Tamara B A1 - Lin, Jing-Ping KW - Blood Pressure KW - Cell Line KW - Cohort Studies KW - Endothelial Cells KW - Erythrocytes KW - Gene Expression KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

Measurements of erythrocytes within the blood are important clinical traits and can indicate various hematological disorders. We report here genome-wide association studies (GWAS) for six erythrocyte traits, including hemoglobin concentration (Hb), hematocrit (Hct), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC) and red blood cell count (RBC). We performed an initial GWAS in cohorts of the CHARGE Consortium totaling 24,167 individuals of European ancestry and replication in additional independent cohorts of the HaemGen Consortium totaling 9,456 individuals. We identified 23 loci significantly associated with these traits in a meta-analysis of the discovery and replication cohorts (combined P values ranging from 5 x 10(-8) to 7 x 10(-86)). Our findings include loci previously associated with these traits (HBS1L-MYB, HFE, TMPRSS6, TFR2, SPTA1) as well as new associations (EPO, TFRC, SH2B3 and 15 other loci). This study has identified new determinants of erythrocyte traits, offering insight into common variants underlying variation in erythrocyte measures.

VL - 41 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19862010?dopt=Abstract ER - TY - JOUR T1 - NRXN3 is a novel locus for waist circumference: a genome-wide association study from the CHARGE Consortium. JF - PLoS Genet Y1 - 2009 A1 - Heard-Costa, Nancy L A1 - Zillikens, M Carola A1 - Monda, Keri L A1 - Johansson, Asa A1 - Harris, Tamara B A1 - Fu, Mao A1 - Haritunians, Talin A1 - Feitosa, Mary F A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Garcia, Melissa A1 - Launer, Lenore J A1 - Smith, Albert V A1 - Mitchell, Braxton D A1 - McArdle, Patrick F A1 - Shuldiner, Alan R A1 - Bielinski, Suzette J A1 - Boerwinkle, Eric A1 - Brancati, Fred A1 - Demerath, Ellen W A1 - Pankow, James S A1 - Arnold, Alice M A1 - Chen, Yii-Der Ida A1 - Glazer, Nicole L A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - Amin, Najaf A1 - Campbell, Harry A1 - Gyllensten, Ulf A1 - Pattaro, Cristian A1 - Pramstaller, Peter P A1 - Rudan, Igor A1 - Struchalin, Maksim A1 - Vitart, Veronique A1 - Gao, Xiaoyi A1 - Kraja, Aldi A1 - Province, Michael A A1 - Zhang, Qunyuan A1 - Atwood, Larry D A1 - Dupuis, Josée A1 - Hirschhorn, Joel N A1 - Jaquish, Cashell E A1 - O'Donnell, Christopher J A1 - Vasan, Ramachandran S A1 - White, Charles C A1 - Aulchenko, Yurii S A1 - Estrada, Karol A1 - Hofman, Albert A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Witteman, Jacqueline C M A1 - Oostra, Ben A A1 - Kaplan, Robert C A1 - Gudnason, Vilmundur A1 - O'Connell, Jeffrey R A1 - Borecki, Ingrid B A1 - van Duijn, Cornelia M A1 - Cupples, L Adrienne A1 - Fox, Caroline S A1 - North, Kari E KW - Aged KW - Body Mass Index KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Nerve Tissue Proteins KW - Obesity KW - Polymorphism, Single Nucleotide KW - Waist Circumference AB -

Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4x10(-7))]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3x10(-8) for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4x10(-6), 0.024 z-score units (0.10 kg/m(2)) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07-1.19; p = 3.2x10(-5) per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.

VL - 5 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19557197?dopt=Abstract ER - TY - JOUR T1 - Obesity and change in estimated GFR among older adults. JF - Am J Kidney Dis Y1 - 2009 A1 - de Boer, Ian H A1 - Katz, Ronit A1 - Fried, Linda F A1 - Ix, Joachim H A1 - Luchsinger, Jose A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Siscovick, David S A1 - Kestenbaum, Bryan KW - Aged KW - Aging KW - Body Composition KW - Body Mass Index KW - Chronic Disease KW - Cohort Studies KW - Creatinine KW - Cystatin C KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Diseases KW - Longitudinal Studies KW - Male KW - Obesity KW - Risk Factors AB -

BACKGROUND: The prevalence of chronic kidney disease is growing most rapidly among older adults; however, determinants of impaired kidney function in this population are not well understood. Obesity assessed in midlife has been associated with chronic kidney disease.

STUDY DESIGN: Cohort study.

SETTING & PARTICIPANTS: 4,295 participants in the community-based Cardiovascular Health Study, aged >or= 65 years.

PREDICTORS: Body mass index, waist circumference, and fat mass measured using bioelectrical impedance.

OUTCOME: Change in glomerular filtration rate (GFR) during 7 years of follow-up.

MEASUREMENTS: Longitudinal estimates of GFR calculated using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation.

RESULTS: Estimated GFR decreased by an average of 0.4 +/- 3.6 mL/min/1.73 m(2)/y, and rapid GFR loss (>3 mL/min/1.73 m(2)/y) occurred in 693 participants (16%). Baseline body mass index, waist circumference, and fat mass were each associated with increased risk of rapid GFR loss: ORs, 1.19 (95% CI, 1.09-1.30) per 5 kg/m(2), 1.25 (95% CI, 1.16-1.36) per 12 cm, and 1.14 (95% CI, 1.05-1.24) per 10 kg after adjustment for age, sex, race, and smoking. The magnitude of increased risk was larger for participants with estimated GFR < 60 mL/min/1.73 m(2) at baseline (P for interaction < 0.05). Associations were substantially attenuated by further adjustment for diabetes, hypertension, and C-reactive protein level. Obesity measurements were not associated with change in GFR estimated using serum cystatin C level.

LIMITATIONS: Few participants with advanced chronic kidney disease at baseline, no direct GFR measurements.

CONCLUSION: Obesity may be a modifiable risk factor for the development and progression of kidney disease in older adults.

VL - 54 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19782454?dopt=Abstract ER - TY - JOUR T1 - Polysomnographic and health-related quality of life correlates of restless legs syndrome in the Sleep Heart Health Study. JF - Sleep Y1 - 2009 A1 - Winkelman, John W A1 - Redline, Susan A1 - Baldwin, Carol M A1 - Resnick, Helaine E A1 - Newman, Anne B A1 - Gottlieb, Daniel J KW - Adult KW - Aged KW - Cohort Studies KW - Comorbidity KW - Cross-Sectional Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Polysomnography KW - Prospective Studies KW - Quality of Life KW - Restless Legs Syndrome KW - Sleep Initiation and Maintenance Disorders KW - Statistics as Topic AB -

STUDY OBJECTIVES: Sleep disturbance is the primary clinical morbidity of restless legs syndrome (RLS). To date, sleep disturbance in RLS has been measured in (1) clinical samples with polysomnography (PSG) or (2) population-based samples by self-report. The objective of this study was to analyze sleep by PSG in a population-based sample with symptoms of RLS.

DESIGN: Cross-sectional observational study.

SETTING: Community-based.

PARTICIPANTS: 3433 older men and women.

INTERVENTIONS: None.

MEASUREMENTS AND RESULTS: RLS was evaluated using an 8-item self-administered questionnaire based on NIH diagnostic criteria and required symptoms occurring > or = five times per month and associated with at least moderate distress. Health-related quality of life (HRQOL) was determined using the SF-36. Unattended, in-home PSG was performed. Data were assessed using general linear models with adjustment for demographic, health-related variables, and apnea-hypopnea index (AHI). Subjects with RLS had longer adjusted mean sleep latency (39.8 vs 26.4 min, P < 0.0001) and higher arousal index (20.1 vs 18.0, P = 0.0145) than those without RLS. Sleep latency increased progressively as the frequency of RLS symptoms increased from 5-15 days per month to 6-7 days per week. No differences in sleep stage percentages were observed between participants with and without RLS. Subjects with RLS also reported poorer HRQOL in all physical domains as well as in the Mental Health and Vitality domains.

CONCLUSIONS: These novel PSG data from a nonclinical, community-based sample of individuals with RLS document sleep disturbance in the home even in individuals with intermittent symptoms.

VL - 32 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19544754?dopt=Abstract ER - TY - JOUR T1 - Predicting risk of dementia in older adults: The late-life dementia risk index. JF - Neurology Y1 - 2009 A1 - Barnes, D E A1 - Covinsky, K E A1 - Whitmer, R A A1 - Kuller, L H A1 - Lopez, O L A1 - Yaffe, K KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Alcohol Drinking KW - Apolipoprotein E4 KW - Body Mass Index KW - Carotid Stenosis KW - Cerebrum KW - Cognition Disorders KW - Cohort Studies KW - Coronary Artery Bypass KW - Dementia KW - Female KW - Genetic Markers KW - Health Status Indicators KW - Humans KW - Logistic Models KW - Male KW - Predictive Value of Tests KW - Risk Assessment KW - Risk Factors KW - Risk Reduction Behavior AB -

OBJECTIVE: To develop a late-life dementia risk index that can accurately stratify older adults into those with a low, moderate, or high risk of developing dementia within 6 years.

METHODS: Subjects were 3,375 participants in the Cardiovascular Health Cognition Study without evidence of dementia at baseline. We used logistic regression to identify those factors most predictive of developing incident dementia within 6 years and developed a point system based on the logistic regression coefficients.

RESULTS: Subjects had a mean age of 76 years at baseline; 59% were women and 15% were African American. Fourteen percent (n = 480) developed dementia within 6 years. The final late-life dementia risk index included older age (1-2 points), poor cognitive test performance (2-4 points), body mass index <18.5 (2 points), > or =1 apolipoprotein E epsilon4 alleles (1 point), cerebral MRI findings of white matter disease (1 point) or ventricular enlargement (1 point), internal carotid artery thickening on ultrasound (1 point), history of bypass surgery (1 point), slow physical performance (1 point), and lack of alcohol consumption (1 point) (c statistic, 0.81; 95% confidence interval, 0.79-0.83). Four percent of subjects with low scores developed dementia over 6 years compared with 23% of subjects with moderate scores and 56% of subjects with high scores.

CONCLUSIONS: The late-life dementia risk index accurately stratified older adults into those with low, moderate, and high risk of developing dementia. This tool could be used in clinical or research settings to target prevention and intervention strategies toward high-risk individuals.

VL - 73 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19439724?dopt=Abstract ER - TY - JOUR T1 - Prevalence of hearing loss in Black and White elders: results of the Cardiovascular Health Study. JF - J Speech Lang Hear Res Y1 - 2009 A1 - Pratt, Sheila R A1 - Kuller, Lewis A1 - Talbott, Evelyn O A1 - McHugh-Pemu, Kathleen A1 - Buhari, Alhaji M A1 - Xu, Xiaohui KW - African Americans KW - Aged KW - Aged, 80 and over KW - Aging KW - Auditory Threshold KW - Cardiovascular Diseases KW - Cohort Studies KW - Cross-Sectional Studies KW - European Continental Ancestry Group KW - Female KW - Hearing Loss KW - Hearing Tests KW - Humans KW - Male KW - Occupations KW - Prevalence KW - Sex Characteristics KW - Smoking KW - Socioeconomic Factors KW - United States AB -

PURPOSE: The goal of this study was to determine the impact of age, gender, and race on the prevalence and severity of hearing loss in elder adults, aged 72-96 years, after accounting for income, education, smoking, and clinical and subclinical cardiovascular disease. Methods Air-conduction thresholds for standard and extended high-frequency pure-tones were obtained from a cohort of 548 (out of 717) elderly adults (ages 72-96 years) who were recruited during the Year 11 clinical visit (1999-2000) of the Cardiovascular Health Study (CHS) at the Pittsburgh, Pennsylvania site. Participant smoking, income, education, and cardiovascular disease histories were obtained from the CHS database and were included as factors.

RESULTS: Hearing loss was more common and more severe for the participants in their 80s than for those in their 70s-the men more than the women and the White participants more than the Black participants. The inclusion of education, income, smoking, and cardiovascular disease (clinical and subclinical) histories as factors did not substantively impact the overall results.

CONCLUSION: Although the data reported in this article were cross-sectional and a cohort phenomenon might have been operational, they suggested that hearing loss is more substantive in the 8th than the 7th decade of life and that race and gender influence this decline in audition. Given the high prevalence in the aging population and the differences across groups, there is a clear need to understand the nature and causes of hearing loss across various groups in order to improve prevention and develop appropriate interventions.

VL - 52 IS - 4 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19380605?dopt=Abstract ER - TY - JOUR T1 - Race, gender, and mortality in adults > or =65 years of age with incident heart failure (from the Cardiovascular Health Study). JF - Am J Cardiol Y1 - 2009 A1 - Parashar, Susmita A1 - Katz, Ronit A1 - Smith, Nicholas L A1 - Arnold, Alice M A1 - Vaccarino, Viola A1 - Wenger, Nanette K A1 - Gottdiener, John S KW - African Americans KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Continental Population Groups KW - European Continental Ancestry Group KW - Female KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Proportional Hazards Models KW - Sex Factors KW - United States AB -

In patients with heart failure (HF), mortality is lower in women versus men. However, it is unknown whether the survival advantage in women compared with men is present in both whites and African Americans with HF. The inception cohort consisted of adults > or =65 years with incident HF after enrollment in the CHS, a prospective population-based study of cardiovascular disease. Of 5,888 CHS subjects, 1,264 developed new HF and were followed up for 3 years. Subjects were categorized into 4 race-gender groups, and Cox proportional hazard regression models were used to examine whether 3-year total and cardiovascular mortality differed among the 4 groups after adjusting for sociodemographic factors, co-morbidities, and treatment. A gender-race interaction was also tested for each outcome. In subjects with incident HF, African Americans had more hypertension and diabetes than whites, and white men had more coronary heart disease than other gender-race groups. Receipt of cardiovascular treatments among the 4 groups was similar. Mortality rates after HF were lower in women compared with men (for white women, African-American women, African-American men, and white men, total mortality was 35.5, 33.6, 44.4, and 40.5/100 person-years, and cardiovascular mortality was 18.4, 19.5, 20.2, and 22.7/100 person-years, respectively). After adjusting for covariates, women had a 15% to 20% lower risk of total and cardiovascular mortality compared with men, but there was no significant difference in outcome by race. The gender-race interaction for either outcome was not significant. In conclusion, in older adults with HF, women had significantly better survival than men irrespective of race, suggesting that gender-based survival differences may be more important than race-based differences.

VL - 103 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19361600?dopt=Abstract ER - TY - JOUR T1 - Replication of findings on the association of genetic variation in 24 hemostasis genes and risk of incident venous thrombosis. JF - J Thromb Haemost Y1 - 2009 A1 - Smith, N L A1 - Wiggins, K L A1 - Reiner, A P A1 - Lange, L A A1 - Cushman, M A1 - Heckbert, S R A1 - Lumley, T A1 - Rice, K M A1 - Folsom, A R A1 - Psaty, B M KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Case-Control Studies KW - Cohort Studies KW - Female KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Haplotypes KW - Hemostasis KW - Humans KW - Incidence KW - Male KW - Menopause KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Reproducibility of Results KW - Risk KW - Thrombophilia KW - Venous Thrombosis KW - Young Adult VL - 7 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19682239?dopt=Abstract ER - TY - JOUR T1 - Sleep-disordered breathing and frailty in the Cardiovascular Health Study Cohort. JF - Am J Epidemiol Y1 - 2009 A1 - Endeshaw, Yohannes W A1 - Unruh, Mark L A1 - Kutner, Michael A1 - Newman, Anne B A1 - Bliwise, Donald L KW - Activities of Daily Living KW - Aged KW - Cardiovascular Diseases KW - Cardiovascular System KW - Cohort Studies KW - Confidence Intervals KW - Exercise Tolerance KW - Female KW - Frail Elderly KW - Hand Strength KW - Humans KW - Logistic Models KW - Male KW - Mobility Limitation KW - Models, Statistical KW - Motor Activity KW - Muscle Strength KW - Odds Ratio KW - Polysomnography KW - Psychometrics KW - Risk Factors KW - Sleep Apnea, Obstructive KW - Weight Loss AB -

Sleep-disordered breathing (SDB) is associated with pathophysiology that may influence the development and progression of frailty. Using data collected in 1995-1996, the authors explored the relation between SDB and components of frailty among 1,042 participants of the Cardiovascular Health Study. Diagnosis of SDB was based on the results of overnight polysomnography, and severe SDB was defined as an apnea-hypopnea index of >30 per hour of sleep. Slow walking speed, low grip strength, exhaustion, low physical activity, and unexplained weight loss were referred to as frailty indicator variables. There were 584 (56%) female and 458 (44%) male participants, and the mean age was 77 (standard deviation, 4) years. There was independent association between severe SDB and 1 or more frailty indicator variables (adjusted odds ratio = 4.85, 95% confidence interval: 1.40, 16.78), slow walking speed (adjusted odds ratio = 2.67, 95% confidence interval: 1.04, 6.84), and low grip strength (adjusted odds ratio = 3.29, 95% confidence interval: 1.36, 7.96) among female study participants. The finding of an independent association between SDB and frailty indicator variables among older women could have important implications in interventions aimed at preventing or delaying the progression of frailty.

VL - 170 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19465743?dopt=Abstract ER - TY - JOUR T1 - Systematically missing confounders in individual participant data meta-analysis of observational cohort studies. JF - Stat Med Y1 - 2009 A1 - Jackson, Dan A1 - White, Ian A1 - Kostis, J B A1 - Wilson, A C A1 - Folsom, A R A1 - Wu, K A1 - Chambless, L A1 - Benderly, M A1 - Goldbourt, U A1 - Willeit, J A1 - Kiechl, S A1 - Yarnell, J W G A1 - Sweetnam, P M A1 - Elwood, P C A1 - Cushman, M A1 - Psaty, B M A1 - Tracy, R P A1 - Tybjaerg-Hansen, A A1 - Haverkate, F A1 - de Maat, M P M A1 - Thompson, S G A1 - Fowkes, F G R A1 - Lee, A J A1 - Smith, F B A1 - Salomaa, V A1 - Harald, K A1 - Rasi, V A1 - Vahtera, E A1 - Jousilahti, P A1 - D'Agostino, R A1 - Kannel, W B A1 - Wilson, P W F A1 - Tofler, G A1 - Levy, D A1 - Marchioli, R A1 - Valagussa, F A1 - Rosengren, A A1 - Wilhelmsen, L A1 - Lappas, G A1 - Eriksson, H A1 - Cremer, P A1 - Nagel, D A1 - Curb, J D A1 - Rodriguez, B A1 - Yano, K A1 - Salonen, J T A1 - Nyyssönen, K A1 - Tuomainen, T-P A1 - Hedblad, B A1 - Engstrom, G A1 - Berglund, G A1 - Loewel, H A1 - Koenig, W A1 - Hense, H W A1 - Meade, T W A1 - Cooper, J A A1 - De Stavola, B A1 - Knottenbelt, C A1 - Miller, G J A1 - Cooper, J A A1 - Bauer, K A A1 - Rosenberg, R D A1 - Sato, S A1 - Kitamura, A A1 - Naito, Y A1 - Iso, H A1 - Salomaa, V A1 - Harald, K A1 - Rasi, V A1 - Vahtera, E A1 - Jousilahti, P A1 - Palosuo, T A1 - Ducimetiere, P A1 - Amouyel, P A1 - Arveiler, D A1 - Evans, A E A1 - Ferrieres, J A1 - Juhan-Vague, I A1 - Bingham, A A1 - Schulte, H A1 - Assmann, G A1 - Cantin, B A1 - Lamarche, B A1 - Després, J-P A1 - Dagenais, G R A1 - Tunstall-Pedoe, H A1 - Lowe, G D O A1 - Woodward, M A1 - Ben-Shlomo, Y A1 - Davey Smith, G A1 - Palmieri, V A1 - Yeh, J L A1 - Meade, T W A1 - Rudnicka, A A1 - Brennan, P A1 - Knottenbelt, C A1 - Cooper, J A A1 - Ridker, P A1 - Rodeghiero, F A1 - Tosetto, A A1 - Shepherd, J A1 - Lowe, G D O A1 - Ford, I A1 - Robertson, M A1 - Brunner, E A1 - Shipley, M A1 - Feskens, E J M A1 - Di Angelantonio, E A1 - Kaptoge, S A1 - Lewington, S A1 - Lowe, G D O A1 - Sarwar, N A1 - Thompson, S G A1 - Walker, M A1 - Watson, S A1 - White, I R A1 - Wood, A M A1 - Danesh, J KW - Cohort Studies KW - Computer Simulation KW - Coronary Disease KW - Data Interpretation, Statistical KW - Female KW - Fibrinogen KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Models, Statistical AB -

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohorts

VL - 28 IS - 8 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19222087?dopt=Abstract ER - TY - JOUR T1 - Total and cause-specific mortality in the cardiovascular health study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2009 A1 - Newman, Anne B A1 - Sachs, Michael C A1 - Arnold, Alice M A1 - Fried, Linda P A1 - Kronmal, Richard A1 - Cushman, Mary A1 - Psaty, Bruce M A1 - Harris, Tamara B A1 - Robbins, John A A1 - Burke, Gregory L A1 - Kuller, Lewis H A1 - Lumley, Thomas KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Cardiovascular Diseases KW - Cause of Death KW - Chronic Disease KW - Cohort Studies KW - Female KW - Geriatric Assessment KW - Health Surveys KW - Humans KW - Kaplan-Meier Estimate KW - Male KW - Probability KW - Proportional Hazards Models KW - Retrospective Studies KW - Risk Assessment KW - Severity of Illness Index KW - Sex Factors KW - Survival Analysis KW - United States AB -

BACKGROUND: Few cohort studies have adequate numbers of carefully reviewed deaths to allow an analysis of unique and shared risk factors for cause-specific mortality. Shared risk factors could be targeted for prevention of premature death and the study of longevity.

METHODS: A total of 5,888 community-dwelling persons aged 65 years or older living in four communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up was 16 years. Total and cause-specific mortality, including cardiovascular disease, stroke, cancer, dementia, pulmonary disease, infection, and other cause, were examined as outcomes. Variables previously associated with total mortality were examined for each cause of death using Cox proportional hazard models.

RESULTS: Multiple risk factors were related to total mortality. When examining specific causes, many factors were related to cardiovascular death, whereas fewer were related to other causes. For most causes, risk factors were specific for that cause. For example, apolipoprotein E epsilon4 was strongly associated for dementia death and forced vital capacity with pulmonary death. Age, male sex, markers of inflammation, and cognitive function were related to multiple causes of death.

CONCLUSIONS: In these older adults, associations of risk factors with a given cause of death were related to specific deficits in that same organ system. Inflammation may represent a common pathway to all causes of death.

VL - 64 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19723772?dopt=Abstract ER - TY - JOUR T1 - Trajectories of dehydroepiandrosterone sulfate predict mortality in older adults: the cardiovascular health study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2009 A1 - Cappola, Anne R A1 - O'Meara, Ellen S A1 - Guo, Wensheng A1 - Bartz, Traci M A1 - Fried, Linda P A1 - Newman, Anne B KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Biomarkers KW - Cardiovascular Diseases KW - Cause of Death KW - Cohort Studies KW - Dehydroepiandrosterone Sulfate KW - Female KW - Geriatric Assessment KW - Humans KW - Longitudinal Studies KW - Male KW - Predictive Value of Tests KW - Proportional Hazards Models KW - Risk Assessment KW - Severity of Illness Index KW - Sex Factors KW - Survival Analysis KW - United States AB -

BACKGROUND: Dehydroepiandrosterone sulfate (DHEAS) has been proposed as an antiaging hormone, but its importance is unclear. Assessment of an individual's ability to maintain a DHEAS set point, through examination of multiple DHEAS levels over time, may provide insight into biologic aging.

METHODS: Using Cox proportional hazard models, we examined the relationship between DHEAS trajectory patterns and all-cause death in 950 individuals aged >or=65 years who were enrolled in the Cardiovascular Health Study and had DHEAS levels measured at three to six time points.

RESULTS: Overall, there was a slight decline in DHEAS levels over time (-0.013 microg/mL/y). Three trajectory components were examined: slope, variability, and baseline DHEAS. When examined individually, a steep decline or extreme variability in DHEAS levels was associated with higher mortality (p < .001 for each), whereas baseline DHEAS level was not. In adjusted models including all three components, steep decline (hazard ratio [HR] 1.75, confidence interval [CI] 1.32-2.33) and extreme variability (HR 1.89, CI 1.47-2.43) remained significant predictors of mortality, whereas baseline DHEAS level remained unpredictive of mortality (HR 0.97 per standard deviation, CI 0.88-1.07). The effect of trajectory pattern was more pronounced in men than in women. Individuals with both a steep decline and extreme variability in DHEAS levels had a significantly higher death rate than those with neither pattern (141 vs 48 deaths per 1,000 person-years, p < .001).

CONCLUSIONS: Our data show significant heterogeneity in the individual trajectories of DHEAS levels and suggest that these trajectories provide important biologic information about the rate of aging, whereas the DHEAS level itself does not.

VL - 64 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19713299?dopt=Abstract ER - TY - JOUR T1 - Alcohol consumption and kidney function decline in the elderly: alcohol and kidney disease. JF - Nephrol Dial Transplant Y1 - 2010 A1 - Menon, Vandana A1 - Katz, Ronit A1 - Mukamal, Kenneth A1 - Kestenbaum, Bryan A1 - de Boer, Ian H A1 - Siscovick, David S A1 - Sarnak, Mark J A1 - Shlipak, Michael G KW - Aged KW - Aging KW - Alcohol Drinking KW - Cohort Studies KW - Cystatin C KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Diseases KW - Male KW - Prospective Studies AB -

BACKGROUND: Alcohol consumption appears to be protective for cardiovascular disease; however, its relationship with kidney disease is unclear.

METHODS: This prospective cohort study included 4343 subjects from the Cardiovascular Health Study, a longitudinal, community-based cohort of persons aged ≥65 from four US communities. We used previously defined categories based on weekly alcohol consumption: none, former, <1 drink, 1-6 drinks, 7-13 drinks and ≥14 drinks. Cystatin C was measured at baseline, year 3 and year 7; eligible subjects had at least two measures. Estimated GFR(cys) was calculated from cystatin C. The primary outcome was rapid kidney function as an annual estimated GFR (eGFR(cys)) loss >3 mL/min/1.73 m(2)/year.

RESULTS: Eight percent of the cohort reported former alcohol use and 52% reported current alcohol consumption. During a mean follow-up of 5.6 years, 1075 (25%) participants had rapid kidney function decline. In adjusted logistic regression models, there was no association between alcohol use and kidney function decline (odds ratio, 95% confidence interval: none = reference; former = 1.18, 0.89-1.56; <1 drink = 1.20, 0.99-1.47; 1-6 = 1.18, 0.95-1.45; 7-13 = 1.10, 0.80-1.53; >14 = 0.89, 0.61-1.13). Results were similar with kidney function decline as a continuous outcome.

CONCLUSIONS: Our results suggest that moderate alcohol consumption has neither adverse nor beneficial effects on kidney function. Although clinicians will need to consider the potential deleterious effects associated with alcohol consumption, there does not appear to be a basis for recommending that older adults discontinue or initiate light to moderate alcohol consumption to protect against kidney disease.

VL - 25 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20400446?dopt=Abstract ER - TY - JOUR T1 - Association between baseline kidney function and change in CRP: an analysis of the cardiovascular health study. JF - Nephron Clin Pract Y1 - 2010 A1 - Rifkin, Dena E A1 - Katz, Ronit A1 - Fried, Linda F A1 - Kestenbaum, Bryan A1 - Jenny, Nancy Swords A1 - Newman, Anne B A1 - Siscovick, David S A1 - Shlipak, Michael G A1 - Sarnak, Mark J KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Follow-Up Studies KW - Glomerular Filtration Rate KW - Humans KW - Kidney Function Tests KW - Longitudinal Studies KW - Male KW - Residence Characteristics AB -

BACKGROUND: In cross-sectional analyses, C-reactive protein (CRP) levels are inversely related to levels of kidney function. The relationship between kidney function and subsequent changes in CRP is unknown.

METHODS: We studied 4,364 individuals from the Cardiovascular Health Study, a longitudinal cohort of community-dwelling older adults. Baseline eGFRcys was estimated using cystatin C. CRP was measured at baseline and after 3 and 7 years of follow-up; slopes of change in CRP were calculated.

RESULTS: The mean (SD) age of the cohort was 72 (5.2) years; mean (SD) eGFRcys was 78.9 (18.4) ml/min/1.73 m(2). The median (interquartile range IQR) baseline CRP was 2.39 (1.22, 4.33) mg/l; the median (IQR) yearly change in CRP was -0.0051 (-0.020 to 0.27) mg/l/year. After adjustment for demographic characteristics and the initial level of CRP, each standard deviation lower baseline eGFR was associated with a small and non-significant yearly increase in CRP (0.032 mg/l/year; 95% CI: -0.005 to 0.070, p = 0.094).

CONCLUSIONS: We did not find a relationship between eGFR and subsequent changes in CRP. The association between kidney function and CRP in cross-sectional analyses may reflect unmeasured confounding by atherosclerosis; alternatively, the burden of comorbidity and interval mortality in this population may have masked a stronger longitudinal association between kidney function and change in CRP. Further study in younger populations may clarify whether impaired kidney function leads to change in inflammation over time.

VL - 115 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20413990?dopt=Abstract ER - TY - JOUR T1 - Association of genome-wide variation with the risk of incident heart failure in adults of European and African ancestry: a prospective meta-analysis from the cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. JF - Circ Cardiovasc Genet Y1 - 2010 A1 - Smith, Nicholas L A1 - Felix, Janine F A1 - Morrison, Alanna C A1 - Demissie, Serkalem A1 - Glazer, Nicole L A1 - Loehr, Laura R A1 - Cupples, L Adrienne A1 - Dehghan, Abbas A1 - Lumley, Thomas A1 - Rosamond, Wayne D A1 - Lieb, Wolfgang A1 - Rivadeneira, Fernando A1 - Bis, Joshua C A1 - Folsom, Aaron R A1 - Benjamin, Emelia A1 - Aulchenko, Yurii S A1 - Haritunians, Talin A1 - Couper, David A1 - Murabito, Joanne A1 - Wang, Ying A A1 - Stricker, Bruno H A1 - Gottdiener, John S A1 - Chang, Patricia P A1 - Wang, Thomas J A1 - Rice, Kenneth M A1 - Hofman, Albert A1 - Heckbert, Susan R A1 - Fox, Ervin R A1 - O'Donnell, Christopher J A1 - Uitterlinden, André G A1 - Rotter, Jerome I A1 - Willerson, James T A1 - Levy, Daniel A1 - van Duijn, Cornelia M A1 - Psaty, Bruce M A1 - Witteman, Jacqueline C M A1 - Boerwinkle, Eric A1 - Vasan, Ramachandran S KW - African Americans KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Endopeptidases KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk KW - Ubiquitin-Specific Proteases AB -

BACKGROUND: Although genetic factors contribute to the onset of heart failure (HF), no large-scale genome-wide investigation of HF risk has been published to date. We have investigated the association of 2,478,304 single-nucleotide polymorphisms with incident HF by meta-analyzing data from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

METHODS AND RESULTS: Eligible participants for these analyses were of European or African ancestry and free of clinical HF at baseline. Each study independently conducted genome-wide scans and imputed data to the approximately 2.5 million single-nucleotide polymorphisms in HapMap. Within each study, Cox proportional hazards regression models provided age- and sex-adjusted estimates of the association between each variant and time to incident HF. Fixed-effect meta-analyses combined results for each single-nucleotide polymorphism from the 4 cohorts to produce an overall association estimate and P value. A genome-wide significance P value threshold was set a priori at 5.0x10(-7). During a mean follow-up of 11.5 years, 2526 incident HF events (12%) occurred in 20 926 European-ancestry participants. The meta-analysis identified a genome-wide significant locus at chromosomal position 15q22 (1.4x10(-8)), which was 58.8 kb from USP3. Among 2895 African-ancestry participants, 466 incident HF events (16%) occurred during a mean follow-up of 13.7 years. One genome-wide significant locus was identified at 12q14 (6.7x10(-8)), which was 6.3 kb from LRIG3.

CONCLUSIONS: We identified 2 loci that were associated with incident HF and exceeded genome-wide significance. The findings merit replication in other community-based settings of incident HF.

VL - 3 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20445134?dopt=Abstract ER - TY - JOUR T1 - Association of serial measures of cardiac troponin T using a sensitive assay with incident heart failure and cardiovascular mortality in older adults. JF - JAMA Y1 - 2010 A1 - deFilippi, Christopher R A1 - de Lemos, James A A1 - Christenson, Robert H A1 - Gottdiener, John S A1 - Kop, Willem J A1 - Zhan, Min A1 - Seliger, Stephen L KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Predictive Value of Tests KW - Risk KW - Sensitivity and Specificity KW - Troponin T KW - United States AB -

CONTEXT: Older adults comprise the majority of new-onset heart failure (HF) diagnoses, but traditional risk-factor prediction models have limited accuracy in this population to identify those at highest risk for hospitalization or death.

OBJECTIVES: To determine if cardiac troponin T (cTnT) measured by a highly sensitive assay would be detectable in the majority of community-dwelling older adults, and if serial measures were associated with risk of HF hospitalization and cardiovascular death.

DESIGN, SETTING, AND PARTICIPANTS: A longitudinal nationwide cohort study (Cardiovascular Health Study) of 4221 community-dwelling adults aged 65 years or older without prior HF who had cTnT measured using a highly sensitive assay at baseline (1989-1990) and repeated after 2 to 3 years (n = 2918).

MAIN OUTCOME MEASURES: New-onset HF and cardiovascular death were examined through June 2008 with respect to cTnT concentrations, accounting for clinical risk predictors.

RESULTS: Cardiac troponin T was detectable (≥3.00 pg/mL) in 2794 participants (66.2%). During a median follow-up of 11.8 years, 1279 participants experienced new-onset HF and 1103 cardiovascular deaths occurred, with a greater risk of both end points associated with higher cTnT concentrations. Among those participants with the highest cTnT concentrations (>12.94 pg/mL), there was an incidence rate per 100 person-years of 6.4 (95% confidence interval [CI], 5.8-7.2; adjusted hazard ratio [aHR], 2.48; 95% CI, 2.04-3.00) for HF and an incidence rate of 4.8 (95% CI, 4.3-5.4; aHR, 2.91; 95% CI, 2.37-3.58) for cardiovascular death compared with participants with undetectable cTnT levels (incidence rate, 1.6; 95% CI, 1.4-1.8 and 1.1; 95% CI, 0.9-1.2 for HF and cardiovascular death, respectively). Among individuals with initially detectable cTnT, a subsequent increase of more than 50% (n = 393, 22%) was associated with a greater risk for HF (aHR, 1.61; 95% CI, 1.32-1.97) and cardiovascular death (aHR, 1.65; 95% CI, 1.35-2.03) and a decrease of more than 50% (n = 247, 14%) was associated with a lower risk for HF (aHR, 0.73; 95% CI, 0.54-0.97) and cardiovascular death (aHR, 0.71; 95% CI, 0.52-0.97) compared with participants with 50% or less change. Addition of baseline cTnT measurements to clinical risk factors was associated with only modest improvement in discrimination, with change in C statistic of 0.015 for HF and 0.013 for cardiovascular death.

CONCLUSION: In this cohort of older adults without known HF, baseline cTnT levels and changes in cTnT levels measured with a highly sensitive assay were significantly associated with incident HF and cardiovascular death.

VL - 304 IS - 22 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21078811?dopt=Abstract ER - TY - JOUR T1 - Associations between renal duplex parameters and adverse cardiovascular events in the elderly: a prospective cohort study. JF - Am J Kidney Dis Y1 - 2010 A1 - Pearce, Jeffrey D A1 - Craven, Timothy E A1 - Edwards, Matthew S A1 - Corriere, Matthew A A1 - Crutchley, Teresa A A1 - Fleming, Shawn H A1 - Hansen, Kimberley J KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Humans KW - Kidney Diseases KW - Male KW - Renal Artery KW - Risk Factors KW - Ultrasonography, Doppler, Duplex AB -

BACKGROUND: Atherosclerotic renovascular disease is associated with an increased risk of cardiovascular disease (CVD) events. This study examines associations between Doppler-derived parameters from the renal artery and renal parenchyma and all-cause mortality and fatal and nonfatal CVD events in a cohort of elderly Americans.

STUDY DESIGN: Cohort study.

SETTING: A subset of participants from the Cardiovascular Health Study (CHS). Through an ancillary study, 870 (70% recruitment) Forsyth County, NC, CHS participants consented to undergo renal duplex sonography to define the prevalence of renovascular disease in the elderly, resulting in 726 (36% men; mean age, 77 years) technically adequate complete studies included in this investigation.

PREDICTOR: Renal duplex sonography-derived Doppler signals from the main renal arteries and renal parenchyma. Spectral analysis from Doppler-shifted frequencies and angle of insonation were used to estimate renal artery peak systolic and end diastolic velocity (both in meters per second). Color Doppler was used to identify the corticomedullary junction. Using a 3-mm Doppler sample, the parenchymal peak systolic and end diastolic frequency shift (both in kilohertz) were obtained. Resistive index was calculated as (1 - [end diastolic frequency shift/peak systolic frequency shift]) using Doppler samples from the hilar arteries of the left or right kidney with the higher main renal artery peak systolic velocity.

OUTCOMES & MEASUREMENTS: Proportional hazard regression analysis was used to determine associations between renal duplex sonography-derived Doppler signals and CVD events and all-cause mortality adjusted for accepted cardiovascular risk factors. Index CVD outcomes were defined as coronary events (angina, myocardial infarction, and coronary artery bypass grafting/percutaneous coronary intervention), cerebrovascular events (stroke or transient ischemic attack), and any CVD event (angina, congestive heart failure, myocardial infarction, stroke, transient ischemic attack, and coronary artery bypass grafting [CABG]/percutaneous transluminal coronary intervention [PTCI]).

RESULTS: During follow-up, 221 deaths (31%), 229 CVD events (32%), 122 coronary events (17%), and 92 cerebrovascular events (13%) were observed. Renal duplex sonography-derived Doppler signals from the renal parenchyma were associated independently with all-cause mortality and CVD outcomes. In particular, increased parenchymal end diastolic frequency shift was associated significantly with any CVD event (HR, 0.73; 95% CI, 0.62-0.87; P < 0.001). Marginally significant associations were observed between increases in parenchymal end diastolic frequency shift and decreased risk of death (HR, 0.86; 95% CI, 0.73-1.00; P = 0.06) and decreased risk of cerebrovascular events (HR, 0.78; 95% CI, 0.61-1.01; P = 0.06). Parenchymal end diastolic frequency shift was not significantly predictive of coronary events (HR, 0.84; 95% CI, 0.67-1.06; P = 0.1).

LIMITATIONS: CHS participants showed a "healthy cohort" effect that may underestimate the rate of CVD events in the general population.

CONCLUSION: Renal duplex sonographic Doppler signals from the renal parenchyma showed significant associations with subsequent CVD events after controlling for other significant risk factors. In particular, a standard deviation increase in parenchymal end diastolic frequency shift was associated with 27% risk reduction in any CVD event.

VL - 55 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20116688?dopt=Abstract ER - TY - JOUR T1 - Associations of PM10 with sleep and sleep-disordered breathing in adults from seven U.S. urban areas. JF - Am J Respir Crit Care Med Y1 - 2010 A1 - Zanobetti, Antonella A1 - Redline, Susan A1 - Schwartz, Joel A1 - Rosen, Dennis A1 - Patel, Sanjay A1 - O'Connor, George T A1 - Lebowitz, Michael A1 - Coull, Brent A A1 - Gold, Diane R KW - Adult KW - Aged KW - Aged, 80 and over KW - Air Pollutants KW - Air Pollution KW - Cities KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Multicenter Studies as Topic KW - Particle Size KW - Particulate Matter KW - Polysomnography KW - Seasons KW - Severity of Illness Index KW - Sleep KW - Sleep Apnea Syndromes KW - Temperature KW - United States KW - Urban Health AB -

RATIONALE: Sleep-disordered breathing (SDB), the recurrent episodic disruption of normal breathing during sleep, affects as much as 17% of U.S. adults, and may be more prevalent in poor urban environments. SDB and air pollution have been linked to increased cardiovascular diseases and mortality, but the association between pollution and SDB is poorly understood.

OBJECTIVES: We used data from the Sleep Heart Health Study (SHHS), a U.S. multicenter cohort study assessing cardiovascular and other consequences of SDB, to examine whether particulate air matter less than 10 μm in aerodynamic diameter (PM(10)) was associated with SDB among persons 39 years of age and older.

METHODS: Using baseline data from SHHS urban sites, outcomes included the following: the respiratory disturbance index (RDI); percentage of sleep time at less than 90% O(2) saturation; and sleep efficiency, measured by overnight in-home polysomnography. We applied a fixed-effect model containing a city effect, controlling for potential predictors. In all models we included both the 365-day moving averages of PM(10) and temperature (long-term effects) and the differences between the daily measures of these two predictors and their 365-day average (short-term effects).

MEASUREMENTS AND MAIN RESULTS: In summer, increases in RDI or percentage of sleep time at less than 90% O(2) saturation, and decreases in sleep efficiency, were all associated with increases in short-term variation in PM(10). Over all seasons, we found that increased RDI was associated with an 11.5% (95% confidence interval: 1.96, 22.01) increase per interquartile range increase (25.5°F) in temperature.

CONCLUSIONS: Reduction in air pollution exposure may decrease the severity of SDB and nocturnal hypoxemia and may improve cardiac risk.

VL - 182 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20508218?dopt=Abstract ER - TY - JOUR T1 - Autonomic nervous system dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with depression. JF - Psychosom Med Y1 - 2010 A1 - Kop, Willem J A1 - Stein, Phyllis K A1 - Tracy, Russell P A1 - Barzilay, Joshua I A1 - Schulz, Richard A1 - Gottdiener, John S KW - Aged KW - Autonomic Nervous System Diseases KW - Biomarkers KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cause of Death KW - Cohort Studies KW - Comorbidity KW - Depressive Disorder KW - Electrocardiography KW - Female KW - Follow-Up Studies KW - Heart Rate KW - Humans KW - Inflammation KW - Interleukin-6 KW - Leukocyte Count KW - Male KW - Risk Factors AB -

OBJECTIVE: To investigate prospectively whether autonomic nervous system (ANS) dysfunction and inflammation play a role in the increased cardiovascular disease (CVD)-related mortality risk associated with depression.

METHODS: Participants in the Cardiovascular Health Study (n = 907; mean age, 71.3 ± 4.6 years; 59.1% women) were evaluated for ANS indices derived from heart rate variability (HRV) analysis (frequency and time domain HRV, and nonlinear indices, including detrended fluctuation analysis (DFA(1)) and heart rate turbulence). Inflammation markers included C-reactive protein, interleukin-6, fibrinogen, and white blood cell count). Depressive symptoms were assessed, using the 10-item Centers for Epidemiological Studies Depression scale. Cox proportional hazards models were used to investigate the mortality risk associated with depression, ANS, and inflammation markers, adjusting for demographic and clinical covariates.

RESULTS: Depression was associated with ANS dysfunction (DFA(1), p = .018), and increased inflammation markers (white blood cell count, p = .012, fibrinogen p = .043) adjusting for covariates. CVD-related mortality occurred in 121 participants during a median follow-up of 13.3 years. Depression was associated with an increased CVD mortality risk (hazard ratio, 1.88; 95% confidence interval, 1.23-2.86). Multivariable analyses showed that depression was an independent predictor of CVD mortality (hazard ratio, 1.72; 95% confidence interval, 1.05-2.83) when adjusting for independent HRV and inflammation predictors (DFA(1), heart rate turbulence, interleukin-6), attenuating the depression-CVD mortality association by 12.7% (p < .001).

CONCLUSION: Autonomic dysfunction and inflammation contribute to the increased cardiovascular mortality risk associated with depression, but a large portion of the predictive value of depression remains unexplained by these neuroimmunological measures.

VL - 72 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20639389?dopt=Abstract ER - TY - JOUR T1 - Cancer linked to Alzheimer disease but not vascular dementia. JF - Neurology Y1 - 2010 A1 - Roe, C M A1 - Fitzpatrick, A L A1 - Xiong, C A1 - Sieh, W A1 - Kuller, L A1 - Miller, J P A1 - Williams, M M A1 - Kopan, R A1 - Behrens, M I A1 - Morris, J C KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Cohort Studies KW - Dementia, Vascular KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Hospitalization KW - Humans KW - Male KW - Neoplasms KW - Nerve Degeneration KW - Parkinson Disease KW - Prevalence KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors AB -

OBJECTIVE: To investigate whether cancer is associated with Alzheimer disease (AD) and vascular dementia (VaD).

METHODS: Cox proportional hazards models were used to test associations between prevalent dementia and risk of future cancer hospitalization, and associations between prevalent cancer and risk of subsequent dementia. Participants in the Cardiovascular Health Study-Cognition Substudy, a prospective cohort study, aged 65 years or older (n = 3,020) were followed a mean of 5.4 years for dementia and 8.3 years for cancer.

RESULTS: The presence of any AD (pure AD + mixed AD/VaD; hazard ratio [HR] = 0.41, 95% confidence interval [CI] = 0.20-0.84) and pure AD (HR = 0.31, 95% CI = 0.12-0.86) was associated with a reduced risk of future cancer hospitalization, adjusted for demographic factors, smoking, obesity, and physical activity. No significant associations were found between dementia at baseline and rate of cancer hospitalizations for participants with diagnoses of VaD. Prevalent cancer was associated with reduced risk of any AD (HR = 0.72; 95% CI = 0.52-0.997) and pure AD (HR = 0.57; 95% CI = 0.36-0.90) among white subjects after adjustment for demographics, number of APOE epsilon4 alleles, hypertension, diabetes, and coronary heart disease; the opposite association was found among minorities, but the sample size was too small to provide stable estimates. No significant association was found between cancer and subsequent development of VaD.

CONCLUSIONS: In white older adults, prevalent Alzheimer disease (AD) was longitudinally associated with a reduced risk of cancer, and a history of cancer was associated with a reduced risk of AD. Together with other work showing associations between cancer and Parkinson disease, these findings suggest the possibility that cancer is linked to neurodegeneration.

VL - 74 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20032288?dopt=Abstract ER - TY - JOUR T1 - Candidate gene association resource (CARe): design, methods, and proof of concept. JF - Circ Cardiovasc Genet Y1 - 2010 A1 - Musunuru, Kiran A1 - Lettre, Guillaume A1 - Young, Taylor A1 - Farlow, Deborah N A1 - Pirruccello, James P A1 - Ejebe, Kenechi G A1 - Keating, Brendan J A1 - Yang, Qiong A1 - Chen, Ming-Huei A1 - Lapchyk, Nina A1 - Crenshaw, Andrew A1 - Ziaugra, Liuda A1 - Rachupka, Anthony A1 - Benjamin, Emelia J A1 - Cupples, L Adrienne A1 - Fornage, Myriam A1 - Fox, Ervin R A1 - Heckbert, Susan R A1 - Hirschhorn, Joel N A1 - Newton-Cheh, Christopher A1 - Nizzari, Marcia M A1 - Paltoo, Dina N A1 - Papanicolaou, George J A1 - Patel, Sanjay R A1 - Psaty, Bruce M A1 - Rader, Daniel J A1 - Redline, Susan A1 - Rich, Stephen S A1 - Rotter, Jerome I A1 - Taylor, Herman A A1 - Tracy, Russell P A1 - Vasan, Ramachandran S A1 - Wilson, James G A1 - Kathiresan, Sekar A1 - Fabsitz, Richard R A1 - Boerwinkle, Eric A1 - Gabriel, Stacey B KW - African Americans KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Databases, Genetic KW - European Continental Ancestry Group KW - Genetic Association Studies KW - Genotype KW - Humans KW - Phenotype KW - Pilot Projects KW - Polymorphism, Single Nucleotide KW - Research Design KW - Triglycerides AB -

BACKGROUND: The National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe), a planned cross-cohort analysis of genetic variation in cardiovascular, pulmonary, hematologic, and sleep-related traits, comprises >40,000 participants representing 4 ethnic groups in 9 community-based cohorts. The goals of CARe include the discovery of new variants associated with traits using a candidate gene approach and the discovery of new variants using the genome-wide association mapping approach specifically in African Americans.

METHODS AND RESULTS: CARe has assembled DNA samples for >40,000 individuals self-identified as European American, African American, Hispanic, or Chinese American, with accompanying data on hundreds of phenotypes that have been standardized and deposited in the CARe Phenotype Database. All participants were genotyped for 7 single-nucleotide polymorphisms (SNPs) selected based on prior association evidence. We performed association analyses relating each of these SNPs to lipid traits, stratified by sex and ethnicity, and adjusted for age and age squared. In at least 2 of the ethnic groups, SNPs near CETP, LIPC, and LPL strongly replicated for association with high-density lipoprotein cholesterol concentrations, PCSK9 with low-density lipoprotein cholesterol levels, and LPL and APOA5 with serum triglycerides. Notably, some SNPs showed varying effect sizes and significance of association in different ethnic groups.

CONCLUSIONS: The CARe Pilot Study validates the operational framework for phenotype collection, SNP genotyping, and analytic pipeline of the CARe project and validates the planned candidate gene study of approximately 2000 biological candidate loci in all participants and genome-wide association study in approximately 8000 African American participants. CARe will serve as a valuable resource for the scientific community.

VL - 3 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20400780?dopt=Abstract ER - TY - JOUR T1 - Change in circulating adiponectin in advanced old age: determinants and impact on physical function and mortality. The Cardiovascular Health Study All Stars Study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2010 A1 - Kizer, Jorge R A1 - Arnold, Alice M A1 - Strotmeyer, Elsa S A1 - Ives, Diane G A1 - Cushman, Mary A1 - Ding, Jingzhong A1 - Kritchevsky, Stephen B A1 - Chaves, Paulo H M A1 - Hirsch, Calvin H A1 - Newman, Anne B KW - Adiponectin KW - Age Factors KW - Aged KW - Aging KW - Analysis of Variance KW - Cardiovascular Diseases KW - Cause of Death KW - Chi-Square Distribution KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Health Status KW - Humans KW - Linear Models KW - Male KW - Physical Fitness KW - Proportional Hazards Models KW - Risk Factors KW - Sex Factors KW - Time Factors KW - United States AB -

BACKGROUND: Cross-sectional studies show that adiponectin is higher in older than in younger adults but long-term change in adiponectin, its determinants, and its relationship to functional decline or survival in the elderly population have not been evaluated.

METHODS: We investigated predictors of longitudinal change in adiponectin, and the association of this adipokine or its antecedent change with physical deterioration and all-cause mortality in 988 participants in a population-based study who completed examinations in 1996-1997 and 2005-2006, had serial adiponectin measurements and underwent follow-up through June 2009.

RESULTS: Adiponectin level rose significantly during follow-up, but the increase was smaller in blacks, was associated with declining weight or fasting glucose and, in men, lower albumin, and was affected by medications. Adiponectin was independently associated with greater physical decline, but the relationship for adiponectin change was driven by concomitant weight decrease. Both adiponectin and its change independently predicted mortality, even after adjustment for weight change. The association for adiponectin and mortality was observed in whites but not in blacks and only for levels in the upper range (hazard ratio = 1.85, 95% confidence interval = 1.36-2.52 per SD ≥ 20 mg/L), whereas that for adiponectin change was linear throughout in both racial groups (hazard ratio = 1.30, 95% confidence interval = 1.10-1.52 per SD).

CONCLUSIONS: Adiponectin levels increase over time in long-lived adults and are associated with greater physical disability and mortality. Such increases may occur in response to age-related homeostatic dysregulation. Additional investigation is required to define the underlying mechanisms and whether this represents a marker or causal factor for mortality in this age group.

VL - 65 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20616148?dopt=Abstract ER - TY - JOUR T1 - Chronic medical conditions and the sex-based disparity in disability: the Cardiovascular Health Study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2010 A1 - Whitson, Heather E A1 - Landerman, Lawrence R A1 - Newman, Anne B A1 - Fried, Linda P A1 - Pieper, Carl F A1 - Cohen, Harvey Jay KW - Aged KW - Arthritis KW - Cardiovascular Diseases KW - Chronic Disease KW - Cohort Studies KW - Comorbidity KW - Cross-Sectional Studies KW - Disabled Persons KW - Emphysema KW - Female KW - Hearing Disorders KW - Humans KW - Male KW - Obesity KW - Prevalence KW - Sex Distribution AB -

BACKGROUND: Older women experience disability more commonly than their male peers. This disparity may be due, in part, to sex-based differences in the prevalence or the disabling effects of common medical conditions. The objectives of this analysis were to (a) quantify the extent to which excess disability in women is explained by higher prevalence of selected medical conditions and (b) evaluate whether the same conditions have differing effects on disability in men and women.

METHODS: We analyzed cross-sectional data from 5,888 community-dwelling older men and women. Disability was defined as difficulty with greater than or equal to one activity of daily living. Thirteen medical conditions were assessed by self-report, testing, or record review.

RESULTS: Controlling for age, race, education, and marital status, women were more likely to experience disability (odds ratio = 1.70, 95% confidence interval = 1.36-2.11). Higher prevalence of arthritis and obesity in women explained 30.2% and 12.9%, respectively, of the sex-based difference in disability rates, whereas male prevalent diseases like vascular conditions and emphysema narrowed the disability gap. Women with arthritis, hearing problems, coronary artery disease, congestive heart failure, stroke, and claudication were more likely to exhibit disability compared with men with the same conditions (p < .001).

CONCLUSIONS: Efforts to lessen sex-based inequality in disability should focus on reducing the prevalence of arthritis and obesity. Future generations may see greater functional disparity if rates of vascular disease and emphysema rise among women. Several conditions were more often associated with disability in women, suggesting additional sex-based differences in the disablement process.

VL - 65 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20675619?dopt=Abstract ER - TY - JOUR T1 - Common genetic determinants of vitamin D insufficiency: a genome-wide association study. JF - Lancet Y1 - 2010 A1 - Wang, Thomas J A1 - Zhang, Feng A1 - Richards, J Brent A1 - Kestenbaum, Bryan A1 - van Meurs, Joyce B A1 - Berry, Diane A1 - Kiel, Douglas P A1 - Streeten, Elizabeth A A1 - Ohlsson, Claes A1 - Koller, Daniel L A1 - Peltonen, Leena A1 - Cooper, Jason D A1 - O'Reilly, Paul F A1 - Houston, Denise K A1 - Glazer, Nicole L A1 - Vandenput, Liesbeth A1 - Peacock, Munro A1 - Shi, Julia A1 - Rivadeneira, Fernando A1 - McCarthy, Mark I A1 - Anneli, Pouta A1 - de Boer, Ian H A1 - Mangino, Massimo A1 - Kato, Bernet A1 - Smyth, Deborah J A1 - Booth, Sarah L A1 - Jacques, Paul F A1 - Burke, Greg L A1 - Goodarzi, Mark A1 - Cheung, Ching-Lung A1 - Wolf, Myles A1 - Rice, Kenneth A1 - Goltzman, David A1 - Hidiroglou, Nick A1 - Ladouceur, Martin A1 - Wareham, Nicholas J A1 - Hocking, Lynne J A1 - Hart, Deborah A1 - Arden, Nigel K A1 - Cooper, Cyrus A1 - Malik, Suneil A1 - Fraser, William D A1 - Hartikainen, Anna-Liisa A1 - Zhai, Guangju A1 - Macdonald, Helen M A1 - Forouhi, Nita G A1 - Loos, Ruth J F A1 - Reid, David M A1 - Hakim, Alan A1 - Dennison, Elaine A1 - Liu, Yongmei A1 - Power, Chris A1 - Stevens, Helen E A1 - Jaana, Laitinen A1 - Vasan, Ramachandran S A1 - Soranzo, Nicole A1 - Bojunga, Jörg A1 - Psaty, Bruce M A1 - Lorentzon, Mattias A1 - Foroud, Tatiana A1 - Harris, Tamara B A1 - Hofman, Albert A1 - Jansson, John-Olov A1 - Cauley, Jane A A1 - Uitterlinden, André G A1 - Gibson, Quince A1 - Jarvelin, Marjo-Riitta A1 - Karasik, David A1 - Siscovick, David S A1 - Econs, Michael J A1 - Kritchevsky, Stephen B A1 - Florez, Jose C A1 - Todd, John A A1 - Dupuis, Josée A1 - Hyppönen, Elina A1 - Spector, Timothy D KW - Canada KW - Chromosomes, Human, Pair 11 KW - Chromosomes, Human, Pair 4 KW - Cohort Studies KW - Dietary Supplements KW - Europe KW - European Continental Ancestry Group KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Heterozygote KW - Homozygote KW - Humans KW - Immunoassay KW - International Cooperation KW - Linkage Disequilibrium KW - Polymorphism, Single Nucleotide KW - Seasons KW - United States KW - Vitamin D KW - Vitamin D Deficiency AB -

BACKGROUND: Vitamin D is crucial for maintenance of musculoskeletal health, and might also have a role in extraskeletal tissues. Determinants of circulating 25-hydroxyvitamin D concentrations include sun exposure and diet, but high heritability suggests that genetic factors could also play a part. We aimed to identify common genetic variants affecting vitamin D concentrations and risk of insufficiency.

METHODS: We undertook a genome-wide association study of 25-hydroxyvitamin D concentrations in 33 996 individuals of European descent from 15 cohorts. Five epidemiological cohorts were designated as discovery cohorts (n=16 125), five as in-silico replication cohorts (n=9367), and five as de-novo replication cohorts (n=8504). 25-hydroxyvitamin D concentrations were measured by radioimmunoassay, chemiluminescent assay, ELISA, or mass spectrometry. Vitamin D insufficiency was defined as concentrations lower than 75 nmol/L or 50 nmol/L. We combined results of genome-wide analyses across cohorts using Z-score-weighted meta-analysis. Genotype scores were constructed for confirmed variants.

FINDINGS: Variants at three loci reached genome-wide significance in discovery cohorts for association with 25-hydroxyvitamin D concentrations, and were confirmed in replication cohorts: 4p12 (overall p=1.9x10(-109) for rs2282679, in GC); 11q12 (p=2.1x10(-27) for rs12785878, near DHCR7); and 11p15 (p=3.3x10(-20) for rs10741657, near CYP2R1). Variants at an additional locus (20q13, CYP24A1) were genome-wide significant in the pooled sample (p=6.0x10(-10) for rs6013897). Participants with a genotype score (combining the three confirmed variants) in the highest quartile were at increased risk of having 25-hydroxyvitamin D concentrations lower than 75 nmol/L (OR 2.47, 95% CI 2.20-2.78, p=2.3x10(-48)) or lower than 50 nmol/L (1.92, 1.70-2.16, p=1.0x10(-26)) compared with those in the lowest quartile.

INTERPRETATION: Variants near genes involved in cholesterol synthesis, hydroxylation, and vitamin D transport affect vitamin D status. Genetic variation at these loci identifies individuals who have substantially raised risk of vitamin D insufficiency.

FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

VL - 376 IS - 9736 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20541252?dopt=Abstract ER - TY - JOUR T1 - Common variants in KCNN3 are associated with lone atrial fibrillation. JF - Nat Genet Y1 - 2010 A1 - Ellinor, Patrick T A1 - Lunetta, Kathryn L A1 - Glazer, Nicole L A1 - Pfeufer, Arne A1 - Alonso, Alvaro A1 - Chung, Mina K A1 - Sinner, Moritz F A1 - de Bakker, Paul I W A1 - Mueller, Martina A1 - Lubitz, Steven A A1 - Fox, Ervin A1 - Darbar, Dawood A1 - Smith, Nicholas L A1 - Smith, Jonathan D A1 - Schnabel, Renate B A1 - Soliman, Elsayed Z A1 - Rice, Kenneth M A1 - Van Wagoner, David R A1 - Beckmann, Britt-M A1 - van Noord, Charlotte A1 - Wang, Ke A1 - Ehret, Georg B A1 - Rotter, Jerome I A1 - Hazen, Stanley L A1 - Steinbeck, Gerhard A1 - Smith, Albert V A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Makino, Seiko A1 - Nelis, Mari A1 - Milan, David J A1 - Perz, Siegfried A1 - Esko, Tõnu A1 - Köttgen, Anna A1 - Moebus, Susanne A1 - Newton-Cheh, Christopher A1 - Li, Man A1 - Möhlenkamp, Stefan A1 - Wang, Thomas J A1 - Kao, W H Linda A1 - Vasan, Ramachandran S A1 - Nöthen, Markus M A1 - MacRae, Calum A A1 - Stricker, Bruno H Ch A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Levy, Daniel A1 - Boerwinkle, Eric A1 - Metspalu, Andres A1 - Topol, Eric J A1 - Chakravarti, Aravinda A1 - Gudnason, Vilmundur A1 - Psaty, Bruce M A1 - Roden, Dan M A1 - Meitinger, Thomas A1 - Wichmann, H-Erich A1 - Witteman, Jacqueline C M A1 - Barnard, John A1 - Arking, Dan E A1 - Benjamin, Emelia J A1 - Heckbert, Susan R A1 - Kääb, Stefan KW - Adolescent KW - Adult KW - Aged KW - Atrial Fibrillation KW - Case-Control Studies KW - Cohort Studies KW - Female KW - Genome-Wide Association Study KW - Humans KW - Introns KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Small-Conductance Calcium-Activated Potassium Channels KW - Young Adult AB -

Atrial fibrillation (AF) is the most common sustained arrhythmia. Previous studies have identified several genetic loci associated with typical AF. We sought to identify common genetic variants underlying lone AF. This condition affects a subset of individuals without overt heart disease and with an increased heritability of AF. We report a meta-analysis of genome-wide association studies conducted using 1,335 individuals with lone AF (cases) and 12,844 unaffected individuals (referents). Cases were obtained from the German AF Network, Heart and Vascular Health Study, the Atherosclerosis Risk in Communities Study, the Cleveland Clinic and Massachusetts General Hospital. We identified an association on chromosome 1q21 to lone AF (rs13376333, adjusted odds ratio = 1.56; P = 6.3 x 10(-12)), and we replicated this association in two independent cohorts with lone AF (overall combined odds ratio = 1.52, 95% CI 1.40-1.64; P = 1.83 x 10(-21)). rs13376333 is intronic to KCNN3, which encodes a potassium channel protein involved in atrial repolarization.

VL - 42 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20173747?dopt=Abstract ER - TY - JOUR T1 - Concurrent change in dehydroepiandrosterone sulfate and functional performance in the oldest old: results from the Cardiovascular Health Study All Stars study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2010 A1 - Sanders, J L A1 - Cappola, A R A1 - Arnold, A M A1 - Boudreau, R M A1 - Chaves, P H A1 - Robbins, J A1 - Cushman, M A1 - Newman, A B KW - Aged, 80 and over KW - Biomarkers KW - Cognition KW - Cohort Studies KW - Dehydroepiandrosterone Sulfate KW - Female KW - Gait KW - Geriatric Assessment KW - Hand Strength KW - Health Surveys KW - Humans KW - Longitudinal Studies KW - Male KW - Neuropsychological Tests KW - Sex Factors KW - United States AB -

INTRODUCTION: The correlation between dehydroepiandrosterone sulfate (DHEAS) decline and age led to the hypothesis that DHEAS might be a marker of primary aging, though conflicting data from observational studies of mortality do not support this. We evaluated concurrent DHEAS and functional decline in a very old cohort to test if DHEAS change tracks with functional change during aging.

METHODS: DHEAS and functional performance (gait speed, grip strength, Modified Mini-Mental State Examination [3MSE] score, and digit symbol substitution test [DSST] score) were measured in 1996-1997 and 2005-2006 in 989 participants in the Cardiovascular Health Study All Stars study (mean age 85.2 years in 2005-2006, 63.5% women and 16.5% African American). We used multivariable linear regression to test the association of DHEAS decline with functional decline.

RESULTS: After adjustment, each standard deviation decrease in DHEAS was associated with greater declines in gait speed (0.12 m/s, p = .01), grip strength (0.09 kg, p = .03), 3MSE score (0.13 points, p < .001), and DSST score (0.14 points, p = .001) in women only. Additional adjustment for baseline DHEAS attenuated the association with grip strength but did not alter other estimates appreciably, and baseline DHEAS was unassociated with functional decline.

CONCLUSIONS: In this cohort of very old individuals, DHEAS decline tracked with declines in gait speed, 3MSE score, and DSST score, but not grip strength, in women independent of baseline DHEAS level. DHEAS decline might be a marker for age-associated performance decline, but its relevance is specific to women.

VL - 65 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20466773?dopt=Abstract ER - TY - JOUR T1 - CRP gene variation and risk of community-acquired pneumonia. JF - Respirology Y1 - 2010 A1 - Mukamal, Kenneth J A1 - Pai, Jennifer K A1 - O'Meara, Ellen S A1 - Tracy, Russell P A1 - Psaty, Bruce M A1 - Kuller, Lewis H A1 - Newman, Anne B A1 - Yende, Sachin A1 - Curhan, Gary C A1 - Siscovick, David S A1 - Rimm, Eric B KW - African Americans KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - C-Reactive Protein KW - Cohort Studies KW - Community-Acquired Infections KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Male KW - Pneumonia KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Risk Factors KW - Smoking AB -

BACKGROUND AND OBJECTIVE: CRP has several potentially antibacterial effects, and variation in the CRP gene is known to influence CRP levels. Whether this variation influences risk of infection, and hence whether CRP has anti-infective activity in humans, is uncertain.

METHODS: We evaluated a series of haplotype-tagging single nucleotide polymorphisms among 5374 individuals in the Cardiovascular Health Study, a cohort of older adults from four communities, who were followed for community-acquired pneumonia for 12-13 years. Secondarily, we evaluated whether these polymorphisms varied among men in the Health Professionals Follow-up Study who self-reported pneumonia on biennial questionnaires.

RESULTS: There were 581 (507 white and 74 black) Cardiovascular Health Study participants with incident hospitalizations for pneumonia. No single nucleotide polymorphism or haplotypes were associated with risk among white Cardiovascular Health Study participants. Among black participants, the haplotype tagged by A790T was associated with lower risk of incident pneumonia (hazard ratio 0.5; 95% confidence interval: 0.3-0.9) and with higher CRP levels. In Health Professionals Follow-up Study, a separate haplotype was associated with less frequent self-reported pneumonia but not with circulating CRP levels.

CONCLUSIONS: Some genetic variants in CRP may be associated with risk of pneumonia, but haplotypes associated with risk are variably associated with baseline CRP levels. If CRP is a relevant component of innate immunity in humans, the inducibility or tissue-specificity of expression may be at least as important as chronic circulating levels.

VL - 15 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19947988?dopt=Abstract ER - TY - JOUR T1 - Four novel Loci (19q13, 6q24, 12q24, and 5q14) influence the microcirculation in vivo. JF - PLoS Genet Y1 - 2010 A1 - Ikram, M Kamran A1 - Sim, Xueling A1 - Xueling, Sim A1 - Jensen, Richard A A1 - Cotch, Mary Frances A1 - Hewitt, Alex W A1 - Ikram, M Arfan A1 - Wang, Jie Jin A1 - Klein, Ronald A1 - Klein, Barbara E K A1 - Breteler, Monique M B A1 - Cheung, Ning A1 - Liew, Gerald A1 - Mitchell, Paul A1 - Uitterlinden, André G A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - de Jong, Paulus T V M A1 - van Duijn, Cornelia M A1 - Kao, Linda A1 - Cheng, Ching-Yu A1 - Smith, Albert Vernon A1 - Glazer, Nicole L A1 - Lumley, Thomas A1 - McKnight, Barbara A1 - Psaty, Bruce M A1 - Jonasson, Fridbert A1 - Eiriksdottir, Gudny A1 - Aspelund, Thor A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Taylor, Kent D A1 - Li, Xiaohui A1 - Iyengar, Sudha K A1 - Xi, Quansheng A1 - Sivakumaran, Theru A A1 - Mackey, David A A1 - Macgregor, Stuart A1 - Martin, Nicholas G A1 - Young, Terri L A1 - Bis, Josh C A1 - Wiggins, Kerri L A1 - Heckbert, Susan R A1 - Hammond, Christopher J A1 - Andrew, Toby A1 - Fahy, Samantha A1 - Attia, John A1 - Holliday, Elizabeth G A1 - Scott, Rodney J A1 - Islam, F M Amirul A1 - Rotter, Jerome I A1 - McAuley, Annie K A1 - Boerwinkle, Eric A1 - Tai, E Shyong A1 - Gudnason, Vilmundur A1 - Siscovick, David S A1 - Vingerling, Johannes R A1 - Wong, Tien Y KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Child KW - Child, Preschool KW - Chromosomes, Human, Pair 12 KW - Chromosomes, Human, Pair 19 KW - Chromosomes, Human, Pair 5 KW - Chromosomes, Human, Pair 6 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Microcirculation KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Retinal Vessels KW - Young Adult AB -

There is increasing evidence that the microcirculation plays an important role in the pathogenesis of cardiovascular diseases. Changes in retinal vascular caliber reflect early microvascular disease and predict incident cardiovascular events. We performed a genome-wide association study to identify genetic variants associated with retinal vascular caliber. We analyzed data from four population-based discovery cohorts with 15,358 unrelated Caucasian individuals, who are members of the Cohort for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium, and replicated findings in four independent Caucasian cohorts (n  =  6,652). All participants had retinal photography and retinal arteriolar and venular caliber measured from computer software. In the discovery cohorts, 179 single nucleotide polymorphisms (SNP) spread across five loci were significantly associated (p<5.0×10(-8)) with retinal venular caliber, but none showed association with arteriolar caliber. Collectively, these five loci explain 1.0%-3.2% of the variation in retinal venular caliber. Four out of these five loci were confirmed in independent replication samples. In the combined analyses, the top SNPs at each locus were: rs2287921 (19q13; p  =  1.61×10(-25), within the RASIP1 locus), rs225717 (6q24; p = 1.25×10(-16), adjacent to the VTA1 and NMBR loci), rs10774625 (12q24; p  =  2.15×10(-13), in the region of ATXN2,SH2B3 and PTPN11 loci), and rs17421627 (5q14; p = 7.32×10(-16), adjacent to the MEF2C locus). In two independent samples, locus 12q24 was also associated with coronary heart disease and hypertension. Our population-based genome-wide association study demonstrates four novel loci associated with retinal venular caliber, an endophenotype of the microcirculation associated with clinical cardiovascular disease. These data provide further insights into the contribution and biological mechanisms of microcirculatory changes that underlie cardiovascular disease.

VL - 6 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21060863?dopt=Abstract ER - TY - JOUR T1 - Fucosyltransferase 2 (FUT2) non-secretor status is associated with Crohn's disease. JF - Hum Mol Genet Y1 - 2010 A1 - McGovern, Dermot P B A1 - Jones, Michelle R A1 - Taylor, Kent D A1 - Marciante, Kristin A1 - Yan, Xiaofei A1 - Dubinsky, Marla A1 - Ippoliti, Andy A1 - Vasiliauskas, Eric A1 - Berel, Dror A1 - Derkowski, Carrie A1 - Dutridge, Deb A1 - Fleshner, Phil A1 - Shih, David Q A1 - Melmed, Gil A1 - Mengesha, Emebet A1 - King, Lily A1 - Pressman, Sheila A1 - Haritunians, Talin A1 - Guo, Xiuqing A1 - Targan, Stephan R A1 - Rotter, Jerome I KW - Adolescent KW - Adult KW - Aged KW - Child KW - Child, Preschool KW - Cohort Studies KW - Crohn Disease KW - Female KW - Fucosyltransferases KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Young Adult AB -

Genetic variation in both innate and adaptive immune systems is associated with Crohn's disease (CD) susceptibility, but much of the heritability to CD remains unknown. We performed a genome-wide association study (GWAS) in 896 CD cases and 3204 healthy controls all of Caucasian origin as defined by multidimensional scaling. We found supportive evidence for 21 out of 40 CD loci identified in a recent CD GWAS meta-analysis, including two loci which had only nominally achieved replication (rs4807569, 19p13; rs991804, CCL2/CCL7). In addition, we identified associations with genes involved in tight junctions/epithelial integrity (ASHL, ARPC1A), innate immunity (EXOC2), dendritic cell biology [CADM1 (IGSF4)], macrophage development (MMD2), TGF-beta signaling (MAP3K7IP1) and FUT2 (a physiological trait that regulates gastrointestinal mucosal expression of blood group A and B antigens) (rs602662, P=3.4x10(-5)). Twenty percent of Caucasians are 'non-secretors' who do not express ABO antigens in saliva as a result of the FUT2 W134X allele. We demonstrated replication in an independent cohort of 1174 CD cases and 357 controls between the four primary FUT2 single nucleotide polymorphisms (SNPs) and CD (rs602662, combined P-value 4.90x10(-8)) and also association with FUT2 W143X (P=2.6x10(-5)). Further evidence of the relevance of this locus to CD pathogenesis was demonstrated by the association of the original four SNPs and CD in the recently published CD GWAS meta-analysis (rs602662, P=0.001). These findings strongly implicate this locus in CD susceptibility and highlight the role of the mucus layer in the development of CD.

VL - 19 IS - 17 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20570966?dopt=Abstract ER - TY - JOUR T1 - Genetic predictors of medically refractory ulcerative colitis. JF - Inflamm Bowel Dis Y1 - 2010 A1 - Haritunians, Talin A1 - Taylor, Kent D A1 - Targan, Stephan R A1 - Dubinsky, Marla A1 - Ippoliti, Andrew A1 - Kwon, Soonil A1 - Guo, Xiuqing A1 - Melmed, Gil Y A1 - Berel, Dror A1 - Mengesha, Emebet A1 - Psaty, Bruce M A1 - Glazer, Nicole L A1 - Vasiliauskas, Eric A A1 - Rotter, Jerome I A1 - Fleshner, Phillip R A1 - McGovern, Dermot P B KW - Acute Disease KW - Adolescent KW - Adult KW - Cohort Studies KW - Colectomy KW - Colitis, Ulcerative KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Major Histocompatibility Complex KW - Male KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Severity of Illness Index KW - Tumor Necrosis Factor Ligand Superfamily Member 15 KW - Young Adult AB -

BACKGROUND: Acute severe ulcerative colitis (UC) remains a significant clinical challenge and the ability to predict, at an early stage, those individuals at risk of colectomy for medically refractory UC (MR-UC) would be a major clinical advance. The aim of this study was to use a genome-wide association study (GWAS) in a well-characterized cohort of UC patients to identify genetic variation that contributes to MR-UC.

METHODS: A GWAS comparing 324 MR-UC patients with 537 non-MR-UC patients was analyzed using logistic regression and Cox proportional hazards methods. In addition, the MR-UC patients were compared with 2601 healthy controls.

RESULTS: MR-UC was associated with more extensive disease (P = 2.7 × 10(-6)) and a positive family history of UC (P = 0.004). A risk score based on the combination of 46 single nucleotide polymorphisms (SNPs) associated with MR-UC explained 48% of the variance for colectomy risk in our cohort. Risk scores divided into quarters showed the risk of colectomy to be 0%, 17%, 74%, and 100% in the four groups. Comparison of the MR-UC subjects with healthy controls confirmed the contribution of the major histocompatibility complex to severe UC (peak association: rs17207986, P = 1.4 × 10(-16)) and provided genome-wide suggestive association at the TNFSF15 (TL1A) locus (peak association: rs11554257, P = 1.4 × 10(-6)).

CONCLUSIONS: A SNP-based risk scoring system, identified here by GWAS analyses, may provide a useful adjunct to clinical parameters for predicting the natural history of UC. Furthermore, discovery of genetic processes underlying disease severity may help to identify pathways for novel therapeutic intervention in severe UC.

VL - 16 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20848476?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis identifies multiple loci related to resting heart rate. JF - Hum Mol Genet Y1 - 2010 A1 - Eijgelsheim, Mark A1 - Newton-Cheh, Christopher A1 - Sotoodehnia, Nona A1 - de Bakker, Paul I W A1 - Müller, Martina A1 - Morrison, Alanna C A1 - Smith, Albert V A1 - Isaacs, Aaron A1 - Sanna, Serena A1 - Dörr, Marcus A1 - Navarro, Pau A1 - Fuchsberger, Christian A1 - Nolte, Ilja M A1 - de Geus, Eco J C A1 - Estrada, Karol A1 - Hwang, Shih-Jen A1 - Bis, Joshua C A1 - Rückert, Ina-Maria A1 - Alonso, Alvaro A1 - Launer, Lenore J A1 - Hottenga, Jouke Jan A1 - Rivadeneira, Fernando A1 - Noseworthy, Peter A A1 - Rice, Kenneth M A1 - Perz, Siegfried A1 - Arking, Dan E A1 - Spector, Tim D A1 - Kors, Jan A A1 - Aulchenko, Yurii S A1 - Tarasov, Kirill V A1 - Homuth, Georg A1 - Wild, Sarah H A1 - Marroni, Fabio A1 - Gieger, Christian A1 - Licht, Carmilla M A1 - Prineas, Ronald J A1 - Hofman, Albert A1 - Rotter, Jerome I A1 - Hicks, Andrew A A1 - Ernst, Florian A1 - Najjar, Samer S A1 - Wright, Alan F A1 - Peters, Annette A1 - Fox, Ervin R A1 - Oostra, Ben A A1 - Kroemer, Heyo K A1 - Couper, David A1 - Völzke, Henry A1 - Campbell, Harry A1 - Meitinger, Thomas A1 - Uda, Manuela A1 - Witteman, Jacqueline C M A1 - Psaty, Bruce M A1 - Wichmann, H-Erich A1 - Harris, Tamara B A1 - Kääb, Stefan A1 - Siscovick, David S A1 - Jamshidi, Yalda A1 - Uitterlinden, André G A1 - Folsom, Aaron R A1 - Larson, Martin G A1 - Wilson, James F A1 - Penninx, Brenda W A1 - Snieder, Harold A1 - Pramstaller, Peter P A1 - van Duijn, Cornelia M A1 - Lakatta, Edward G A1 - Felix, Stephan B A1 - Gudnason, Vilmundur A1 - Pfeufer, Arne A1 - Heckbert, Susan R A1 - Stricker, Bruno H Ch A1 - Boerwinkle, Eric A1 - O'Donnell, Christopher J KW - Adult KW - Aged KW - Base Pairing KW - Cohort Studies KW - Female KW - Genetic Loci KW - Genome, Human KW - Genome-Wide Association Study KW - Heart Rate KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Rest AB -

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

VL - 19 IS - 19 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20639392?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association identifies OBFC1 as a locus involved in human leukocyte telomere biology. JF - Proc Natl Acad Sci U S A Y1 - 2010 A1 - Levy, Daniel A1 - Neuhausen, Susan L A1 - Hunt, Steven C A1 - Kimura, Masayuki A1 - Hwang, Shih-Jen A1 - Chen, Wei A1 - Bis, Joshua C A1 - Fitzpatrick, Annette L A1 - Smith, Erin A1 - Johnson, Andrew D A1 - Gardner, Jeffrey P A1 - Srinivasan, Sathanur R A1 - Schork, Nicholas A1 - Rotter, Jerome I A1 - Herbig, Utz A1 - Psaty, Bruce M A1 - Sastrasinh, Malinee A1 - Murray, Sarah S A1 - Vasan, Ramachandran S A1 - Province, Michael A A1 - Glazer, Nicole L A1 - Lu, Xiaobin A1 - Cao, Xiaojian A1 - Kronmal, Richard A1 - Mangino, Massimo A1 - Soranzo, Nicole A1 - Spector, Tim D A1 - Berenson, Gerald S A1 - Aviv, Abraham KW - Cohort Studies KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Leukocytes KW - Polymorphism, Single Nucleotide KW - Receptors, CXCR4 KW - Telomere KW - Telomere-Binding Proteins AB -

Telomeres are engaged in a host of cellular functions, and their length is regulated by multiple genes. Telomere shortening, in the course of somatic cell replication, ultimately leads to replicative senescence. In humans, rare mutations in genes that regulate telomere length have been identified in monogenic diseases such as dyskeratosis congenita and idiopathic pulmonary fibrosis, which are associated with shortened leukocyte telomere length (LTL) and increased risk for aplastic anemia. Shortened LTL is observed in a host of aging-related complex genetic diseases and is associated with diminished survival in the elderly. We report results of a genome-wide association study of LTL in a consortium of four observational studies (n = 3,417 participants with LTL and genome-wide genotyping). SNPs in the regions of the oligonucleotide/oligosaccharide-binding folds containing one gene (OBFC1; rs4387287; P = 3.9 x 10(-9)) and chemokine (C-X-C motif) receptor 4 gene (CXCR4; rs4452212; P = 2.9 x 10(-8)) were associated with LTL at a genome-wide significance level (P < 5 x 10(-8)). We attempted replication of the top SNPs at these loci through de novo genotyping of 1,893 additional individuals and in silico lookup in another observational study (n = 2,876), and we confirmed the association findings for OBFC1 but not CXCR4. In addition, we confirmed the telomerase RNA component (TERC) as a gene associated with LTL (P = 1.1 x 10(-5)). The identification of OBFC1 through genome-wide association as a locus for interindividual variation in LTL in the general population advances the understanding of telomere biology in humans and may provide insights into aging-related disorders linked to altered LTL dynamics.

VL - 107 IS - 20 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20421499?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies of MRI-defined brain infarcts: meta-analysis from the CHARGE Consortium. JF - Stroke Y1 - 2010 A1 - Debette, Stephanie A1 - Bis, Joshua C A1 - Fornage, Myriam A1 - Schmidt, Helena A1 - Ikram, M Arfan A1 - Sigurdsson, Sigurdur A1 - Heiss, Gerardo A1 - Struchalin, Maksim A1 - Smith, Albert V A1 - van der Lugt, Aad A1 - DeCarli, Charles A1 - Lumley, Thomas A1 - Knopman, David S A1 - Enzinger, Christian A1 - Eiriksdottir, Gudny A1 - Koudstaal, Peter J A1 - DeStefano, Anita L A1 - Psaty, Bruce M A1 - Dufouil, Carole A1 - Catellier, Diane J A1 - Fazekas, Franz A1 - Aspelund, Thor A1 - Aulchenko, Yurii S A1 - Beiser, Alexa A1 - Rotter, Jerome I A1 - Tzourio, Christophe A1 - Shibata, Dean K A1 - Tscherner, Maria A1 - Harris, Tamara B A1 - Rivadeneira, Fernando A1 - Atwood, Larry D A1 - Rice, Kenneth A1 - Gottesman, Rebecca F A1 - van Buchem, Mark A A1 - Uitterlinden, André G A1 - Kelly-Hayes, Margaret A1 - Cushman, Mary A1 - Zhu, Yicheng A1 - Boerwinkle, Eric A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Romero, Jose R A1 - Lopez, Oscar A1 - van Duijn, Cornelia M A1 - Au, Rhoda A1 - Heckbert, Susan R A1 - Wolf, Philip A A1 - Mosley, Thomas H A1 - Seshadri, Sudha A1 - Breteler, Monique M B A1 - Schmidt, Reinhold A1 - Launer, Lenore J A1 - Longstreth, W T KW - African Americans KW - Aged KW - Brain KW - Brain Infarction KW - Cohort Studies KW - DNA Mutational Analysis KW - Female KW - Gene Frequency KW - Genetic Markers KW - Genetic Predisposition to Disease KW - Genetic Testing KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Linkage Disequilibrium KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Prospective Studies AB -

BACKGROUND AND PURPOSE: Previous studies examining genetic associations with MRI-defined brain infarct have yielded inconsistent findings. We investigated genetic variation underlying covert MRI infarct in persons without histories of transient ischemic attack or stroke. We performed meta-analysis of genome-wide association studies of white participants in 6 studies comprising the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Using 2.2 million genotyped and imputed single nucleotide polymorphisms, each study performed cross-sectional genome-wide association analysis of MRI infarct using age- and sex-adjusted logistic regression models. Study-specific findings were combined in an inverse-variance-weighted meta-analysis, including 9401 participants with mean age 69.7 (19.4% of whom had >or=1 MRI infarct).

RESULTS: The most significant association was found with rs2208454 (minor allele frequency, 20%), located in intron 3 of MACRO domain containing 2 gene and in the downstream region of fibronectin leucine-rich transmembrane protein 3 gene. Each copy of the minor allele was associated with lower risk of MRI infarcts (odds ratio, 0.76; 95% confidence interval, 0.68-0.84; P=4.64x10(-7)). Highly suggestive associations (P<1.0x10(-5)) were also found for 22 other single nucleotide polymorphisms in linkage disequilibrium (r(2)>0.64) with rs2208454. The association with rs2208454 did not replicate in independent samples of 1822 white and 644 black participants, although 4 single nucleotide polymorphisms within 200 kb from rs2208454 were associated with MRI infarcts in the black population sample.

CONCLUSIONS: This first community-based, genome-wide association study on covert MRI infarcts uncovered novel associations. Although replication of the association with top single nucleotide polymorphisms failed, possibly because of insufficient power, results in the black population sample are encouraging, and further efforts at replication are needed.

VL - 41 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20044523?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study identifies GPC5 as a novel genetic locus protective against sudden cardiac arrest. JF - PLoS One Y1 - 2010 A1 - Arking, Dan E A1 - Reinier, Kyndaron A1 - Post, Wendy A1 - Jui, Jonathan A1 - Hilton, Gina A1 - O'Connor, Ashley A1 - Prineas, Ronald J A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Tomaselli, Gordon F A1 - Rea, Thomas A1 - Sotoodehnia, Nona A1 - Siscovick, David S A1 - Burke, Gregory L A1 - Marbán, Eduardo A1 - Spooner, Peter M A1 - Chakravarti, Aravinda A1 - Chugh, Sumeet S KW - Aged KW - Alleles KW - Case-Control Studies KW - Cohort Studies KW - Death, Sudden, Cardiac KW - Ethnic Groups KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glypicans KW - Heart Diseases KW - Humans KW - Male KW - Middle Aged KW - Models, Genetic KW - Oligonucleotide Array Sequence Analysis KW - Oregon KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: Existing studies indicate a significant genetic component for sudden cardiac arrest (SCA) and genome-wide association studies (GWAS) provide an unbiased approach for identification of novel genes. We performed a GWAS to identify genetic determinants of SCA.

METHODOLOGY/PRINCIPAL FINDINGS: We used a case-control design within the ongoing Oregon Sudden Unexpected Death Study (Oregon-SUDS). Cases (n = 424) were SCAs with coronary artery disease (CAD) among residents of Portland, OR (2002-07, population approximately 1,000,000) and controls (n = 226) were residents with CAD, but no history of SCA. All subjects were of White-European ancestry and GWAS was performed using Affymetrix 500K/5.0 and 6.0 arrays. High signal markers were genotyped in SCA cases (n = 521) identified from the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS) (combined n = 19,611). No SNPs reached genome-wide significance (p<5x10(-8)). SNPs at 6 loci were prioritized for follow-up primarily based on significance of p<10(-4) and proximity to a known gene (CSMD2, GPR37L1, LIN9, B4GALNT3, GPC5, and ZNF592). The minor allele of GPC5 (GLYPICAN 5, rs3864180) was associated with a lower risk of SCA in Oregon-SUDS, an effect that was also observed in ARIC/CHS whites (p<0.05) and blacks (p<0.04). In a combined Cox proportional hazards model analysis that adjusted for race, the minor allele exhibited a hazard ratio of 0.85 (95% CI 0.74 to 0.98; p<0.01).

CONCLUSIONS/SIGNIFICANCE: A novel genetic locus for SCA, GPC5, was identified from Oregon-SUDS and successfully validated in the ARIC and CHS cohorts. Three other members of the Glypican family have been previously implicated in human disease, including cardiac conditions. The mechanism of this specific association requires further study.

VL - 5 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20360844?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of PR interval. JF - Nat Genet Y1 - 2010 A1 - Pfeufer, Arne A1 - van Noord, Charlotte A1 - Marciante, Kristin D A1 - Arking, Dan E A1 - Larson, Martin G A1 - Smith, Albert Vernon A1 - Tarasov, Kirill V A1 - Müller, Martina A1 - Sotoodehnia, Nona A1 - Sinner, Moritz F A1 - Verwoert, Germaine C A1 - Li, Man A1 - Kao, W H Linda A1 - Köttgen, Anna A1 - Coresh, Josef A1 - Bis, Joshua C A1 - Psaty, Bruce M A1 - Rice, Kenneth A1 - Rotter, Jerome I A1 - Rivadeneira, Fernando A1 - Hofman, Albert A1 - Kors, Jan A A1 - Stricker, Bruno H C A1 - Uitterlinden, André G A1 - van Duijn, Cornelia M A1 - Beckmann, Britt M A1 - Sauter, Wiebke A1 - Gieger, Christian A1 - Lubitz, Steven A A1 - Newton-Cheh, Christopher A1 - Wang, Thomas J A1 - Magnani, Jared W A1 - Schnabel, Renate B A1 - Chung, Mina K A1 - Barnard, John A1 - Smith, Jonathan D A1 - Van Wagoner, David R A1 - Vasan, Ramachandran S A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Harris, Tamara B A1 - Launer, Lenore J A1 - Najjar, Samer S A1 - Lakatta, Edward A1 - Schlessinger, David A1 - Uda, Manuela A1 - Abecasis, Goncalo R A1 - Müller-Myhsok, Bertram A1 - Ehret, Georg B A1 - Boerwinkle, Eric A1 - Chakravarti, Aravinda A1 - Soliman, Elsayed Z A1 - Lunetta, Kathryn L A1 - Perz, Siegfried A1 - Wichmann, H-Erich A1 - Meitinger, Thomas A1 - Levy, Daniel A1 - Gudnason, Vilmundur A1 - Ellinor, Patrick T A1 - Sanna, Serena A1 - Kääb, Stefan A1 - Witteman, Jacqueline C M A1 - Alonso, Alvaro A1 - Benjamin, Emelia J A1 - Heckbert, Susan R KW - Aged KW - Atrial Fibrillation KW - Cohort Studies KW - Electrocardiography KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Heart Conduction System KW - Humans KW - Male KW - Meta-Analysis as Topic AB -

The electrocardiographic PR interval (or PQ interval) reflects atrial and atrioventricular nodal conduction, disturbances of which increase risk of atrial fibrillation. We report a meta-analysis of genome-wide association studies for PR interval from seven population-based European studies in the CHARGE Consortium: AGES, ARIC, CHS, FHS, KORA, Rotterdam Study, and SardiNIA (N = 28,517). We identified nine loci associated with PR interval at P < 5 x 10(-8). At the 3p22.2 locus, we observed two independent associations in voltage-gated sodium channel genes, SCN10A and SCN5A. Six of the loci were near cardiac developmental genes, including CAV1-CAV2, NKX2-5 (CSX1), SOX5, WNT11, MEIS1, and TBX5-TBX3, providing pathophysiologically interesting candidate genes. Five of the loci, SCN5A, SCN10A, NKX2-5, CAV1-CAV2, and SOX5, were also associated with atrial fibrillation (N = 5,741 cases, P < 0.0056). This suggests a role for common variation in ion channel and developmental genes in atrial and atrioventricular conduction as well as in susceptibility to atrial fibrillation.

VL - 42 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20062060?dopt=Abstract ER - TY - JOUR T1 - Genomic variation associated with mortality among adults of European and African ancestry with heart failure: the cohorts for heart and aging research in genomic epidemiology consortium. JF - Circ Cardiovasc Genet Y1 - 2010 A1 - Morrison, Alanna C A1 - Felix, Janine F A1 - Cupples, L Adrienne A1 - Glazer, Nicole L A1 - Loehr, Laura R A1 - Dehghan, Abbas A1 - Demissie, Serkalem A1 - Bis, Joshua C A1 - Rosamond, Wayne D A1 - Aulchenko, Yurii S A1 - Wang, Ying A A1 - Haritunians, Talin A1 - Folsom, Aaron R A1 - Rivadeneira, Fernando A1 - Benjamin, Emelia J A1 - Lumley, Thomas A1 - Couper, David A1 - Stricker, Bruno H A1 - O'Donnell, Christopher J A1 - Rice, Kenneth M A1 - Chang, Patricia P A1 - Hofman, Albert A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Fox, Ervin R A1 - Uitterlinden, André G A1 - Wang, Thomas J A1 - Psaty, Bruce M A1 - Willerson, James T A1 - van Duijn, Cornelia M A1 - Boerwinkle, Eric A1 - Witteman, Jacqueline C M A1 - Vasan, Ramachandran S A1 - Smith, Nicholas L KW - African Americans KW - Aged KW - Aged, 80 and over KW - Chemokines KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Heart Failure KW - Humans KW - Introns KW - Male KW - MARVEL Domain-Containing Proteins KW - Membrane Proteins KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

BACKGROUND: Prognosis and survival are significant concerns for individuals with heart failure (HF). To better understand the pathophysiology of HF prognosis, the association between 2,366,858 single-nucleotide polymorphisms (SNPs) and all-cause mortality was evaluated among individuals with incident HF from 4 community-based prospective cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study.

METHODS AND RESULTS: Participants were 2526 individuals of European ancestry and 466 individuals of African ancestry who experienced an incident HF event during follow-up in the respective cohorts. Within each study, the association between genetic variants and time to mortality among individuals with HF was assessed by Cox proportional hazards models that included adjustment for sex and age at the time of the HF event. Prospective fixed-effect meta-analyses were conducted for the 4 study populations of European ancestry (N=1645 deaths) and for the 2 populations of African ancestry (N=281 deaths). Genome-wide significance was set at P=5.0x10(-7). Meta-analytic findings among individuals of European ancestry revealed 1 genome-wide significant locus on chromosome 3p22 in an intron of CKLF-like MARVEL transmembrane domain containing 7 (CMTM7, P=3.2x10(-7)). Eight additional loci in individuals of European ancestry and 4 loci in individuals of African ancestry were identified by high-signal SNPs (P<1.0x10(-5)) but did not meet genome-wide significance.

CONCLUSIONS: This study identified a novel locus associated with all-cause mortality among individuals of European ancestry with HF. This finding warrants additional investigation, including replication, in other studies of HF.

VL - 3 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20400778?dopt=Abstract ER - TY - JOUR T1 - Glycosylated hemoglobin and the risk of death and cardiovascular mortality in the elderly. JF - Nutr Metab Cardiovasc Dis Y1 - 2010 A1 - Chonchol, M A1 - Katz, R A1 - Fried, L F A1 - Sarnak, M J A1 - Siscovick, D S A1 - Newman, A B A1 - Strotmeyer, E S A1 - Bertoni, A A1 - Shlipak, M G KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Cardiovascular Diseases KW - Cohort Studies KW - Disease Progression KW - Female KW - Glycated Hemoglobin A KW - Health Surveys KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Myocardial Infarction KW - Risk Factors KW - Statistics as Topic KW - Stroke KW - United States AB -

BACKGROUND AND AIMS: Glycosylated hemoglobin (HbA(1c)) has been associated with incident cardiovascular disease (CVD), but the findings are inconsistent. We tested the hypothesis that HbA(1c) may be associated with an increased risk of death and cardiovascular mortality in older adults.

METHODS AND RESULTS: We evaluated the association between HbA(1c) with all-cause and cardiovascular mortality in 810 participants without a history of diabetes in a sub-study of the Cardiovascular Health Study (CHS), a community cohort study of individuals > or =65 years of age. Glycosylated hemoglobin was measured at baseline and all-cause and cardiovascular mortality was assessed during the follow-up period. The relation between baseline HbA(1c) and death was evaluated with multivariate Cox proportional hazards regression models. After a median follow-up of 14.2 years, 416 deaths were observed. The crude incidence rates of all-cause mortality across HbA(1c) groups were: 4.4% per year, 4.3% per year and 4.6% per year for tertile 1 (< or =5.6%), tertile 2 (5.61-6.20%) and tertile 3 (> or =6.21%), respectively. In unadjusted and fully adjusted analyses, baseline HbA(1c) was not associated with all-cause mortality and cardiovascular mortality (hazard ratio: 1.16 [95% confidence interval 0.91-1.47] and hazard ratio: 1.31 [95% confidence interval 0.90-1.93], respectively for the highest HbA(1c) tertile compared with the lowest).

CONCLUSION: These results suggest that HbA(1c) does not significantly predict all-cause and cardiovascular mortality in non-diabetic community-dwelling older adults.

VL - 20 IS - 1 U1 - https://www.ncbi.nlm.nih.gov/pubmed/19364638?dopt=Abstract ER - TY - JOUR T1 - Impaired kidney function and atrial fibrillation in elderly subjects. JF - J Card Fail Y1 - 2010 A1 - Deo, Rajat A1 - Katz, Ronit A1 - Kestenbaum, Bryan A1 - Fried, Linda A1 - Sarnak, Mark J A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Shlipak, Michael G KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Follow-Up Studies KW - Glomerular Filtration Rate KW - Humans KW - Kidney Diseases KW - Kidney Function Tests KW - Male AB -

BACKGROUND: Impaired kidney function is associated with increased risk for cardiovascular events. We evaluated whether kidney function is associated with atrial fibrillation (AF) risk in elderly persons.

METHODS AND RESULTS: Subjects were participants in the Cardiovascular Health Study (CHS), a population-based cohort of ambulatory elderly. Measures of kidney function were cystatin C and creatinine-based estimated glomerular filtration rate (eGFR). Among the 4663 participants, 342 (7%) had AF at baseline and 579 (13%) developed incident AF during follow-up (mean 7.4 years). In unadjusted analyses, cystatin C quartiles were strongly associated with prevalent AF with a nearly 3-fold odds in the highest quartile compared with the lowest (HR=1.19, 95% CI [0.80-1.76] in quartile 2; HR=2.00, 95% CI [1.38-2.88] in quartile 3; and HR=2.87, 95% CI [2.03-4.07] in quartile 4). This increased risk for prevalent AF remained significant after multivariate adjustment. The risk for incident AF increased across cystatin C quartiles in the unadjusted analysis (HR=1.37, 95% CI [1.07-1.75] in quartile 2; HR=1.43, 95% CI [1.11-1.84] in quartile 3; and HR=1.88, 95% CI [1.47-2.41] in quartile 4); however, after multivariate adjustment, these findings were no longer significant. An estimated GFR <60 mL.min.1.73m(2) was associated with prevalent and incident AF in unadjusted, but not multivariate analyses.

CONCLUSIONS: Impaired kidney function, as measured by cystatin C, is an independent marker of prevalent AF; however, neither cystatin C nor eGFR are predictors of incident AF.

VL - 16 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20123319?dopt=Abstract ER - TY - JOUR T1 - Inflammatory biomarkers and decline in kidney function in the elderly: the Cardiovascular Health Study. JF - Nephrol Dial Transplant Y1 - 2010 A1 - Keller, Christopher A1 - Katz, Ronit A1 - Sarnak, Mark J A1 - Fried, Linda F A1 - Kestenbaum, Bryan A1 - Cushman, Mary A1 - Shlipak, Michael G KW - Aged KW - Biomarkers KW - C-Reactive Protein KW - Cohort Studies KW - Cystatin C KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Inflammation KW - Intercellular Adhesion Molecule-1 KW - Interleukin-6 KW - Kidney KW - Logistic Models KW - Longitudinal Studies KW - Male KW - Prospective Studies KW - Serum Albumin AB -

BACKGROUND: Cross-sectional studies have demonstrated a consistent and linear association between circulating inflammatory markers and kidney function. The objective of this study was to determine whether elevated markers of inflammation are independently associated with longitudinal kidney function decline.

METHODS: This study included 4128 subjects from the Cardiovascular Health Study. Cystatin C was measured at baseline, 3 years later and 7 years later; eligible subjects had at least two measures. Cystatin C-based estimated glomerular filtration rate (eGFR(cysC)) was estimated, and rapid kidney function decline was defined as an annual loss of eGFR(cysC) >3 mL/min/1.73 m(2). Predictors included ten inflammatory and procoagulant biomarkers: C-reactive protein, interleukin-6, intercellular adhesion molecule-1, white blood cell count, fibrinogen, factor VII, factor VIII, D-dimer, plasmin-antiplasmin complex and serum albumin.

RESULTS: During the study, 1059 subjects (26%) had a rapid decline in kidney function. In contrast to the other nine inflammatory or procoagulant biomarkers, serum albumin had a consistent and inverse association with rapid kidney function decline [final adjusted logistic regression model: 1.14-fold increased odds (95% CI 1.06-1.23) of rapid decline per standard deviation lower albumin]. The lowest quartile of albumin had an odds ratio of 1.55 (95% CI 1.23-1.96) for rapid decline compared with the highest quartile. These associations persisted after adjusting the albumin models for CRP, IL-6 and fibrinogen.

CONCLUSIONS: In contrast to nine other inflammatory and procoagulant markers, only lower baseline levels of serum albumin were consistently associated with a rapid decline in kidney function, as measured by cystatin C-based eGFR.

VL - 25 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/19734138?dopt=Abstract ER - TY - JOUR T1 - A meta-analysis of four genome-wide association studies of survival to age 90 years or older: the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium. JF - J Gerontol A Biol Sci Med Sci Y1 - 2010 A1 - Newman, Anne B A1 - Walter, Stefan A1 - Lunetta, Kathryn L A1 - Garcia, Melissa E A1 - Slagboom, P Eline A1 - Christensen, Kaare A1 - Arnold, Alice M A1 - Aspelund, Thor A1 - Aulchenko, Yurii S A1 - Benjamin, Emelia J A1 - Christiansen, Lene A1 - D'Agostino, Ralph B A1 - Fitzpatrick, Annette L A1 - Franceschini, Nora A1 - Glazer, Nicole L A1 - Gudnason, Vilmundur A1 - Hofman, Albert A1 - Kaplan, Robert A1 - Karasik, David A1 - Kelly-Hayes, Margaret A1 - Kiel, Douglas P A1 - Launer, Lenore J A1 - Marciante, Kristin D A1 - Massaro, Joseph M A1 - Miljkovic, Iva A1 - Nalls, Michael A A1 - Hernandez, Dena A1 - Psaty, Bruce M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome A1 - Seshadri, Sudha A1 - Smith, Albert V A1 - Taylor, Kent D A1 - Tiemeier, Henning A1 - Uh, Hae-Won A1 - Uitterlinden, André G A1 - Vaupel, James W A1 - Walston, Jeremy A1 - Westendorp, Rudi G J A1 - Harris, Tamara B A1 - Lumley, Thomas A1 - van Duijn, Cornelia M A1 - Murabito, Joanne M KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Alleles KW - Cohort Studies KW - Confidence Intervals KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Longevity KW - Male KW - Middle Aged KW - Odds Ratio KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: Genome-wide association studies (GWAS) may yield insights into longevity.

METHODS: We performed a meta-analysis of GWAS in Caucasians from four prospective cohort studies: the Age, Gene/Environment Susceptibility-Reykjavik Study, the Cardiovascular Health Study, the Framingham Heart Study, and the Rotterdam Study participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Longevity was defined as survival to age 90 years or older (n = 1,836); the comparison group comprised cohort members who died between the ages of 55 and 80 years (n = 1,955). In a second discovery stage, additional genotyping was conducted in the Leiden Longevity Study cohort and the Danish 1905 cohort.

RESULTS: There were 273 single-nucleotide polymorphism (SNP) associations with p < .0001, but none reached the prespecified significance level of 5 x 10(-8). Of the most significant SNPs, 24 were independent signals, and 16 of these SNPs were successfully genotyped in the second discovery stage, with one association for rs9664222, reaching 6.77 x 10(-7) for the combined meta-analysis of CHARGE and the stage 2 cohorts. The SNP lies in a region near MINPP1 (chromosome 10), a well-conserved gene involved in regulation of cellular proliferation. The minor allele was associated with lower odds of survival past age 90 (odds ratio = 0.82). Associations of interest in a homologue of the longevity assurance gene (LASS3) and PAPPA2 were not strengthened in the second stage.

CONCLUSION: Survival studies of larger size or more extreme or specific phenotypes may support or refine these initial findings.

VL - 65 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20304771?dopt=Abstract ER - TY - JOUR T1 - New loci associated with kidney function and chronic kidney disease. JF - Nat Genet Y1 - 2010 A1 - Köttgen, Anna A1 - Pattaro, Cristian A1 - Böger, Carsten A A1 - Fuchsberger, Christian A1 - Olden, Matthias A1 - Glazer, Nicole L A1 - Parsa, Afshin A1 - Gao, Xiaoyi A1 - Yang, Qiong A1 - Smith, Albert V A1 - O'Connell, Jeffrey R A1 - Li, Man A1 - Schmidt, Helena A1 - Tanaka, Toshiko A1 - Isaacs, Aaron A1 - Ketkar, Shamika A1 - Hwang, Shih-Jen A1 - Johnson, Andrew D A1 - Dehghan, Abbas A1 - Teumer, Alexander A1 - Paré, Guillaume A1 - Atkinson, Elizabeth J A1 - Zeller, Tanja A1 - Lohman, Kurt A1 - Cornelis, Marilyn C A1 - Probst-Hensch, Nicole M A1 - Kronenberg, Florian A1 - Tönjes, Anke A1 - Hayward, Caroline A1 - Aspelund, Thor A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Harris, Tamara B A1 - Rampersaud, Evadnie A1 - Mitchell, Braxton D A1 - Arking, Dan E A1 - Boerwinkle, Eric A1 - Struchalin, Maksim A1 - Cavalieri, Margherita A1 - Singleton, Andrew A1 - Giallauria, Francesco A1 - Metter, Jeffrey A1 - de Boer, Ian H A1 - Haritunians, Talin A1 - Lumley, Thomas A1 - Siscovick, David A1 - Psaty, Bruce M A1 - Zillikens, M Carola A1 - Oostra, Ben A A1 - Feitosa, Mary A1 - Province, Michael A1 - de Andrade, Mariza A1 - Turner, Stephen T A1 - Schillert, Arne A1 - Ziegler, Andreas A1 - Wild, Philipp S A1 - Schnabel, Renate B A1 - Wilde, Sandra A1 - Munzel, Thomas F A1 - Leak, Tennille S A1 - Illig, Thomas A1 - Klopp, Norman A1 - Meisinger, Christa A1 - Wichmann, H-Erich A1 - Koenig, Wolfgang A1 - Zgaga, Lina A1 - Zemunik, Tatijana A1 - Kolcic, Ivana A1 - Minelli, Cosetta A1 - Hu, Frank B A1 - Johansson, Asa A1 - Igl, Wilmar A1 - Zaboli, Ghazal A1 - Wild, Sarah H A1 - Wright, Alan F A1 - Campbell, Harry A1 - Ellinghaus, David A1 - Schreiber, Stefan A1 - Aulchenko, Yurii S A1 - Felix, Janine F A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Hofman, Albert A1 - Imboden, Medea A1 - Nitsch, Dorothea A1 - Brandstätter, Anita A1 - Kollerits, Barbara A1 - Kedenko, Lyudmyla A1 - Mägi, Reedik A1 - Stumvoll, Michael A1 - Kovacs, Peter A1 - Boban, Mladen A1 - Campbell, Susan A1 - Endlich, Karlhans A1 - Völzke, Henry A1 - Kroemer, Heyo K A1 - Nauck, Matthias A1 - Völker, Uwe A1 - Polasek, Ozren A1 - Vitart, Veronique A1 - Badola, Sunita A1 - Parker, Alexander N A1 - Ridker, Paul M A1 - Kardia, Sharon L R A1 - Blankenberg, Stefan A1 - Liu, Yongmei A1 - Curhan, Gary C A1 - Franke, Andre A1 - Rochat, Thierry A1 - Paulweber, Bernhard A1 - Prokopenko, Inga A1 - Wang, Wei A1 - Gudnason, Vilmundur A1 - Shuldiner, Alan R A1 - Coresh, Josef A1 - Schmidt, Reinhold A1 - Ferrucci, Luigi A1 - Shlipak, Michael G A1 - van Duijn, Cornelia M A1 - Borecki, Ingrid A1 - Krämer, Bernhard K A1 - Rudan, Igor A1 - Gyllensten, Ulf A1 - Wilson, James F A1 - Witteman, Jacqueline C A1 - Pramstaller, Peter P A1 - Rettig, Rainer A1 - Hastie, Nick A1 - Chasman, Daniel I A1 - Kao, W H A1 - Heid, Iris M A1 - Fox, Caroline S KW - Cohort Studies KW - Creatinine KW - Cystatin C KW - Diet KW - Europe KW - Genetic Markers KW - Genome-Wide Association Study KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Models, Genetic KW - Risk Factors AB -

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

VL - 42 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20383146?dopt=Abstract ER - TY - JOUR T1 - A novel approach to prediction of mild obstructive sleep disordered breathing in a population-based sample: the Sleep Heart Health Study. JF - Sleep Y1 - 2010 A1 - Caffo, Brian A1 - Diener-West, Marie A1 - Punjabi, Naresh M A1 - Samet, Jonathan KW - Age Factors KW - Aged KW - Algorithms KW - Body Mass Index KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Predictive Value of Tests KW - Risk Factors KW - ROC Curve KW - Sleep Apnea Syndromes KW - Snoring KW - Waist Circumference AB -

This manuscript considers a data-mining approach for the prediction of mild obstructive sleep disordered breathing, defined as an elevated respiratory disturbance index (RDI), in 5,530 participants in a community-based study, the Sleep Heart Health Study. The prediction algorithm was built using modern ensemble learning algorithms, boosting in specific, which allowed for assessing potential high-dimensional interactions between predictor variables or classifiers. To evaluate the performance of the algorithm, the data were split into training and validation sets for varying thresholds for predicting the probability of a high RDI (≥7 events per hour in the given results). Based on a moderate classification threshold from the boosting algorithm, the estimated post-test odds of a high RDI were 2.20 times higher than the pre-test odds given a positive test, while the corresponding post-test odds were decreased by 52% given a negative test (sensitivity and specificity of 0.66 and 0.70, respectively). In rank order, the following variables had the largest impact on prediction performance: neck circumference, body mass index, age, snoring frequency, waist circumference, and snoring loudness.

VL - 33 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21120126?dopt=Abstract ER - TY - JOUR T1 - Obesity is linked with lower brain volume in 700 AD and MCI patients. JF - Neurobiol Aging Y1 - 2010 A1 - Ho, April J A1 - Raji, Cyrus A A1 - Becker, James T A1 - Lopez, Oscar L A1 - Kuller, Lewis H A1 - Hua, Xue A1 - Lee, Suh A1 - Hibar, Derrek A1 - Dinov, Ivo D A1 - Stein, Jason L A1 - Jack, Clifford R A1 - Weiner, Michael W A1 - Toga, Arthur W A1 - Thompson, Paul M KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Atrophy KW - Body Mass Index KW - Brain KW - Cognition Disorders KW - Cohort Studies KW - Female KW - Humans KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Obesity KW - Organ Size KW - Prospective Studies KW - Risk Factors AB -

Obesity is associated with lower brain volumes in cognitively normal elderly subjects, but no study has yet investigated the effects of obesity on brain structure in patients with mild cognitive impairment (MCI) or Alzheimer's disease (AD). To determine if higher body mass index (BMI) is associated with brain volume deficits in cognitively impaired elderly subjects, we analyzed brain magnetic resonance imaging (MRI) scans of 700 MCI or AD patients from 2 different cohorts: the Alzheimer's Disease Neuroimaging Initiative (ADNI) and the Cardiovascular Health Study-Cognition Study (CHS-CS). Tensor-based morphometry (TBM) was used to create 3-dimensional maps of regional tissue excess or deficits in subjects with MCI (ADNI, n = 399; CHS-CS, n = 77) and AD (ADNI, n = 188; CHS, n = 36). In both AD and MCI groups, higher body mass index was associated with brain volume deficits in frontal, temporal, parietal, and occipital lobes; the atrophic pattern was consistent in both ADNI and CHS populations. Cardiovascular risk factors, especially obesity, should be considered as influencing brain structure in those already afflicted by cognitive impairment and dementia.

VL - 31 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20570405?dopt=Abstract ER - TY - JOUR T1 - Physical activity and years of healthy life in older adults: results from the cardiovascular health study. JF - J Aging Phys Act Y1 - 2010 A1 - Hirsch, Calvin H A1 - Diehr, Paula A1 - Newman, Anne B A1 - Gerrior, Shirley A A1 - Pratt, Charlotte A1 - Lebowitz, Michael D A1 - Jackson, Sharon A KW - Activities of Daily Living KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - Exercise KW - Female KW - Health Behavior KW - Health Status KW - Humans KW - Leisure Activities KW - Life Style KW - Male KW - Quality-Adjusted Life Years KW - Sex Factors AB -

Little is known about how many years of life and disability-free years seniors can gain through exercise. Using data from the Cardiovascular Health Study, the authors estimated the extra years of life and self-reported healthy life (over 11 years) and years without impairment in activities of daily living (over 6 years) associated with quintiles of physical activity (PA) in older adults from different age groups. They estimated PA from the Minnesota Leisure Time Activities Questionnaire. Multivariable linear regression adjusted for health-related covariates. The relative gains in survival and years of healthy life (YHL) generally were proportionate to the amount of PA, greater among those 75+, and higher in men. Compared with being sedentary, the most active men 75+ had 1.49 more YHL (95% CI: 0.79, 2.19), and the most active women 75+ had 1.06 more YHL (95% CI: 0.44, 1.68). Seniors over age 74 experience the largest relative gains in survival and healthy life from physical activity.

VL - 18 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20651417?dopt=Abstract ER - TY - JOUR T1 - Post hoc Parkinson's disease: identifying an uncommon disease in the Cardiovascular Health Study. JF - Neuroepidemiology Y1 - 2010 A1 - Ton, T G A1 - Jain, S A1 - Boudreau, R A1 - Thacker, E L A1 - Strotmeyer, E S A1 - Newman, A B A1 - Longstreth, W T A1 - Checkoway, H KW - Aged KW - Aged, 80 and over KW - Cardiovascular System KW - Cohort Studies KW - Female KW - Health Status KW - Humans KW - Incidence KW - Male KW - Odds Ratio KW - Parkinson Disease KW - Prevalence KW - Prospective Studies KW - Risk Factors KW - Smoking KW - Surveys and Questionnaires KW - United States AB -

BACKGROUND: Although ongoing cohort studies offer a unique opportunity to apply existing information collected prospectively to further the scientific understanding of Parkinson's disease (PD), they typically have limited information for clinical diagnosis.

METHODS: We used combinations of self-report, International Classification of Diseases - 9th edition codes and antiparkinsonian medications to identify PD in the Cardiovascular Health Study. To determine whether the expected inverse association between smoking and PD is evident using our outcome definitions, we assessed baseline smoking characteristics for various definitions of PD.

RESULTS: We identified 60 cases with prevalent PD (1.0%; 95% confidence interval, CI = 0.8-1.3%) and 154 with incident PD by year 14. Clear associations were observed for current smokers (odds ratio, OR = 0.50; 95% CI = 0.26-0.95) and for those who smoked ≥50 pack-years (OR = 0.53; 95% CI = 0.29-0.96). Estimates for smoking were similar when ≥2 data sources were required. Estimates for self-report alone were attenuated towards null.

CONCLUSIONS: Using multiple data sources to identify PD represents an alternative method of outcome identification in a cohort that would otherwise not be possible for PD research. Ongoing cohort studies can provide settings in which rapid replication and explorations of new hypotheses for PD are possible.

VL - 35 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20881426?dopt=Abstract ER - TY - JOUR T1 - Prevalence, incidence, and persistence of major depressive symptoms in the Cardiovascular Health Study. JF - Aging Ment Health Y1 - 2010 A1 - Thielke, Stephen M A1 - Diehr, Paula A1 - Unutzer, Jurgen KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Cohort Studies KW - Depression KW - Depressive Disorder, Major KW - Female KW - Geriatric Assessment KW - Health Status KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Personality Assessment KW - Prevalence KW - Psychiatric Status Rating Scales KW - Quality of Life KW - Sex Factors KW - Surveys and Questionnaires AB -

PURPOSE: To explore the association of major depressive symptoms with advancing age, sex, and self-rated health among older adults.

DESIGN AND METHODS: We analyzed 10 years of annual assessments in a longitudinal cohort of 5888 Medicare recipients in the Cardiovascular Health Study. Self-rated health was assessed with a single question, and subjects categorized as healthy or sick. Major depressive symptoms were assessed using the Center for Epidemiologic Studies Short Depression Scale, with subjects categorized as nondepressed (score < 10) or depressed (> or =10). Age-, sex-, and health-specific prevalence of depression and the probabilities of transition between depressed and nondepressed states were estimated.

RESULTS: The prevalence of a major depressive state was higher in women, and increased with advancing age. The probability of becoming depressed increased with advancing age among the healthy but not the sick. Women showed a greater probability than men of becoming depressed, regardless of health status. Major depressive symptoms persisted over one-year intervals in about 60% of the healthy and 75% of the sick, with little difference between men and women.

IMPLICATIONS: Clinically significant depressive symptoms occur commonly in older adults, especially women, increase with advancing age, are associated with poor self-rated health, and are largely intransigent. In order to limit the deleterious consequences of depression among older adults, increased attention to prevention, screening, and treatment is warranted. A self-rated health item could be used in clinical settings to refine the prognosis of late-life depression.

VL - 14 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20336548?dopt=Abstract ER - TY - JOUR T1 - Sleep disturbances, quality of life, and ethnicity: the Sleep Heart Health Study. JF - J Clin Sleep Med Y1 - 2010 A1 - Baldwin, Carol M A1 - Ervin, Ann-Margret A1 - Mays, Mary Z A1 - Robbins, John A1 - Shafazand, Shirin A1 - Walsleben, Joyce A1 - Weaver, Terri KW - African Americans KW - Cohort Studies KW - Ethnic Groups KW - European Continental Ancestry Group KW - Female KW - Health Status KW - Heart Diseases KW - Hispanic Americans KW - Humans KW - Longitudinal Studies KW - Male KW - Mental Health KW - Middle Aged KW - Polysomnography KW - Prevalence KW - Quality of Life KW - Sleep Apnea, Obstructive KW - Sleep Initiation and Maintenance Disorders KW - Sleep Wake Disorders KW - Snoring KW - Surveys and Questionnaires KW - United States AB -

STUDY OBJECTIVES: To compare health-related quality of life (HR-QOL) across subgroups defined by sleep disturbances and ethnicity.

METHODS: Men (47%) and women (53%) Sleep Heart Health Study participants age 40 and older (N = 5237) underwent overnight polysomnography and completed self-report questionnaires on symptoms of sleep disturbances. The physical and mental composite scales (PCS and MCS) of the Medical Outcomes Study 36-item short form survey assessed HR-QOL and were compared to sleep data.

RESULTS: Participants self-identified as Caucasian/White (n = 4482, 86%), African American/Black (n = 490, 9%), or Hispanic/Mexican American (n = 265, 5%). The prevalence of obstructive sleep apnea (OSA) was 17%, frequent snoring was 34%, difficulty initiating or maintaining sleep (DIMS; insomnia symptoms) was 30%, and excessive daytime sleepiness (EDS) was 25%. African American participants with frequent snoring, insomnia symptoms, or EDS had significantly poorer physical health compared to Caucasians (p < 0.001). Hispanics with frequent snoring, insomnia symptoms, or EDS had significantly poorer mental health than Caucasian participants (p <0.001). Neither PCS nor MCS scores differed significantly across ethnic subgroups for participants with moderate to severe OSA (respiratory disturbance index > 15, 4% desaturation).

CONCLUSIONS: Across ethnic/racial subgroups, sleep disturbances are associated with worse physical and better mental HR-QOL than the U.S. norm, but this relationship may be moderated by comorbid health conditions. This study replicates and extends prior research indicating differences among minority and non-minority participants and highlights the need for future studies of sleep disturbances with larger samples of minorities that control for comorbid health conditions.

VL - 6 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20411696?dopt=Abstract ER - TY - JOUR T1 - Utility of sleep stage transitions in assessing sleep continuity. JF - Sleep Y1 - 2010 A1 - Laffan, Alison A1 - Caffo, Brian A1 - Swihart, Bruce J A1 - Punjabi, Naresh M KW - Age Factors KW - Aged KW - Arousal KW - Body Mass Index KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Polysomnography KW - Predictive Value of Tests KW - Risk Factors KW - Sex Factors KW - Sleep Stages KW - Sleep Wake Disorders AB -

STUDY OBJECTIVES: Sleep continuity is commonly assessed with polysomnographic measures such as sleep efficiency, sleep stage percentages, and the arousal index. The aim of this study was to examine whether the transition rate between different sleep stages could be used as an index of sleep continuity to predict self-reported sleep quality independent of other commonly used metrics.

DESIGN AND SETTING: Analysis of the Sleep Heart Health Study polysomnographic data.

PARTICIPANTS: A community cohort.

MEASUREMENTS AND RESULTS: Sleep recordings on 5,684 participants were deemed to be of sufficient quality to allow visual scoring of NREM and REM sleep. For each participant, we tabulated the frequency of transitions between wake, NREM sleep, and REM sleep. An overall transition rate was determined as the number of all transitions per hour sleep. Stage-specific transition rates between wake, NREM sleep, and REM sleep were also determined. A 5-point Likert scale was used to assess the subjective experience of restless and light sleep the morning after the sleep study. Multivariable regression models showed that a high overall sleep stage transition rate was associated with restless and light sleep independent of several covariates including total sleep time, percentages of sleep stages, wake time after sleep onset, and the arousal index. Compared to the lowest quartile of the overall transition rate (<7.76 events/h), the odds ratios for restless sleep were 1.27, 1.42, and 1.38, for the second (7.77-10.10 events/h), third (10.11-13.34 events/h), and fourth (≥13.35 events/h) quartiles, respectively. Analysis of stage-specific transition rates showed that transitions between wake and NREM sleep were also independently associated with restless and light sleep.

CONCLUSIONS: Assessing overall and stage-specific transition rates provides a complementary approach for assessing sleep continuity. Incorporating such measures, along with conventional metrics, could yield useful insights into the significance of sleep continuity for clinical outcomes.

VL - 33 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21120130?dopt=Abstract ER - TY - JOUR T1 - Validation of an atrial fibrillation risk algorithm in whites and African Americans. JF - Arch Intern Med Y1 - 2010 A1 - Schnabel, Renate B A1 - Aspelund, Thor A1 - Li, Guo A1 - Sullivan, Lisa M A1 - Suchy-Dicey, Astrid A1 - Harris, Tamara B A1 - Pencina, Michael J A1 - D'Agostino, Ralph B A1 - Levy, Daniel A1 - Kannel, William B A1 - Wang, Thomas J A1 - Kronmal, Richard A A1 - Wolf, Philip A A1 - Burke, Gregory L A1 - Launer, Lenore J A1 - Vasan, Ramachandran S A1 - Psaty, Bruce M A1 - Benjamin, Emelia J A1 - Gudnason, Vilmundur A1 - Heckbert, Susan R KW - African Continental Ancestry Group KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Algorithms KW - Atrial Fibrillation KW - Blood Pressure KW - Body Mass Index KW - Cohort Studies KW - Electrocardiography KW - Europe KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Heart Failure KW - Humans KW - Hypertension KW - Incidence KW - Kaplan-Meier Estimate KW - Male KW - Middle Aged KW - Proportional Hazards Models KW - Risk Factors KW - Sex Factors KW - Systole KW - United States AB -

BACKGROUND: We sought to validate a recently published risk algorithm for incident atrial fibrillation (AF) in independent cohorts and other racial groups.

METHODS: We evaluated the performance of a Framingham Heart Study (FHS)-derived risk algorithm modified for 5-year incidence of AF in the FHS (n = 4764 participants) and 2 geographically and racially diverse cohorts in the age range 45 to 95 years: AGES (the Age, Gene/Environment Susceptibility-Reykjavik Study) (n = 4238) and CHS (the Cardiovascular Health Study) (n = 5410, of whom 874 [16.2%] were African Americans). The risk algorithm included age, sex, body mass index, systolic blood pressure, electrocardiographic PR interval, hypertension treatment, and heart failure.

RESULTS: We found 1359 incident AF events in 100 074 person-years of follow-up. Unadjusted 5-year event rates differed by cohort (AGES, 12.8 cases/1000 person-years; CHS whites, 22.7 cases/1000 person-years; and FHS, 4.5 cases/1000 person-years) and by race (CHS African Americans, 18.4 cases/1000 person-years). The strongest risk factors in all samples were age and heart failure. The relative risks for incident AF associated with risk factors were comparable across cohorts and race groups. After recalibration for baseline incidence and risk factor distribution, the Framingham algorithm, reported in C statistic, performed reasonably well in all samples: AGES, 0.67 (95% confidence interval [CI], 0.64-0.71); CHS whites, 0.68 (95% CI, 0.66-0.70); and CHS African Americans, 0.66 (95% CI, 0.61-0.71). Risk factors combined in the algorithm explained between 47.0% (AGES) and 63.6% (FHS) of the population-attributable risk.

CONCLUSIONS: Risk of incident AF in community-dwelling whites and African Americans can be assessed reliably by routinely available and potentially modifiable clinical variables. Seven risk factors accounted for up to 64% of risk.

VL - 170 IS - 21 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21098350?dopt=Abstract ER - TY - JOUR T1 - Validation of the health ABC heart failure model for incident heart failure risk prediction: the Cardiovascular Health Study. JF - Circ Heart Fail Y1 - 2010 A1 - Kalogeropoulos, Andreas A1 - Psaty, Bruce M A1 - Vasan, Ramachandran S A1 - Georgiopoulou, Vasiliki A1 - Smith, Andrew L A1 - Smith, Nicholas L A1 - Kritchevsky, Stephen B A1 - Wilson, Peter W F A1 - Newman, Anne B A1 - Harris, Tamara B A1 - Butler, Javed KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Cause of Death KW - Cohort Studies KW - Confidence Intervals KW - Disease Progression KW - Echocardiography, Doppler KW - Female KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Models, Statistical KW - Predictive Value of Tests KW - Prognosis KW - Severity of Illness Index KW - Sex Distribution KW - Survival Analysis KW - United States AB -

BACKGROUND: The recently developed and internally validated Health ABC HF model uses 9 routinely available clinical variables to determine incident heart failure risk. In this study, we sought to externally validate the Health ABC HF model.

METHODS AND RESULTS: Observed 5-year incidence of heart failure, defined as first hospitalization for new-onset heart failure, was compared with 5-year risk estimates derived from the Health ABC HF model among participants without heart failure at baseline in the Cardiovascular Health Study. During follow-up, 400 of 5335 (7.5%) participants developed heart failure over 5 years versus 364 (6.8%) predicted by the Health ABC HF model (predicted-to-observed ratio, 0.90). Observed versus predicted 5-year heart failure probabilities were 3.2% versus 2.8%, 9.0% versus 7.0%, 15.9% versus 13.7%, and 24.6% versus 30.8% for the <5%, 5% to 10%, 10% to 20%, and >20% 5-year risk categories, respectively. The Hosmer-Lemeshow chi(2) was 14.72 (degrees of freedom, 10; P=0.14), and the C index was 0.74 (95% CI, 0.72 to 0.76). Calibration and discrimination demonstrated adequate performance across sex and race overall; however, risk was underestimated in white men, especially in the 5% to 10% risk category. Model performance was optimal when participants with normal left ventricular function at baseline were assessed separately. Performance was consistent across age groups. Analyses with death as a competing risk yielded similar results.

CONCLUSIONS: The Health ABC HF model adequately predicted 5-year heart failure risk in a large community-based study, providing support for the external validity of the model. This tool may be used to identify individuals to whom to target heart failure prevention efforts.

VL - 3 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20427700?dopt=Abstract ER - TY - JOUR T1 - Association of annular calcification and aortic valve sclerosis with brain findings on magnetic resonance imaging in community dwelling older adults: the cardiovascular health study. JF - J Am Coll Cardiol Y1 - 2011 A1 - Rodriguez, Carlos J A1 - Bartz, Traci M A1 - Longstreth, W T A1 - Kizer, Jorge R A1 - Barasch, Eddy A1 - Lloyd-Jones, Donald M A1 - Gottdiener, John S KW - Aged KW - Aortic Valve Stenosis KW - Brain KW - Brain Infarction KW - Calcinosis KW - Cohort Studies KW - Female KW - Humans KW - Magnetic Resonance Imaging KW - Male KW - Mitral Valve Stenosis KW - Retrospective Studies AB -

OBJECTIVES: The objective of this study was to investigate the associations of mitral annular calcification, aortic annular calcification, and aortic valve sclerosis with covert magnetic resonance imaging (MRI)-defined brain infarcts.

BACKGROUND: Clinically silent brain infarcts defined by MRI are associated with increased risk for cognitive decline, dementia, and future overt stroke. Left-sided cardiac valvular and annular calcifications are suspected as risk factors for clinical ischemic stroke.

METHODS: A total of 2,680 CHS (Cardiovascular Health Study) participants without clinical histories of stroke or transient ischemic attack underwent brain MRI in 1992 and 1993, 1 to 2 years before echocardiographic exams (1994 to 1995).

RESULTS: The mean age of the participants was 74.5 ± 4.8 years, and 39.3% were men. The presence of any annular or valvular calcification (mitral annular calcification, aortic annular calcification, or aortic valve sclerosis), mitral annular calcification alone, or aortic annular calcification alone was significantly associated with a higher prevalence of covert brain infarcts in unadjusted analyses (p < 0.01 for all). In models adjusted for age, sex, race, body mass index, physical activity, creatinine, systolic blood pressure, total cholesterol, high-density lipoprotein cholesterol, smoking, diabetes, coronary heart disease, and congestive heart failure, the presence of any annular or valve calcification remained associated with covert brain infarcts (risk ratio: 1.24; 95% confidence interval: 1.05 to 1.47). The degree of annular or valvular calcification severity showed a direct relation with the presence of covert MRI findings.

CONCLUSIONS: Left-sided cardiac annular and valvular calcifications are associated with covert MRI-defined brain infarcts. Further study is warranted to identify mechanisms and determine whether intervening in the progression of annular and valvular calcification could reduce the incidence of covert brain infarcts as well as the associated risk for cognitive impairment and future stroke.

VL - 57 IS - 21 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21596233?dopt=Abstract ER - TY - JOUR T1 - Association of coagulation-related and inflammation-related genes and factor VIIc levels with stroke: the Cardiovascular Health Study. JF - J Thromb Haemost Y1 - 2011 A1 - Zakai, N A A1 - Lange, L A1 - Longstreth, W T A1 - O'Meara, E S A1 - Kelley, J L A1 - Fornage, M A1 - Nikerson, D A1 - Cushman, M A1 - Reiner, A P KW - Blood Coagulation Factors KW - Cardiovascular Diseases KW - Cohort Studies KW - Factor VII KW - Female KW - Humans KW - Inflammation KW - Male KW - Polymorphism, Single Nucleotide KW - Prospective Studies KW - Risk Factors KW - Stroke AB -

BACKGROUND: Thrombosis and inflammation are critical in stroke etiology, but associations of coagulation and inflammation gene variants with stroke, and particularly factor VII levels, are inconclusive.

OBJECTIVES: To test the associations between 736 single-nucleotide polymorphisms (SNPs) between tagging haplotype patterns of 130 coagulation and inflammation genes, and stroke events, in the 5888 participants aged ≥ 65 years of the observational Cardiovascular Health Study cohort.

PATIENTS/METHODS: With 16 years of follow-up, age-adjusted and sex-adjusted Cox models were used to estimate associations of SNPs and FVIIc levels with future stroke.

RESULTS: Eight hundred and fifteen strokes occurred in 5255 genotyped participants without baseline stroke (748 ischemic strokes; 586 among whites). Among whites, six SNPs were associated with stroke, with a nominal P-value of < 0.01: rs6046 and rs3093261 (F7); rs4918851 and rs3781387 (HABP2); and rs3138055 (NFKB1A) and rs4648004 (NFKB1). Two of these SNPs were associated with FVIIc levels (units of percentage activity): rs6046 (β = -18.5, P = 2.38 × 10(-83)) and rs3093261 (β = 2.99, P = 3.93 × 10(-6)). After adjustment for age, sex, race, and cardiovascular risk factors, the association of FVIIc quintiles (Q) with stroke were as follows (hazard ratio; 95% confidence interval): Q1, reference; Q2, 1.4, 1.1-1.9); Q3, 1.1, 0.8-1.5); Q4, 1.5, 1.1-2.0); and Q5, 1.6, 1.2-2.2). Associations between SNPs and stroke were independent of FVIIc levels.

CONCLUSIONS: Variations in FVII-related genes and FVIIc levels were associated with risk of incident ischemic stroke in this elderly cohort, suggesting a potential causal role for FVII in stroke etiology.

VL - 9 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21114618?dopt=Abstract ER - TY - JOUR T1 - Association of genetic variation with systolic and diastolic blood pressure among African Americans: the Candidate Gene Association Resource study. JF - Hum Mol Genet Y1 - 2011 A1 - Fox, Ervin R A1 - Young, J Hunter A1 - Li, Yali A1 - Dreisbach, Albert W A1 - Keating, Brendan J A1 - Musani, Solomon K A1 - Liu, Kiang A1 - Morrison, Alanna C A1 - Ganesh, Santhi A1 - Kutlar, Abdullah A1 - Ramachandran, Vasan S A1 - Polak, Josef F A1 - Fabsitz, Richard R A1 - Dries, Daniel L A1 - Farlow, Deborah N A1 - Redline, Susan A1 - Adeyemo, Adebowale A1 - Hirschorn, Joel N A1 - Sun, Yan V A1 - Wyatt, Sharon B A1 - Penman, Alan D A1 - Palmas, Walter A1 - Rotter, Jerome I A1 - Townsend, Raymond R A1 - Doumatey, Ayo P A1 - Tayo, Bamidele O A1 - Mosley, Thomas H A1 - Lyon, Helen N A1 - Kang, Sun J A1 - Rotimi, Charles N A1 - Cooper, Richard S A1 - Franceschini, Nora A1 - Curb, J David A1 - Martin, Lisa W A1 - Eaton, Charles B A1 - Kardia, Sharon L R A1 - Taylor, Herman A A1 - Caulfield, Mark J A1 - Ehret, Georg B A1 - Johnson, Toby A1 - Chakravarti, Aravinda A1 - Zhu, Xiaofeng A1 - Levy, Daniel KW - Adult KW - African Americans KW - Aged KW - Blood Pressure KW - Cohort Studies KW - Diastole KW - European Continental Ancestry Group KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Systole AB -

The prevalence of hypertension in African Americans (AAs) is higher than in other US groups; yet, few have performed genome-wide association studies (GWASs) in AA. Among people of European descent, GWASs have identified genetic variants at 13 loci that are associated with blood pressure. It is unknown if these variants confer susceptibility in people of African ancestry. Here, we examined genome-wide and candidate gene associations with systolic blood pressure (SBP) and diastolic blood pressure (DBP) using the Candidate Gene Association Resource (CARe) consortium consisting of 8591 AAs. Genotypes included genome-wide single-nucleotide polymorphism (SNP) data utilizing the Affymetrix 6.0 array with imputation to 2.5 million HapMap SNPs and candidate gene SNP data utilizing a 50K cardiovascular gene-centric array (ITMAT-Broad-CARe [IBC] array). For Affymetrix data, the strongest signal for DBP was rs10474346 (P= 3.6 × 10(-8)) located near GPR98 and ARRDC3. For SBP, the strongest signal was rs2258119 in C21orf91 (P= 4.7 × 10(-8)). The top IBC association for SBP was rs2012318 (P= 6.4 × 10(-6)) near SLC25A42 and for DBP was rs2523586 (P= 1.3 × 10(-6)) near HLA-B. None of the top variants replicated in additional AA (n = 11 882) or European-American (n = 69 899) cohorts. We replicated previously reported European-American blood pressure SNPs in our AA samples (SH2B3, P= 0.009; TBX3-TBX5, P= 0.03; and CSK-ULK3, P= 0.0004). These genetic loci represent the best evidence of genetic influences on SBP and DBP in AAs to date. More broadly, this work supports that notion that blood pressure among AAs is a trait with genetic underpinnings but also with significant complexity.

VL - 20 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21378095?dopt=Abstract ER - TY - JOUR T1 - Association of genomic loci from a cardiovascular gene SNP array with fibrinogen levels in European Americans and African-Americans from six cohort studies: the Candidate Gene Association Resource (CARe). JF - Blood Y1 - 2011 A1 - Wassel, Christina L A1 - Lange, Leslie A A1 - Keating, Brendan J A1 - Taylor, Kira C A1 - Johnson, Andrew D A1 - Palmer, Cameron A1 - Ho, Lindsey A A1 - Smith, Nicholas L A1 - Lange, Ethan M A1 - Li, Yun A1 - Yang, Qiong A1 - Delaney, Joseph A A1 - Tang, Weihong A1 - Tofler, Geoffrey A1 - Redline, Susan A1 - Taylor, Herman A A1 - Wilson, James G A1 - Tracy, Russell P A1 - Jacobs, David R A1 - Folsom, Aaron R A1 - Green, David A1 - O'Donnell, Christopher J A1 - Reiner, Alexander P KW - Adult KW - African Americans KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Fibrinogen KW - Genetic Predisposition to Disease KW - Haplotypes KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

Several common genomic loci, involving various immunity- and metabolism-related genes, have been associated with plasma fibrinogen in European Americans (EAs). The genetic determinants of fibrinogen in African Americans (AAs) are poorly characterized. Using a vascular gene-centric array in 23,634 EA and 6657 AA participants from 6 studies comprising the Candidate Gene Association Resource project, we examined the association of 47,539 common and lower frequency variants with fibrinogen concentration. We identified a rare Pro265Leu variant in FGB (rs6054) associated with lower fibrinogen. Common fibrinogen gene single nucleotide polymorphisms (FGB rs1800787 and FGG rs2066861) significantly associated with fibrinogen in EAs were prevalent in AAs and showed consistent associations. Several fibrinogen locus single nucleotide polymorphism associated with lower fibrinogen were exclusive to AAs; these include a newly reported association with FGA rs10050257. For IL6R, IL1RN, and NLRP3 inflammatory gene loci, associations with fibrinogen were concordant between EAs and AAs, but not at other loci (CPS1, PCCB, and SCL22A5-IRF1). The association of FGG rs2066861 with fibrinogen differed according to assay type used to measure fibrinogen. Further characterization of common and lower-frequency genetic variants that contribute to interpopulation differences in fibrinogen phenotype may help refine our understanding of the contribution of hemostasis and inflammation to atherothrombotic risk.

VL - 117 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20978265?dopt=Abstract ER - TY - JOUR T1 - Association of HSP70 and its co-chaperones with Alzheimer's disease. JF - J Alzheimers Dis Y1 - 2011 A1 - Broer, Linda A1 - Ikram, Mohammad Arfan A1 - Schuur, Maaike A1 - DeStefano, Anita L A1 - Bis, Joshua C A1 - Liu, Fan A1 - Rivadeneira, Fernando A1 - Uitterlinden, André G A1 - Beiser, Alexa S A1 - Longstreth, William T A1 - Hofman, Albert A1 - Aulchenko, Yurii A1 - Seshadri, Sudha A1 - Fitzpatrick, Annette L A1 - Oostra, Ben A A1 - Breteler, Monique M B A1 - van Duijn, Cornelia M KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Cohort Studies KW - Genetic Association Studies KW - Genetic Variation KW - HSP70 Heat-Shock Proteins KW - Humans KW - Middle Aged KW - Molecular Chaperones KW - Polymorphism, Single Nucleotide AB -

The heat shock protein (HSP) 70 family has been implicated in the pathology of Alzheimer's disease (AD). In this study, we examined common genetic variations in the 80 genes encoding HSP70 and its co-chaperones. We conducted a study in a series of 462 patients and 5238 unaffected participants derived from the Rotterdam Study, a population-based study including 7983 persons aged 55 years and older. We genotyped a total of 12,053 Single Nucleotide Polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. Replication was performed in two independent cohort studies, the Framingham Heart study (FHS; n = 806) and Cardiovascular Health Study (CHS; n = 2150). When adjusting for multiple testing, we found a small but consistent, though not significant effect of rs12118313 located 32 kb from PFDN2, with an OR of 1.19 (p-value from meta-analysis = 0.003). However this SNP was in the intron of another gene, suggesting it is unlikely this SNP reflects the effect of PFDN2. In a formal pathway analysis we found nominally significant evidence for an association of BAG, DNAJA and prefoldin with AD. These findings corroborate with those of a study of 2032 AD patients and 5328 controls, in which several members of the prefoldin family showed evidence for association to AD. Our study did not reveal evidence for a genetic variant if the HSP70 family with a major effect on AD. However, our findings of the single SNP analysis and pathway analysis suggest that multiple genetic variants in prefoldin are associated with AD.

VL - 25 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21403392?dopt=Abstract ER - TY - JOUR T1 - Carotid intima-media thickness, electrocardiographic left ventricular hypertrophy, and incidence of intracerebral hemorrhage. JF - Stroke Y1 - 2011 A1 - Folsom, Aaron R A1 - Yatsuya, Hiroshi A1 - Psaty, Bruce M A1 - Shahar, Eyal A1 - Longstreth, W T KW - Carotid Intima-Media Thickness KW - Cerebral Hemorrhage KW - Cohort Studies KW - Electrocardiography KW - Female KW - Follow-Up Studies KW - Humans KW - Hypertrophy, Left Ventricular KW - Incidence KW - Male KW - Middle Aged KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND AND PURPOSE: Carotid intima-media thickness and electrocardiographic left ventricular hypertrophy are 2 subclinical cardiovascular disease measures associated with increased risk of total and ischemic strokes. Increased intima-media thickness and electrocardiographic left ventricular hypertrophy also may reflect end-organ hypertensive effects. Information is scant on the associations of these subclinical measures with intracerebral hemorrhage (ICH). We hypothesized that greater carotid intima-media thickness and the presence of electrocardiographic left ventricular hypertrophy would be independently associated with increased ICH incidence.

METHODS: Among 18,155 participants initially free of stroke in the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS), we assessed carotid intima-media thickness, carotid plaque, and electrocardiographic left ventricular hypertrophy. Over a median of 18 years of follow-up, 162 incident ICH events occurred.

RESULTS: After adjustment for other ICH risk factors, carotid intima-media thickness was associated positively with incidence of ICH in both ARIC and CHS. The risk was lowest in study-specific Quartile 1, elevated 1.6- to 2.6-fold in Quartiles 2 to 3, and elevated 2.5 to 3.7-fold in Quartile 4 (P<0.05 for both studies). In CHS, having a carotid plaque was associated with a 2-fold (95% CI, 1.1-3.4) greater ICH risk than having no plaque, but only 1.2-fold (95% CI, 0.76-2.0) greater ICH risk in ARIC. Electrocardiographic left ventricular hypertrophy carried a hazard ratio of ICH of 1.7 (95% CI, 0.77-3.7) in CHS and 2.8 (95% CI, 1.2-6.4) in ARIC.

CONCLUSIONS: Our data suggest that people with carotid atherosclerosis and possibly left ventricular hypertrophy are at increased risk not only of ischemic stroke, but also of ICH.

VL - 42 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21940954?dopt=Abstract ER - TY - JOUR T1 - Chronic kidney disease and the risk of end-stage renal disease versus death. JF - J Gen Intern Med Y1 - 2011 A1 - Dalrymple, Lorien S A1 - Katz, Ronit A1 - Kestenbaum, Bryan A1 - Shlipak, Michael G A1 - Sarnak, Mark J A1 - Stehman-Breen, Catherine A1 - Seliger, Stephen A1 - Siscovick, David A1 - Newman, Anne B A1 - Fried, Linda KW - Aged KW - Aged, 80 and over KW - Cause of Death KW - Cohort Studies KW - Female KW - Follow-Up Studies KW - Humans KW - Kidney Failure, Chronic KW - Longitudinal Studies KW - Male KW - Prospective Studies KW - Renal Insufficiency, Chronic KW - Risk Factors KW - Treatment Outcome AB -

BACKGROUND: Among older adults with chronic kidney disease (CKD), the comparative event rates of end-stage renal disease (ESRD) and cause-specific death are unknown.

OBJECTIVE: To compare the rates of ESRD, cardiovascular and non-cardiovascular death and examine risk factors for ESRD and all-cause mortality in Cardiovascular Health Study (CHS) participants.

DESIGN: The CHS is a longitudinal cohort study of community-dwelling adults aged 65 years and older.

PARTICIPANTS: 1,268 participants with an estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m(2) were followed until the time of first event (ESRD, cardiovascular or non-cardiovascular death) or until March 31, 2003.

MAIN MEASURES: The outcomes were ESRD, cardiovascular- and non-cardiovascular death. Rates of each event were calculated, and a Cox Proportional Hazards Model with a competing risk framework was used to examine risk factors for ESRD as compared with death. Predictors included age, gender, race, BMI, hypertension, diabetes, cardiovascular disease, heart failure, tobacco use, eGFR, and total cholesterol.

KEY RESULTS: During 9.7 years of follow-up, 5% of the cohort progressed to ESRD, and 61% of the cohort died. The rate (per 100 person-years) was 0.5 for ESRD and 6.8 for all-cause mortality (3.0 for cardiovascular and 3.8 for non-cardiovascular mortality). In the competing risk framework, lower eGFR, male gender, African-American race, and higher BMI were associated with an increased risk of ESRD.

CONCLUSIONS: Older adults with CKD are 13-fold more likely to die from any cause than progress to ESRD and are 6-fold more likely to die from cardiovascular causes than develop ESRD.

VL - 26 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/20853156?dopt=Abstract ER - TY - JOUR T1 - Fatty acids in the de novo lipogenesis pathway and risk of coronary heart disease: the Cardiovascular Health Study. JF - Am J Clin Nutr Y1 - 2011 A1 - Wu, Jason H Y A1 - Lemaitre, Rozenn N A1 - Imamura, Fumiaki A1 - King, Irena B A1 - Song, Xiaoling A1 - Spiegelman, Donna A1 - Siscovick, David S A1 - Mozaffarian, Dariush KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Coronary Disease KW - Death, Sudden, Cardiac KW - Diet KW - Fatty Acids KW - Female KW - Humans KW - Lipogenesis KW - Male KW - Phospholipids KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: De novo lipogenesis (DNL) is an endogenous pathway whereby carbohydrates and proteins are converted to fatty acids. DNL could affect coronary heart disease (CHD) or sudden cardiac arrest (SCA) via generation of specific fatty acids. Whether these fatty acids are prospectively associated with SCA or other CHD events is unknown.

OBJECTIVE: The objective was to investigate the relations of 4 fatty acids in the DNL pathway-palmitic acid (16:0), palmitoleic acid (16:1n-7), 7-hexadecenoic acid (16:1n-9), and cis-vaccenic acid (18:1n-7)-with incident CHD, including fatal CHD, nonfatal myocardial infarction (NFMI), and SCA.

DESIGN: A community-based prospective study was conducted in 2890 men and women aged ≥65 y, who were free of known CHD at baseline and who were followed from 1992 to 2006. Cardiovascular disease risk factors and plasma phospholipid fatty acids were measured at baseline by using standardized methods. Incident CHD was ascertained prospectively and was centrally adjudicated by using medical records. Risk was assessed by using multivariable-adjusted Cox proportional hazards.

RESULTS: During 29,835 person-years of follow-up, 631 CHD and 71 SCA events occurred. Both 18:1n-7 and 16:1n-9 were associated with a higher risk of SCA [multivariable-adjusted hazard ratio (95% CI) for the interquintile range: 7.63 (2.58, 22.6) for 18:1n-7 and 2.30 (1.16, 4.55) for 16:1n-9] but not of total CHD, fatal CHD, or NFMI. In secondary analyses censored to mid-follow-up (7 y) to minimize the effects of changes in concentrations over time, 16:1n-9 was also associated with a significantly higher risk of total CHD (2.11; 1.76, 2.54), including a higher risk of CHD death, NFMI, and SCA; 16:0 and 16:1n-7 were not associated with clinical CHD outcomes.

CONCLUSION: Higher plasma phospholipid 18:1n-7 and 16:1n-9 concentrations were prospectively associated with an elevated risk of SCA but not of other CHD events, except in secondary analyses.

VL - 94 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21697077?dopt=Abstract ER - TY - JOUR T1 - Gait speed and survival in older adults. JF - JAMA Y1 - 2011 A1 - Studenski, Stephanie A1 - Perera, Subashan A1 - Patel, Kushang A1 - Rosano, Caterina A1 - Faulkner, Kimberly A1 - Inzitari, Marco A1 - Brach, Jennifer A1 - Chandler, Julie A1 - Cawthon, Peggy A1 - Connor, Elizabeth Barrett A1 - Nevitt, Michael A1 - Visser, Marjolein A1 - Kritchevsky, Stephen A1 - Badinelli, Stefania A1 - Harris, Tamara A1 - Newman, Anne B A1 - Cauley, Jane A1 - Ferrucci, Luigi A1 - Guralnik, Jack KW - Aged KW - Cohort Studies KW - Female KW - Gait KW - Geriatric Assessment KW - Humans KW - Life Expectancy KW - Male KW - Survival Analysis KW - United States AB -

CONTEXT: Survival estimates help individualize goals of care for geriatric patients, but life tables fail to account for the great variability in survival. Physical performance measures, such as gait speed, might help account for variability, allowing clinicians to make more individualized estimates.

OBJECTIVE: To evaluate the relationship between gait speed and survival.

DESIGN, SETTING, AND PARTICIPANTS: Pooled analysis of 9 cohort studies (collected between 1986 and 2000), using individual data from 34,485 community-dwelling older adults aged 65 years or older with baseline gait speed data, followed up for 6 to 21 years. Participants were a mean (SD) age of 73.5 (5.9) years; 59.6%, women; and 79.8%, white; and had a mean (SD) gait speed of 0.92 (0.27) m/s.

MAIN OUTCOME MEASURES: Survival rates and life expectancy.

RESULTS: There were 17,528 deaths; the overall 5-year survival rate was 84.8% (confidence interval [CI], 79.6%-88.8%) and 10-year survival rate was 59.7% (95% CI, 46.5%-70.6%). Gait speed was associated with survival in all studies (pooled hazard ratio per 0.1 m/s, 0.88; 95% CI, 0.87-0.90; P < .001). Survival increased across the full range of gait speeds, with significant increments per 0.1 m/s. At age 75, predicted 10-year survival across the range of gait speeds ranged from 19% to 87% in men and from 35% to 91% in women. Predicted survival based on age, sex, and gait speed was as accurate as predicted based on age, sex, use of mobility aids, and self-reported function or as age, sex, chronic conditions, smoking history, blood pressure, body mass index, and hospitalization.

CONCLUSION: In this pooled analysis of individual data from 9 selected cohorts, gait speed was associated with survival in older adults.

VL - 305 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21205966?dopt=Abstract ER - TY - JOUR T1 - Gender differences in tea, coffee, and cognitive decline in the elderly: the Cardiovascular Health Study. JF - J Alzheimers Dis Y1 - 2011 A1 - Arab, Lenore A1 - Biggs, Mary L A1 - O'Meara, Ellen S A1 - Longstreth, W T A1 - Crane, Paul K A1 - Fitzpatrick, Annette L KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Coffee KW - Cognition Disorders KW - Cohort Studies KW - Female KW - Follow-Up Studies KW - Humans KW - Longitudinal Studies KW - Male KW - Prospective Studies KW - Sex Characteristics KW - Tea AB -

Although caffeine can enhance cognitive function acutely, long-term effects of consumption of caffeine-containing beverages such as tea and coffee are uncertain. Data on 4,809 participants aged 65 and older from the Cardiovascular Health Study (CHS) were used to examine the relationship of consumption of tea and coffee, assessed by food frequency questionnaire, on change in cognitive function by gender. Cognitive performance was assessed using serial Modified Mini-Mental State (3MS) examinations, which were administered annually up to 9 times. Linear mixed models were used to estimate rates of change in standard 3MS scores and scores modeled using item response theory (IRT). Models were adjusted for age, education, smoking status, clinic site, diabetes, hypertension, stroke, coronary heart disease, depression score, and APOE genotype. Over the median 7.9 years of follow-up, participants who did not consume tea or coffee declined annually an average of 1.30 points (women) and 1.11 points (men) on standard 3MS scores. In fully adjusted models using either standard or IRT 3MS scores, we found modestly reduced rates of cognitive decline for some, but not all, levels of coffee and tea consumption for women, with no consistent effect for men. Caffeine consumption was also associated with attenuation in cognitive decline in women. Dose-response relationships were not linear. These longitudinal analyses suggest a somewhat attenuated rate of cognitive decline among tea and coffee consumers compared to non-consumers in women but not in men. Whether this association is causal or due to unmeasured confounding requires further study.

VL - 27 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21841254?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis of soluble ICAM-1 concentration reveals novel associations at the NFKBIK, PNPLA3, RELA, and SH2B3 loci. JF - PLoS Genet Y1 - 2011 A1 - Paré, Guillaume A1 - Ridker, Paul M A1 - Rose, Lynda A1 - Barbalic, Maja A1 - Dupuis, Josée A1 - Dehghan, Abbas A1 - Bis, Joshua C A1 - Benjamin, Emelia J A1 - Shiffman, Dov A1 - Parker, Alexander N A1 - Chasman, Daniel I KW - ABO Blood-Group System KW - Cohort Studies KW - Female KW - Gene Frequency KW - Genetic Loci KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - I-kappa B Kinase KW - Intercellular Adhesion Molecule-1 KW - Lipase KW - Membrane Proteins KW - Models, Genetic KW - Multifactorial Inheritance KW - Polymorphism, Single Nucleotide KW - Proteins KW - Transcription Factor RelA AB -

Soluble ICAM-1 (sICAM-1) is an endothelium-derived inflammatory marker that has been associated with diverse conditions such as myocardial infarction, diabetes, stroke, and malaria. Despite evidence for a heritable component to sICAM-1 levels, few genetic loci have been identified so far. To comprehensively address this issue, we performed a genome-wide association analysis of sICAM-1 concentration in 22,435 apparently healthy women from the Women's Genome Health Study. While our results confirm the previously reported associations at the ABO and ICAM1 loci, four novel associations were identified in the vicinity of NFKBIK (rs3136642, P = 5.4 × 10(-9)), PNPLA3 (rs738409, P  =  5.8 × 10(-9)), RELA (rs1049728, P =  2.7 × 10(-16)), and SH2B3 (rs3184504, P =  2.9 × 10(-17)). Two loci, NFKBIB and RELA, are involved in NFKB signaling pathway; PNPLA3 is known for its association with fatty liver disease; and SH3B2 has been associated with a multitude of traits and disease including myocardial infarction. These associations provide insights into the genetic regulation of sICAM-1 levels and implicate these loci in the regulation of endothelial function.

VL - 7 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21533024?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association studies of cerebral white matter lesion burden: the CHARGE consortium. JF - Ann Neurol Y1 - 2011 A1 - Fornage, Myriam A1 - Debette, Stephanie A1 - Bis, Joshua C A1 - Schmidt, Helena A1 - Ikram, M Arfan A1 - Dufouil, Carole A1 - Sigurdsson, Sigurdur A1 - Lumley, Thomas A1 - DeStefano, Anita L A1 - Fazekas, Franz A1 - Vrooman, Henri A A1 - Shibata, Dean K A1 - Maillard, Pauline A1 - Zijdenbos, Alex A1 - Smith, Albert V A1 - Gudnason, Haukur A1 - de Boer, Renske A1 - Cushman, Mary A1 - Mazoyer, Bernard A1 - Heiss, Gerardo A1 - Vernooij, Meike W A1 - Enzinger, Christian A1 - Glazer, Nicole L A1 - Beiser, Alexa A1 - Knopman, David S A1 - Cavalieri, Margherita A1 - Niessen, Wiro J A1 - Harris, Tamara B A1 - Petrovic, Katja A1 - Lopez, Oscar L A1 - Au, Rhoda A1 - Lambert, Jean-Charles A1 - Hofman, Albert A1 - Gottesman, Rebecca F A1 - Garcia, Melissa A1 - Heckbert, Susan R A1 - Atwood, Larry D A1 - Catellier, Diane J A1 - Uitterlinden, André G A1 - Yang, Qiong A1 - Smith, Nicholas L A1 - Aspelund, Thor A1 - Romero, Jose R A1 - Rice, Kenneth A1 - Taylor, Kent D A1 - Nalls, Michael A A1 - Rotter, Jerome I A1 - Sharrett, Richey A1 - van Duijn, Cornelia M A1 - Amouyel, Philippe A1 - Wolf, Philip A A1 - Gudnason, Vilmundur A1 - van der Lugt, Aad A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Seshadri, Sudha A1 - Tzourio, Christophe A1 - Breteler, Monique M B A1 - Mosley, Thomas H A1 - Schmidt, Reinhold A1 - Longstreth, W T A1 - DeCarli, Charles A1 - Launer, Lenore J KW - Aged KW - Aged, 80 and over KW - Cerebral Cortex KW - Chromosomes, Human, Pair 17 KW - Cognition Disorders KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Leukoencephalopathies KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Movement Disorders KW - Nerve Fibers, Myelinated KW - Polymorphism, Single Nucleotide KW - Residence Characteristics KW - RNA, Messenger AB -

OBJECTIVE: White matter hyperintensities (WMHs) detectable by magnetic resonance imaging are part of the spectrum of vascular injury associated with aging of the brain and are thought to reflect ischemic damage to the small deep cerebral vessels. WMHs are associated with an increased risk of cognitive and motor dysfunction, dementia, depression, and stroke. Despite a significant heritability, few genetic loci influencing WMH burden have been identified.

METHODS: We performed a meta-analysis of genome-wide association studies (GWASs) for WMH burden in 9,361 stroke-free individuals of European descent from 7 community-based cohorts. Significant findings were tested for replication in 3,024 individuals from 2 additional cohorts.

RESULTS: We identified 6 novel risk-associated single nucleotide polymorphisms (SNPs) in 1 locus on chromosome 17q25 encompassing 6 known genes including WBP2, TRIM65, TRIM47, MRPL38, FBF1, and ACOX1. The most significant association was for rs3744028 (p(discovery) = 4.0 × 10(-9) ; p(replication) = 1.3 × 10(-7) ; p(combined) = 4.0 × 10(-15) ). Other SNPs in this region also reaching genome-wide significance were rs9894383 (p = 5.3 × 10(-9) ), rs11869977 (p = 5.7 × 10(-9) ), rs936393 (p = 6.8 × 10(-9) ), rs3744017 (p = 7.3 × 10(-9) ), and rs1055129 (p = 4.1 × 10(-8) ). Variant alleles at these loci conferred a small increase in WMH burden (4-8% of the overall mean WMH burden in the sample).

INTERPRETATION: This large GWAS of WMH burden in community-based cohorts of individuals of European descent identifies a novel locus on chromosome 17. Further characterization of this locus may provide novel insights into the pathogenesis of cerebral WMH.

VL - 69 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21681796?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study identifies novel loci associated with circulating IGF-I and IGFBP-3. JF - Hum Mol Genet Y1 - 2011 A1 - Kaplan, Robert C A1 - Petersen, Ann-Kristin A1 - Chen, Ming-Huei A1 - Teumer, Alexander A1 - Glazer, Nicole L A1 - Döring, Angela A1 - Lam, Carolyn S P A1 - Friedrich, Nele A1 - Newman, Anne A1 - Müller, Martina A1 - Yang, Qiong A1 - Homuth, Georg A1 - Cappola, Anne A1 - Klopp, Norman A1 - Smith, Holly A1 - Ernst, Florian A1 - Psaty, Bruce M A1 - Wichmann, H-Erich A1 - Sawyer, Douglas B A1 - Biffar, Reiner A1 - Rotter, Jerome I A1 - Gieger, Christian A1 - Sullivan, Lisa S A1 - Völzke, Henry A1 - Rice, Kenneth A1 - Spyroglou, Ariadni A1 - Kroemer, Heyo K A1 - Ida Chen, Y-D A1 - Manolopoulou, Jenny A1 - Nauck, Matthias A1 - Strickler, Howard D A1 - Goodarzi, Mark O A1 - Reincke, Martin A1 - Pollak, Michael N A1 - Bidlingmaier, Martin A1 - Vasan, Ramachandran S A1 - Wallaschofski, Henri KW - Aged KW - Chromosomes, Human, Pair 7 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Polymorphism, Single Nucleotide AB -

Insulin-like growth factor-I (IGF-I) and insulin-like growth factor-binding protein-3 (IGFBP-3) are involved in cell replication, proliferation, differentiation, protein synthesis, carbohydrate homeostasis and bone metabolism. Circulating IGF-I and IGFBP-3 concentrations predict anthropometric traits and risk of cancer and cardiovascular disease. In a genome-wide association study of 10 280 middle-aged and older men and women from four community-based cohort studies, we confirmed a known association of single nucleotide polymorphisms in the IGFBP3 gene region on chromosome 7p12.3 with IGFBP-3 concentrations using a significance threshold of P < 5 × 10(-8) (P = 3.3 × 10(-101)). Furthermore, the same IGFBP3 gene locus (e.g. rs11977526) that was associated with IGFBP-3 concentrations was also associated with the opposite direction of effect, with IGF-I concentration after adjustment for IGFBP-3 concentration (P = 1.9 × 10(-26)). A novel and independent locus on chromosome 7p12.3 (rs700752) had genome-wide significant associations with higher IGFBP-3 (P = 4.4 × 10(-21)) and higher IGF-I (P = 4.9 × 10(-9)) concentrations; when the two measurements were adjusted for one another, the IGF-I association was attenuated but the IGFBP-3 association was not. Two additional loci demonstrated genome-wide significant associations with IGFBP-3 concentration (rs1065656, chromosome 16p13.3, P = 1.2 × 10(-11), IGFALS, a confirmatory finding; and rs4234798, chromosome 4p16.1, P = 4.5 × 10(-10), SORCS2, a novel finding). Together, the four genome-wide significant loci explained 6.5% of the population variation in IGFBP-3 concentration. Furthermore, we observed a borderline statistically significant association between IGF-I concentration and FOXO3 (rs2153960, chromosome 6q21, P = 5.1 × 10(-7)), a locus associated with longevity. These genetic loci deserve further investigation to elucidate the biological basis for the observed associations and clarify their possible role in IGF-mediated regulation of cell growth and metabolism.

VL - 20 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21216879?dopt=Abstract ER - TY - JOUR T1 - Health and function of participants in the Long Life Family Study: A comparison with other cohorts. JF - Aging (Albany NY) Y1 - 2011 A1 - Newman, Anne B A1 - Glynn, Nancy W A1 - Taylor, Christopher A A1 - Sebastiani, Paola A1 - Perls, Thomas T A1 - Mayeux, Richard A1 - Christensen, Kaare A1 - Zmuda, Joseph M A1 - Barral, Sandra A1 - Lee, Joseph H A1 - Simonsick, Eleanor M A1 - Walston, Jeremy D A1 - Yashin, Anatoli I A1 - Hadley, Evan KW - Aged KW - Aged, 80 and over KW - Aging KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Gait KW - Humans KW - Longevity KW - Male KW - Middle Aged KW - Psychomotor Performance KW - Research Design AB -

Individuals from families recruited for the Long Life Family Study (LLFS) (n= 4559) were examined and compared to individuals from other cohorts to determine whether the recruitment targeting longevity resulted in a cohort of individuals with better health and function. Other cohorts with similar data included the Cardiovascular Health Study, the Framingham Heart Study, and the New England Centenarian Study. Diabetes, chronic pulmonary disease and peripheral artery disease tended to be less common in LLFS probands and offspring compared to similar aged persons in the other cohorts. Pulse pressure and triglycerides were lower, high density lipids were higher, and a perceptual speed task and gait speed were better in LLFS. Age-specific comparisons showed differences that would be consistent with a higher peak, later onset of decline or slower rate of change across age in LLFS participants. These findings suggest several priority phenotypes for inclusion in future genetic analysis to identify loci contributing to exceptional survival.

VL - 3 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21258136?dopt=Abstract ER - TY - JOUR T1 - Higher serum free testosterone concentration in older women is associated with greater bone mineral density, lean body mass, and total fat mass: the cardiovascular health study. JF - J Clin Endocrinol Metab Y1 - 2011 A1 - Rariy, Chevon M A1 - Ratcliffe, Sarah J A1 - Weinstein, Rachel A1 - Bhasin, Shalender A1 - Blackman, Marc R A1 - Cauley, Jane A A1 - Robbins, John A1 - Zmuda, Joseph M A1 - Harris, Tamara B A1 - Cappola, Anne R KW - Adipose Tissue KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Bone Density KW - Cardiovascular Physiological Phenomena KW - Cohort Studies KW - Female KW - Health KW - Humans KW - Organ Size KW - Osmolar Concentration KW - Osteoporosis, Postmenopausal KW - Testosterone KW - Thinness KW - Up-Regulation AB -

CONTEXT: The physiological importance of endogenous testosterone (T) in older women is poorly understood.

OBJECTIVE: The aim of the study was to determine the association of higher total and free T levels with bone mineral density (BMD), lean body mass, and fat mass in elderly women.

DESIGN: Total and free T were measured using sensitive assays in 232 community-dwelling women aged 67-94 yr who were enrolled in the Cardiovascular Health Study and had dual-energy x-ray absorptiometry scans. Cross-sectional analyses were performed to examine associations between total and free T and BMD and body composition.

RESULTS: In adjusted models, total T was directly associated with BMD at the lumbar spine (P = 0.04) and hip (P = 0.001), but not body composition outcomes, in all women, and after excluding estrogen users and adjusting for estradiol (P = 0.04 and 0.01, respectively). Free T was positively related to hip BMD, lean body mass, and body fat (all P < 0.05), with more than 10% differences in each outcome between women at the highest and lowest ends of the free T range, with attenuation after excluding estrogen users and adjusting for estradiol.

CONCLUSIONS: In the setting of the low estradiol levels found in older women, circulating T levels were associated with bone density. Women with higher free T levels had greater lean body mass, consistent with the anabolic effect of T, and, in contrast to men, greater fat mass. Mechanistic studies are required to determine whether a causal relationship exists between T, bone, and body composition in this population and the degree to which any T effects are estrogen-independent.

VL - 96 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21289255?dopt=Abstract ER - TY - JOUR T1 - Hospitalization for infection and risk of acute ischemic stroke: the Cardiovascular Health Study. JF - Stroke Y1 - 2011 A1 - Elkind, Mitchell S V A1 - Carty, Cara L A1 - O'Meara, Ellen S A1 - Lumley, Thomas A1 - Lefkowitz, David A1 - Kronmal, Richard A A1 - Longstreth, W T KW - Bacterial Infections KW - Brain Ischemia KW - Cardiology KW - Cohort Studies KW - Cross-Over Studies KW - Female KW - Follow-Up Studies KW - Hospitalization KW - Humans KW - Male KW - Odds Ratio KW - Proportional Hazards Models KW - Regression Analysis KW - Risk KW - Stroke KW - Time Factors AB -

BACKGROUND AND PURPOSE: Little is known about the acute precipitants of ischemic stroke, although evidence suggests infections contribute to risk. We hypothesized that acute hospitalization for infection is associated with the short-term risk of stroke.

METHODS: The case-crossover design was used to compare hospitalization for infection during case periods (90, 30, or 14 days before an incident ischemic stroke) and control periods (equivalent time periods exactly 1 or 2 years before stroke) in the Cardiovascular Health Study, a population-based cohort of 5888 elderly participants from 4 US sites. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by conditional logistic regression. Confirmatory analyses assessed hazard ratios of stroke from Cox regression models, with hospitalization for infection as a time-varying exposure.

RESULTS: During a median follow-up of 12.2 years, 669 incident ischemic strokes were observed in participants without a baseline history of stroke. Hospitalization for infection was more likely during case than control time periods; for 90 days before stroke, OR=3.4 (95% CI, 1.8 to 6.5). The point estimates of risks were higher when we examined shorter intervals: for 30 days, OR=7.3 (95% CI, 1.9 to 40.9), and for 14 days, OR=8.0 (95% CI, 1.7 to 77.3). In survival analyses, risk of stroke was associated with hospitalization for infection in the preceding 90 days, adjusted hazard ratio=2.4 (95% CI, 1.6 to 3.4).

CONCLUSIONS: Hospitalization for infection is associated with a short-term increased risk of stroke, with higher risks observed for shorter intervals preceding stroke.

VL - 42 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21546476?dopt=Abstract ER - TY - JOUR T1 - Identification of patients with sleep disordered breathing: comparing the four-variable screening tool, STOP, STOP-Bang, and Epworth Sleepiness Scales. JF - J Clin Sleep Med Y1 - 2011 A1 - Silva, Graciela E A1 - Vana, Kimberly D A1 - Goodwin, James L A1 - Sherrill, Duane L A1 - Quan, Stuart F KW - Blood Pressure KW - Body Mass Index KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Mass Screening KW - Middle Aged KW - Polysomnography KW - Predictive Value of Tests KW - Prospective Studies KW - Risk KW - ROC Curve KW - Sensitivity and Specificity KW - Severity of Illness Index KW - Sleep Apnea Syndromes KW - Snoring KW - Surveys and Questionnaires AB -

STUDY OBJECTIVE: The Epworth Sleepiness Scale (ESS) has been used to detect patients with potential sleep disordered breathing (SDB). Recently, a 4-Variable screening tool was proposed to identify patients with SDB, in addition to the STOP and STOP-Bang questionnaires. This study evaluated the abilities of the 4-Variable screening tool, STOP, STOP-Bang, and ESS questionnaires in identifying subjects at risk for SDB.

METHODS: A total of 4,770 participants who completed polysomnograms in the baseline evaluation of the Sleep Heart Health Study (SHHS) were included. Subjects with RDIs ≥ 15 and ≥ 30 were considered to have moderate-to-severe or severe SDB, respectively. Variables were constructed to approximate those in the questionnaires. The risk of SDB was calculated by the 4-Variable screening tool according to Takegami et al. The STOP and STOP-Bang questionnaires were evaluated including variables for snoring, tiredness/sleepiness, observed apnea, blood pressure, body mass index, age, neck circumference, and gender. Sleepiness was evaluated using the ESS questionnaire and scores were dichotomized into < 11 and ≥ 11.

RESULTS: The STOP-Bang questionnaire had higher sensitivity to predict moderate-to-severe (87.0%) and severe (70.4%) SDB, while the 4-Variable screening tool had higher specificity to predict moderate-to-severe and severe SDB (93.2% for both).

CONCLUSIONS: In community populations such as the SHHS, high specificities may be more useful in excluding low-risk patients, while avoiding false positives. However, sleep clinicians may prefer to use screening tools with high sensitivities, like the STOP-Bang, in order to avoid missing cases that may lead to adverse health consequences and increased healthcare costs.

VL - 7 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22003341?dopt=Abstract ER - TY - JOUR T1 - Large-scale candidate gene analysis in whites and African Americans identifies IL6R polymorphism in relation to atrial fibrillation: the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource (CARe) project. JF - Circ Cardiovasc Genet Y1 - 2011 A1 - Schnabel, Renate B A1 - Kerr, Kathleen F A1 - Lubitz, Steven A A1 - Alkylbekova, Ermeg L A1 - Marcus, Gregory M A1 - Sinner, Moritz F A1 - Magnani, Jared W A1 - Wolf, Philip A A1 - Deo, Rajat A1 - Lloyd-Jones, Donald M A1 - Lunetta, Kathryn L A1 - Mehra, Reena A1 - Levy, Daniel A1 - Fox, Ervin R A1 - Arking, Dan E A1 - Mosley, Thomas H A1 - Müller-Nurasyid, Martina A1 - Young, Taylor R A1 - Wichmann, H-Erich A1 - Seshadri, Sudha A1 - Farlow, Deborah N A1 - Rotter, Jerome I A1 - Soliman, Elsayed Z A1 - Glazer, Nicole L A1 - Wilson, James G A1 - Breteler, Monique M B A1 - Sotoodehnia, Nona A1 - Newton-Cheh, Christopher A1 - Kääb, Stefan A1 - Ellinor, Patrick T A1 - Alonso, Alvaro A1 - Benjamin, Emelia J A1 - Heckbert, Susan R KW - African Americans KW - Aged KW - Alleles KW - Atrial Fibrillation KW - Chromosomes, Human, Pair 4 KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Humans KW - Male KW - Middle Aged KW - National Heart, Lung, and Blood Institute (U.S.) KW - Polymorphism, Single Nucleotide KW - Receptors, Interleukin-6 KW - Risk Factors KW - Stroke KW - United States AB -

BACKGROUND: The genetic background of atrial fibrillation (AF) in whites and African Americans is largely unknown. Genes in cardiovascular pathways have not been systematically investigated.

METHODS AND RESULTS: We examined a panel of approximately 50,000 common single-nucleotide polymorphisms (SNPs) in 2095 cardiovascular candidate genes and AF in 3 cohorts with participants of European (n=18,524; 2260 cases) or African American descent (n=3662; 263 cases) in the National Heart, Lung, and Blood Institute's Candidate Gene Association Resource. Results in whites were followed up in the German Competence Network for AF (n=906, 468 cases). The top result was assessed in relation to incident ischemic stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology Stroke Consortium (n=19,602 whites, 1544 incident strokes). SNP rs4845625 in the IL6R gene was associated with AF (relative risk [RR] C allele, 0.90; 95% confidence interval [CI], 0.85-0.95; P=0.0005) in whites but did not reach statistical significance in African Americans (RR, 0.86; 95% CI, 0.72-1.03; P=0.09). The results were comparable in the German AF Network replication, (RR, 0.71; 95% CI, 0.57-0.89; P=0.003). No association between rs4845625 and stroke was observed in whites. The known chromosome 4 locus near PITX2 in whites also was associated with AF in African Americans (rs4611994; hazard ratio, 1.40; 95% CI, 1.16-1.69; P=0.0005).

CONCLUSIONS: In a community-based cohort meta-analysis, we identified genetic association in IL6R with AF in whites. Additionally, we demonstrated that the chromosome 4 locus known from recent genome-wide association studies in whites is associated with AF in African Americans.

VL - 4 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21846873?dopt=Abstract ER - TY - JOUR T1 - Left ventricular ejection fraction assessment in older adults: an adjunct to natriuretic peptide testing to identify risk of new-onset heart failure and cardiovascular death? JF - J Am Coll Cardiol Y1 - 2011 A1 - deFilippi, Christopher R A1 - Christenson, Robert H A1 - Kop, Willem J A1 - Gottdiener, John S A1 - Zhan, Min A1 - Seliger, Stephen L KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Cohort Studies KW - Death KW - Female KW - Follow-Up Studies KW - Heart Failure KW - Humans KW - Male KW - Natriuretic Peptide, Brain KW - Peptide Fragments KW - Prospective Studies KW - Risk Factors KW - Stroke Volume KW - Survival Rate KW - Ventricular Function, Left AB -

OBJECTIVES: The goal of this paper was to determine whether assessment of left ventricular ejection fraction (LVEF) enhances prediction of new-onset heart failure (HF) and cardiovascular mortality over and above N-terminal pro-B-type natriuretic peptide (NT-proBNP) level in older adults.

BACKGROUND: Elevated NT-proBNP levels are common in older adults and are associated with increased risk of HF.

METHODS: NT-proBNP and LVEF were measured in 4,137 older adults free of HF. Repeat measures of NT-proBNP were performed 2 to 3 years later and echocardiography was repeated 5 years later (n = 2,375), with a median follow-up of 10.7 years. The addition of an abnormal (<55%) LVEF (n = 317 [7.7%]) to initially elevated or rising NT-proBNP levels was evaluated to determine risk of HF or cardiovascular mortality. Changes in NT-proBNP levels were also assessed for estimating the risk of conversion from a normal to abnormal LVEF.

RESULTS: For participants with a low baseline NT-proBNP level (<190 pg/ml; n = 2,918), addition of an abnormal LVEF did not improve the estimation of risk of HF and identified a moderate increase in adjusted risk for cardiovascular mortality (hazard ratio: 1.69 [95% confidence interval: 1.22 to 2.31]). Among those whose NT-proBNP subsequently increased ≥25% to ≥190 pg/ml, an abnormal LVEF was likewise associated with an increased risk of cardiovascular mortality but not HF. Participants with an initially high NT-proBNP level (≥190 pg/ml) were at greater risk overall for both outcomes, and those with an abnormal LVEF were at the highest risk. However, an abnormal LVEF did not improve model classification or risk stratification for either endpoint when added to demographic factors and change in NT-proBNP. An initially elevated NT-proBNP or rising level was associated with an increased risk of developing an abnormal LVEF.

CONCLUSIONS: Assessment of LVEF in HF-free older adults based on NT-proBNP levels should be considered on an individual basis, as such assessments do not routinely improve prognostication.

VL - 58 IS - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21939835?dopt=Abstract ER - TY - JOUR T1 - Longitudinal association of depressive symptoms with rapid kidney function decline and adverse clinical renal disease outcomes. JF - Clin J Am Soc Nephrol Y1 - 2011 A1 - Kop, Willem J A1 - Seliger, Stephen L A1 - Fink, Jeffrey C A1 - Katz, Ronit A1 - Odden, Michelle C A1 - Fried, Linda F A1 - Rifkin, Dena E A1 - Sarnak, Mark J A1 - Gottdiener, John S KW - Acute Kidney Injury KW - Aged KW - Chronic Disease KW - Cohort Studies KW - Comorbidity KW - Depression KW - Female KW - Follow-Up Studies KW - Glomerular Filtration Rate KW - Humans KW - Kidney Diseases KW - Longitudinal Studies KW - Male AB -

BACKGROUND AND OBJECTIVES: Depression is a risk indicator for adverse outcomes in dialysis patients, but its prognostic impact in individuals who are not yet on dialysis is unknown. This study examines whether depressive symptoms are longitudinally associated with renal function decline, new-onset chronic kidney disease (CKD), ESRD, or hospitalization with acute kidney injury (AKI).

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Depressive symptoms were measured in a longitudinal cohort study with the 10-item Centers for Epidemiologic Studies Depression scale using a previously validated cut-off value (≥8). CKD at study entry and during follow-up was defined as an estimated GFR (eGFR) < 60 ml/min per m(2). Outcomes were rapid decline in eGFR (>3 ml/min per m(2) per year), new-onset CKD, ESRD (U.S. Renal Data System-based), and AKI (based on adjudicated medical record review). The median follow-up duration was 10.5 years.

RESULTS: Depressed participants (21.2%) showed a higher prevalence of CKD at baseline compared with nondepressed participants in multivariable analysis. Depression was associated with a subsequent risk of rapid decline in eGFR, incident ESRD, and AKI, but not incident CKD in unadjusted models. In multivariable analyses, only associations of depressive symptoms with AKI remained significant.

CONCLUSIONS: Elevated depressive symptoms are associated with subsequent adverse renal disease outcomes. The depression-related elevated risk of AKI was independent of traditional renal disease risk factors and may in part be explained by the predictive value of depression for acute coronary syndromes and heart failure hospitalizations that can be complicated by AKI.

VL - 6 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21393483?dopt=Abstract ER - TY - JOUR T1 - Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. JF - Kidney Int Y1 - 2011 A1 - Gansevoort, Ron T A1 - Matsushita, Kunihiro A1 - van der Velde, Marije A1 - Astor, Brad C A1 - Woodward, Mark A1 - Levey, Andrew S A1 - de Jong, Paul E A1 - Coresh, Josef KW - Aged KW - Albuminuria KW - Cohort Studies KW - Creatinine KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Prognosis KW - Proportional Hazards Models KW - Risk Factors AB -

Both a low estimated glomerular filtration rate (eGFR) and albuminuria are known risk factors for end-stage renal disease (ESRD). To determine their joint contribution to ESRD and other kidney outcomes, we performed a meta-analysis of nine general population cohorts with 845,125 participants and an additional eight cohorts with 173,892 patients, the latter selected because of their high risk for chronic kidney disease (CKD). In the general population, the risk for ESRD was unrelated to eGFR at values between 75 and 105 ml/min per 1.73 m(2) but increased exponentially at lower levels. Hazard ratios for eGFRs averaging 60, 45, and 15 were 4, 29, and 454, respectively, compared with an eGFR of 95, after adjustment for albuminuria and cardiovascular risk factors. Log albuminuria was linearly associated with log ESRD risk without thresholds. Adjusted hazard ratios at albumin-to-creatinine ratios of 30, 300, and 1000 mg/g were 5, 13, and 28, respectively, compared with an albumin-to-creatinine ratio of 5. Albuminuria and eGFR were associated with ESRD, without evidence for multiplicative interaction. Similar associations were found for acute kidney injury and progressive CKD. In high-risk cohorts, the findings were generally comparable. Thus, lower eGFR and higher albuminuria are risk factors for ESRD, acute kidney injury and progressive CKD in both general and high-risk populations, independent of each other and of cardiovascular risk factors.

VL - 80 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21289597?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of genome-wide association studies from the CHARGE consortium identifies common variants associated with carotid intima media thickness and plaque. JF - Nat Genet Y1 - 2011 A1 - Bis, Joshua C A1 - Kavousi, Maryam A1 - Franceschini, Nora A1 - Isaacs, Aaron A1 - Abecasis, Goncalo R A1 - Schminke, Ulf A1 - Post, Wendy S A1 - Smith, Albert V A1 - Cupples, L Adrienne A1 - Markus, Hugh S A1 - Schmidt, Reinhold A1 - Huffman, Jennifer E A1 - Lehtimäki, Terho A1 - Baumert, Jens A1 - Münzel, Thomas A1 - Heckbert, Susan R A1 - Dehghan, Abbas A1 - North, Kari A1 - Oostra, Ben A1 - Bevan, Steve A1 - Stoegerer, Eva-Maria A1 - Hayward, Caroline A1 - Raitakari, Olli A1 - Meisinger, Christa A1 - Schillert, Arne A1 - Sanna, Serena A1 - Völzke, Henry A1 - Cheng, Yu-Ching A1 - Thorsson, Bolli A1 - Fox, Caroline S A1 - Rice, Kenneth A1 - Rivadeneira, Fernando A1 - Nambi, Vijay A1 - Halperin, Eran A1 - Petrovic, Katja E A1 - Peltonen, Leena A1 - Wichmann, H Erich A1 - Schnabel, Renate B A1 - Dörr, Marcus A1 - Parsa, Afshin A1 - Aspelund, Thor A1 - Demissie, Serkalem A1 - Kathiresan, Sekar A1 - Reilly, Muredach P A1 - Taylor, Kent A1 - Uitterlinden, Andre A1 - Couper, David J A1 - Sitzer, Matthias A1 - Kähönen, Mika A1 - Illig, Thomas A1 - Wild, Philipp S A1 - Orrù, Marco A1 - Lüdemann, Jan A1 - Shuldiner, Alan R A1 - Eiriksdottir, Gudny A1 - White, Charles C A1 - Rotter, Jerome I A1 - Hofman, Albert A1 - Seissler, Jochen A1 - Zeller, Tanja A1 - Usala, Gianluca A1 - Ernst, Florian A1 - Launer, Lenore J A1 - D'Agostino, Ralph B A1 - O'Leary, Daniel H A1 - Ballantyne, Christie A1 - Thiery, Joachim A1 - Ziegler, Andreas A1 - Lakatta, Edward G A1 - Chilukoti, Ravi Kumar A1 - Harris, Tamara B A1 - Wolf, Philip A A1 - Psaty, Bruce M A1 - Polak, Joseph F A1 - Li, Xia A1 - Rathmann, Wolfgang A1 - Uda, Manuela A1 - Boerwinkle, Eric A1 - Klopp, Norman A1 - Schmidt, Helena A1 - Wilson, James F A1 - Viikari, Jorma A1 - Koenig, Wolfgang A1 - Blankenberg, Stefan A1 - Newman, Anne B A1 - Witteman, Jacqueline A1 - Heiss, Gerardo A1 - Duijn, Cornelia van A1 - Scuteri, Angelo A1 - Homuth, Georg A1 - Mitchell, Braxton D A1 - Gudnason, Vilmundur A1 - O'Donnell, Christopher J KW - Adult KW - Aged KW - Aging KW - Atherosclerosis KW - Carotid Intima-Media Thickness KW - Cohort Studies KW - Coronary Artery Disease KW - European Continental Ancestry Group KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Genotype KW - Heart KW - Humans KW - Middle Aged KW - Phenotype KW - Plaque, Atherosclerotic KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

Carotid intima media thickness (cIMT) and plaque determined by ultrasonography are established measures of subclinical atherosclerosis that each predicts future cardiovascular disease events. We conducted a meta-analysis of genome-wide association data in 31,211 participants of European ancestry from nine large studies in the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. We then sought additional evidence to support our findings among 11,273 individuals using data from seven additional studies. In the combined meta-analysis, we identified three genomic regions associated with common carotid intima media thickness and two different regions associated with the presence of carotid plaque (P < 5 × 10(-8)). The associated SNPs mapped in or near genes related to cellular signaling, lipid metabolism and blood pressure homeostasis, and two of the regions were associated with coronary artery disease (P < 0.006) in the Coronary Artery Disease Genome-Wide Replication and Meta-Analysis (CARDIoGRAM) consortium. Our findings may provide new insight into pathways leading to subclinical atherosclerosis and subsequent cardiovascular events.

VL - 43 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21909108?dopt=Abstract ER - TY - JOUR T1 - N-terminal pro-B-type natriuretic peptide is associated with sudden cardiac death risk: the Cardiovascular Health Study. JF - Heart Rhythm Y1 - 2011 A1 - Patton, Kristen K A1 - Sotoodehnia, Nona A1 - DeFilippi, Christopher A1 - Siscovick, David S A1 - Gottdiener, John S A1 - Kronmal, Richard A KW - Age Distribution KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Cohort Studies KW - Confidence Intervals KW - Death, Sudden, Cardiac KW - Female KW - Humans KW - Incidence KW - Kaplan-Meier Estimate KW - Male KW - Middle Aged KW - Natriuretic Peptide, Brain KW - Peptide Fragments KW - Predictive Value of Tests KW - Proportional Hazards Models KW - Retrospective Studies KW - Risk Assessment KW - Sex Distribution KW - Time Factors KW - United States AB -

BACKGROUND: Sudden cardiac death (SCD), the cause of 250,000-450,000 deaths per year, is a major public health problem. The majority of those affected do not have a prior cardiovascular diagnosis. Elevated B-type natriuretic peptide levels have been associated with the risk of heart failure and mortality as well as with sudden death in women.

OBJECTIVE: The purpose of this study was to examine the relationship between N-terminal pro-B-type natriuretic peptide (NT-proBNP) and SCD in the Cardiovascular Health Study population.

METHODS: The risk of SCD associated with baseline NT-proBNP was examined in 5,447 participants. Covariate-adjusted Cox model regressions were used to estimate the hazard ratios of developing SCD as a function of baseline NT-proBNP.

RESULTS: Over a median follow-up of 12.5 years (maximum 16), there were 289 cases of SCD. Higher NT-proBNP levels were strongly associated with SCD, with an unadjusted hazard ratio of 4.2 (95% confidence interval [2.9, 6.1]; P <.001) in the highest quintile compared with in the lowest. NT-proBNP remained associated with SCD even after adjustment for numerous clinical characteristics and risk factors (age, sex, race, and other associated conditions), with an adjusted hazard ratio for the fifth versus the first quintile of 2.5 (95% confidence interval [1.6, 3.8]; P <.001).

CONCLUSION: NT-proBNP provides information regarding the risk of SCD in a community-based population of older adults, beyond other traditional risk factors. This biomarker may ultimately prove useful in targeting the population at risk with aggressive medical management of comorbid conditions.

VL - 8 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21044699?dopt=Abstract ER - TY - JOUR T1 - The relationship between serum markers of collagen turnover and cardiovascular outcome in the elderly: the Cardiovascular Health Study. JF - Circ Heart Fail Y1 - 2011 A1 - Barasch, Eddy A1 - Gottdiener, John S A1 - Aurigemma, Gerard A1 - Kitzman, Dalane W A1 - Han, Jing A1 - Kop, Willem J A1 - Tracy, Russell P KW - Aged KW - Aged, 80 and over KW - Aging KW - Biomarkers KW - Cardiovascular Diseases KW - Case-Control Studies KW - Cohort Studies KW - Collagen KW - Collagen Type I KW - Female KW - Follow-Up Studies KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Peptide Fragments KW - Peptides KW - Predictive Value of Tests KW - Procollagen KW - Prospective Studies KW - Stroke Volume KW - Survival Rate AB -

BACKGROUND: The deposition of collagen fibrils in the myocardial extracellular matrix increases with age and plays a key role in the pathophysiology of heart failure (HF). We sought to determine the predictive value of serum markers of collagen turnover for incident HF and cardiovascular (CV) morbidity, mortality, and all-cause mortality in elderly individuals.

METHODS AND RESULTS: In 880 participants in the Cardiovascular Health Study (mean age, 77±6 years; 48% women), serum levels of carboxyl-terminal peptide of procollagen type I (PIP), carboxyl-terminal telopeptide of collagen type I (CITP), and amino-terminal peptide of procollagen type III (PIIINP) were measured in 4 groups: HF with reduced ejection fraction (HFREF; n=146, EF <55%); HF with preserved EF (HFPEF; n=175, EF ≥55%), control subjects with CV risk factors but not HF (CVD; n=280), and healthy control subjects free of CV disease (n=279). Relationships between these serum markers and outcome at follow-up of 12±4 years (range, 3-17 years) was determined in six models including those adjusted for conventional risk factors, renal function, NT-proBNP and agents which interfere with collagen synthesis. For the entire cohort, in unadjusted and adjusted models, both PIIINP and CITP were associated with myocardial infarction, incident HF, hospitalization for HF, cardiovascular and all-cause mortality. In healthy control subjects, CITP and PIIINP were associated with all-cause death. In control subjects with risk factors, CITP was associated with incident HF, and in participants with HFPEF, CITP was associated with hospitalization for HF. No collagen biomarker was associated with outcome in participants with HFREF, and PIP was not associated with outcome in the cohort or its subgroups.

CONCLUSIONS: In both healthy and elderly individuals with CV disease at risk of developing HF, CITP and PIIINP are significantly associated with multiple adverse cardiac outcomes including myocardial infarction, HF, and death. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT00005133.

VL - 4 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21900186?dopt=Abstract ER - TY - JOUR T1 - The risk of Parkinson disease associated with urate in a community-based cohort of older adults. JF - Neuroepidemiology Y1 - 2011 A1 - Jain, S A1 - Ton, T G A1 - Boudreau, R M A1 - Yang, M A1 - Thacker, E L A1 - Studenski, S A1 - Longstreth, W T A1 - Strotmeyer, E S A1 - Newman, A B KW - Aged KW - California KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Maryland KW - North Carolina KW - Parkinson Disease KW - Pennsylvania KW - Prospective Studies KW - Risk Factors KW - Sex Distribution KW - Sex Factors KW - Uric Acid AB -

BACKGROUND/AIMS: Studies suggest an inverse association between urate concentration and the risk of Parkinson disease (PD). We investigated this in the Cardiovascular Health Study in an elderly community-based cohort of adults.

METHODS: The association of baseline urate (µmol/l) and incident PD over 14 years was assessed with locally weighted scatterplot smoothing (LOESS) regression from which categories of low (<300 µmol/l), middle (300-500 µmol/l), and high (>500 µmol/l) urate ranges were derived. Multivariate logistic regression models assessed the risk of PD for each urate range. Linear and quadratic terms were tested when modeling the association between urate and the risk of PD.

RESULTS: Women had significantly lower urate concentrations than did men [316.8 µmol/l (SD 88.0) vs. 367.4 µmol/l (SD 87.7), p < 0.0001] and in women no associations between urate and PD risk were observed. In men, LOESS curves suggested a U-shaped or threshold effect between urate and PD risk. With the middle range as reference, the risk of developing PD was significantly increased for urate <300 µmol/l (OR 1.69, 95% CI 1.03-2.78) but not for urate >500 µmol/l (OR 1.55, 95% CI 0.72-3.32) in men. A negative linear term was significant for urate <500 µmol/l, and across the entire range a convex quadratic term was significant.

CONCLUSIONS: Results suggest a more complex relationship than previously reported between urate levels and the risk of PD in men. Low urate concentrations were associated with a higher PD risk and high urate concentrations were not associated with a further decrease in PD risk.

VL - 36 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21677446?dopt=Abstract ER - TY - JOUR T1 - Surrogate screening models for the low physical activity criterion of frailty. JF - Aging Clin Exp Res Y1 - 2011 A1 - Eckel, Sandrah P A1 - Bandeen-Roche, Karen A1 - Chaves, Paulo H M A1 - Fried, Linda P A1 - Louis, Thomas A KW - Activities of Daily Living KW - Aged KW - Cohort Studies KW - Exercise KW - Female KW - Follow-Up Studies KW - Frail Elderly KW - Geriatric Assessment KW - Humans KW - Leisure Activities KW - Logistic Models KW - Male KW - Motor Activity KW - Prospective Studies KW - Surveys and Questionnaires KW - Women's Health AB -

BACKGROUND AND AIMS: Low physical activity, one of five criteria in a validated clinical phenotype of frailty, is assessed by a standardized, semiquantitative questionnaire on up to 20 leisure time activities. Because of the time demanded to collect the interview data, it has been challenging to translate to studies other than the Cardiovascular Health Study (CHS), for which it was developed. Considering subsets of activities, we identified and evaluated streamlined surrogate assessment methods and compared them to one implemented in the Women's Health and Aging Study (WHAS).

METHODS: Using data on men and women ages 65 and older from the CHS, we applied logistic regression models to rank activities by "relative influence" in predicting low physical activity.We considered subsets of the most influential activities as inputs to potential surrogate models (logistic regressions). We evaluated predictive accuracy and predictive validity using the area under receiver operating characteristic curves and assessed criterion validity using proportional hazards models relating frailty status (defined using the surrogate) to mortality.

RESULTS: Walking for exercise and moderately strenuous household chores were highly influential for both genders. Women required fewer activities than men for accurate classification. The WHAS model (8 CHS activities) was an effective surrogate, but a surrogate using 6 activities (walking, chores, gardening, general exercise, mowing and golfing) was also highly predictive.

CONCLUSIONS: We recommend a 6 activity questionnaire to assess physical activity for men and women. If efficiency is essential and the study involves only women, fewer activities can be included.

VL - 23 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21993168?dopt=Abstract ER - TY - JOUR T1 - Total zinc intake may modify the glucose-raising effect of a zinc transporter (SLC30A8) variant: a 14-cohort meta-analysis. JF - Diabetes Y1 - 2011 A1 - Kanoni, Stavroula A1 - Nettleton, Jennifer A A1 - Hivert, Marie-France A1 - Ye, Zheng A1 - van Rooij, Frank J A A1 - Shungin, Dmitry A1 - Sonestedt, Emily A1 - Ngwa, Julius S A1 - Wojczynski, Mary K A1 - Lemaitre, Rozenn N A1 - Gustafsson, Stefan A1 - Anderson, Jennifer S A1 - Tanaka, Toshiko A1 - Hindy, George A1 - Saylor, Georgia A1 - Renstrom, Frida A1 - Bennett, Amanda J A1 - van Duijn, Cornelia M A1 - Florez, Jose C A1 - Fox, Caroline S A1 - Hofman, Albert A1 - Hoogeveen, Ron C A1 - Houston, Denise K A1 - Hu, Frank B A1 - Jacques, Paul F A1 - Johansson, Ingegerd A1 - Lind, Lars A1 - Liu, Yongmei A1 - McKeown, Nicola A1 - Ordovas, Jose A1 - Pankow, James S A1 - Sijbrands, Eric J G A1 - Syvänen, Ann-Christine A1 - Uitterlinden, André G A1 - Yannakoulia, Mary A1 - Zillikens, M Carola A1 - Wareham, Nick J A1 - Prokopenko, Inga A1 - Bandinelli, Stefania A1 - Forouhi, Nita G A1 - Cupples, L Adrienne A1 - Loos, Ruth J A1 - Hallmans, Göran A1 - Dupuis, Josée A1 - Langenberg, Claudia A1 - Ferrucci, Luigi A1 - Kritchevsky, Stephen B A1 - McCarthy, Mark I A1 - Ingelsson, Erik A1 - Borecki, Ingrid B A1 - Witteman, Jacqueline C M A1 - Orho-Melander, Marju A1 - Siscovick, David S A1 - Meigs, James B A1 - Franks, Paul W A1 - Dedoussis, George V KW - Blood Glucose KW - Cation Transport Proteins KW - Cohort Studies KW - Humans KW - Polymorphism, Single Nucleotide KW - Zinc KW - Zinc Transporter 8 AB -

OBJECTIVE: Many genetic variants have been associated with glucose homeostasis and type 2 diabetes in genome-wide association studies. Zinc is an essential micronutrient that is important for β-cell function and glucose homeostasis. We tested the hypothesis that zinc intake could influence the glucose-raising effect of specific variants.

RESEARCH DESIGN AND METHODS: We conducted a 14-cohort meta-analysis to assess the interaction of 20 genetic variants known to be related to glycemic traits and zinc metabolism with dietary zinc intake (food sources) and a 5-cohort meta-analysis to assess the interaction with total zinc intake (food sources and supplements) on fasting glucose levels among individuals of European ancestry without diabetes.

RESULTS: We observed a significant association of total zinc intake with lower fasting glucose levels (β-coefficient ± SE per 1 mg/day of zinc intake: -0.0012 ± 0.0003 mmol/L, summary P value = 0.0003), while the association of dietary zinc intake was not significant. We identified a nominally significant interaction between total zinc intake and the SLC30A8 rs11558471 variant on fasting glucose levels (β-coefficient ± SE per A allele for 1 mg/day of greater total zinc intake: -0.0017 ± 0.0006 mmol/L, summary interaction P value = 0.005); this result suggests a stronger inverse association between total zinc intake and fasting glucose in individuals carrying the glucose-raising A allele compared with individuals who do not carry it. None of the other interaction tests were statistically significant.

CONCLUSIONS: Our results suggest that higher total zinc intake may attenuate the glucose-raising effect of the rs11558471 SLC30A8 (zinc transporter) variant. Our findings also support evidence for the association of higher total zinc intake with lower fasting glucose levels.

VL - 60 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21810599?dopt=Abstract ER - TY - JOUR T1 - Vitamin D, parathyroid hormone, and cardiovascular events among older adults. JF - J Am Coll Cardiol Y1 - 2011 A1 - Kestenbaum, Bryan A1 - Katz, Ronit A1 - de Boer, Ian A1 - Hoofnagle, Andy A1 - Sarnak, Mark J A1 - Shlipak, Michael G A1 - Jenny, Nancy S A1 - Siscovick, David S KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Follow-Up Studies KW - Humans KW - Male KW - Parathyroid Hormone KW - Prospective Studies KW - Vitamin D AB -

OBJECTIVES: The aim of this study was to evaluate associations of 25-hydroxyvitamin D (25-OHD) and parathyroid hormone (PTH) concentrations separately and in combination with incident cardiovascular events and mortality during 14 years of follow-up in the CHS (Cardiovascular Health Study).

BACKGROUND: Vitamin D deficiency and PTH excess are common in older adults and may adversely affect cardiovascular health.

METHODS: A total of 2,312 participants who were free of cardiovascular disease at baseline were studied. Vitamin D and intact PTH were measured from previously frozen serum using mass spectrometry and a 2-site immunoassay. Outcomes were adjudicated cases of myocardial infarction, heart failure, cardiovascular death, and all-cause mortality.

RESULTS: There were 384 participants (17%) with serum 25-OHD concentrations <15 ng/ml and 570 (25%) with serum PTH concentrations ≥ 65 pg/ml. After adjustment, each 10 ng/ml lower 25-OHD concentration was associated with a 9% greater (95% confidence interval [CI]: 2% to 17% greater) relative hazard of mortality and a 25% greater (95% CI: 8% to 44% greater) relative hazard of myocardial infarction. Serum 25-OHD concentrations <15 ng/ml were associated with a 29% greater (95% CI: 5% to 55% greater) risk for mortality. Serum PTH concentrations ≥ 65 pg/ml were associated with a 30% greater risk for heart failure (95% CI: 6% to 61% greater) but not other outcomes. There was no evidence of an interaction between serum 25-OHD and PTH concentrations and cardiovascular events.

CONCLUSIONS: Among older adults, 25-OHD deficiency is associated with myocardial infarction and mortality; PTH excess is associated with heart failure. Vitamin D and PTH might influence cardiovascular risk through divergent pathways.

VL - 58 IS - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21939825?dopt=Abstract ER - TY - JOUR T1 - Age and association of kidney measures with mortality and end-stage renal disease. JF - JAMA Y1 - 2012 A1 - Hallan, Stein I A1 - Matsushita, Kunihiro A1 - Sang, Yingying A1 - Mahmoodi, Bakhtawar K A1 - Black, Corri A1 - Ishani, Areef A1 - Kleefstra, Nanne A1 - Naimark, David A1 - Roderick, Paul A1 - Tonelli, Marcello A1 - Wetzels, Jack F M A1 - Astor, Brad C A1 - Gansevoort, Ron T A1 - Levin, Adeera A1 - Wen, Chi-Pang A1 - Coresh, Josef KW - Adolescent KW - Adult KW - Age Factors KW - Aged KW - Albuminuria KW - Cohort Studies KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Risk KW - Young Adult AB -

CONTEXT: Chronic kidney disease (CKD) is prevalent in older individuals, but the risk implications of low estimated glomerular filtration rate (eGFR) and high albuminuria across the full age range are controversial.

OBJECTIVE: To evaluate possible effect modification (interaction) by age of the association of eGFR and albuminuria with clinical risk, examining both relative and absolute risks.

DESIGN, SETTING, AND PARTICIPANTS: Individual-level meta-analysis including 2,051,244 participants from 33 general population or high-risk (of vascular disease) cohorts and 13 CKD cohorts from Asia, Australasia, Europe, and North/South America, conducted in 1972-2011 with a mean follow-up time of 5.8 years (range, 0-31 years).

MAIN OUTCOME MEASURES: Hazard ratios (HRs) of mortality and end-stage renal disease (ESRD) according to eGFR and albuminuria were meta-analyzed across age categories after adjusting for sex, race, cardiovascular disease, diabetes, systolic blood pressure, cholesterol, body mass index, and smoking. Absolute risks were estimated using HRs and average incidence rates.

RESULTS: Mortality (112,325 deaths) and ESRD (8411 events) risks were higher at lower eGFR and higher albuminuria in every age category. In general and high-risk cohorts, relative mortality risk for reduced eGFR decreased with increasing age; eg, adjusted HRs at an eGFR of 45 mL/min/1.73 m2 vs 80 mL/min/1.73 m2 were 3.50 (95% CI, 2.55-4.81), 2.21 (95% CI, 2.02-2.41), 1.59 (95% CI, 1.42-1.77), and 1.35 (95% CI, 1.23-1.48) in age categories 18-54, 55-64, 65-74, and ≥75 years, respectively (P <.05 for age interaction). Absolute risk differences for the same comparisons were higher at older age (9.0 [95% CI, 6.0-12.8], 12.2 [95% CI, 10.3-14.3], 13.3 [95% CI, 9.0-18.6], and 27.2 [95% CI, 13.5-45.5] excess deaths per 1000 person-years, respectively). For increased albuminuria, reduction of relative risk with increasing age was less evident, while differences in absolute risk were higher in older age categories (7.5 [95% CI, 4.3-11.9], 12.2 [95% CI, 7.9-17.6], 22.7 [95% CI, 15.3-31.6], and 34.3 [95% CI, 19.5-52.4] excess deaths per 1000 person-years, respectively by age category, at an albumin-creatinine ratio of 300 mg/g vs 10 mg/g). In CKD cohorts, adjusted relative hazards of mortality did not decrease with age. In all cohorts, ESRD relative risks and absolute risk differences at lower eGFR or higher albuminuria were comparable across age categories.

CONCLUSIONS: Both low eGFR and high albuminuria were independently associated with mortality and ESRD regardless of age across a wide range of populations. Mortality showed lower relative risk but higher absolute risk differences at older age.

VL - 308 IS - 22 ER - TY - JOUR T1 - Assessment of gene-by-sex interaction effect on bone mineral density. JF - J Bone Miner Res Y1 - 2012 A1 - Liu, Ching-Ti A1 - Estrada, Karol A1 - Yerges-Armstrong, Laura M A1 - Amin, Najaf A1 - Evangelou, Evangelos A1 - Li, Guo A1 - Minster, Ryan L A1 - Carless, Melanie A A1 - Kammerer, Candace M A1 - Oei, Ling A1 - Zhou, Yanhua A1 - Alonso, Nerea A1 - Dailiana, Zoe A1 - Eriksson, Joel A1 - García-Giralt, Natalia A1 - Giroux, Sylvie A1 - Husted, Lise Bjerre A1 - Khusainova, Rita I A1 - Koromila, Theodora A1 - Kung, Annie Waichee A1 - Lewis, Joshua R A1 - Masi, Laura A1 - Mencej-Bedrac, Simona A1 - Nogues, Xavier A1 - Patel, Millan S A1 - Prezelj, Janez A1 - Richards, J Brent A1 - Sham, Pak Chung A1 - Spector, Timothy A1 - Vandenput, Liesbeth A1 - Xiao, Su-Mei A1 - Zheng, Hou-Feng A1 - Zhu, Kun A1 - Balcells, Susana A1 - Brandi, Maria Luisa A1 - Frost, Morten A1 - Goltzman, David A1 - González-Macías, Jesús A1 - Karlsson, Magnus A1 - Khusnutdinova, Elza K A1 - Kollia, Panagoula A1 - Langdahl, Bente Lomholt A1 - Ljunggren, Osten A1 - Lorentzon, Mattias A1 - Marc, Janja A1 - Mellström, Dan A1 - Ohlsson, Claes A1 - Olmos, José M A1 - Ralston, Stuart H A1 - Riancho, José A A1 - Rousseau, François A1 - Urreizti, Roser A1 - Van Hul, Wim A1 - Zarrabeitia, María T A1 - Castano-Betancourt, Martha A1 - Demissie, Serkalem A1 - Grundberg, Elin A1 - Herrera, Lizbeth A1 - Kwan, Tony A1 - Medina-Gómez, Carolina A1 - Pastinen, Tomi A1 - Sigurdsson, Gunnar A1 - Thorleifsson, Gudmar A1 - Vanmeurs, Joyce Bj A1 - Blangero, John A1 - Hofman, Albert A1 - Liu, Yongmei A1 - Mitchell, Braxton D A1 - O'Connell, Jeffrey R A1 - Oostra, Ben A A1 - Rotter, Jerome I A1 - Stefansson, Kari A1 - Streeten, Elizabeth A A1 - Styrkarsdottir, Unnur A1 - Thorsteinsdottir, Unnur A1 - Tylavsky, Frances A A1 - Uitterlinden, Andre A1 - Cauley, Jane A A1 - Harris, Tamara B A1 - Ioannidis, John Pa A1 - Psaty, Bruce M A1 - Robbins, John A A1 - Zillikens, M Carola A1 - Vanduijn, Cornelia M A1 - Prince, Richard L A1 - Karasik, David A1 - Rivadeneira, Fernando A1 - Kiel, Douglas P A1 - Cupples, L Adrienne A1 - Hsu, Yi-Hsiang KW - Bone Density KW - Cohort Studies KW - Female KW - Genes KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci KW - Reproducibility of Results KW - Sex Characteristics AB -

Sexual dimorphism in various bone phenotypes, including bone mineral density (BMD), is widely observed; however, the extent to which genes explain these sex differences is unclear. To identify variants with different effects by sex, we examined gene-by-sex autosomal interactions genome-wide, and performed expression quantitative trait loci (eQTL) analysis and bioinformatics network analysis. We conducted an autosomal genome-wide meta-analysis of gene-by-sex interaction on lumbar spine (LS) and femoral neck (FN) BMD in 25,353 individuals from 8 cohorts. In a second stage, we followed up the 12 top single-nucleotide polymorphisms (SNPs; p < 1 × 10(-5) ) in an additional set of 24,763 individuals. Gene-by-sex interaction and sex-specific effects were examined in these 12 SNPs. We detected one novel genome-wide significant interaction associated with LS-BMD at the Chr3p26.1-p25.1 locus, near the GRM7 gene (male effect = 0.02 and p = 3.0 × 10(-5) ; female effect = -0.007 and p = 3.3 × 10(-2) ), and 11 suggestive loci associated with either FN- or LS-BMD in discovery cohorts. However, there was no evidence for genome-wide significant (p < 5 × 10(-8) ) gene-by-sex interaction in the joint analysis of discovery and replication cohorts. Despite the large collaborative effort, no genome-wide significant evidence for gene-by-sex interaction was found to influence BMD variation in this screen of autosomal markers. If they exist, gene-by-sex interactions for BMD probably have weak effects, accounting for less than 0.08% of the variation in these traits per implicated SNP. © 2012 American Society for Bone and Mineral Research.

VL - 27 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22692763?dopt=Abstract ER - TY - JOUR T1 - Association between chromosome 9p21 variants and the ankle-brachial index identified by a meta-analysis of 21 genome-wide association studies. JF - Circ Cardiovasc Genet Y1 - 2012 A1 - Murabito, Joanne M A1 - White, Charles C A1 - Kavousi, Maryam A1 - Sun, Yan V A1 - Feitosa, Mary F A1 - Nambi, Vijay A1 - Lamina, Claudia A1 - Schillert, Arne A1 - Coassin, Stefan A1 - Bis, Joshua C A1 - Broer, Linda A1 - Crawford, Dana C A1 - Franceschini, Nora A1 - Frikke-Schmidt, Ruth A1 - Haun, Margot A1 - Holewijn, Suzanne A1 - Huffman, Jennifer E A1 - Hwang, Shih-Jen A1 - Kiechl, Stefan A1 - Kollerits, Barbara A1 - Montasser, May E A1 - Nolte, Ilja M A1 - Rudock, Megan E A1 - Senft, Andrea A1 - Teumer, Alexander A1 - van der Harst, Pim A1 - Vitart, Veronique A1 - Waite, Lindsay L A1 - Wood, Andrew R A1 - Wassel, Christina L A1 - Absher, Devin M A1 - Allison, Matthew A A1 - Amin, Najaf A1 - Arnold, Alice A1 - Asselbergs, Folkert W A1 - Aulchenko, Yurii A1 - Bandinelli, Stefania A1 - Barbalic, Maja A1 - Boban, Mladen A1 - Brown-Gentry, Kristin A1 - Couper, David J A1 - Criqui, Michael H A1 - Dehghan, Abbas A1 - den Heijer, Martin A1 - Dieplinger, Benjamin A1 - Ding, Jingzhong A1 - Dörr, Marcus A1 - Espinola-Klein, Christine A1 - Felix, Stephan B A1 - Ferrucci, Luigi A1 - Folsom, Aaron R A1 - Fraedrich, Gustav A1 - Gibson, Quince A1 - Goodloe, Robert A1 - Gunjaca, Grgo A1 - Haltmayer, Meinhard A1 - Heiss, Gerardo A1 - Hofman, Albert A1 - Kieback, Arne A1 - Kiemeney, Lambertus A A1 - Kolcic, Ivana A1 - Kullo, Iftikhar J A1 - Kritchevsky, Stephen B A1 - Lackner, Karl J A1 - Li, Xiaohui A1 - Lieb, Wolfgang A1 - Lohman, Kurt A1 - Meisinger, Christa A1 - Melzer, David A1 - Mohler, Emile R A1 - Mudnic, Ivana A1 - Mueller, Thomas A1 - Navis, Gerjan A1 - Oberhollenzer, Friedrich A1 - Olin, Jeffrey W A1 - O'Connell, Jeff A1 - O'Donnell, Christopher J A1 - Palmas, Walter A1 - Penninx, Brenda W A1 - Petersmann, Astrid A1 - Polasek, Ozren A1 - Psaty, Bruce M A1 - Rantner, Barbara A1 - Rice, Ken A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Seldenrijk, Adrie A1 - Stadler, Marietta A1 - Summerer, Monika A1 - Tanaka, Toshiko A1 - Tybjaerg-Hansen, Anne A1 - Uitterlinden, André G A1 - van Gilst, Wiek H A1 - Vermeulen, Sita H A1 - Wild, Sarah H A1 - Wild, Philipp S A1 - Willeit, Johann A1 - Zeller, Tanja A1 - Zemunik, Tatijana A1 - Zgaga, Lina A1 - Assimes, Themistocles L A1 - Blankenberg, Stefan A1 - Boerwinkle, Eric A1 - Campbell, Harry A1 - Cooke, John P A1 - de Graaf, Jacqueline A1 - Herrington, David A1 - Kardia, Sharon L R A1 - Mitchell, Braxton D A1 - Murray, Anna A1 - Münzel, Thomas A1 - Newman, Anne B A1 - Oostra, Ben A A1 - Rudan, Igor A1 - Shuldiner, Alan R A1 - Snieder, Harold A1 - van Duijn, Cornelia M A1 - Völker, Uwe A1 - Wright, Alan F A1 - Wichmann, H-Erich A1 - Wilson, James F A1 - Witteman, Jacqueline C M A1 - Liu, Yongmei A1 - Hayward, Caroline A1 - Borecki, Ingrid B A1 - Ziegler, Andreas A1 - North, Kari E A1 - Cupples, L Adrienne A1 - Kronenberg, Florian KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Alleles KW - Ankle Brachial Index KW - Chromosomes, Human, Pair 9 KW - Cohort Studies KW - Cyclin-Dependent Kinase Inhibitor p15 KW - Female KW - Genome-Wide Association Study KW - Genotype KW - HapMap Project KW - Humans KW - Logistic Models KW - Male KW - Middle Aged KW - Peripheral Vascular Diseases KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Sex Factors AB -

BACKGROUND: Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.

METHODS AND RESULTS: Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026).

CONCLUSIONS: Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.

VL - 5 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22199011?dopt=Abstract ER - TY - JOUR T1 - Association of mild to moderate chronic kidney disease with venous thromboembolism: pooled analysis of five prospective general population cohorts. JF - Circulation Y1 - 2012 A1 - Mahmoodi, Bakhtawar K A1 - Gansevoort, Ron T A1 - Næss, Inger Anne A1 - Lutsey, Pamela L A1 - Brækkan, Sigrid K A1 - Veeger, Nic J G M A1 - Brodin, Ellen E A1 - Meijer, Karina A1 - Sang, Yingying A1 - Matsushita, Kunihiro A1 - Hallan, Stein I A1 - Hammerstrøm, Jens A1 - Cannegieter, Suzanne C A1 - Astor, Brad C A1 - Coresh, Josef A1 - Folsom, Aaron R A1 - Hansen, John-Bjarne A1 - Cushman, Mary KW - Aged KW - Cohort Studies KW - Europe KW - Female KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Prevalence KW - Renal Insufficiency, Chronic KW - Risk Factors KW - Severity of Illness Index KW - Venous Thromboembolism AB -

BACKGROUND: Recent findings suggest that chronic kidney disease (CKD) may be associated with an increased risk of venous thromboembolism (VTE). Given the high prevalence of mild-to-moderate CKD in the general population, in depth analysis of this association is warranted.

METHODS AND RESULTS: We pooled individual participant data from 5 community-based cohorts from Europe (second Nord-Trøndelag Health Study [HUNT2], Prevention of Renal and Vascular End-stage Disease [PREVEND], and the Tromsø study) and the United States (Atherosclerosis Risks in Communities [ARIC] and Cardiovascular Health Study [CHS]) to assess the association of estimated glomerular filtration rate (eGFR), albuminuria, and CKD with objectively verified VTE. To estimate adjusted hazard ratios for VTE, categorical and continuous spline models were fit by using Cox regression with shared-frailty or random-effect meta-analysis. A total of 1178 VTE events occurred over 599 453 person-years follow-up. Relative to eGFR 100 mL/min per 1.73 m(2), hazard ratios for VTE were 1.29 (95% confidence interval, 1.04-1.59) for eGFR 75, 1.31 (1.00-1.71) for eGFR 60, 1.82 (1.27-2.60) for eGFR 45, and 1.95 (1.26-3.01) for eGFR 30 mL/min per 1.73 m(2). In comparison with an albumin-to-creatinine ratio (ACR) of 5.0 mg/g, the hazard ratios for VTE were 1.34 (1.04-1.72) for ACR 30 mg/g, 1.60 (1.08-2.36) for ACR 300 mg/g, and 1.92 (1.19-3.09) for ACR 1000 mg/g. There was no interaction between clinical categories of eGFR and ACR (P=0.20). The adjusted hazard ratio for CKD, defined as eGFR <60 mL/min per 1.73 m(2) or albuminuria ≥30 mg/g, (versus no CKD) was 1.54 (95% confidence interval, 1.15-2.06). Associations were consistent in subgroups according to age, sex, and comorbidities, and for unprovoked versus provoked VTE, as well.

CONCLUSIONS: Both eGFR and ACR are independently associated with increased risk of VTE in the general population, even across the normal eGFR and ACR ranges.

VL - 126 IS - 16 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22977129?dopt=Abstract ER - TY - JOUR T1 - Bootstrap-based inference on the difference in the means of two correlated functional processes. JF - Stat Med Y1 - 2012 A1 - Crainiceanu, Ciprian M A1 - Staicu, Ana-Maria A1 - Ray, Shubankar A1 - Punjabi, Naresh KW - Biostatistics KW - Cohort Studies KW - Confidence Intervals KW - Humans KW - Models, Statistical KW - Sleep Apnea Syndromes KW - Statistics, Nonparametric AB -

We propose nonparametric inference methods on the mean difference between two correlated functional processes. We compare methods that (1) incorporate different levels of smoothing of the mean and covariance; (2) preserve the sampling design; and (3) use parametric and nonparametric estimation of the mean functions. We apply our method to estimating the mean difference between average normalized δ power of sleep electroencephalograms for 51 subjects with severe sleep apnea and 51 matched controls in the first 4  h after sleep onset. We obtain data from the Sleep Heart Health Study, the largest community cohort study of sleep. Although methods are applied to a single case study, they can be applied to a large number of studies that have correlated functional data.

VL - 31 IS - 26 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22855258?dopt=Abstract ER - TY - JOUR T1 - Cardiovascular physiology in premotor Parkinson's disease: a neuroepidemiologic study. JF - Mov Disord Y1 - 2012 A1 - Jain, Samay A1 - Ton, Thanh G A1 - Perera, Subashan A1 - Zheng, Yan A1 - Stein, Phyllis K A1 - Thacker, Evan A1 - Strotmeyer, Elsa S A1 - Newman, Anne B A1 - Longstreth, Will T KW - Aged KW - Antiparkinson Agents KW - Cardiovascular Physiological Phenomena KW - Carotid Stenosis KW - Cohort Studies KW - Data Interpretation, Statistical KW - Dizziness KW - Electrocardiography KW - Female KW - Heart Rate KW - Hospitalization KW - Humans KW - Longitudinal Studies KW - Male KW - Movement Disorders KW - Neurologic Examination KW - Parkinson Disease KW - Risk KW - Ultrasonography AB -

Changes in cardiovascular physiology in Parkinson's disease (PD) are common and may occur prior to diagnostic parkinsonian motor signs. We investigated associations of electrocardiographic (ECG) abnormalities, orthostasis, heart rate variability, and carotid stenosis with the risk of PD diagnosis in the Cardiovascular Health Study, a community-based cohort of older adults. ECG abnormality, orthostasis (symptomatic or asymptomatic), heart rate variability (24-hour Holter monitoring), and any carotid stenosis (≥1%) by ultrasound were modeled as primary predictors of incident PD diagnosis using multivariable logistic regression. Incident PD cases were identified by at least 1 of the following: self-report, antiparkinsonian medication use, and ICD-9. If unadjusted models were significant, they were adjusted or stratified by age, sex, and smoking status, and those in which predictors were still significant (P ≤ .05) were also adjusted for race, diabetes, total cholesterol, low-density lipoprotein, blood pressure, body mass index, physical activity, education level, stroke, and C-reactive protein. Of 5888 participants, 154 incident PD cases were identified over 14 years of follow-up. After adjusting models with all covariates, those with any ECG abnormality (odds ratio [OR], 1.45; 95% CI, 1.02-2.07; P = .04) or any carotid stenosis (OR, 2.40; 95% CI, 1.40-4.09; P = .001) at baseline had a higher risk of incident PD diagnosis. Orthostasis and heart rate variability were not significant predictors. This exploratory study suggests that carotid stenosis and ECG abnormalities occur prior to motor signs in PD, thus serving as potential premotor features or risk factors for PD diagnosis. Replication is needed in a population with more thorough ascertainment of PD onset.

VL - 27 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22700356?dopt=Abstract ER - TY - JOUR T1 - Common genetic variants differentially influence the transition from clinically defined states of fasting glucose metabolism. JF - Diabetologia Y1 - 2012 A1 - Walford, G A A1 - Green, T A1 - Neale, B A1 - Isakova, T A1 - Rotter, J I A1 - Grant, S F A A1 - Fox, C S A1 - Pankow, J S A1 - Wilson, J G A1 - Meigs, J B A1 - Siscovick, D S A1 - Bowden, D W A1 - Daly, M J A1 - Florez, J C KW - Adult KW - Aged KW - Blood Glucose KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Disease Progression KW - Fasting KW - Female KW - Genetic Variation KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Models, Genetic KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Regression Analysis KW - Risk AB -

AIMS/HYPOTHESIS: Common genetic variants have been associated with type 2 diabetes. We hypothesised that a subset of these variants may have different effects on the transition from normal fasting glucose (NFG) to impaired fasting glucose (IFG) than on that from IFG to diabetes.

METHODS: We identified 16 type 2 diabetes risk variants from the Illumina Broad Candidate-gene Association Resource (CARe) array genotyped in 26,576 CARe participants. Participants were categorised at baseline as NFG, IFG or type 2 diabetic (n = 16,465, 8,017 or 2,291, respectively). Using Cox proportional hazards and likelihood ratio tests (LRTs), we compared rates of progression by genotype for 4,909 (NFG to IFG) and 1,518 (IFG to type 2 diabetes) individuals, respectively. We then performed multinomial regression analyses at baseline, comparing the risk of assignment to the NFG, IFG or diabetes groups by genotype.

RESULTS: The rate of progression from NFG to IFG was significantly greater in participants carrying the risk allele at MTNR1B (p = 1 × 10(-4)), nominally greater at GCK and SLC30A8 (p < 0.05) and nominally smaller at IGF2BP2 (p = 0.01) than the rate of progression from IFG to diabetes by the LRT. Results of the baseline, multinomial regression model were consistent with these findings.

CONCLUSIONS/INTERPRETATION: Common genetic risk variants at GCK, SLC30A8, IGF2BP2 and MTNR1B influence to different extents the development of IFG and the transition from IFG to type 2 diabetes. Our findings may have implications for understanding the genetic contribution of these variants to the development of IFG and type 2 diabetes.

VL - 55 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22038522?dopt=Abstract ER - TY - JOUR T1 - Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate. JF - JAMA Y1 - 2012 A1 - Matsushita, Kunihiro A1 - Mahmoodi, Bakhtawar K A1 - Woodward, Mark A1 - Emberson, Jonathan R A1 - Jafar, Tazeen H A1 - Jee, Sun Ha A1 - Polkinghorne, Kevan R A1 - Shankar, Anoop A1 - Smith, David H A1 - Tonelli, Marcello A1 - Warnock, David G A1 - Wen, Chi-Pang A1 - Coresh, Josef A1 - Gansevoort, Ron T A1 - Hemmelgarn, Brenda R A1 - Levey, Andrew S KW - African Continental Ancestry Group KW - Aged KW - Algorithms KW - Asian Continental Ancestry Group KW - Cardiovascular Diseases KW - Cohort Studies KW - Decision Support Techniques KW - European Continental Ancestry Group KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Models, Theoretical KW - Risk Assessment KW - Sex Factors AB -

CONTEXT: The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation more accurately estimates glomerular filtration rate (GFR) than the Modification of Diet in Renal Disease (MDRD) Study equation using the same variables, especially at higher GFR, but definitive evidence of its risk implications in diverse settings is lacking.

OBJECTIVE: To evaluate risk implications of estimated GFR using the CKD-EPI equation compared with the MDRD Study equation in populations with a broad range of demographic and clinical characteristics.

DESIGN, SETTING, AND PARTICIPANTS: A meta-analysis of data from 1.1 million adults (aged ≥ 18 years) from 25 general population cohorts, 7 high-risk cohorts (of vascular disease), and 13 CKD cohorts. Data transfer and analyses were conducted between March 2011 and March 2012.

MAIN OUTCOME MEASURES: All-cause mortality (84,482 deaths from 40 cohorts), cardiovascular mortality (22,176 events from 28 cohorts), and end-stage renal disease (ESRD) (7644 events from 21 cohorts) during 9.4 million person-years of follow-up; the median of mean follow-up time across cohorts was 7.4 years (interquartile range, 4.2-10.5 years).

RESULTS: Estimated GFR was classified into 6 categories (≥90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m(2)) by both equations. Compared with the MDRD Study equation, 24.4% and 0.6% of participants from general population cohorts were reclassified to a higher and lower estimated GFR category, respectively, by the CKD-EPI equation, and the prevalence of CKD stages 3 to 5 (estimated GFR <60 mL/min/1.73 m(2)) was reduced from 8.7% to 6.3%. In estimated GFR of 45 to 59 mL/min/1.73 m(2) by the MDRD Study equation, 34.7% of participants were reclassified to estimated GFR of 60 to 89 mL/min/1.73 m(2) by the CKD-EPI equation and had lower incidence rates (per 1000 person-years) for the outcomes of interest (9.9 vs 34.5 for all-cause mortality, 2.7 vs 13.0 for cardiovascular mortality, and 0.5 vs 0.8 for ESRD) compared with those not reclassified. The corresponding adjusted hazard ratios were 0.80 (95% CI, 0.74-0.86) for all-cause mortality, 0.73 (95% CI, 0.65-0.82) for cardiovascular mortality, and 0.49 (95% CI, 0.27-0.88) for ESRD. Similar findings were observed in other estimated GFR categories by the MDRD Study equation. Net reclassification improvement based on estimated GFR categories was significantly positive for all outcomes (range, 0.06-0.13; all P < .001). Net reclassification improvement was similarly positive in most subgroups defined by age (<65 years and ≥65 years), sex, race/ethnicity (white, Asian, and black), and presence or absence of diabetes and hypertension. The results in the high-risk and CKD cohorts were largely consistent with the general population cohorts.

CONCLUSION: The CKD-EPI equation classified fewer individuals as having CKD and more accurately categorized the risk for mortality and ESRD than did the MDRD Study equation across a broad range of populations.

VL - 307 IS - 18 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22570462?dopt=Abstract ER - TY - JOUR T1 - Effect of Alzheimer's disease risk genes on trajectories of cognitive function in the Cardiovascular Health Study. JF - Am J Psychiatry Y1 - 2012 A1 - Sweet, Robert A A1 - Seltman, Howard A1 - Emanuel, James E A1 - Lopez, Oscar L A1 - Becker, James T A1 - Bis, Joshua C A1 - Weamer, Elise A A1 - Demichele-Sweet, Mary Ann A A1 - Kuller, Lewis H KW - Age of Onset KW - Aged KW - Alleles KW - Alzheimer Disease KW - Apolipoprotein E4 KW - Bayes Theorem KW - Clusterin KW - Cohort Studies KW - Dementia KW - Disease Progression KW - Female KW - Genetic Predisposition to Disease KW - Humans KW - Male KW - Models, Psychological KW - Monomeric Clathrin Assembly Proteins KW - Polymorphism, Single Nucleotide KW - Receptors, Complement 3b KW - Risk Factors AB -

OBJECTIVE: The trajectory of cognitive decline in patients with late-onset Alzheimer's disease varies widely. Genetic variations in CLU, PICALM, and CR1 are associated with Alzheimer's disease, but it is unknown whether they exert their effects by altering cognitive trajectory in elderly individuals at risk for the disease.

METHOD: The authors developed a Bayesian model to fit cognitive trajectories in a cohort of elderly subjects and test for genetic effects. They first validated the model's ability to detect the previously established effects of APOE ε4 alleles on age at cognitive decline and of psychosis on the rate of cognitive decline in 802 subjects from the Cardiovascular Health Cognition Study who did not have dementia at study entry and developed incident dementia during follow-up. The authors then evaluated the effects of CLU, PICALM, and CR1 on age and rate of decline in 1,831 subjects who did not have dementia at study entry and then did or did not develop incident dementia by study's end.

RESULTS: The model generated robust fits to the observed cognitive trajectory data, and validation analysis supported the model's utility. CLU and CR1 were associated with more rapid cognitive decline. PICALM was associated with an earlier age at midpoint of cognitive decline. Associations remained after accounting for the effects of APOE and demographic factors.

CONCLUSIONS: Evaluation of cognitive trajectories provides a powerful approach to dissecting genetic effects on the processes leading to cognitive deterioration and Alzheimer's disease.

VL - 169 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22952074?dopt=Abstract ER - TY - JOUR T1 - Evaluation of the metabochip genotyping array in African Americans and implications for fine mapping of GWAS-identified loci: the PAGE study. JF - PLoS One Y1 - 2012 A1 - Buyske, Steven A1 - Wu, Ying A1 - Carty, Cara L A1 - Cheng, Iona A1 - Assimes, Themistocles L A1 - Dumitrescu, Logan A1 - Hindorff, Lucia A A1 - Mitchell, Sabrina A1 - Ambite, Jose Luis A1 - Boerwinkle, Eric A1 - Bůzková, Petra A1 - Carlson, Chris S A1 - Cochran, Barbara A1 - Duggan, David A1 - Eaton, Charles B A1 - Fesinmeyer, Megan D A1 - Franceschini, Nora A1 - Haessler, Jeffrey A1 - Jenny, Nancy A1 - Kang, Hyun Min A1 - Kooperberg, Charles A1 - Lin, Yi A1 - Le Marchand, Loïc A1 - Matise, Tara C A1 - Robinson, Jennifer G A1 - Rodriguez, Carlos A1 - Schumacher, Fredrick R A1 - Voight, Benjamin F A1 - Young, Alicia A1 - Manolio, Teri A A1 - Mohlke, Karen L A1 - Haiman, Christopher A A1 - Peters, Ulrike A1 - Crawford, Dana C A1 - North, Kari E KW - African Americans KW - Cardiovascular Diseases KW - Cholesterol Ester Transfer Proteins KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Chromosomes, Human KW - Cohort Studies KW - Gene Frequency KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Metabolic Diseases KW - Polymorphism, Single Nucleotide KW - Quantitative Trait Loci AB -

The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.

VL - 7 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22539988?dopt=Abstract ER - TY - JOUR T1 - Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes. JF - JAMA Y1 - 2012 A1 - Levin, Gregory P A1 - Robinson-Cohen, Cassianne A1 - de Boer, Ian H A1 - Houston, Denise K A1 - Lohman, Kurt A1 - Liu, Yongmei A1 - Kritchevsky, Stephen B A1 - Cauley, Jane A A1 - Tanaka, Toshiko A1 - Ferrucci, Luigi A1 - Bandinelli, Stefania A1 - Patel, Kushang V A1 - Hagström, Emil A1 - Michaëlsson, Karl A1 - Melhus, Håkan A1 - Wang, Thomas A1 - Wolf, Myles A1 - Psaty, Bruce M A1 - Siscovick, David A1 - Kestenbaum, Bryan KW - 25-Hydroxyvitamin D3 1-alpha-Hydroxylase KW - Aged KW - Chronic Disease KW - Cohort Studies KW - Female KW - Genetic Variation KW - Genotype KW - Hip Fractures KW - Humans KW - Low Density Lipoprotein Receptor-Related Protein-2 KW - Male KW - Meta-Analysis as Topic KW - Myocardial Infarction KW - Neoplasms KW - Polymorphism, Single Nucleotide KW - Receptors, Calcitriol KW - Receptors, Cell Surface KW - Risk KW - Steroid Hydroxylases KW - Vitamin D KW - Vitamin D3 24-Hydroxylase AB -

CONTEXT: Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large, prospective community-based studies. Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity, and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D.

OBJECTIVE: To investigate whether common variation within genes encoding the vitamin D-binding protein, megalin, cubilin, CYP27B1, CYP24A1, and the vitamin D receptor (VDR) modify associations of low 25-hydroxyvitamin D with major clinical outcomes.

DESIGN, SETTING, AND PARTICIPANTS: Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants (who were recruited from 4 US regions) from the community-based Cardiovascular Health Study. Participants had serum 25-hydroxyvitamin D measurements in 1992-1993 and were followed up for a median of 11 years (through 2006). Replication meta-analyses were conducted across the independent, community-based US Health, Aging, and Body Composition (n = 922; follow-up: 1998-1999 through 2005), Italian Invecchiare in Chianti (n = 835; follow-up: 1998-2000 through 2006), and Swedish Uppsala Longitudinal Study of Adult Men (n = 970; follow-up: 1991-1995 through 2008) cohort studies.

MAIN OUTCOME MEASURE: Composite outcome of incident hip facture, myocardial infarction, cancer, and mortality over long-term follow-up.

RESULTS: Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta-analysis. Among Cardiovascular Health Study participants, low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 (95% CI, 1.12-1.74) for those who had 1 minor allele at rs7968585 and 1.82 (95% CI, 1.31-2.54) for those with 2 minor alleles at rs7968585. In contrast, there was no evidence of an association (estimated hazard ratio, 0.93 [95% CI, 0.70-1.24]) among participants who had 0 minor alleles at this single-nucleotide polymorphism.

CONCLUSION: Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor.

VL - 308 IS - 18 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23150009?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study for circulating levels of PAI-1 provides novel insights into its regulation. JF - Blood Y1 - 2012 A1 - Huang, Jie A1 - Sabater-Lleal, Maria A1 - Asselbergs, Folkert W A1 - Tregouet, David A1 - Shin, So-Youn A1 - Ding, Jingzhong A1 - Baumert, Jens A1 - Oudot-Mellakh, Tiphaine A1 - Folkersen, Lasse A1 - Johnson, Andrew D A1 - Smith, Nicholas L A1 - Williams, Scott M A1 - Ikram, Mohammad A A1 - Kleber, Marcus E A1 - Becker, Diane M A1 - Truong, Vinh A1 - Mychaleckyj, Josyf C A1 - Tang, Weihong A1 - Yang, Qiong A1 - Sennblad, Bengt A1 - Moore, Jason H A1 - Williams, Frances M K A1 - Dehghan, Abbas A1 - Silbernagel, Günther A1 - Schrijvers, Elisabeth M C A1 - Smith, Shelly A1 - Karakas, Mahir A1 - Tofler, Geoffrey H A1 - Silveira, Angela A1 - Navis, Gerjan J A1 - Lohman, Kurt A1 - Chen, Ming-Huei A1 - Peters, Annette A1 - Goel, Anuj A1 - Hopewell, Jemma C A1 - Chambers, John C A1 - Saleheen, Danish A1 - Lundmark, Per A1 - Psaty, Bruce M A1 - Strawbridge, Rona J A1 - Boehm, Bernhard O A1 - Carter, Angela M A1 - Meisinger, Christa A1 - Peden, John F A1 - Bis, Joshua C A1 - McKnight, Barbara A1 - Ohrvik, John A1 - Taylor, Kent A1 - Franzosi, Maria Grazia A1 - Seedorf, Udo A1 - Collins, Rory A1 - Franco-Cereceda, Anders A1 - Syvänen, Ann-Christine A1 - Goodall, Alison H A1 - Yanek, Lisa R A1 - Cushman, Mary A1 - Müller-Nurasyid, Martina A1 - Folsom, Aaron R A1 - Basu, Saonli A1 - Matijevic, Nena A1 - van Gilst, Wiek H A1 - Kooner, Jaspal S A1 - Hofman, Albert A1 - Danesh, John A1 - Clarke, Robert A1 - Meigs, James B A1 - Kathiresan, Sekar A1 - Reilly, Muredach P A1 - Klopp, Norman A1 - Harris, Tamara B A1 - Winkelmann, Bernhard R A1 - Grant, Peter J A1 - Hillege, Hans L A1 - Watkins, Hugh A1 - Spector, Timothy D A1 - Becker, Lewis C A1 - Tracy, Russell P A1 - März, Winfried A1 - Uitterlinden, André G A1 - Eriksson, Per A1 - Cambien, Francois A1 - Morange, Pierre-Emmanuel A1 - Koenig, Wolfgang A1 - Soranzo, Nicole A1 - van der Harst, Pim A1 - Liu, Yongmei A1 - O'Donnell, Christopher J A1 - Hamsten, Anders KW - Adaptor Proteins, Signal Transducing KW - ARNTL Transcription Factors KW - ATPases Associated with Diverse Cellular Activities KW - Cell Line KW - Cell Line, Tumor KW - Cohort Studies KW - Coronary Artery Disease KW - Diabetes Mellitus, Type 2 KW - Gene Expression Profiling KW - Gene Expression Regulation KW - Gene Frequency KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - LIM Domain Proteins KW - Meta-Analysis as Topic KW - Monocytes KW - Mucin-3 KW - Plasminogen Activator Inhibitor 1 KW - Polymorphism, Single Nucleotide KW - PPAR gamma KW - Proteasome Endopeptidase Complex KW - RNA Interference KW - Transcription Factors AB -

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery meta-analysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10(-8)) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P = 3.4 × 10(-10)); chromosome 11p15.2 within ARNTL (rs6486122, discovery P = 3.0 × 10(-8)); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10(-8)). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1.

VL - 120 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22990020?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries. JF - Hum Mol Genet Y1 - 2012 A1 - Li, Xiaohui A1 - Bykhovskaya, Yelena A1 - Haritunians, Talin A1 - Siscovick, David A1 - Aldave, Anthony A1 - Szczotka-Flynn, Loretta A1 - Iyengar, Sudha K A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Rabinowitz, Yaron S KW - Case-Control Studies KW - Chromosomes, Human, Pair 2 KW - Cohort Studies KW - Corneal Transplantation KW - Developed Countries KW - Genome-Wide Association Study KW - Humans KW - Keratoconus KW - Polymorphism, Single Nucleotide AB -

Keratoconus is a condition in which the cornea progressively thins over time, and is a major cause for cornea transplantation. To identify keratoconus susceptibility regions, we performed a comprehensive genome-wide association study (GWAS) using a discovery and replication design. A discovery panel of 222 keratoconus Caucasian patients and 3324 Caucasian controls was genotyped using Illumina 370K beadchips. Further associated and fine-mapping single nucleotide polymorphisms (SNPs) (n= 4905) were genotyped in an independent replication case-control panel of 304 cases and 518 controls and a family panel of 307 subjects in 70 families. Logistic regression models implemented in PLINK were performed to test associations in case-control samples with and without principal component (PC) adjustments. Generalized estimation equation models accounting for familial correlations implemented in GWAF were used for association testing in families. No genome-wide associations were identified in the discovery GWAS panel. From the initial testing without adjustments for PCs, the top three SNPs located at 3p26 (rs6442925), 2q21.3 (rs4954218) and 19q13.3 (rs1428642) were identified with unadjusted P-values of 6.5 × 10(-8), 2.4 × 10(-7) and 3.1 × 10(-7), respectively. After adjustments for PCs, rs1428642 became the most significant through the genome with a P-value of 1.4 × 10(-6), while rs6442925 and rs4954218 were less significant (P= 1.9 × 10(-5) and 2.6 × 10(-4)). SNP rs4954218 was confirmed in two independent replication panels with P-values of 0.004 and 0.009, respectively. Meta-analysis revealed a highest association at rs4954218 with adjusted P= 1.6 × 10(-7) (unadjusted P= 1.2 × 10(-9)). These findings suggest SNP rs4954218, located near the RAB3GAP1 gene, previously reported to be associated with corneal malformation, is a potential susceptibility locus for keratoconus.

VL - 21 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21979947?dopt=Abstract ER - TY - JOUR T1 - Impact of blood pressure and blood pressure change during middle age on the remaining lifetime risk for cardiovascular disease: the cardiovascular lifetime risk pooling project. JF - Circulation Y1 - 2012 A1 - Allen, Norrina A1 - Berry, Jarett D A1 - Ning, Hongyan A1 - Van Horn, Linda A1 - Dyer, Alan A1 - Lloyd-Jones, Donald M KW - Aged KW - Aged, 80 and over KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Follow-Up Studies KW - Humans KW - Hypertension KW - Life Tables KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Risk Factors AB -

BACKGROUND: Prior estimates of lifetime risk (LTR) for cardiovascular disease (CVD) examined the impact of blood pressure (BP) at the index age and did not account for changes in BP over time. We examined how changes in BP during middle age affect LTR for CVD, coronary heart disease, and stroke.

METHODS AND RESULTS: Data from 7 diverse US cohort studies were pooled. Remaining LTRs for CVD, coronary heart disease, and stroke were estimated for white and black men and women with death free of CVD as a competing event. LTRs for CVD by BP strata and by changes in BP over an average of 14 years were estimated. Starting at 55 years of age, we followed up 61 585 men and women for 700 000 person-years. LTR for CVD was 52.5% (95% confidence interval, 51.3-53.7) for men and 39.9% (95% confidence interval, 38.7-41.0) for women. LTR for CVD was higher for blacks and increased with increasing BP at index age. Individuals who maintained or decreased their BP to normal levels had the lowest remaining LTR for CVD, 22% to 41%, compared with individuals who had or developed hypertension by 55 years of age, 42% to 69%, suggesting a dose-response effect for the length of time at high BP levels.

CONCLUSIONS: Individuals who experience increases or decreases in BP in middle age have associated higher and lower remaining LTR for CVD. Prevention efforts should continue to emphasize the importance of lowering BP and avoiding or delaying the incidence of hypertension to reduce the LTR for CVD.

VL - 125 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22184621?dopt=Abstract ER - TY - JOUR T1 - Insulin resistance, cystatin C, and mortality among older adults. JF - Diabetes Care Y1 - 2012 A1 - de Boer, Ian H A1 - Katz, Ronit A1 - Chonchol, Michel B A1 - Fried, Linda F A1 - Ix, Joachim H A1 - Kestenbaum, Bryan A1 - Mukamal, Kenneth J A1 - Peralta, Carmen A A1 - Siscovick, David S KW - Aged KW - Aged, 80 and over KW - Blood Glucose KW - Blood Pressure KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Cystatin C KW - Fasting KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Insulin Resistance KW - Life Style KW - Male KW - Mortality KW - Predictive Value of Tests KW - Proportional Hazards Models KW - Renal Insufficiency KW - Risk Factors KW - Triglycerides KW - Waist Circumference AB -

OBJECTIVE: Insulin resistance is a risk factor for cardiovascular and noncardiovascular diseases. Impaired kidney function is linked with insulin resistance and may affect relationships of insulin resistance with health outcomes.

RESEARCH DESIGN AND METHODS: We performed a cohort study of 3,138 Cardiovascular Health Study participants (age ≥ 65 years) without diabetes. Insulin sensitivity index (ISI) was calculated from fasting and 2-h postload insulin and glucose concentrations. Associations of ISI and fasting insulin concentration with all-cause mortality were tested using Cox proportional hazards models, adjusting for demographic variables, prevalent cardiovascular disease, lifestyle variables, waist circumference, and LDL cholesterol. Subsequent models were additionally adjusted for or stratified by glomerular filtration rate estimated using serum cystatin C (eGFR).

RESULTS: A total of 1,810 participants died during the 14.7-year median follow-up. Compared with the highest quartile of ISI, the lowest quartile (most insulin resistant) was associated with 21% (95% CI 6-41) and 11% (-3 to 29) higher risks of death without and with adjustment for eGFR, respectively. Compared with the lowest quartile of fasting insulin concentration, the highest quartile was associated with 22% (4-43) and 4% (-12 to 22) higher risks of death without and with adjustment for eGFR, respectively. Similar attenuation by eGFR was observed when blood pressure, triglycerides, HDL cholesterol, and C-reactive protein were included in models.

CONCLUSIONS: Insulin resistance measured as ISI or fasting insulin concentration is associated with increased risk of death among older adults, adjusting for conventional confounding characteristics. Impaired kidney function may mediate or confound this relationship.

VL - 35 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22432118?dopt=Abstract ER - TY - JOUR T1 - Lifetime risk and years lived free of total cardiovascular disease. JF - JAMA Y1 - 2012 A1 - Wilkins, John T A1 - Ning, Hongyan A1 - Berry, Jarett A1 - Zhao, Lihui A1 - Dyer, Alan R A1 - Lloyd-Jones, Donald M KW - Adult KW - Aged KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Diabetes Mellitus KW - Female KW - Forecasting KW - Humans KW - Kaplan-Meier Estimate KW - Male KW - Middle Aged KW - Morbidity KW - Risk KW - Risk Factors KW - Smoking AB -

CONTEXT: Estimates of lifetime risk for total cardiovascular disease (CVD) may provide projections of the future population burden of CVD and may assist in clinician-patient risk communication. To date, no lifetime risk estimates of total CVD have been reported.

OBJECTIVES: To calculate lifetime risk estimates of total CVD by index age (45, 55, 65, 75 years) and risk factor strata and to estimate years lived free of CVD across risk factor strata.

DESIGN, SETTING, AND PARTICIPANTS: Pooled survival analysis of as many as 905,115 person-years of data from 1964 through 2008 from 5 National Heart, Lung, and Blood Institute-funded community-based cohorts: Framingham Heart Study, Framingham Offspring Study, Atherosclerosis Risk in Communities Study, Chicago Heart Association Detection Project in Industry Study, and Cardiovascular Health Study. All participants were free of CVD at baseline with risk factor data (blood pressure [BP], total cholesterol [TC], diabetes, and smoking status) and total CVD outcome data.

MAIN OUTCOME MEASURES: Any total CVD event (including fatal and nonfatal coronary heart disease, all forms of stroke, congestive heart failure, and other CVD deaths).

RESULTS: At an index age of 45 years, overall lifetime risk for total CVD was 60.3% (95% CI, 59.3%-61.2%) for men and 55.6% (95% CI, 54.5%-56.7%) for women. Men had higher lifetime risk estimates than women across all index ages. At index ages 55 and 65 years, men and women with at least 1 elevated risk factor (BP, 140-149/90-99 mm Hg; or TC, 200-239 mg/dL; but no diabetes or smoking), 1 major risk factor, or at least 2 major risk factors (BP, ≥160/100 mm Hg or receiving treatment; TC, ≥240 mg/dL or receiving treatment; diabetes mellitus; or current smoking) had lifetime risk estimates to age 95 years that exceeded 50%. Despite an optimal risk factor profile (BP, <120/80 mm Hg; TC, <180 mg/dL; and no smoking or diabetes), men and women at the index age of 55 years had lifetime risks (through 85 years of age) for total CVD of greater than 40% and 30%, respectively. Compared with participants with at least 2 major risk factors, those with an optimal risk factor profile lived up to 14 years longer free of total CVD.

CONCLUSIONS: Lifetime risk estimates for total CVD were high (>30%) for all individuals, even those with optimal risk factors in middle age. However, maintenance of optimal risk factor levels in middle age was associated with substantially longer morbidity-free survival.

VL - 308 IS - 17 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23117780?dopt=Abstract ER - TY - JOUR T1 - Lipid-related markers and cardiovascular disease prediction. JF - JAMA Y1 - 2012 A1 - Di Angelantonio, Emanuele A1 - Gao, Pei A1 - Pennells, Lisa A1 - Kaptoge, Stephen A1 - Caslake, Muriel A1 - Thompson, Alexander A1 - Butterworth, Adam S A1 - Sarwar, Nadeem A1 - Wormser, David A1 - Saleheen, Danish A1 - Ballantyne, Christie M A1 - Psaty, Bruce M A1 - Sundström, Johan A1 - Ridker, Paul M A1 - Nagel, Dorothea A1 - Gillum, Richard F A1 - Ford, Ian A1 - Ducimetiere, Pierre A1 - Kiechl, Stefan A1 - Koenig, Wolfgang A1 - Dullaart, Robin P F A1 - Assmann, Gerd A1 - D'Agostino, Ralph B A1 - Dagenais, Gilles R A1 - Cooper, Jackie A A1 - Kromhout, Daan A1 - Onat, Altan A1 - Tipping, Robert W A1 - Gómez-de-la-Cámara, Agustín A1 - Rosengren, Annika A1 - Sutherland, Susan E A1 - Gallacher, John A1 - Fowkes, F Gerry R A1 - Casiglia, Edoardo A1 - Hofman, Albert A1 - Salomaa, Veikko A1 - Barrett-Connor, Elizabeth A1 - Clarke, Robert A1 - Brunner, Eric A1 - Jukema, J Wouter A1 - Simons, Leon A A1 - Sandhu, Manjinder A1 - Wareham, Nicholas J A1 - Khaw, Kay-Tee A1 - Kauhanen, Jussi A1 - Salonen, Jukka T A1 - Howard, William J A1 - Nordestgaard, Børge G A1 - Wood, Angela M A1 - Thompson, Simon G A1 - Boekholdt, S Matthijs A1 - Sattar, Naveed A1 - Packard, Chris A1 - Gudnason, Vilmundur A1 - Danesh, John KW - Aged KW - Biomarkers KW - Cardiovascular Diseases KW - Cholesterol, HDL KW - Cohort Studies KW - Female KW - Humans KW - Lipoproteins KW - Male KW - Middle Aged KW - Risk Assessment AB -

CONTEXT: The value of assessing various emerging lipid-related markers for prediction of first cardiovascular events is debated.

OBJECTIVE: To determine whether adding information on apolipoprotein B and apolipoprotein A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 to total cholesterol and high-density lipoprotein cholesterol (HDL-C) improves cardiovascular disease (CVD) risk prediction.

DESIGN, SETTING, AND PARTICIPANTS: Individual records were available for 165,544 participants without baseline CVD in 37 prospective cohorts (calendar years of recruitment: 1968-2007) with up to 15,126 incident fatal or nonfatal CVD outcomes (10,132 CHD and 4994 stroke outcomes) during a median follow-up of 10.4 years (interquartile range, 7.6-14 years).

MAIN OUTCOME MEASURES: Discrimination of CVD outcomes and reclassification of participants across predicted 10-year risk categories of low (<10%), intermediate (10%-<20%), and high (≥20%) risk.

RESULTS: The addition of information on various lipid-related markers to total cholesterol, HDL-C, and other conventional risk factors yielded improvement in the model's discrimination: C-index change, 0.0006 (95% CI, 0.0002-0.0009) for the combination of apolipoprotein B and A-I; 0.0016 (95% CI, 0.0009-0.0023) for lipoprotein(a); and 0.0018 (95% CI, 0.0010-0.0026) for lipoprotein-associated phospholipase A2 mass. Net reclassification improvements were less than 1% with the addition of each of these markers to risk scores containing conventional risk factors. We estimated that for 100,000 adults aged 40 years or older, 15,436 would be initially classified at intermediate risk using conventional risk factors alone. Additional testing with a combination of apolipoprotein B and A-I would reclassify 1.1%; lipoprotein(a), 4.1%; and lipoprotein-associated phospholipase A2 mass, 2.7% of people to a 20% or higher predicted CVD risk category and, therefore, in need of statin treatment under Adult Treatment Panel III guidelines.

CONCLUSION: In a study of individuals without known CVD, the addition of information on the combination of apolipoprotein B and A-I, lipoprotein(a), or lipoprotein-associated phospholipase A2 mass to risk scores containing total cholesterol and HDL-C led to slight improvement in CVD prediction.

VL - 307 IS - 23 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22797450?dopt=Abstract ER - TY - JOUR T1 - Long-term assessment of inflammation and healthy aging in late life: the Cardiovascular Health Study All Stars. JF - J Gerontol A Biol Sci Med Sci Y1 - 2012 A1 - Jenny, Nancy S A1 - French, Benjamin A1 - Arnold, Alice M A1 - Strotmeyer, Elsa S A1 - Cushman, Mary A1 - Chaves, Paulo H M A1 - Ding, Jingzhong A1 - Fried, Linda P A1 - Kritchevsky, Stephen B A1 - Rifkin, Dena E A1 - Sarnak, Mark J A1 - Newman, Anne B KW - Aged KW - Aged, 80 and over KW - Aging KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cognition KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Humans KW - Inflammation KW - Inflammation Mediators KW - Interleukin-6 KW - Longitudinal Studies KW - Male KW - Risk Factors KW - Vermont AB -

BACKGROUND: Associations of inflammation with age-related pathologies are documented; however, it is not understood how changes in inflammation over time impact healthy aging.

METHODS: We examined associations of long-term change in C-reactive protein (CRP) and interleukin-6 (IL-6) with concurrent onset of physical and cognitive impairment, subsequent cardiovascular disease (CVD), and mortality in 1,051 participants in the Cardiovascular Health Study All Stars Study. Biomarkers were measured in 1996-1997 and 2005-2006.

RESULTS: In 2005-2006, median age was 84.9 years, 63% were women and 17% non-white; 21% had at least a doubling in CRP over time and 23% had at least a doubling in IL-6. Adjusting for demographics, CVD risk factors, and 1996-1997 CRP level, each doubling in CRP change over 9 years was associated with higher risk of physical or cognitive impairment (odds ratio 1.29; 95% confidence interval 1.15, 1.45). Results were similar for IL-6 (1.45; 1.20, 1.76). A doubling in IL-6 change over time, but not CRP, was associated with incident CVD events; hazard ratio (95% confidence interval) 1.34 (1.03, 1.75). Doubling in change in each biomarker was individually associated with mortality (CRP: 1.12 [1.03, 1.22]; IL-6 1.39 [1.16, 1.65]). In models containing both change and 2005-2006 level, only level was associated with CVD events and mortality.

CONCLUSIONS: Although increases in inflammation markers over 9 years were associated with higher concurrent risk of functional impairment and subsequent CVD events and mortality, final levels of each biomarker appeared to be more important in determining risk of subsequent events than change over time.

VL - 67 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22367431?dopt=Abstract ER - TY - JOUR T1 - Markers of cholesterol metabolism in the brain show stronger associations with cerebrovascular disease than Alzheimer's disease. JF - J Alzheimers Dis Y1 - 2012 A1 - Hughes, Timothy M A1 - Kuller, Lewis H A1 - Lopez, Oscar L A1 - Becker, James T A1 - Evans, Rhobert W A1 - Sutton-Tyrrell, Kim A1 - Rosano, Caterina KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Apolipoprotein E4 KW - Brain KW - Cerebrovascular Disorders KW - Cognition Disorders KW - Cohort Studies KW - Female KW - Humans KW - Hydroxycholesterols KW - Magnetic Resonance Imaging KW - Male KW - Retrospective Studies AB -

Cholesterol metabolism is believed to play a role in the development of Alzheimer's disease (AD). Oxysterol metabolites of cholesterol, 24S-hydroxycholesterol (24-OHC, a brain-derived oxysterol) and 27-hydroxycholesterol (27-OHC, a peripherally derived oxysterol) cross the blood brain barrier and have been associated with AD. We investigated whether oxysterols were associated with markers of cerebrovascular disease prior to the onset of cognitive impairment. Oxysterols were quantified in 105 participants (average age: 80 ± 4 years) from the Pittsburgh Cardiovascular Health Study Cognition Study who remained cognitively normal at blood draw in 2002, had MRI in 1992 and 1998, and annual cognitive assessment for incident AD and mild cognitive impairment made by consensus conference between 1998 and 2010. Higher plasma levels of 24-OHC were associated with age, gender, the presence of high grade white matter hyperintensities, and brain infarcts on prior MRI. Participants with higher plasma 24-OHC and a greater ratio of 24-OHC/27-OHC were also more likely to develop incident cognitive impairment over 8 years of follow-up. Higher levels of 24-OHC suggest increased cholesterol metabolism occurring in the brains of participants with cerebrovascular disease prior to the onset of cognitive impairment. Measurement of oxysterols may provide information about cholesterol metabolism and brain disease over the cognitive impairment process.

VL - 30 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22377780?dopt=Abstract ER - TY - JOUR T1 - The natural history of subclinical hypothyroidism in the elderly: the cardiovascular health study. JF - J Clin Endocrinol Metab Y1 - 2012 A1 - Somwaru, Lily L A1 - Rariy, Chevon M A1 - Arnold, Alice M A1 - Cappola, Anne R KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Autoantibodies KW - Cardiovascular Diseases KW - Cohort Studies KW - Disease Progression KW - Female KW - Humans KW - Hypothyroidism KW - Iodide Peroxidase KW - Logistic Models KW - Longitudinal Studies KW - Male KW - Prevalence KW - Risk Factors KW - Seroepidemiologic Studies KW - Severity of Illness Index KW - Sex Distribution KW - Thyrotropin AB -

CONTEXT: Studies of long-term outcomes of subclinical hypothyroidism have assessed only baseline thyroid function, despite natural transitions to euthyroidism and overt hypothyroidism over time.

OBJECTIVE: We provide estimates of persistence, resolution, and progression of subclinical hypothyroidism over 4 yr, stratified by baseline TSH, anti-thyroid peroxidase antibody (TPOAb) status, age, and sex.

DESIGN, SETTING, AND PARTICIPANTS: Participants were 3996 U.S. individuals at least 65 yr old enrolled in the Cardiovascular Health Study. Subclinical hypothyroidism was detected at baseline in 459 individuals not taking thyroid medication.

MAIN OUTCOME MEASURE: Thyroid function was evaluated at 2 and 4 yr and initiation of thyroid medication annually. Results were stratified by baseline TSH, TPOAb status, age, and sex.

RESULTS: Persistence of subclinical hypothyroidism was 56% at 2 and 4 yr. At 2 yr, resolution was more common with a TSH of 4.5-6.9 mU/liter (46 vs. 10% with TSH 7-9.9 mU/liter and 7% with TSH ≥10 mU/liter; P < 0.001) and with TPOAb negativity (48 vs. 15% for positive; P < 0.001). Higher TSH and TPOAb positivity were independently associated with lower likelihood of reversion to euthyroidism (P < 0.05). TSH of 10 mU/liter or higher was independently associated with progression to overt hypothyroidism (P < 0.05). Transitions between euthyroidism and subclinical hypothyroidism were common between 2 and 4 yr. Age and sex did not affect transitions.

CONCLUSIONS: Subclinical hypothyroidism persists for 4 yr in just over half of older individuals, with high rates of reversion to euthyroidism in individuals with lower TSH concentrations and TPOAb negativity. Future studies should examine the impact of transitions in thyroid status on clinical outcomes.

VL - 97 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22438233?dopt=Abstract ER - TY - JOUR T1 - Novel circulating fatty acid patterns and risk of cardiovascular disease: the Cardiovascular Health Study. JF - Am J Clin Nutr Y1 - 2012 A1 - Imamura, Fumiaki A1 - Lemaitre, Rozenn N A1 - King, Irena B A1 - Song, Xiaoling A1 - Lichtenstein, Alice H A1 - Matthan, Nirupa R A1 - Herrington, David M A1 - Siscovick, David S A1 - Mozaffarian, Dariush KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Cardiovascular Diseases KW - Cohort Studies KW - Coronary Artery Disease KW - Disease Progression KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Myocardial Ischemia KW - Principal Component Analysis KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Stroke KW - Trans Fatty Acids KW - United States AB -

BACKGROUND: Complex interplays of diet and metabolism influence circulating fatty acids (FAs), possibly constituting FA patterns related to cardiovascular disease (CVD) risk.

OBJECTIVES: We aimed to derive FA patterns from circulating FAs, relate the patterns to CVD incidence, and extend the derived patterns to atherosclerosis progression in another independent cohort.

DESIGN: We used principal component analysis (PCA) to derive FA patterns from 38 plasma phospholipid FAs in 2972 older adults in the Cardiovascular Health Study (CHS). Identified patterns were evaluated for prospective associations with 14-y incidence of CVD [ischemic heart disease (IHD) or stroke]. In another independent cohort of postmenopausal women with IHD, we evaluated associations of the CHS-derived patterns with 3.2-y progression of angiographically defined coronary atherosclerosis.

RESULTS: Three distinct patterns were identified, characterized by higher proportions of trans FAs, de novo lipogenesis (DNL) FAs, and long-chain MUFAs (LCMUFAs). During 32,265 person-years, 780 incident CVD events occurred. The trans FA pattern was associated with higher CVD risk (multivariable-adjusted HR for the highest compared with the lowest quintiles = 1.58; 95% CI: 1.17, 2.12; P-trend = 0.006), primarily attributable to higher risk of stroke (HR: 2.46; 95% CI: 1.54, 3.92; P-trend = 0.005). The DNL and LCMUFA patterns were not associated with CVD incidence or with IHD or stroke (P-trend > 0.11 each). In the second cohort, the trans FA pattern, but not the other 2 patterns, was positively associated with progression of coronary atherosclerosis (P-trend < 0.05).

CONCLUSIONS: PCA appears to provide informative circulating FA patterns. A pattern driven mainly by trans FA levels related to greater CVD risk in older adults and coronary atherosclerosis progression in women with IHD.

VL - 96 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23097270?dopt=Abstract ER - TY - JOUR T1 - Novel loci associated with PR interval in a genome-wide association study of 10 African American cohorts. JF - Circ Cardiovasc Genet Y1 - 2012 A1 - Butler, Anne M A1 - Yin, Xiaoyan A1 - Evans, Daniel S A1 - Nalls, Michael A A1 - Smith, Erin N A1 - Tanaka, Toshiko A1 - Li, Guo A1 - Buxbaum, Sarah G A1 - Whitsel, Eric A A1 - Alonso, Alvaro A1 - Arking, Dan E A1 - Benjamin, Emelia J A1 - Berenson, Gerald S A1 - Bis, Josh C A1 - Chen, Wei A1 - Deo, Rajat A1 - Ellinor, Patrick T A1 - Heckbert, Susan R A1 - Heiss, Gerardo A1 - Hsueh, Wen-Chi A1 - Keating, Brendan J A1 - Kerr, Kathleen F A1 - Li, Yun A1 - Limacher, Marian C A1 - Liu, Yongmei A1 - Lubitz, Steven A A1 - Marciante, Kristin D A1 - Mehra, Reena A1 - Meng, Yan A A1 - Newman, Anne B A1 - Newton-Cheh, Christopher A1 - North, Kari E A1 - Palmer, Cameron D A1 - Psaty, Bruce M A1 - Quibrera, P Miguel A1 - Redline, Susan A1 - Reiner, Alex P A1 - Rotter, Jerome I A1 - Schnabel, Renate B A1 - Schork, Nicholas J A1 - Singleton, Andrew B A1 - Smith, J Gustav A1 - Soliman, Elsayed Z A1 - Srinivasan, Sathanur R A1 - Zhang, Zhu-Ming A1 - Zonderman, Alan B A1 - Ferrucci, Luigi A1 - Murray, Sarah S A1 - Evans, Michele K A1 - Sotoodehnia, Nona A1 - Magnani, Jared W A1 - Avery, Christy L KW - Adult KW - African Americans KW - Cohort Studies KW - Electrocardiography KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

BACKGROUND: The PR interval, as measured by the resting, standard 12-lead ECG, reflects the duration of atrial/atrioventricular nodal depolarization. Substantial evidence exists for a genetic contribution to PR, including genome-wide association studies that have identified common genetic variants at 9 loci influencing PR in populations of European and Asian descent. However, few studies have examined loci associated with PR in African Americans.

METHODS AND RESULTS: We present results from the largest genome-wide association study to date of PR in 13 415 adults of African descent from 10 cohorts. We tested for association between PR (ms) and ≈2.8 million genotyped and imputed single-nucleotide polymorphisms. Imputation was performed using HapMap 2 YRI and CEU panels. Study-specific results, adjusted for global ancestry and clinical correlates of PR, were meta-analyzed using the inverse variance method. Variation in genome-wide test statistic distributions was noted within studies (λ range: 0.9-1.1), although not after genomic control correction was applied to the overall meta-analysis (λ: 1.008). In addition to generalizing previously reported associations with MEIS1, SCN5A, ARHGAP24, CAV1, and TBX5 to African American populations at the genome-wide significance level (P<5.0 × 10(-8)), we also identified a novel locus: ITGA9, located in a region previously implicated in SCN5A expression. The 3p21 region harboring SCN5A also contained 2 additional independent secondary signals influencing PR (P<5.0 × 10(-8)).

CONCLUSIONS: This study demonstrates the ability to map novel loci in African Americans as well as the generalizability of loci associated with PR across populations of African, European, and Asian descent.

VL - 5 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23139255?dopt=Abstract ER - TY - JOUR T1 - Probabilistic sleep architecture models in patients with and without sleep apnea. JF - J Sleep Res Y1 - 2012 A1 - Bianchi, Matt T A1 - Eiseman, Nathaniel A A1 - Cash, Sydney S A1 - Mietus, Joseph A1 - Peng, Chung-Kang A1 - Thomas, Robert J KW - Cohort Studies KW - Computer Simulation KW - Humans KW - Models, Theoretical KW - Polysomnography KW - Probability KW - Sleep Apnea Syndromes KW - Sleep Stages KW - Sleep, REM KW - Time Factors AB -

Sleep fragmentation of any cause is disruptive to the rejuvenating value of sleep. However, methods to quantify sleep architecture remain limited. We have previously shown that human sleep-wake stage distributions exhibit multi-exponential dynamics, which are fragmented by obstructive sleep apnea (OSA), suggesting that Markov models may be a useful method to quantify architecture in health and disease. Sleep stage data were obtained from two subsets of the Sleep Heart Health Study database: control subjects with no medications, no OSA, no medical co-morbidities and no sleepiness (n = 374); and subjects with severe OSA (n = 338). Sleep architecture was simplified into three stages: wake after sleep onset (WASO); non-rapid eye movement (NREM) sleep; and rapid eye movement (REM) sleep. The connectivity and transition rates among eight 'generator' states of a first-order continuous-time Markov model were inferred from the observed ('phenotypic') distributions: three exponentials each of NREM sleep and WASO; and two exponentials of REM sleep. Ultradian REM cycling was accomplished by imposing time-variation to REM state entry rates. Fragmentation in subjects with severe OSA involved faster transition probabilities as well as additional state transition paths within the model. The Markov models exhibit two important features of human sleep architecture: multi-exponential stage dynamics (accounting for observed bout distributions); and probabilistic transitions (an inherent source of variability). In addition, the model quantifies the fragmentation associated with severe OSA. Markov sleep models may prove important for quantifying sleep disruption to provide objective metrics to correlate with endpoints ranging from sleepiness to cardiovascular morbidity.

VL - 21 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21955148?dopt=Abstract ER - TY - JOUR T1 - Racial differences in risks for first cardiovascular events and noncardiovascular death: the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. JF - Circulation Y1 - 2012 A1 - Feinstein, Matthew A1 - Ning, Hongyan A1 - Kang, Joseph A1 - Bertoni, Alain A1 - Carnethon, Mercedes A1 - Lloyd-Jones, Donald M KW - African Continental Ancestry Group KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Atherosclerosis KW - Cardiovascular Diseases KW - Cohort Studies KW - Continental Population Groups KW - Ethnic Groups KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Residence Characteristics KW - Risk Factors AB -

BACKGROUND: No studies have compared first cardiovascular disease (CVD) events and non-CVD death between races in a competing risks framework, which examines risks for numerous events simultaneously.

METHODS AND RESULTS: We used competing Cox models to estimate hazards for first CVD events and non-CVD death within and between races in 3 multicenter, National Heart, Lung, and Blood Institute-sponsored cohorts. Of 14 569 Atherosclerosis Risk in Communities (ARIC) study participants aged 45 to 64 years with mean follow-up of 10.5 years, 11.6% had CVD and 5.0% had non-CVD death as first events; among 4237 Cardiovascular Health Study (CHS) study participants aged 65 to 84 years and followed for 8.5 years, these figures were 43.2% and 15.7%, respectively. Middle-aged blacks were significantly more likely than whites to experience any CVD as a first event; this disparity disappeared by older adulthood and after adjustment for CVD risk factors. The pattern of results was similar for Multi-Ethnic Study of Atherosclerosis (MESA) participants. Traditional Cox and competing risks models yielded different results for coronary heart disease risk. Black men appeared somewhat more likely than white men to experience coronary heart disease with use of a standard Cox model (hazard ratio 1.06; 95% CI 0.90, 1.26), whereas they appeared less likely than white men to have a first coronary heart disease event with use of a competing risks model (hazard ratio, 0.77; 95% CI, 0.60, 1.00).

CONCLUSIONS: CVD affects blacks at an earlier age than whites; this may be attributable in part to elevated CVD risk factor levels among blacks. Racial disparities in first CVD incidence disappear by older adulthood. Competing risks analyses may yield somewhat different results than traditional Cox models and provide a complementary approach to examining risks for first CVD events.

VL - 126 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22693351?dopt=Abstract ER - TY - JOUR T1 - The risk of infection-related hospitalization with decreased kidney function. JF - Am J Kidney Dis Y1 - 2012 A1 - Dalrymple, Lorien S A1 - Katz, Ronit A1 - Kestenbaum, Bryan A1 - de Boer, Ian H A1 - Fried, Linda A1 - Sarnak, Mark J A1 - Shlipak, Michael G KW - Aged KW - Cohort Studies KW - Female KW - Glomerular Filtration Rate KW - Hospitalization KW - Humans KW - Infection KW - Kidney KW - Male KW - Risk Factors AB -

BACKGROUND: Moderate kidney disease may predispose to infection. We sought to determine whether decreased kidney function, estimated by serum cystatin C level, was associated with the risk of infection-related hospitalization in older individuals.

STUDY DESIGN: Cohort study.

SETTING & PARTICIPANTS: 5,142 Cardiovascular Health Study (CHS) participants with measured serum creatinine and cystatin C and without estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m(2) at enrollment.

PREDICTOR: The primary exposure of interest was eGFR using serum cystatin C level (eGFR(SCysC)).

OUTCOME: Infection-related hospitalizations during a median follow-up of 11.5 years.

RESULTS: In adjusted analyses, eGFR(SCysC) categories of 60-89, 45-59, and 15-44 mL/min/1.73 m(2) were associated with 16%, 37%, and 64% greater risk of all-cause infection-related hospitalization, respectively, compared with eGFR(SCysC) ≥90 mL/min/1.73 m(2). When cause-specific infection was examined, eGFR(SCysC) of 15-44 mL/min/1.73 m(2) was associated with an 80% greater risk of pulmonary and 160% greater risk of genitourinary infection compared with eGFR(SCysC) ≥90 mL/min/1.73 m(2).

LIMITATIONS: No measures of urinary protein, study limited to principal discharge diagnosis.

CONCLUSIONS: Lower kidney function, estimated using cystatin C level, was associated with a linear and graded risk of infection-related hospitalization. These findings highlight that even moderate degrees of decreased kidney function are associated with clinically significant higher risks of serious infection in older individuals.

VL - 59 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/21906862?dopt=Abstract ER - TY - JOUR T1 - Risk of intraparenchymal hemorrhage with magnetic resonance imaging-defined leukoaraiosis and brain infarcts. JF - Ann Neurol Y1 - 2012 A1 - Folsom, Aaron R A1 - Yatsuya, Hiroshi A1 - Mosley, Thomas H A1 - Psaty, Bruce M A1 - Longstreth, W T KW - Cerebral Infarction KW - Cohort Studies KW - Female KW - Humans KW - Incidence KW - Intracranial Hemorrhages KW - Leukoaraiosis KW - Magnetic Resonance Imaging KW - Male KW - Middle Aged KW - Risk Factors AB -

OBJECTIVE: To determine whether the burden of leukoaraiosis and the number of brain infarcts, defined by magnetic resonance imaging (MRI), are prospectively and independently associated with intraparenchymal hemorrhage (IPH) incidence in a pooled population-based study.

METHODS: Among 4,872 participants initially free of clinical stroke in the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study, we assessed white matter grade (range, 0-9), reflecting increasing leukoaraiosis, and brain infarcts using MRI. Over a median of 13 years of follow-up, 71 incident, spontaneous IPH events occurred.

RESULTS: After adjustment for other IPH risk factors, the hazard ratios (95% confidence intervals) across white matter grades 0 to 1, 2, 3, and 4 to 9 were 1.00, 1.68 (0.86-3.30), 3.52 (1.80-6.89), and 3.96 (1.90-8.27), respectively (p for trend <0.0001). These hazard ratios were weakened only modestly (p for trend = 0.0003) with adjustment for MRI-defined brain infarcts. The IPH hazard ratios for 0, 1, 2, or ≥3 MRI-defined brain infarcts were 1.00, 1.97 (1.10-3.54), 2.00 (0.83-4.78), and 3.12 (1.31-7.43) (p for trend = 0.002), but these were substantially attenuated when adjusted for white matter grade (p for trend = 0.049).

INTERPRETATION: Greater MRI-defined burden of leukoaraiosis is a risk factor for spontaneous IPH. Spontaneous IPH should be added to the growing list of potential poor outcomes in people with leukoaraiosis.

VL - 71 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22522444?dopt=Abstract ER - TY - JOUR T1 - Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. JF - Arch Intern Med Y1 - 2012 A1 - Collet, Tinh-Hai A1 - Gussekloo, Jacobijn A1 - Bauer, Douglas C A1 - den Elzen, Wendy P J A1 - Cappola, Anne R A1 - Balmer, Philippe A1 - Iervasi, Giorgio A1 - Asvold, Bjørn O A1 - Sgarbi, José A A1 - Völzke, Henry A1 - Gencer, Bariş A1 - Maciel, Rui M B A1 - Molinaro, Sabrina A1 - Bremner, Alexandra A1 - Luben, Robert N A1 - Maisonneuve, Patrick A1 - Cornuz, Jacques A1 - Newman, Anne B A1 - Khaw, Kay-Tee A1 - Westendorp, Rudi G J A1 - Franklyn, Jayne A A1 - Vittinghoff, Eric A1 - Walsh, John P A1 - Rodondi, Nicolas KW - Adolescent KW - Adult KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Cause of Death KW - Cohort Studies KW - Coronary Artery Disease KW - Female KW - Humans KW - Hyperthyroidism KW - Male KW - Middle Aged KW - Prognosis KW - Prospective Studies KW - Risk Assessment KW - Severity of Illness Index KW - Sex Distribution KW - Survival Analysis KW - Switzerland KW - Thyroid Function Tests KW - Thyrotropin KW - Young Adult AB -

BACKGROUND: Data from prospective cohort studies regarding the association between subclinical hyperthyroidism and cardiovascular outcomes are conflicting.We aimed to assess the risks of total and coronary heart disease (CHD) mortality, CHD events, and atrial fibrillation (AF) associated with endogenous subclinical hyperthyroidism among all available large prospective cohorts.

METHODS: Individual data on 52 674 participants were pooled from 10 cohorts. Coronary heart disease events were analyzed in 22 437 participants from 6 cohorts with available data, and incident AF was analyzed in 8711 participants from 5 cohorts. Euthyroidism was defined as thyrotropin level between 0.45 and 4.49 mIU/L and endogenous subclinical hyperthyroidism as thyrotropin level lower than 0.45 mIU/L with normal free thyroxine levels, after excluding those receiving thyroid-altering medications.

RESULTS: Of 52 674 participants, 2188 (4.2%) had subclinical hyperthyroidism. During follow-up, 8527 participants died (including 1896 from CHD), 3653 of 22 437 had CHD events, and 785 of 8711 developed AF. In age- and sex-adjusted analyses, subclinical hyperthyroidism was associated with increased total mortality (hazard ratio[HR], 1.24, 95% CI, 1.06-1.46), CHD mortality (HR,1.29; 95% CI, 1.02-1.62), CHD events (HR, 1.21; 95%CI, 0.99-1.46), and AF (HR, 1.68; 95% CI, 1.16-2.43).Risks did not differ significantly by age, sex, or preexisting cardiovascular disease and were similar after further adjustment for cardiovascular risk factors, with attributable risk of 14.5% for total mortality to 41.5% forAF in those with subclinical hyperthyroidism. Risks for CHD mortality and AF (but not other outcomes) were higher for thyrotropin level lower than 0.10 mIU/L compared with thyrotropin level between 0.10 and 0.44 mIU/L(for both, P value for trend, .03).

CONCLUSION: Endogenous subclinical hyperthyroidism is associated with increased risks of total, CHD mortality, and incident AF, with highest risks of CHD mortality and AF when thyrotropin level is lower than 0.10 mIU/L.

VL - 172 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22529182?dopt=Abstract ER - TY - JOUR T1 - Telomere-associated polymorphisms correlate with cardiovascular disease mortality in Caucasian women: the Cardiovascular Health Study. JF - Mech Ageing Dev Y1 - 2012 A1 - Burnett-Hartman, Andrea N A1 - Fitzpatrick, Annette L A1 - Kronmal, Richard A A1 - Psaty, Bruce M A1 - Jenny, Nancy S A1 - Bis, Josh C A1 - Tracy, Russ P A1 - Kimura, Masayuki A1 - Aviv, Abraham KW - Aged KW - Aged, 80 and over KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Humans KW - Leukocytes KW - Male KW - Polymorphism, Genetic KW - Polymorphism, Single Nucleotide KW - Risk KW - RNA KW - Sex Factors KW - Telomerase KW - Telomere AB -

Leukocyte telomere length (LTL) is linked to cardiovascular disease (CVD); however, it is unclear if LTL has an etiologic role in CVD. To gain insight into the LTL and CVD relationship, a cohort study of CVD mortality and single nucleotide polymorphisms (SNPs) in OBFC1 and TERC, genes related to LTL, was conducted among 3271 Caucasian participants ages ≥65 years enrolled 1989-1990 in the Cardiovascular Health Study. Leukocyte DNA was genotyped for SNPs in OBFC1 (rs4387287 and rs9419958) and TERC (rs3772190) that were previously associated with LTL through genome-wide association studies. Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). The OBFC1 SNPs were in linkage disequilibrium (r(2)=0.99), and both SNPs were similarly associated with CVD mortality in women. For women, there was a decreased risk of CVD death associated with the minor allele (rs4387287), HR=0.7; 95% CI: 0.5-0.9 (CC vs. AC) and HR=0.5; 95% CI: 0.20-1.4 (CC vs. AA) (P-trend <0.01). For men there was no association, HR=1.0; 95% CI: 0.7-1.3 (CC vs. AC) and HR=1.7; 95% CI: 0.8-3.6 (CC vs. AA) (P-trend=0.64). These findings support the hypothesis that telomere biology and associated genes may play a role in CVD-related death, particularly among women.

VL - 133 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22449406?dopt=Abstract ER - TY - JOUR T1 - Trans-fatty acid consumption and heart rate variability in 2 separate cohorts of older and younger adults. JF - Circ Arrhythm Electrophysiol Y1 - 2012 A1 - Soares-Miranda, Luisa A1 - Stein, Phyllis K A1 - Imamura, Fumiaki A1 - Sattelmair, Jacob A1 - Lemaitre, Rozenn N A1 - Siscovick, David S A1 - Mota, Jorge A1 - Mozaffarian, Dariush KW - Adolescent KW - Age Factors KW - Aged KW - Aging KW - Arrhythmias, Cardiac KW - Cohort Studies KW - Cross-Sectional Studies KW - Dietary Fats KW - Electrocardiography, Ambulatory KW - Feeding Behavior KW - Female KW - Heart Rate KW - Humans KW - Linear Models KW - Longitudinal Studies KW - Male KW - Multivariate Analysis KW - Portugal KW - Predictive Value of Tests KW - Prospective Studies KW - Risk Assessment KW - Risk Factors KW - Surveys and Questionnaires KW - Trans Fatty Acids KW - United States KW - Young Adult AB -

BACKGROUND: Trans-fatty acid (TFA) consumption is associated with risk of coronary heart disease, and trans-18:2, but not trans-18:1, in red blood cell membranes has been associated with sudden cardiac arrest. Abnormal heart rate variability (HRV) reflects autonomic dysfunction and predicts cardiac death. Relationships between TFA consumption and HRV remain understudied. We determined whether total TFA consumption, as well as trans-18:1 and trans-18:2 TFA consumption, was independently associated with HRV in 2 independent cohorts in the United States and Portugal.

METHODS AND RESULTS: In 2 independent cohorts of older US adults (Cardiovascular Health Study [CHS], age 72±5 years, 1989/1995) and young Portuguese adults (Porto, age 19±2 years, 2008/2010), we assessed habitual TFA intake by food frequency questionnaires in CHS (separately estimating trans-18:1 and trans-18:2) and multiple 24-hour recalls in Porto (estimating total TFA only, which in a subset correlated with circulating trans-18:2 but not trans-18:1, suggesting that we captured the former). HRV was assessed using 24-hour Holters in CHS (n=1076) and repeated short-term (5-minute) ECGs in Porto (n=160). We used multivariate-adjusted linear regression to relate TFA consumption to HRV cross-sectionally (CHS, Porto) and longitudinally (CHS). In CHS, higher trans-18:2 consumption was associated with lower 24-hour SD of all normal-to-normal intervals both cross-sectionally (-12%; 95% CI, -19% to -6%; P=0.001) and longitudinally (-15%; 95% CI, -25% to -4%; P= 0.009) and lower 24-hour SD of 5-minute average N-N intervals and mean of the 5-minute SD of N-N intervals calculated over 24 hours (P<0.05 each). Higher trans-18:1 consumption in CHS was associated with more favorable 24-hour HRV in particular time-domain indices (24-hour SD of all normal-to-normal intervals, SD of 5-minute average N-N intervals, mean of the 5-minute SD of N-N intervals calculated over 24 hours; P<0.05 each). In Porto, each higher SD TFA consumption was associated with 4% lower 5-minute 24-hour SD of all normal-to-normal intervals (95% CI, -8% to -1%; P=0.04) and 7% lower 5-minute square root of the mean of the squares of successive N-N differences (95% CI, -13% to -1%; P=0.04).

CONCLUSIONS: Trans-18:2 consumption is associated with specific, less favorable indices of HRV in both older and young adults. Trans-18:1 consumption is associated with more favorable HRV indices in older adults. Our results support the need to investigate potential HRV-related mechanisms, whereby trans-18:2 may increase arrhythmic risk.

VL - 5 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22772898?dopt=Abstract ER - TY - JOUR T1 - Adhesion molecules, endothelin-1 and lung function in seven population-based cohorts. JF - Biomarkers Y1 - 2013 A1 - Oelsner, E C A1 - Pottinger, T D A1 - Burkart, K M A1 - Allison, M A1 - Buxbaum, S G A1 - Hansel, N N A1 - Kumar, R A1 - Larkin, E K A1 - Lange, L A A1 - Loehr, L R A1 - London, S J A1 - O'Connor, G T A1 - Papanicolaou, G A1 - Petrini, M F A1 - Rabinowitz, D A1 - Raghavan, S A1 - Redline, S A1 - Thyagarajan, B A1 - Tracy, R P A1 - Wilk, J B A1 - White, W B A1 - Rich, S S A1 - Barr, R G KW - African Continental Ancestry Group KW - Biomarkers KW - Cohort Studies KW - E-Selectin KW - Endothelin-1 KW - Endothelium, Vascular KW - European Continental Ancestry Group KW - Female KW - Gene Expression KW - Humans KW - Intercellular Adhesion Molecule-1 KW - Lung KW - Male KW - Middle Aged KW - P-Selectin KW - Pulmonary Disease, Chronic Obstructive KW - Respiratory Function Tests KW - Spirometry AB -

CONTEXT: Endothelial function is abnormal in chronic obstructive pulmonary disease (COPD); whether endothelial dysfunction causes COPD is unknown.

OBJECTIVE: Test associations of endothelial biomarkers with FEV1 using instrumental variables.

METHODS: Among 26 907 participants with spirometry, ICAM-1, P-selectin, E-selectin and endothelin-1 were measured in subsets.

RESULTS: ICAM-1 and P-selectin were inversely associated with FEV1 among European-Americans (-29 mL and -34 mL per standard deviation of log-transformed biomarker, p < 0.001), as was endothelin-1 among African-Americans (-22 mL, p = 0.008). Genetically-estimated ICAM-1 and P-selectin were not significantly associated with FEV1. The instrumental variable for endothelin-1 was non-informative.

CONCLUSION: Although ICAM-1, P-selectin and endothelin-1 were inversely associated with FEV1, associations for ICAM-1 and P-selectin do not appear causal.

VL - 18 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23557128?dopt=Abstract ER - TY - JOUR T1 - Best practices and joint calling of the HumanExome BeadChip: the CHARGE Consortium. JF - PLoS One Y1 - 2013 A1 - Grove, Megan L A1 - Yu, Bing A1 - Cochran, Barbara J A1 - Haritunians, Talin A1 - Bis, Joshua C A1 - Taylor, Kent D A1 - Hansen, Mark A1 - Borecki, Ingrid B A1 - Cupples, L Adrienne A1 - Fornage, Myriam A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Kathiresan, Sekar A1 - Kraaij, Robert A1 - Launer, Lenore J A1 - Levy, Daniel A1 - Liu, Yongmei A1 - Mosley, Thomas A1 - Peloso, Gina M A1 - Psaty, Bruce M A1 - Rich, Stephen S A1 - Rivadeneira, Fernando A1 - Siscovick, David S A1 - Smith, Albert V A1 - Uitterlinden, Andre A1 - van Duijn, Cornelia M A1 - Wilson, James G A1 - O'Donnell, Christopher J A1 - Rotter, Jerome I A1 - Boerwinkle, Eric KW - Aging KW - Alleles KW - Cluster Analysis KW - Cohort Studies KW - Continental Population Groups KW - Exome KW - Female KW - Gene Frequency KW - Genomics KW - Genotype KW - Heart KW - Humans KW - Male KW - Oligonucleotide Array Sequence Analysis KW - Polymorphism, Single Nucleotide KW - Sample Size KW - Self Report KW - Sequence Analysis, DNA AB -

Genotyping arrays are a cost effective approach when typing previously-identified genetic polymorphisms in large numbers of samples. One limitation of genotyping arrays with rare variants (e.g., minor allele frequency [MAF] <0.01) is the difficulty that automated clustering algorithms have to accurately detect and assign genotype calls. Combining intensity data from large numbers of samples may increase the ability to accurately call the genotypes of rare variants. Approximately 62,000 ethnically diverse samples from eleven Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium cohorts were genotyped with the Illumina HumanExome BeadChip across seven genotyping centers. The raw data files for the samples were assembled into a single project for joint calling. To assess the quality of the joint calling, concordance of genotypes in a subset of individuals having both exome chip and exome sequence data was analyzed. After exclusion of low performing SNPs on the exome chip and non-overlap of SNPs derived from sequence data, genotypes of 185,119 variants (11,356 were monomorphic) were compared in 530 individuals that had whole exome sequence data. A total of 98,113,070 pairs of genotypes were tested and 99.77% were concordant, 0.14% had missing data, and 0.09% were discordant. We report that joint calling allows the ability to accurately genotype rare variation using array technology when large sample sizes are available and best practices are followed. The cluster file from this experiment is available at www.chargeconsortium.com/main/exomechip.

VL - 8 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23874508?dopt=Abstract ER - TY - JOUR T1 - Blood pressure components and decline in kidney function in community-living older adults: the Cardiovascular Health Study. JF - Am J Hypertens Y1 - 2013 A1 - Rifkin, Dena E A1 - Katz, Ronit A1 - Chonchol, Michel A1 - Shlipak, Michael G A1 - Sarnak, Mark J A1 - Fried, Linda F A1 - Newman, Anne B A1 - Siscovick, David S A1 - Peralta, Carmen A KW - Aged KW - Blood Pressure KW - Cohort Studies KW - Cystatin C KW - Diastole KW - Disease Progression KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Hypertension KW - Logistic Models KW - Longitudinal Studies KW - Male KW - Pulse KW - Renal Insufficiency, Chronic KW - Systole AB -

BACKGROUND: Although hypertension contributes to kidney dysfunction in the general population, the contributions of elevated systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP) to kidney function decline in community-dwelling older adults are unknown.

METHODS: We used linear and logistic regression to examine the separate and combined associations of SBP, DBP, and PP at baseline with kidney function decline among 4,365 older adults in the Cardiovascular Health Study. We used cystatin C to estimate glomerular filtration rate on 3 occasions over 7 years of follow-up. We defined rapid decline ≥ 3ml/min/year.

RESULTS: Average age was 72.2 and mean (standard deviation) SBP, DBP, and PP were 135 (21), 71 (11), and 65 (18) mm Hg, respectively. SBP and PP, rather than DBP, were most significantly associated with kidney function decline. In adjusted linear models, each 10-mm Hg increment in SBP and PP was associated with 0.13ml/min/year (-0.19, -0.08, P < 0.001) and 0.15-ml/min/year faster decline (-0.21, -0.09, P < 0.001), respectively. Each 10-mm Hg increment in DBP was associated with a nonsignificant 0.10-ml/min/year faster decline (95% confidence interval, -0.20, 0.01). In adjusted logistic models, SBP had the strongest associations with rapid decline, with 14% increased hazard of rapid decline (95% confidence interval, 10% to 17%, P < 0.01) per 10mm Hg. In models combining BP components, only SBP consistently had independent associations with rapid decline.

CONCLUSIONS: Our findings suggest that elevated BP, particularly SBP, contributes to declining kidney function in older adults.

VL - 26 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23709568?dopt=Abstract ER - TY - JOUR T1 - Blood pressure variability and the risk of all-cause mortality, incident myocardial infarction, and incident stroke in the cardiovascular health study. JF - Am J Hypertens Y1 - 2013 A1 - Suchy-Dicey, Astrid M A1 - Wallace, Erin R A1 - Mitchell, S V Elkind A1 - Aguilar, Maria A1 - Gottesman, Rebecca F A1 - Rice, Kenneth A1 - Kronmal, Richard A1 - Psaty, Bruce M A1 - Longstreth, W T KW - Aged KW - Blood Pressure KW - Cohort Studies KW - Female KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Mortality KW - Myocardial Infarction KW - Risk KW - Stroke KW - United States AB -

BACKGROUND: Recent reports have linked variability in visit-to-visit systolic blood pressure (SBP) to risk of mortality and stroke, independent of the effect of mean SBP level. This study aimed to evaluate whether variability in SBP is associated with all-cause mortality, incident myocardial infarction (MI), and incident stroke, independent of mean SBP or trends in SBP levels over time.

METHODS: The Cardiovascular Health Study is a longitudinal cohort study of vascular risk factors and disease in the elderly. Participants who attended their first 5 annual clinic visits and experienced no event before the 5th visit were eligible (n = 3,852). Primary analyses were restricted to participants not using antihypertensive medications throughout the first 5 clinic visits (n = 1,642). Intraindividual SBP variables were defined using each participant's 5-visit blood pressure measures. Cox proportional hazards models estimated adjusted hazard ratios (HRs) per SD increase in intraindividual SBP variability, adjusted for intraindividual SBP mean and change over time.

RESULTS: Over a mean follow-up of 9.9 years, there were 844 deaths, 203 MIs, and 195 strokes. Intraindividual SBP variability was significantly associated with increased risk of mortality (HR = 1.13; 95% confidence interval (CI) = 1.05-1.21) and of incident MI (HR = 1.20; 95%CI = 1.06-1.36), independent of the effect from adjustment factors. Intraindividual SBP variability was not associated with risk of stroke (HR = 1.03; 95% CI = 0.89-1.21).

CONCLUSIONS: Long-term visit-to-visit SBP variability was independently associated with a higher risk of subsequent mortality and MI but not stroke. More research is needed to determine the relationship of BP variability with cardiovascular risk and the clinical implications.

VL - 26 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23744496?dopt=Abstract ER - TY - JOUR T1 - The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium as a model of collaborative science. JF - Epidemiology Y1 - 2013 A1 - Psaty, Bruce M A1 - Sitlani, Colleen KW - Aging KW - Cohort Studies KW - Cooperative Behavior KW - Genome-Wide Association Study KW - Heart Failure KW - Humans KW - Incidence KW - Multicenter Studies as Topic KW - Myocardial Infarction KW - Research Support as Topic KW - Stroke KW - United States VL - 24 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23549178?dopt=Abstract ER - TY - JOUR T1 - Common FABP4 genetic variants and plasma levels of fatty acid binding protein 4 in older adults. JF - Lipids Y1 - 2013 A1 - Mukamal, Kenneth J A1 - Wilk, Jemma B A1 - Biggs, Mary L A1 - Jensen, Majken K A1 - Ix, Joachim H A1 - Kizer, Jorge R A1 - Tracy, Russell P A1 - Zieman, Susan J A1 - Mozaffarian, Dariush A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Djoussé, Luc KW - African Americans KW - Aged KW - Aged, 80 and over KW - Blood Glucose KW - Body Mass Index KW - Cohort Studies KW - European Continental Ancestry Group KW - Fatty Acid-Binding Proteins KW - Female KW - Gene Frequency KW - Genetic Association Studies KW - Haplotypes KW - Humans KW - Insulin KW - Linkage Disequilibrium KW - Male KW - Polymorphism, Single Nucleotide AB -

We examined common variants in the fatty acid binding protein 4 gene (FABP4) and plasma levels of FABP4 in adults aged 65 and older from the Cardiovascular Health Study. We genotyped rs16909187, rs1054135, rs16909192, rs10808846, rs7018409, rs2290201, and rs6992708 and measured circulating FABP4 levels among 3190 European Americans and 660 African Americans. Among European Americans, the minor alleles of six single nucleotide polymorphisms (SNP) were associated with lower FABP4 levels (all p ≤ 0.01). Among African Americans, the SNP with the lowest minor allele frequency was associated with lower FABP4 levels (p = 0.015). The C-A haplotype of rs16909192 and rs2290201 was associated with lower FABP4 levels in both European Americans (frequency = 16 %; p = 0.001) and African Americans (frequency = 8 %; p = 0.04). The haplotype combined a SNP in the first intron with one in the 3'untranslated region. However, the alleles associated with lower FABP4 levels were associated with higher fasting glucose in meta-analyses from the MAGIC consortium. These results demonstrate associations of common SNP and haplotypes in the FABP4 gene with lower plasma FABP4 but higher fasting glucose levels.

VL - 48 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24043587?dopt=Abstract ER - TY - JOUR T1 - Decline in health for older adults: five-year change in 13 key measures of standardized health. JF - J Gerontol A Biol Sci Med Sci Y1 - 2013 A1 - Diehr, Paula H A1 - Thielke, Stephen M A1 - Newman, Anne B A1 - Hirsch, Calvin A1 - Tracy, Russell KW - Activities of Daily Living KW - Aged KW - Aging KW - Cohort Studies KW - Female KW - Gait KW - Health Status KW - Health Status Indicators KW - Hospitalization KW - Humans KW - Longitudinal Studies KW - Male KW - Mental Health KW - Quality of Life KW - Self Report KW - United States AB -

BACKGROUND: The health of older adults declines over time, but there are many ways of measuring health. It is unclear whether all health measures decline at the same rate or whether some aspects of health are less sensitive to aging than others.

METHODS: We compared the decline in 13 measures of physical, mental, and functional health from the Cardiovascular Health Study: hospitalization, bed days, cognition, extremity strength, feelings about life as a whole, satisfaction with the purpose of life, self-rated health, depression, digit symbol substitution test, grip strength, activities of daily living, instrumental activities of daily living, and gait speed. Each measure was standardized against self-rated health. We compared the 5-year change to see which of the 13 measures declined the fastest and the slowest.

RESULTS: The 5-year change in standardized health varied from a decline of 12 points (out of 100) for hospitalization to a decline of 17 points for gait speed. In most comparisons, standardized health from hospitalization and bed days declined the least, whereas health measured by activities of daily living, instrumental activities of daily living, and gait speed declined the most. These rankings were independent of age, sex, mortality patterns, and the method of standardization.

CONCLUSIONS: All of the health variables declined, on average, with advancing age, but at significantly different rates. Standardized measures of mental health, cognition, quality of life, and hospital utilization did not decline as fast as gait speed, activities of daily living, and instrumental activities of daily living. Public health interventions to address problems with gait speed, activities of daily living, and instrumental activities of daily living may help older adults to remain healthier in all dimensions.

VL - 68 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23666944?dopt=Abstract ER - TY - JOUR T1 - Effects of respiratory and non-respiratory factors on disability among older adults with airway obstruction: the Cardiovascular Health Study. JF - COPD Y1 - 2013 A1 - Locke, Emily A1 - Thielke, Stephen A1 - Diehr, Paula A1 - Wilsdon, Anthony G A1 - Barr, R Graham A1 - Hansel, Nadia A1 - Kapur, Vishesh K A1 - Krishnan, Jerry A1 - Enright, Paul A1 - Heckbert, Susan R A1 - Kronmal, Richard A A1 - Fan, Vincent S KW - Activities of Daily Living KW - Aged KW - Cognition Disorders KW - Cohort Studies KW - Comorbidity KW - Depression KW - Diabetes Mellitus KW - Disease Progression KW - Dyspnea KW - Female KW - Heart Failure KW - Humans KW - Linear Models KW - Longitudinal Studies KW - Male KW - Muscle Weakness KW - Myocardial Ischemia KW - Osteoporosis KW - Pulmonary Disease, Chronic Obstructive KW - Severity of Illness Index KW - Spirometry AB -

BACKGROUND: High rates of disability associated with chronic airway obstruction may be caused by impaired pulmonary function, pulmonary symptoms, other chronic diseases, or systemic inflammation.

METHODS: We analyzed data from the Cardiovascular Health Study, a longitudinal cohort of 5888 older adults. Categories of lung function (normal; restricted; borderline, mild-moderate, and severe obstruction) were delineated by baseline spirometry (without bronchodilator). Disability-free years were calculated as total years alive and without self-report of difficulty performing &γτ;1 Instrumental Activities of Daily Living over 6 years of follow-up. Using linear regression, we compared disability-free years by lung disease category, adjusting for demographic factors, body mass index, smoking, cognition, and other chronic co-morbidities. Among participants with airflow obstruction, we examined the association of respiratory factors (FEV1 and dyspnea) and non-respiratory factors (ischemic heart disease, congestive heart failure, diabetes, muscle weakness, osteoporosis, depression and cognitive impairment) on disability-free years.

RESULTS: The average disability free years were 4.0 out of a possible 6 years. Severe obstruction was associated with 1 fewer disability-free year compared to normal spirometry in the adjusted model. For the 1,048 participants with airway obstruction, both respiratory factors (FEV1 and dyspnea) and non-respiratory factors (heart disease, coronary artery disease, diabetes, depression, osteoporosis, cognitive function, and weakness) were associated with decreased disability-free years.

CONCLUSIONS: Severe obstruction is associated with greater disability compared to patients with normal spirometery. Both respiratory and non-respiratory factors contribute to disability in older adults with abnormal spirometry.

VL - 10 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23819728?dopt=Abstract ER - TY - JOUR T1 - Fatty acid-binding protein 4 and incident heart failure: the Cardiovascular Health Study. JF - Eur J Heart Fail Y1 - 2013 A1 - Djoussé, Luc A1 - Bartz, Traci M A1 - Ix, Joachim H A1 - Kochar, Jinesh A1 - Kizer, Jorge R A1 - Gottdiener, John S A1 - Tracy, Russell P A1 - Mozaffarian, Dariush A1 - Siscovick, David S A1 - Mukamal, Kenneth J A1 - Zieman, Susan J KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Cohort Studies KW - Fatty Acid-Binding Proteins KW - Female KW - Follow-Up Studies KW - Glomerular Filtration Rate KW - Heart Failure KW - Humans KW - Male KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - United States KW - Ventricular Function, Left AB -

AIM: To examine the association of plasma fatty acid-binding protein 4 (FABP4) with incident heart failure.

METHODS AND RESULTS: In a prospective study of 4179 participants from the Cardiovascular Health Study, we measured plasma FABP4 on blood specimens collected between 1992 and 1993. Incident heart failure was adjudicated by an endpoint committee and we used a Cox proportional hazards model to calculate hazard ratios (HRs) of heart failure. The average age at baseline was 75 years. During a median follow-up of 10.7 years, 1182 cases of incident heart failure occurred. We observed a positive association between FABP4 and heart failure in the minimally adjusted models [HR 1.32, 95% confidence interval (CI) 1.25-1.38 per 1 SD higher FABP4] that was attenuated upon adjustment for potential confounders, mostly kidney function and body mass index (corresponding HR 1.09, 95% CI 1.01-1.17). In a subsample of heart failure cases with available data on LV systolic function, FABP4 was not associated with heart failure with or without preserved LV systolic function. Exclusion of people with unintentional weight loss and self-reported fair/poor health status did not alter the conclusion.

CONCLUSION: An elevated plasma concentration of FABP4 was associated with a modestly higher risk of heart failure in older adults in the USA after adjustment for confounding factors.

VL - 15 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23223158?dopt=Abstract ER - TY - JOUR T1 - Gene-centric meta-analyses of 108 912 individuals confirm known body mass index loci and reveal three novel signals. JF - Hum Mol Genet Y1 - 2013 A1 - Guo, Yiran A1 - Lanktree, Matthew B A1 - Taylor, Kira C A1 - Hakonarson, Hakon A1 - Lange, Leslie A A1 - Keating, Brendan J KW - Body Mass Index KW - Cohort Studies KW - Ethnic Groups KW - Humans KW - Polymorphism, Single Nucleotide AB -

Recent genetic association studies have made progress in uncovering components of the genetic architecture of the body mass index (BMI). We used the ITMAT-Broad-Candidate Gene Association Resource (CARe) (IBC) array comprising up to 49 320 single nucleotide polymorphisms (SNPs) across ~2100 metabolic and cardiovascular-related loci to genotype up to 108 912 individuals of European ancestry (EA), African-Americans, Hispanics and East Asians, from 46 studies, to provide additional insight into SNPs underpinning BMI. We used a five-phase study design: Phase I focused on meta-analysis of EA studies providing individual level genotype data; Phase II performed a replication of cohorts providing summary level EA data; Phase III meta-analyzed results from the first two phases; associated SNPs from Phase III were used for replication in Phase IV; finally in Phase V, a multi-ethnic meta-analysis of all samples from four ethnicities was performed. At an array-wide significance (P < 2.40E-06), we identify novel BMI associations in loci translocase of outer mitochondrial membrane 40 homolog (yeast) - apolipoprotein E - apolipoprotein C-I (TOMM40-APOE-APOC1) (rs2075650, P = 2.95E-10), sterol regulatory element binding transcription factor 2 (SREBF2, rs5996074, P = 9.43E-07) and neurotrophic tyrosine kinase, receptor, type 2 [NTRK2, a brain-derived neurotrophic factor (BDNF) receptor gene, rs1211166, P = 1.04E-06] in the Phase IV meta-analysis. Of 10 loci with previous evidence for BMI association represented on the IBC array, eight were replicated, with the remaining two showing nominal significance. Conditional analyses revealed two independent BMI-associated signals in BDNF and melanocortin 4 receptor (MC4R) regions. Of the 11 array-wide significant SNPs, three are associated with gene expression levels in both primary B-cells and monocytes; with rs4788099 in SH2B adaptor protein 1 (SH2B1) notably being associated with the expression of multiple genes in cis. These multi-ethnic meta-analyses expand our knowledge of BMI genetics.

VL - 22 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23001569?dopt=Abstract ER - TY - JOUR T1 - A genome-wide association study for venous thromboembolism: the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) consortium. JF - Genet Epidemiol Y1 - 2013 A1 - Tang, Weihong A1 - Teichert, Martina A1 - Chasman, Daniel I A1 - Heit, John A A1 - Morange, Pierre-Emmanuel A1 - Li, Guo A1 - Pankratz, Nathan A1 - Leebeek, Frank W A1 - Paré, Guillaume A1 - de Andrade, Mariza A1 - Tzourio, Christophe A1 - Psaty, Bruce M A1 - Basu, Saonli A1 - Ruiter, Rikje A1 - Rose, Lynda A1 - Armasu, Sebastian M A1 - Lumley, Thomas A1 - Heckbert, Susan R A1 - Uitterlinden, André G A1 - Lathrop, Mark A1 - Rice, Kenneth M A1 - Cushman, Mary A1 - Hofman, Albert A1 - Lambert, Jean-Charles A1 - Glazer, Nicole L A1 - Pankow, James S A1 - Witteman, Jacqueline C A1 - Amouyel, Philippe A1 - Bis, Joshua C A1 - Bovill, Edwin G A1 - Kong, Xiaoxiao A1 - Tracy, Russell P A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Trégouët, David-Alexandre A1 - Loth, Daan W A1 - Stricker, Bruno H Ch A1 - Ridker, Paul M A1 - Folsom, Aaron R A1 - Smith, Nicholas L KW - Aged KW - Aging KW - Case-Control Studies KW - Cohort Studies KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Regression Analysis KW - Risk Factors KW - Venous Thromboembolism AB -

Venous thromboembolism (VTE) is a common, heritable disease resulting in high rates of hospitalization and mortality. Yet few associations between VTE and genetic variants, all in the coagulation pathway, have been established. To identify additional genetic determinants of VTE, we conducted a two-stage genome-wide association study (GWAS) among individuals of European ancestry in the extended cohorts for heart and aging research in genomic epidemiology (CHARGE) VTE consortium. The discovery GWAS comprised 1,618 incident VTE cases out of 44,499 participants from six community-based studies. Genotypes for genome-wide single-nucleotide polymorphisms (SNPs) were imputed to approximately 2.5 million SNPs in HapMap and association with VTE assessed using study-design appropriate regression methods. Meta-analysis of these results identified two known loci, in F5 and ABO. Top 1,047 tag SNPs (P ≤ 0.0016) from the discovery GWAS were tested for association in an additional 3,231 cases and 3,536 controls from three case-control studies. In the combined data from these two stages, additional genome-wide significant associations were observed on 4q35 at F11 (top SNP rs4253399, intronic to F11) and on 4q28 at FGG (rs6536024, 9.7 kb from FGG; P < 5.0 × 10(-13) for both). The associations at the FGG locus were not completely explained by previously reported variants. Loci at or near SUSD1 and OTUD7A showed borderline yet novel associations (P < 5.0 × 10(-6) ) and constitute new candidate genes. In conclusion, this large GWAS replicated key genetic associations in F5 and ABO, and confirmed the importance of F11 and FGG loci for VTE. Future studies are warranted to better characterize the associations with F11 and FGG and to replicate the new candidate associations.

VL - 37 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23650146?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study identifies novel loci associated with concentrations of four plasma phospholipid fatty acids in the de novo lipogenesis pathway: results from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortiu JF - Circ Cardiovasc Genet Y1 - 2013 A1 - Wu, Jason H Y A1 - Lemaitre, Rozenn N A1 - Manichaikul, Ani A1 - Guan, Weihua A1 - Tanaka, Toshiko A1 - Foy, Millennia A1 - Kabagambe, Edmond K A1 - Djoussé, Luc A1 - Siscovick, David A1 - Fretts, Amanda M A1 - Johnson, Catherine A1 - King, Irena B A1 - Psaty, Bruce M A1 - McKnight, Barbara A1 - Rich, Stephen S A1 - Chen, Yii-der I A1 - Nettleton, Jennifer A A1 - Tang, Weihong A1 - Bandinelli, Stefania A1 - Jacobs, David R A1 - Browning, Brian L A1 - Laurie, Cathy C A1 - Gu, Xiangjun A1 - Tsai, Michael Y A1 - Steffen, Lyn M A1 - Ferrucci, Luigi A1 - Fornage, Myriam A1 - Mozaffarian, Dariush KW - Adult KW - Aged KW - Chromosomes, Human, Pair 2 KW - Cohort Studies KW - Coronary Disease KW - Diabetes Mellitus, Type 2 KW - Fatty Acids, Monounsaturated KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Linkage Disequilibrium KW - Lipogenesis KW - Male KW - Middle Aged KW - Oleic Acid KW - Palmitic Acid KW - Polymorphism, Single Nucleotide KW - Stearic Acids AB -

BACKGROUND- Palmitic acid (16:0), stearic acid (18:0), palmitoleic acid (16:1n-7), and oleic acid (18:1n-9) are major saturated and monounsaturated fatty acids that affect cellular signaling and metabolic pathways. They are synthesized via de novo lipogenesis and are the main saturated and monounsaturated fatty acids in the diet. Levels of these fatty acids have been linked to diseases including type 2 diabetes mellitus and coronary heart disease. METHODS AND RESULTS- Genome-wide association studies were conducted in 5 population-based cohorts comprising 8961 participants of European ancestry to investigate the association of common genetic variation with plasma levels of these 4 fatty acids. We identified polymorphisms in 7 novel loci associated with circulating levels of ≥1 of these fatty acids. ALG14 (asparagine-linked glycosylation 14 homolog) polymorphisms were associated with higher 16:0 (P=2.7×10(-11)) and lower 18:0 (P=2.2×10(-18)). FADS1 and FADS2 (desaturases) polymorphisms were associated with higher 16:1n-7 (P=6.6×10(-13)) and 18:1n-9 (P=2.2×10(-32)) and lower 18:0 (P=1.3×10(-20)). LPGAT1 (lysophosphatidylglycerol acyltransferase) polymorphisms were associated with lower 18:0 (P=2.8×10(-9)). GCKR (glucokinase regulator; P=9.8×10(-10)) and HIF1AN (factor inhibiting hypoxia-inducible factor-1; P=5.7×10(-9)) polymorphisms were associated with higher 16:1n-7, whereas PKD2L1 (polycystic kidney disease 2-like 1; P=5.7×10(-15)) and a locus on chromosome 2 (not near known genes) were associated with lower 16:1n-7 (P=4.1×10(-8)). CONCLUSIONS- Our findings provide novel evidence that common variations in genes with diverse functions, including protein-glycosylation, polyunsaturated fatty acid metabolism, phospholipid modeling, and glucose- and oxygen-sensing pathways, are associated with circulating levels of 4 fatty acids in the de novo lipogenesis pathway. These results expand our knowledge of genetic factors relevant to de novo lipogenesis and fatty acid biology.

VL - 6 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23362303?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of cardiac structure and systolic function in African Americans: the Candidate Gene Association Resource (CARe) study. JF - Circ Cardiovasc Genet Y1 - 2013 A1 - Fox, Ervin R A1 - Musani, Solomon K A1 - Barbalic, Maja A1 - Lin, Honghuang A1 - Yu, Bing A1 - Ogunyankin, Kofo O A1 - Smith, Nicholas L A1 - Kutlar, Abdullah A1 - Glazer, Nicole L A1 - Post, Wendy S A1 - Paltoo, Dina N A1 - Dries, Daniel L A1 - Farlow, Deborah N A1 - Duarte, Christine W A1 - Kardia, Sharon L A1 - Meyers, Kristin J A1 - Sun, Yan V A1 - Arnett, Donna K A1 - Patki, Amit A A1 - Sha, Jin A1 - Cui, Xiangqui A1 - Samdarshi, Tandaw E A1 - Penman, Alan D A1 - Bibbins-Domingo, Kirsten A1 - Bůzková, Petra A1 - Benjamin, Emelia J A1 - Bluemke, David A A1 - Morrison, Alanna C A1 - Heiss, Gerardo A1 - Carr, J Jeffrey A1 - Tracy, Russell P A1 - Mosley, Thomas H A1 - Taylor, Herman A A1 - Psaty, Bruce M A1 - Heckbert, Susan R A1 - Cappola, Thomas P A1 - Vasan, Ramachandran S KW - African Americans KW - Aged KW - Cohort Studies KW - Diastole KW - Echocardiography KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Heart KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Systole AB -

BACKGROUND: Using data from 4 community-based cohorts of African Americans, we tested the association between genome-wide markers (single-nucleotide polymorphisms) and cardiac phenotypes in the Candidate-gene Association Resource study.

METHODS AND RESULTS: Among 6765 African Americans, we related age, sex, height, and weight-adjusted residuals for 9 cardiac phenotypes (assessed by echocardiogram or magnetic resonance imaging) to 2.5 million single-nucleotide polymorphisms genotyped using Genome-wide Affymetrix Human SNP Array 6.0 (Affy6.0) and the remainder imputed. Within the cohort, genome-wide association analysis was conducted, followed by meta-analysis across cohorts using inverse variance weights (genome-wide significance threshold=4.0 ×10(-7)). Supplementary pathway analysis was performed. We attempted replication in 3 smaller cohorts of African ancestry and tested lookups in 1 consortium of European ancestry (EchoGEN). Across the 9 phenotypes, variants in 4 genetic loci reached genome-wide significance: rs4552931 in UBE2V2 (P=1.43×10(-7)) for left ventricular mass, rs7213314 in WIPI1 (P=1.68×10(-7)) for left ventricular internal diastolic diameter, rs1571099 in PPAPDC1A (P=2.57×10(-8)) for interventricular septal wall thickness, and rs9530176 in KLF5 (P=4.02×10(-7)) for ejection fraction. Associated variants were enriched in 3 signaling pathways involved in cardiac remodeling. None of the 4 loci replicated in cohorts of African ancestry was confirmed in lookups in EchoGEN.

CONCLUSIONS: In the largest genome-wide association study of cardiac structure and function to date in African Americans, we identified 4 genetic loci related to left ventricular mass, interventricular septal wall thickness, left ventricular internal diastolic diameter, and ejection fraction, which reached genome-wide significance. Replication results suggest that these loci may be unique to individuals of African ancestry. Additional large-scale studies are warranted for these complex phenotypes.

VL - 6 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23275298?dopt=Abstract ER - TY - JOUR T1 - Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD. JF - Hum Genet Y1 - 2013 A1 - Hansel, Nadia N A1 - Ruczinski, Ingo A1 - Rafaels, Nicholas A1 - Sin, Don D A1 - Daley, Denise A1 - Malinina, Alla A1 - Huang, Lili A1 - Sandford, Andrew A1 - Murray, Tanda A1 - Kim, Yoonhee A1 - Vergara, Candelaria A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Li, Guo A1 - Elliott, W Mark A1 - Aminuddin, Farzian A1 - Dupuis, Josée A1 - O'Connor, George T A1 - Doheny, Kimberly A1 - Scott, Alan F A1 - Boezen, H Marike A1 - Postma, Dirkje S A1 - Smolonska, Joanna A1 - Zanen, Pieter A1 - Mohamed Hoesein, Firdaus A A1 - de Koning, Harry J A1 - Crystal, Ronald G A1 - Tanaka, Toshiko A1 - Ferrucci, Luigi A1 - Silverman, Edwin A1 - Wan, Emily A1 - Vestbo, Jorgen A1 - Lomas, David A A1 - Connett, John A1 - Wise, Robert A A1 - Neptune, Enid R A1 - Mathias, Rasika A A1 - Paré, Peter D A1 - Beaty, Terri H A1 - Barnes, Kathleen C KW - Adult KW - Ankyrins KW - Chromosomes, Human, Pair 10 KW - Chromosomes, Human, Pair 14 KW - Cohort Studies KW - Female KW - Genome-Wide Association Study KW - Hepatocyte Nuclear Factor 3-alpha KW - Humans KW - Linkage Disequilibrium KW - Lung KW - Male KW - Membrane Proteins KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Pulmonary Disease, Chronic Obstructive AB -

Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.

VL - 132 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/22986903?dopt=Abstract ER - TY - JOUR T1 - Hypertension and low HDL cholesterol were associated with reduced kidney function across the age spectrum: a collaborative study. JF - Ann Epidemiol Y1 - 2013 A1 - Odden, Michelle C A1 - Tager, Ira B A1 - Gansevoort, Ron T A1 - Bakker, Stephan J L A1 - Fried, Linda F A1 - Newman, Anne B A1 - Katz, Ronit A1 - Satterfield, Suzanne A1 - Harris, Tamara B A1 - Sarnak, Mark J A1 - Siscovick, David A1 - Shlipak, Michael G KW - Adult KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Aging KW - Causality KW - Cholesterol, LDL KW - Cohort Studies KW - Comorbidity KW - Cross-Sectional Studies KW - Cystatin C KW - Female KW - Humans KW - Hypertension KW - Kidney Function Tests KW - Male KW - Netherlands KW - Obesity KW - Prevalence KW - Renal Insufficiency, Chronic KW - Risk Factors KW - Smoking KW - United States AB -

PURPOSE: To determine if the associations among established risk factors and reduced kidney function vary by age.

METHODS: We pooled cross-sectional data from 14,788 nondiabetics aged 40 to 100 years in 4 studies: Cardiovascular Health Study, Health, Aging, and Body Composition Study, Multi-Ethnic Study of Atherosclerosis, and Prevention of Renal and Vascular End-Stage Disease cohort.

RESULTS: Hypertension and low high-density lipoprotein (HDL) cholesterol were associated with reduced cystatin C-based estimated glomerular filtration rate (eGFR) across the age spectrum. In adjusted analyses, hypertension was associated with a 2.3 (95% confidence interval [CI], 0.1, 4.4), 5.1 (95% CI, 4.1, 6.1), and 6.9 (95% CI, 3.0, 10.4) mL/min/1.73 m(2) lower eGFR in participants 40 to 59, 60 to 79, and at least 80 years, respectively (P for interaction < .001). The association of low HDL cholesterol with reduced kidney function was also greater in the older age groups: 4.9 (95% CI, 3.5, 6.3), 7.1 (95% CI, 6.0, 8.3), 8.9 (95% CI, 5.4, 11.9) mL/min/1.73 m(2) (P for interaction < .001). Smoking and obesity were associated with reduced kidney function in participants under 80 years. All estimates of the potential population impact of the risk factors were modest.

CONCLUSIONS: Hypertension, obesity, smoking, and low HDL cholesterol are modestly associated with reduced kidney function in nondiabetics. The associations of hypertension and HDL cholesterol with reduced kidney function seem to be stronger in older adults.

VL - 23 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23313266?dopt=Abstract ER - TY - JOUR T1 - Inflammation and sudden cardiac death in a community-based population of older adults: the Cardiovascular Health Study. JF - Heart Rhythm Y1 - 2013 A1 - Hussein, Ayman A A1 - Gottdiener, John S A1 - Bartz, Traci M A1 - Sotoodehnia, Nona A1 - DeFilippi, Christopher A1 - See, Vincent A1 - Deo, Rajat A1 - Siscovick, David A1 - Stein, Phyllis K A1 - Lloyd-Jones, Donald KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - C-Reactive Protein KW - Case-Control Studies KW - Cohort Studies KW - Death, Sudden, Cardiac KW - Female KW - Humans KW - Inflammation KW - Interleukin-6 KW - Male KW - Risk Factors AB -

BACKGROUND: Inflammation is linked to adverse cardiovascular events, but its association with sudden cardiac death (SCD) has been controversial. Older subjects, who are at particular risk for SCD, were underrepresented in previous studies addressing this issue.

OBJECTIVE: The purpose of this study was to study the association between inflammation and SCD in a community-based population of older adults.

METHODS: In the Cardiovascular Health Study, 5806 and 5382 participants had measurements of C-reactive protein (CRP) and interleukin-6 (IL6), respectively, and were followed for up to 17 years. SCD risk as a function of baseline IL-6 and CRP was assessed in the overall population and in a group of participants without known prevalent cardiac disease.

RESULTS: In univariate analyses, both IL-6 (hazard ratio [HR] 1.79 for 1+ log IL-6, 95% confidence interval [CI] 1.50-2.13; 5th vs 1st quintile HR 3.36, 95% CI 2.24-5.05) and CRP (HR 1.31 for 1+ log CRP, 95% CI 1.18-1.45; 5th vs 1st quintile HR 2.00, 95% CI 1.40-2.87) were associated with SCD risk. In covariate-adjusted analyses, accounting for baseline risk factors, incident myocardial infarction, and heart failure, the association with SCD risk persisted for IL-6 (HR 1.26 for 1+ log IL-6, 95% CI 1.02-1.56; 5th vs 1st quintile HR 1.63, 95% CI 1.03-2.56) but was significantly attenuated for CRP (HR 1.13 for 1+ log CRP, 95% CI 1.00-1.28; 5th vs 1st quintile HR 1.34, 95% CI 0.88-2.05). Similar findings were observed in participants without prevalent cardiac disease.

CONCLUSION: Greater burden of inflammation, assessed by IL-6 levels, is associated with SCD risk beyond traditional risk factors, incident myocardial infarction, and heart failure.

VL - 10 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23906927?dopt=Abstract ER - TY - JOUR T1 - The influence of obesity-related single nucleotide polymorphisms on BMI across the life course: the PAGE study. JF - Diabetes Y1 - 2013 A1 - Graff, Mariaelisa A1 - Gordon-Larsen, Penny A1 - Lim, Unhee A1 - Fowke, Jay H A1 - Love, Shelly-Ann A1 - Fesinmeyer, Megan A1 - Wilkens, Lynne R A1 - Vertilus, Shawyntee A1 - Ritchie, Marilyn D A1 - Prentice, Ross L A1 - Pankow, Jim A1 - Monroe, Kristine A1 - Manson, JoAnn E A1 - Le Marchand, Loïc A1 - Kuller, Lewis H A1 - Kolonel, Laurence N A1 - Hong, Ching P A1 - Henderson, Brian E A1 - Haessler, Jeff A1 - Gross, Myron D A1 - Goodloe, Robert A1 - Franceschini, Nora A1 - Carlson, Christopher S A1 - Buyske, Steven A1 - Bůzková, Petra A1 - Hindorff, Lucia A A1 - Matise, Tara C A1 - Crawford, Dana C A1 - Haiman, Christopher A A1 - Peters, Ulrike A1 - North, Kari E KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Body Mass Index KW - Cohort Studies KW - Cross-Sectional Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Association Studies KW - Health Surveys KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Proteins KW - United States KW - Young Adult AB -

Evidence is limited as to whether heritable risk of obesity varies throughout adulthood. Among >34,000 European Americans, aged 18-100 years, from multiple U.S. studies in the Population Architecture using Genomics and Epidemiology (PAGE) Consortium, we examined evidence for heterogeneity in the associations of five established obesity risk variants (near FTO, GNPDA2, MTCH2, TMEM18, and NEGR1) with BMI across four distinct epochs of adulthood: 1) young adulthood (ages 18-25 years), adulthood (ages 26-49 years), middle-age adulthood (ages 50-69 years), and older adulthood (ages ≥70 years); or 2) by menopausal status in women and stratification by age 50 years in men. Summary-effect estimates from each meta-analysis were compared for heterogeneity across the life epochs. We found heterogeneity in the association of the FTO (rs8050136) variant with BMI across the four adulthood epochs (P = 0.0006), with larger effects in young adults relative to older adults (β [SE] = 1.17 [0.45] vs. 0.09 [0.09] kg/m², respectively, per A allele) and smaller intermediate effects. We found no evidence for heterogeneity in the association of GNPDA2, MTCH2, TMEM18, and NEGR1 with BMI across adulthood. Genetic predisposition to obesity may have greater effects on body weight in young compared with older adulthood for FTO, suggesting changes by age, generation, or secular trends. Future research should compare and contrast our findings with results using longitudinal data.

VL - 62 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23300277?dopt=Abstract ER - TY - JOUR T1 - Ischemic stroke is associated with the ABO locus: the EuroCLOT study. JF - Ann Neurol Y1 - 2013 A1 - Williams, Frances M K A1 - Carter, Angela M A1 - Hysi, Pirro G A1 - Surdulescu, Gabriela A1 - Hodgkiss, Dylan A1 - Soranzo, Nicole A1 - Traylor, Matthew A1 - Bevan, Steve A1 - Dichgans, Martin A1 - Rothwell, Peter M W A1 - Sudlow, Cathie A1 - Farrall, Martin A1 - Silander, Kaisa A1 - Kaunisto, Mari A1 - Wagner, Peter A1 - Saarela, Olli A1 - Kuulasmaa, Kari A1 - Virtamo, Jarmo A1 - Salomaa, Veikko A1 - Amouyel, Philippe A1 - Arveiler, Dominique A1 - Ferrieres, Jean A1 - Wiklund, Per-Gunnar A1 - Ikram, M Arfan A1 - Hofman, Albert A1 - Boncoraglio, Giorgio B A1 - Parati, Eugenio A A1 - Helgadottir, Anna A1 - Gretarsdottir, Solveig A1 - Thorsteinsdottir, Unnur A1 - Thorleifsson, Gudmar A1 - Stefansson, Kari A1 - Seshadri, Sudha A1 - DeStefano, Anita A1 - Gschwendtner, Andreas A1 - Psaty, Bruce A1 - Longstreth, Will A1 - Mitchell, Braxton D A1 - Cheng, Yu-Ching A1 - Clarke, Robert A1 - Ferrario, Marco A1 - Bis, Joshua C A1 - Levi, Christopher A1 - Attia, John A1 - Holliday, Elizabeth G A1 - Scott, Rodney J A1 - Fornage, Myriam A1 - Sharma, Pankaj A1 - Furie, Karen L A1 - Rosand, Jonathan A1 - Nalls, Mike A1 - Meschia, James A1 - Mosely, Thomas H A1 - Evans, Alun A1 - Palotie, Aarno A1 - Markus, Hugh S A1 - Grant, Peter J A1 - Spector, Tim D KW - ABO Blood-Group System KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Blood Coagulation KW - Brain Ischemia KW - Cohort Studies KW - Europe KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Stroke KW - Young Adult AB -

OBJECTIVE: End-stage coagulation and the structure/function of fibrin are implicated in the pathogenesis of ischemic stroke. We explored whether genetic variants associated with end-stage coagulation in healthy volunteers account for the genetic predisposition to ischemic stroke and examined their influence on stroke subtype.

METHODS: Common genetic variants identified through genome-wide association studies of coagulation factors and fibrin structure/function in healthy twins (n = 2,100, Stage 1) were examined in ischemic stroke (n = 4,200 cases) using 2 independent samples of European ancestry (Stage 2). A third clinical collection having stroke subtyping (total 8,900 cases, 55,000 controls) was used for replication (Stage 3).

RESULTS: Stage 1 identified 524 single nucleotide polymorphisms (SNPs) from 23 linkage disequilibrium blocks having significant association (p < 5 × 10(-8)) with 1 or more coagulation/fibrin phenotypes. The most striking associations included SNP rs5985 with factor XIII activity (p = 2.6 × 10(-186)), rs10665 with FVII (p = 2.4 × 10(-47)), and rs505922 in the ABO gene with both von Willebrand factor (p = 4.7 × 10(-57)) and factor VIII (p = 1.2 × 10(-36)). In Stage 2, the 23 independent SNPs were examined in stroke cases/noncases using MOnica Risk, Genetics, Archiving and Monograph (MORGAM) and Wellcome Trust Case Control Consortium 2 collections. SNP rs505922 was nominally associated with ischemic stroke (odds ratio = 0.94, 95% confidence interval = 0.88-0.99, p = 0.023). Independent replication in Meta-Stroke confirmed the rs505922 association with stroke, beta (standard error, SE) = 0.066 (0.02), p = 0.001, a finding specific to large-vessel and cardioembolic stroke (p = 0.001 and p = < 0.001, respectively) but not seen with small-vessel stroke (p = 0.811).

INTERPRETATION: ABO gene variants are associated with large-vessel and cardioembolic stroke but not small-vessel disease. This work sheds light on the different pathogenic mechanisms underpinning stroke subtype.

VL - 73 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23381943?dopt=Abstract ER - TY - JOUR T1 - Lifetime risk for heart failure among white and black Americans: cardiovascular lifetime risk pooling project. JF - J Am Coll Cardiol Y1 - 2013 A1 - Huffman, Mark D A1 - Berry, Jarett D A1 - Ning, Hongyan A1 - Dyer, Alan R A1 - Garside, Daniel B A1 - Cai, Xuan A1 - Daviglus, Martha L A1 - Lloyd-Jones, Donald M KW - Adolescent KW - Adult KW - African Americans KW - Age Factors KW - Aged KW - Anthropometry KW - Body Mass Index KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Health Surveys KW - Heart Failure KW - Humans KW - Kaplan-Meier Estimate KW - Male KW - Middle Aged KW - Predictive Value of Tests KW - Prognosis KW - Risk Assessment KW - Severity of Illness Index KW - Sex Factors KW - Survival Analysis KW - Time Factors KW - United States KW - Young Adult AB -

OBJECTIVES: This study sought to estimate lifetime risk for heart failure (HF) by sex and race.

BACKGROUND: Prior estimates of lifetime risk for developing HF range from 20% to 33% in predominantly white cohorts. Short-term risks for HF appear higher for blacks than whites, but only limited comparisons of lifetime risk for HF have been made.

METHODS: Using public-release and internal datasets from National Heart, Lung, and Blood Institute-sponsored cohorts, we estimated lifetime risks for developing HF to age 95 years, with death free of HF as the competing event, among participants in the CHA (Chicago Heart Association Detection Project in Industry), ARIC (Atherosclerosis Risk in Communities), and CHS (Cardiovascular Health Study) cohorts.

RESULTS: There were 39,578 participants (33,652 [85%] white; 5,926 [15%] black) followed for 716,976 person-years; 5,983 participants developed HF. At age 45 years, lifetime risks for HF through age 95 years in CHA and CHS were 30% to 42% in white men, 20% to 29% in black men, 32% to 39% in white women, and 24% to 46% in black women. Results for ARIC demonstrated similar lifetime risks for HF in blacks and whites through age 75 years (limit of follow-up). Lifetime risk for HF was higher with higher blood pressure and body mass index at all ages in both blacks and whites, and did not diminish substantially with advancing index age.

CONCLUSIONS: These are among the first data to compare lifetime risks for HF between blacks and whites. Lifetime risks for HF are high and appear similar for black and white women, yet are somewhat lower for black compared with white men due to competing risks.

VL - 61 IS - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23500287?dopt=Abstract ER - TY - JOUR T1 - Long-term outcomes of left anterior fascicular block in the absence of overt cardiovascular disease. JF - JAMA Y1 - 2013 A1 - Mandyam, Mala C A1 - Soliman, Elsayed Z A1 - Heckbert, Susan R A1 - Vittinghoff, Eric A1 - Marcus, Gregory M KW - Aged KW - Atrial Fibrillation KW - Biomarkers KW - Bundle-Branch Block KW - Cohort Studies KW - Electrocardiography KW - Endomyocardial Fibrosis KW - Female KW - Heart Failure KW - Humans KW - Kaplan-Meier Estimate KW - Male KW - Prognosis KW - Risk VL - 309 IS - 15 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23592102?dopt=Abstract ER - TY - JOUR T1 - Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. JF - Nat Genet Y1 - 2013 A1 - Lambert, J C A1 - Ibrahim-Verbaas, C A A1 - Harold, D A1 - Naj, A C A1 - Sims, R A1 - Bellenguez, C A1 - DeStafano, A L A1 - Bis, J C A1 - Beecham, G W A1 - Grenier-Boley, B A1 - Russo, G A1 - Thorton-Wells, T A A1 - Jones, N A1 - Smith, A V A1 - Chouraki, V A1 - Thomas, C A1 - Ikram, M A A1 - Zelenika, D A1 - Vardarajan, B N A1 - Kamatani, Y A1 - Lin, C F A1 - Gerrish, A A1 - Schmidt, H A1 - Kunkle, B A1 - Dunstan, M L A1 - Ruiz, A A1 - Bihoreau, M T A1 - Choi, S H A1 - Reitz, C A1 - Pasquier, F A1 - Cruchaga, C A1 - Craig, D A1 - Amin, N A1 - Berr, C A1 - Lopez, O L A1 - De Jager, P L A1 - Deramecourt, V A1 - Johnston, J A A1 - Evans, D A1 - Lovestone, S A1 - Letenneur, L A1 - Morón, F J A1 - Rubinsztein, D C A1 - Eiriksdottir, G A1 - Sleegers, K A1 - Goate, A M A1 - Fiévet, N A1 - Huentelman, M W A1 - Gill, M A1 - Brown, K A1 - Kamboh, M I A1 - Keller, L A1 - Barberger-Gateau, P A1 - McGuiness, B A1 - Larson, E B A1 - Green, R A1 - Myers, A J A1 - Dufouil, C A1 - Todd, S A1 - Wallon, D A1 - Love, S A1 - Rogaeva, E A1 - Gallacher, J A1 - St George-Hyslop, P A1 - Clarimon, J A1 - Lleo, A A1 - Bayer, A A1 - Tsuang, D W A1 - Yu, L A1 - Tsolaki, M A1 - Bossù, P A1 - Spalletta, G A1 - Proitsi, P A1 - Collinge, J A1 - Sorbi, S A1 - Sanchez-Garcia, F A1 - Fox, N C A1 - Hardy, J A1 - Deniz Naranjo, M C A1 - Bosco, P A1 - Clarke, R A1 - Brayne, C A1 - Galimberti, D A1 - Mancuso, M A1 - Matthews, F A1 - Moebus, S A1 - Mecocci, P A1 - Del Zompo, M A1 - Maier, W A1 - Hampel, H A1 - Pilotto, A A1 - Bullido, M A1 - Panza, F A1 - Caffarra, P A1 - Nacmias, B A1 - Gilbert, J R A1 - Mayhaus, M A1 - Lannefelt, L A1 - Hakonarson, H A1 - Pichler, S A1 - Carrasquillo, M M A1 - Ingelsson, M A1 - Beekly, D A1 - Alvarez, V A1 - Zou, F A1 - Valladares, O A1 - Younkin, S G A1 - Coto, E A1 - Hamilton-Nelson, K L A1 - Gu, W A1 - Razquin, C A1 - Pastor, P A1 - Mateo, I A1 - Owen, M J A1 - Faber, K M A1 - Jonsson, P V A1 - Combarros, O A1 - O'Donovan, M C A1 - Cantwell, L B A1 - Soininen, H A1 - Blacker, D A1 - Mead, S A1 - Mosley, T H A1 - Bennett, D A A1 - Harris, T B A1 - Fratiglioni, L A1 - Holmes, C A1 - de Bruijn, R F A1 - Passmore, P A1 - Montine, T J A1 - Bettens, K A1 - Rotter, J I A1 - Brice, A A1 - Morgan, K A1 - Foroud, T M A1 - Kukull, W A A1 - Hannequin, D A1 - Powell, J F A1 - Nalls, M A A1 - Ritchie, K A1 - Lunetta, K L A1 - Kauwe, J S A1 - Boerwinkle, E A1 - Riemenschneider, M A1 - Boada, M A1 - Hiltuenen, M A1 - Martin, E R A1 - Schmidt, R A1 - Rujescu, D A1 - Wang, L S A1 - Dartigues, J F A1 - Mayeux, R A1 - Tzourio, C A1 - Hofman, A A1 - Nöthen, M M A1 - Graff, C A1 - Psaty, B M A1 - Jones, L A1 - Haines, J L A1 - Holmans, P A A1 - Lathrop, M A1 - Pericak-Vance, M A A1 - Launer, L J A1 - Farrer, L A A1 - van Duijn, C M A1 - Van Broeckhoven, C A1 - Moskvina, V A1 - Seshadri, S A1 - Williams, J A1 - Schellenberg, G D A1 - Amouyel, P KW - Age of Onset KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Case-Control Studies KW - Cohort Studies KW - Female KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide AB -

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

VL - 45 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24162737?dopt=Abstract ER - TY - JOUR T1 - No evidence of interaction between known lipid-associated genetic variants and smoking in the multi-ethnic PAGE population. JF - Hum Genet Y1 - 2013 A1 - Dumitrescu, Logan A1 - Carty, Cara L A1 - Franceschini, Nora A1 - Hindorff, Lucia A A1 - Cole, Shelley A A1 - Bůzková, Petra A1 - Schumacher, Fredrick R A1 - Eaton, Charles B A1 - Goodloe, Robert J A1 - Duggan, David J A1 - Haessler, Jeff A1 - Cochran, Barbara A1 - Henderson, Brian E A1 - Cheng, Iona A1 - Johnson, Karen C A1 - Carlson, Chris S A1 - Love, Shelly-Anne A1 - Brown-Gentry, Kristin A1 - Nato, Alejandro Q A1 - Quibrera, Miguel A1 - Shohet, Ralph V A1 - Ambite, Jose Luis A1 - Wilkens, Lynne R A1 - Le Marchand, Loïc A1 - Haiman, Christopher A A1 - Buyske, Steven A1 - Kooperberg, Charles A1 - North, Kari E A1 - Fornage, Myriam A1 - Crawford, Dana C KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Ethnic Groups KW - Female KW - Gene Frequency KW - Gene-Environment Interaction KW - Genetics, Population KW - Genome-Wide Association Study KW - Humans KW - Lipid Metabolism KW - Male KW - Polymorphism, Single Nucleotide KW - Prevalence KW - Smoking KW - Triglycerides KW - Young Adult AB -

Genome-wide association studies (GWAS) have identified many variants that influence high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and/or triglycerides. However, environmental modifiers, such as smoking, of these known genotype-phenotype associations are just recently emerging in the literature. We have tested for interactions between smoking and 49 GWAS-identified variants in over 41,000 racially/ethnically diverse samples with lipid levels from the Population Architecture Using Genomics and Epidemiology (PAGE) study. Despite their biological plausibility, we were unable to detect significant SNP × smoking interactions.

VL - 132 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24100633?dopt=Abstract ER - TY - JOUR T1 - The QT interval and risk of incident atrial fibrillation. JF - Heart Rhythm Y1 - 2013 A1 - Mandyam, Mala C A1 - Soliman, Elsayed Z A1 - Alonso, Alvaro A1 - Dewland, Thomas A A1 - Heckbert, Susan R A1 - Vittinghoff, Eric A1 - Cummings, Steven R A1 - Ellinor, Patrick T A1 - Chaitman, Bernard R A1 - Stocke, Karen A1 - Applegate, William B A1 - Arking, Dan E A1 - Butler, Javed A1 - Loehr, Laura R A1 - Magnani, Jared W A1 - Murphy, Rachel A A1 - Satterfield, Suzanne A1 - Newman, Anne B A1 - Marcus, Gregory M KW - Aged KW - Atrial Fibrillation KW - Cohort Studies KW - Electrocardiography KW - Female KW - Humans KW - Incidence KW - Long QT Syndrome KW - Male KW - Middle Aged KW - Risk Factors AB -

BACKGROUND: Abnormal atrial repolarization is important in the development of atrial fibrillation (AF), but no direct measurement is available in clinical medicine.

OBJECTIVE: To determine whether the QT interval, a marker of ventricular repolarization, could be used to predict incident AF.

METHODS: We examined a prolonged QT interval corrected by using the Framingham formula (QT(Fram)) as a predictor of incident AF in the Atherosclerosis Risk in Communities (ARIC) study. The Cardiovascular Health Study (CHS) and Health, Aging, and Body Composition (ABC) study were used for validation. Secondary predictors included QT duration as a continuous variable, a short QT interval, and QT intervals corrected by using other formulas.

RESULTS: Among 14,538 ARIC study participants, a prolonged QT(Fram) predicted a roughly 2-fold increased risk of AF (hazard ratio [HR] 2.05; 95% confidence interval [CI] 1.42-2.96; P < .001). No substantive attenuation was observed after adjustment for age, race, sex, study center, body mass index, hypertension, diabetes, coronary disease, and heart failure. The findings were validated in Cardiovascular Health Study and Health, Aging, and Body Composition study and were similar across various QT correction methods. Also in the ARIC study, each 10-ms increase in QT(Fram) was associated with an increased unadjusted (HR 1.14; 95% CI 1.10-1.17; P < .001) and adjusted (HR 1.11; 95% CI 1.07-1.14; P < .001) risk of AF. Findings regarding a short QT interval were inconsistent across cohorts.

CONCLUSIONS: A prolonged QT interval is associated with an increased risk of incident AF.

VL - 10 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23872693?dopt=Abstract ER - TY - JOUR T1 - Simple risk model predicts incidence of atrial fibrillation in a racially and geographically diverse population: the CHARGE-AF consortium. JF - J Am Heart Assoc Y1 - 2013 A1 - Alonso, Alvaro A1 - Krijthe, Bouwe P A1 - Aspelund, Thor A1 - Stepas, Katherine A A1 - Pencina, Michael J A1 - Moser, Carlee B A1 - Sinner, Moritz F A1 - Sotoodehnia, Nona A1 - Fontes, João D A1 - Janssens, A Cecile J W A1 - Kronmal, Richard A A1 - Magnani, Jared W A1 - Witteman, Jacqueline C A1 - Chamberlain, Alanna M A1 - Lubitz, Steven A A1 - Schnabel, Renate B A1 - Agarwal, Sunil K A1 - McManus, David D A1 - Ellinor, Patrick T A1 - Larson, Martin G A1 - Burke, Gregory L A1 - Launer, Lenore J A1 - Hofman, Albert A1 - Levy, Daniel A1 - Gottdiener, John S A1 - Kääb, Stefan A1 - Couper, David A1 - Harris, Tamara B A1 - Soliman, Elsayed Z A1 - Stricker, Bruno H C A1 - Gudnason, Vilmundur A1 - Heckbert, Susan R A1 - Benjamin, Emelia J KW - African Americans KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Cohort Studies KW - Diabetes Mellitus KW - European Continental Ancestry Group KW - Female KW - Heart Failure KW - Humans KW - Hypertension KW - Iceland KW - Incidence KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Netherlands KW - Proportional Hazards Models KW - Risk Assessment KW - Smoking KW - United States AB -

BACKGROUND: Tools for the prediction of atrial fibrillation (AF) may identify high-risk individuals more likely to benefit from preventive interventions and serve as a benchmark to test novel putative risk factors.

METHODS AND RESULTS: Individual-level data from 3 large cohorts in the United States (Atherosclerosis Risk in Communities [ARIC] study, the Cardiovascular Health Study [CHS], and the Framingham Heart Study [FHS]), including 18 556 men and women aged 46 to 94 years (19% African Americans, 81% whites) were pooled to derive predictive models for AF using clinical variables. Validation of the derived models was performed in 7672 participants from the Age, Gene and Environment-Reykjavik study (AGES) and the Rotterdam Study (RS). The analysis included 1186 incident AF cases in the derivation cohorts and 585 in the validation cohorts. A simple 5-year predictive model including the variables age, race, height, weight, systolic and diastolic blood pressure, current smoking, use of antihypertensive medication, diabetes, and history of myocardial infarction and heart failure had good discrimination (C-statistic, 0.765; 95% CI, 0.748 to 0.781). Addition of variables from the electrocardiogram did not improve the overall model discrimination (C-statistic, 0.767; 95% CI, 0.750 to 0.783; categorical net reclassification improvement, -0.0032; 95% CI, -0.0178 to 0.0113). In the validation cohorts, discrimination was acceptable (AGES C-statistic, 0.664; 95% CI, 0.632 to 0.697 and RS C-statistic, 0.705; 95% CI, 0.664 to 0.747) and calibration was adequate.

CONCLUSION: A risk model including variables readily available in primary care settings adequately predicted AF in diverse populations from the United States and Europe.

VL - 2 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23537808?dopt=Abstract ER - TY - JOUR T1 - Sleep and insulin-like growth factors in the Cardiovascular Health Study. JF - J Clin Sleep Med Y1 - 2013 A1 - Shah, Neomi A1 - Rice, Tom A1 - Tracy, Daniel A1 - Rohan, Thomas A1 - Bůzková, Petra A1 - Newman, Anne A1 - Kaplan, Robert C KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Geriatric Assessment KW - Health Surveys KW - Humans KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Sex Distribution KW - Sleep KW - Sleep Apnea, Obstructive KW - Somatomedins KW - United States AB -

STUDY OBJECTIVES: Sleep and sleep disordered breathing (obstructive sleep apnea [OSA]) are known to affect the growth hormone/insulin-like growth factor (GH/IGF) axis. There are few relevant population studies in this area, particularly in the elderly. We conducted this study to investigate the relationship between sleep (architecture and OSA) and circulating IGF-I (insulin-like growth factor-1), IGFBP-1 (insulin-like growth factor binding protein-1), and IGFBP-3 (insulin-like growth factor binding protein-3) levels in an elderly population.

DESIGN SETTING: Cross-sectional analysis of participants from the year 9 visit of the Cardiovascular Health Study (CHS) who were enrolled in the Sleep Heart Health Study (SHHS).

PATIENTS OR PARTICIPANTS: 1,233 elderly participants from the CHS and SHHS.

MEASUREMENTS AND RESULTS: The mean age of males (n = 526) and females (n = 697) was 77 years. The mean value of IGF-I (ng/mL) in males was 112.4 vs. 97.1 in females (p < 0.01). Mean IGFBP-1 and IGFBP-3 levels were higher in females than males (p < 0.01). As expected, slow wave sleep was better preserved in females compared to males (22% total sleep time vs. 9% total sleep time, p < 0.01). Furthermore, as expected, OSA (apneahypopnea index [AHI] ≥ 5/h) was more prevalent in males compared to females (60% vs. 46%, p < 0.01). Multivariable linear regression was used to determine the relationship between objective sleep parameters and circulating IGF-I, IGFBP-1, and IGFBP-3 levels, with adjustment for age, sex, race, BMI, diabetes, estrogen use, progestin use, and physical activity. We did not detect a significant association between slow wave sleep (SWS) (per 5 min) and IGF-I, IGFBP-1, and IGFBP-3 levels (ng/mL). We found no significant linear association between OSA (AHI ≥ 5/h) and IGF-I, IGFBP-1, and IGFBP-3 levels. Gender-stratification of the entire cohort did not alter these findings. Sensitivity analyses excluding diabetics revealed that moderate OSA (AHI ≥ 5 and < 15) is inversely associated with IGFBP-3 levels in women. Conclusions The relationship between SWS and GH/IGF system is not significant in the elderly. Furthermore, OSA does not appear to adversely influence the GH/IGF axis, as reported in younger individuals. Whether our study findings are due to diminished GH/IGF-I axis activity in elderly needs further investigation by replication in other large population based elderly cohorts.

VL - 9 IS - 12 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24340285?dopt=Abstract ER - TY - JOUR T1 - Strategy to control type I error increases power to identify genetic variation using the full biological trajectory. JF - Genet Epidemiol Y1 - 2013 A1 - Benke, K S A1 - Wu, Y A1 - Fallin, D M A1 - Maher, B A1 - Palmer, L J KW - Cohort Studies KW - Computer Simulation KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Linear Models KW - Models, Genetic KW - Polymorphism, Single Nucleotide AB -

Genome-wide association studies have been successful in identifying loci that underlie continuous traits measured at a single time point. To additionally consider continuous traits longitudinally, it is desirable to look at SNP effects at baseline and over time using linear-mixed effects models. Estimation and interpretation of two coefficients in the same model raises concern regarding the optimal control of type I error. To investigate this issue, we calculate type I error and power under an alternative for joint tests, including the two degree of freedom likelihood ratio test, and compare this to single degree of freedom tests for each effect separately at varying alpha levels. We show which joint tests are the optimal way to control the type I error and also illustrate that information can be gained by joint testing in situations where either or both SNP effects are underpowered. We also show that closed form power calculations can approximate simulated power for the case of balanced data, provide reasonable approximations for imbalanced data, but overestimate power for complicated residual error structures. We conclude that a two degree of freedom test is an attractive strategy in a hypothesis-free genome-wide setting and recommend its use for genome-wide studies employing linear-mixed effects models.

VL - 37 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23633177?dopt=Abstract ER - TY - JOUR T1 - Total and high-molecular-weight adiponectin and risk of coronary heart disease and ischemic stroke in older adults. JF - J Clin Endocrinol Metab Y1 - 2013 A1 - Kizer, Jorge R A1 - Benkeser, David A1 - Arnold, Alice M A1 - Djoussé, Luc A1 - Zieman, Susan J A1 - Mukamal, Kenneth J A1 - Tracy, Russell P A1 - Mantzoros, Christos S A1 - Siscovick, David S A1 - Gottdiener, John S A1 - Ix, Joachim H KW - Adiponectin KW - Adult KW - Aged KW - Aged, 80 and over KW - Brain Ischemia KW - Cardiovascular Diseases KW - Case-Control Studies KW - Cohort Studies KW - Coronary Disease KW - Female KW - Humans KW - Male KW - Molecular Weight KW - Residence Characteristics KW - Risk Factors KW - Stroke AB -

CONTEXT: Adiponectin is atheroprotective in the laboratory, but prospective studies have shown opposite associations with cardiovascular disease (CVD) in healthy middle-aged populations (protective) and older cohorts (adverse). Whether this relates to different proportions of high-molecular-weight (HMW) adiponectin is unknown.

OBJECTIVE: The aim of the study was to test the hypothesis that total adiponectin is directly associated, but HMW adiponectin is inversely related, with CVD in older adults.

DESIGN, SETTING, AND PARTICIPANTS: We evaluated 3290 participants free of prevalent CVD in a longitudinal cohort study of U.S. adults aged 65 yr and older.

MAIN OUTCOME MEASURES: We measured incident CVD (n = 1291), comprising coronary heart disease and ischemic stroke.

RESULTS: Total and HMW adiponectin were tightly correlated (r = 0.94). Cubic splines adjusted for potential confounders revealed that the associations of total and HMW adiponectin with CVD were U-shaped, with inflection points of 20 and 10 mg/liter, respectively. After controlling for potential confounding, levels of total and HMW adiponectin below these cutpoints tended to be inversely associated with incident CVD, driven by their significant or near-significant relations with coronary heart disease [hazard ratio (HR), 0.85 per sd increase; 95% confidence interval (CI), 0.75-96; and HR, 0.87; 95% CI, 0.75-1.01, respectively]. These associations were abrogated by additional inclusion of putative metabolic intermediates. Above these cutpoints, however, both total and HMW adiponectin were significantly directly associated with CVD after adjustment for confounders and, particularly, mediators (HR, 1.20 per sd increase; 95% CI, 1.06-1.35; and HR, 1.12; 95% CI, 1.02-1.24, respectively).

CONCLUSION: In community-living elders, total and HMW adiponectin showed similar U-shaped relationships with CVD. The inverse relation in the lower range, but not the direct association at the higher end, disappeared after inclusion of putative intermediates, suggesting that high levels may reflect adverse processes separate from adiponectin's beneficial glycometabolic properties.

VL - 98 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23162097?dopt=Abstract ER - TY - JOUR T1 - Use of antihypertensive medications and breast cancer risk. JF - Cancer Causes Control Y1 - 2013 A1 - Saltzman, Babette S A1 - Weiss, Noel S A1 - Sieh, Weiva A1 - Fitzpatrick, Annette L A1 - McTiernan, Anne A1 - Daling, Janet R A1 - Li, Christopher I KW - Aged KW - Aged, 80 and over KW - Antihypertensive Agents KW - Breast Neoplasms KW - Cohort Studies KW - Female KW - Humans KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - United States AB -

PURPOSE: Use of specific antihypertensive medications (AHTs) has been hypothesized to increase breast cancer risk, but results across published studies are inconsistent.

METHODS: We re-evaluated the relationship between AHT use and breast cancer risk in a prospective cohort of 3,201 women ≥65 years of age at recruitment now with more than double the length of follow-up (12 vs. 5 years) and substantially more breast cancer diagnoses (188 compared with 75 cases). We estimated the association between AHT use overall as well as use of specific formulations (based on data collected annually) and breast cancer risk using multivariate-adjusted Cox regression.

RESULTS: Compared with women who reported no use of AHTs, women who had used calcium channel blockers (CCB) within the past two years had a 1.6-fold increased risk of breast cancer (95 % confidence interval (CI): 1.0-2.5), and in particular, recent users of immediate-release CCBs had a 2.4-fold increased risk (95 % CI: 1.3-4.5). Neither ever nor recent use of any other type of AHT was associated with breast cancer risk.

CONCLUSIONS: While the observed association between immediate-release CCBs and breast cancer risk is based on a small sample size and needs to be interpreted cautiously, this result is consistent with others in the literature. However, given declines in use of these preparations in favor of sustained-release CCBs, which was not related to risk, the potential clinical and public health impact of this association is limited. This study also adds to the evidence that other commonly used AHTs are not strongly related to breast cancer risk.

VL - 24 IS - 2 ER - TY - JOUR T1 - ADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - London, Stephanie J A1 - Gao, Wei A1 - Gharib, Sina A A1 - Hancock, Dana B A1 - Wilk, Jemma B A1 - House, John S A1 - Gibbs, Richard A A1 - Muzny, Donna M A1 - Lumley, Thomas A1 - Franceschini, Nora A1 - North, Kari E A1 - Psaty, Bruce M A1 - Kovar, Christie L A1 - Coresh, Josef A1 - Zhou, Yanhua A1 - Heckbert, Susan R A1 - Brody, Jennifer A A1 - Morrison, Alanna C A1 - Dupuis, Josée KW - ADAM Proteins KW - Aged KW - Aged, 80 and over KW - Aging KW - Cohort Studies KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Heart Diseases KW - Humans KW - Lung KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA AB -

BACKGROUND: The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes: ADAM19 and HTR4.

METHODS AND RESULTS: We sequenced ADAM19 and its promoter region along with the ≈21-kb portion of HTR4 harboring GWAS single-nucleotide polymorphisms for pulmonary function and analyzed associations with FEV1/FVC among 3983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Meta-analysis of common variants in each region identified statistically significant associations (316 tests; P<1.58×10(-4)) with FEV1/FVC for 14 ADAM19 single-nucleotide polymorphisms and 24 HTR4 single-nucleotide polymorphisms. After conditioning on the sentinel GWASs hit in each gene (ADAM19 rs1422795, minor allele frequency=0.33 and HTR4 rs11168048, minor allele frequency=0.40], 1 single-nucleotide polymorphism remained statistically significant (ADAM19 rs13155908, minor allele frequency=0.12; P=1.56×10(-4)). Analysis of rare variants (minor allele frequency <1%) using sequence kernel association test did not identify associations with either region.

CONCLUSIONS: Sequencing identified 1 common variant associated with FEV1/FVC independent of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not seem to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951661?dopt=Abstract ER - TY - JOUR T1 - Advanced glycation/glycoxidation endproduct carboxymethyl-lysine and incidence of coronary heart disease and stroke in older adults. JF - Atherosclerosis Y1 - 2014 A1 - Kizer, Jorge R A1 - Benkeser, David A1 - Arnold, Alice M A1 - Ix, Joachim H A1 - Mukamal, Kenneth J A1 - Djoussé, Luc A1 - Tracy, Russell P A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Zieman, Susan J KW - Aged KW - Albumins KW - Antihypertensive Agents KW - Blood Pressure KW - Cardiovascular Diseases KW - Cohort Studies KW - Coronary Disease KW - Creatinine KW - Female KW - Glomerular Filtration Rate KW - Glycation End Products, Advanced KW - Humans KW - Immunoassay KW - Incidence KW - Lysine KW - Male KW - Oxidative Stress KW - Proportional Hazards Models KW - Stroke KW - Treatment Outcome AB -

BACKGROUND: Advanced glycation/glycoxidation endproducts (AGEs) accumulate in settings of increased oxidative stress--such as diabetes, chronic kidney disease and aging--where they promote vascular stiffness and atherogenesis, but the prospective association between AGEs and cardiovascular events in elders has not been previously examined.

METHODS: To test the hypothesis that circulating levels of N(ɛ)-carboxymethyl-lysine (CML), a major AGE, increase the risk of incident coronary heart disease and stroke in older adults, we measured serum CML by immunoassay in 2111 individuals free of prevalent cardiovascular disease participating in a population-based study of U.S. adults ages 65 and older.

RESULTS: During median follow-up of 9.1 years, 625 cardiovascular events occurred. CML was positively associated with incident cardiovascular events after adjustment for age, sex, race, systolic blood pressure, anti-hypertensive treatment, diabetes, smoking status, triglycerides, albumin, and self-reported health status (hazard ratio [HR] per SD [0.99 pmol/l] increase=1.11, 95% confidence interval [CI]=1.03-1.19). This association was not materially attenuated by additional adjustment for C-reactive protein, estimated glomerular filtration rate (eGFR), and urine albumin/creatinine ratio. Findings were similar for the component endpoints of coronary heart disease and stroke.

CONCLUSIONS: In this large older cohort, CML was associated with an increased risk of cardiovascular events independent of a wide array of potential confounders and mediators. Although the moderate association limits CML's value for risk prediction, these community-based findings provide support for clinical trials to test AGE-lowering therapies for cardiovascular prevention in this population.

VL - 235 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24825341?dopt=Abstract ER - TY - JOUR T1 - Age- and sex-dependent upper reference limits for the high-sensitivity cardiac troponin T assay. JF - J Am Coll Cardiol Y1 - 2014 A1 - Gore, M Odette A1 - Seliger, Stephen L A1 - deFilippi, Christopher R A1 - Nambi, Vijay A1 - Christenson, Robert H A1 - Hashim, Ibrahim A A1 - Hoogeveen, Ron C A1 - Ayers, Colby R A1 - Sun, Wensheng A1 - McGuire, Darren K A1 - Ballantyne, Christie M A1 - de Lemos, James A KW - Adult KW - Age Factors KW - Aged KW - Biological Assay KW - Biomarkers KW - Blood Chemical Analysis KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Humans KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Reference Values KW - Risk Assessment KW - Sensitivity and Specificity KW - Severity of Illness Index KW - Sex Factors KW - Troponin T AB -

OBJECTIVES: The study sought to determine the 99th percentile upper reference limit for the high-sensitivity cardiac troponin T assay (hs-cTnT) in 3 large independent cohorts.

BACKGROUND: The presently recommended 14 ng/l cut point for the diagnosis of myocardial infarction using the hs-cTnT assay was derived from small studies of presumably healthy individuals, with relatively little phenotypic characterization.

METHODS: Data were included from 3 well-characterized population-based studies: the Dallas Heart Study (DHS), the Atherosclerosis Risk in Communities (ARIC) Study, and the Cardiovascular Health Study (CHS). Within each cohort, reference subcohorts were defined excluding individuals with recent hospitalization, overt cardiovascular disease, and kidney disease (subcohort 1), and further excluding those with subclinical structural heart disease (subcohort 2). Data were analyzed stratified by age, sex, and race.

RESULTS: The 99th percentile values for the hs-cTnT assay in DHS, ARIC, and CHS were 18, 22, and 36 ng/l (subcohort 1) and 14, 21, and 28 ng/l (subcohort 2), respectively. These differences in 99th percentile values paralleled age differences across cohorts. Analyses within sex/age strata yielded similar results between cohorts. Within each cohort, 99th percentile values increased with age and were higher in men. More than 10% of men 65 to 74 years of age with no cardiovascular disease in our study had cardiac troponin T values above the current myocardial infarction threshold.

CONCLUSIONS: Use of a uniform 14 ng/l cutoff for the hs-cTnT assay may lead to over-diagnosis of myocardial infarction, particularly in men and the elderly. Clinical validation is needed of new age- and sex-specific cutoff values for this assay.

VL - 63 IS - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24530665?dopt=Abstract ER - TY - JOUR T1 - Analysis of secondary outcomes in nested case-control study designs. JF - Stat Med Y1 - 2014 A1 - Kim, Ryung S A1 - Kaplan, Robert C KW - Aged KW - Aged, 80 and over KW - C-Reactive Protein KW - Case-Control Studies KW - Cohort Studies KW - Computer Simulation KW - Data Interpretation, Statistical KW - Female KW - Heart Failure KW - Humans KW - Intermittent Claudication KW - Male KW - Sample Size KW - Treatment Outcome AB -

One of the main perceived advantages of using a case-cohort design compared with a nested case-control design in an epidemiologic study is the ability to evaluate with the same subcohort outcomes other than the primary outcome of interest. In this paper, we show that valid inferences about secondary outcomes can also be achieved in nested case-control studies by using the inclusion probability weighting method in combination with an approximate jackknife standard error that can be computed using existing software. Simulation studies demonstrate that when the sample size is sufficient, this approach yields valid type 1 error and coverage rates for the analysis of secondary outcomes in nested case-control designs. Interestingly, the statistical power of the nested case-control design was comparable with that of the case-cohort design when the primary and secondary outcomes were positively correlated. The proposed method is illustrated with the data from a cohort in Cardiovascular Health Study to study the association of C-reactive protein levels and the incidence of congestive heart failure.

VL - 33 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24919979?dopt=Abstract ER - TY - JOUR T1 - Association between the metabolic syndrome, its individual components, and unprovoked venous thromboembolism: results of a patient-level meta-analysis. JF - Arterioscler Thromb Vasc Biol Y1 - 2014 A1 - Ageno, Walter A1 - Di Minno, Matteo N D A1 - Ay, Cihan A1 - Jang, Moon Ju A1 - Hansen, John-Bjarne A1 - Steffen, Lyn M A1 - Vaya, Amparo A1 - Rattazzi, Marcello A1 - Pabinger, Ingrid A1 - Oh, Doyeun A1 - Di Minno, Giovanni A1 - Braekkan, Sigrid K A1 - Cushman, Mary A1 - Bonet, Elena A1 - Pauletto, Paolo A1 - Squizzato, Alessandro A1 - Dentali, Francesco KW - Adult KW - Aged KW - Case-Control Studies KW - Cohort Studies KW - Female KW - Humans KW - Logistic Models KW - Male KW - Metabolic Syndrome KW - Middle Aged KW - Obesity, Abdominal KW - Risk Factors KW - Venous Thromboembolism AB -

OBJECTIVE: The metabolic syndrome (MetS) may contribute to the pathogenesis of venous thromboembolism (VTE), but this association requires additional investigation.

APPROACH AND RESULTS: We performed a patient-level meta-analysis of case-control and cohort studies that evaluated the role of MetS and risk of unprovoked VTE. For case-control studies, odds ratios and 95% confidence intervals were calculated using logistic regression analysis to estimate the influence of individual variables on the risk of VTE; χ(2) tests for trend were used to investigate the effect of increasing number of components of MetS on the risk of VTE and to explore the influence of abdominal obesity on this relationship. For cohort studies, hazard ratios and 95% confidence interval were calculated using multivariable Cox regression analysis. Six case-control studies were included (908 cases with unprovoked VTE and 1794 controls): in multivariate analysis, MetS was independently associated with VTE (odds ratio, 1.91; 95% confidence interval, 1.57-2.33), and both MetS and abdominal obesity were better predictors of unprovoked VTE than obesity defined by the body mass index. Two prospective cohort studies were included (26,531 subjects and 289 unprovoked VTE events): age, obesity, and abdominal obesity, but not MetS were associated with VTE.

CONCLUSIONS: Case-control but not prospective cohort studies support an association between MetS and VTE. Abdominal adiposity is a strong risk factor for VTE.

VL - 34 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25212233?dopt=Abstract ER - TY - JOUR T1 - Association of levels of fasting glucose and insulin with rare variants at the chromosome 11p11.2-MADD locus: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Cornes, Belinda K A1 - Brody, Jennifer A A1 - Nikpoor, Naghmeh A1 - Morrison, Alanna C A1 - Chu, Huan A1 - Ahn, Byung Soo A1 - Wang, Shuai A1 - Dauriz, Marco A1 - Barzilay, Joshua I A1 - Dupuis, Josée A1 - Florez, Jose C A1 - Coresh, Josef A1 - Gibbs, Richard A A1 - Kao, W H Linda A1 - Liu, Ching-Ti A1 - McKnight, Barbara A1 - Muzny, Donna A1 - Pankow, James S A1 - Reid, Jeffrey G A1 - White, Charles C A1 - Johnson, Andrew D A1 - Wong, Tien Y A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Rotter, Jerome I A1 - Siscovick, David S A1 - Sladek, Robert A1 - Meigs, James B KW - Aged KW - Aged, 80 and over KW - Aging KW - Blood Glucose KW - Chromosomes, Human, Pair 11 KW - Cohort Studies KW - Death Domain Receptor Signaling Adaptor Proteins KW - Diabetes Mellitus, Type 2 KW - Fasting KW - Female KW - Gene Frequency KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Guanine Nucleotide Exchange Factors KW - Heart Diseases KW - Humans KW - Insulin KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA AB -

BACKGROUND: Common variation at the 11p11.2 locus, encompassing MADD, ACP2, NR1H3, MYBPC3, and SPI1, has been associated in genome-wide association studies with fasting glucose and insulin (FI). In the Cohorts for Heart and Aging Research in Genomic Epidemiology Targeted Sequencing Study, we sequenced 5 gene regions at 11p11.2 to identify rare, potentially functional variants influencing fasting glucose or FI levels.

METHODS AND RESULTS: Sequencing (mean depth, 38×) across 16.1 kb in 3566 individuals without diabetes mellitus identified 653 variants, 79.9% of which were rare (minor allele frequency <1%) and novel. We analyzed rare variants in 5 gene regions with FI or fasting glucose using the sequence kernel association test. At NR1H3, 53 rare variants were jointly associated with FI (P=2.73×10(-3)); of these, 7 were predicted to have regulatory function and showed association with FI (P=1.28×10(-3)). Conditioning on 2 previously associated variants at MADD (rs7944584, rs10838687) did not attenuate this association, suggesting that there are >2 independent signals at 11p11.2. One predicted regulatory variant, chr11:47227430 (hg18; minor allele frequency=0.00068), contributed 20.6% to the overall sequence kernel association test score at NR1H3, lies in intron 2 of NR1H3, and is a predicted binding site for forkhead box A1 (FOXA1), a transcription factor associated with insulin regulation. In human HepG2 hepatoma cells, the rare chr11:47227430 A allele disrupted FOXA1 binding and reduced FOXA1-dependent transcriptional activity.

CONCLUSIONS: Sequencing at 11p11.2-NR1H3 identified rare variation associated with FI. One variant, chr11:47227430, seems to be functional, with the rare A allele reducing transcription factor FOXA1 binding and FOXA1-dependent transcriptional activity.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951664?dopt=Abstract ER - TY - JOUR T1 - Association of low-frequency and rare coding-sequence variants with blood lipids and coronary heart disease in 56,000 whites and blacks. JF - Am J Hum Genet Y1 - 2014 A1 - Peloso, Gina M A1 - Auer, Paul L A1 - Bis, Joshua C A1 - Voorman, Arend A1 - Morrison, Alanna C A1 - Stitziel, Nathan O A1 - Brody, Jennifer A A1 - Khetarpal, Sumeet A A1 - Crosby, Jacy R A1 - Fornage, Myriam A1 - Isaacs, Aaron A1 - Jakobsdottir, Johanna A1 - Feitosa, Mary F A1 - Davies, Gail A1 - Huffman, Jennifer E A1 - Manichaikul, Ani A1 - Davis, Brian A1 - Lohman, Kurt A1 - Joon, Aron Y A1 - Smith, Albert V A1 - Grove, Megan L A1 - Zanoni, Paolo A1 - Redon, Valeska A1 - Demissie, Serkalem A1 - Lawson, Kim A1 - Peters, Ulrike A1 - Carlson, Christopher A1 - Jackson, Rebecca D A1 - Ryckman, Kelli K A1 - Mackey, Rachel H A1 - Robinson, Jennifer G A1 - Siscovick, David S A1 - Schreiner, Pamela J A1 - Mychaleckyj, Josyf C A1 - Pankow, James S A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Harris, Tamara B A1 - Taylor, Kent D A1 - Stafford, Jeanette M A1 - Reynolds, Lindsay M A1 - Marioni, Riccardo E A1 - Dehghan, Abbas A1 - Franco, Oscar H A1 - Patel, Aniruddh P A1 - Lu, Yingchang A1 - Hindy, George A1 - Gottesman, Omri A1 - Bottinger, Erwin P A1 - Melander, Olle A1 - Orho-Melander, Marju A1 - Loos, Ruth J F A1 - Duga, Stefano A1 - Merlini, Piera Angelica A1 - Farrall, Martin A1 - Goel, Anuj A1 - Asselta, Rosanna A1 - Girelli, Domenico A1 - Martinelli, Nicola A1 - Shah, Svati H A1 - Kraus, William E A1 - Li, Mingyao A1 - Rader, Daniel J A1 - Reilly, Muredach P A1 - McPherson, Ruth A1 - Watkins, Hugh A1 - Ardissino, Diego A1 - Zhang, Qunyuan A1 - Wang, Judy A1 - Tsai, Michael Y A1 - Taylor, Herman A A1 - Correa, Adolfo A1 - Griswold, Michael E A1 - Lange, Leslie A A1 - Starr, John M A1 - Rudan, Igor A1 - Eiriksdottir, Gudny A1 - Launer, Lenore J A1 - Ordovas, Jose M A1 - Levy, Daniel A1 - Chen, Y-D Ida A1 - Reiner, Alexander P A1 - Hayward, Caroline A1 - Polasek, Ozren A1 - Deary, Ian J A1 - Borecki, Ingrid B A1 - Liu, Yongmei A1 - Gudnason, Vilmundur A1 - Wilson, James G A1 - van Duijn, Cornelia M A1 - Kooperberg, Charles A1 - Rich, Stephen S A1 - Psaty, Bruce M A1 - Rotter, Jerome I A1 - O'Donnell, Christopher J A1 - Rice, Kenneth A1 - Boerwinkle, Eric A1 - Kathiresan, Sekar A1 - Cupples, L Adrienne KW - 1-Alkyl-2-acetylglycerophosphocholine Esterase KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Alleles KW - Animals KW - Cholesterol, HDL KW - Cholesterol, LDL KW - Cohort Studies KW - Coronary Disease KW - European Continental Ancestry Group KW - Female KW - Gene Frequency KW - Genetic Association Studies KW - Genetic Code KW - Genetic Variation KW - Humans KW - Linear Models KW - Male KW - Mice KW - Mice, Inbred C57BL KW - Microtubule-Associated Proteins KW - Middle Aged KW - Phenotype KW - Sequence Analysis, DNA KW - Subtilisins KW - Triglycerides AB -

Low-frequency coding DNA sequence variants in the proprotein convertase subtilisin/kexin type 9 gene (PCSK9) lower plasma low-density lipoprotein cholesterol (LDL-C), protect against risk of coronary heart disease (CHD), and have prompted the development of a new class of therapeutics. It is uncertain whether the PCSK9 example represents a paradigm or an isolated exception. We used the "Exome Array" to genotype >200,000 low-frequency and rare coding sequence variants across the genome in 56,538 individuals (42,208 European ancestry [EA] and 14,330 African ancestry [AA]) and tested these variants for association with LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides. Although we did not identify new genes associated with LDL-C, we did identify four low-frequency (frequencies between 0.1% and 2%) variants (ANGPTL8 rs145464906 [c.361C>T; p.Gln121*], PAFAH1B2 rs186808413 [c.482C>T; p.Ser161Leu], COL18A1 rs114139997 [c.331G>A; p.Gly111Arg], and PCSK7 rs142953140 [c.1511G>A; p.Arg504His]) with large effects on HDL-C and/or triglycerides. None of these four variants was associated with risk for CHD, suggesting that examples of low-frequency coding variants with robust effects on both lipids and CHD will be limited.

VL - 94 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24507774?dopt=Abstract ER - TY - JOUR T1 - Association of sick sinus syndrome with incident cardiovascular disease and mortality: the Atherosclerosis Risk in Communities study and Cardiovascular Health Study. JF - PLoS One Y1 - 2014 A1 - Alonso, Alvaro A1 - Jensen, Paul N A1 - Lopez, Faye L A1 - Chen, Lin Y A1 - Psaty, Bruce M A1 - Folsom, Aaron R A1 - Heckbert, Susan R KW - Age Distribution KW - Atherosclerosis KW - Cohort Studies KW - Continental Population Groups KW - Female KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Residence Characteristics KW - Risk KW - Sex Distribution KW - Sick Sinus Syndrome AB -

BACKGROUND: Sick sinus syndrome (SSS) is a common indication for pacemaker implantation. Limited information exists on the association of sick sinus syndrome (SSS) with mortality and cardiovascular disease (CVD) in the general population.

METHODS: We studied 19,893 men and women age 45 and older in the Atherosclerosis Risk in Communities (ARIC) study and the Cardiovascular Health Study (CHS), two community-based cohorts, who were without a pacemaker or atrial fibrillation (AF) at baseline. Incident SSS cases were validated by review of medical charts. Incident CVD and mortality were ascertained using standardized protocols. Multivariable Cox models were used to estimate the association of incident SSS with selected outcomes.

RESULTS: During a mean follow-up of 17 years, 213 incident SSS events were identified and validated (incidence, 0.6 events per 1,000 person-years). After adjustment for confounders, SSS incidence was associated with increased mortality (hazard ratio [HR] 1.39, 95% confidence interval [CI] 1.14-1.70), coronary heart disease (HR 1.72, 95%CI 1.11-2.66), heart failure (HR 2.87, 95%CI 2.17-3.80), stroke (HR 1.56, 95%CI 0.99-2.46), AF (HR 5.75, 95%CI 4.43-7.46), and pacemaker implantation (HR 53.7, 95%CI 42.9-67.2). After additional adjustment for other incident CVD during follow-up, SSS was no longer associated with increased mortality, coronary heart disease, or stroke, but remained associated with higher risk of heart failure (HR 2.00, 95%CI 1.51-2.66), AF (HR 4.25, 95%CI 3.28-5.51), and pacemaker implantation (HR 25.2, 95%CI 19.8-32.1).

CONCLUSION: Individuals who develop SSS are at increased risk of death and CVD. The mechanisms underlying these associations warrant further investigation.

VL - 9 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25285853?dopt=Abstract ER - TY - JOUR T1 - Brain imaging findings in elderly adults and years of life, healthy life, and able life over the ensuing 16 years: the Cardiovascular Health Study. JF - J Am Geriatr Soc Y1 - 2014 A1 - Longstreth, W T A1 - Diehr, Paula H A1 - Yee, Laura M A1 - Newman, Anne B A1 - Beauchamp, Norman J KW - Activities of Daily Living KW - Aged KW - Atrophy KW - Brain KW - Brain Infarction KW - Cohort Studies KW - Disability Evaluation KW - Female KW - Health Status KW - Humans KW - Leukoaraiosis KW - Longevity KW - Longitudinal Studies KW - Magnetic Resonance Imaging KW - Male KW - Prognosis KW - Regression Analysis KW - United States AB -

OBJECTIVES: To determine whether elderly people with different patterns of magnetic resonance imaging (MRI) findings have different long-term outcomes.

DESIGN: Longitudinal cohort study.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Individuals aged 65 and older were recruited (N = 5,888); 3,660 of these underwent MRI, and 3,230 without a stroke before MRI were included in these analyses.

MEASUREMENTS: Cluster analysis of brain MRI findings was previously used to define five clusters: normal, atrophy, simple infarct, leukoaraiosis, and complex infarct. Participants were subsequently classified as healthy if they rated their health as excellent, very good, or good and as able if they did not report any limitations in activities of daily living (ADLs). Mean years of life (YoL), years of healthy life (YHL), and years of able life (YAL) were calculated over 16 years after the MRI and compared between clusters using unadjusted and adjusted regression analyses.

RESULTS: Mean age of participants was 75.0. With 16 years of follow-up, mean YoL was 11.3; YHL, 8.0; and YAL, 8.4. Outcomes differed significantly between clusters. With or without adjustments, outcomes were all significantly better in the normal than complex infarct cluster. The three remaining clusters had intermediate results, significantly different from the normal and complex infarct clusters but not usually from one another. Over 16 years of follow-up, participants in the complex infarct cluster (n = 368) spent the largest percentage of their 8.4 years alive being sick (38%) and not able (38%).

CONCLUSION: Findings on MRI scans in elderly adults are associated not only with long-term survival, but also with long-term self-rated health and limitation in ADLs. The combination of infarcts and leukoaraiosis carried the worst prognosis, presumably reflecting small vessel disease.

VL - 62 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25333525?dopt=Abstract ER - TY - JOUR T1 - Circulating omega-6 polyunsaturated fatty acids and total and cause-specific mortality: the Cardiovascular Health Study. JF - Circulation Y1 - 2014 A1 - Wu, Jason H Y A1 - Lemaitre, Rozenn N A1 - King, Irena B A1 - Song, Xiaoling A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Mozaffarian, Dariush KW - Aged KW - Arachidonic Acid KW - Biomarkers KW - Cohort Studies KW - Coronary Disease KW - Fatty Acids, Omega-3 KW - Fatty Acids, Omega-6 KW - Fatty Acids, Unsaturated KW - Female KW - Follow-Up Studies KW - Humans KW - Linoleic Acid KW - Male KW - Prospective Studies KW - Regression Analysis KW - Risk Factors KW - Stroke KW - Survival Rate KW - United States AB -

BACKGROUND: Although omega-6 polyunsaturated fatty acids (n-6 PUFA) have been recommended to reduce coronary heart disease (CHD), controversy remains about benefits versus harms, including concerns over theorized proinflammatory effects of n-6 PUFA. We investigated associations of circulating n-6 PUFA including linoleic acid (the major dietary PUFA), γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid, with total and cause-specific mortality in the Cardiovascular Health Study, a community-based U.S. cohort.

METHODS AND RESULTS: Among 2792 participants(aged ≥65 years) free of cardiovascular disease at baseline, plasma phospholipid n-6 PUFA were measured at baseline using standardized methods. All-cause and cause-specific mortality, and total incident CHD and stroke, were assessed and adjudicated centrally. Associations of PUFA with risk were assessed by Cox regression. During 34 291 person-years of follow-up (1992-2010), 1994 deaths occurred (678 cardiovascular deaths), with 427 fatal and 418 nonfatal CHD, and 154 fatal and 399 nonfatal strokes. In multivariable models, higher linoleic acid was associated with lower total mortality, with extreme-quintile hazard ratio =0.87 (P trend=0.005). Lower death was largely attributable to cardiovascular disease causes, especially nonarrhythmic CHD mortality (hazard ratio, 0.51; 95% confidence interval, 0.32-0.82; P trend=0.001). Circulating γ-linolenic acid, dihomo-γ-linolenic acid, and arachidonic acid were not significantly associated with total or cause-specific mortality (eg, for arachidonic acid and CHD death, the extreme-quintile hazard ratio was 0.97; 95% confidence interval, 0.70-1.34; P trend=0.87). Evaluated semiparametrically, linoleic acid showed graded inverse associations with total mortality (P=0.005). There was little evidence that associations of n-6 PUFA with total mortality varied by age, sex, race, or plasma n-3 PUFA. Evaluating both n-6 and n-3 PUFA, lowest risk was evident with highest levels of both.

CONCLUSIONS: High circulating linoleic acid, but not other n-6 PUFA, was inversely associated with total and CHD mortality in older adults.

VL - 130 IS - 15 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25124495?dopt=Abstract ER - TY - JOUR T1 - Common carotid intima-media thickness measurements do not improve cardiovascular risk prediction in individuals with elevated blood pressure: the USE-IMT collaboration. JF - Hypertension Y1 - 2014 A1 - Bots, Michiel L A1 - Groenewegen, Karlijn A A1 - Anderson, Todd J A1 - Britton, Annie R A1 - Dekker, Jacqueline M A1 - Engström, Gunnar A1 - Evans, Greg W A1 - de Graaf, Jacqueline A1 - Grobbee, Diederick E A1 - Hedblad, Bo A1 - Hofman, Albert A1 - Holewijn, Suzanne A1 - Ikeda, Ai A1 - Kavousi, Maryam A1 - Kitagawa, Kazuo A1 - Kitamura, Akihiko A1 - Ikram, M Arfan A1 - Lonn, Eva M A1 - Lorenz, Matthias W A1 - Mathiesen, Ellisiv B A1 - Nijpels, Giel A1 - Okazaki, Shuhei A1 - O'Leary, Daniel H A1 - Polak, Joseph F A1 - Price, Jacqueline F A1 - Robertson, Christine A1 - Rembold, Christopher M A1 - Rosvall, Maria A1 - Rundek, Tatjana A1 - Salonen, Jukka T A1 - Sitzer, Matthias A1 - Stehouwer, Coen D A A1 - Franco, Oscar H A1 - Peters, Sanne A E A1 - den Ruijter, Hester M KW - Adult KW - Aged KW - Antihypertensive Agents KW - Blood Pressure KW - Cardiovascular Diseases KW - Carotid Artery, Common KW - Carotid Intima-Media Thickness KW - Cohort Studies KW - Female KW - Humans KW - Hypertension KW - Male KW - Meta-Analysis as Topic KW - Middle Aged KW - Risk Assessment KW - Risk Factors AB -

Carotid intima-media thickness (CIMT) is a marker of cardiovascular risk. It is unclear whether measurement of mean common CIMT improves 10-year risk prediction of first-time myocardial infarction or stroke in individuals with elevated blood pressure. We performed an analysis among individuals with elevated blood pressure (i.e., a systolic blood pressure ≥140 mm Hg and a diastolic blood pressure ≥ 90 mm Hg) in USE-IMT, a large ongoing individual participant data meta-analysis. We refitted the risk factors of the Framingham Risk Score on asymptomatic individuals (baseline model) and expanded this model with mean common CIMT (CIMT model) measurements. From both models, 10-year risks to develop a myocardial infarction or stroke were estimated. In individuals with elevated blood pressure, we compared discrimination and calibration of the 2 models and calculated the net reclassification improvement (NRI). We included 17 254 individuals with elevated blood pressure from 16 studies. During a median follow-up of 9.9 years, 2014 first-time myocardial infarctions or strokes occurred. The C-statistics of the baseline and CIMT models were similar (0.73). NRI with the addition of mean common CIMT was small and not significant (1.4%; 95% confidence intervals, -1.1 to 3.7). In those at intermediate risk (n=5008, 10-year absolute risk of 10% to 20%), the NRI was 5.6% (95% confidence intervals, 1.6-10.4). There is no added value of measurement of mean common CIMT in individuals with elevated blood pressure for improving cardiovascular risk prediction. For those at intermediate risk, the addition of mean common CIMT to an existing cardiovascular risk score is small but statistically significant.

VL - 63 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24614213?dopt=Abstract ER - TY - JOUR T1 - A common SCN5A variant is associated with PR interval and atrial fibrillation among African Americans. JF - J Cardiovasc Electrophysiol Y1 - 2014 A1 - Ilkhanoff, Leonard A1 - Arking, Dan E A1 - Lemaitre, Rozenn N A1 - Alonso, Alvaro A1 - Chen, Lin Y A1 - Durda, Peter A1 - Hesselson, Stephanie E A1 - Kerr, Kathleen F A1 - Magnani, Jared W A1 - Marcus, Gregory M A1 - Schnabel, Renate B A1 - Smith, J Gustav A1 - Soliman, Elsayed Z A1 - Reiner, Alexander P A1 - Sotoodehnia, Nona KW - Adult KW - African Americans KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Case-Control Studies KW - Cohort Studies KW - Death, Sudden, Cardiac KW - Female KW - Genetic Variation KW - Humans KW - Male KW - Middle Aged KW - NAV1.5 Voltage-Gated Sodium Channel KW - Prospective Studies KW - Risk Factors KW - Single-Blind Method AB -

OBJECTIVE: We examined the association of rs7626962 (S1103Y) or rs7629265, a variant in high linkage disequilibrium with S1103Y (r(2) = 0.87 - 1), with sudden cardiac death (SCD) and atrial fibrillation (AF) among African Americans.

BACKGROUND: The SCN5A missense variant S1103Y has been associated with SCD among African Americans in small case-control studies, but larger population-based studies are needed to validate these findings. The association of this variant with AF has not been fully explored.

METHODS: Using genotyping data on over 7,000 African Americans from 5 cohorts (Atherosclerosis Risk in Communities [ARIC], Cleveland Family Study [CFS], Jackson Heart Study [JHS], Multi-Ethnic Study of Atherosclerosis [MESA], Cardiovascular Health Study [CHS]), we examined the association of rs7629265 with electrocardiographic PR, QRS, and QT intervals, and with incident AF and SCD. We examined association of S1103Y (rs7626962) with SCD using a population-based case-control study of SCD Cardiac Arrest Blood Study (CABS).

RESULTS: Meta-analyses across 5 cohorts demonstrated that rs7629265 was significantly associated with PR duration (β = -4.1 milliseconds; P = 2.2×10(-6) ), but not significantly associated with QRS or QT intervals. In meta-analyses of prospectively followed ARIC and CHS participants (n = 3,656), rs7629265 was associated with increased AF risk (n = 299 AF cases; HR = 1.74, P = 1.9 × 10(-4) ). By contrast, rs7629265 was not significantly associated with SCD risk in ARIC (n = 83 SCD cases; P = 0.30) or CHS (n = 54 SCD cases; P = 0.47). Similarly, S1103Y was not significantly associated with SCD risk in CABS (n = 225 SCD cases; P = 0.29).

CONCLUSION: The common SCN5A variant, rs7629265, is associated with increased AF risk and shorter PR interval among African Americans. In contrast to prior reports, we found no evidence of association of rs7629265 or rs7626962 (S1103Y) with SCD risk in the general population.

VL - 25 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25065297?dopt=Abstract ER - TY - JOUR T1 - Decline in estimated glomerular filtration rate and subsequent risk of end-stage renal disease and mortality. JF - JAMA Y1 - 2014 A1 - Coresh, Josef A1 - Turin, Tanvir Chowdhury A1 - Matsushita, Kunihiro A1 - Sang, Yingying A1 - Ballew, Shoshana H A1 - Appel, Lawrence J A1 - Arima, Hisatomi A1 - Chadban, Steven J A1 - Cirillo, Massimo A1 - Djurdjev, Ognjenka A1 - Green, Jamie A A1 - Heine, Gunnar H A1 - Inker, Lesley A A1 - Irie, Fujiko A1 - Ishani, Areef A1 - Ix, Joachim H A1 - Kovesdy, Csaba P A1 - Marks, Angharad A1 - Ohkubo, Takayoshi A1 - Shalev, Varda A1 - Shankar, Anoop A1 - Wen, Chi Pang A1 - de Jong, Paul E A1 - Iseki, Kunitoshi A1 - Stengel, Bénédicte A1 - Gansevoort, Ron T A1 - Levey, Andrew S KW - Adult KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Creatinine KW - Disease Progression KW - Endpoint Determination KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Reference Values KW - Risk AB -

IMPORTANCE: The established chronic kidney disease (CKD) progression end point of end-stage renal disease (ESRD) or a doubling of serum creatinine concentration (corresponding to a change in estimated glomerular filtration rate [GFR] of −57% or greater) is a late event.

OBJECTIVE: To characterize the association of decline in estimated GFR with subsequent progression to ESRD with implications for using lesser declines in estimated GFR as potential alternative end points for CKD progression. Because most people with CKD die before reaching ESRD, mortality risk also was investigated.

DATA SOURCES AND STUDY SELECTION: Individual meta-analysis of 1.7 million participants with 12,344 ESRD events and 223,944 deaths from 35 cohorts in the CKD Prognosis Consortium with a repeated measure of serum creatinine concentration over 1 to 3 years and outcome data.

DATA EXTRACTION AND SYNTHESIS: Transfer of individual participant data or standardized analysis of outputs for random-effects meta-analysis conducted between July 2012 and September 2013, with baseline estimated GFR values collected from 1975 through 2012.

MAIN OUTCOMES AND MEASURES: End-stage renal disease (initiation of dialysis or transplantation) or all-cause mortality risk related to percentage change in estimated GFR over 2 years, adjusted for potential confounders and first estimated GFR.

RESULTS: The adjusted hazard ratios (HRs) of ESRD and mortality were higher with larger estimated GFR decline. Among participants with baseline estimated GFR of less than 60 mL/min/1.73 m2, the adjusted HRs for ESRD were 32.1 (95% CI, 22.3-46.3) for changes of −57% in estimated GFR and 5.4 (95% CI, 4.5-6.4) for changes of −30%. However, changes of −30% or greater (6.9% [95% CI, 6.4%-7.4%] of the entire consortium) were more common than changes of −57% (0.79% [95% CI, 0.52%-1.06%]). This association was strong and consistent across the length of the baseline period (1 to 3 years), baseline estimated GFR, age, diabetes status, or albuminuria. Average adjusted 10-year risk of ESRD (in patients with a baseline estimated GFR of 35 mL/min/1.73 m2) was 99% (95% CI, 95%-100%) for estimated GFR change of −57%, was 83% (95% CI, 71%-93%) for estimated GFR change of −40%, and was 64% (95% CI, 52%-77%) for estimated GFR change of −30% vs 18% (95% CI, 15%-22%) for estimated GFR change of 0%. Corresponding mortality risks were 77% (95% CI, 71%-82%), 60% (95% CI, 56%-63%), and 50% (95% CI, 47%-52%) vs 32% (95% CI, 31%-33%), showing a similar but weaker pattern.

CONCLUSIONS AND RELEVANCE: Declines in estimated GFR smaller than a doubling of serum creatinine concentration occurred more commonly and were strongly and consistently associated with the risk of ESRD and mortality, supporting consideration of lesser declines in estimated GFR (such as a 30% reduction over 2 years) as an alternative end point for CKD progression.

VL - 311 IS - 24 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24892770?dopt=Abstract ER - TY - JOUR T1 - Development and validation of a brief dementia screening indicator for primary care. JF - Alzheimers Dement Y1 - 2014 A1 - Barnes, Deborah E A1 - Beiser, Alexa S A1 - Lee, Anne A1 - Langa, Kenneth M A1 - Koyama, Alain A1 - Preis, Sarah R A1 - Neuhaus, John A1 - McCammon, Ryan J A1 - Yaffe, Kristine A1 - Seshadri, Sudha A1 - Haan, Mary N A1 - Weir, David R KW - Aged KW - Cohort Studies KW - Dementia KW - Female KW - Humans KW - Male KW - Mass Screening KW - Predictive Value of Tests KW - Primary Health Care KW - Proportional Hazards Models KW - Risk Assessment AB -

BACKGROUND: Detection of "any cognitive impairment" is mandated as part of the Medicare annual wellness visit, but screening all patients may result in excessive false positives.

METHODS: We developed and validated a brief Dementia Screening Indicator using data from four large, ongoing cohort studies (the Cardiovascular Health Study [CHS]; the Framingham Heart Study [FHS]; the Health and Retirement Study [HRS]; the Sacramento Area Latino Study on Aging [SALSA]) to help clinicians identify a subgroup of high-risk patients to target for cognitive screening.

RESULTS: The final Dementia Screening Indicator included age (1 point/year; ages, 65-79 years), less than 12 years of education (9 points), stroke (6 points), diabetes mellitus (3 points), body mass index less than 18.5 kg/m(2) (8 points), requiring assistance with money or medications (10 points), and depressive symptoms (6 points). Accuracy was good across the cohorts (Harrell's C statistic: CHS, 0.68; FHS, 0.77; HRS, 0.76; SALSA, 0.78).

CONCLUSIONS: The Dementia Screening Indicator is a simple tool that may be useful in primary care settings to identify high-risk patients to target for cognitive screening.

VL - 10 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24491321?dopt=Abstract ER - TY - JOUR T1 - Do changes in circulating biomarkers track with each other and with functional changes in older adults? JF - J Gerontol A Biol Sci Med Sci Y1 - 2014 A1 - Sanders, Jason L A1 - Ding, Victoria A1 - Arnold, Alice M A1 - Kaplan, Robert C A1 - Cappola, Anne R A1 - Kizer, Jorge R A1 - Boudreau, Robert M A1 - Cushman, Mary A1 - Newman, Anne B KW - Adiponectin KW - Aged KW - Aged, 80 and over KW - Aging KW - Biomarkers KW - Cholesterol KW - Cognition KW - Cohort Studies KW - Dehydroepiandrosterone Sulfate KW - Female KW - Gait KW - Hand Strength KW - Humans KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Interleukin-6 KW - Male KW - Neuropsychological Tests KW - Psychomotor Performance KW - Time Factors AB -

BACKGROUND: It is unclear if changes in proposed circulating biomarkers of aging are strongly correlated to each other or functional change. We tested if biomarker changes track with each other and with functional measures over 9 years in older adults.

METHODS: Dehydroepiandrosterone sulfate (DHEAS), adiponectin, insulin-like growth factor 1 (IGF-1), IGF binding proteins 1 (IGFBP-1) and 3 (IGFBP-3), interleukin-6 (IL-6), cholesterol, and function (gait speed, grip strength, Modified Mini Mental Status Exam [3MSE] and Digit Symbol Substitution Test [DSST] scores) were measured in 1996-1997 and 2005-2006 in the Cardiovascular Health Study All Stars study (N = 901, mean [standard deviation, SD] age 85.3 [3.6] years in 2005-2006). Adjusted Pearson correlations illustrated if biomarkers tracked together. Multivariable linear regression demonstrated if biomarker changes tracked with functional changes.

RESULTS: Correlations among biomarker changes were mostly <0.2. In models with each biomarker entered separately, a 1-SD increase biomarker change was associated with change in function as follows: grip strength (DHEAS β = 0.61kg, p = .001; IL-6 β = -0.46kg, p = .012; cholesterol men β = 0.79kg, p = .016); gait speed (DHEAS β = 0.02 meters per second, p = .039; IL-6 β = -0.018 meters per second, p = .049); and DSST score (DHEAS women β = 1.46, p = .004; IL-6 β = -0.83, p = .027). When biomarkers were entered in the same model, significant associations remaining were as follows: grip strength (DHEAS β = 0.54kg, p = .005; IL-6 β = -0.43kg, p = .022); 3MSE score (IGF-1 β = 0.96, p = .04; IGFBP-3 β = -1.07, p = .024); and DSST score (DHEAS women β = 1.27, p = .012; IL-6 β = -0.80, p = .04).

CONCLUSION: Changes in biomarkers were poorly correlated, supporting a model of stochastic, independent change across systems. DHEAS and IL-6 tracked most closely with function, illustrating that changes in inflammation and sex steroids may play dominant roles in changes of these functional outcomes.

VL - 69 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23811185?dopt=Abstract ER - TY - JOUR T1 - Effect of genetic variants associated with plasma homocysteine levels on stroke risk. JF - Stroke Y1 - 2014 A1 - Cotlarciuc, Ioana A1 - Malik, Rainer A1 - Holliday, Elizabeth G A1 - Ahmadi, Kourosh R A1 - Paré, Guillaume A1 - Psaty, Bruce M A1 - Fornage, Myriam A1 - Hasan, Nazeeha A1 - Rinne, Paul E A1 - Ikram, M Arfan A1 - Markus, Hugh S A1 - Rosand, Jonathan A1 - Mitchell, Braxton D A1 - Kittner, Steven J A1 - Meschia, James F A1 - van Meurs, Joyce B J A1 - Uitterlinden, André G A1 - Worrall, Bradford B A1 - Dichgans, Martin A1 - Sharma, Pankaj KW - Brain Ischemia KW - Cohort Studies KW - Europe KW - Genetic Association Studies KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome KW - Homocysteine KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk KW - Stroke AB -

BACKGROUND AND PURPOSE: Elevated total plasma homocysteine (tHcy) levels are known to be associated with increased risk of ischemic stroke (IS). Given that both tHcy and IS are heritable traits, we investigated a potential genetic relationship between homocysteine levels and stroke risk by assessing 18 polymorphisms previously associated with tHcy levels for their association with IS and its subtypes.

METHODS: Previous meta-analysis results from an international stroke collaborative network, METASTROKE, were used to assess association of the 18 tHcy-associated single-nucleotide polymorphisms (SNPs) in 12 389 IS cases and 62 004 controls. We also investigated the associations in regions located within 50 kb from the 18 tHcy-related SNPs and the association of a genetic risk score, including the 18 SNPs.

RESULTS: One SNP located in the RASIP1 gene and a cluster of 3 SNPs located at and near SLC17A3 were significantly associated with IS (P<0.0003) after correcting for multiple testing. For stroke subtypes, the sentinel SNP located upstream of MUT was significantly associated with small-vessel disease (P=0.0022), whereas 1 SNP located in MTHFR was significantly associated with large-vessel disease (P=0.00019). A genetic risk score, including the 18 SNPs, did not show significant association with IS or its subtypes.

CONCLUSIONS: This study found several potential associations with IS and its subtypes: an association of an MUT variant with small-vessel disease, an MTHFR variant with large-vessel disease, and associations of RASIP1 and SLC17A3 variants with overall IS.

VL - 45 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24846872?dopt=Abstract ER - TY - JOUR T1 - Enhancing case ascertainment of Parkinson's disease using Medicare claims data in a population-based cohort: the Cardiovascular Health Study. JF - Pharmacoepidemiol Drug Saf Y1 - 2014 A1 - Ton, Thanh G N A1 - Biggs, Mary Lou A1 - Comer, Diane A1 - Curtis, Lesley A1 - Hu, Shu-Ching A1 - Thacker, Evan L A1 - Searles Nielsen, Susan A1 - Delaney, Joseph A A1 - Landsittel, Douglas A1 - Longstreth, William T A1 - Checkoway, Harvey A1 - Jain, Samay KW - Aged KW - Aged, 80 and over KW - Algorithms KW - Antiparkinson Agents KW - Cohort Studies KW - Databases, Factual KW - Female KW - Hospitalization KW - Humans KW - Incidence KW - Logistic Models KW - Male KW - Medicare KW - Parkinson Disease KW - Prevalence KW - Prospective Studies KW - Smoking KW - Time Factors KW - United States AB -

PURPOSE: We sought to improve a previous algorithm to ascertain Parkinson's disease (PD) in the Cardiovascular Health Study by incorporating additional data from Medicare outpatient claims. We compared our results to the previous algorithm in terms of baseline prevalence and incidence of PD, as well as associations with baseline smoking characteristics.

METHODS: Our original case ascertainment used self-reported diagnosis, antiparkinsonian medication, and hospitalization discharge International Classification of Diseases-Ninth version code. In this study, we incorporated additional data from fee-for-service Medicare claims, extended follow-up time, review of hospitalization records, and adjudicated cause of death. Two movement disorders specialists adjudicated final PD status. We used logistic regression models and controlled for age, sex, African American race, and education.

RESULTS: We identified 75 additional cases but reclassified 80 previously identified cases as not having PD. We observed significant inverse association with smoking status (odds ratio = 0.42; 95% confidence interval (CI) = 0.22, 0.79), and inverse linear trends with pack-years (p = 0.005), and cigarettes per day (p = 0.019) with incident PD. All estimates were stronger than those from the previous algorithm.

CONCLUSIONS: Our enhanced method did not alter prevalence and incidence estimates compared with our previous algorithm. However, our enhanced method provided stronger estimates of association, potentially due to reduced level of disease misclassification.

VL - 23 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24357102?dopt=Abstract ER - TY - JOUR T1 - Estimated GFR and circulating 24,25-dihydroxyvitamin D3 concentration: a participant-level analysis of 5 cohort studies and clinical trials. JF - Am J Kidney Dis Y1 - 2014 A1 - de Boer, Ian H A1 - Sachs, Michael C A1 - Chonchol, Michel A1 - Himmelfarb, Jonathan A1 - Hoofnagle, Andrew N A1 - Ix, Joachim H A1 - Kremsdorf, Robin A A1 - Lin, Yvonne S A1 - Mehrotra, Rajnish A1 - Robinson-Cohen, Cassianne A1 - Siscovick, David S A1 - Steffes, Michael W A1 - Thummel, Kenneth E A1 - Tracy, Russell P A1 - Wang, Zhican A1 - Kestenbaum, Bryan KW - 24,25-Dihydroxyvitamin D 3 KW - Adult KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Cohort Studies KW - Cross-Sectional Studies KW - Diabetes Mellitus KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Observational Studies as Topic KW - Randomized Controlled Trials as Topic KW - Young Adult AB -

BACKGROUND: Decreased glomerular filtration rate (GFR) leads to reduced production of 1,25-dihydroxyvitamin D3 from 25-hydroxyvitamin D3 (25[OH]D3). Effects of low GFR on vitamin D catabolism are less well understood. We tested associations of estimated GFR (eGFR) with the circulating concentration of 24,25-dihydroxyvitamin D3 (24,25[OH]2D3), the most abundant product of 25(OH)D3 catabolism, across populations with a wide range of GFRs.

STUDY DESIGN: Cross-sectional study.

SETTING & PARTICIPANTS: 9,596 participants in 5 cohort studies and clinical trials: the Diabetes Control and Complications Trial (N=1,193), Multi-Ethnic Study of Atherosclerosis (N=6,470), Cardiovascular Health Study (N=932), Seattle Kidney Study (N=289), and Hemodialysis Study (N=712).

PREDICTOR: eGFR.

OUTCOME: Circulating 24,25(OH)2D3 concentration.

MEASUREMENTS: GFR was estimated from serum creatinine using the Chronic Kidney Disease Epidemiology Collaboration equation. Vitamin D metabolites were measured by mass spectrometry.

RESULTS: Circulating 24,25(OH)2D3 concentration was correlated with circulating 25(OH)D3 concentration (Pearson r range, 0.64-0.88). This correlation was weaker with lower eGFRs. Moreover, the increment in 24,25(OH)2D3 concentration associated with higher 25(OH)D3 concentration (slope) was lower with lower eGFRs: 2.06 (95% CI, 2.01-2.10), 1.77 (95% CI, 1.74-1.81), 1.55 (95% CI, 1.48-1.62), 1.17 (95% CI, 1.05-1.29), 0.92 (95% CI, 0.74-1.10), 0.61 (95% CI, 0.22-1.00), and 0.37 (95% CI, 0.35-0.39) ng/mL of 24,25(OH)2D3 per 10 ng/mL of 25(OH)D3 for eGFRs≥90, 60-89, 45-59, 30-44, 15-29, and <15 mL/min/1.73 m2 and end-stage renal disease treated with hemodialysis, respectively. As a result, at a 25(OH)D3 concentration of 20 ng/mL, mean 24,25(OH)2D3 concentrations were 2.92 (95% CI, 2.87-2.96), 2.68 (95% CI, 2.64-2.72), 2.35 (95% CI, 2.26-2.45), 1.92 (95% CI, 1.74-2.10), 1.69 (95% CI, 1.43-1.95), 1.14 (95% CI, 0.62-1.66), and 1.04 (95% CI,1.02-1.07) ng/mL for each category, respectively. This interaction was independent of other relevant clinical characteristics. Race, diabetes, urine albumin excretion, and circulating parathyroid hormone and fibroblast growth factor 23 concentrations more modestly modified the association of 24,25(OH)2D3 with 25(OH)D3.

LIMITATIONS: Lack of direct pharmacokinetic measurements of vitamin D catabolism.

CONCLUSIONS: Lower eGFR is associated strongly with reduced vitamin D catabolism, as measured by circulating 24,25(OH)2D3 concentration.

VL - 64 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24703961?dopt=Abstract ER - TY - JOUR T1 - Gene-age interactions in blood pressure regulation: a large-scale investigation with the CHARGE, Global BPgen, and ICBP Consortia. JF - Am J Hum Genet Y1 - 2014 A1 - Simino, Jeannette A1 - Shi, Gang A1 - Bis, Joshua C A1 - Chasman, Daniel I A1 - Ehret, Georg B A1 - Gu, Xiangjun A1 - Guo, Xiuqing A1 - Hwang, Shih-Jen A1 - Sijbrands, Eric A1 - Smith, Albert V A1 - Verwoert, Germaine C A1 - Bragg-Gresham, Jennifer L A1 - Cadby, Gemma A1 - Chen, Peng A1 - Cheng, Ching-Yu A1 - Corre, Tanguy A1 - de Boer, Rudolf A A1 - Goel, Anuj A1 - Johnson, Toby A1 - Khor, Chiea-Chuen A1 - Lluís-Ganella, Carla A1 - Luan, Jian'an A1 - Lyytikäinen, Leo-Pekka A1 - Nolte, Ilja M A1 - Sim, Xueling A1 - Sõber, Siim A1 - van der Most, Peter J A1 - Verweij, Niek A1 - Zhao, Jing Hua A1 - Amin, Najaf A1 - Boerwinkle, Eric A1 - Bouchard, Claude A1 - Dehghan, Abbas A1 - Eiriksdottir, Gudny A1 - Elosua, Roberto A1 - Franco, Oscar H A1 - Gieger, Christian A1 - Harris, Tamara B A1 - Hercberg, Serge A1 - Hofman, Albert A1 - James, Alan L A1 - Johnson, Andrew D A1 - Kähönen, Mika A1 - Khaw, Kay-Tee A1 - Kutalik, Zoltán A1 - Larson, Martin G A1 - Launer, Lenore J A1 - Li, Guo A1 - Liu, Jianjun A1 - Liu, Kiang A1 - Morrison, Alanna C A1 - Navis, Gerjan A1 - Ong, Rick Twee-Hee A1 - Papanicolau, George J A1 - Penninx, Brenda W A1 - Psaty, Bruce M A1 - Raffel, Leslie J A1 - Raitakari, Olli T A1 - Rice, Kenneth A1 - Rivadeneira, Fernando A1 - Rose, Lynda M A1 - Sanna, Serena A1 - Scott, Robert A A1 - Siscovick, David S A1 - Stolk, Ronald P A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - van der Klauw, Melanie M A1 - Vasan, Ramachandran S A1 - Vithana, Eranga Nishanthie A1 - Völker, Uwe A1 - Völzke, Henry A1 - Watkins, Hugh A1 - Young, Terri L A1 - Aung, Tin A1 - Bochud, Murielle A1 - Farrall, Martin A1 - Hartman, Catharina A A1 - Laan, Maris A1 - Lakatta, Edward G A1 - Lehtimäki, Terho A1 - Loos, Ruth J F A1 - Lucas, Gavin A1 - Meneton, Pierre A1 - Palmer, Lyle J A1 - Rettig, Rainer A1 - Snieder, Harold A1 - Tai, E Shyong A1 - Teo, Yik-Ying A1 - van der Harst, Pim A1 - Wareham, Nicholas J A1 - Wijmenga, Cisca A1 - Wong, Tien Yin A1 - Fornage, Myriam A1 - Gudnason, Vilmundur A1 - Levy, Daniel A1 - Palmas, Walter A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - van Duijn, Cornelia M A1 - Witteman, Jacqueline C M A1 - Chakravarti, Aravinda A1 - Rao, Dabeeru C KW - Adolescent KW - Adult KW - Age Factors KW - Aged KW - Blood Pressure KW - Cohort Studies KW - Humans KW - Middle Aged KW - Young Adult AB -

Although age-dependent effects on blood pressure (BP) have been reported, they have not been systematically investigated in large-scale genome-wide association studies (GWASs). We leveraged the infrastructure of three well-established consortia (CHARGE, GBPgen, and ICBP) and a nonstandard approach (age stratification and metaregression) to conduct a genome-wide search of common variants with age-dependent effects on systolic (SBP), diastolic (DBP), mean arterial (MAP), and pulse (PP) pressure. In a two-staged design using 99,241 individuals of European ancestry, we identified 20 genome-wide significant (p ≤ 5 × 10(-8)) loci by using joint tests of the SNP main effect and SNP-age interaction. Nine of the significant loci demonstrated nominal evidence of age-dependent effects on BP by tests of the interactions alone. Index SNPs in the EHBP1L1 (DBP and MAP), CASZ1 (SBP and MAP), and GOSR2 (PP) loci exhibited the largest age interactions, with opposite directions of effect in the young versus the old. The changes in the genetic effects over time were small but nonnegligible (up to 1.58 mm Hg over 60 years). The EHBP1L1 locus was discovered through gene-age interactions only in whites but had DBP main effects replicated (p = 8.3 × 10(-4)) in 8,682 Asians from Singapore, indicating potential interethnic heterogeneity. A secondary analysis revealed 22 loci with evidence of age-specific effects (e.g., only in 20 to 29-year-olds). Age can be used to select samples with larger genetic effect sizes and more homogenous phenotypes, which may increase statistical power. Age-dependent effects identified through novel statistical approaches can provide insight into the biology and temporal regulation underlying BP associations.

VL - 95 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24954895?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association analysis identifies six new loci associated with forced vital capacity. JF - Nat Genet Y1 - 2014 A1 - Loth, Daan W A1 - Soler Artigas, Maria A1 - Gharib, Sina A A1 - Wain, Louise V A1 - Franceschini, Nora A1 - Koch, Beate A1 - Pottinger, Tess D A1 - Smith, Albert Vernon A1 - Duan, Qing A1 - Oldmeadow, Chris A1 - Lee, Mi Kyeong A1 - Strachan, David P A1 - James, Alan L A1 - Huffman, Jennifer E A1 - Vitart, Veronique A1 - Ramasamy, Adaikalavan A1 - Wareham, Nicholas J A1 - Kaprio, Jaakko A1 - Wang, Xin-Qun A1 - Trochet, Holly A1 - Kähönen, Mika A1 - Flexeder, Claudia A1 - Albrecht, Eva A1 - Lopez, Lorna M A1 - de Jong, Kim A1 - Thyagarajan, Bharat A1 - Alves, Alexessander Couto A1 - Enroth, Stefan A1 - Omenaas, Ernst A1 - Joshi, Peter K A1 - Fall, Tove A1 - Viñuela, Ana A1 - Launer, Lenore J A1 - Loehr, Laura R A1 - Fornage, Myriam A1 - Li, Guo A1 - Wilk, Jemma B A1 - Tang, Wenbo A1 - Manichaikul, Ani A1 - Lahousse, Lies A1 - Harris, Tamara B A1 - North, Kari E A1 - Rudnicka, Alicja R A1 - Hui, Jennie A1 - Gu, Xiangjun A1 - Lumley, Thomas A1 - Wright, Alan F A1 - Hastie, Nicholas D A1 - Campbell, Susan A1 - Kumar, Rajesh A1 - Pin, Isabelle A1 - Scott, Robert A A1 - Pietiläinen, Kirsi H A1 - Surakka, Ida A1 - Liu, Yongmei A1 - Holliday, Elizabeth G A1 - Schulz, Holger A1 - Heinrich, Joachim A1 - Davies, Gail A1 - Vonk, Judith M A1 - Wojczynski, Mary A1 - Pouta, Anneli A1 - Johansson, Asa A1 - Wild, Sarah H A1 - Ingelsson, Erik A1 - Rivadeneira, Fernando A1 - Völzke, Henry A1 - Hysi, Pirro G A1 - Eiriksdottir, Gudny A1 - Morrison, Alanna C A1 - Rotter, Jerome I A1 - Gao, Wei A1 - Postma, Dirkje S A1 - White, Wendy B A1 - Rich, Stephen S A1 - Hofman, Albert A1 - Aspelund, Thor A1 - Couper, David A1 - Smith, Lewis J A1 - Psaty, Bruce M A1 - Lohman, Kurt A1 - Burchard, Esteban G A1 - Uitterlinden, André G A1 - Garcia, Melissa A1 - Joubert, Bonnie R A1 - McArdle, Wendy L A1 - Musk, A Bill A1 - Hansel, Nadia A1 - Heckbert, Susan R A1 - Zgaga, Lina A1 - van Meurs, Joyce B J A1 - Navarro, Pau A1 - Rudan, Igor A1 - Oh, Yeon-Mok A1 - Redline, Susan A1 - Jarvis, Deborah L A1 - Zhao, Jing Hua A1 - Rantanen, Taina A1 - O'Connor, George T A1 - Ripatti, Samuli A1 - Scott, Rodney J A1 - Karrasch, Stefan A1 - Grallert, Harald A1 - Gaddis, Nathan C A1 - Starr, John M A1 - Wijmenga, Cisca A1 - Minster, Ryan L A1 - Lederer, David J A1 - Pekkanen, Juha A1 - Gyllensten, Ulf A1 - Campbell, Harry A1 - Morris, Andrew P A1 - Gläser, Sven A1 - Hammond, Christopher J A1 - Burkart, Kristin M A1 - Beilby, John A1 - Kritchevsky, Stephen B A1 - Gudnason, Vilmundur A1 - Hancock, Dana B A1 - Williams, O Dale A1 - Polasek, Ozren A1 - Zemunik, Tatijana A1 - Kolcic, Ivana A1 - Petrini, Marcy F A1 - Wjst, Matthias A1 - Kim, Woo Jin A1 - Porteous, David J A1 - Scotland, Generation A1 - Smith, Blair H A1 - Viljanen, Anne A1 - Heliövaara, Markku A1 - Attia, John R A1 - Sayers, Ian A1 - Hampel, Regina A1 - Gieger, Christian A1 - Deary, Ian J A1 - Boezen, H Marike A1 - Newman, Anne A1 - Jarvelin, Marjo-Riitta A1 - Wilson, James F A1 - Lind, Lars A1 - Stricker, Bruno H A1 - Teumer, Alexander A1 - Spector, Timothy D A1 - Melén, Erik A1 - Peters, Marjolein J A1 - Lange, Leslie A A1 - Barr, R Graham A1 - Bracke, Ken R A1 - Verhamme, Fien M A1 - Sung, Joohon A1 - Hiemstra, Pieter S A1 - Cassano, Patricia A A1 - Sood, Akshay A1 - Hayward, Caroline A1 - Dupuis, Josée A1 - Hall, Ian P A1 - Brusselle, Guy G A1 - Tobin, Martin D A1 - London, Stephanie J KW - Cohort Studies KW - Databases, Genetic KW - Follow-Up Studies KW - Forced Expiratory Volume KW - Genetic Loci KW - Genetic Predisposition to Disease KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Lung Diseases KW - Meta-Analysis as Topic KW - Polymorphism, Single Nucleotide KW - Prognosis KW - Quantitative Trait Loci KW - Respiratory Function Tests KW - Spirometry KW - Vital Capacity AB -

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

VL - 46 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24929828?dopt=Abstract ER - TY - JOUR T1 - Genome-wide association study of L-arginine and dimethylarginines reveals novel metabolic pathway for symmetric dimethylarginine. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Lüneburg, Nicole A1 - Lieb, Wolfgang A1 - Zeller, Tanja A1 - Chen, Ming-Huei A1 - Maas, Renke A1 - Carter, Angela M A1 - Xanthakis, Vanessa A1 - Glazer, Nicole L A1 - Schwedhelm, Edzard A1 - Seshadri, Sudha A1 - Ikram, Mohammad Arfan A1 - Longstreth, William T A1 - Fornage, Myriam A1 - König, Inke R A1 - Loley, Christina A1 - Ojeda, Francisco M A1 - Schillert, Arne A1 - Wang, Thomas J A1 - Sticht, Heinrich A1 - Kittel, Anja A1 - König, Jörg A1 - Benjamin, Emelia J A1 - Sullivan, Lisa M A1 - Bernges, Isabel A1 - Anderssohn, Maike A1 - Ziegler, Andreas A1 - Gieger, Christian A1 - Illig, Thomas A1 - Meisinger, Christa A1 - Wichmann, H-Erich A1 - Wild, Philipp S A1 - Schunkert, Heribert A1 - Psaty, Bruce M A1 - Wiggins, Kerri L A1 - Heckbert, Susan R A1 - Smith, Nicholas A1 - Lackner, Karl A1 - Lunetta, Kathryn L A1 - Blankenberg, Stefan A1 - Erdmann, Jeanette A1 - Münzel, Thomas A1 - Grant, Peter J A1 - Vasan, Ramachandran S A1 - Böger, Rainer H KW - Adult KW - Aged KW - Amidohydrolases KW - Arginine KW - Binding Sites KW - Cohort Studies KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genotype KW - HEK293 Cells KW - Humans KW - Male KW - Mediator Complex KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Protein Structure, Tertiary KW - Risk Factors KW - Stroke KW - Substrate Specificity KW - Transaminases AB -

BACKGROUND: Dimethylarginines (DMA) interfere with nitric oxide formation by inhibiting nitric oxide synthase (asymmetrical DMA [ADMA]) and l-arginine uptake into the cell (ADMA and symmetrical DMA [SDMA]). In prospective clinical studies, ADMA has been characterized as a cardiovascular risk marker, whereas SDMA is a novel marker for renal function and associated with all-cause mortality after ischemic stroke. The aim of the current study was to characterize the environmental and genetic contributions to interindividual variability of these biomarkers.

METHODS AND RESULTS: This study comprised a genome-wide association analysis of 3 well-characterized population-based cohorts (Framingham Heart Study [FHS; n=2992], Gutenberg Health Study [GHS; n=4354], and Multinational Monitoring of Trends and Determinants in Cardiovascular Disease Study [MONICA]/Cooperative Health Research in the Augsburg Area, Augsburg, Bavaria, Germany [KORA] F3 [n=581]) and identified replicated loci (DDAH1, MED23, Arg1, and AGXT2) associated with the interindividual variability in ADMA, l-arginine, and SDMA. Experimental in silico and in vitro studies confirmed functional significance of the identified AGXT2 variants. Clinical outcome analysis in 384 patients of the Leeds stroke study demonstrated an association between increased plasma levels of SDMA, AGXT2 variants, and various cardiometabolic risk factors. AGXT2 variants were not associated with poststroke survival in the Leeds study or were they associated with incident stroke in the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

CONCLUSIONS: These genome-wide association study support the importance of DDAH1 and MED23/Arg1 in regulating ADMA and l-arginine metabolism, respectively, and identify a novel regulatory renal pathway for SDMA by AGXT2. AGXT2 variants might explain part of the pathogenic link between SDMA, renal function, and outcome. An association between AGXT2 variants and stroke is unclear and warrants further investigation.

VL - 7 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25245031?dopt=Abstract ER - TY - JOUR T1 - Incidence of and risk factors for sick sinus syndrome in the general population. JF - J Am Coll Cardiol Y1 - 2014 A1 - Jensen, Paul N A1 - Gronroos, Noelle N A1 - Chen, Lin Y A1 - Folsom, Aaron R A1 - deFilippi, Chris A1 - Heckbert, Susan R A1 - Alonso, Alvaro KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Population Surveillance KW - Prospective Studies KW - Risk Factors KW - Sick Sinus Syndrome AB -

BACKGROUND: Little is known about the incidence of and risk factors for sick sinus syndrome (SSS), a common indication for pacemaker implantation.

OBJECTIVES: This study sought to describe the epidemiology of SSS.

METHODS: This analysis included 20,572 participants (mean baseline age 59 years, 43% male) in the ARIC (Atherosclerosis Risk In Communities) study and the CHS (Cardiovascular Health Study), who at baseline were free of prevalent atrial fibrillation and pacemaker therapy, had a heart rate of ≥ 50 beats/min unless using beta blockers, and were identified as of white or black race. Incident SSS cases were identified by hospital discharge International Classification of Disease-revision 9-Clinical Modification code 427.81 and validated by medical record review.

RESULTS: During an average 17 years of follow-up, 291 incident SSS cases were identified (unadjusted rate 0.8 per 1,000 person-years). Incidence increased with age (hazard ratio [HR]: 1.73; 95% confidence interval [CI]: 1.47 to 2.05 per 5-year increment), and blacks had a 41% lower risk of SSS than whites (HR: 0.59; 95% CI: 0.37 to 0.98). Incident SSS was associated with greater baseline body mass index, height, N-terminal pro-B-type natriuretic peptide, and cystatin C, with longer QRS interval, with lower heart rate, and with prevalent hypertension, right bundle branch block, and cardiovascular disease. We project that the annual number of new SSS cases in the United States will increase from 78,000 in 2012 to 172,000 in 2060.

CONCLUSIONS: Blacks have a lower risk of SSS than whites, and several cardiovascular risk factors were associated with incident SSS. With the aging of the population, the number of Americans with SSS will increase dramatically over the next 50 years.

VL - 64 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25104519?dopt=Abstract ER - TY - JOUR T1 - The influence of sex on cardiovascular outcomes associated with diabetes among older black and white adults. JF - J Diabetes Complications Y1 - 2014 A1 - Vimalananda, Varsha G A1 - Biggs, Mary L A1 - Rosenzweig, James L A1 - Carnethon, Mercedes R A1 - Meigs, James B A1 - Thacker, Evan L A1 - Siscovick, David S A1 - Mukamal, Kenneth J KW - African Continental Ancestry Group KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Coronary Disease KW - Diabetes Complications KW - European Continental Ancestry Group KW - Female KW - Heart Failure KW - Humans KW - Incidence KW - Longitudinal Studies KW - Male KW - Prospective Studies KW - Regression Analysis KW - Retrospective Studies KW - Risk Factors KW - Sex Factors KW - Survival Rate AB -

AIMS: It is unknown whether sex differences in the association of diabetes with cardiovascular outcomes vary by race. We examined sex differences in the associations of diabetes with incident congestive heart failure (CHF) and coronary heart disease (CHD) between older black and white adults.

METHODS: We analyzed data from the Cardiovascular Health Study (CHS), a prospective cohort study of community-dwelling individuals aged ≥65 from four US counties. We included 4817 participants (476 black women, 279 black men, 2447 white women and 1625 white men). We estimated event rates and multivariate-adjusted hazard ratios for incident CHF, CHD, and all-cause mortality by Cox regression and competing risk analyses.

RESULTS: Over a median follow-up of 12.5years, diabetes was more strongly associated with CHF among black women (HR, 2.42 [95% CI, 1.70-3.40]) than black men (1.39 [0.83-2.34]); this finding did not reach statistical significance (P for interaction=0.08). Female sex conferred a higher risk for a composite outcome of CHF and CHD among black participants (2.44 [1.82-3.26]) vs. (1.44 [0.97-2.12]), P for interaction=0.03). There were no significant sex differences in the HRs associated with diabetes for CHF among whites, or for CHD or all-cause mortality among blacks or whites. The three-way interaction between sex, race, and diabetes on risk of cardiovascular outcomes was not significant (P=0.07).

CONCLUSIONS: Overall, sex did not modify the cardiovascular risk associated with diabetes among older black or white adults. However, our results suggest that a possible sex interaction among older blacks merits further study.

VL - 28 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24461547?dopt=Abstract ER - TY - JOUR T1 - Multilocus genetic risk score associates with ischemic stroke in case-control and prospective cohort studies. JF - Stroke Y1 - 2014 A1 - Malik, Rainer A1 - Bevan, Steve A1 - Nalls, Michael A A1 - Holliday, Elizabeth G A1 - Devan, William J A1 - Cheng, Yu-Ching A1 - Ibrahim-Verbaas, Carla A A1 - Verhaaren, Benjamin F J A1 - Bis, Joshua C A1 - Joon, Aron Y A1 - de Stefano, Anita L A1 - Fornage, Myriam A1 - Psaty, Bruce M A1 - Ikram, M Arfan A1 - Launer, Lenore J A1 - van Duijn, Cornelia M A1 - Sharma, Pankaj A1 - Mitchell, Braxton D A1 - Rosand, Jonathan A1 - Meschia, James F A1 - Levi, Christopher A1 - Rothwell, Peter M A1 - Sudlow, Cathie A1 - Markus, Hugh S A1 - Seshadri, Sudha A1 - Dichgans, Martin KW - Adult KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Blood Pressure KW - Brain Ischemia KW - Case-Control Studies KW - Cohort Studies KW - Coronary Artery Disease KW - Female KW - Genetic Predisposition to Disease KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Multilocus Sequence Typing KW - Polymorphism, Single Nucleotide KW - Population KW - Prospective Studies KW - Reproducibility of Results KW - Risk Assessment KW - Risk Factors KW - Sex Factors KW - Stroke AB -

BACKGROUND AND PURPOSE: Genome-wide association studies have revealed multiple common variants associated with known risk factors for ischemic stroke (IS). However, their aggregate effect on risk is uncertain. We aimed to generate a multilocus genetic risk score (GRS) for IS based on genome-wide association studies data from clinical-based samples and to establish its external validity in prospective population-based cohorts.

METHODS: Three thousand five hundred forty-eight clinic-based IS cases and 6399 controls from the Wellcome Trust Case Control Consortium 2 were used for derivation of the GRS. Subjects from the METASTROKE consortium served as a replication sample. The validation sample consisted of 22 751 participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. We selected variants that had reached genome-wide significance in previous association studies on established risk factors for IS.

RESULTS: A combined GRS for atrial fibrillation, coronary artery disease, hypertension, and systolic blood pressure significantly associated with IS both in the case-control samples and in the prospective population-based studies. Subjects in the top quintile of the combined GRS had >2-fold increased risk of IS compared with subjects in the lowest quintile. Addition of the combined GRS to a simple model based on sex significantly improved the prediction of IS in the combined clinic-based samples but not in the population-based studies, and there was no significant improvement in net reclassification.

CONCLUSIONS: A multilocus GRS based on common variants for established cardiovascular risk factors was significantly associated with IS both in clinic-based samples and in the general population. However, the improvement in clinical risk prediction was found to be small.

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24436234?dopt=Abstract ER - TY - JOUR T1 - Plasma phospholipid and dietary α-linolenic acid, mortality, CHD and stroke: the Cardiovascular Health Study. JF - Br J Nutr Y1 - 2014 A1 - Fretts, Amanda M A1 - Mozaffarian, Dariush A1 - Siscovick, David S A1 - Sitlani, Colleen A1 - Psaty, Bruce M A1 - Rimm, Eric B A1 - Song, Xiaoling A1 - McKnight, Barbara A1 - Spiegelman, Donna A1 - King, Irena B A1 - Lemaitre, Rozenn N KW - Aged KW - alpha-Linolenic Acid KW - Cardiovascular Diseases KW - Cohort Studies KW - Coronary Disease KW - Diet KW - Female KW - Humans KW - Male KW - Mortality KW - Phospholipids KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Stroke KW - United States AB -

Previous studies have suggested that long-chain n-3 fatty acids derived from seafood are associated with a lower risk of mortality, CHD and stroke. Whether α-linolenic acid (ALA, 18 : 3n-3), a plant-derived long-chain essential n-3 fatty acid, is associated with a lower risk of these outcomes is unclear. The aim of the present study was to examine the associations of plasma phospholipid and dietary ALA with the risk of mortality, CHD and stroke among older adults who participated in the Cardiovascular Health Study, a cohort study of adults aged ≥ 65 years. A total of 2709 participants were included in the plasma phospholipid ALA analysis and 2583 participants were included in the dietary ALA analysis. Cox regression was used to assess the associations of plasma phospholipid and dietary ALA with the risk of mortality, incident CHD and stroke. In minimally and multivariable-adjusted models, plasma phospholipid ALA was found to be not associated with the risk of mortality, incident CHD or stroke. After adjustment for age, sex, race, enrolment site, education, smoking status, diabetes, BMI, alcohol consumption, treated hypertension and total energy intake, higher dietary ALA intake was found to be associated with a lower risk of total and non-cardiovascular mortality; on comparing the highest quintiles of dietary ALA with the lowest quintiles, the HR for total mortality and non-cardiovascular mortality were found to be 0·73 (95 % CI 0·61, 0·88) and 0·64 (95 % CI 0·52, 0·80), respectively. Dietary ALA was found to be not associated with the risk of cardiovascular mortality, incident CHD or stroke. In conclusion, the results of the present suggest study that dietary ALA, but not plasma phospholipid ALA, is associated with a lower risk of total and non-cardiovascular mortality in older adults.

VL - 112 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25159901?dopt=Abstract ER - TY - JOUR T1 - Plasma phospholipid trans-fatty acids levels, cardiovascular diseases, and total mortality: the cardiovascular health study. JF - J Am Heart Assoc Y1 - 2014 A1 - Wang, Qianyi A1 - Imamura, Fumiaki A1 - Lemaitre, Rozenn N A1 - Rimm, Eric B A1 - Wang, Molin A1 - King, Irena B A1 - Song, Xiaoling A1 - Siscovick, David A1 - Mozaffarian, Dariush KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Cardiovascular Diseases KW - Cohort Studies KW - Dietary Fats KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Male KW - Mortality KW - Phospholipids KW - Prognosis KW - Proportional Hazards Models KW - Prospective Studies KW - Trans Fatty Acids AB -

BACKGROUND: While self-reported trans-fatty acid (TFA) consumption is linked to coronary heart disease (CHD), relationships between objective biomarkers of TFA subtypes (t-16:1n9, total t-18:1, and cis/trans-(c/t-), t/c- and t/t-18:2) and cardiovascular disease (CVD) or total mortality are not well established.

METHODS AND RESULTS: We evaluated 2742 adults in the Cardiovascular Health Study, aged 74±5 years and free of prevalent CVD, with plasma phospholipid TFA measures in 1992. Incident fatal and nonfatal CHD events, CVD and non-CVD mortality, and total mortality were centrally adjudicated through 2010. Risks were assessed using Cox proportional hazards. During 31 494 person-years, 1735 total deaths and 639 total CHD events occurred. In the multivariate model including mutual adjustment for the 5 TFA subtypes, circulating t/t-18:2 was associated with higher total mortality (extreme quintile hazard ratio (HR)=1.23, 95% CI=1.04 to 1.44, P-trend=0.01), CVD mortality (HR=1.40, 95% CI=1.05 to 1.86, P-trend=0.02), and total CHD (HR=1.39, 95% CI=1.06 to 1.83, P-trend=0.01). t/c-18:2 was positively related to total mortality (HR=1.19, P-trend=0.05), total CHD (HR=1.67, P-trend=0.002), and nonfatal CHD (HR=2.06, P-trend=0.002) after mutual adjustment; these associations were insignificant without mutual adjustment. Neither t-16:1n9 nor t-18:1 was significantly associated with total mortality or CVD, nor was c/t-18:2 if we excluded early cases.

CONCLUSIONS: Among circulating TFAs, t/t-18:2 was most adversely associated with total mortality, mainly due to the increased risk of CVD. t/c-18:2 was also positively associated with total mortality and CHD, but only after adjustment for other TFAs. These results highlight the need for further investigation of dietary sources, nondietary determinants, and health effects of specific TFA subtypes, especially t-18:2 isomers.

VL - 3 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25164946?dopt=Abstract ER - TY - JOUR T1 - Predicting stroke through genetic risk functions: the CHARGE Risk Score Project. JF - Stroke Y1 - 2014 A1 - Ibrahim-Verbaas, Carla A A1 - Fornage, Myriam A1 - Bis, Joshua C A1 - Choi, Seung Hoan A1 - Psaty, Bruce M A1 - Meigs, James B A1 - Rao, Madhu A1 - Nalls, Mike A1 - Fontes, João D A1 - O'Donnell, Christopher J A1 - Kathiresan, Sekar A1 - Ehret, Georg B A1 - Fox, Caroline S A1 - Malik, Rainer A1 - Dichgans, Martin A1 - Schmidt, Helena A1 - Lahti, Jari A1 - Heckbert, Susan R A1 - Lumley, Thomas A1 - Rice, Kenneth A1 - Rotter, Jerome I A1 - Taylor, Kent D A1 - Folsom, Aaron R A1 - Boerwinkle, Eric A1 - Rosamond, Wayne D A1 - Shahar, Eyal A1 - Gottesman, Rebecca F A1 - Koudstaal, Peter J A1 - Amin, Najaf A1 - Wieberdink, Renske G A1 - Dehghan, Abbas A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - DeStefano, Anita L A1 - Debette, Stephanie A1 - Xue, Luting A1 - Beiser, Alexa A1 - Wolf, Philip A A1 - DeCarli, Charles A1 - Ikram, M Arfan A1 - Seshadri, Sudha A1 - Mosley, Thomas H A1 - Longstreth, W T A1 - van Duijn, Cornelia M A1 - Launer, Lenore J KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Area Under Curve KW - Case-Control Studies KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Regression Analysis KW - Risk Factors KW - ROC Curve KW - Sex Factors KW - Stroke AB -

BACKGROUND AND PURPOSE: Beyond the Framingham Stroke Risk Score, prediction of future stroke may improve with a genetic risk score (GRS) based on single-nucleotide polymorphisms associated with stroke and its risk factors.

METHODS: The study includes 4 population-based cohorts with 2047 first incident strokes from 22,720 initially stroke-free European origin participants aged ≥55 years, who were followed for up to 20 years. GRSs were constructed with 324 single-nucleotide polymorphisms implicated in stroke and 9 risk factors. The association of the GRS to first incident stroke was tested using Cox regression; the GRS predictive properties were assessed with area under the curve statistics comparing the GRS with age and sex, Framingham Stroke Risk Score models, and reclassification statistics. These analyses were performed per cohort and in a meta-analysis of pooled data. Replication was sought in a case-control study of ischemic stroke.

RESULTS: In the meta-analysis, adding the GRS to the Framingham Stroke Risk Score, age and sex model resulted in a significant improvement in discrimination (all stroke: Δjoint area under the curve=0.016, P=2.3×10(-6); ischemic stroke: Δjoint area under the curve=0.021, P=3.7×10(-7)), although the overall area under the curve remained low. In all the studies, there was a highly significantly improved net reclassification index (P<10(-4)).

CONCLUSIONS: The single-nucleotide polymorphisms associated with stroke and its risk factors result only in a small improvement in prediction of future stroke compared with the classical epidemiological risk factors for stroke.

VL - 45 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24436238?dopt=Abstract ER - TY - JOUR T1 - Racial and regional differences in venous thromboembolism in the United States in 3 cohorts. JF - Circulation Y1 - 2014 A1 - Zakai, Neil A A1 - McClure, Leslie A A1 - Judd, Suzanne E A1 - Safford, Monika M A1 - Folsom, Aaron R A1 - Lutsey, Pamela L A1 - Cushman, Mary KW - African Continental Ancestry Group KW - Aged KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Prevalence KW - Proportional Hazards Models KW - Prospective Studies KW - Residence Characteristics KW - Risk Factors KW - United States KW - Venous Thromboembolism AB -

BACKGROUND: Blacks are thought to have a higher risk of venous thromboembolism (VTE) than whites. However, prior studies are limited to administrative databases that lack specific information on VTE risk factors or have limited geographic scope.

METHODS AND RESULTS: We ascertained VTE from 3 prospective studies: the Atherosclerosis Risk in Communities Study (ARIC), the Cardiovascular Health Study (CHS), and the Reasons for Geographic and Racial Differences in Stroke study (REGARDS). We tested the association of race with VTE using Cox proportional hazard models adjusted for VTE risk factors. Over 438 090 person-years, 916 incident VTE events (302 in blacks) occurred in 51 149 individuals (17 318 blacks) who were followed up. In risk factor-adjusted models, blacks had a higher rate of VTE than whites in the CHS (hazard ratio, 1.81; 95% confidence interval, 1.20-2.73) but not ARIC (hazard ratio, 1.21; 95% confidence interval, 0.96-1.54). In REGARDS, there was a significant region-by-race interaction (P=0.01): Blacks in the Southeast had a significantly higher rate of VTE than blacks in the rest of the United States (hazard ratio, 1.63; 95% confidence interval, 1.08-2.48) that was not seen in whites (hazard ratio, 0.83; 95% confidence interval, 0.61-1.14).

CONCLUSIONS: The association of race with VTE differed in each cohort, which may reflect the different time periods of the studies or different regional rates of VTE. Further studies of environmental and genetic risk factors for VTE are needed to determine which underlie racial and perhaps regional differences in VTE.

VL - 129 IS - 14 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24508826?dopt=Abstract ER - TY - JOUR T1 - Relative risks of chronic kidney disease for mortality and end-stage renal disease across races are similar. JF - Kidney Int Y1 - 2014 A1 - Wen, Chi Pang A1 - Matsushita, Kunihiro A1 - Coresh, Josef A1 - Iseki, Kunitoshi A1 - Islam, Muhammad A1 - Katz, Ronit A1 - McClellan, William A1 - Peralta, Carmen A A1 - Wang, Haiyan A1 - de Zeeuw, Dick A1 - Astor, Brad C A1 - Gansevoort, Ron T A1 - Levey, Andrew S A1 - Levin, Adeera KW - Adult KW - African Continental Ancestry Group KW - Aged KW - Aged, 80 and over KW - Albuminuria KW - Asian Continental Ancestry Group KW - Cardiovascular Diseases KW - Cohort Studies KW - Creatinine KW - European Continental Ancestry Group KW - Female KW - Glomerular Filtration Rate KW - Humans KW - Kidney Failure, Chronic KW - Male KW - Middle Aged KW - Odds Ratio KW - Renal Insufficiency, Chronic KW - Risk Factors AB -

Some suggest race-specific cutpoints for kidney measures to define and stage chronic kidney disease (CKD), but evidence for race-specific clinical impact is limited. To address this issue, we compared hazard ratios of estimated glomerular filtration rates (eGFR) and albuminuria across races using meta-regression in 1.1 million adults (75% Asians, 21% Whites, and 4% Blacks) from 45 cohorts. Results came mainly from 25 general population cohorts comprising 0.9 million individuals. The associations of lower eGFR and higher albuminuria with mortality and end-stage renal disease (ESRD) were largely similar across races. For example, in Asians, Whites, and Blacks, the adjusted hazard ratios (95% confidence interval) for eGFR 45-59 versus 90-104 ml/min per 1.73 m(2) were 1.3 (1.2-1.3), 1.1 (1.0-1.2), and 1.3 (1.1-1.7) for all-cause mortality, 1.6 (1.5-1.7), 1.4 (1.2-1.7), and 1.4 (0.7-2.9) for cardiovascular mortality, and 27.6 (11.1-68.7), 11.2 (6.0-20.9), and 4.1 (2.2-7.5) for ESRD, respectively. The corresponding hazard ratios for urine albumin-to-creatinine ratio 30-299 mg/g or dipstick 1+ versus an albumin-to-creatinine ratio under 10 or dipstick negative were 1.6 (1.4-1.8), 1.7 (1.5-1.9), and 1.8 (1.7-2.1) for all-cause mortality, 1.7 (1.4-2.0), 1.8 (1.5-2.1), and 2.8 (2.2-3.6) for cardiovascular mortality, and 7.4 (2.0-27.6), 4.0 (2.8-5.9), and 5.6 (3.4-9.2) for ESRD, respectively. Thus, the relative mortality or ESRD risks of lower eGFR and higher albuminuria were largely similar among three major races, supporting similar clinical approach to CKD definition and staging, across races.

VL - 86 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24522492?dopt=Abstract ER - TY - JOUR T1 - Sequence analysis of six blood pressure candidate regions in 4,178 individuals: the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) targeted sequencing study. JF - PLoS One Y1 - 2014 A1 - Morrison, Alanna C A1 - Bis, Joshua C A1 - Hwang, Shih-Jen A1 - Ehret, Georg B A1 - Lumley, Thomas A1 - Rice, Kenneth A1 - Muzny, Donna A1 - Gibbs, Richard A A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Chakravarti, Aravinda A1 - Levy, Daniel KW - Aging KW - Blood Pressure KW - Cohort Studies KW - Heart KW - Humans KW - Sequence Analysis AB -

BACKGROUND: Genome-wide association studies (GWAS) identified multiple loci for blood pressure (BP) and hypertension. Six genes--ATP2B1, CACNB2, CYP17A1, JAG1, PLEKHA7, and SH2B3--were evaluated for sequence variation with large effects on systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), and mean arterial pressure (MAP).

METHODS AND RESULTS: Targeted genomic sequence was determined in 4,178 European ancestry participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Common variants (≥50 minor allele copies) were evaluated individually and rare variants (minor allele frequency, MAF≤1%) were aggregated by locus. 464 common variants were identified across the 6 genes. An upstream CYP17A1 variant, rs11191416 (MAF = 0.09), was the most significant association for SBP (P = 0.0005); however the association was attenuated (P = 0.0469) after conditioning on the GWAS index single nucleotide polymorphism (SNP). A PLEKHA7 intronic variant was the strongest DBP association (rs12806040, MAF = 0.007, P = 0.0006) and was not in LD (r² = 0.01) with the GWAS SNP. A CACNB2 intronic SNP, rs1571787, was the most significant association with PP (MAF = 0.27, P = 0.0003), but was not independent from the GWAS SNP (r² = 0.34). Three variants (rs6163 and rs743572 in the CYP17A1 region and rs112467382 in PLEKHA7) were associated with BP traits (P<0.001). Rare variation, aggregately assessed in the 6 regions, was not significantly associated with BP measures.

CONCLUSION: Six targeted gene regions, previously identified by GWAS, did not harbor novel variation with large effects on BP in this sample.

VL - 9 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25275628?dopt=Abstract ER - TY - JOUR T1 - Sequence variation in TMEM18 in association with body mass index: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Liu, Ching-Ti A1 - Young, Kristin L A1 - Brody, Jennifer A A1 - Olden, Matthias A1 - Wojczynski, Mary K A1 - Heard-Costa, Nancy A1 - Li, Guo A1 - Morrison, Alanna C A1 - Muzny, Donna A1 - Gibbs, Richard A A1 - Reid, Jeffrey G A1 - Shao, Yaming A1 - Zhou, Yanhua A1 - Boerwinkle, Eric A1 - Heiss, Gerardo A1 - Wagenknecht, Lynne A1 - McKnight, Barbara A1 - Borecki, Ingrid B A1 - Fox, Caroline S A1 - North, Kari E A1 - Cupples, L Adrienne KW - Adult KW - Aged KW - Aging KW - Body Mass Index KW - Cohort Studies KW - Female KW - Genetic Association Studies KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Heart Diseases KW - Humans KW - Male KW - Membrane Proteins KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA KW - Young Adult AB -

BACKGROUND: Genome-wide association studies for body mass index (BMI) previously identified a locus near TMEM18. We conducted targeted sequencing of this region to investigate the role of common, low-frequency, and rare variants influencing BMI.

METHODS AND RESULTS: We sequenced TMEM18 and regions downstream of TMEM18 on chromosome 2 in 3976 individuals of European ancestry from 3 community-based cohorts (Atherosclerosis Risk in Communities, Cardiovascular Health Study, and Framingham Heart Study), including 200 adults selected for high BMI. We examined the association between BMI and variants identified in the region from nucleotide position 586 432 to 677 539 (hg18). Rare variants (minor allele frequency, <1%) were analyzed using a burden test and the sequence kernel association test. Results from the 3 cohort studies were meta-analyzed. We estimate that mean BMI is 0.43 kg/m(2) higher for each copy of the G allele of single-nucleotide polymorphism rs7596758 (minor allele frequency, 29%; P=3.46×10(-4)) using a Bonferroni threshold of P<4.6×10(-4). Analyses conditional on previous genome-wide association study single-nucleotide polymorphisms associated with BMI in the region led to attenuation of this signal and uncovered another independent (r(2)<0.2), statistically significant association, rs186019316 (P=2.11×10(-4)). Both rs186019316 and rs7596758 or proxies are located in transcription factor binding regions. No significant association with rare variants was found in either the exons of TMEM18 or the 3' genome-wide association study region.

CONCLUSIONS: Targeted sequencing around TMEM18 identified 2 novel BMI variants with possible regulatory function.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951660?dopt=Abstract ER - TY - JOUR T1 - Sequencing of 2 subclinical atherosclerosis candidate regions in 3669 individuals: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Bis, Joshua C A1 - White, Charles C A1 - Franceschini, Nora A1 - Brody, Jennifer A1 - Zhang, Xiaoling A1 - Muzny, Donna A1 - Santibanez, Jireh A1 - Gibbs, Richard A1 - Liu, Xiaoming A1 - Lin, Honghuang A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - North, Kari E A1 - Cupples, L Adrienne A1 - O'Donnell, Christopher J KW - Aged KW - Aged, 80 and over KW - Aging KW - Atherosclerosis KW - Class Ib Phosphatidylinositol 3-Kinase KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA KW - Sodium-Phosphate Cotransporter Proteins, Type I AB -

BACKGROUND: Atherosclerosis, the precursor to coronary heart disease and stroke, is characterized by an accumulation of fatty cells in the arterial intimal-medial layers. Common carotid intima media thickness (cIMT) and plaque are subclinical atherosclerosis measures that predict cardiovascular disease events. Previously, genome-wide association studies demonstrated evidence for association with cIMT (SLC17A4) and plaque (PIK3CG).

METHODS AND RESULTS: We sequenced 120 kb around SLC17A4 (6p22.2) and 251 kb around PIK3CG (7q22.3) among 3669 European ancestry participants from the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), and Framingham Heart Study (FHS) in Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Primary analyses focused on 438 common variants (minor allele frequency ≥1%), which were independently meta-analyzed. A 3' untranslated region CCDC71L variant (rs2286149), upstream from PIK3CG, was the most significant finding in cIMT (P=0.00033) and plaque (P=0.0004) analyses. A SLC17A4 intronic variant was also associated with cIMT (P=0.008). Both were in low linkage disequilibrium with the genome-wide association study single nucleotide polymorphisms. Gene-based tests including T1 count and sequence kernel association test for rare variants (minor allele frequency <1%) did not yield statistically significant associations. However, we observed nominal associations for rare variants in CCDC71L and SLC17A3 with cIMT and of the entire 7q22 region with plaque (P=0.05).

CONCLUSIONS: Common and rare variants in PIK3CG and SLC17A4 regions demonstrated modest association with subclinical atherosclerosis traits. Although not conclusive, these findings may help to understand the genetic architecture of regions previously implicated by genome-wide association studies and identify variants within these regions for further investigation in larger samples.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951662?dopt=Abstract ER - TY - JOUR T1 - Sequencing of SCN5A identifies rare and common variants associated with cardiac conduction: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Magnani, Jared W A1 - Brody, Jennifer A A1 - Prins, Bram P A1 - Arking, Dan E A1 - Lin, Honghuang A1 - Yin, Xiaoyan A1 - Liu, Ching-Ti A1 - Morrison, Alanna C A1 - Zhang, Feng A1 - Spector, Tim D A1 - Alonso, Alvaro A1 - Bis, Joshua C A1 - Heckbert, Susan R A1 - Lumley, Thomas A1 - Sitlani, Colleen M A1 - Cupples, L Adrienne A1 - Lubitz, Steven A A1 - Soliman, Elsayed Z A1 - Pulit, Sara L A1 - Newton-Cheh, Christopher A1 - O'Donnell, Christopher J A1 - Ellinor, Patrick T A1 - Benjamin, Emelia J A1 - Muzny, Donna M A1 - Gibbs, Richard A A1 - Santibanez, Jireh A1 - Taylor, Herman A A1 - Rotter, Jerome I A1 - Lange, Leslie A A1 - Psaty, Bruce M A1 - Jackson, Rebecca A1 - Rich, Stephen S A1 - Boerwinkle, Eric A1 - Jamshidi, Yalda A1 - Sotoodehnia, Nona KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Cohort Studies KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Heart Conduction System KW - Heart Diseases KW - Humans KW - Male KW - Middle Aged KW - NAV1.5 Voltage-Gated Sodium Channel KW - Polymorphism, Single Nucleotide KW - Sequence Analysis, DNA AB -

BACKGROUND: The cardiac sodium channel SCN5A regulates atrioventricular and ventricular conduction. Genetic variants in this gene are associated with PR and QRS intervals. We sought to characterize further the contribution of rare and common coding variation in SCN5A to cardiac conduction.

METHODS AND RESULTS: In Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study, we performed targeted exonic sequencing of SCN5A (n=3699, European ancestry individuals) and identified 4 common (minor allele frequency >1%) and 157 rare variants. Common and rare SCN5A coding variants were examined for association with PR and QRS intervals through meta-analysis of European ancestry participants from CHARGE, National Heart, Lung, and Blood Institute's Exome Sequencing Project (n=607), and the UK10K (n=1275) and by examining Exome Sequencing Project African ancestry participants (n=972). Rare coding SCN5A variants in aggregate were associated with PR interval in European and African ancestry participants (P=1.3×10(-3)). Three common variants were associated with PR and QRS interval duration among European ancestry participants and one among African ancestry participants. These included 2 well-known missense variants: rs1805124 (H558R) was associated with PR and QRS shortening in European ancestry participants (P=6.25×10(-4) and P=5.2×10(-3), respectively) and rs7626962 (S1102Y) was associated with PR shortening in those of African ancestry (P=2.82×10(-3)). Among European ancestry participants, 2 novel synonymous variants, rs1805126 and rs6599230, were associated with cardiac conduction. Our top signal, rs1805126 was associated with PR and QRS lengthening (P=3.35×10(-7) and P=2.69×10(-4), respectively) and rs6599230 was associated with PR shortening (P=2.67×10(-5)).

CONCLUSIONS: By sequencing SCN5A, we identified novel common and rare coding variants associated with cardiac conduction.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951663?dopt=Abstract ER - TY - JOUR T1 - Simple biologically informed inflammatory index of two serum cytokines predicts 10 year all-cause mortality in older adults. JF - J Gerontol A Biol Sci Med Sci Y1 - 2014 A1 - Varadhan, Ravi A1 - Yao, Wenliang A1 - Matteini, Amy A1 - Beamer, Brock A A1 - Xue, Qian-Li A1 - Yang, Huanle A1 - Manwani, Bhavish A1 - Reiner, Alexander A1 - Jenny, Nancy A1 - Parekh, Neel A1 - Fallin, M Daniele A1 - Newman, Anne A1 - Bandeen-Roche, Karen A1 - Tracy, Russell A1 - Ferrucci, Luigi A1 - Walston, Jeremy KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - C-Reactive Protein KW - Cohort Studies KW - Female KW - Humans KW - Inflammation KW - Interleukin 1 Receptor Antagonist Protein KW - Interleukin-18 KW - Interleukin-6 KW - Longevity KW - Male KW - Receptors, Tumor Necrosis Factor, Type I KW - Risk Factors AB -

BACKGROUND: Individual measurements of inflammation have been utilized to assess adverse outcomes risk in older adults with varying degrees of success. This study was designed to identify biologically informed, aggregate measures of inflammation for optimal risk assessment and to inform further biological study of inflammatory pathways.

METHODS: In total, 15 nuclear factor-kappa B-mediated pathway markers of inflammation were first measured in baseline serum samples of 1,155 older participants in the InCHIANTI population. Of these, C-reactive protein, interleukin-1-receptor antagonist, interleukin-6, interleukin-18, and soluble tumor necrosis factor-α receptor-1 were independent predictors of 5-year mortality. These five inflammatory markers were measured in baseline serum samples of 5,600 Cardiovascular Health Study participants. A weighted summary score, the first principal component summary score, and an inflammation index score were developed from these five log-transformed inflammatory markers, and their prediction of 10-year all-cause mortality was evaluated in Cardiovascular Health Study and then validated in InCHIANTI.

RESULTS: The inflammation index score that included interleukin-6 and soluble tumor necrosis factor-α receptor-1 was the best predictor of 10-year all-cause mortality in Cardiovascular Health Study, after adjusting for age, sex, education, race, smoking, and body mass index (hazards ratio = 1.62; 95% CI: 1.54, 1.70) compared with all other single and combined measures. The inflammation index score was also the best predictor of mortality in the InCHIANTI validation study (hazards ratio 1.33; 95% CI: 1.17-1.52). Stratification by sex and CVD status further strengthened the association of inflammation index score with mortality.

CONCLUSION: A simple additive index of serum interleukin-6 and soluble tumor necrosis factor-α receptor-1 best captures the effect of chronic inflammation on mortality in older adults among the 15 biomarkers measured.

VL - 69 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23689826?dopt=Abstract ER - TY - JOUR T1 - Strategies to design and analyze targeted sequencing data: cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. JF - Circ Cardiovasc Genet Y1 - 2014 A1 - Lin, Honghuang A1 - Wang, Min A1 - Brody, Jennifer A A1 - Bis, Joshua C A1 - Dupuis, Josée A1 - Lumley, Thomas A1 - McKnight, Barbara A1 - Rice, Kenneth M A1 - Sitlani, Colleen M A1 - Reid, Jeffrey G A1 - Bressler, Jan A1 - Liu, Xiaoming A1 - Davis, Brian C A1 - Johnson, Andrew D A1 - O'Donnell, Christopher J A1 - Kovar, Christie L A1 - Dinh, Huyen A1 - Wu, Yuanqing A1 - Newsham, Irene A1 - Chen, Han A1 - Broka, Andi A1 - DeStefano, Anita L A1 - Gupta, Mayetri A1 - Lunetta, Kathryn L A1 - Liu, Ching-Ti A1 - White, Charles C A1 - Xing, Chuanhua A1 - Zhou, Yanhua A1 - Benjamin, Emelia J A1 - Schnabel, Renate B A1 - Heckbert, Susan R A1 - Psaty, Bruce M A1 - Muzny, Donna M A1 - Cupples, L Adrienne A1 - Morrison, Alanna C A1 - Boerwinkle, Eric KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Cohort Studies KW - Female KW - Genetic Variation KW - Genome-Wide Association Study KW - Genomics KW - Heart Diseases KW - Humans KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Research Design KW - Sequence Analysis, DNA AB -

BACKGROUND: Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits.

METHODS AND RESULTS: The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case-cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with ≥1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency ≥1%), we performed unweighted regression analyses to obtain P values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test.

CONCLUSIONS: We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.

VL - 7 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24951659?dopt=Abstract ER - TY - JOUR T1 - Subclinical hypothyroidism, weight change, and body composition in the elderly: the Cardiovascular Health Study. JF - J Clin Endocrinol Metab Y1 - 2014 A1 - Garin, Margaret C A1 - Arnold, Alice M A1 - Lee, Jennifer S A1 - Tracy, Russell P A1 - Cappola, Anne R KW - Aged KW - Aged, 80 and over KW - Asymptomatic Diseases KW - Body Composition KW - Body Mass Index KW - Cohort Studies KW - Female KW - Humans KW - Hypothyroidism KW - Male KW - Thyroid Gland KW - Weight Loss AB -

BACKGROUND: Subclinical hypothyroidism is common in the elderly, yet its relationship with weight and body composition is unclear.

OBJECTIVE: We examined the relationship between subclinical hypothyroidism and weight change and body composition in older adults.

METHODS: A total of 427 subclinically hypothyroid and 2864 euthyroid U.S. individuals ≥65 years old enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of 6-year weight change were performed, compared by thyroid status. A cross-sectional analysis of thyroid status and body composition was performed in a subset of 1276 participants who had dual-energy x-ray absorptiometry scans. Models were risk factor-adjusted and stratified by sex.

RESULTS: Overall, participants lost weight during follow-up (-0.38 kg/y in men, -0.37 kg/y in women). Subclinical hypothyroidism, when assessed at a single time point or persisting over 2 years, was not associated with a difference in weight change compared with euthyroidism. Subclinical hypothyroidism was also not associated with differences in lean mass, fat mass, or percent fat compared with euthyroidism. A TSH level 1 mU/L higher within the euthyroid or subclinical hypothyroid range was associated with a 0.51-kg higher baseline weight in women only (P < .001) but not with weight change in either sex. A 1 ng/dL higher free T4 level was associated with lower baseline weight and 0.32 kg/y greater weight loss in women only (P = .003). Baseline weight and weight change did not differ by T3 levels.

CONCLUSIONS: Our data do not support a clinically significant impact of subclinical hypothyroidism on weight status in the elderly.

VL - 99 IS - 4 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24432998?dopt=Abstract ER - TY - JOUR T1 - Subclinical thyroid dysfunction and hip fracture and bone mineral density in older adults: the cardiovascular health study. JF - J Clin Endocrinol Metab Y1 - 2014 A1 - Garin, Margaret C A1 - Arnold, Alice M A1 - Lee, Jennifer S A1 - Robbins, John A1 - Cappola, Anne R KW - Absorptiometry, Photon KW - Aged KW - Aged, 80 and over KW - Asymptomatic Diseases KW - Bone Density KW - Cardiovascular System KW - Cohort Studies KW - Cross-Sectional Studies KW - Female KW - Hip Fractures KW - Humans KW - Male KW - Osteoporotic Fractures KW - Risk Factors KW - Sex Factors KW - Thyroid Diseases AB -

BACKGROUND: Subclinical thyroid dysfunction is common in the elderly, yet its relationship with hip fracture and bone mineral density (BMD) is unclear.

OBJECTIVE: We examined the association between endogenous subclinical hyper- and hypothyroidism and hip fracture and BMD in older adults.

METHODS: A total of 4936 US individuals 65 years old or older enrolled in the Cardiovascular Health Study and not taking thyroid preparations were included. Analyses of incident hip fracture were performed by thyroid status, over a median follow-up of 12 years. A cross-sectional analysis of thyroid status and BMD was performed in a subset of 1317 participants who had dual-energy x-ray absorptiometry scans. Models were adjusted for risk factors and stratified by sex.

RESULTS: No association was found between subclinical hypothyroidism and incident hip fracture compared with euthyroidism, when assessed at a single time point or persisting at two time points, in either women [hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.69-1.20 for a single and HR 0.79, 95% CI 0.52-1.21 for two time points] or men (HR 1.27, 95% CI 0.82-1.95 for a single and HR 1.09, 95% CI 0.57-2.10 for two time points). Likewise, no association was found between subclinical hyperthyroidism and incident hip fracture in either sex (HR 1.11, 95% CI 0.55-2.25 in women and HR 1.78, 95% CI 0.56-5.66 in men). No association was found between subclinical thyroid dysfunction and BMD at the lumbar spine, total hip, or femoral neck sites.

CONCLUSIONS: Our data suggest no association between subclinical hypothyroidism or subclinical hyperthyroidism and hip fracture risk or BMD in older men and women. Additional data are needed to improve the precision of estimates for subclinical hyperthyroidism and in men.

VL - 99 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24878045?dopt=Abstract ER - TY - JOUR T1 - Subclinical vascular disease burden and longer survival. JF - J Am Geriatr Soc Y1 - 2014 A1 - Odden, Michelle C A1 - Yee, Laura M A1 - Arnold, Alice M A1 - Sanders, Jason L A1 - Hirsch, Calvin A1 - DeFilippi, Christopher A1 - Kizer, Jorge R A1 - Inzitari, Marco A1 - Newman, Anne B KW - Aged KW - Aged, 80 and over KW - C-Reactive Protein KW - Carotid Intima-Media Thickness KW - Cohort Studies KW - Cystatin C KW - Depression KW - Diabetes Mellitus KW - Electrocardiography KW - Female KW - Humans KW - Inflammation KW - Kidney Diseases KW - Male KW - Smoking KW - Survival Analysis KW - United States KW - Vascular Diseases AB -

OBJECTIVES: To determine the contribution of gradations of subclinical vascular disease (SVD) to the likelihood of longer survival and to determine what allows some individuals with SVD to live longer.

DESIGN: Cohort study.

SETTING: Cardiovascular Health Study.

PARTICIPANTS: Individuals born between June 30, 1918, and June 30, 1921 (N = 2,082; aged 70-75 at baseline (1992-93)).

MEASUREMENTS: A SVD index was scored as 0 for no abnormalities, 1 for mild abnormalities, and 2 for severe abnormalities on ankle-arm index, electrocardiogram, and common carotid intima-media thickness measured at baseline. Survival groups were categorized as 80 and younger, 81 to 84, 85 to 89, and 90 and older.

RESULTS: A 1-point lower SVD score was associated with 1.22 greater odds (95% confidence interval = 1.14-1.31) of longer survival, independent of potential confounders. This association was unchanged after adjustment for intermediate incident cardiovascular events. There was suggestion of an interaction between kidney function, smoking, and C-reactive protein and SVD; the association between SVD and longer survival appeared to be modestly greater in persons with poor kidney function, inflammation, or a history of smoking.

CONCLUSION: A lower burden of SVD is associated with longer survival, independent of intermediate cardiovascular events. Abstinence from smoking, better kidney function, and lower inflammation may attenuate the effects of higher SVD and promote longer survival.

VL - 62 IS - 9 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25243681?dopt=Abstract ER - TY - JOUR T1 - Whole-exome sequencing identifies rare and low-frequency coding variants associated with LDL cholesterol. JF - Am J Hum Genet Y1 - 2014 A1 - Lange, Leslie A A1 - Hu, Youna A1 - Zhang, He A1 - Xue, Chenyi A1 - Schmidt, Ellen M A1 - Tang, Zheng-Zheng A1 - Bizon, Chris A1 - Lange, Ethan M A1 - Smith, Joshua D A1 - Turner, Emily H A1 - Jun, Goo A1 - Kang, Hyun Min A1 - Peloso, Gina A1 - Auer, Paul A1 - Li, Kuo-Ping A1 - Flannick, Jason A1 - Zhang, Ji A1 - Fuchsberger, Christian A1 - Gaulton, Kyle A1 - Lindgren, Cecilia A1 - Locke, Adam A1 - Manning, Alisa A1 - Sim, Xueling A1 - Rivas, Manuel A A1 - Holmen, Oddgeir L A1 - Gottesman, Omri A1 - Lu, Yingchang A1 - Ruderfer, Douglas A1 - Stahl, Eli A A1 - Duan, Qing A1 - Li, Yun A1 - Durda, Peter A1 - Jiao, Shuo A1 - Isaacs, Aaron A1 - Hofman, Albert A1 - Bis, Joshua C A1 - Correa, Adolfo A1 - Griswold, Michael E A1 - Jakobsdottir, Johanna A1 - Smith, Albert V A1 - Schreiner, Pamela J A1 - Feitosa, Mary F A1 - Zhang, Qunyuan A1 - Huffman, Jennifer E A1 - Crosby, Jacy A1 - Wassel, Christina L A1 - Do, Ron A1 - Franceschini, Nora A1 - Martin, Lisa W A1 - Robinson, Jennifer G A1 - Assimes, Themistocles L A1 - Crosslin, David R A1 - Rosenthal, Elisabeth A A1 - Tsai, Michael A1 - Rieder, Mark J A1 - Farlow, Deborah N A1 - Folsom, Aaron R A1 - Lumley, Thomas A1 - Fox, Ervin R A1 - Carlson, Christopher S A1 - Peters, Ulrike A1 - Jackson, Rebecca D A1 - van Duijn, Cornelia M A1 - Uitterlinden, André G A1 - Levy, Daniel A1 - Rotter, Jerome I A1 - Taylor, Herman A A1 - Gudnason, Vilmundur A1 - Siscovick, David S A1 - Fornage, Myriam A1 - Borecki, Ingrid B A1 - Hayward, Caroline A1 - Rudan, Igor A1 - Chen, Y Eugene A1 - Bottinger, Erwin P A1 - Loos, Ruth J F A1 - Sætrom, Pål A1 - Hveem, Kristian A1 - Boehnke, Michael A1 - Groop, Leif A1 - McCarthy, Mark A1 - Meitinger, Thomas A1 - Ballantyne, Christie M A1 - Gabriel, Stacey B A1 - O'Donnell, Christopher J A1 - Post, Wendy S A1 - North, Kari E A1 - Reiner, Alexander P A1 - Boerwinkle, Eric A1 - Psaty, Bruce M A1 - Altshuler, David A1 - Kathiresan, Sekar A1 - Lin, Dan-Yu A1 - Jarvik, Gail P A1 - Cupples, L Adrienne A1 - Kooperberg, Charles A1 - Wilson, James G A1 - Nickerson, Deborah A A1 - Abecasis, Goncalo R A1 - Rich, Stephen S A1 - Tracy, Russell P A1 - Willer, Cristen J KW - Adult KW - Aged KW - Apolipoproteins E KW - Cholesterol, LDL KW - Cohort Studies KW - Dyslipidemias KW - Exome KW - Female KW - Follow-Up Studies KW - Gene Frequency KW - Genetic Code KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Lipase KW - Male KW - Middle Aged KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Proprotein Convertase 9 KW - Proprotein Convertases KW - Receptors, LDL KW - Sequence Analysis, DNA KW - Serine Endopeptidases AB -

Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.

VL - 94 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24507775?dopt=Abstract ER - TY - JOUR T1 - Association between hospitalization for pneumonia and subsequent risk of cardiovascular disease. JF - JAMA Y1 - 2015 A1 - Corrales-Medina, Vicente F A1 - Alvarez, Karina N A1 - Weissfeld, Lisa A A1 - Angus, Derek C A1 - Chirinos, Julio A A1 - Chang, Chung-Chou H A1 - Newman, Anne A1 - Loehr, Laura A1 - Folsom, Aaron R A1 - Elkind, Mitchell S A1 - Lyles, Mary F A1 - Kronmal, Richard A A1 - Yende, Sachin KW - Aged KW - Atherosclerosis KW - Cardiovascular Diseases KW - Cohort Studies KW - Comorbidity KW - Female KW - Hospitalization KW - Humans KW - Male KW - Middle Aged KW - Pneumonia KW - Risk Factors AB -

IMPORTANCE: The risk of cardiovascular disease (CVD) after infection is poorly understood.

OBJECTIVE: To determine whether hospitalization for pneumonia is associated with an increased short-term and long-term risk of CVD.

DESIGN, SETTINGS, AND PARTICIPANTS: We examined 2 community-based cohorts: the Cardiovascular Health Study (CHS, n = 5888; enrollment age, ≥65 years; enrollment period, 1989-1994) and the Atherosclerosis Risk in Communities study (ARIC, n = 15,792; enrollment age, 45-64 years; enrollment period, 1987-1989). Participants were followed up through December 31, 2010. We matched each participant hospitalized with pneumonia to 2 controls. Pneumonia cases and controls were followed for occurrence of CVD over 10 years after matching. We estimated hazard ratios (HRs) for CVD at different time intervals, adjusting for demographics, CVD risk factors, subclinical CVD, comorbidities, and functional status.

EXPOSURES: Hospitalization for pneumonia.

MAIN OUTCOMES AND MEASURES: Incident CVD (myocardial infarction, stroke, and fatal coronary heart disease).

RESULTS: Of 591 pneumonia cases in CHS, 206 had CVD events over 10 years after pneumonia hospitalization. CVD risk after pneumonia was highest in the first year. CVD occurred in 54 cases and 6 controls in the first 30 days (HR, 4.07; 95% CI, 2.86-5.27); 11 cases and 9 controls between 31 and 90 days (HR, 2.94; 95% CI, 2.18-3.70); and 22 cases and 55 controls between 91 days and 1 year (HR, 2.10; 95% CI, 1.59-2.60). Additional CVD risk remained elevated into the tenth year, when 4 cases and 12 controls developed CVD (HR, 1.86; 95% CI, 1.18-2.55). In ARIC, of 680 pneumonia cases, 112 had CVD over 10 years after hospitalization. CVD occurred in 4 cases and 3 controls in the first 30 days (HR, 2.38; 95% CI, 1.12-3.63); 4 cases and 0 controls between 31 and 90 days (HR, 2.40; 95% CI, 1.23-3.47); 11 cases and 8 controls between 91 days and 1 year (HR, 2.19; 95% CI, 1.20-3.19); and 8 cases and 7 controls during the second year (HR, 1.88; 95% CI, 1.10-2.66). After the second year, the HRs were no longer statistically significant.

CONCLUSIONS AND RELEVANCE: Hospitalization for pneumonia was associated with increased short-term and long-term risk of CVD, suggesting that pneumonia may be a risk factor for CVD.

VL - 313 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25602997?dopt=Abstract ER - TY - JOUR T1 - Association of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study. JF - Respir Res Y1 - 2015 A1 - Hansen, J G A1 - Gao, W A1 - Dupuis, J A1 - O'Connor, G T A1 - Tang, W A1 - Kowgier, M A1 - Sood, A A1 - Gharib, S A A1 - Palmer, L J A1 - Fornage, M A1 - Heckbert, S R A1 - Psaty, B M A1 - Booth, S L A1 - Cassano, Patricia A KW - Adult KW - Aged KW - Cohort Studies KW - Cross-Sectional Studies KW - DNA-Binding Proteins KW - Female KW - Genetic Variation KW - Humans KW - Longitudinal Studies KW - Male KW - Massachusetts KW - Metabolic Networks and Pathways KW - Middle Aged KW - Nuclear Proteins KW - Polymorphism, Single Nucleotide KW - Vitamin D AB -

BACKGROUND: Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults.

METHODS: We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts.

RESULTS: We found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P=0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P=0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene-based P<0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P=0.09).

CONCLUSIONS: Serum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies.

VL - 16 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26122139?dopt=Abstract ER - TY - JOUR T1 - Association of exome sequences with plasma C-reactive protein levels in >9000 participants. JF - Hum Mol Genet Y1 - 2015 A1 - Schick, Ursula M A1 - Auer, Paul L A1 - Bis, Joshua C A1 - Lin, Honghuang A1 - Wei, Peng A1 - Pankratz, Nathan A1 - Lange, Leslie A A1 - Brody, Jennifer A1 - Stitziel, Nathan O A1 - Kim, Daniel S A1 - Carlson, Christopher S A1 - Fornage, Myriam A1 - Haessler, Jeffery A1 - Hsu, Li A1 - Jackson, Rebecca D A1 - Kooperberg, Charles A1 - Leal, Suzanne M A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - Tracy, Russell A1 - Ardissino, Diego A1 - Shah, Svati A1 - Willer, Cristen A1 - Loos, Ruth A1 - Melander, Olle A1 - McPherson, Ruth A1 - Hovingh, Kees A1 - Reilly, Muredach A1 - Watkins, Hugh A1 - Girelli, Domenico A1 - Fontanillas, Pierre A1 - Chasman, Daniel I A1 - Gabriel, Stacey B A1 - Gibbs, Richard A1 - Nickerson, Deborah A A1 - Kathiresan, Sekar A1 - Peters, Ulrike A1 - Dupuis, Josée A1 - Wilson, James G A1 - Rich, Stephen S A1 - Morrison, Alanna C A1 - Benjamin, Emelia J A1 - Gross, Myron D A1 - Reiner, Alex P KW - Adult KW - African Americans KW - C-Reactive Protein KW - Cardiovascular Diseases KW - Cohort Studies KW - European Continental Ancestry Group KW - Exome KW - Female KW - Gene Frequency KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Hepatocyte Nuclear Factor 1-alpha KW - Humans KW - Male KW - Plasma KW - Polymorphism, Single Nucleotide KW - Receptors, Interleukin-6 KW - Risk Factors AB -

C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.

VL - 24 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25187575?dopt=Abstract ER - TY - JOUR T1 - Burden of Comorbidities and Functional and Cognitive Impairments in Elderly Patients at the Initial Diagnosis of Heart Failure and Their Impact on Total Mortality: The Cardiovascular Health Study. JF - JACC Heart Fail Y1 - 2015 A1 - Murad, Khalil A1 - Goff, David C A1 - Morgan, Timothy M A1 - Burke, Gregory L A1 - Bartz, Traci M A1 - Kizer, Jorge R A1 - Chaudhry, Sarwat I A1 - Gottdiener, John S A1 - Kitzman, Dalane W KW - Activities of Daily Living KW - Aged KW - Aged, 80 and over KW - Atrial Fibrillation KW - Cognition Disorders KW - Cohort Studies KW - Comorbidity KW - Coronary Disease KW - Female KW - Heart Failure KW - Humans KW - Hypertension KW - Incidence KW - Longitudinal Studies KW - Male KW - Peripheral Arterial Disease KW - Physical Fitness KW - Prevalence KW - Proportional Hazards Models KW - Pulmonary Disease, Chronic Obstructive AB -

OBJECTIVES: The purpose of this study was to determine the prevalence of clinically relevant comorbidities and measures of physical and cognitive impairment in elderly persons with incident heart failure (HF).

BACKGROUND: Comorbidities and functional and cognitive impairments are common in the elderly and often associated with greater mortality risk.

METHODS: We examined the prevalence of 9 comorbidities and 4 measures of functional and cognitive impairments in 558 participants from the Cardiovascular Health Study who developed incident HF between 1990 and 2002. Participants were followed prospectively until mid-2008 to determine their mortality risk.

RESULTS: Mean age of participants was 79.2 ± 6.3 years with 52% being men. Sixty percent of participants had ≥3 comorbidities, and only 2.5% had none. Twenty-two percent and 44% of participants had ≥1 activity of daily living (ADL) and ≥1 instrumental activity of daily living (IADL) impaired respectively. Seventeen percent of participants had cognitive impairment (modified mini-mental state exam score <80, scores range between 0 and 100). During follow up, 504 participants died, with 1-, 5-, and 10-year mortality rates of 19%, 56%, and 83%, respectively. In a multivariable-adjusted model, the following were significantly associated with greater total mortality risk: diabetes mellitus (hazard ratio [HR]: 1.64; 95% confidence interval [CI]: 1.33 to 2.03), chronic kidney disease (HR: 1.32; 95% CI: 1.07 to 1.62 for moderate disease; HR: 3.00; 95% CI: 1.82 to 4.95 for severe), cerebrovascular disease (HR: 1.53; 95% CI: 1.22 to 1.92), depression (HR: 1.44; 95% CI: 1.09 to 1.90), functional impairment (HR: 1.30; 95% CI: 1.04 to 1.63 for 1 IADL impaired; HR: 1.49; 95% CI: 1.07 to 2.04 for ≥2 IADL impaired), and cognitive impairment (HR: 1.33; 95% CI: 1.02 to 1.73). Other comorbidities (hypertension, coronary heart disease, peripheral arterial disease, atrial fibrillation, and obstructive airway disease) and measures of functional impairments (ADLs and 15-ft walk time) were not associated with mortality.

CONCLUSIONS: Elderly patients with incident HF have a high burden of comorbidities and functional and cognitive impairments. Some of these conditions are associated with greater mortality risk.

VL - 3 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26160370?dopt=Abstract ER - TY - JOUR T1 - Changes in insulin-like growth factor-I and its binding proteins are associated with diabetes mellitus in older adults. JF - J Am Geriatr Soc Y1 - 2015 A1 - Aneke-Nash, Chino S A1 - Parrinello, Christina M A1 - Rajpathak, Swapnil N A1 - Rohan, Thomas E A1 - Strotmeyer, Elsa S A1 - Kritchevsky, Stephen B A1 - Psaty, Bruce M A1 - Bůzková, Petra A1 - Kizer, Jorge R A1 - Newman, Anne B A1 - Strickler, Howard D A1 - Kaplan, Robert C KW - Aged KW - Blood Glucose KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Female KW - Humans KW - Insulin-Like Growth Factor Binding Protein 1 KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Male KW - Retrospective Studies AB -

OBJECTIVES: To determine whether changes in insulin-like growth factor (IGF) protein levels are greater in participants with type 2 diabetes mellitus or worsening glycemia than in normoglycemic individuals over a 9-year follow-up period.

DESIGN: Retrospective analysis of a cohort study.

SETTING: Participants were recruited from North Carolina, California, Maryland, and Pennsylvania.

PARTICIPANTS: Cardiovascular Health Study All Stars participants, a cohort study of community-dwelling adults aged 65 and older (N=897).

MEASUREMENTS: Plasma IGF-I, IGF binding protein (IGFBP)-1, and IGFBP-3 levels were assessed and American Diabetes Association cut-points for impaired glucose tolerance (IGT), impaired fasting glucose (IFG), and diabetes mellitus were used to classify participants at baseline (1996-97) and follow-up (2005-06).

RESULTS: At baseline, mean age was 76.3±3.6, and 18.5% had diabetes mellitus. Participants with IFG alone and IGT plus IFG had higher IGF-I levels and lower IGFBP-1 levels than those with normoglycemia or diabetes mellitus. The greatest percentage change in IGF levels occurred in those who had diabetes mellitus at baseline (9-year changes: -9.3% for IGF-I, 59.7% for IGFBP-1, -13.4% for IGFBP-3), the smallest in individuals who remained normoglycemic at follow-up (9-year changes: -3.7% for IGF-I, 25.6% for IGFBP-1, -6.4% for IGFBP-3), and intermediate in those who were normoglycemic but developed IFG at follow-up.

CONCLUSION: Degrees of glycemic impairment are associated with varying degrees of change in IGF protein levels. The changes observed in the diabetes mellitus group have been previously shown to be associated with heart failure, cancer, and noncancer mortality.

VL - 63 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25989565?dopt=Abstract ER - TY - JOUR T1 - Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians. JF - Am J Clin Nutr Y1 - 2015 A1 - Fretts, Amanda M A1 - Follis, Jack L A1 - Nettleton, Jennifer A A1 - Lemaitre, Rozenn N A1 - Ngwa, Julius S A1 - Wojczynski, Mary K A1 - Kalafati, Ioanna Panagiota A1 - Varga, Tibor V A1 - Frazier-Wood, Alexis C A1 - Houston, Denise K A1 - Lahti, Jari A1 - Ericson, Ulrika A1 - van den Hooven, Edith H A1 - Mikkilä, Vera A1 - Kiefte-de Jong, Jessica C A1 - Mozaffarian, Dariush A1 - Rice, Kenneth A1 - Renstrom, Frida A1 - North, Kari E A1 - McKeown, Nicola M A1 - Feitosa, Mary F A1 - Kanoni, Stavroula A1 - Smith, Caren E A1 - Garcia, Melissa E A1 - Tiainen, Anna-Maija A1 - Sonestedt, Emily A1 - Manichaikul, Ani A1 - van Rooij, Frank J A A1 - Dimitriou, Maria A1 - Raitakari, Olli A1 - Pankow, James S A1 - Djoussé, Luc A1 - Province, Michael A A1 - Hu, Frank B A1 - Lai, Chao-Qiang A1 - Keller, Margaux F A1 - Perälä, Mia-Maria A1 - Rotter, Jerome I A1 - Hofman, Albert A1 - Graff, Misa A1 - Kähönen, Mika A1 - Mukamal, Kenneth A1 - Johansson, Ingegerd A1 - Ordovas, Jose M A1 - Liu, Yongmei A1 - Männistö, Satu A1 - Uitterlinden, André G A1 - Deloukas, Panos A1 - Seppälä, Ilkka A1 - Psaty, Bruce M A1 - Cupples, L Adrienne A1 - Borecki, Ingrid B A1 - Franks, Paul W A1 - Arnett, Donna K A1 - Nalls, Mike A A1 - Eriksson, Johan G A1 - Orho-Melander, Marju A1 - Franco, Oscar H A1 - Lehtimäki, Terho A1 - Dedoussis, George V A1 - Meigs, James B A1 - Siscovick, David S KW - Blood Glucose KW - Cohort Studies KW - Genetic Association Studies KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Hyperglycemia KW - Hyperinsulinism KW - Insulin KW - Insulin Resistance KW - Insulin-Secreting Cells KW - Meat KW - Meat Products KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Risk Factors AB -

BACKGROUND: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown.

OBJECTIVE: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus.

DESIGN: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations.

RESULTS: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049-ln-pmol/L (95% CI: 0.035, 0.063-ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic loci known to influence fasting glucose or insulin resistance.

CONCLUSION: The association of higher fasting glucose and insulin concentrations with meat consumption was not modified by an index of glucose- and insulin-related single-nucleotide polymorphisms. Six of the participating studies are registered at clinicaltrials.gov as NCT0000513 (Atherosclerosis Risk in Communities), NCT00149435 (Cardiovascular Health Study), NCT00005136 (Family Heart Study), NCT00005121 (Framingham Heart Study), NCT00083369 (Genetics of Lipid Lowering Drugs and Diet Network), and NCT00005487 (Multi-Ethnic Study of Atherosclerosis).

VL - 102 IS - 5 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26354543?dopt=Abstract ER - TY - JOUR T1 - Contribution of Major Lifestyle Risk Factors for Incident Heart Failure in Older Adults: The Cardiovascular Health Study. JF - JACC Heart Fail Y1 - 2015 A1 - Del Gobbo, Liana C A1 - Kalantarian, Shadi A1 - Imamura, Fumiaki A1 - Lemaitre, Rozenn A1 - Siscovick, David S A1 - Psaty, Bruce M A1 - Mozaffarian, Dariush KW - Aged KW - Alcohol Drinking KW - Cohort Studies KW - Diet KW - Female KW - Heart Failure KW - Humans KW - Incidence KW - Male KW - Motor Activity KW - Obesity KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Factors KW - Sedentary Lifestyle KW - Smoking KW - United States AB -

OBJECTIVES: The goal of this study was to determine the relative contribution of major lifestyle factors on the development of heart failure (HF) in older adults.

BACKGROUND: HF incurs high morbidity, mortality, and health care costs among adults ≥65 years of age, which is the most rapidly growing segment of the U.S.

METHODS: We prospectively investigated separate and combined associations of lifestyle risk factors with incident HF (1,380 cases) over 21.5 years among 4,490 men and women in the Cardiovascular Health Study, which is a community-based cohort of older adults. Lifestyle factors included 4 dietary patterns (Alternative Healthy Eating Index, Dietary Approaches to Stop Hypertension, an American Heart Association 2020 dietary goals score, and a Biologic pattern, which was constructed using previous knowledge of cardiovascular disease dietary risk factors), 4 physical activity metrics (exercise intensity, walking pace, energy expended in leisure activity, and walking distance), alcohol intake, smoking, and obesity.

RESULTS: No dietary pattern was associated with developing HF (p > 0.05). Walking pace and leisure activity were associated with a 26% and 22% lower risk of HF, respectively (pace >3 mph vs. <2 mph; hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.63 to 0.86; leisure activity ≥845 kcal/week vs. <845 kcal/week; HR: 0.78; 95% CI: 0.69 to 0.87). Modest alcohol intake, maintaining a body mass index <30 kg/m(2), and not smoking were also independently associated with a lower risk of HF. Participants with ≥4 healthy lifestyle factors had a 45% (HR: 0.55; 95% CI: 0.42 to 0.74) lower risk of HF. Heterogeneity by age, sex, cardiovascular disease, hypertension medication use, and diabetes was not observed.

CONCLUSIONS: Among older U.S. adults, physical activity, modest alcohol intake, avoiding obesity, and not smoking, but not dietary patterns, were associated with a lower risk of HF.

VL - 3 IS - 7 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26160366?dopt=Abstract ER - TY - JOUR T1 - Gene-Environment Interactions of Circadian-Related Genes for Cardiometabolic Traits. JF - Diabetes Care Y1 - 2015 A1 - Dashti, Hassan S A1 - Follis, Jack L A1 - Smith, Caren E A1 - Tanaka, Toshiko A1 - Garaulet, Marta A1 - Gottlieb, Daniel J A1 - Hruby, Adela A1 - Jacques, Paul F A1 - Kiefte-de Jong, Jessica C A1 - Lamon-Fava, Stefania A1 - Scheer, Frank A J L A1 - Bartz, Traci M A1 - Kovanen, Leena A1 - Wojczynski, Mary K A1 - Frazier-Wood, Alexis C A1 - Ahluwalia, Tarunveer S A1 - Perälä, Mia-Maria A1 - Jonsson, Anna A1 - Muka, Taulant A1 - Kalafati, Ioanna P A1 - Mikkilä, Vera A1 - Ordovas, Jose M KW - Adult KW - Alleles KW - Blood Glucose KW - Circadian Rhythm Signaling Peptides and Proteins KW - Cohort Studies KW - Diabetes Mellitus, Type 2 KW - Diet, Fat-Restricted KW - European Continental Ancestry Group KW - Fasting KW - Female KW - Gene-Environment Interaction KW - Humans KW - Insulin Resistance KW - Male KW - Middle Aged KW - Multicenter Studies as Topic KW - Observational Studies as Topic KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Sleep KW - Waist Circumference AB -

OBJECTIVE: Common circadian-related gene variants associate with increased risk for metabolic alterations including type 2 diabetes. However, little is known about whether diet and sleep could modify associations between circadian-related variants (CLOCK-rs1801260, CRY2-rs11605924, MTNR1B-rs1387153, MTNR1B-rs10830963, NR1D1-rs2314339) and cardiometabolic traits (fasting glucose [FG], HOMA-insulin resistance, BMI, waist circumference, and HDL-cholesterol) to facilitate personalized recommendations.

RESEARCH DESIGN AND METHODS: We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations and interactions between dietary intake/sleep duration and selected variants on cardiometabolic traits from 15 cohort studies including up to 28,190 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium.

RESULTS: We observed significant associations between relative macronutrient intakes and glycemic traits and short sleep duration (<7 h) and higher FG and replicated known MTNR1B associations with glycemic traits. No interactions were evident after accounting for multiple comparisons. However, we observed nominally significant interactions (all P < 0.01) between carbohydrate intake and MTNR1B-rs1387153 for FG with a 0.003 mmol/L higher FG with each additional 1% carbohydrate intake in the presence of the T allele, between sleep duration and CRY2-rs11605924 for HDL-cholesterol with a 0.010 mmol/L higher HDL-cholesterol with each additional hour of sleep in the presence of the A allele, and between long sleep duration (≥9 h) and MTNR1B-rs1387153 for BMI with a 0.60 kg/m(2) higher BMI with long sleep duration in the presence of the T allele relative to normal sleep duration (≥7 to <9 h).

CONCLUSIONS: Our results suggest that lower carbohydrate intake and normal sleep duration may ameliorate cardiometabolic abnormalities conferred by common circadian-related genetic variants. Until further mechanistic examination of the nominally significant interactions is conducted, recommendations applicable to the general population regarding diet—specifically higher carbohydrate and lower fat composition—and normal sleep duration should continue to be emphasized among individuals with the investigated circadian-related gene variants.

VL - 38 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26084345?dopt=Abstract ER - TY - JOUR T1 - Generalized estimating equations for genome-wide association studies using longitudinal phenotype data. JF - Stat Med Y1 - 2015 A1 - Sitlani, Colleen M A1 - Rice, Kenneth M A1 - Lumley, Thomas A1 - McKnight, Barbara A1 - Cupples, L Adrienne A1 - Avery, Christy L A1 - Noordam, Raymond A1 - Stricker, Bruno H C A1 - Whitsel, Eric A A1 - Psaty, Bruce M KW - Aged KW - Aging KW - Cardiovascular Diseases KW - Cohort Studies KW - Computer Simulation KW - Cross-Sectional Studies KW - Epidemiologic Research Design KW - Gene-Environment Interaction KW - Genetic Variation KW - Genome, Human KW - Genome-Wide Association Study KW - Humans KW - Longitudinal Studies KW - Meta-Analysis as Topic KW - Models, Genetic KW - Pharmacogenetics KW - Risk Assessment KW - United States AB -

Many longitudinal cohort studies have both genome-wide measures of genetic variation and repeated measures of phenotypes and environmental exposures. Genome-wide association study analyses have typically used only cross-sectional data to evaluate quantitative phenotypes and binary traits. Incorporation of repeated measures may increase power to detect associations, but also requires specialized analysis methods. Here, we discuss one such method-generalized estimating equations (GEE)-in the contexts of analysis of main effects of rare genetic variants and analysis of gene-environment interactions. We illustrate the potential for increased power using GEE analyses instead of cross-sectional analyses. We also address challenges that arise, such as the need for small-sample corrections when the minor allele frequency of a genetic variant and/or the prevalence of an environmental exposure is low. To illustrate methods for detection of gene-drug interactions on a genome-wide scale, using repeated measures data, we conduct single-study analyses and meta-analyses across studies in three large cohort studies participating in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium-the Atherosclerosis Risk in Communities study, the Cardiovascular Health Study, and the Rotterdam Study.

VL - 34 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25297442?dopt=Abstract ER - TY - JOUR T1 - Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949). JF - Mol Psychiatry Y1 - 2015 A1 - Davies, G A1 - Armstrong, N A1 - Bis, J C A1 - Bressler, J A1 - Chouraki, V A1 - Giddaluru, S A1 - Hofer, E A1 - Ibrahim-Verbaas, C A A1 - Kirin, M A1 - Lahti, J A1 - van der Lee, S J A1 - Le Hellard, S A1 - Liu, T A1 - Marioni, R E A1 - Oldmeadow, C A1 - Postmus, I A1 - Smith, A V A1 - Smith, J A A1 - Thalamuthu, A A1 - Thomson, R A1 - Vitart, V A1 - Wang, J A1 - Yu, L A1 - Zgaga, L A1 - Zhao, W A1 - Boxall, R A1 - Harris, S E A1 - Hill, W D A1 - Liewald, D C A1 - Luciano, M A1 - Adams, H A1 - Ames, D A1 - Amin, N A1 - Amouyel, P A1 - Assareh, A A A1 - Au, R A1 - Becker, J T A1 - Beiser, A A1 - Berr, C A1 - Bertram, L A1 - Boerwinkle, E A1 - Buckley, B M A1 - Campbell, H A1 - Corley, J A1 - De Jager, P L A1 - Dufouil, C A1 - Eriksson, J G A1 - Espeseth, T A1 - Faul, J D A1 - Ford, I A1 - Gottesman, R F A1 - Griswold, M E A1 - Gudnason, V A1 - Harris, T B A1 - Heiss, G A1 - Hofman, A A1 - Holliday, E G A1 - Huffman, J A1 - Kardia, S L R A1 - Kochan, N A1 - Knopman, D S A1 - Kwok, J B A1 - Lambert, J-C A1 - Lee, T A1 - Li, G A1 - Li, S-C A1 - Loitfelder, M A1 - Lopez, O L A1 - Lundervold, A J A1 - Lundqvist, A A1 - Mather, K A A1 - Mirza, S S A1 - Nyberg, L A1 - Oostra, B A A1 - Palotie, A A1 - Papenberg, G A1 - Pattie, A A1 - Petrovic, K A1 - Polasek, O A1 - Psaty, B M A1 - Redmond, P A1 - Reppermund, S A1 - Rotter, J I A1 - Schmidt, H A1 - Schuur, M A1 - Schofield, P W A1 - Scott, R J A1 - Steen, V M A1 - Stott, D J A1 - van Swieten, J C A1 - Taylor, K D A1 - Trollor, J A1 - Trompet, S A1 - Uitterlinden, A G A1 - Weinstein, G A1 - Widen, E A1 - Windham, B G A1 - Jukema, J W A1 - Wright, A F A1 - Wright, M J A1 - Yang, Q A1 - Amieva, H A1 - Attia, J R A1 - Bennett, D A A1 - Brodaty, H A1 - de Craen, A J M A1 - Hayward, C A1 - Ikram, M A A1 - Lindenberger, U A1 - Nilsson, L-G A1 - Porteous, D J A1 - Räikkönen, K A1 - Reinvang, I A1 - Rudan, I A1 - Sachdev, P S A1 - Schmidt, R A1 - Schofield, P R A1 - Srikanth, V A1 - Starr, J M A1 - Turner, S T A1 - Weir, D R A1 - Wilson, J F A1 - van Duijn, C A1 - Launer, L A1 - Fitzpatrick, A L A1 - Seshadri, S A1 - Mosley, T H A1 - Deary, I J KW - Aged KW - Aged, 80 and over KW - Atherosclerosis KW - Cognition KW - Cognition Disorders KW - Cohort Studies KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - HMGN1 Protein KW - Humans KW - Male KW - Middle Aged KW - Neuropsychological Tests KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Scotland AB -

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

VL - 20 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25644384?dopt=Abstract ER - TY - JOUR T1 - Genetic loci associated with circulating levels of very long-chain saturated fatty acids. JF - J Lipid Res Y1 - 2015 A1 - Lemaitre, Rozenn N A1 - King, Irena B A1 - Kabagambe, Edmond K A1 - Wu, Jason H Y A1 - McKnight, Barbara A1 - Manichaikul, Ani A1 - Guan, Weihua A1 - Sun, Qi A1 - Chasman, Daniel I A1 - Foy, Millennia A1 - Wang, Lu A1 - Zhu, Jingwen A1 - Siscovick, David S A1 - Tsai, Michael Y A1 - Arnett, Donna K A1 - Psaty, Bruce M A1 - Djoussé, Luc A1 - Chen, Yii-der I A1 - Tang, Weihong A1 - Weng, Lu-Chen A1 - Wu, Hongyu A1 - Jensen, Majken K A1 - Chu, Audrey Y A1 - Jacobs, David R A1 - Rich, Stephen S A1 - Mozaffarian, Dariush A1 - Steffen, Lyn A1 - Rimm, Eric B A1 - Hu, Frank B A1 - Ridker, Paul M A1 - Fornage, Myriam A1 - Friedlander, Yechiel KW - Cohort Studies KW - Fatty Acids KW - Genetic Loci KW - Genetic Variation KW - Genome-Wide Association Study KW - Humans AB -

Very long-chain saturated fatty acids (VLSFAs) are saturated fatty acids with 20 or more carbons. In contrast to the more abundant saturated fatty acids, such as palmitic acid, there is growing evidence that circulating VLSFAs may have beneficial biological properties. Whether genetic factors influence circulating levels of VLSFAs is not known. We investigated the association of common genetic variation with plasma phospholipid/erythrocyte levels of three VLSFAs by performing genome-wide association studies in seven population-based cohorts comprising 10,129 subjects of European ancestry. We observed associations of circulating VLSFA concentrations with common variants in two genes, serine palmitoyl-transferase long-chain base subunit 3 (SPTLC3), a gene involved in the rate-limiting step of de novo sphingolipid synthesis, and ceramide synthase 4 (CERS4). The SPTLC3 variant at rs680379 was associated with higher arachidic acid (20:0 , P = 5.81 × 10(-13)). The CERS4 variant at rs2100944 was associated with higher levels of 20:0 (P = 2.65 × 10(-40)) and in analyses that adjusted for 20:0, with lower levels of behenic acid (P = 4.22 × 10(-26)) and lignoceric acid (P = 3.20 × 10(-21)). These novel associations suggest an inter-relationship of circulating VLSFAs and sphingolipid synthesis.

VL - 56 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25378659?dopt=Abstract ER - TY - JOUR T1 - Genetic overlap between diagnostic subtypes of ischemic stroke. JF - Stroke Y1 - 2015 A1 - Holliday, Elizabeth G A1 - Traylor, Matthew A1 - Malik, Rainer A1 - Bevan, Steve A1 - Falcone, Guido A1 - Hopewell, Jemma C A1 - Cheng, Yu-Ching A1 - Cotlarciuc, Ioana A1 - Bis, Joshua C A1 - Boerwinkle, Eric A1 - Boncoraglio, Giorgio B A1 - Clarke, Robert A1 - Cole, John W A1 - Fornage, Myriam A1 - Furie, Karen L A1 - Ikram, M Arfan A1 - Jannes, Jim A1 - Kittner, Steven J A1 - Lincz, Lisa F A1 - Maguire, Jane M A1 - Meschia, James F A1 - Mosley, Thomas H A1 - Nalls, Mike A A1 - Oldmeadow, Christopher A1 - Parati, Eugenio A A1 - Psaty, Bruce M A1 - Rothwell, Peter M A1 - Seshadri, Sudha A1 - Scott, Rodney J A1 - Sharma, Pankaj A1 - Sudlow, Cathie A1 - Wiggins, Kerri L A1 - Worrall, Bradford B A1 - Rosand, Jonathan A1 - Mitchell, Braxton D A1 - Dichgans, Martin A1 - Markus, Hugh S A1 - Levi, Christopher A1 - Attia, John A1 - Wray, Naomi R KW - Alleles KW - Atherosclerosis KW - Cerebral Small Vessel Diseases KW - Cohort Studies KW - Data Interpretation, Statistical KW - Embolism KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Ischemia KW - Linear Models KW - Meta-Analysis as Topic KW - Phenotype KW - Polymorphism, Single Nucleotide KW - Stroke AB -

BACKGROUND AND PURPOSE: Despite moderate heritability, the phenotypic heterogeneity of ischemic stroke has hampered gene discovery, motivating analyses of diagnostic subtypes with reduced sample sizes. We assessed evidence for a shared genetic basis among the 3 major subtypes: large artery atherosclerosis (LAA), cardioembolism, and small vessel disease (SVD), to inform potential cross-subtype analyses.

METHODS: Analyses used genome-wide summary data for 12 389 ischemic stroke cases (including 2167 LAA, 2405 cardioembolism, and 1854 SVD) and 62 004 controls from the Metastroke consortium. For 4561 cases and 7094 controls, individual-level genotype data were also available. Genetic correlations between subtypes were estimated using linear mixed models and polygenic profile scores. Meta-analysis of a combined LAA-SVD phenotype (4021 cases and 51 976 controls) was performed to identify shared risk alleles.

RESULTS: High genetic correlation was identified between LAA and SVD using linear mixed models (rg=0.96, SE=0.47, P=9×10(-4)) and profile scores (rg=0.72; 95% confidence interval, 0.52-0.93). Between LAA and cardioembolism and SVD and cardioembolism, correlation was moderate using linear mixed models but not significantly different from zero for profile scoring. Joint meta-analysis of LAA and SVD identified strong association (P=1×10(-7)) for single nucleotide polymorphisms near the opioid receptor μ1 (OPRM1) gene.

CONCLUSIONS: Our results suggest that LAA and SVD, which have been hitherto treated as genetically distinct, may share a substantial genetic component. Combined analyses of LAA and SVD may increase power to identify small-effect alleles influencing shared pathophysiological processes.

VL - 46 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25613305?dopt=Abstract ER - TY - JOUR T1 - Genome-wide studies of verbal declarative memory in nondemented older people: the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. JF - Biol Psychiatry Y1 - 2015 A1 - Debette, Stephanie A1 - Ibrahim Verbaas, Carla A A1 - Bressler, Jan A1 - Schuur, Maaike A1 - Smith, Albert A1 - Bis, Joshua C A1 - Davies, Gail A1 - Wolf, Christiane A1 - Gudnason, Vilmundur A1 - Chibnik, Lori B A1 - Yang, Qiong A1 - DeStefano, Anita L A1 - de Quervain, Dominique J F A1 - Srikanth, Velandai A1 - Lahti, Jari A1 - Grabe, Hans J A1 - Smith, Jennifer A A1 - Priebe, Lutz A1 - Yu, Lei A1 - Karbalai, Nazanin A1 - Hayward, Caroline A1 - Wilson, James F A1 - Campbell, Harry A1 - Petrovic, Katja A1 - Fornage, Myriam A1 - Chauhan, Ganesh A1 - Yeo, Robin A1 - Boxall, Ruth A1 - Becker, James A1 - Stegle, Oliver A1 - Mather, Karen A A1 - Chouraki, Vincent A1 - Sun, Qi A1 - Rose, Lynda M A1 - Resnick, Susan A1 - Oldmeadow, Christopher A1 - Kirin, Mirna A1 - Wright, Alan F A1 - Jonsdottir, Maria K A1 - Au, Rhoda A1 - Becker, Albert A1 - Amin, Najaf A1 - Nalls, Mike A A1 - Turner, Stephen T A1 - Kardia, Sharon L R A1 - Oostra, Ben A1 - Windham, Gwen A1 - Coker, Laura H A1 - Zhao, Wei A1 - Knopman, David S A1 - Heiss, Gerardo A1 - Griswold, Michael E A1 - Gottesman, Rebecca F A1 - Vitart, Veronique A1 - Hastie, Nicholas D A1 - Zgaga, Lina A1 - Rudan, Igor A1 - Polasek, Ozren A1 - Holliday, Elizabeth G A1 - Schofield, Peter A1 - Choi, Seung Hoan A1 - Tanaka, Toshiko A1 - An, Yang A1 - Perry, Rodney T A1 - Kennedy, Richard E A1 - Sale, Michèle M A1 - Wang, Jing A1 - Wadley, Virginia G A1 - Liewald, David C A1 - Ridker, Paul M A1 - Gow, Alan J A1 - Pattie, Alison A1 - Starr, John M A1 - Porteous, David A1 - Liu, Xuan A1 - Thomson, Russell A1 - Armstrong, Nicola J A1 - Eiriksdottir, Gudny A1 - Assareh, Arezoo A A1 - Kochan, Nicole A A1 - Widen, Elisabeth A1 - Palotie, Aarno A1 - Hsieh, Yi-Chen A1 - Eriksson, Johan G A1 - Vogler, Christian A1 - van Swieten, John C A1 - Shulman, Joshua M A1 - Beiser, Alexa A1 - Rotter, Jerome A1 - Schmidt, Carsten O A1 - Hoffmann, Wolfgang A1 - Nöthen, Markus M A1 - Ferrucci, Luigi A1 - Attia, John A1 - Uitterlinden, André G A1 - Amouyel, Philippe A1 - Dartigues, Jean-François A1 - Amieva, Hélène A1 - Räikkönen, Katri A1 - Garcia, Melissa A1 - Wolf, Philip A A1 - Hofman, Albert A1 - Longstreth, W T A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - DeJager, Philip L A1 - Sachdev, Perminder S A1 - Schmidt, Reinhold A1 - Breteler, Monique M B A1 - Teumer, Alexander A1 - Lopez, Oscar L A1 - Cichon, Sven A1 - Chasman, Daniel I A1 - Grodstein, Francine A1 - Müller-Myhsok, Bertram A1 - Tzourio, Christophe A1 - Papassotiropoulos, Andreas A1 - Bennett, David A A1 - Ikram, M Arfan A1 - Deary, Ian J A1 - van Duijn, Cornelia M A1 - Launer, Lenore A1 - Fitzpatrick, Annette L A1 - Seshadri, Sudha A1 - Mosley, Thomas H KW - Aged KW - Aged, 80 and over KW - Aging KW - Apolipoproteins E KW - Claudin-5 KW - Cohort Studies KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Memory Disorders KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Proteins KW - Proteoglycans KW - Regression Analysis KW - Sulfotransferases KW - Verbal Learning AB -

BACKGROUND: Memory performance in older persons can reflect genetic influences on cognitive function and dementing processes. We aimed to identify genetic contributions to verbal declarative memory in a community setting.

METHODS: We conducted genome-wide association studies for paragraph or word list delayed recall in 19 cohorts from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, comprising 29,076 dementia- and stroke-free individuals of European descent, aged ≥45 years. Replication of suggestive associations (p < 5 × 10(-6)) was sought in 10,617 participants of European descent, 3811 African-Americans, and 1561 young adults.

RESULTS: rs4420638, near APOE, was associated with poorer delayed recall performance in discovery (p = 5.57 × 10(-10)) and replication cohorts (p = 5.65 × 10(-8)). This association was stronger for paragraph than word list delayed recall and in the oldest persons. Two associations with specific tests, in subsets of the total sample, reached genome-wide significance in combined analyses of discovery and replication (rs11074779 [HS3ST4], p = 3.11 × 10(-8), and rs6813517 [SPOCK3], p = 2.58 × 10(-8)) near genes involved in immune response. A genetic score combining 58 independent suggestive memory risk variants was associated with increasing Alzheimer disease pathology in 725 autopsy samples. Association of memory risk loci with gene expression in 138 human hippocampus samples showed cis-associations with WDR48 and CLDN5, both related to ubiquitin metabolism.

CONCLUSIONS: This largest study to date exploring the genetics of memory function in ~40,000 older individuals revealed genome-wide associations and suggested an involvement of immune and ubiquitin pathways.

VL - 77 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25648963?dopt=Abstract ER - TY - JOUR T1 - GWAS of longevity in CHARGE consortium confirms APOE and FOXO3 candidacy. JF - J Gerontol A Biol Sci Med Sci Y1 - 2015 A1 - Broer, Linda A1 - Buchman, Aron S A1 - Deelen, Joris A1 - Evans, Daniel S A1 - Faul, Jessica D A1 - Lunetta, Kathryn L A1 - Sebastiani, Paola A1 - Smith, Jennifer A A1 - Smith, Albert V A1 - Tanaka, Toshiko A1 - Yu, Lei A1 - Arnold, Alice M A1 - Aspelund, Thor A1 - Benjamin, Emelia J A1 - De Jager, Philip L A1 - Eirkisdottir, Gudny A1 - Evans, Denis A A1 - Garcia, Melissa E A1 - Hofman, Albert A1 - Kaplan, Robert C A1 - Kardia, Sharon L R A1 - Kiel, Douglas P A1 - Oostra, Ben A A1 - Orwoll, Eric S A1 - Parimi, Neeta A1 - Psaty, Bruce M A1 - Rivadeneira, Fernando A1 - Rotter, Jerome I A1 - Seshadri, Sudha A1 - Singleton, Andrew A1 - Tiemeier, Henning A1 - Uitterlinden, André G A1 - Zhao, Wei A1 - Bandinelli, Stefania A1 - Bennett, David A A1 - Ferrucci, Luigi A1 - Gudnason, Vilmundur A1 - Harris, Tamara B A1 - Karasik, David A1 - Launer, Lenore J A1 - Perls, Thomas T A1 - Slagboom, P Eline A1 - Tranah, Gregory J A1 - Weir, David R A1 - Newman, Anne B A1 - van Duijn, Cornelia M A1 - Murabito, Joanne M KW - Aged KW - Aged, 80 and over KW - Apolipoproteins E KW - Cell Adhesion Molecules KW - Cohort Studies KW - Female KW - Forkhead Box Protein O3 KW - Forkhead Transcription Factors KW - Genome-Wide Association Study KW - Humans KW - Longevity KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Receptors, Kainic Acid AB -

BACKGROUND: The genetic contribution to longevity in humans has been estimated to range from 15% to 25%. Only two genes, APOE and FOXO3, have shown association with longevity in multiple independent studies.

METHODS: We conducted a meta-analysis of genome-wide association studies including 6,036 longevity cases, age ≥90 years, and 3,757 controls that died between ages 55 and 80 years. We additionally attempted to replicate earlier identified single nucleotide polymorphism (SNP) associations with longevity.

RESULTS: In our meta-analysis, we found suggestive evidence for the association of SNPs near CADM2 (odds ratio [OR] = 0.81; p value = 9.66 × 10(-7)) and GRIK2 (odds ratio = 1.24; p value = 5.09 × 10(-8)) with longevity. When attempting to replicate findings earlier identified in genome-wide association studies, only the APOE locus consistently replicated. In an additional look-up of the candidate gene FOXO3, we found that an earlier identified variant shows a highly significant association with longevity when including published data with our meta-analysis (odds ratio = 1.17; p value = 1.85×10(-10)).

CONCLUSIONS: We did not identify new genome-wide significant associations with longevity and did not replicate earlier findings except for APOE and FOXO3. Our inability to find new associations with survival to ages ≥90 years because longevity represents multiple complex traits with heterogeneous genetic underpinnings, or alternatively, that longevity may be regulated by rare variants that are not captured by standard genome-wide genotyping and imputation of common variants.

VL - 70 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25199915?dopt=Abstract ER - TY - JOUR T1 - Habitual sleep duration is associated with BMI and macronutrient intake and may be modified by CLOCK genetic variants. JF - Am J Clin Nutr Y1 - 2015 A1 - Dashti, Hassan S A1 - Follis, Jack L A1 - Smith, Caren E A1 - Tanaka, Toshiko A1 - Cade, Brian E A1 - Gottlieb, Daniel J A1 - Hruby, Adela A1 - Jacques, Paul F A1 - Lamon-Fava, Stefania A1 - Richardson, Kris A1 - Saxena, Richa A1 - Scheer, Frank A J L A1 - Kovanen, Leena A1 - Bartz, Traci M A1 - Perälä, Mia-Maria A1 - Jonsson, Anna A1 - Frazier-Wood, Alexis C A1 - Kalafati, Ioanna-Panagiota A1 - Mikkilä, Vera A1 - Partonen, Timo A1 - Lemaitre, Rozenn N A1 - Lahti, Jari A1 - Hernandez, Dena G A1 - Toft, Ulla A1 - Johnson, W Craig A1 - Kanoni, Stavroula A1 - Raitakari, Olli T A1 - Perola, Markus A1 - Psaty, Bruce M A1 - Ferrucci, Luigi A1 - Grarup, Niels A1 - Highland, Heather M A1 - Rallidis, Loukianos A1 - Kähönen, Mika A1 - Havulinna, Aki S A1 - Siscovick, David S A1 - Räikkönen, Katri A1 - Jørgensen, Torben A1 - Rotter, Jerome I A1 - Deloukas, Panos A1 - Viikari, Jorma S A A1 - Mozaffarian, Dariush A1 - Linneberg, Allan A1 - Seppälä, Ilkka A1 - Hansen, Torben A1 - Salomaa, Veikko A1 - Gharib, Sina A A1 - Eriksson, Johan G A1 - Bandinelli, Stefania A1 - Pedersen, Oluf A1 - Rich, Stephen S A1 - Dedoussis, George A1 - Lehtimäki, Terho A1 - Ordovas, Jose M KW - Adult KW - Body Mass Index KW - CLOCK Proteins KW - Cohort Studies KW - Cross-Sectional Studies KW - Diet KW - Dietary Proteins KW - Energy Intake KW - European Continental Ancestry Group KW - Fatty Acids, Unsaturated KW - Female KW - Gene-Environment Interaction KW - Genetic Predisposition to Disease KW - Humans KW - Male KW - Middle Aged KW - Obesity KW - Polymorphism, Single Nucleotide KW - Sleep KW - Young Adult AB -

BACKGROUND: Short sleep duration has been associated with greater risks of obesity, hypertension, diabetes, and cardiovascular disease. Also, common genetic variants in the human Circadian Locomotor Output Cycles Kaput (CLOCK) show associations with ghrelin and total energy intake.

OBJECTIVES: We examined associations between habitual sleep duration, body mass index (BMI), and macronutrient intake and assessed whether CLOCK variants modify these associations.

DESIGN: We conducted inverse-variance weighted, fixed-effect meta-analyses of results of adjusted associations of sleep duration and BMI and macronutrient intake as percentages of total energy as well as interactions with CLOCK variants from 9 cohort studies including up to 14,906 participants of European descent from the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium.

RESULTS: We observed a significant association between sleep duration and lower BMI (β ± SE = 0.16 ± 0.04, P < 0.0001) in the overall sample; however, associations between sleep duration and relative macronutrient intake were evident in age- and sex-stratified analyses only. We observed a significant association between sleep duration and lower saturated fatty acid intake in younger (aged 20-64 y) adults (men: 0.11 ± 0.06%, P = 0.03; women: 0.10 ± 0.05%, P = 0.04) and with lower carbohydrate (-0.31 ± 0.12%, P < 0.01), higher total fat (0.18 ± 0.09%, P = 0.05), and higher PUFA (0.05 ± 0.02%, P = 0.02) intakes in older (aged 65-80 y) women. In addition, the following 2 nominally significant interactions were observed: between sleep duration and rs12649507 on PUFA intake and between sleep duration and rs6858749 on protein intake.

CONCLUSIONS: Our results indicate that longer habitual sleep duration is associated with lower BMI and age- and sex-specific favorable dietary behaviors. Differences in the relative intake of specific macronutrients associated with short sleep duration could, at least in part, explain previously reported associations between short sleep duration and chronic metabolic abnormalities. In addition, the influence of obesity-associated CLOCK variants on the association between sleep duration and macronutrient intake suggests that longer habitual sleep duration could ameliorate the genetic predisposition to obesity via a favorable dietary profile.

VL - 101 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25527757?dopt=Abstract ER - TY - JOUR T1 - Meta-Analysis of Genome-Wide Association Studies Identifies Genetic Risk Factors for Stroke in African Americans. JF - Stroke Y1 - 2015 A1 - Carty, Cara L A1 - Keene, Keith L A1 - Cheng, Yu-Ching A1 - Meschia, James F A1 - Chen, Wei-Min A1 - Nalls, Mike A1 - Bis, Joshua C A1 - Kittner, Steven J A1 - Rich, Stephen S A1 - Tajuddin, Salman A1 - Zonderman, Alan B A1 - Evans, Michele K A1 - Langefeld, Carl D A1 - Gottesman, Rebecca A1 - Mosley, Thomas H A1 - Shahar, Eyal A1 - Woo, Daniel A1 - Yaffe, Kristine A1 - Liu, Yongmei A1 - Sale, Michèle M A1 - Dichgans, Martin A1 - Malik, Rainer A1 - Longstreth, W T A1 - Mitchell, Braxton D A1 - Psaty, Bruce M A1 - Kooperberg, Charles A1 - Reiner, Alexander A1 - Worrall, Bradford B A1 - Fornage, Myriam KW - African Americans KW - Case-Control Studies KW - Cohort Studies KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Polymorphism, Single Nucleotide KW - Risk Factors KW - Stroke AB -

BACKGROUND AND PURPOSE: The majority of genome-wide association studies (GWAS) of stroke have focused on European-ancestry populations; however, none has been conducted in African Americans, despite the disproportionately high burden of stroke in this population. The Consortium of Minority Population Genome-Wide Association Studies of Stroke (COMPASS) was established to identify stroke susceptibility loci in minority populations.

METHODS: Using METAL, we conducted meta-analyses of GWAS in 14 746 African Americans (1365 ischemic and 1592 total stroke cases) from COMPASS, and tested genetic variants with P<10(-6) for validation in METASTROKE, a consortium of ischemic stroke genetic studies in European-ancestry populations. We also evaluated stroke loci previously identified in European-ancestry populations.

RESULTS: The 15q21.3 locus linked with lipid levels and hypertension was associated with total stroke (rs4471613; P=3.9×10(-8)) in African Americans. Nominal associations (P<10(-6)) for total or ischemic stroke were observed for 18 variants in or near genes implicated in cell cycle/mRNA presplicing (PTPRG, CDC5L), platelet function (HPS4), blood-brain barrier permeability (CLDN17), immune response (ELTD1, WDFY4, and IL1F10-IL1RN), and histone modification (HDAC9). Two of these loci achieved nominal significance in METASTROKE: 5q35.2 (P=0.03), and 1p31.1 (P=0.018). Four of 7 previously reported ischemic stroke loci (PITX2, HDAC9, CDKN2A/CDKN2B, and ZFHX3) were nominally associated (P<0.05) with stroke in COMPASS.

CONCLUSIONS: We identified a novel genetic variant associated with total stroke in African Americans and found that ischemic stroke loci identified in European-ancestry populations may also be relevant for African Americans. Our findings support investigation of diverse populations to identify and characterize genetic risk factors, and the importance of shared genetic risk across populations.

VL - 46 IS - 8 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26089329?dopt=Abstract ER - TY - JOUR T1 - Multisystem physiologic impairments and changes in gait speed of older adults. JF - J Gerontol A Biol Sci Med Sci Y1 - 2015 A1 - Rosso, Andrea L A1 - Sanders, Jason L A1 - Arnold, Alice M A1 - Boudreau, Robert M A1 - Hirsch, Calvin H A1 - Carlson, Michelle C A1 - Rosano, Caterina A1 - Kritchevsky, Stephen B A1 - Newman, Anne B KW - Age Factors KW - Aged KW - Aged, 80 and over KW - Brain KW - Cardiovascular Physiological Phenomena KW - Cohort Studies KW - Female KW - Gait KW - Geriatric Assessment KW - Glucose KW - Health Status Indicators KW - Humans KW - Kidney KW - Lung KW - Male KW - Sensitivity and Specificity KW - Time Factors AB -

BACKGROUND: Slowed gait is an important health indicator in older adults but a single identifiable cause is often lacking. We assessed whether a summary index measuring impairments across multiple physiologic systems was associated with slowed gait in older individuals.

METHODS: Data from the Cardiovascular Health Study (n = 3,010) were used to assess associations between baseline physiologic index (measuring vasculature, brain, kidneys, lungs, and glucose metabolism; range 0-10 with 0-2 points/system and lower score indicating higher function) and annual gait speed (m/s) over 6 years. Participants with complete data on the physiologic index and at least two gait speed measures were included. Mean gait speed and 95% confidence intervals (CI) by category of index were calculated using mixed effects models.

RESULTS: Those with scores of three or higher on the index had significantly slower gait speed at baseline compared to those with scores of 0-2 (7-10: mean speed = 0.83 m/s, 95% CI: 0.80, 0.84; 0-2: mean speed = 1.01 m/s, 95% CI: 0.99, 1.03). Those with higher indices also had faster decline in gait speed compared to those with lower scores after adjustment for demographic and health characteristics (7-10: change in speed = -0.020 m/s/year, 95% CI: -0.024, -0.016; 0-2: change in speed= -0.010 m/s/year, 95% CI: -0.014, -0.006).

CONCLUSIONS: Greater impairment across five organ systems was associated with slower gait speed and greater declines in gait speed over 6 years. Impairments accumulated over multiple physiologic systems may make older adults more vulnerable to slow gait speed.

VL - 70 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25380599?dopt=Abstract ER - TY - JOUR T1 - Plasma Levels of Soluble Interleukin-2 Receptor α: Associations With Clinical Cardiovascular Events and Genome-Wide Association Scan. JF - Arterioscler Thromb Vasc Biol Y1 - 2015 A1 - Durda, Peter A1 - Sabourin, Jeremy A1 - Lange, Ethan M A1 - Nalls, Mike A A1 - Mychaleckyj, Josyf C A1 - Jenny, Nancy Swords A1 - Li, Jin A1 - Walston, Jeremy A1 - Harris, Tamara B A1 - Psaty, Bruce M A1 - Valdar, William A1 - Liu, Yongmei A1 - Cushman, Mary A1 - Reiner, Alex P A1 - Tracy, Russell P A1 - Lange, Leslie A KW - Adult KW - African Americans KW - Age Distribution KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Coronary Artery Disease KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Incidence KW - Interleukin-2 Receptor alpha Subunit KW - Kaplan-Meier Estimate KW - Male KW - Middle Aged KW - Polymorphism, Single Nucleotide KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Sex Distribution KW - Survival Analysis AB -

OBJECTIVE: Interleukin (IL) -2 receptor subunit α regulates lymphocyte activation, which plays an important role in atherosclerosis. Associations between soluble IL-2Rα (sIL-2Rα) and cardiovascular disease (CVD) have not been widely studied and little is known about the genetic determinants of sIL-2Rα levels.

APPROACH AND RESULTS: We measured baseline levels of sIL-2Rα in 4408 European American (EA) and 766 African American (AA) adults from the Cardiovascular Health Study (CHS) and examined associations with baseline CVD risk factors, subclinical CVD, and incident CVD events. We also performed a genome-wide association study for sIL-2Rα in CHS (2964 EAs and 683 AAs) and further combined CHS EA results with those from two other EA cohorts in a meta-analysis (n=4464 EAs). In age, sex- and race- adjusted models, sIL-2Rα was positively associated with current smoking, type 2 diabetes mellitus, hypertension, insulin, waist circumference, C-reactive protein, IL-6, fibrinogen, internal carotid wall thickness, all-cause mortality, CVD mortality, and incident CVD, stroke, and heart failure. When adjusted for baseline CVD risk factors and subclinical CVD, associations with all-cause mortality, CVD mortality, and heart failure remained significant in both EAs and AAs. In the EA genome-wide association study analysis, we observed 52 single-nucleotide polymorphisms in the chromosome 10p15-14 region, which contains IL2RA, IL15RA, and RMB17, that reached genome-wide significance (P<5×10(-8)). The most significant single-nucleotide polymorphism was rs7911500 (P=1.31×10(-75)). The EA meta-analysis results were highly consistent with CHS-only results. No single-nucleotide polymorphisms reached statistical significance in the AAs.

CONCLUSIONS: These results support a role for sIL-2Rα in atherosclerosis and provide evidence for multiple-associated single-nucleotide polymorphisms at chromosome 10p15-14.

VL - 35 IS - 10 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26293465?dopt=Abstract ER - TY - JOUR T1 - Potassium and glucose measures in older adults: the Cardiovascular Health Study. JF - J Gerontol A Biol Sci Med Sci Y1 - 2015 A1 - Chatterjee, Ranee A1 - Biggs, Mary L A1 - de Boer, Ian H A1 - Brancati, Frederick L A1 - Svetkey, Laura P A1 - Barzilay, Joshua A1 - Djoussé, Luc A1 - Ix, Joachim H A1 - Kizer, Jorge R A1 - Siscovick, David S A1 - Mozaffarian, Dariush A1 - Edelman, David A1 - Mukamal, Kenneth J KW - Aged KW - Blood Glucose KW - Cohort Studies KW - Cross-Sectional Studies KW - Diabetes Mellitus KW - Female KW - Humans KW - Insulin KW - Insulin Resistance KW - Longitudinal Studies KW - Male KW - Multivariate Analysis KW - Potassium KW - Potassium, Dietary KW - Risk Factors KW - United States AB -

BACKGROUND: We sought to determine the impacts of serum and dietary potassium measures on glucose metabolism and diabetes risk in older adults.

METHODS: Among participants of the Cardiovascular Health Study, a community-based cohort of older American adults, we examined a) cross-sectional associations between potassium and measures of insulin sensitivity and secretion estimated from oral glucose tolerance tests and b) longitudinal associations of serum and dietary potassium with diabetes risk.

RESULTS: Among 4,754 participants aged ≥65 years at baseline, there were 445 cases of incident diabetes during a median follow-up of 12 years. In multivariate models, baseline serum and dietary potassium were both associated with lower insulin sensitivity and greater insulin secretion. Compared with those with a serum potassium ≥4.5 mEq/L, participants with a serum potassium <4.0mEq/L had an adjusted mean difference in Matsuda insulin sensitivity index of -0.18 (-0.39, 0.02). Compared with those in the highest quartile, participants in the lowest quartile of dietary potassium intake had a corresponding adjusted mean difference in Matsuda insulin sensitivity index of -0.61 (-0.94, -0.29). In multivariate models, neither serum nor dietary potassium intake was associated with long-term diabetes risk.

CONCLUSIONS: Although we did not identify serum and dietary potassium as risk factors for incident diabetes in older adults, results from cross-sectional analyses suggest that both may be associated with increased insulin resistance. This relationship with insulin resistance needs to be confirmed, and its importance on diabetes risk, cardiovascular risk, and conditions specific to older adults should be determined as well.

VL - 70 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/24895271?dopt=Abstract ER - TY - JOUR T1 - Prospective association of fatty acids in the de novo lipogenesis pathway with risk of type 2 diabetes: the Cardiovascular Health Study. JF - Am J Clin Nutr Y1 - 2015 A1 - Ma, Wenjie A1 - Wu, Jason H Y A1 - Wang, Qianyi A1 - Lemaitre, Rozenn N A1 - Mukamal, Kenneth J A1 - Djoussé, Luc A1 - King, Irena B A1 - Song, Xiaoling A1 - Biggs, Mary L A1 - Delaney, Joseph A A1 - Kizer, Jorge R A1 - Siscovick, David S A1 - Mozaffarian, Dariush KW - Aged KW - Biomarkers KW - Cohort Studies KW - Cross-Sectional Studies KW - Diabetes Mellitus, Type 2 KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Lipogenesis KW - Liver KW - Male KW - Palmitic Acid KW - Phospholipids KW - Prevalence KW - Proportional Hazards Models KW - Risk Factors KW - Stearic Acids KW - United States KW - Up-Regulation AB -

BACKGROUND: Experimental evidence suggests that hepatic de novo lipogenesis (DNL) affects insulin homeostasis via synthesis of saturated fatty acids (SFAs) and monounsaturated fatty acids (MUFAs). Few prospective studies have used fatty acid biomarkers to assess associations with type 2 diabetes.

OBJECTIVES: We investigated associations of major circulating SFAs [palmitic acid (16:0) and stearic acid (18:0)] and MUFA [oleic acid (18:1n-9)] in the DNL pathway with metabolic risk factors and incident diabetes in community-based older U.S. adults in the Cardiovascular Health Study. We secondarily assessed other DNL fatty acid biomarkers [myristic acid (14:0), palmitoleic acid (16:1n-7), 7-hexadecenoic acid (16:1n-9), and vaccenic acid (18:1n-7)] and estimated dietary SFAs and MUFAs.

DESIGN: In 3004 participants free of diabetes, plasma phospholipid fatty acids were measured in 1992, and incident diabetes was identified by medication use and blood glucose. Usual diets were assessed by using repeated food-frequency questionnaires. Multivariable linear and Cox regression were used to assess associations with metabolic risk factors and incident diabetes, respectively.

RESULTS: At baseline, circulating palmitic acid and stearic acid were positively associated with adiposity, triglycerides, inflammation biomarkers, and insulin resistance (P-trend < 0.01 each), whereas oleic acid showed generally beneficial associations (P-trend < 0.001 each). During 30,763 person-years, 297 incident diabetes cases occurred. With adjustment for demographics and lifestyle, palmitic acid (extreme-quintile HR: 1.89; 95% CI: 1.27, 2.83; P-trend = 0.001) and stearic acid (HR: 1.62; 95% CI: 1.09, 2.41; P-trend = 0.006) were associated with higher diabetes risk, whereas oleic acid was not significantly associated. In secondary analyses, vaccenic acid was inversely associated with diabetes (HR: 0.56; 95% CI: 0.38, 0.83; P-trend = 0.005). Other fatty acid biomarkers and estimated dietary SFAs or MUFAs were not significantly associated with incident diabetes.

CONCLUSIONS: In this large prospective cohort, circulating palmitic acid and stearic acid were associated with higher diabetes risk, and vaccenic acid was associated with lower diabetes risk. These results indicate a need for additional investigation of biological mechanisms linking specific fatty acids in the DNL pathway to the pathogenesis of diabetes.

VL - 101 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25527759?dopt=Abstract ER - TY - JOUR T1 - Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. JF - Blood Y1 - 2015 A1 - Huffman, Jennifer E A1 - de Vries, Paul S A1 - Morrison, Alanna C A1 - Sabater-Lleal, Maria A1 - Kacprowski, Tim A1 - Auer, Paul L A1 - Brody, Jennifer A A1 - Chasman, Daniel I A1 - Chen, Ming-Huei A1 - Guo, Xiuqing A1 - Lin, Li-An A1 - Marioni, Riccardo E A1 - Müller-Nurasyid, Martina A1 - Yanek, Lisa R A1 - Pankratz, Nathan A1 - Grove, Megan L A1 - de Maat, Moniek P M A1 - Cushman, Mary A1 - Wiggins, Kerri L A1 - Qi, Lihong A1 - Sennblad, Bengt A1 - Harris, Sarah E A1 - Polasek, Ozren A1 - Riess, Helene A1 - Rivadeneira, Fernando A1 - Rose, Lynda M A1 - Goel, Anuj A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Uitterlinden, André G A1 - Vaidya, Dhananjay A1 - Yao, Jie A1 - Tang, Weihong A1 - Levy, Daniel A1 - Waldenberger, Melanie A1 - Becker, Diane M A1 - Folsom, Aaron R A1 - Giulianini, Franco A1 - Greinacher, Andreas A1 - Hofman, Albert A1 - Huang, Chiang-Ching A1 - Kooperberg, Charles A1 - Silveira, Angela A1 - Starr, John M A1 - Strauch, Konstantin A1 - Strawbridge, Rona J A1 - Wright, Alan F A1 - McKnight, Barbara A1 - Franco, Oscar H A1 - Zakai, Neil A1 - Mathias, Rasika A A1 - Psaty, Bruce M A1 - Ridker, Paul M A1 - Tofler, Geoffrey H A1 - Völker, Uwe A1 - Watkins, Hugh A1 - Fornage, Myriam A1 - Hamsten, Anders A1 - Deary, Ian J A1 - Boerwinkle, Eric A1 - Koenig, Wolfgang A1 - Rotter, Jerome I A1 - Hayward, Caroline A1 - Dehghan, Abbas A1 - Reiner, Alex P A1 - O'Donnell, Christopher J A1 - Smith, Nicholas L KW - Cohort Studies KW - Factor VII KW - Factor VIII KW - Fibrinogen KW - Gene Frequency KW - Genetic Association Studies KW - Genetic Variation KW - Humans KW - Nerve Tissue Proteins KW - Polymorphism, Single Nucleotide KW - Potassium Channels KW - von Willebrand Factor AB -

Fibrinogen, coagulation factor VII (FVII), and factor VIII (FVIII) and its carrier von Willebrand factor (vWF) play key roles in hemostasis. Previously identified common variants explain only a small fraction of the trait heritabilities, and additional variations may be explained by associations with rarer variants with larger effects. The aim of this study was to identify low-frequency (minor allele frequency [MAF] ≥0.01 and <0.05) and rare (MAF <0.01) variants that influence plasma concentrations of these 4 hemostatic factors by meta-analyzing exome chip data from up to 76,000 participants of 4 ancestries. We identified 12 novel associations of low-frequency (n = 2) and rare (n = 10) variants across the fibrinogen, FVII, FVIII, and vWF traits that were independent of previously identified associations. Novel loci were found within previously reported genes and had effect sizes much larger than and independent of previously identified common variants. In addition, associations at KCNT1, HID1, and KATNB1 identified new candidate genes related to hemostasis for follow-up replication and functional genomic analysis. Newly identified low-frequency and rare-variant associations accounted for modest amounts of trait variance and therefore are unlikely to increase predicted trait heritability but provide new information for understanding individual variation in hemostasis pathways.

VL - 126 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26105150?dopt=Abstract ER - TY - JOUR T1 - Resting heart rate and risk of incident heart failure: three prospective cohort studies and a systematic meta-analysis. JF - J Am Heart Assoc Y1 - 2015 A1 - Khan, Hassan A1 - Kunutsor, Setor A1 - Kalogeropoulos, Andreas P A1 - Georgiopoulou, Vasiliki V A1 - Newman, Anne B A1 - Harris, Tamara B A1 - Bibbins-Domingo, Kirsten A1 - Kauhanen, Jussi A1 - Gheorghiade, Mihai A1 - Fonarow, Gregg C A1 - Kritchevsky, Stephen B A1 - Laukkanen, Jari A A1 - Butler, Javed KW - Age Distribution KW - Aged KW - Aged, 80 and over KW - Aging KW - Cohort Studies KW - Female KW - Heart Failure KW - Heart Rate KW - Humans KW - Incidence KW - Japan KW - Male KW - Predictive Value of Tests KW - Prospective Studies KW - Rest KW - Risk Assessment KW - Severity of Illness Index KW - Sex Distribution KW - Survival Rate AB -

BACKGROUND: The relationship between resting heart rate (RHR) and incident heart failure (HF) has been questioned.

METHODS AND RESULTS: RHR was assessed at baseline in 7073 participants in 3 prospective cohorts (Cardiovascular Health Study, Health ABC study and Kuopio Ischemic Heart Disease Study) that recorded 1189 incident HF outcomes during 92 702 person-years of follow-up. Mean age of participants was 67 (9.9) years and mean RHR was 64.6 (11.1) bpm. Baseline RHR correlated (P<0.001) positively with body mass index (r=0.10), fasting glucose (r=0.18), and C-reactive protein (r=0.20); and inversely with serum creatinine (r=-0.05) and albumin (r=-0.05). Baseline RHR was non-linearly associated with HF risk. The age and sex-adjusted hazard ratio for HF comparing the top (>72 bpm) versus the bottom (<57 bpm) quartile of baseline RHR was 1.48 (95% confidence interval [CI] 1.26 to 1.74) and was modestly attenuated (1.30, 95% CI 1.10 to 1.53) with further adjustment for body mass index, history of diabetes, hypertension, smoking status, serum creatinine, and left ventricular hypertrophy. These findings remained consistent in analyses accounting for incident coronary heart disease, excluding individuals with prior cardiovascular events, or those taking beta-blockers; and in subgroups defined by several individual participant characteristics. In a pooled random effects meta-analysis of 7 population-based studies (43 051 participants and 3476 HF events), the overall hazard ratio comparing top versus bottom fourth of RHR was 1.40 (95% CI: 1.19 to 1.64).

CONCLUSIONS: There is a non-linear association between RHR and incident HF. Further research is needed to understand the physiologic foundations of this association.

VL - 4 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25589535?dopt=Abstract ER - TY - JOUR T1 - Serum urate levels and the risk of hip fractures: data from the Cardiovascular Health Study. JF - Metabolism Y1 - 2015 A1 - Mehta, Tapan A1 - Bůzková, Petra A1 - Sarnak, Mark J A1 - Chonchol, Michel A1 - Cauley, Jane A A1 - Wallace, Erin A1 - Fink, Howard A A1 - Robbins, John A1 - Jalal, Diana KW - Aged KW - Aged, 80 and over KW - Body Mass Index KW - Cohort Studies KW - Estrogen Replacement Therapy KW - Female KW - Health Surveys KW - Hip Fractures KW - Humans KW - Kaplan-Meier Estimate KW - Male KW - Prospective Studies KW - Risk KW - Sex Factors KW - United States KW - Uric Acid AB -

PURPOSE: Uric acid inhibits vitamin D activation experimentally and higher serum urate levels are associated with higher parathyroid hormone levels in humans suggesting a link between uric acid and bone health. We hypothesized that hyperuricemia may increase the risk of fractures in older adults.

METHODS: 1963 men and 2729 women ≥65 years of age who participated in the Cardiovascular Health Study and had baseline serum urate levels were included in the study. The primary outcome was incident hip fracture, assessed prospectively through June, 2008 by inpatient and outpatient records. The analysis was stratified by sex a priori.

RESULTS: There was a U-shaped relationship between serum urate levels and hip fractures in men. Men in the lowest and the highest urate quartiles (<4.88 and ≥6.88 mg/dL respectively) had a significantly higher rate of fractures in unadjusted analysis. However, upon multivariate adjustment, only the HR for hip fracture in highest quartile versus the reference remained significant (HR 1.9; 95% C.I. 1.1, 3.1; p value 0.02). High serum urate levels were not associated with hip fractures in women.

CONCLUSION: In this large prospective cohort of community-dwelling older adults, increased serum urate levels were associated with an increased risk of hip fractures in men. Further studies are needed to confirm these findings and to understand the mechanisms that underlie them.

VL - 64 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25491429?dopt=Abstract ER - TY - JOUR T1 - Thyroid function within the normal range and risk of coronary heart disease: an individual participant data analysis of 14 cohorts. JF - JAMA Intern Med Y1 - 2015 A1 - Asvold, Bjørn O A1 - Vatten, Lars J A1 - Bjøro, Trine A1 - Bauer, Douglas C A1 - Bremner, Alexandra A1 - Cappola, Anne R A1 - Ceresini, Graziano A1 - den Elzen, Wendy P J A1 - Ferrucci, Luigi A1 - Franco, Oscar H A1 - Franklyn, Jayne A A1 - Gussekloo, Jacobijn A1 - Iervasi, Giorgio A1 - Imaizumi, Misa A1 - Kearney, Patricia M A1 - Khaw, Kay-Tee A1 - Maciel, Rui M B A1 - Newman, Anne B A1 - Peeters, Robin P A1 - Psaty, Bruce M A1 - Razvi, Salman A1 - Sgarbi, José A A1 - Stott, David J A1 - Trompet, Stella A1 - Vanderpump, Mark P J A1 - Völzke, Henry A1 - Walsh, John P A1 - Westendorp, Rudi G J A1 - Rodondi, Nicolas KW - Cohort Studies KW - Coronary Disease KW - Humans KW - Hypothyroidism KW - Thyrotropin AB -

IMPORTANCE: Some experts suggest that serum thyrotropin levels in the upper part of the current reference range should be considered abnormal, an approach that would reclassify many individuals as having mild hypothyroidism. Health hazards associated with such thyrotropin levels are poorly documented, but conflicting evidence suggests that thyrotropin levels in the upper part of the reference range may be associated with an increased risk of coronary heart disease (CHD).

OBJECTIVE: To assess the association between differences in thyroid function within the reference range and CHD risk.

DESIGN, SETTING, AND PARTICIPANTS: Individual participant data analysis of 14 cohorts with baseline examinations between July 1972 and April 2002 and with median follow-up ranging from 3.3 to 20.0 years. Participants included 55,412 individuals with serum thyrotropin levels of 0.45 to 4.49 mIU/L and no previously known thyroid or cardiovascular disease at baseline.

EXPOSURES: Thyroid function as expressed by serum thyrotropin levels at baseline.

MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) of CHD mortality and CHD events according to thyrotropin levels after adjustment for age, sex, and smoking status.

RESULTS: Among 55,412 individuals, 1813 people (3.3%) died of CHD during 643,183 person-years of follow-up. In 10 cohorts with information on both nonfatal and fatal CHD events, 4666 of 48,875 individuals (9.5%) experienced a first-time CHD event during 533,408 person-years of follow-up. For each 1-mIU/L higher thyrotropin level, the HR was 0.97 (95% CI, 0.90-1.04) for CHD mortality and 1.00 (95% CI, 0.97-1.03) for a first-time CHD event. Similarly, in analyses by categories of thyrotropin, the HRs of CHD mortality (0.94 [95% CI, 0.74-1.20]) and CHD events (0.97 [95% CI, 0.83-1.13]) were similar among participants with the highest (3.50-4.49 mIU/L) compared with the lowest (0.45-1.49 mIU/L) thyrotropin levels. Subgroup analyses by sex and age group yielded similar results.

CONCLUSIONS AND RELEVANCE: Thyrotropin levels within the reference range are not associated with risk of CHD events or CHD mortality. This finding suggests that differences in thyroid function within the population reference range do not influence the risk of CHD. Increased CHD risk does not appear to be a reason for lowering the upper thyrotropin reference limit.

VL - 175 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25893284?dopt=Abstract ER - TY - JOUR T1 - White Matter Lesion Progression: Genome-Wide Search for Genetic Influences. JF - Stroke Y1 - 2015 A1 - Hofer, Edith A1 - Cavalieri, Margherita A1 - Bis, Joshua C A1 - DeCarli, Charles A1 - Fornage, Myriam A1 - Sigurdsson, Sigurdur A1 - Srikanth, Velandai A1 - Trompet, Stella A1 - Verhaaren, Benjamin F J A1 - Wolf, Christiane A1 - Yang, Qiong A1 - Adams, Hieab H H A1 - Amouyel, Philippe A1 - Beiser, Alexa A1 - Buckley, Brendan M A1 - Callisaya, Michele A1 - Chauhan, Ganesh A1 - de Craen, Anton J M A1 - Dufouil, Carole A1 - van Duijn, Cornelia M A1 - Ford, Ian A1 - Freudenberger, Paul A1 - Gottesman, Rebecca F A1 - Gudnason, Vilmundur A1 - Heiss, Gerardo A1 - Hofman, Albert A1 - Lumley, Thomas A1 - Martinez, Oliver A1 - Mazoyer, Bernard A1 - Moran, Chris A1 - Niessen, Wiro J A1 - Phan, Thanh A1 - Psaty, Bruce M A1 - Satizabal, Claudia L A1 - Sattar, Naveed A1 - Schilling, Sabrina A1 - Shibata, Dean K A1 - Slagboom, P Eline A1 - Smith, Albert A1 - Stott, David J A1 - Taylor, Kent D A1 - Thomson, Russell A1 - Töglhofer, Anna M A1 - Tzourio, Christophe A1 - van Buchem, Mark A1 - Wang, Jing A1 - Westendorp, Rudi G J A1 - Windham, B Gwen A1 - Vernooij, Meike W A1 - Zijdenbos, Alex A1 - Beare, Richard A1 - Debette, Stephanie A1 - Ikram, M Arfan A1 - Jukema, J Wouter A1 - Launer, Lenore J A1 - Longstreth, W T A1 - Mosley, Thomas H A1 - Seshadri, Sudha A1 - Schmidt, Helena A1 - Schmidt, Reinhold KW - Adult KW - Aged KW - Cohort Studies KW - Disease Progression KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Leukoencephalopathies KW - Male KW - Middle Aged KW - Prospective Studies KW - White Matter AB -

BACKGROUND AND PURPOSE: White matter lesion (WML) progression on magnetic resonance imaging is related to cognitive decline and stroke, but its determinants besides baseline WML burden are largely unknown. Here, we estimated heritability of WML progression, and sought common genetic variants associated with WML progression in elderly participants from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium.

METHODS: Heritability of WML progression was calculated in the Framingham Heart Study. The genome-wide association study included 7773 elderly participants from 10 cohorts. To assess the relative contribution of genetic factors to progression of WML, we compared in 7 cohorts risk models including demographics, vascular risk factors plus single-nucleotide polymorphisms that have been shown to be associated cross-sectionally with WML in the current and previous association studies.

RESULTS: A total of 1085 subjects showed WML progression. The heritability estimate for WML progression was low at 6.5%, and no single-nucleotide polymorphisms achieved genome-wide significance (P<5×10(-8)). Four loci were suggestive (P<1×10(-5)) of an association with WML progression: 10q24.32 (rs10883817, P=1.46×10(-6)); 12q13.13 (rs4761974, P=8.71×10(-7)); 20p12.1 (rs6135309, P=3.69×10(-6)); and 4p15.31 (rs7664442, P=2.26×10(-6)). Variants that have been previously related to WML explained only 0.8% to 11.7% more of the variance in WML progression than age, vascular risk factors, and baseline WML burden.

CONCLUSIONS: Common genetic factors contribute little to the progression of age-related WML in middle-aged and older adults. Future research on determinants of WML progression should focus more on environmental, lifestyle, or host-related biological factors.

VL - 46 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26451028?dopt=Abstract ER - TY - JOUR T1 - Common variants in DRD2 are associated with sleep duration: the CARe consortium. JF - Hum Mol Genet Y1 - 2016 A1 - Cade, Brian E A1 - Gottlieb, Daniel J A1 - Lauderdale, Diane S A1 - Bennett, David A A1 - Buchman, Aron S A1 - Buxbaum, Sarah G A1 - De Jager, Philip L A1 - Evans, Daniel S A1 - Fulop, Tibor A1 - Gharib, Sina A A1 - Johnson, W Craig A1 - Kim, Hyun A1 - Larkin, Emma K A1 - Lee, Seung Ku A1 - Lim, Andrew S A1 - Punjabi, Naresh M A1 - Shin, Chol A1 - Stone, Katie L A1 - Tranah, Gregory J A1 - Weng, Jia A1 - Yaffe, Kristine A1 - Zee, Phyllis C A1 - Patel, Sanjay R A1 - Zhu, Xiaofeng A1 - Redline, Susan A1 - Saxena, Richa KW - Cohort Studies KW - Ethnic Groups KW - Humans KW - Polymorphism, Single Nucleotide KW - Polysomnography KW - Receptors, Dopamine D2 KW - Sleep KW - Time Factors AB -

Sleep duration is implicated in the etiologies of chronic diseases and premature mortality. However, the genetic basis for sleep duration is poorly defined. We sought to identify novel genetic components influencing sleep duration in a multi-ethnic sample. Meta-analyses were conducted of genetic associations with self-reported, habitual sleep duration from seven Candidate Gene Association Resource (CARe) cohorts of over 25 000 individuals of African, Asian, European and Hispanic American ancestry. All individuals were genotyped for ∼50 000 SNPs from 2000 candidate heart, lung, blood and sleep genes. African-Americans had additional genome-wide genotypes. Four cohorts provided replication. A SNP (rs17601612) in the dopamine D2 receptor gene (DRD2) was significantly associated with sleep duration (P = 9.8 × 10(-7)). Conditional analysis identified a second DRD2 signal with opposite effects on sleep duration. In exploratory analysis, suggestive association was observed for rs17601612 with polysomnographically determined sleep latency (P = 0.002). The lead DRD2 signal was recently identified in a schizophrenia GWAS, and a genetic risk score of 11 additional schizophrenia GWAS loci genotyped on the IBC array was also associated with longer sleep duration (P = 0.03). These findings support a role for DRD2 in influencing sleep duration. Our work motivates future pharmocogenetics research on alerting agents such as caffeine and modafinil that interact with the dopaminergic pathway and further investigation of genetic overlap between sleep and neuro-psychiatric traits.

VL - 25 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26464489?dopt=Abstract ER - TY - JOUR T1 - Gait Speed Predicts Incident Disability: A Pooled Analysis. JF - J Gerontol A Biol Sci Med Sci Y1 - 2016 A1 - Perera, Subashan A1 - Patel, Kushang V A1 - Rosano, Caterina A1 - Rubin, Susan M A1 - Satterfield, Suzanne A1 - Harris, Tamara A1 - Ensrud, Kristine A1 - Orwoll, Eric A1 - Lee, Christine G A1 - Chandler, Julie M A1 - Newman, Anne B A1 - Cauley, Jane A A1 - Guralnik, Jack M A1 - Ferrucci, Luigi A1 - Studenski, Stephanie A KW - Activities of Daily Living KW - Aged KW - Aged, 80 and over KW - Aging KW - Cohort Studies KW - Disability Evaluation KW - Disabled Persons KW - Female KW - Gait KW - Geriatric Assessment KW - Humans KW - Independent Living KW - Male KW - Mobility Limitation KW - Predictive Value of Tests KW - Prognosis KW - Psychomotor Performance KW - Risk Assessment KW - Risk Factors KW - ROC Curve KW - Survival Analysis KW - United States AB -

BACKGROUND: Functional independence with aging is an important goal for individuals and society. Simple prognostic indicators can inform health promotion and care planning, but evidence is limited by heterogeneity in measures of function.

METHODS: We performed a pooled analysis of data from seven studies of 27,220 community-dwelling older adults aged 65 or older with baseline gait speed, followed for disability and mortality. Outcomes were incident inability or dependence on another person in bathing or dressing; and difficulty walking ¼ - ½ mile or climbing 10 steps within 3 years.

RESULTS: Participants with faster baseline gait had lower rates of incident disability. In subgroups (defined by 0.2 m/s-wide intervals from <0.4 to ≥ 1.4 m/s) with increasingly greater gait speed, 3-year rates of bathing or dressing dependence trended from 10% to 1% in men, and from 15% to 1% in women, while mobility difficulty trended from 47% to 4% in men and 40% to 6% in women. The age-adjusted relative risk ratio per 0.1 m/s greater speed for bathing or dressing dependence in men was 0.68 (0.57-0.81) and in women: 0.74 (0.66-0.82); for mobility difficulty, men: 0.75 (0.68-0.82), women: 0.73 (0.67-0.80). Results were similar for combined disability and mortality. Effects were largely consistent across subgroups based on age, gender, race, body mass index, prior hospitalization, and selected chronic conditions. In the presence of multiple other risk factors for disability, gait speed significantly increased the area under the receiver operator characteristic curve.

CONCLUSION: In older adults, gait speed predicts 3 year incidence of bathing or dressing dependence, mobility difficulty, and a composite outcome of disability and mortality.

VL - 71 IS - 1 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26297942?dopt=Abstract ER - TY - JOUR T1 - Galectin-3 and Soluble ST2 and Kidney Function Decline in Older Adults: The Cardiovascular Health Study (CHS). JF - Am J Kidney Dis Y1 - 2016 A1 - Bansal, Nisha A1 - Katz, Ronit A1 - Seliger, Stephen A1 - DeFilippi, Christopher A1 - Sarnak, Mark J A1 - Delaney, Joseph A A1 - Christenson, Robert A1 - de Boer, Ian H A1 - Kestenbaum, Bryan A1 - Robinson-Cohen, Cassianne A1 - Ix, Joachim H A1 - Shlipak, Michael G KW - Aged KW - Cohort Studies KW - Creatinine KW - Cystatin C KW - Female KW - Galectin 3 KW - Glomerular Filtration Rate KW - Humans KW - Interleukin-1 Receptor-Like 1 Protein KW - Logistic Models KW - Longitudinal Studies KW - Male KW - Prognosis KW - Renal Insufficiency, Chronic VL - 67 IS - 6 ER - TY - JOUR T1 - Genome-Wide Association Study for Incident Myocardial Infarction and Coronary Heart Disease in Prospective Cohort Studies: The CHARGE Consortium. JF - PLoS One Y1 - 2016 A1 - Dehghan, Abbas A1 - Bis, Joshua C A1 - White, Charles C A1 - Smith, Albert Vernon A1 - Morrison, Alanna C A1 - Cupples, L Adrienne A1 - Trompet, Stella A1 - Chasman, Daniel I A1 - Lumley, Thomas A1 - Völker, Uwe A1 - Buckley, Brendan M A1 - Ding, Jingzhong A1 - Jensen, Majken K A1 - Folsom, Aaron R A1 - Kritchevsky, Stephen B A1 - Girman, Cynthia J A1 - Ford, Ian A1 - Dörr, Marcus A1 - Salomaa, Veikko A1 - Uitterlinden, André G A1 - Eiriksdottir, Gudny A1 - Vasan, Ramachandran S A1 - Franceschini, Nora A1 - Carty, Cara L A1 - Virtamo, Jarmo A1 - Demissie, Serkalem A1 - Amouyel, Philippe A1 - Arveiler, Dominique A1 - Heckbert, Susan R A1 - Ferrieres, Jean A1 - Ducimetiere, Pierre A1 - Smith, Nicholas L A1 - Wang, Ying A A1 - Siscovick, David S A1 - Rice, Kenneth M A1 - Wiklund, Per-Gunnar A1 - Taylor, Kent D A1 - Evans, Alun A1 - Kee, Frank A1 - Rotter, Jerome I A1 - Karvanen, Juha A1 - Kuulasmaa, Kari A1 - Heiss, Gerardo A1 - Kraft, Peter A1 - Launer, Lenore J A1 - Hofman, Albert A1 - Markus, Marcello R P A1 - Rose, Lynda M A1 - Silander, Kaisa A1 - Wagner, Peter A1 - Benjamin, Emelia J A1 - Lohman, Kurt A1 - Stott, David J A1 - Rivadeneira, Fernando A1 - Harris, Tamara B A1 - Levy, Daniel A1 - Liu, Yongmei A1 - Rimm, Eric B A1 - Jukema, J Wouter A1 - Völzke, Henry A1 - Ridker, Paul M A1 - Blankenberg, Stefan A1 - Franco, Oscar H A1 - Gudnason, Vilmundur A1 - Psaty, Bruce M A1 - Boerwinkle, Eric A1 - O'Donnell, Christopher J KW - Aged KW - Cohort Studies KW - Cooperative Behavior KW - Coronary Artery Disease KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Polymorphism, Single Nucleotide KW - Prospective Studies AB -

BACKGROUND: Data are limited on genome-wide association studies (GWAS) for incident coronary heart disease (CHD). Moreover, it is not known whether genetic variants identified to date also associate with risk of CHD in a prospective setting.

METHODS: We performed a two-stage GWAS analysis of incident myocardial infarction (MI) and CHD in a total of 64,297 individuals (including 3898 MI cases, 5465 CHD cases). SNPs that passed an arbitrary threshold of 5×10-6 in Stage I were taken to Stage II for further discovery. Furthermore, in an analysis of prognosis, we studied whether known SNPs from former GWAS were associated with total mortality in individuals who experienced MI during follow-up.

RESULTS: In Stage I 15 loci passed the threshold of 5×10-6; 8 loci for MI and 8 loci for CHD, for which one locus overlapped and none were reported in previous GWAS meta-analyses. We took 60 SNPs representing these 15 loci to Stage II of discovery. Four SNPs near QKI showed nominally significant association with MI (p-value<8.8×10-3) and three exceeded the genome-wide significance threshold when Stage I and Stage II results were combined (top SNP rs6941513: p = 6.2×10-9). Despite excellent power, the 9p21 locus SNP (rs1333049) was only modestly associated with MI (HR = 1.09, p-value = 0.02) and marginally with CHD (HR = 1.06, p-value = 0.08). Among an inception cohort of those who experienced MI during follow-up, the risk allele of rs1333049 was associated with a decreased risk of subsequent mortality (HR = 0.90, p-value = 3.2×10-3).

CONCLUSIONS: QKI represents a novel locus that may serve as a predictor of incident CHD in prospective studies. The association of the 9p21 locus both with increased risk of first myocardial infarction and longer survival after MI highlights the importance of study design in investigating genetic determinants of complex disorders.

VL - 11 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26950853?dopt=Abstract ER - TY - JOUR T1 - Interaction of methylation-related genetic variants with circulating fatty acids on plasma lipids: a meta-analysis of 7 studies and methylation analysis of 3 studies in the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium. JF - Am J Clin Nutr Y1 - 2016 A1 - Ma, Yiyi A1 - Follis, Jack L A1 - Smith, Caren E A1 - Tanaka, Toshiko A1 - Manichaikul, Ani W A1 - Chu, Audrey Y A1 - Samieri, Cecilia A1 - Zhou, Xia A1 - Guan, Weihua A1 - Wang, Lu A1 - Biggs, Mary L A1 - Chen, Yii-der I A1 - Hernandez, Dena G A1 - Borecki, Ingrid A1 - Chasman, Daniel I A1 - Rich, Stephen S A1 - Ferrucci, Luigi A1 - Irvin, Marguerite Ryan A1 - Aslibekyan, Stella A1 - Zhi, Degui A1 - Tiwari, Hemant K A1 - Claas, Steven A A1 - Sha, Jin A1 - Kabagambe, Edmond K A1 - Lai, Chao-Qiang A1 - Parnell, Laurence D A1 - Lee, Yu-Chi A1 - Amouyel, Philippe A1 - Lambert, Jean-Charles A1 - Psaty, Bruce M A1 - King, Irena B A1 - Mozaffarian, Dariush A1 - McKnight, Barbara A1 - Bandinelli, Stefania A1 - Tsai, Michael Y A1 - Ridker, Paul M A1 - Ding, Jingzhong A1 - Mstat, Kurt Lohmant A1 - Liu, Yongmei A1 - Sotoodehnia, Nona A1 - Barberger-Gateau, Pascale A1 - Steffen, Lyn M A1 - Siscovick, David S A1 - Absher, Devin A1 - Arnett, Donna K A1 - Ordovas, Jose M A1 - Lemaitre, Rozenn N KW - Apolipoproteins E KW - ATP Binding Cassette Transporter 1 KW - Cholesterol, HDL KW - Cohort Studies KW - Diet KW - DNA Methylation KW - Eicosapentaenoic Acid KW - Epigenesis, Genetic KW - Fatty Acids KW - Gene Expression Regulation KW - Humans KW - Lipids KW - Polymorphism, Single Nucleotide KW - Promoter Regions, Genetic KW - Triglycerides AB -

BACKGROUND: DNA methylation is influenced by diet and single nucleotide polymorphisms (SNPs), and methylation modulates gene expression.

OBJECTIVE: We aimed to explore whether the gene-by-diet interactions on blood lipids act through DNA methylation.

DESIGN: We selected 7 SNPs on the basis of predicted relations in fatty acids, methylation, and lipids. We conducted a meta-analysis and a methylation and mediation analysis with the use of data from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium and the ENCODE (Encyclopedia of DNA Elements) consortium.

RESULTS: On the basis of the meta-analysis of 7 cohorts in the CHARGE consortium, higher plasma HDL cholesterol was associated with fewer C alleles at ATP-binding cassette subfamily A member 1 (ABCA1) rs2246293 (β = -0.6 mg/dL, P = 0.015) and higher circulating eicosapentaenoic acid (EPA) (β = 3.87 mg/dL, P = 5.62 × 10(21)). The difference in HDL cholesterol associated with higher circulating EPA was dependent on genotypes at rs2246293, and it was greater for each additional C allele (β = 1.69 mg/dL, P = 0.006). In the GOLDN (Genetics of Lipid Lowering Drugs and Diet Network) study, higher ABCA1 promoter cg14019050 methylation was associated with more C alleles at rs2246293 (β = 8.84%, P = 3.51 × 10(18)) and lower circulating EPA (β = -1.46%, P = 0.009), and the mean difference in methylation of cg14019050 that was associated with higher EPA was smaller with each additional C allele of rs2246293 (β = -2.83%, P = 0.007). Higher ABCA1 cg14019050 methylation was correlated with lower ABCA1 expression (r = -0.61, P = 0.009) in the ENCODE consortium and lower plasma HDL cholesterol in the GOLDN study (r = -0.12, P = 0.0002). An additional mediation analysis was meta-analyzed across the GOLDN study, Cardiovascular Health Study, and the Multi-Ethnic Study of Atherosclerosis. Compared with the model without the adjustment of cg14019050 methylation, the model with such adjustment provided smaller estimates of the mean plasma HDL cholesterol concentration in association with both the rs2246293 C allele and EPA and a smaller difference by rs2246293 genotypes in the EPA-associated HDL cholesterol. However, the differences between 2 nested models were NS (P > 0.05).

CONCLUSION: We obtained little evidence that the gene-by-fatty acid interactions on blood lipids act through DNA methylation.

VL - 103 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26791180?dopt=Abstract ER - TY - JOUR T1 - Lifetime Risk of Venous Thromboembolism in Two Cohort Studies. JF - Am J Med Y1 - 2016 A1 - Bell, Elizabeth J A1 - Lutsey, Pamela L A1 - Basu, Saonli A1 - Cushman, Mary A1 - Heckbert, Susan R A1 - Lloyd-Jones, Donald M A1 - Folsom, Aaron R KW - African Continental Ancestry Group KW - Aged KW - Anemia, Sickle Cell KW - Cohort Studies KW - Factor V KW - Follow-Up Studies KW - Heterozygote KW - Humans KW - Kaplan-Meier Estimate KW - Middle Aged KW - Obesity KW - Risk KW - Sickle Cell Trait KW - United States KW - Venous Thromboembolism AB -

BACKGROUND: Greater public awareness of venous thromboembolism may be an important next step for optimizing venous thromboembolism prevention and treatment. "Lifetime risk" is an easily interpretable way of presenting risk information. Therefore, we sought to calculate the lifetime risk of venous thromboembolism (deep vein thrombosis or pulmonary embolism) using data from 2 large, prospective cohort studies: the Cardiovascular Health Study (CHS) and the Atherosclerosis Risk in Communities (ARIC) study.

METHODS: We followed participants aged 45-64 years in ARIC (n = 14,185) and ≥65 in CHS (n = 5414) at baseline visits (1987-1989 in ARIC, 1989-1990 and 1992-1993 in CHS) for incident venous thromboembolism (n = 728 in ARIC through 2011 and n = 172 in CHS through 2001). We estimated lifetime risks and 95% confidence intervals of incident venous thromboembolism using a modified Kaplan-Meier method, accounting for the competing risk of death from other causes.

RESULTS: At age 45 years, the remaining lifetime risk of venous thromboembolism in ARIC was 8.1% (95% confidence interval, 7.1-8.7). High-risk groups were African Americans (11.5% lifetime risk), those with obesity (10.9%), heterozygous for the factor V Leiden (17.1%), or with sickle cell trait or disease (18.2%). Lifetime risk estimates differed by cohort; these differences were explained by differences in time period of venous thromboembolism ascertainment.

CONCLUSIONS: At least 1 in 12 middle-aged adults will develop venous thromboembolism in their remaining lifetime. This estimate of lifetime risk may be useful to promote awareness of venous thromboembolism and guide decisions at both clinical and policy levels.

VL - 129 IS - 3 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26597668?dopt=Abstract ER - TY - JOUR T1 - The Association Between IGF-I and IGFBP-3 and Incident Diabetes in an Older Population of Men and Women in the Cardiovascular Health Study. JF - J Clin Endocrinol Metab Y1 - 2017 A1 - Aneke-Nash, Chino S A1 - Xue, XiaoNan A1 - Qi, Qibin A1 - Biggs, Mary L A1 - Cappola, Anne A1 - Kuller, Lewis A1 - Pollak, Michael A1 - Psaty, Bruce M A1 - Siscovick, David A1 - Mukamal, Kenneth A1 - Strickler, Howard D A1 - Kaplan, Robert C KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Blood Glucose KW - Cardiovascular Diseases KW - Cohort Studies KW - Diabetes Mellitus KW - Female KW - Humans KW - Incidence KW - Insulin-Like Growth Factor Binding Protein 3 KW - Insulin-Like Growth Factor I KW - Longitudinal Studies KW - Male KW - New England KW - Prospective Studies KW - Risk AB -

Context: Insulin-like growth factor-I (IGF-I) has structural and functional similarities to insulin and may play a role in glucose homeostasis, along with insulin-like growth factor binding protein-3 (IGFBP-3), which binds the majority of circulating IGF-I.

Objective: To assess whether IGF-I and IGFBP-3 are associated with a higher risk of incident diabetes in older adults.

Design: Participants in the Cardiovascular Health Study (n = 3133), a cohort of adults aged ≥65 years, were observed for 16 years (n = 3133) for the development of incident diabetes. Statistical models were fit separately for men and women because of interactions with sex (P interaction: IGF-I, 0.02; IGFBP-3, 0.009) and were adjusted for relevant covariates.

Setting: General community.

Participants: Older adults who were nondiabetic at baseline and who did not develop diabetes within the first year of follow-up.

Interventions: Not applicable.

Main Outcome Measure: Incident diabetes as measured by fasting plasma glucose (FPG) ≥126 mg/dL, non-FPG ≥200 mg/dL, use of pharmacological treatment of diabetes, or existence of two or more inpatient or three or more outpatient or (at least one inpatient and at least one outpatient) Centers for Medicare & Medicaid Services claims with the diagnostic International Classification of Diseases, Ninth Revision, Clinical Modification code of 250.xx.

Results: In women, higher IGFBP-3 (hazard ratio tertile 3 vs tertile 1 = 2.30; 95% confidence interval, 1.55 to 3.40; P trend < 0.0001) was significantly associated with incident diabetes. Total IGF-I was not significantly associated with incident diabetes. In men, neither IGF-I nor IGFBP-3 was significantly associated with incident diabetes.

Conclusions: We confirmed a previously reported association between circulating IGFBP-3 and diabetes risk in the older adult population, establishing that this association is present among women but could not be shown to be associated in men.

VL - 102 IS - 12 ER - TY - JOUR T1 - Disability Trajectories Before and After Stroke and Myocardial Infarction: The Cardiovascular Health Study. JF - JAMA Neurol Y1 - 2017 A1 - Dhamoon, Mandip S A1 - Longstreth, W T A1 - Bartz, Traci M A1 - Kaplan, Robert C A1 - Elkind, Mitchell S V KW - Activities of Daily Living KW - Aged KW - Brain Ischemia KW - Cohort Studies KW - Disabled Persons KW - Disease Progression KW - Female KW - Humans KW - Male KW - Myocardial Infarction KW - Prospective Studies KW - Stroke AB -

Importance: Ischemic strokes may accelerate long-term functional decline apart from their acute effects on neurologic function.

Objective: To test whether the increase in long-term disability is steeper after than before the event for ischemic stroke but not myocardial infarction (MI).

Design, Settings, and Participants: In the population-based, prospective cohort Cardiovascular Health Study (1989-2013), longitudinal follow-up was conducted for a mean (SD) of 13 (6.2) years. Follow-up data were used until September 1, 2013; data analysis was performed from August 1, 2013, to June 1, 2016. Models based on generalized estimating equations adjusted for baseline covariates and included a test for different slopes of disability before and after the event. Participants included 5888 Medicare-eligible individuals 65 years or older who were not institutionalized, expected to reside in the area for 3 or more years, and able to provide informed consent. Exclusions were needing a wheelchair, receiving hospice care, and undergoing radiotherapy or chemotherapy.

Exposures: Ischemic stroke and MI.

Main Outcomes and Measures: Annual assessments with a disability scale (measuring activities of daily living [ADLs] and instrumental ADLs). The number of ADLs and instrumental ADLs (range, 0-12) that the participant could not perform was analyzed continuously.

Results: The mean (SD) age of the entire cohort (n = 5888) was 72.8 (5.6) years; 2495 (42.4%) were male. During follow-up, 382 (6.5%) participants had ischemic stroke and 395 (6.7%) had MI with 1 or more disability assessment after the event. There was a mean of 3.7 (2.4) visits before stroke and 3.7 (2.3) visits after stroke; there was a mean of 3.8 (2.5) visits before MI and 3.8 (2.4) visits after MI. The increase in disability near the time of the event was greater for stroke (0.88 points on the disability scale; 95% CI, 0.57 to 1.20; P < .001) than MI (0.20 points on the disability scale; 95% CI, 0.06 to 0.35; P = .006). The annual increase in disability before stroke (0.06 points per year; 95% CI, 0.002 to 0.12; P = .04) more than tripled after stroke (0.15 additional points per year; 95% CI, 0.004 to 0.30; P = .04). The annual increase in disability before MI (0.04 points per year; 95% CI, 0.004 to 0.08; P = .03) did not change significantly after MI (0.02 additional points per year; 95% CI, -0.07 to 0.11; P = .69).

Conclusions and Relevance: In this large, population-based study, a trajectory of increasing disability became significantly steeper after stroke but not after MI. Thus, in addition to the acute brain injury and consequent impairment, ischemic stroke may also be associated with potentially treatable long-term adverse effects on the brain that lead to accelerated functional decline.

VL - 74 IS - 12 ER - TY - JOUR T1 - Factors Associated With Ischemic Stroke Survival and Recovery in Older Adults. JF - Stroke Y1 - 2017 A1 - Winovich, Divya Thekkethala A1 - Longstreth, William T A1 - Arnold, Alice M A1 - Varadhan, Ravi A1 - Zeki Al Hazzouri, Adina A1 - Cushman, Mary A1 - Newman, Anne B A1 - Odden, Michelle C KW - Activities of Daily Living KW - Aged KW - Aged, 80 and over KW - Brain Ischemia KW - Cohort Studies KW - Female KW - Follow-Up Studies KW - Frail Elderly KW - Humans KW - Male KW - Recovery of Function KW - Risk Factors KW - Stroke KW - Survival Rate AB -

BACKGROUND AND PURPOSE: Little is known about factors that predispose older adults to poor recovery after a stroke. In this study, we sought to evaluate prestroke measures of frailty and related factors as markers of vulnerability to poor outcomes after ischemic stroke.

METHODS: In participants aged 65 to 99 years with incident ischemic strokes from the Cardiovascular Health Study, we evaluated the association of several risk factors (frailty, frailty components, C-reactive protein, interleukin-6, and cystatin C) assessed before stroke with stroke outcomes of survival, cognitive decline (≥5 points on Modified Mini-Mental State Examination), and activities of daily living decline (increase in limitations).

RESULTS: Among 717 participants with incident ischemic stroke with survival data, slow walking speed, low grip strength, and cystatin C were independently associated with shorter survival. Among participants <80 years of age, frailty and interleukin-6 were also associated with shorter survival. Among 509 participants with recovery data, slow walking speed, and low grip strength were associated with both cognitive and activities of daily living decline poststroke. C-reactive protein and interleukin-6 were associated with poststroke cognitive decline among men only. Frailty status was associated with activities of daily living decline among women only.

CONCLUSIONS: Markers of physical function-walking speed and grip strength-were consistently associated with survival and recovery after ischemic stroke. Inflammation, kidney function, and frailty also seemed to be determinants of survival and recovery after an ischemic stroke. These markers of vulnerability may identify targets for differing pre and poststroke medical management and rehabilitation among older adults at risk of poor stroke outcomes.

VL - 48 IS - 7 ER - TY - JOUR T1 - Genome-wide association meta-analysis of fish and EPA+DHA consumption in 17 US and European cohorts. JF - PLoS One Y1 - 2017 A1 - Mozaffarian, Dariush A1 - Dashti, Hassan S A1 - Wojczynski, Mary K A1 - Chu, Audrey Y A1 - Nettleton, Jennifer A A1 - Männistö, Satu A1 - Kristiansson, Kati A1 - Reedik, Mägi A1 - Lahti, Jari A1 - Houston, Denise K A1 - Cornelis, Marilyn C A1 - van Rooij, Frank J A A1 - Dimitriou, Maria A1 - Kanoni, Stavroula A1 - Mikkilä, Vera A1 - Steffen, Lyn M A1 - de Oliveira Otto, Marcia C A1 - Qi, Lu A1 - Psaty, Bruce A1 - Djoussé, Luc A1 - Rotter, Jerome I A1 - Harald, Kennet A1 - Perola, Markus A1 - Rissanen, Harri A1 - Jula, Antti A1 - Krista, Fischer A1 - Mihailov, Evelin A1 - Feitosa, Mary F A1 - Ngwa, Julius S A1 - Xue, Luting A1 - Jacques, Paul F A1 - Perälä, Mia-Maria A1 - Palotie, Aarno A1 - Liu, Yongmei A1 - Nalls, Nike A A1 - Ferrucci, Luigi A1 - Hernandez, Dena A1 - Manichaikul, Ani A1 - Tsai, Michael Y A1 - Kiefte-de Jong, Jessica C A1 - Hofman, Albert A1 - Uitterlinden, André G A1 - Rallidis, Loukianos A1 - Ridker, Paul M A1 - Rose, Lynda M A1 - Buring, Julie E A1 - Lehtimäki, Terho A1 - Kähönen, Mika A1 - Viikari, Jorma A1 - Lemaitre, Rozenn A1 - Salomaa, Veikko A1 - Knekt, Paul A1 - Metspalu, Andres A1 - Borecki, Ingrid B A1 - Cupples, L Adrienne A1 - Eriksson, Johan G A1 - Kritchevsky, Stephen B A1 - Bandinelli, Stefania A1 - Siscovick, David A1 - Franco, Oscar H A1 - Deloukas, Panos A1 - Dedoussis, George A1 - Chasman, Daniel I A1 - Raitakari, Olli A1 - Tanaka, Toshiko KW - Adult KW - Aged KW - Cohort Studies KW - Docosahexaenoic Acids KW - Eicosapentaenoic Acid KW - Europe KW - European Continental Ancestry Group KW - Female KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Seafood KW - United States AB -

BACKGROUND: Regular fish and omega-3 consumption may have several health benefits and are recommended by major dietary guidelines. Yet, their intakes remain remarkably variable both within and across populations, which could partly owe to genetic influences.

OBJECTIVE: To identify common genetic variants that influence fish and dietary eicosapentaenoic acid plus docosahexaenoic acid (EPA+DHA) consumption.

DESIGN: We conducted genome-wide association (GWA) meta-analysis of fish (n = 86,467) and EPA+DHA (n = 62,265) consumption in 17 cohorts of European descent from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium Nutrition Working Group. Results from cohort-specific GWA analyses (additive model) for fish and EPA+DHA consumption were adjusted for age, sex, energy intake, and population stratification, and meta-analyzed separately using fixed-effect meta-analysis with inverse variance weights (METAL software). Additionally, heritability was estimated in 2 cohorts.

RESULTS: Heritability estimates for fish and EPA+DHA consumption ranged from 0.13-0.24 and 0.12-0.22, respectively. A significant GWA for fish intake was observed for rs9502823 on chromosome 6: each copy of the minor allele (FreqA = 0.015) was associated with 0.029 servings/day (~1 serving/month) lower fish consumption (P = 1.96x10-8). No significant association was observed for EPA+DHA, although rs7206790 in the obesity-associated FTO gene was among top hits (P = 8.18x10-7). Post-hoc calculations demonstrated 95% statistical power to detect a genetic variant associated with effect size of 0.05% for fish and 0.08% for EPA+DHA.

CONCLUSIONS: These novel findings suggest that non-genetic personal and environmental factors are principal determinants of the remarkable variation in fish consumption, representing modifiable targets for increasing intakes among all individuals. Genes underlying the signal at rs72838923 and mechanisms for the association warrant further investigation.

VL - 12 IS - 12 ER - TY - JOUR T1 - Omega-3 Fatty Acids and Incident Ischemic Stroke and Its Atherothrombotic and Cardioembolic Subtypes in 3 US Cohorts. JF - Stroke Y1 - 2017 A1 - Saber, Hamidreza A1 - Yakoob, Mohammad Yawar A1 - Shi, Peilin A1 - Longstreth, W T A1 - Lemaitre, Rozenn N A1 - Siscovick, David A1 - Rexrode, Kathryn M A1 - Willett, Walter C A1 - Mozaffarian, Dariush KW - Adult KW - Aged KW - Aged, 80 and over KW - Biomarkers KW - Brain Ischemia KW - Cardiovascular Diseases KW - Case-Control Studies KW - Cohort Studies KW - Fatty Acids, Omega-3 KW - Female KW - Follow-Up Studies KW - Humans KW - Incidence KW - Intracranial Arteriosclerosis KW - Intracranial Embolism KW - Intracranial Thrombosis KW - Male KW - Middle Aged KW - Prospective Studies KW - Random Allocation KW - Risk Factors KW - Stroke KW - United States AB -

BACKGROUND AND PURPOSE: The associations of individual long-chain n-3 polyunsaturated fatty acids with incident ischemic stroke and its main subtypes are not well established. We aimed to investigate prospectively the relationship of circulating eicosapentaenoic acid, docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) with risk of total ischemic, atherothrombotic, and cardioembolic stroke.

METHODS: We measured circulating phospholipid fatty acids at baseline in 3 separate US cohorts: CHS (Cardiovascular Health Study), NHS (Nurses' Health Study), and HPFS (Health Professionals Follow-Up Study). Ischemic strokes were prospectively adjudicated and classified into atherothrombotic (large- and small-vessel infarctions) or cardioembolic by imaging studies and medical records. Risk according to fatty acid levels was assessed using Cox proportional hazards (CHS) or conditional logistic regression (NHS, HPFS) according to study design. Cohort findings were pooled using fixed-effects meta-analysis.

RESULTS: A total of 953 incident ischemic strokes were identified (408 atherothrombotic, 256 cardioembolic, and 289 undetermined subtypes) during median follow-up of 11.2 years (CHS) and 8.3 years (pooled, NHS and HPFS). After multivariable adjustment, lower risk of total ischemic stroke was seen with higher DPA (highest versus lowest quartiles; pooled hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.58-0.92) and DHA (HR, 0.80; 95% CI, 0.64-1.00) but not eicosapentaenoic acid (HR, 0.94; 95% CI, 0.77-1.19). DHA was associated with lower risk of atherothrombotic stroke (HR, 0.53; 95% CI, 0.34-0.83) and DPA with lower risk of cardioembolic stroke (HR, 0.58; 95% CI, 0.37-0.92). Findings in each individual cohort were consistent with pooled results.

CONCLUSIONS: In 3 large US cohorts, higher circulating levels of DHA were inversely associated with incident atherothrombotic stroke and DPA with cardioembolic stroke. These novel findings suggest differential pathways of benefit for DHA, DPA, and eicosapentaenoic acid.

VL - 48 IS - 10 ER - TY - JOUR T1 - Short telomere length is associated with impaired cognitive performance in European ancestry cohorts. JF - Transl Psychiatry Y1 - 2017 A1 - Hägg, S A1 - Zhan, Y A1 - Karlsson, R A1 - Gerritsen, L A1 - Ploner, A A1 - van der Lee, S J A1 - Broer, L A1 - Deelen, J A1 - Marioni, R E A1 - Wong, A A1 - Lundquist, A A1 - Zhu, G A1 - Hansell, N K A1 - Sillanpää, E A1 - Fedko, I O A1 - Amin, N A A1 - Beekman, M A1 - de Craen, A J M A1 - Degerman, S A1 - Harris, S E A1 - Kan, K-J A1 - Martin-Ruiz, C M A1 - Montgomery, G W A1 - Adolfsson, A N A1 - Reynolds, C A A1 - Samani, N J A1 - Suchiman, H E D A1 - Viljanen, A A1 - von Zglinicki, T A1 - Wright, M J A1 - Hottenga, J-J A1 - Boomsma, D I A1 - Rantanen, T A1 - Kaprio, J A A1 - Nyholt, D R A1 - Martin, N G A1 - Nyberg, L A1 - Adolfsson, R A1 - Kuh, D A1 - Starr, J M A1 - Deary, I J A1 - Slagboom, P E A1 - van Duijn, C M A1 - Codd, V A1 - Pedersen, N L KW - Adult KW - Aged KW - Apolipoprotein E4 KW - Cognitive Dysfunction KW - Cohort Studies KW - European Continental Ancestry Group KW - Female KW - Genetic Carrier Screening KW - Genotype KW - Humans KW - Male KW - Mendelian Randomization Analysis KW - Middle Aged KW - Neuropsychological Tests KW - Psychometrics KW - Statistics as Topic KW - Telomere AB -

The association between telomere length (TL) dynamics on cognitive performance over the life-course is not well understood. This study meta-analyses observational and causal associations between TL and six cognitive traits, with stratifications on APOE genotype, in a Mendelian Randomization (MR) framework. Twelve European cohorts (N=17 052; mean age=59.2±8.8 years) provided results for associations between qPCR-measured TL (T/S-ratio scale) and general cognitive function, mini-mental state exam (MMSE), processing speed by digit symbol substitution test (DSST), visuospatial functioning, memory and executive functioning (STROOP). In addition, a genetic risk score (GRS) for TL including seven known genetic variants for TL was calculated, and used in associations with cognitive traits as outcomes in all cohorts. Observational analyses showed that longer telomeres were associated with better scores on DSST (β=0.051 per s.d.-increase of TL; 95% confidence interval (CI): 0.024, 0.077; P=0.0002), and MMSE (β=0.025; 95% CI: 0.002, 0.047; P=0.03), and faster STROOP (β=-0.053; 95% CI: -0.087, -0.018; P=0.003). Effects for DSST were stronger in APOE ɛ4 non-carriers (β=0.081; 95% CI: 0.045, 0.117; P=1.0 × 10-5), whereas carriers performed better in STROOP (β=-0.074; 95% CI: -0.140, -0.009; P=0.03). Causal associations were found for STROOP only (β=-0.598 per s.d.-increase of TL; 95% CI: -1.125, -0.072; P=0.026), with a larger effect in ɛ4-carriers (β=-0.699; 95% CI: -1.330, -0.069; P=0.03). Two-sample replication analyses using CHARGE summary statistics showed causal effects between TL and general cognitive function and DSST, but not with STROOP. In conclusion, we suggest causal effects from longer TL on better cognitive performance, where APOE ɛ4-carriers might be at differential risk.

VL - 7 IS - 4 ER - TY - JOUR T1 - Visit-to-Visit Blood Pressure Variability and Mortality and Cardiovascular Outcomes Among Older Adults: The Health, Aging, and Body Composition Study. JF - Am J Hypertens Y1 - 2017 A1 - Wu, Chenkai A1 - Shlipak, Michael G A1 - Stawski, Robert S A1 - Peralta, Carmen A A1 - Psaty, Bruce M A1 - Harris, Tamara B A1 - Satterfield, Suzanne A1 - Shiroma, Eric J A1 - Newman, Anne B A1 - Odden, Michelle C KW - Aged KW - Aging KW - Blood Pressure KW - Blood Pressure Determination KW - Body Composition KW - California KW - Cohort Studies KW - Female KW - Health Status KW - Humans KW - Hypertension KW - Incidence KW - Longitudinal Studies KW - Male KW - Myocardial Infarction KW - Office Visits KW - Prognosis KW - Retrospective Studies KW - Risk Factors KW - Stroke KW - Survival Rate AB -

BACKGROUND: Level of blood pressure (BP) is strongly associated with cardiovascular (CV) events and mortality. However, it is questionable whether mean BP can fully capture BP-related vascular risk. Increasing attention has been given to the value of visit-to-visit BP variability.

METHODS: We examined the association of visit-to-visit BP variability with mortality, incident myocardial infarction (MI), and incident stroke among 1,877 well-functioning elders in the Health, Aging, and Body Composition Study. We defined visit-to-visit diastolic BP (DBP) and systolic BP (SBP) variability as the root-mean-square error of person-specific linear regression of BP as a function of time. Alternatively, we counted the number of considerable BP increases and decreases (separately; 10mm Hg for DBP and 20mm Hg for SBP) between consecutive visits for each individual.

RESULTS: Over an average follow-up of 8.5 years, 623 deaths (207 from CV disease), 153 MIs, and 156 strokes occurred. The median visit-to-visit DBP and SBP variability was 4.96 mmHg and 8.53 mmHg, respectively. After multivariable adjustment, visit-to-visit DBP variability was related to higher all-cause (hazard ratio (HR) = 1.18 per 1 SD, 95% confidence interval (CI) = 1.01-1.37) and CV mortality (HR = 1.35, 95% CI = 1.05-1.73). Additionally, individuals having more considerable decreases of DBP (≥10mm Hg between 2 consecutive visits) had higher risk of all-cause (HR = 1.13, 95% CI = 0.99-1.28) and CV mortality (HR = 1.30, 95% CI = 1.05-1.61); considerable increases of SBP (≥20mm Hg) were associated with higher risk of all-cause (HR = 1.18, 95% CI = 1.03-1.36) and CV mortality (HR = 1.37, 95% CI = 1.08-1.74).

CONCLUSIONS: Visit-to-visit DBP variability and considerable changes in DBP and SBP were risk factors for mortality in the elderly.

VL - 30 IS - 2 ER - TY - JOUR T1 - Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease. JF - Circulation Y1 - 2019 A1 - Agha, Golareh A1 - Mendelson, Michael M A1 - Ward-Caviness, Cavin K A1 - Joehanes, Roby A1 - Huan, Tianxiao A1 - Gondalia, Rahul A1 - Salfati, Elias A1 - Brody, Jennifer A A1 - Fiorito, Giovanni A1 - Bressler, Jan A1 - Chen, Brian H A1 - Ligthart, Symen A1 - Guarrera, Simonetta A1 - Colicino, Elena A1 - Just, Allan C A1 - Wahl, Simone A1 - Gieger, Christian A1 - Vandiver, Amy R A1 - Tanaka, Toshiko A1 - Hernandez, Dena G A1 - Pilling, Luke C A1 - Singleton, Andrew B A1 - Sacerdote, Carlotta A1 - Krogh, Vittorio A1 - Panico, Salvatore A1 - Tumino, Rosario A1 - Li, Yun A1 - Zhang, Guosheng A1 - Stewart, James D A1 - Floyd, James S A1 - Wiggins, Kerri L A1 - Rotter, Jerome I A1 - Multhaup, Michael A1 - Bakulski, Kelly A1 - Horvath, Steven A1 - Tsao, Philip S A1 - Absher, Devin M A1 - Vokonas, Pantel A1 - Hirschhorn, Joel A1 - Fallin, M Daniele A1 - Liu, Chunyu A1 - Bandinelli, Stefania A1 - Boerwinkle, Eric A1 - Dehghan, Abbas A1 - Schwartz, Joel D A1 - Psaty, Bruce M A1 - Feinberg, Andrew P A1 - Hou, Lifang A1 - Ferrucci, Luigi A1 - Sotoodehnia, Nona A1 - Matullo, Giuseppe A1 - Peters, Annette A1 - Fornage, Myriam A1 - Assimes, Themistocles L A1 - Whitsel, Eric A A1 - Levy, Daniel A1 - Baccarelli, Andrea A KW - Adult KW - Aged KW - Cohort Studies KW - Coronary Disease KW - CpG Islands KW - DNA Methylation KW - Europe KW - Female KW - Genome-Wide Association Study KW - Humans KW - Incidence KW - Leukocytes KW - Male KW - Middle Aged KW - Myocardial Infarction KW - Population Groups KW - Prognosis KW - Prospective Studies KW - Risk KW - United States AB -

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.

METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.

RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.

CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

VL - 140 IS - 8 ER - TY - JOUR T1 - Discriminative Accuracy of FEV1:FVC Thresholds for COPD-Related Hospitalization and Mortality. JF - JAMA Y1 - 2019 A1 - Bhatt, Surya P A1 - Balte, Pallavi P A1 - Schwartz, Joseph E A1 - Cassano, Patricia A A1 - Couper, David A1 - Jacobs, David R A1 - Kalhan, Ravi A1 - O'Connor, George T A1 - Yende, Sachin A1 - Sanders, Jason L A1 - Umans, Jason G A1 - Dransfield, Mark T A1 - Chaves, Paulo H A1 - White, Wendy B A1 - Oelsner, Elizabeth C KW - Aged KW - Aged, 80 and over KW - Cohort Studies KW - Female KW - Forced Expiratory Volume KW - Hospitalization KW - Humans KW - Male KW - Middle Aged KW - Prognosis KW - Proportional Hazards Models KW - Pulmonary Disease, Chronic Obstructive KW - Risk Assessment KW - Vital Capacity AB -

Importance: According to numerous current guidelines, the diagnosis of chronic obstructive pulmonary disease (COPD) requires a ratio of the forced expiratory volume in the first second to the forced vital capacity (FEV1:FVC) of less than 0.70, yet this fixed threshold is based on expert opinion and remains controversial.

Objective: To determine the discriminative accuracy of various FEV1:FVC fixed thresholds for predicting COPD-related hospitalization and mortality.

Design, Setting, and Participants: The National Heart, Lung, and Blood Institute (NHLBI) Pooled Cohorts Study harmonized and pooled data from 4 US general population-based cohorts (Atherosclerosis Risk in Communities Study; Cardiovascular Health Study; Health, Aging, and Body Composition Study; and Multi-Ethnic Study of Atherosclerosis). Participants aged 45 to 102 years were enrolled from 1987 to 2000 and received follow-up longitudinally through 2016.

Exposures: Presence of airflow obstruction, which was defined by a baseline FEV1:FVC less than a range of fixed thresholds (0.75 to 0.65) or less than the lower limit of normal as defined by Global Lung Initiative reference equations (LLN).

Main Outcomes and Measures: The primary outcome was a composite of COPD hospitalization and COPD-related mortality, defined by adjudication or administrative criteria. The optimal fixed FEV1:FVC threshold was defined by the best discrimination for these COPD-related events as indexed using the Harrell C statistic from unadjusted Cox proportional hazards models. Differences in C statistics were compared with respect to less than 0.70 and less than LLN thresholds using a nonparametric approach.

Results: Among 24 207 adults in the pooled cohort (mean [SD] age at enrollment, 63 [10.5] years; 12 990 [54%] women; 16 794 [69%] non-Hispanic white; 15 181 [63%] ever smokers), complete follow-up was available for 11 077 (77%) at 15 years. During a median follow-up of 15 years, 3925 participants experienced COPD-related events over 340 757 person-years of follow-up (incidence density rate, 11.5 per 1000 person-years), including 3563 COPD-related hospitalizations and 447 COPD-related deaths. With respect to discrimination of COPD-related events, the optimal fixed threshold (0.71; C statistic for optimal fixed threshold, 0.696) was not significantly different from the 0.70 threshold (difference, 0.001 [95% CI, -0.002 to 0.004]) but was more accurate than the LLN threshold (difference, 0.034 [95% CI, 0.028 to 0.041]). The 0.70 threshold provided optimal discrimination in the subgroup analysis of ever smokers and in adjusted models.

Conclusions and Relevance: Defining airflow obstruction as FEV1:FVC less than 0.70 provided discrimination of COPD-related hospitalization and mortality that was not significantly different or was more accurate than other fixed thresholds and the LLN. These results support the use of FEV1:FVC less than 0.70 to identify individuals at risk of clinically significant COPD.

VL - 321 IS - 24 ER - TY - JOUR T1 - Alzheimer Disease Pathology-Associated Polymorphism in a Complex Variable Number of Tandem Repeat Region Within the MUC6 Gene, Near the AP2A2 Gene. JF - J Neuropathol Exp Neurol Y1 - 2020 A1 - Katsumata, Yuriko A1 - Fardo, David W A1 - Bachstetter, Adam D A1 - Artiushin, Sergey C A1 - Wang, Wang-Xia A1 - Wei, Angela A1 - Brzezinski, Lena J A1 - Nelson, Bela G A1 - Huang, Qingwei A1 - Abner, Erin L A1 - Anderson, Sonya A1 - Patel, Indumati A1 - Shaw, Benjamin C A1 - Price, Douglas A A1 - Niedowicz, Dana M A1 - Wilcock, Donna W A1 - Jicha, Gregory A A1 - Neltner, Janna H A1 - Van Eldik, Linda J A1 - Estus, Steven A1 - Nelson, Peter T KW - Adaptor Protein Complex 2 KW - Adaptor Protein Complex alpha Subunits KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Autopsy KW - Cohort Studies KW - Female KW - Genome-Wide Association Study KW - Genotype KW - Humans KW - Male KW - Minisatellite Repeats KW - Mucin-6 KW - Neurofibrillary Tangles KW - Polymorphism, Genetic KW - Polymorphism, Single Nucleotide KW - TDP-43 Proteinopathies AB -

We found evidence of late-onset Alzheimer disease (LOAD)-associated genetic polymorphism within an exon of Mucin 6 (MUC6) and immediately downstream from another gene: Adaptor Related Protein Complex 2 Subunit Alpha 2 (AP2A2). PCR analyses on genomic DNA samples confirmed that the size of the MUC6 variable number tandem repeat (VNTR) region was highly polymorphic. In a cohort of autopsied subjects with quantitative digital pathology data (n = 119), the size of the polymorphic region was associated with the severity of pTau pathology in neocortex. In a separate replication cohort of autopsied subjects (n = 173), more pTau pathology was again observed in subjects with longer VNTR regions (p = 0.031). Unlike MUC6, AP2A2 is highly expressed in human brain. AP2A2 expression was lower in a subset analysis of brain samples from persons with longer versus shorter VNTR regions (p = 0.014 normalizing with AP2B1 expression). Double-label immunofluorescence studies showed that AP2A2 protein often colocalized with neurofibrillary tangles in LOAD but was not colocalized with pTau proteinopathy in progressive supranuclear palsy, or with TDP-43 proteinopathy. In summary, polymorphism in a repeat-rich region near AP2A2 was associated with neocortical pTau proteinopathy (because of the unique repeats, prior genome-wide association studies were probably unable to detect this association), and AP2A2 was often colocalized with neurofibrillary tangles in LOAD.

VL - 79 IS - 1 ER - TY - JOUR T1 - Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts. JF - Lancet Respir Med Y1 - 2020 A1 - Moll, Matthew A1 - Sakornsakolpat, Phuwanat A1 - Shrine, Nick A1 - Hobbs, Brian D A1 - DeMeo, Dawn L A1 - John, Catherine A1 - Guyatt, Anna L A1 - McGeachie, Michael J A1 - Gharib, Sina A A1 - Obeidat, Ma'en A1 - Lahousse, Lies A1 - Wijnant, Sara R A A1 - Brusselle, Guy A1 - Meyers, Deborah A A1 - Bleecker, Eugene R A1 - Li, Xingnan A1 - Tal-Singer, Ruth A1 - Manichaikul, Ani A1 - Rich, Stephen S A1 - Won, Sungho A1 - Kim, Woo Jin A1 - Do, Ah Ra A1 - Washko, George R A1 - Barr, R Graham A1 - Psaty, Bruce M A1 - Bartz, Traci M A1 - Hansel, Nadia N A1 - Barnes, Kathleen A1 - Hokanson, John E A1 - Crapo, James D A1 - Lynch, David A1 - Bakke, Per A1 - Gulsvik, Amund A1 - Hall, Ian P A1 - Wain, Louise A1 - Weiss, Scott T A1 - Silverman, Edwin K A1 - Dudbridge, Frank A1 - Tobin, Martin D A1 - Cho, Michael H KW - Adult KW - Case-Control Studies KW - Cohort Studies KW - Female KW - Forced Expiratory Volume KW - Genome-Wide Association Study KW - Humans KW - Male KW - Middle Aged KW - Phenotype KW - Pulmonary Disease, Chronic Obstructive KW - Risk Factors KW - Vital Capacity AB -

BACKGROUND: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes.

METHODS: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV and FEV/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV/FVC <0·7 and FEV <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth.

FINDINGS: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern.

INTERPRETATION: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.

FUNDING: US National Institutes of Health, Wellcome Trust.

VL - 8 IS - 7 ER - TY - JOUR T1 - A Dyadic Growth Modeling Approach for Examining Associations Between Weight Gain and Lung Function Decline. JF - Am J Epidemiol Y1 - 2020 A1 - Cornelius, Talea A1 - Schwartz, Joseph E A1 - Balte, Pallavi A1 - Bhatt, Surya P A1 - Cassano, Patricia A A1 - Currow, David A1 - Jacobs, David R A1 - Johnson, Miriam A1 - Kalhan, Ravi A1 - Kronmal, Richard A1 - Loehr, Laura A1 - O'Connor, George T A1 - Smith, Benjamin A1 - White, Wendy B A1 - Yende, Sachin A1 - Oelsner, Elizabeth C KW - Adult KW - Aged KW - Body Mass Index KW - Cohort Studies KW - Humans KW - Linear Models KW - Lung KW - Middle Aged KW - Respiratory Function Tests KW - Weight Gain AB -

The relationship between body weight and lung function is complex. Using a dyadic multilevel linear modeling approach, treating body mass index (BMI; weight (kg)/height (m)2) and lung function as paired, within-person outcomes, we tested the hypothesis that persons with more rapid increase in BMI exhibit more rapid decline in lung function, as measured by forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and their ratio (FEV1:FVC). Models included random intercepts and slopes and adjusted for sociodemographic and smoking-related factors. A sample of 9,115 adults with paired measurements of BMI and lung function taken at ≥3 visits were selected from a pooled set of 5 US population-based cohort studies (1983-2018; mean age at baseline = 46 years; median follow-up, 19 years). At age 46 years, average annual rates of change in BMI, FEV1, FVC, and FEV1:FVC ratio were 0.22 kg/m2/year, -25.50 mL/year, -21.99 mL/year, and -0.24%/year, respectively. Persons with steeper BMI increases had faster declines in FEV1 (r = -0.16) and FVC (r = -0.26) and slower declines in FEV1:FVC ratio (r = 0.11) (all P values < 0.0001). Results were similar in subgroup analyses. Residual correlations were negative (P < 0.0001), suggesting additional interdependence between BMI and lung function. Results show that greater rates of weight gain are associated with greater rates of lung function loss.

VL - 189 IS - 10 ER - TY - JOUR T1 - Performance of the Pooled Cohort Equations to Estimate Atherosclerotic Cardiovascular Disease Risk by Body Mass Index. JF - JAMA Netw Open Y1 - 2020 A1 - Khera, Rohan A1 - Pandey, Ambarish A1 - Ayers, Colby R A1 - Carnethon, Mercedes R A1 - Greenland, Philip A1 - Ndumele, Chiadi E A1 - Nambi, Vijay A1 - Seliger, Stephen L A1 - Chaves, Paulo H M A1 - Safford, Monika M A1 - Cushman, Mary A1 - Xanthakis, Vanessa A1 - Vasan, Ramachandran S A1 - Mentz, Robert J A1 - Correa, Adolfo A1 - Lloyd-Jones, Donald M A1 - Berry, Jarett D A1 - de Lemos, James A A1 - Neeland, Ian J KW - Adult KW - Aged KW - Body Mass Index KW - Cardiovascular Diseases KW - Cohort Studies KW - Correlation of Data KW - Female KW - Humans KW - Longitudinal Studies KW - Male KW - Middle Aged KW - Proportional Hazards Models KW - Prospective Studies KW - Risk Assessment KW - Risk Factors AB -

Importance: Obesity is a global health challenge and a risk factor for atherosclerotic cardiovascular disease (ASVCD). Performance of the pooled cohort equations (PCE) for ASCVD risk by body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) is unknown.

Objective: To assess performance of the PCE across clinical BMI categories.

Design, Setting, and Participants: This cohort study used pooled individual-level data from 8 community-based, prospective, longitudinal cohort studies with 10-year ASCVD event follow-up from 1996 to 2016. We included all adults ages 40 to 79 years without baseline ASCVD or statin use, resulting in a sample size of 37 311 participants. Data were analyzed from August 2017 to July 2020.

Exposures: Participant BMI category: underweight (<18.5), normal weight (18.5 to <25), overweight (25 to <30), mild obesity (30 to <35), and moderate to severe obesity (≥35).

Main Outcomes and Measures: Discrimination (Harrell C statistic) and calibration (Nam-D'Agostino χ2 goodness-of-fit test) of the PCE across BMI categories. Improvement in discrimination and net reclassification with addition of BMI, waist circumference, and high-sensitivity C-reactive protein (hsCRP) to the PCE.

Results: Among 37 311 participants (mean [SD] age, 58.6 [11.8] years; 21 897 [58.7%] women), 380 604 person-years of follow-up were conducted. Mean (SD) baseline BMI was 29.0 (6.2), and 360 individuals (1.0%) were in the underweight category, 9937 individuals (26.6%) were in the normal weight category, 13 601 individuals (36.4%) were in the overweight category, 7783 individuals (20.9%) were in the mild obesity category, and 5630 individuals (15.1%) were in the moderate to severe obesity category. Median (interquartile range [IQR]) 10-year estimated ASCVD risk was 7.1% (2.5%-15.4%), and 3709 individuals (9.9%) developed ASCVD over a median (IQR) 10.8 [8.5-12.6] years. The PCE overestimated ASCVD risk in the overall cohort (estimated/observed [E/O] risk ratio, 1.22; 95% CI, 1.18-1.26) and across all BMI categories except the underweight category. Calibration was better near the clinical decision threshold in all BMI groups but worse among individuals with moderate or severe obesity (E/O risk ratio, 1.36; 95% CI, 1.25-1.47) and among those with the highest estimated ASCVD risk ≥20%. The PCE C statistic overall was 0.760 (95% CI, 0.753-0.767), with lower discrimination in the moderate or severe obesity group (C statistic, 0.742; 95% CI, 0.721-0.763) compared with the normal-range BMI group (C statistic, 0.785; 95% CI, 0.772-0.798). Waist circumference (hazard ratio, 1.07 per 1-SD increase; 95% CI, 1.03-1.11) and hsCRP (hazard ratio, 1.07 per 1-SD increase; 95% CI, 1.05-1.09), but not BMI, were associated with increased ASCVD risk when added to the PCE. However, these factors did not improve model performance (C statistic, 0.760; 95% CI, 0.753-0.767) with or without added metrics.

Conclusions and Relevance: These findings suggest that the PCE had acceptable model discrimination and were well calibrated at clinical decision thresholds but overestimated risk of ASCVD for individuals in overweight and obese categories, particularly individuals with high estimated risk. Incorporation of the usual clinical measures of obesity did not improve risk estimation of the PCE. Future research is needed to determine whether incorporation of alternative high-risk obesity markers (eg, weight trajectory or measures of visceral or ectopic fat) into the PCE may improve risk prediction.

VL - 3 IS - 10 ER - TY - JOUR T1 - Cardiovascular Risk Factors Across the Life Course and Cognitive Decline: A Pooled Cohort Study. JF - Neurology Y1 - 2021 A1 - Yaffe, Kristine A1 - Vittinghoff, Eric A1 - Hoang, Tina A1 - Matthews, Karen A1 - Golden, Sherita H A1 - Zeki Al Hazzouri, Adina KW - Adolescent KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Blood Pressure KW - Cardiovascular Diseases KW - Cognition KW - Cognitive Dysfunction KW - Cohort Studies KW - Female KW - Heart Disease Risk Factors KW - Humans KW - Hypertension KW - Male KW - Middle Aged KW - Risk Factors KW - Young Adult AB -

OBJECTIVE: Cardiovascular risk factors (CVRFs) are associated with increased risk of cognitive decline, but little is known about how early adult CVRFs and those across the life course might influence late-life cognition. To test the hypothesis that CVRFs across the adult life course are associated with late-life cognitive changes, we pooled data from 4 prospective cohorts (n = 15,001, ages 18-95).

METHODS: We imputed trajectories of body mass index (BMI), fasting glucose (FG), systolic blood pressure (SBP), and total cholesterol (TC) for older adults. We used linear mixed models to determine the association of early adult, midlife, and late-life CVRFs with late-life decline on global cognition (Modified Mini-Mental State Examination [3MS]) and processing speed (Digit Symbol Substitution Test [DSST]), adjusting for demographics, education, and cohort.

RESULTS: Elevated BMI, FG, and SBP (but not TC) at each time period were associated with greater late-life decline. Early life CVRFs were associated with the greatest change, an approximate doubling of mean 10-year decline (an additional 3-4 points for 3MS or DSST). Late-life CVRFs were associated with declines in early late life (<80 years) but with gains in very late life (≥80 years). After adjusting for CVRF exposures at all time periods, the associations for early adult and late-life CVRFs persisted.

CONCLUSIONS: We found that imputed CVRFs across the life course, especially in early adulthood, were associated with greater late-life cognitive decline. Our results suggest that CVRF treatment in early adulthood could benefit late-life cognition, but that treatment in very late life may not be as helpful for these outcomes.

VL - 96 IS - 17 ER - TY - JOUR T1 - Depressive Symptoms Imputed Across the Life Course Are Associated with Cognitive Impairment and Cognitive Decline. JF - J Alzheimers Dis Y1 - 2021 A1 - Brenowitz, Willa D A1 - Zeki Al Hazzouri, Adina A1 - Vittinghoff, Eric A1 - Golden, Sherita H A1 - Fitzpatrick, Annette L A1 - Yaffe, Kristine KW - Adult KW - Aged KW - Aged, 80 and over KW - Aging KW - Cognitive Dysfunction KW - Cohort Studies KW - Dementia KW - Depression KW - Female KW - Humans KW - Male KW - Middle Aged KW - Prodromal Symptoms KW - Risk Factors AB -

BACKGROUND: Depressive symptoms may increase risk for dementia, but findings are controversial because late-life depression may be a prodromal dementia symptom. Life course data on depression and dementia risk may clarify this association; however, data is limited.

OBJECTIVE: To impute adult depressive symptoms trajectories across adult life stages and estimate the association with cognitive impairment and decline.

METHODS: Using a pooled study of 4 prospective cohorts (ages 20-89), we imputed adult life course depressive symptoms trajectories based on Center for Epidemiologic Studies Depression Scale-10 (CESD-10) and calculated time-weighted averages for early adulthood (ages 20-49), mid-life (ages 50-69), and late-life (ages 70-89) for 6,122 older participants. Adjusted pooled logistic and mixed-effects models estimated associations of imputed depressive symptoms with two cognitive outcomes: cognitive impairment defined by established criteria and a composite cognitive score.

RESULTS: In separate models, elevated depressive symptoms in each life stage were associated with cognitive outcomes: early adulthood OR for cognitive impairment = 1.59 (95%CI: 1.35,1.87); mid-life OR = 1.94 (95%CI:1.16, 3.26); and late-life OR = 1.77 (95%CI:1.42, 2.21). When adjusted for depressive symptoms in the other life-stages, elevated depressive symptoms in early adulthood (OR = 1.73; 95%CI: 1.42,2.11) and late-life (OR = 1.43; 95%CI: 1.08,1.89) remained associated with cognitive impairment and were also associated with faster rates of cognitive decline (p < 0.05).

CONCLUSION: Imputing depressive symptom trajectories from pooled cohorts may help expand data across the life course. Our findings suggest early adulthood depressive symptoms may be a risk factor for cognitive impairment independent of mid- or late-life depressive symptoms.

VL - 83 IS - 3 ER - TY - JOUR T1 - Egg consumption, overall diet quality, and risk of type 2 diabetes and coronary heart disease: A pooling project of US prospective cohorts. JF - Clin Nutr Y1 - 2021 A1 - Djoussé, Luc A1 - Zhou, Guohai A1 - McClelland, Robyn L A1 - Ma, Nanxun A1 - Zhou, Xia A1 - Kabagambe, Edmond K A1 - Talegawkar, Sameera A A1 - Judd, Suzanne E A1 - Biggs, Mary L A1 - Fitzpatrick, Annette L A1 - Clark, Cheryl R A1 - Gagnon, David R A1 - Steffen, Lyn M A1 - Gaziano, J Michael A1 - Lee, I-Min A1 - Buring, Julie E A1 - Manson, JoAnn E KW - Adult KW - Aged KW - Cohort Studies KW - Coronary Disease KW - Diabetes Mellitus, Type 2 KW - Diet KW - Eggs KW - Humans KW - Middle Aged KW - Prospective Studies KW - Risk Factors KW - United States AB -

BACKGROUND AND AIMS: Data on the relation of egg consumption with risk of type 2 diabetes (T2D) and coronary heart disease (CHD) are limited and inconsistent. Few studies have controlled for overall dietary patterns in egg-T2D or egg-CHD analyses, and it is unclear whether any observed elevated risks of T2D and CHD with frequent egg consumption is real or due to confounding by dietary habits. We tested the hypothesis that frequent egg consumption is associated with a higher risk of T2D and CHD risk after adjustment for overall dietary patterns among adults.

DESIGN: We used prospective cohort design to complete time-to-event analyses.

METHODS: We pooled de novo, harmonized, individual-level analyses from nine US cohorts (n = 103,811). Cox regression was used to estimate hazard ratios separately in each cohort adjusting for age, ethnicity, body mass index (BMI), exercise, smoking, alcohol intake, and dietary patterns. We pooled cohort-specific results using an inverse-variance weighted method to estimate summary relative risks.

RESULTS: Median age ranged from 25 to 72 years. Median egg consumption was 1 egg per week in most of the cohorts. While egg consumption up to one per week was not associated with T2D risk, consumption of ≥2 eggs per week was associated with elevated risk [27% elevated risk of T2D comparing 7+ eggs/week with none (95% CI: 16%-37%)]. There was little evidence for heterogeneity across cohorts and we observed similar conclusions when stratified by BMI. Overall, egg consumption was not associated with the risk of CHD. However, in a sensitivity analysis, there was a 30% higher risk of CHD (95% CI: 3%-56%) restricted to older adults consuming 5-6 eggs/week.

CONCLUSIONS: Our data showed an elevated risk of T2D with egg consumption of ≥2 eggs per week but not with <2 eggs/week. While there was no overall association of egg consumption with CHD risk, the elevated CHD observed with consumption of 5-6 eggs/week in older cohorts merits further investigation.

VL - 40 IS - 5 ER - TY - JOUR T1 - Epigenome-wide association study of serum urate reveals insights into urate co-regulation and the SLC2A9 locus. JF - Nat Commun Y1 - 2021 A1 - Tin, Adrienne A1 - Schlosser, Pascal A1 - Matias-Garcia, Pamela R A1 - Thio, Chris H L A1 - Joehanes, Roby A1 - Liu, Hongbo A1 - Yu, Zhi A1 - Weihs, Antoine A1 - Hoppmann, Anselm A1 - Grundner-Culemann, Franziska A1 - Min, Josine L A1 - Kuhns, Victoria L Halperin A1 - Adeyemo, Adebowale A A1 - Agyemang, Charles A1 - Arnlöv, Johan A1 - Aziz, Nasir A A1 - Baccarelli, Andrea A1 - Bochud, Murielle A1 - Brenner, Hermann A1 - Bressler, Jan A1 - Breteler, Monique M B A1 - Carmeli, Cristian A1 - Chaker, Layal A1 - Coresh, Josef A1 - Corre, Tanguy A1 - Correa, Adolfo A1 - Cox, Simon R A1 - Delgado, Graciela E A1 - Eckardt, Kai-Uwe A1 - Ekici, Arif B A1 - Endlich, Karlhans A1 - Floyd, James S A1 - Fraszczyk, Eliza A1 - Gao, Xu A1 - Gào, Xīn A1 - Gelber, Allan C A1 - Ghanbari, Mohsen A1 - Ghasemi, Sahar A1 - Gieger, Christian A1 - Greenland, Philip A1 - Grove, Megan L A1 - Harris, Sarah E A1 - Hemani, Gibran A1 - Henneman, Peter A1 - Herder, Christian A1 - Horvath, Steve A1 - Hou, Lifang A1 - Hurme, Mikko A A1 - Hwang, Shih-Jen A1 - Kardia, Sharon L R A1 - Kasela, Silva A1 - Kleber, Marcus E A1 - Koenig, Wolfgang A1 - Kooner, Jaspal S A1 - Kronenberg, Florian A1 - Kuhnel, Brigitte A1 - Ladd-Acosta, Christine A1 - Lehtimäki, Terho A1 - Lind, Lars A1 - Liu, Dan A1 - Lloyd-Jones, Donald M A1 - Lorkowski, Stefan A1 - Lu, Ake T A1 - Marioni, Riccardo E A1 - März, Winfried A1 - McCartney, Daniel L A1 - Meeks, Karlijn A C A1 - Milani, Lili A1 - Mishra, Pashupati P A1 - Nauck, Matthias A1 - Nowak, Christoph A1 - Peters, Annette A1 - Prokisch, Holger A1 - Psaty, Bruce M A1 - Raitakari, Olli T A1 - Ratliff, Scott M A1 - Reiner, Alex P A1 - Schöttker, Ben A1 - Schwartz, Joel A1 - Sedaghat, Sanaz A1 - Smith, Jennifer A A1 - Sotoodehnia, Nona A1 - Stocker, Hannah R A1 - Stringhini, Silvia A1 - Sundström, Johan A1 - Swenson, Brenton R A1 - van Meurs, Joyce B J A1 - van Vliet-Ostaptchouk, Jana V A1 - Venema, Andrea A1 - Völker, Uwe A1 - Winkelmann, Juliane A1 - Wolffenbuttel, Bruce H R A1 - Zhao, Wei A1 - Zheng, Yinan A1 - Loh, Marie A1 - Snieder, Harold A1 - Waldenberger, Melanie A1 - Levy, Daniel A1 - Akilesh, Shreeram A1 - Woodward, Owen M A1 - Susztak, Katalin A1 - Teumer, Alexander A1 - Köttgen, Anna KW - Amino Acid Transport System y+ KW - Cohort Studies KW - CpG Islands KW - DNA Methylation KW - Epigenome KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Glucose Transport Proteins, Facilitative KW - Gout KW - Humans KW - Male KW - Uric Acid AB -

Elevated serum urate levels, a complex trait and major risk factor for incident gout, are correlated with cardiometabolic traits via incompletely understood mechanisms. DNA methylation in whole blood captures genetic and environmental influences and is assessed in transethnic meta-analysis of epigenome-wide association studies (EWAS) of serum urate (discovery, n = 12,474, replication, n = 5522). The 100 replicated, epigenome-wide significant (p < 1.1E-7) CpGs explain 11.6% of the serum urate variance. At SLC2A9, the serum urate locus with the largest effect in genome-wide association studies (GWAS), five CpGs are associated with SLC2A9 gene expression. Four CpGs at SLC2A9 have significant causal effects on serum urate levels and/or gout, and two of these partly mediate the effects of urate-associated GWAS variants. In other genes, including SLC7A11 and PHGDH, 17 urate-associated CpGs are associated with conditions defining metabolic syndrome, suggesting that these CpGs may represent a blood DNA methylation signature of cardiometabolic risk factors. This study demonstrates that EWAS can provide new insights into GWAS loci and the correlation of serum urate with other complex traits.

VL - 12 IS - 1 ER - TY - JOUR T1 - Sex Differences in Cognitive Decline Among US Adults. JF - JAMA Netw Open Y1 - 2021 A1 - Levine, Deborah A A1 - Gross, Alden L A1 - Briceño, Emily M A1 - Tilton, Nicholas A1 - Giordani, Bruno J A1 - Sussman, Jeremy B A1 - Hayward, Rodney A A1 - Burke, James F A1 - Hingtgen, Stephanie A1 - Elkind, Mitchell S V A1 - Manly, Jennifer J A1 - Gottesman, Rebecca F A1 - Gaskin, Darrell J A1 - Sidney, Stephen A1 - Sacco, Ralph L A1 - Tom, Sarah E A1 - Wright, Clinton B A1 - Yaffe, Kristine A1 - Galecki, Andrzej T KW - Aged KW - Cognitive Dysfunction KW - Cognitive Reserve KW - Cohort Studies KW - Executive Function KW - Humans KW - Memory KW - Middle Aged KW - Risk KW - Sex Factors KW - Time Factors KW - United States AB -

Importance: Sex differences in dementia risk are unclear, but some studies have found greater risk for women.

Objective: To determine associations between sex and cognitive decline in order to better understand sex differences in dementia risk.

Design, Setting, and Participants: This cohort study used pooled analysis of individual participant data from 5 cohort studies for years 1971 to 2017: Atherosclerosis Risk in Communities Study, Coronary Artery Risk Development in Young Adults Study, Cardiovascular Health Study, Framingham Offspring Study, and Northern Manhattan Study. Linear mixed-effects models were used to estimate changes in each continuous cognitive outcome over time by sex. Data analysis was completed from March 2019 to October 2020.

Exposure: Sex.

Main Outcomes and Measures: The primary outcome was change in global cognition. Secondary outcomes were change in memory and executive function. Outcomes were standardized as t scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition.

Results: Among 34 349 participants, 26 088 who self-reported Black or White race, were free of stroke and dementia, and had covariate data at or before the first cognitive assessment were included for analysis. Median (interquartile range) follow-up was 7.9 (5.3-20.5) years. There were 11 775 (44.7%) men (median [interquartile range] age, 58 [51-66] years at first cognitive assessment; 2229 [18.9%] Black) and 14 313 women (median [interquartile range] age, 58 [51-67] years at first cognitive assessment; 3636 [25.4%] Black). Women had significantly higher baseline performance than men in global cognition (2.20 points higher; 95% CI, 2.04 to 2.35 points; P < .001), executive function (2.13 points higher; 95% CI, 1.98 to 2.29 points; P < .001), and memory (1.89 points higher; 95% CI, 1.72 to 2.06 points; P < .001). Compared with men, women had significantly faster declines in global cognition (-0.07 points/y faster; 95% CI, -0.08 to -0.05 points/y; P < .001) and executive function (-0.06 points/y faster; 95% CI, -0.07 to -0.05 points/y; P < .001). Men and women had similar declines in memory (-0.004 points/y faster; 95% CI, -0.023 to 0.014; P = .61).

Conclusions and Relevance: The results of this cohort study suggest that women may have greater cognitive reserve but faster cognitive decline than men, which could contribute to sex differences in late-life dementia.

VL - 4 IS - 2 ER - TY - JOUR T1 - Total carotenoid intake is associated with reduced loss of grip strength and gait speed over time in adults: The Framingham Offspring Study. JF - Am J Clin Nutr Y1 - 2021 A1 - Sahni, Shivani A1 - Dufour, Alyssa B A1 - Fielding, Roger A A1 - Newman, Anne B A1 - Kiel, Douglas P A1 - Hannan, Marian T A1 - Jacques, Paul F KW - Adult KW - Aged KW - Aged, 80 and over KW - Carotenoids KW - Cohort Studies KW - Diet KW - Female KW - Hand Strength KW - Humans KW - Male KW - Middle Aged KW - Prospective Studies KW - Walking Speed AB -

BACKGROUND: Lower antioxidant serum concentrations have been linked to declines in lean mass and physical function in older adults. Yet population data on the effect of dietary antioxidants on loss of muscle strength and physical function are lacking.

OBJECTIVE: We sought to determine the association of antioxidant intake [vitamin C, vitamin E, and total and individual carotenoids (α-carotene, β-carotene, β-cryptoxanthin, lycopene, and lutein + zeaxanthin)] with annualized change in grip strength and gait speed in adults from the Framingham Offspring study.

METHODS: This prospective cohort study included participants with a valid FFQ at the index examination and up to 2 prior examinations and at ≥2 measures of primary outcomes: grip strength (n = 2452) and/or gait speed (n = 2422) measured over 3 subsequent examinations. Annualized change in grip strength (kg/y) and change in gait speed (m/s/y) over the follow-up period were used. Linear regression was used to calculate β coefficients and P values, adjusting for covariates.

RESULTS: Mean ± SD age of participants was 61 ± 9 y (range: 33-88 y). Median intakes (IQR, mg/d) of vitamin C, vitamin E, and total carotenoid across available examinations were 209.2 (133.1-394.2), 27.1 (7.4-199.0), and 15.3 (10.4-21.3), respectively. The mean follow-up time was ∼12 ± 2 y (range: 4.5-15.4 y). In the sex-combined sample, higher intakes of total carotenoids, lycopene, and lutein + zeaxanthin were associated with increased annualized change in grip strength [β (SE) per 10-mg higher intake/d, range: 0.0316 (0.0146) to 0.1223 (0.0603) kg/y)]. All antioxidants except for vitamin C were associated with faster gait speed [β (SE) per 10-mg higher intake/d, range: 0.00008 (0.00004) to 0.0187 (0.0081) m/s/y].

CONCLUSIONS: Higher antioxidant intake was associated with increase in grip strength and faster gait speed in this cohort of adults. This finding highlights the need for a randomized controlled trial of dietary antioxidants and their effect on muscle strength and physical function.

VL - 113 IS - 2 ER - TY - JOUR T1 - Association of Trimethylamine N-Oxide and Metabolites With Mortality in Older Adults. JF - JAMA Netw Open Y1 - 2022 A1 - Fretts, Amanda M A1 - Hazen, Stanley L A1 - Jensen, Paul A1 - Budoff, Matthew A1 - Sitlani, Colleen M A1 - Wang, Meng A1 - de Oliveira Otto, Marcia C A1 - DiDonato, Joseph A A1 - Lee, Yujin A1 - Psaty, Bruce M A1 - Siscovick, David S A1 - Sotoodehnia, Nona A1 - Tang, W H Wilson A1 - Lai, Heidi A1 - Lemaitre, Rozenn N A1 - Mozaffarian, Dariush KW - Aged KW - Betaine KW - Cardiovascular Diseases KW - Carnitine KW - Choline KW - Cohort Studies KW - Female KW - Humans KW - Male KW - Methylamines KW - Prospective Studies AB -

Importance: Little is known about the association of trimethylamine N-oxide (TMAO), a novel plasma metabolite derived from L-carnitine and phosphatidylcholine, and related metabolites (ie, choline, betaine, carnitine, and butyrobetaine) with risk of death among older adults in the general population.

Objective: To investigate the associations of serial measures of plasma TMAO and related metabolites with risk of total and cause-specific death (ie, deaths from cardiovascular diseases [CVDs] and non-CVDs) among older adults in the US.

Design, Setting, and Participants: This prospective cohort study involved 5333 participants from the Cardiovascular Health Study-a community-based longitudinal cohort of adults aged 65 years or older-who were followed up from June 1, 1989, to December 31, 2015. Participants were from 4 communities in the US (Forsyth County, North Carolina; Sacramento County, California; Washington County, Maryland; and Allegheny County, Pennsylvania). Data were analyzed from March 17 to June 23, 2021.

Exposures: Plasma TMAO, choline, betaine, carnitine, and butyrobetaine levels were measured using stored samples from baseline (June 1, 1989, to May 31, 1990, or November 1, 1992, to June 31, 1993) and follow-up examination (June 1, 1996, to May 31, 1997). Measurements were performed through stable-isotope dilution liquid chromatography with tandem mass spectrometry using high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry.

Main Outcomes and Measures: Deaths (total and cause specific) were adjudicated by a centralized Cardiovascular Health Study events committee based on information from medical records, laboratory and diagnostic reports, death certificates, and/or interviews with next of kin. The associations of each metabolite with mortality were assessed using Cox proportional hazards regression models.

Results: Among 5333 participants in the analytic sample, the mean (SD) age was 73 (6) years; 2149 participants (40.3%) were male, 3184 (59.7%) were female, 848 (15.9%) were African American, 4450 (83.4%) were White, and 35 (0.01%) were of other races (12 were American Indian or Alaska Native, 4 were Asian or Pacific Islander, and 19 were of other races or ethnicities). During a median follow-up of 13.2 years (range, 0-26.9 years), 4791 deaths occurred. After adjustment for potential confounders, the hazard ratios for death from any cause (ie, total mortality) comparing extreme quintiles (fifth vs first) of plasma concentrations were 1.30 (95% CI, 1.17-1.44) for TMAO, 1.19 (95% CI, 1.08-1.32) for choline, 1.26 (95% CI, 1.15-1.40) for carnitine, and 1.26 (95% CI, 1.13-1.40) for butyrobetaine. Plasma betaine was not associated with risk of death. The extent of risk estimates was similar for CVD and non-CVD mortality.

Conclusions and Relevance: In this cohort study, plasma concentrations of TMAO and related metabolites were positively associated with risk of death. These findings suggest that circulating TMAO is an important novel risk factor associated with death among older adults.

VL - 5 IS - 5 ER - TY - JOUR T1 - Diabetes Status Modifies the Association Between Different Measures of Obesity and Heart Failure Risk Among Older Adults: A Pooled Analysis of Community-Based NHLBI Cohorts. JF - Circulation Y1 - 2022 A1 - Patel, Kershaw V A1 - Segar, Matthew W A1 - Lavie, Carl J A1 - Kondamudi, Nitin A1 - Neeland, Ian J A1 - Almandoz, Jaime P A1 - Martin, Corby K A1 - Carbone, Salvatore A1 - Butler, Javed A1 - Powell-Wiley, Tiffany M A1 - Pandey, Ambarish KW - Aged KW - Cohort Studies KW - Diabetes Mellitus KW - Female KW - Heart Failure KW - Humans KW - Male KW - National Heart, Lung, and Blood Institute (U.S.) KW - Obesity KW - Risk Factors KW - United States AB -

BACKGROUND: Obesity and diabetes are associated with a higher risk of heart failure (HF). The interrelationships between different measures of adiposity-overall obesity, central obesity, fat mass (FM)-and diabetes status for HF risk are not well-established.

METHODS: Participant-level data from the ARIC study (Atherosclerosis Risk in Communities; visit 5) and the CHS (Cardiovascular Health Study; visit 1) cohorts were obtained from the National Heart, Lung, and Blood Institute Biologic Specimen and Data Repository Information Coordinating Center, harmonized, and pooled for the present analysis, excluding individuals with prevalent HF. FM was estimated in all participants using established anthropometric prediction equations additionally validated using the bioelectrical impedance-based FM in the ARIC subgroup. Incident HF events on follow-up were captured across both cohorts using similar adjudication methods. Multivariable-adjusted Fine-Gray models were created to evaluate the associations of body mass index (BMI), waist circumference (WC), and FM with risk of HF in the overall cohort as well as among those with versus without diabetes at baseline. The population attributable risk of overall obesity (BMI≥30 kg/m), abdominal obesity (WC>88 and 102 cm in women and men, respectively), and high FM (above sex-specific median) for incident HF was evaluated among participants with and without diabetes.

RESULTS: The study included 10 387 participants (52.9% ARIC; 25.1% diabetes; median age, 74 years). The correlation between predicted and bioelectrical impedance-based FM was high (=0.90; n=5038). During a 5-year follow-up, 447 participants developed HF (4.3%). Higher levels of each adiposity measure were significantly associated with higher HF risk (hazard ratio [95% CI] per 1 SD higher BMI=1.15 [1.05, 1.27], WC=1.22 [1.10, 1.36]; FM=1.13 [1.02, 1.25]). A significant interaction was noted between diabetes status and measures of BMI ( interaction=0.04) and WC ( interaction=0.004) for the risk of HF. In stratified analysis, higher measures of each adiposity parameter were significantly associated with higher HF risk in individuals with diabetes (hazard ratio [95% CI] per 1 SD higher BMI=1.29 [1.14-1.47]; WC=1.48 [1.29-1.70]; FM=1.25 [1.09-1.43]) but not those without diabetes, including participants with prediabetes and euglycemia. The population attributable risk percentage of overall obesity, abdominal obesity, and high FM for incident HF was higher among participants with diabetes (12.8%, 29.9%, and 13.7%, respectively) versus those without diabetes (≤1% for each).

CONCLUSIONS: Higher BMI, WC, and FM are strongly associated with greater risk of HF among older adults, particularly among those with prevalent diabetes.

VL - 145 IS - 4 ER - TY - JOUR T1 - Intake and Sources of Dietary Fiber, Inflammation, and Cardiovascular Disease in Older US Adults. JF - JAMA Netw Open Y1 - 2022 A1 - Shivakoti, Rupak A1 - Biggs, Mary L A1 - Djoussé, Luc A1 - Durda, Peter Jon A1 - Kizer, Jorge R A1 - Psaty, Bruce A1 - Reiner, Alex P A1 - Tracy, Russell P A1 - Siscovick, David A1 - Mukamal, Kenneth J KW - Adult KW - Aged KW - Cardiovascular Diseases KW - Cohort Studies KW - Dietary Fiber KW - Female KW - Humans KW - Inflammation KW - Middle Aged KW - Risk Factors AB -

Importance: Higher intake of dietary fiber has been associated with lower inflammation, but whether there are differences in this association by source of dietary fiber (ie, cereal, vegetable, or fruit) has not been studied to date.

Objectives: To evaluate the associations of total fiber intake and source (ie, cereal, vegetable, and fruit fiber intake) with inflammation and to evaluate whether inflammation mediates the inverse association between dietary fiber intake and cardiovascular disease (CVD).

Design, Setting, and Participants: At the baseline visit (1989-1990) of 4125 adults aged 65 years or older in an ongoing US cohort study, dietary intake was assessed by a food frequency questionnaire among study participants without prevalent CVD (stroke and myocardial infarction) at enrollment. Inflammation was assessed from blood samples collected at baseline with immunoassays for markers of inflammation. Multivariable linear regression models tested the association of dietary fiber intake with inflammation. Also assessed was whether each inflammatory marker and its composite derived from principal component analysis mediated the association of baseline cereal fiber intake with development of CVD (stroke, myocardial infarction, and atherosclerotic cardiovascular death) through June 2015. Data from June 1, 1989, through June 30, 2015, were analyzed.

Exposures: Total fiber intake and sources of fiber (cereal, vegetable, and fruit).

Main Outcomes and Measures: Systemic markers of inflammation. Cardiovascular disease was the outcome in the mediation analysis.

Results: Of 4125 individuals, 0.1% (n = 3) were Asian or Pacific Islander, 4.4% (n = 183) were Black, 0.3% (n = 12) were Native American, 95.0% (n = 3918) were White, and 0.2% (n = 9) were classified as other. Among these 4125 individuals (2473 women [60%]; mean [SD] age, 72.6 [5.5] years; 183 Black individuals [4.4%]; and 3942 individuals of other races and ethnicitites [95.6%] [ie, race and ethnicity other than Black, self-classified by participant]), an increase in total fiber intake of 5 g/d was associated with significantly lower concentrations of C-reactive protein (adjusted mean difference, -0.05 SD; 95% CI, -0.08 to -0.01 SD; P = .007) and interleukin 1 receptor antagonist (adjusted mean difference, -0.04 SD; 95% CI, -0.07 to -0.01 SD; P < .02) but with higher concentrations of soluble CD163 (adjusted mean difference, 0.05 SD; 95% CI, 0.02-0.09 SD; P = .005). Among fiber sources, only cereal fiber was consistently associated with lower inflammation. Similarly, cereal fiber intake was associated with lower CVD incidence (adjusted hazard ratio, 0.90; 95% CI, 0.81-1.00; 1941 incident cases). The proportion of the observed association of cereal fiber with CVD mediated by inflammatory markers ranged from 1.5% for interleukin 18 to 14.2% for C-reactive protein, and 16.1% for their primary principal component.

Conclusions and Relevance: Results of this study suggest that cereal fiber intake was associated with lower levels of various inflammatory markers and lower risk of CVD and that inflammation mediated approximately one-sixth of the association between cereal fiber intake and CVD.

VL - 5 IS - 3 ER - TY - JOUR T1 - Longitudinal Changes in Hearing and Visual Impairments and Risk of Dementia in Older Adults in the United States. JF - JAMA Netw Open Y1 - 2022 A1 - Hwang, Phillip H A1 - Longstreth, W T A1 - Thielke, Stephen M A1 - Francis, Courtney E A1 - Carone, Marco A1 - Kuller, Lewis H A1 - Fitzpatrick, Annette L KW - Aged KW - Alzheimer Disease KW - Cohort Studies KW - Female KW - Hearing KW - Hearing Loss KW - Humans KW - Male KW - Medicare KW - Prospective Studies KW - United States KW - Vision Disorders AB -

Importance: Hearing and vision problems are individually associated with increased dementia risk, but the impact of having concurrent hearing and vision deficits, ie, dual sensory impairment (DSI), on risk of dementia, including its major subtypes Alzheimer disease (AD) and vascular dementia (VaD), is not well known.

Objective: To evaluate whether DSI is associated with incident dementia in older adults.

Design, Setting, and Participants: This prospective cohort study from the Cardiovascular Health Study (CHS) was conducted between 1992 and 1999, with as many as 8 years of follow-up. The multicenter, population-based sample was recruited from Medicare eligibility files in 4 US communities with academic medical centers. Of 5888 participants aged 65 years and older in CHS, 3602 underwent cranial magnetic resonance imaging and completed the modified Mini-Mental State Examination in 1992 to 1994 as part of the CHS Cognition Study. A total of 227 participants were excluded due to prevalent dementia, leaving a total of 3375 participants without dementia at study baseline. The study hypothesis was that DSI would be associated with increased risk of dementia compared with no sensory impairment. The association between the duration of DSI with risk of dementia was also evaluated. Data analysis was conducted from November 2019 to February 2020.

Exposures: Hearing and vision impairments were collected via self-report at baseline and as many as 5 follow-up visits.

Main Outcomes and Measures: All-cause dementia, AD, and VaD, classified by a multidisciplinary committee using standardized criteria.

Results: A total of 2927 participants with information on hearing and vision at all available study visits were included in the analysis (mean [SD] age, 74.6 [4.8] years; 1704 [58.2%] women; 455 [15.5%] African American or Black; 2472 [85.5%] White). Compared with no sensory impairment, DSI was associated with increased risk of all-cause dementia (hazard ratio [HR], 2.60; 95% CI, 1.66-2.06; P < .001), AD (HR, 3.67; 95% CI, 2.04-6.60; P < .001) but not VaD (HR, 2.03; 95% CI, 1.00-4.09; P = .05).

Conclusions and Relevance: In this cohort study, DSI was associated with increased risk of dementia, particularly AD. Evaluation of hearing and vision in older adults may help to identify those at high risk of developing dementia.

VL - 5 IS - 5 ER - TY - JOUR T1 - Multi-Scalar Data Integration Links Glomerular Angiopoietin-Tie Signaling Pathway Activation With Progression of Diabetic Kidney Disease. JF - Diabetes Y1 - 2022 A1 - Liu, Jiahao A1 - Nair, Viji A1 - Zhao, Yi-Yang A1 - Chang, Dong-Yuan A1 - Limonte, Christine A1 - Bansal, Nisha A1 - Fermin, Damian A1 - Eichinger, Felix A1 - Tanner, Emily C A1 - Bellovich, Keith A A1 - Steigerwalt, Susan A1 - Bhat, Zeenat A1 - Hawkins, Jennifer J A1 - Subramanian, Lalita A1 - Rosas, Sylvia E A1 - Sedor, John R A1 - Vasquez, Miguel A A1 - Waikar, Sushrut S A1 - Bitzer, Markus A1 - Pennathur, Subramaniam A1 - Brosius, Frank C A1 - de Boer, Ian A1 - Chen, Min A1 - Kretzler, Matthias A1 - Ju, Wenjun KW - Angiopoietin-1 KW - Angiopoietin-2 KW - Angiopoietins KW - Biomarkers KW - Cohort Studies KW - Diabetes Mellitus KW - Diabetic Nephropathies KW - Disease Progression KW - Endothelial Cells KW - Humans KW - Kidney Failure, Chronic KW - Receptor, TIE-2 KW - Signal Transduction AB -

Diabetic kidney disease (DKD) is the leading cause of end-stage kidney disease (ESKD). Prognostic biomarkers reflective of underlying molecular mechanisms are critically needed for effective management of DKD. A three-marker panel was derived from a proteomics analysis of plasma samples by an unbiased machine learning approach from participants (N = 58) in the Clinical Phenotyping and Resource Biobank study. In combination with standard clinical parameters, this panel improved prediction of the composite outcome of ESKD or a 40% decline in glomerular filtration rate. The panel was validated in an independent group (N = 68), who also had kidney transcriptomic profiles. One marker, plasma angiopoietin 2 (ANGPT2), was significantly associated with outcomes in cohorts from the Cardiovascular Health Study (N = 3,183) and the Chinese Cohort Study of Chronic Kidney Disease (N = 210). Glomerular transcriptional angiopoietin/Tie (ANG-TIE) pathway scores, derived from the expression of 154 ANG-TIE signaling mediators, correlated positively with plasma ANGPT2 levels and kidney outcomes. Higher receptor expression in glomeruli and higher ANG-TIE pathway scores in endothelial cells corroborated potential functional effects in the kidney from elevated plasma ANGPT2 levels. Our work suggests that ANGPT2 is a promising prognostic endothelial biomarker with likely functional impact on glomerular pathogenesis in DKD.

VL - 71 IS - 12 ER - TY - JOUR T1 - Plasma Levels of Advanced Glycation Endproducts and Risk of Cardiovascular Events: Findings From 2 Prospective Cohorts. JF - J Am Heart Assoc Y1 - 2022 A1 - Lamprea-Montealegre, Julio A A1 - Arnold, Alice M A1 - McClelland, Robyn L A1 - Mukamal, Kenneth J A1 - Djoussé, Luc A1 - Biggs, Mary L A1 - Siscovick, David S A1 - Tracy, Russell P A1 - Beisswenger, Paul J A1 - Psaty, Bruce M A1 - Ix, Joachim H A1 - Kizer, Jorge R KW - Atherosclerosis KW - Cardiovascular Diseases KW - Cohort Studies KW - Glycation End Products, Advanced KW - Humans KW - Middle Aged KW - Risk Factors AB -

Background Advanced glycation endproducts (AGEs) have been linked to cardiovascular disease (CVD) in cohorts with and without diabetes. Data are lacking on prospective associations of various α-dicarbonyl-derived AGEs and incident CVD in the general population. We tested the hypothesis that major plasma AGEs are associated with new-onset CVD in 2 population-based cohorts of differing age and comorbidities. Methods and Results Analyses involved a random subcohort (n=466) from the Cardiovascular Health Study and a case-cohort sample (n=1631) from the Multi-Ethnic Study of Atherosclerosis. Five AGEs and 2 oxidative products were measured by liquid chromatography tandem mass spectrometry. Associations with CVD (myocardial infarction and stroke) were evaluated with Cox regression. Participants in the Cardiovascular Health Study were older than the Multi-Ethnic Study of Atherosclerosis, and had more comorbidities, along with higher levels of all AGEs. During median follow-up of 11 years, 439 participants in the Multi-Ethnic Study of Atherosclerosis and 200 in the Cardiovascular Health Study developed CVD. After multivariable adjustment, carboxymethyl-lysine, 3-deoxyglucosone hydroimidazolones and a summary variable of all measured AGEs (principal component 1) were significantly associated with incident CVD in the Cardiovascular Health Study (HRs [95% CI]: 1.20 [1.01, 1.42], 1.45 [1.23, 1.72], and 1.29 [1.06, 1.56], respectively), but not the Multi-Ethnic Study of Atherosclerosis. Oxidative products were not associated with CVD in either cohort. Conclusions We found α-dicarbonyl-derived AGEs to be associated with CVD in an older cohort, but not in a healthier middle-aged/older cohort. Our results suggest that AGEs may exert detrimental cardiovascular effects only under conditions of marked dicarbonyl and oxidative stress. Further investigation of α-dicarbonyl derivatives could lead to potential new strategies for CVD prevention in high-risk older populations.

VL - 11 IS - 15 ER - TY - JOUR T1 - PUFA ω-3 and ω-6 biomarkers and sleep: a pooled analysis of cohort studies on behalf of the Fatty Acids and Outcomes Research Consortium (FORCE). JF - Am J Clin Nutr Y1 - 2022 A1 - Murphy, Rachel A A1 - Tintle, Nathan A1 - Harris, William S A1 - Darvishian, Maryam A1 - Marklund, Matti A1 - Virtanen, Jyrki K A1 - Hantunen, Sari A1 - de Mello, Vanessa D A1 - Tuomilehto, Jaakko A1 - Lindström, Jaana A1 - Bolt, Matthew A A1 - Brouwer, Ingeborg A A1 - Wood, Alexis C A1 - Senn, Mackenzie A1 - Redline, Susan A1 - Tsai, Michael Y A1 - Gudnason, Vilmundur A1 - Eiriksdottir, Gudny A1 - Lindberg, Eva A1 - Shadyab, Aladdin H A1 - Liu, Buyun A1 - Carnethon, Mercedes A1 - Uusitupa, Matti A1 - Djoussé, Luc A1 - Riserus, Ulf A1 - Lind, Lars A1 - van Dam, Rob M A1 - Koh, Woon-Puay A1 - Shi, Peilin A1 - Siscovick, David A1 - Lemaitre, Rozenn N A1 - Mozaffarian, Dariush KW - Biomarkers KW - Cohort Studies KW - Cross-Sectional Studies KW - Fatty Acids KW - Fatty Acids, Omega-3 KW - Humans KW - Outcome Assessment, Health Care KW - Sleep AB -

BACKGROUND: n-3 and n-6 PUFAs have physiologic roles in sleep processes, but little is known regarding circulating n-3 and n-6 PUFA and sleep parameters.

OBJECTIVES: We sought to assess associations between biomarkers of n-3 and n-6 PUFA intake with self-reported sleep duration and difficulty falling sleeping in the Fatty Acids and Outcome Research Consortium.

METHODS: Harmonized, de novo, individual-level analyses were performed and pooled across 12 cohorts. Participants were 35-96 y old and from 5 nations. Circulating measures included α-linolenic acid (ALA), EPA, docosapentaenoic acid (DPA), DHA, EPA + DPA + DHA, linoleic acid, and arachidonic acid. Sleep duration (10 cohorts, n = 18,791) was categorized as short (≤6 h), 7-8 h (reference), or long (≥9 h). Difficulty falling asleep (8 cohorts, n = 12,500) was categorized as yes or no. Associations between PUFAs, sleep duration, and difficulty falling sleeping were assessed by cross-sectional multinomial logistic regression using standardized protocols and covariates. Cohort-specific multivariable-adjusted ORs per quintile of PUFAs were pooled with inverse-variance weighted meta-analysis.

RESULTS: In pooled analysis adjusted for sociodemographic characteristics and health status, participants with higher very long-chain n-3 PUFAs were less likely to have long sleep duration. In the top compared with the bottom quintiles, the multivariable-adjusted ORs (95% CIs) for long sleep were 0.78 (95% CI: 0.65, 0.95) for DHA and 0.76 (95% CI: 0.63, 0.93) for EPA + DPA + DHA. Significant associations for ALA and n-6 PUFA with short sleep duration or difficulty falling sleeping were not identified.

CONCLUSIONS: Participants with higher concentrations of very long-chain n-3 PUFAs were less likely to have long sleep duration. While objective biomarkers reduce recall bias and misclassification, the cross-sectional design limits assessment of the temporal nature of this relation. These novel findings across 12 cohorts highlight the need for experimental and biological assessments of very long-chain n-3 PUFAs and sleep duration.

VL - 115 IS - 3 ER - TY - JOUR T1 - Association between 5-year change in cardiovascular risk and the incidence of atherosclerotic cardiovascular diseases: a multi-cohort study. JF - J Transl Med Y1 - 2023 A1 - Yi, Jiayi A1 - Wang, Lili A1 - Guo, Xinli A1 - Ren, Xiangpeng KW - Atherosclerosis KW - Cardiovascular Diseases KW - Cohort Studies KW - Female KW - Heart Disease Risk Factors KW - Humans KW - Incidence KW - Male KW - Middle Aged KW - Prospective Studies KW - Risk Factors AB -

BACKGROUND: The influence of the historical cardiovascular risk status on future risk of atherosclerotic cardiovascular disease (ASCVD) is poorly understood. We aimed to investigate the association between 5-year changes in cardiovascular risk and ASCVD incidence.

METHODS: We analyzed pooled data from seven community-based prospective cohort studies with up to 20 years of follow-up data. The study populations included White or Black participants aged 40-75 years without prevalent ASCVD. Cardiovascular risk was assessed using the pooled cohort equation and was categorized into non-high (< 20%) or high risk (≥ 20%). Changes in cardiovascular disease (CVD) risk over a 5-year interval were recorded. The main outcome was incident ASCVD.

RESULTS: Among 11,026 participants (mean [SD] age, 60.0 [8.1] years), 4272 (38.7%) were female and 3127 (28.4%) were Black. During a median follow-up period of 9.9 years, 2560 (23.2%) ASCVD events occurred. In comparison with individuals showing a consistently high CVD risk, participants whose CVD risk changed from non-high to high (hazard ratio [HR], 0.67; 95% confidence interval [CI] 0.59-0.77) or high to non-high (HR, 0.57; 95% CI 0.41-0.80) and those with a consistently non-high risk (HR, 0.33; 95% CI 0.29-0.37) had a lower risk of incident ASCVD. In comparison with individuals showing a consistently non-high CVD risk, participants whose CVD risk changed from high to non-high (HR, 1.74; 95% CI 1.26-2.41) or from non-high to high risk (HR, 2.04; 95% CI 1.84-2.27) and those with a consistently high risk (HR 3.03; 95% CI 2.69-3.42) also showed an increased risk of incident ASCVD.

CONCLUSIONS: Individuals with the same current CVD risk status but different historical CVD risks exhibited varying risks of future ASCVD incidents. Dynamic risk evaluation may enable more accurate cardiovascular risk stratification, and decision-making regarding preventive interventions should take the historical risk status into account.

VL - 21 IS - 1 ER - TY - JOUR T1 - CogDrisk, ANU-ADRI, CAIDE, and LIBRA Risk Scores for Estimating Dementia Risk. JF - JAMA Netw Open Y1 - 2023 A1 - Huque, Md Hamidul A1 - Kootar, Scherazad A1 - Eramudugolla, Ranmalee A1 - Han, S Duke A1 - Carlson, Michelle C A1 - Lopez, Oscar L A1 - Bennett, David A A1 - Peters, Ruth A1 - Anstey, Kaarin J KW - Aged KW - Aged, 80 and over KW - Alzheimer Disease KW - Australia KW - Cohort Studies KW - Female KW - Heart Disease Risk Factors KW - Humans KW - Male KW - Risk Factors AB -

IMPORTANCE: While the Australian National University-Alzheimer Disease Risk Index (ANU-ADRI), Cardiovascular Risk Factors, Aging, and Dementia (CAIDE), and Lifestyle for Brain Health (LIBRA) dementia risk tools have been widely used, a large body of new evidence has emerged since their publication. Recently, Cognitive Health and Dementia Risk Index (CogDrisk) and CogDrisk for Alzheimer disease (CogDrisk-AD) risk tools have been developed for the assessment of dementia and AD risk, respectively, using contemporary evidence; comparison of the relative performance of these risk tools is limited.

OBJECTIVE: To evaluate the performance of CogDrisk, ANU-ADRI, CAIDE, LIBRA, and modified LIBRA (LIBRA with age and sex estimates from ANU-ADRI) in estimating dementia and AD risks (with CogDrisk-AD and ANU-ADRI).

DESIGN, SETTING, AND PARTICIPANTS: This population-based cohort study obtained data from the Rush Memory and Aging Project (MAP), the Cardiovascular Health Study Cognition Study (CHS-CS), and the Health and Retirement Study-Aging, Demographics and Memory Study (HRS-ADAMS). Participants who were free of dementia at baseline were included. The factors were component variables in the risk tools that included self-reported baseline demographics, medical risk factors, and lifestyle habits. The study was conducted between November 2021 and March 2023, and statistical analysis was performed from January to June 2023.

MAIN OUTCOMES AND MEASURES: Risk scores were calculated based on available factors in each of these cohorts. Area under the receiver operating characteristic curve (AUC) was calculated to measure the performance of each risk score. Multiple imputation was used to assess whether missing data may have affected estimates for dementia risk.

RESULTS: Among the 6107 participants in 3 validation cohorts included for this study, 2184 participants without dementia at baseline were available from MAP (mean [SD] age, 80.0 [7.6] years; 1606 [73.5%] female), 548 participants without dementia at baseline were available from HRS-ADAMS (mean [SD] age, 79.5 [6.3] years; 288 [52.5%] female), and 3375 participants without dementia at baseline were available from CHS-CS (mean [SD] age, 74.8 [4.9] years; 1994 [59.1%] female). In all 3 cohorts, a similar AUC for dementia was obtained using CogDrisk, ANU-ADRI, and modified LIBRA (MAP cohort: CogDrisk AUC, 0.65 [95% CI, 0.61-0.69]; ANU-ADRI AUC, 0.65 [95% CI, 0.61-0.69]; modified LIBRA AUC, 0.65 [95% CI, 0.61-0.69]; HRS-ADAMS cohort: CogDrisk AUC, 0.75 [95% CI, 0.71-0.79]; ANU-ADRI AUC, 0.74 [95% CI, 0.70-0.78]; modified LIBRA AUC, 0.75 [95% CI, 0.71-0.79]; CHS-CS cohort: CogDrisk AUC, 0.70 [95% CI, 0.67-0.72]; ANU-ADRI AUC, 0.69 [95% CI, 0.66-0.72]; modified LIBRA AUC, 0.70 [95% CI, 0.68-0.73]). The CAIDE and LIBRA also provided similar but lower AUCs than the 3 aforementioned tools (eg, MAP cohort: CAIDE AUC, 0.50 [95% CI, 0.46-0.54]; LIBRA AUC, 0.53 [95% CI, 0.48-0.57]). The performance of CogDrisk-AD and ANU-ADRI in estimating AD risks was also similar.

CONCLUSIONS AND RELEVANCE: CogDrisk and CogDrisk-AD performed similarly to ANU-ADRI in estimating dementia and AD risks. These results suggest that CogDrisk and CogDrisk-AD, with a greater range of modifiable risk factors compared with other risk tools in this study, may be more informative for risk reduction.

VL - 6 IS - 8 ER - TY - JOUR T1 - Plasma Ceramides and Sphingomyelins and Sudden Cardiac Death in the Cardiovascular Health Study. JF - JAMA Netw Open Y1 - 2023 A1 - Bockus, Lee B A1 - Jensen, Paul N A1 - Fretts, Amanda M A1 - Hoofnagle, Andrew N A1 - McKnight, Barbara A1 - Sitlani, Colleen M A1 - Siscovick, David S A1 - King, Irena B A1 - Psaty, Bruce M A1 - Sotoodehnia, Nona A1 - Lemaitre, Rozenn N KW - Aged KW - Ceramides KW - Cohort Studies KW - Death, Sudden, Cardiac KW - Eicosanoic Acids KW - Fatty Acids KW - Female KW - Humans KW - Male KW - Sphingolipids KW - Sphingomyelins AB -

IMPORTANCE: Sphingolipids, including ceramides and sphingomyelins, may influence the pathophysiology and risk of sudden cardiac death (SCD) through multiple biological activities. Whether the length of the fatty acid acylated to plasma sphingolipid species is associated with SCD risk is not known.

OBJECTIVE: To determine whether the saturated fatty acid length of plasma ceramides and sphingomyelins influences the association with SCD risk.

DESIGN, SETTING, AND PARTICIPANTS: In this cohort study, multivariable Cox proportional hazards regression models were used to examine the association of sphingolipid species with SCD risk. The study population included 4612 participants in the Cardiovascular Health Study followed up prospectively for a median of 10.2 (IQR, 5.5-11.6) years. Baseline data were collected from January 1992 to December 1995 during annual examinations. Data were analyzed from February 11, 2020, to September 9, 2023.

EXPOSURES: Eight plasma sphingolipid species (4 ceramides and 4 sphingomyelins) with saturated fatty acids of 16, 20, 22, and 24 carbons.

MAIN OUTCOME AND MEASURE: Association of plasma ceramides and sphingomyelins with saturated fatty acids of different lengths with SCD risk.

RESULTS: Among the 4612 CHS participants included in the analysis (mean [SD] age, 77 [5] years; 2724 [59.1%] women; 6 [0.1%] American Indian; 4 [0.1%] Asian; 718 [15.6%] Black; 3869 [83.9%] White, and 15 [0.3%] Other), 215 SCD cases were identified. In adjusted Cox proportional hazards regression analyses, plasma ceramides and sphingomyelins with palmitic acid (Cer-16 and SM-16) were associated with higher SCD risk per higher SD of log sphingolipid levels (hazard ratio [HR] for Cer-16, 1.34 [95% CI, 1.12-1.59]; HR for SM-16, 1.37 [95% CI, 1.12-1.67]). Associations did not differ by baseline age, sex, race, or body mass index. No significant association of SCD with sphingolipids with very-long-chain saturated fatty acids was observed after correction for multiple testing (HR for ceramide with arachidic acid, 1.06 [95% CI, 0.90-1.24]; HR for ceramide with behenic acid, 0.92 [95% CI, 0.77-1.10]; HR for ceramide with lignoceric acid, 0.92 [95% CI, 0.77-1.09]; HR for sphingomyelin with arachidic acid, 0.83 [95% CI, 0.71-0.98]; HR for sphingomyelin with behenic acid, 0.84 [95% CI, 0.70-1.00]; HR for sphingomyelin with lignoceric acid, 0.86 [95% CI, 0.72-1.03]).

CONCLUSIONS AND RELEVANCE: The findings of this large, population-based cohort study of SCD identified that higher plasma levels of Cer-16 and SM-16 were associated with higher risk of SCD. Future studies are needed to examine the underlying mechanism of these associations.

VL - 6 IS - 11 ER - TY - JOUR T1 - Validation of the CogDrisk Instrument as Predictive of Dementia in Four General Community-Dwelling Populations. JF - J Prev Alzheimers Dis Y1 - 2023 A1 - Kootar, S A1 - Huque, M H A1 - Eramudugolla, R A1 - Rizzuto, D A1 - Carlson, M C A1 - Odden, M C A1 - Lopez, O L A1 - Qiu, C A1 - Fratiglioni, L A1 - Han, S D A1 - Bennett, D A A1 - Peters, R A1 - Anstey, K J KW - Aging KW - Alzheimer Disease KW - Cohort Studies KW - Dementia KW - Humans KW - Independent Living AB -

BACKGROUND: Lack of external validation of dementia risk tools is a major limitation for generalizability and translatability of prediction scores in clinical practice and research.

OBJECTIVES: We aimed to validate a new dementia prediction risk tool called CogDrisk and a version, CogDrisk-AD for predicting Alzheimer's disease (AD) using cohort studies.

DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS: Four cohort studies were identified that included majority of the dementia risk factors from the CogDrisk tool. Participants who were free of dementia at baseline were included. The predictors were component variables in the CogDrisk tool that include self-reported demographics, medical risk factors and lifestyle habits. Risk scores for Any Dementia and AD were computed and Area Under the Curve (AUC) was assessed. To examine modifiable risk factors for dementia, the CogDrisk tool was tested by excluding age and sex estimates from the model.

RESULTS: The performance of the tool varied between studies. The overall AUC and 95% CI for predicting dementia was 0.77 (0.57, 0.97) for the Swedish National study on Aging and Care in Kungsholmen, 0.76 (0.70, 0.83) for the Health and Retirement Study - Aging, Demographics and Memory Study, 0.70 (0.67,0.72) for the Cardiovascular Health Study Cognition Study, and 0.66 (0.62,0.70) for the Rush Memory and Aging Project.

CONCLUSIONS: The CogDrisk and CogDrisk-AD performed well in the four studies. Overall, this tool can be used to assess individualized risk factors of dementia and AD in various population settings.

VL - 10 IS - 3 ER -