%0 Conference Proceedings %B ACC %D 1992 %T Respondent Burden in Studies of the Elderly: Experience from the Cardiovascular Health Study (CHS) %A Manolio, TA %A Hermanson, B %A Hill, J %A Meyer, M %A Cruise, G %A Anton-Culver, H %K Health %K respondent burden %X ACC Workshop entitled "Inclusion of Elderly Individuals in Clinical Trials" September 15-16, 1992 %B ACC %I Marion Merrell Dow Inc %P 135-152 %8 1993-01-01 %G eng %0 Journal Article %J Ann Epidemiol %D 1993 %T Recruitment of adults 65 years and older as participants in the Cardiovascular Health Study. %A Tell, G S %A Fried, L P %A Hermanson, B %A Manolio, T A %A Newman, A B %A Borhani, N O %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cohort Studies %K Epidemiologic Methods %K Female %K Humans %K Male %X

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)

%B Ann Epidemiol %V 3 %P 358-66 %8 1993 Jul %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/8275211?dopt=Abstract %0 Journal Article %J Circulation %D 1994 %T 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. %A Tell, G S %A Polak, J F %A Ward, B J %A Kittner, S J %A Savage, P J %A Robbins, J %K Aged %K Aged, 80 and over %K Carotid Arteries %K Carotid Stenosis %K Cohort Studies %K Female %K Humans %K Male %K Smoking %K Ultrasonography %X

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.

%B Circulation %V 90 %P 2905-8 %8 1994 Dec %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/7994837?dopt=Abstract %0 Journal Article %J Am J Respir Crit Care Med %D 1994 %T Respiratory muscle strength in the elderly. Correlates and reference values. Cardiovascular Health Study Research Group. %A Enright, P L %A Kronmal, R A %A Manolio, T A %A Schenker, M B %A Hyatt, R E %K Aged %K Aged, 80 and over %K Aging %K Body Constitution %K Cardiovascular Diseases %K Female %K Humans %K Male %K Prospective Studies %K Reference Values %K Respiratory Function Tests %K Respiratory Muscles %K Risk Factors %K Sex Characteristics %K Smoking %X

Maximal inspiratory pressure (MIP) was assessed in 4,443 ambulatory participants of the Cardiovascular Health Study, 65 yr of age and older, sampled from four communities. Maximal expiratory pressure (MEP) was also measured in 790 participants from a single clinic. Positive predictors of MIP included male sex, FVC, handgrip strength, and higher levels of lean body mass (or low bioelectric resistance). Negative predictors were age, current smoking, self-reported fair to poor general health, and waist size. Both participant and technician learning effects were noted, but there was no independent effect of race, hypertension, cardiovascular disease, or diabetes. A healthy subgroup was identified by excluding current smokers, those with fair to poor general health, or an FEV1 less than 65% of predicted. Mean values determined from the healthy group were 57/116 cm H2O (MIP/MEP) for women, and 83/174 for men. Lower limits of the normal range (fifth percentiles) were 45 to 60% of the mean predicted values. The reference equations derived from this group of healthy 65 to 85-yr-olds may be used by pulmonary function laboratories and respiratory therapists who evaluate the respiratory muscle strength of elderly patients.

%B Am J Respir Crit Care Med %V 149 %P 430-8 %8 1994 Feb %G eng %N 2 Pt 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/8306041?dopt=Abstract %R 10.1164/ajrccm.149.2.8306041 %0 Journal Article %J Chest %D 1995 %T Reduced vital capacity in elderly persons with hypertension, coronary heart disease, or left ventricular hypertrophy. The Cardiovascular Health Study. %A Enright, P L %A Kronmal, R A %A Smith, V E %A Gardin, J M %A Schenker, M B %A Manolio, T A %K Age Factors %K Aged %K Aged, 80 and over %K Coronary Disease %K Female %K Forced Expiratory Volume %K Humans %K Hypertension %K Hypertrophy, Left Ventricular %K Male %K Middle Aged %K Ventricular Function, Left %K Vital Capacity %X

The Cardiovascular Health Study provided the opportunity to determine the association of subclinical and clinical cardiovascular disease with pulmonary function in a population sample of elderly adults. Included were 2,955 women and 2,246 men over age 64 years who were recruited for this observational study from four communities and completed extensive examinations that included spirometry, echocardiograms, and blood pressure. Current smokers, past smokers with >20 pack-years of smoking, and persons with a history of asthma, chronic bronchitis, or emphysema were excluded from this analysis, leaving 2,784 (55%) of the cohort. Systolic hypertension or coronary artery disease was associated with 40- to 100-mL decrements in FEV1, and 50- to 150-mL decrements in FVC, while a history of congestive heart failure was associated with 200 to 300 mL lower FEV1 and FVC values (p < 0.0001), after correcting for age, height, and waist size. Higher left ventricular (LV) mass was also significantly associated with a decrease in FEV1 and FVC in multivariate models. This relationship was strongest with the end-diastolic LV posterior wall thickness component of LV mass. In summary, FEV1 and FVC are reduced in elderly persons with hypertension, ischemic heart disease, higher disease, higher LV mass, and congestive heart failure, though the magnitude of these associations is relatively small unless heart failure supervenes. Substantial decrements in percent predicted FEV1 and FVC should not be attributed to the presence of uncomplicated ischemic heart disease or hypertension alone.

%B Chest %V 107 %P 28-35 %8 1995 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/7813294?dopt=Abstract %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 1996 %T Risk factors for abdominal aortic aneurysms in older adults enrolled in The Cardiovascular Health Study. %A Alcorn, H G %A Wolfson, S K %A Sutton-Tyrrell, K %A Kuller, L H %A O'Leary, D %K Aged %K Anthropometry %K Aortic Aneurysm, Abdominal %K Blood Pressure %K Cardiovascular Diseases %K Cohort Studies %K Comorbidity %K Female %K Humans %K Male %K Middle Aged %K Pilot Projects %K Prevalence %K Reproducibility of Results %K Risk Factors %K Smoking %K Ultrasonography %K United States %X

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.

%B Arterioscler Thromb Vasc Biol %V 16 %P 963-70 %8 1996 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/8696960?dopt=Abstract %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 1997 %T Relationship of C-reactive protein to risk of cardiovascular disease in the elderly. Results from the Cardiovascular Health Study and the Rural Health Promotion Project. %A Tracy, R P %A Lemaitre, R N %A Psaty, B M %A Ives, D G %A Evans, R W %A Cushman, M %A Meilahn, E N %A Kuller, L H %K Aged %K Aging %K C-Reactive Protein %K Cardiovascular Diseases %K Case-Control Studies %K Female %K Humans %K Male %K Prospective Studies %K Sex Factors %X

Markers of inflammation, such as C-reactive protein (CRP), are related to risk of cardiovascular disease (CVD) events in those with angina, but little is known about individuals without prevalent clinical CVD. We performed a prospective, nested case-control study in the Cardiovascular Health Study (CHS; 5201 healthy elderly men and women). Case subjects (n = 146 men and women with incident CVD events including angina, myocardial infarction, and death) and control subjects (n = 146) were matched on the basis of sex and the presence or absence of significant subclinical CVD at baseline (average follow-up, 2.4 years). In women but not men, the mean CRP level was higher for case subjects than for control subjects (P < or = .05). In general, CRP was higher in those with subclinical disease. Most of the association of CRP with female case subjects versus control subjects was in the subgroup with subclinical disease; 3.33 versus 1.90 mg/L, P < .05, adjusted for age and time of follow-up. Case-control differences were greatest when the time between baseline and the CVD event was shortest. The strongest associations were with myocardial infarction, and there was an overall odds ratio for incident myocardial infarction for men and women with subclinical disease (upper quartile versus lower three quartiles) of 2.67 (confidence interval [CI] = 1.04 to 6.81), with the relationship being stronger in women (4.50 [CI = 0.97 to 20.8]) than in men (1.75 [CI = 0.51 to 5.98]). We performed a similar study in the Rural Health Promotion Project, in which mean values of CRP were higher for female case subjects than for female control subjects, but no differences were apparent for men. Comparing the upper quintile with the lower four, the odds ratio for CVD case subjects was 2.7 (CI = 1.10 to 6.60). In conclusion, CRP was associated with incident events in the elderly, especially in those with subclinical disease at baseline.

%B Arterioscler Thromb Vasc Biol %V 17 %P 1121-7 %8 1997 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/9194763?dopt=Abstract %0 Journal Article %J Stroke %D 1998 %T Relationship between ApoE, MRI findings, and cognitive function in the Cardiovascular Health Study. %A Kuller, L H %A Shemanski, L %A Manolio, T %A Haan, M %A Fried, L %A Bryan, N %A Burke, G L %A Tracy, R %A Bhadelia, R %K African Continental Ancestry Group %K Aged %K Apolipoproteins E %K Brain %K Cardiovascular Diseases %K Cerebral Infarction %K Cognition %K Cognition Disorders %K European Continental Ancestry Group %K Female %K Genotype %K Health Status %K Humans %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Polymerase Chain Reaction %K Risk Factors %K Sex Factors %K United States %X

BACKGROUND AND PURPOSE: We determined the relationship between apolipoprotein (Apo)E, MRI, and low cognitive scores.

METHODS: The relationship between age, education, ApoE genotype, MRI examination of the brain, subclinical and clinical cardiovascular disease, and low (<80) score on the Modified Mini-Mental State Examination (3MSE, as modified by Teng and Chui) was evaluated for 3469 black and white participants in the Cardiovascular Health Study (CHS) in years 5 and 6 of the study. The participants were followed for up to 3 years.

RESULTS: The prevalence of scores <80 in years 5 and 6 of the CHS was 8.2% for participants without and 20.4% for those with prior history of stroke. Age, race, and education were important determinants of low 3MSE scores. The prevalence of ApoE-4 (odds ratio [OR], 1.6 [1.1 to 2.1]) was directly related to scores <80, as was high ventricular volume (OR, 1.6 [1.2 to 2.3]), high white matter grade (OR, 1.4 [1.1 to 1.9]), and infarctlike lesions (OR, 1.6 [1.2 to 2.1]) on the MRI in the multivariate analysis. A five-point or greater decline in scores over up to 3 years was more often observed for participants with low 3MSE scores at year 5, at older ages, with lower education, and experiencing incident stroke (OR, 3.6 [1.2 to 10.6]), ApoE-4 genotype (OR, 1.8 [1.4 to 2.3]), and with MRI findings of high ventricular volume (OR, 2.0 [1.5 to 2.7]), and infarctlike lesions (OR, 1.2 [0.9 to 1.5]).

CONCLUSIONS: These results demonstrate that vascular changes on MRI, measures of brain atrophy, ApoE-4, and age, education, and race are associated with low cognitive scores among older individuals. The MRI of the brain provides valuable information related to cognitive tests and decline over time. The potential exists for using MRI measurements to identify high-risk individuals for dementia and to test potential interventions to reduce the risk of dementia.

%B Stroke %V 29 %P 388-98 %8 1998 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/9472879?dopt=Abstract %0 Journal Article %J Arch Neurol %D 1998 %T Relationship between balance and abnormalities in cerebral magnetic resonance imaging in older adults. %A Tell, G S %A Lefkowitz, D S %A Diehr, P %A Elster, A D %K Accidental Falls %K Aged %K Aging %K Cerebral Cortex %K Female %K Humans %K Magnetic Resonance Imaging %K Male %K Postural Balance %K Risk Factors %X

BACKGROUND: Falling is a major cause of disability and morbidity among older adults. Because poor balance is a major reason for frequent falls, assessment of balance and its risk factors are important. In this study, we postulated that cerebral changes identified on magnetic resonance (MR) imaging are related to balance, and that older adults with balance problems would have significantly greater prevalence of such brain abnormalities than older adults without balance problems.

DESIGN AND MEASUREMENTS: Several measures of balance were examined in more than 700 community-dwelling older men and women, blacks and whites. Balance measures included dynamic posturography, functional reach, Romberg and 1-foot stand tests, tandem stand, and 1-foot stand. Cerebral MR imaging assessments included ventricular size, sulcal widening, white matter disease, and ischemic infarctions. Cardiovascular disease and hypertension were determined and controlled for in the analyses.

RESULTS: A summary of the balance measures was significantly related to each of the 4 MR imaging measures, with those with poorer balance having more disease. The strongest associations with balance were seen for white matter disease and ventricular size. All but the ischemic infarction variable remained significantly associated with balance after adjustments for sex, race, age, cardiovascular disease, and hypertension.

CONCLUSION: Cerebral changes identified by MR imaging are associated with poorer balance among older adults.

%B Arch Neurol %V 55 %P 73-9 %8 1998 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/9443713?dopt=Abstract %0 Journal Article %J Sleep %D 1998 %T Reliability of scoring respiratory disturbance indices and sleep staging. %A Whitney, C W %A Gottlieb, D J %A Redline, S %A Norman, R G %A Dodge, R R %A Shahar, E %A Surovec, S %A Nieto, F J %K Humans %K Polysomnography %K Reproducibility of Results %K Research Design %K Sleep Apnea Syndromes %K Sleep Stages %X

STUDY OBJECTIVES: Unattended, home-based polysomnography (PSG) is increasingly used in both research and clinical settings as an alternative to traditional laboratory-based studies, although the reliability of the scoring of these studies has not been described. The purpose of this study is to describe the reliability of the PSG scoring in the Sleep Heart Health Study (SHHS), a multicenter study of the relation between sleep-disordered breathing measured by unattended, in-home PSG using a portable sleep monitor, and cardiovascular outcomes.

DESIGN: The reliability of SHHS scorers was evaluated based on 20 randomly selected studies per scorer, assessing both interscorer and intrascorer reliability.

RESULTS: Both inter- and intrascorer comparisons on epoch-by-epoch sleep staging showed excellent reliability (kappa statistics >0.80), with stage 1 having the greatest discrepancies in scoring and stage 3/4 being the most reliably discriminated. The arousal index (number of arousals per hour of sleep) was moderately reliable, with an intraclass correlation (ICC) of 0.54. The scorers were highly reliable on various respiratory disturbance indices (RDIs), which incorporate an associated oxygen desaturation in the definition of respiratory events (2% to 5%) with or without the additional use of associated EEG arousal in the definition of respiratory events (ICC>0.90). When RDI was defined without considering oxygen desaturation or arousals to define respiratory events, the RDI was moderately reliable (ICC=0.74). The additional use of associated EEG arousals, but not oxygen desaturation, in defining respiratory events did little to increase the reliability of the RDI measure (ICC=0.77).

CONCLUSIONS: The SHHS achieved a high degree of intrascorer and interscorer reliability for the scoring of sleep stage and RDI in unattended in-home PSG studies.

%B Sleep %V 21 %P 749-57 %8 1998 Nov 01 %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/11286351?dopt=Abstract %R 10.1093/sleep/21.7.749 %0 Journal Article %J JAMA %D 1998 %T Risk factors for 5-year mortality in older adults: the Cardiovascular Health Study. %A Fried, L P %A Kronmal, R A %A Newman, A B %A Bild, D E %A Mittelmark, M B %A Polak, J F %A Robbins, J A %A Gardin, J M %K African Americans %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cohort Studies %K Female %K Follow-Up Studies %K Health Surveys %K Humans %K Male %K Mortality %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K United States %X

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.

%B JAMA %V 279 %P 585-92 %8 1998 Feb 25 %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/9486752?dopt=Abstract %0 Journal Article %J J Gerontol B Psychol Sci Soc Sci %D 1998 %T The role of neuroticism and mastery in spouse caregivers' assessment of and response to a contextual stressor. %A Bookwala, J %A Schulz, R %K Aged %K Caregivers %K Depression %K Female %K Humans %K Male %K Neurotic Disorders %K Personality %K Personality Assessment %K Stress, Psychological %X

Data from more than 300 spousal caregivers and their care recipients were analyzed to demonstrate the effects of caregivers' personality attributes--neuroticism and mastery--on their assessment of a contextual stressor (the care recipient's behavioral and functional impairment) and on their experience of distress associated with that stressor. Caregivers who were high in neuroticism and/or low in mastery reported higher levels of behavioral and functional impairment in their disabled spouse and experienced more strain and depressive symptoms associated with caregiving relative to caregivers with lower neuroticism or higher mastery scores. We further showed that the widely reported association between caregiver-assessed impairment of the care recipient and caregiver outcomes can in part be explained by caregivers' personality attributes, such as neuroticism and mastery. Our findings that caregivers' personality variables are related to their assessment of a given objective stressor and their response to a given level of stress have implications for interventions targeting caregivers and for the use of caregivers as proxy informants.

%B J Gerontol B Psychol Sci Soc Sci %V 53 %P P155-64 %8 1998 May %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/9602831?dopt=Abstract %0 Journal Article %J Neurology %D 1999 %T Relation of education to brain size in normal aging: implications for the reserve hypothesis. %A Coffey, C E %A Saxton, J A %A Ratcliff, G %A Bryan, R N %A Lucke, J F %K Aged %K Aged, 80 and over %K Atrophy %K Brain %K Cerebral Cortex %K Cerebrospinal Fluid %K Educational Status %K Female %K Functional Laterality %K Health Status %K Humans %K Magnetic Resonance Imaging %K Male %K Mental Status Schedule %K Regression Analysis %K Sex Characteristics %X

OBJECTIVE: To examine the relations between education and age-related changes in brain structure in a nonclinical sample of elderly adults.

BACKGROUND: Education may protect against cognitive decline in late life--an observation that has led to the "reserve" hypothesis of brain aging. Little is known, however, about the effect of education on age-related changes in brain structure.

METHODS: Quantitative MRI of the brain was performed in 320 elderly volunteers (age range, 66 to 90 years) living independently in the community (Mini-Mental State Examination scores > or =24), all of whom were participants in the Cardiovascular Health Study. Blinded measurements of global and regional brain size were made from T1-weighted axial images using computer-assisted edge detection and trace methodology. High measurement reliabilities were obtained.

RESULTS: Regression analyses (adjusting for the effects of intracranial size, sex, age, age-by-sex interactions, and potential confounders) revealed significant main effects of education on peripheral (sulcal) CSF volume-a marker of cortical atrophy. Each year of education was associated with an increase in peripheral CSF volume of 1.77 mL (p<0.03). As reported previously, main effects of age (but not education) were observed for all of the remaining brain regions examined, including cerebral hemisphere volume, frontal region area, temporoparietal region area, parieto-occipital region area, lateral (Sylvian) fissure volume, lateral ventricular volume, and third ventricle volume.

CONCLUSIONS: The authors' findings demonstrate a relation between education and age-related cortical atrophy in a nonclinical sample of elderly persons, and are consistent with the reserve hypothesis as well as with a small number of brain imaging studies in patients with dementia. The neurobiological basis and functional correlates of this education effect require additional investigation.

%B Neurology %V 53 %P 189-96 %8 1999 Jul 13 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/10408558?dopt=Abstract %R 10.1212/wnl.53.1.189 %0 Journal Article %J Am J Respir Crit Care Med %D 1999 %T Relation of sleepiness to respiratory disturbance index: the Sleep Heart Health Study. %A Gottlieb, D J %A Whitney, C W %A Bonekat, W H %A Iber, C %A James, G D %A Lebowitz, M %A Nieto, F J %A Rosenberg, C E %K Aged %K Cardiovascular Diseases %K Cross-Sectional Studies %K Disorders of Excessive Somnolence %K Female %K Humans %K Male %K Middle Aged %K Polysomnography %K Respiration %K Retrospective Studies %K Severity of Illness Index %K Sleep Apnea Syndromes %K Surveys and Questionnaires %X

Obstructive sleep apnea syndrome is a well recognized cause of excessive sleepiness; however, the relation of sleepiness to mild sleep-disordered breathing (SDB), which affects as much as half the adult population, is uncertain. In order to explore this relation, we conducted a cross-sectional cohort study of community-dwelling adults participating in the Sleep Heart Health Study, a longitudinal study of the cardiovascular consequences of SDB. The study sample comprises 886 men and 938 women, with a mean age of 65 (SD 11) yr. Sleepiness was quantified using the Epworth Sleepiness Scale (ESS). Sleep-disordered breathing was quantified by the respiratory disturbance index (RDI), defined as the number of apneas plus hypopneas per hour of sleep, measured during in-home polysomnography. When RDI was categorized into four groups (< 5, 5 to < 15, 15 to < 30, >/= 30), a significantly progressive increase in mean ESS score was seen across all four levels of SDB, from 7.2 (4.3) in subjects with RDI < 5 to 9.3 (4.9) in subjects with RDI >/= 30 (p < 0.001). There was no significant modification of this effect by age, sex, body mass index, or evidence of chronic restriction of sleep time or periodic limb movement disorder. The percentage of subjects with excessive sleepiness, defined as an ESS score >/= 11, increased from 21% in subjects with RDI < 5 to 35% in those with RDI >/= 30 (p < 0. 001). We conclude that SDB is associated with excess sleepiness in community-dwelling, middle-aged and older adults, not limited to those with clinically apparent sleep apnea.

%B Am J Respir Crit Care Med %V 159 %P 502-7 %8 1999 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/9927364?dopt=Abstract %R 10.1164/ajrccm.159.2.9804051 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 1999 %T The relationship of fibrinogen and factors VII and VIII to incident cardiovascular disease and death in the elderly: results from the cardiovascular health study. %A Tracy, R P %A Arnold, A M %A Ettinger, W %A Fried, L %A Meilahn, E %A Savage, P %K Aged %K Cardiovascular Diseases %K Factor VII %K Factor VIII %K Female %K Fibrinogen %K Humans %K Male %K Multivariate Analysis %K Risk Factors %X

Little is known about the prospective associations of fibrinogen, factor VII, or factor VIII with cardiovascular disease (CVD) and mortality in the elderly. At baseline in the Cardiovascular Health Study (5888 white and African American men and women; aged >/=65 years), we measured fibrinogen, factor VIII, and factor VII. We used sex-stratified stepwise Cox survival analysis to determine relative risks (RRs) for CVD events and all-cause mortality (up to 5 years of follow-up), both unadjusted and adjusted for CVD risk factors and subclinical CVD. After adjustment, comparing the fifth quintile to the first, fibrinogen was significantly associated in men with coronary heart disease events (RR=2.1) and stroke or transient ischemic attack (RR=1.3), and also with mortality within 2.5 years of follow-up (RR=5.8) and later (RR=1.7). Factor VIII was significantly associated in men with coronary heart disease events (RR=1.5) and mortality (RR=1.8), and in women with stroke/transient ischemic attack (RR=1.4). For both factors, values were higher in those who died, whether causes were CVD-related or non-CVD-related, but highest in CVD death. Factor VII exhibited associations with incident angina (RR=1.44) in men and with death in women (RR, middle quintile compared with first=0.66). However, in general, factor VII was not consistently associated with CVD events in this population. We conclude that, if confirmed in other studies, the measurement of fibrinogen and/or factor VIII may help identify older individuals at higher risk for CVD events and mortality.

%B Arterioscler Thromb Vasc Biol %V 19 %P 1776-83 %8 1999 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/10397698?dopt=Abstract %R 10.1161/01.atv.19.7.1776 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 1999 %T Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women. %A Sakkinen, P A %A Cushman, M %A Psaty, B M %A Rodriguez, B %A Boineau, R %A Kuller, L H %A Tracy, R P %K Aged %K Aged, 80 and over %K alpha-2-Antiplasmin %K Antifibrinolytic Agents %K Asian Continental Ancestry Group %K Cohort Studies %K Coronary Disease %K Diabetes Mellitus, Type 2 %K European Continental Ancestry Group %K Female %K Fibrinolysin %K Fibrinolysis %K Humans %K Insulin Resistance %K Male %K Multivariate Analysis %K Myocardial Infarction %K Plasminogen Activator Inhibitor 1 %K Risk Factors %X

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, %B Arterioscler Thromb Vasc Biol %V 19 %P 499-504 %8 1999 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/10073949?dopt=Abstract %R 10.1161/01.atv.19.3.499 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 1999 %T Relationships of cerebral MRI findings to ultrasonographic carotid atherosclerosis in older adults : the Cardiovascular Health Study. CHS Collaborative Research Group. %A Manolio, T A %A Burke, G L %A O'Leary, D H %A Evans, G %A Beauchamp, N %A Knepper, L %A Ward, B %K Aged %K Arteriosclerosis %K Brain %K Cardiovascular System %K Carotid Artery Diseases %K Cerebral Infarction %K Cohort Studies %K Cross-Sectional Studies %K Echoencephalography %K Female %K Health Status %K Humans %K Magnetic Resonance Imaging %K Male %K Prevalence %X

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.

%B Arterioscler Thromb Vasc Biol %V 19 %P 356-65 %8 1999 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/9974419?dopt=Abstract %0 Journal Article %J J Clin Epidemiol %D 1999 %T The reliability of medication inventory methods compared to serum levels of cardiovascular drugs in the elderly. %A Smith, N L %A Psaty, B M %A Heckbert, S R %A Tracy, R P %A Cornell, E S %K Aged %K Aspirin %K Cardiovascular Agents %K Digoxin %K Humans %K Hydrochlorothiazide %K Patient Compliance %K Propranolol %K Reproducibility of Results %X

Medication inventory is more reliable than self-report in assessing prescription drug use in elderly populations. It is not known how strongly medication inventory reflects actual medication use as measured by serum drug levels. In the Cardiovascular Health Study, medication data were collected annually by study interviewers from medication containers brought to the clinic visit. At the fourth clinic visit, venipuncture was performed under 12-hour fasting conditions. Participants were told to take medications as usual. Based on medication inventory results, we randomly selected 55 users and 55 non-users of four cardiovascular drugs: aspirin, propranolol, hydrochlorothiazide, and digoxin. All 110 blood samples for each of the four drugs were analyzed; cut points were based on detectable levels given laboratory limitations. Kappa statistics (K) tested degree of agreement between medication inventory findings and serum detection. Assays were completed on 400 samples (91%). Agreement for aspirin (n=102) was poor: K=0.16 (95% CI: 0.0-0.32). Agreement for propranolol (n = 98) was fair: K=0.43 (95% CI: 0.27-0.59). Agreement for hydrochlorothiazide (n=100) was good: K=0.62 (95% CI: 0.53-0.91). Agreement for digoxin (n=100) was excellent: K=0.94 (95% CI: 0.74-1.0). For four all drugs, lack of agreement was confined primarily to participants who reported use but did not have detectable levels. Excluding aspirin users, only one non-user (0.7%) had drug detected in serum. The medication inventory is a reasonably sensitive and a fairly reliable method for ascertaining non-aspirin cardiovascular drug use in the elderly even though this method may overestimate use as assessed by serum level.

%B J Clin Epidemiol %V 52 %P 143-6 %8 1999 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/10201655?dopt=Abstract %R 10.1016/s0895-4356(98)00141-3 %0 Journal Article %J JAMA %D 1999 %T The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons. %A Haan, M N %A Shemanski, L %A Jagust, W J %A Manolio, T A %A Kuller, L %K Aged %K Aging %K Alleles %K Apolipoproteins E %K Cardiovascular Diseases %K Cognition Disorders %K Cohort Studies %K Diabetes Mellitus %K Genotype %K Humans %K Mental Status Schedule %K Prospective Studies %K Risk Factors %X

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.

%B JAMA %V 282 %P 40-6 %8 1999 Jul 07 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/10404910?dopt=Abstract %R 10.1001/jama.282.1.40 %0 Journal Article %J J Electrocardiol %D 2000 %T Race- and sex-specific ECG models for left ventricular mass in older populations. Factors influencing overestimation of left ventricular hypertrophy prevalence by ECG criteria in African-Americans. %A Rautaharju, P M %A Park, L P %A Gottdiener, J S %A Siscovick, D %A Boineau, R %A Smith, V %A Powe, N R %K African Continental Ancestry Group %K Age Factors %K Aged %K Anthropometry %K Electrocardiography %K European Continental Ancestry Group %K Female %K Humans %K Hypertrophy, Left Ventricular %K Male %K Predictive Value of Tests %K Prevalence %K Sex Factors %K Ultrasonography %X

The validity of the reported high prevalence of left ventricular hypertrophy (LVH) among African-American men and women has been questioned owing to conflicting echocardiographic evidence. We used echocardiographic left ventricular mass (LVM) from M-mode measurements to evaluate associations between LVM, body size, and electrocardiographic (ECG) variables in 3,627 white and African-American men and women 65 years of age and older who were participants of the Cardiovascular Health Study (CHS), a multicenter cohort study of risk factors for coronary heart disease and stroke. ECG amplitudes used in LVH criteria were substantially higher in African-Americans, with apparent LVH prevalence 2 to 3 times higher in African American men and women than in white men and women, although there was no significant racial difference in echocardiographic LVM. The higher apparent LVH prevalence by Sokolow-Lyon criteria in African-American men is in part owing to smaller lateral chest diameter. In women, reasons for racial differences in ECG LVH prevalence remain largely unexplained although a small part of the excess LVH in African-American women by the Sokolow-Lyon criteria appears to be owing to a larger lateral chest semidiameter in white women. ECG variables alone were too inaccurate for LVM prediction, and it was necessary to incorporate in all ECG models body weight that was properly adjusted for race and sex. This resulted in modest LVM prediction accuracy, with R-square values ranging from .22 to .36. Race- and sex-specific ECG models introduced for LVM estimation with an appropriate adjustment for body size differences are expected to facilitate evaluation of LVH status in contrasting racial population groups.

%B J Electrocardiol %V 33 %P 205-18 %8 2000 Jul %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/10954373?dopt=Abstract %R 10.1054/jelc.2000.7667 %0 Journal Article %J Sleep %D 2000 %T Rates of sensor loss in unattended home polysomnography: the influence of age, gender, obesity, and sleep-disordered breathing. %A Kapur, V K %A Rapoport, D M %A Sanders, M H %A Enright, P %A Hill, J %A Iber, C %A Romaniuk, J %K Age Factors %K Cross-Sectional Studies %K Electroencephalography %K Electromyography %K Electrooculography %K Equipment Failure %K Female %K Humans %K Male %K Middle Aged %K Obesity %K Polysomnography %K Prospective Studies %K Severity of Illness Index %K Sex Factors %K Sleep Apnea Syndromes %X

OBJECTIVES: To evaluate study failure and sensor loss in unattended home polysomnography and their relationship to age, gender, obesity, and severity of sleep-disordered breathing (SDB).

DESIGN: A cross-sectional analysis of data gathered prospectively for the Sleep Heart Health Study (SHHS).

SETTING: Unattended polysomnography was performed in participants' homes by the staff of the sites that are involved in SHHS.

PARTICIPANTS: 6,802 individuals who met the inclusion criteria (age >40 years, no history of treatment of sleep apnea, no tracheostomy, no current home oxygen therapy) for SHHS.

RESULTS: A total of 6802 participants had 7151 studies performed. 6161 of 6802 initial studies (90.6%) were acceptable. Obesity was associated with a decreased likelihood of a successful initial study. After one or more attempts, 6440 participants (94.7%) had studies that were judged as acceptable. The mean duration of scorable signals for specific channels ranged from 5.7 to 6.8 hours. The magnitudes of the effects of age, gender, BMI, and RDI on specific signal durations were not clinically significant.

CONCLUSION: Unattended home PSG as performed for SHHS was usually successful. Participant characteristics had very weak associations with duration of scorable signal. This study suggests that unattended home PSG, when performed with proper protocols and quality controls, has reasonable success rates and signal quality for the evaluation of SDB in clinical and research settings.

%B Sleep %V 23 %P 682-8 %8 2000 Aug 01 %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/10947036?dopt=Abstract %0 Journal Article %J J Hypertens %D 2001 %T Relation of hemodynamics and risk factors to ventricular-vascular interactions in the elderly: the Cardiovascular Health Study. %A de Simone, G %A McClelland, R %A Gottdiener, J S %A Celentano, A %A Kronmal, R A %A Gardin, J M %K Aged %K Aged, 80 and over %K Blood Pressure %K Carotid Arteries %K Compliance %K Cross-Sectional Studies %K Echocardiography %K Female %K Hemodynamics %K Humans %K Hypertension %K Hypertrophy, Left Ventricular %K Male %K Reference Values %K Risk Factors %K Stroke Volume %K Tunica Intima %K Tunica Media %K Ventricular Function, Left %X

OBJECTIVE: To investigate the interaction between left ventricular (LV) geometry, carotid structure and arterial compliance in relation to hemodynamic stimuli and risk factors (plasma cholesterol, body mass index, insulin resistance, smoking habit, age, sex and race).

DESIGN: Cross-sectional.

METHODS: Echocardiography and carotid ultrasound were performed in 2375 elderly subjects without signs or history of prevalent cardiovascular disease, diabetes or renal disease (795 men; 298 non-whites; 1215 hypertensive), from the cohort of the Cardiovascular Health Study. Arterial compliance was estimated by the prognostically validated ratio of stroke volume to pulse pressure (SV/PP) as the percent deviation (Delta%) from the value predicted by individual age, heart rate and body weight.

RESULTS: Intima-medial thickness (IMT) was higher in the presence of LV hypertrophy (LVH) in normotensive and hypertensive subjects and was greatest in the presence of concentric LVH. Maximum carotid lumen diameter (CLD) was also higher in the presence of LVH (and was greatest with eccentric LVH, in association with relatively high values for stroke volume). After adjusting for blood pressure, maximum carotid lumen diameter was directly correlated with stroke volume, and IMT to LV mass (all P < 0.001). Similarly, IMT was also related to maximum carotid lumen diameter, independently of prevalent risk factors (P < 0.001). SV/PP-Delta% was reduced in both groups with concentric LV remodeling (both P < 0.0001) or concentric LVH (both P < 0.05). Adjusting for risk factors did not affect these associations in normotensives, but made them insignificant in hypertensives. In normotensives, IMT was inversely related to SV/PP-Delta% (P < 0.001), independently of risk factors, whereas no significant relation was found in hypertensives.

CONCLUSIONS: The magnitudes of carotid intima-medial thickness and lumen diameter parallel levels of LV mass and geometry, and are directly related to stroke volume and arterial stiffness; this interaction is most evident in the presence of normal blood pressure, whereas it is affected by other cardiovascular risk factors when arterial hypertension is present.

%B J Hypertens %V 19 %P 1893-903 %8 2001 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/11593112?dopt=Abstract %R 10.1097/00004872-200110000-00026 %0 Journal Article %J Diabetes %D 2001 %T The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. %A Barzilay, J I %A Abraham, L %A Heckbert, S R %A Cushman, M %A Kuller, L H %A Resnick, H E %A Tracy, R P %K Aged %K Biomarkers %K Blood Glucose %K C-Reactive Protein %K Cardiovascular Diseases %K Cohort Studies %K Diabetes Mellitus %K Female %K Humans %K Hypoglycemia %K Inflammation %K Longitudinal Studies %K Male %K Reference Values %K Risk Factors %X

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.

%B Diabetes %V 50 %P 2384-9 %8 2001 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/11574423?dopt=Abstract %R 10.2337/diabetes.50.10.2384 %0 Journal Article %J Am J Epidemiol %D 2001 %T Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. %A Newman, A B %A Nieto, F J %A Guidry, U %A Lind, B K %A Redline, S %A Pickering, T G %A Quan, S F %K Adult %K Aged %K Analysis of Variance %K Cardiovascular Diseases %K Chi-Square Distribution %K Cross-Sectional Studies %K Female %K Humans %K Linear Models %K Longitudinal Studies %K Male %K Middle Aged %K Polysomnography %K Risk Factors %K Sleep Apnea Syndromes %K United States %X

Associations between sleep-disordered breathing and cardiovascular disease (CVD) may be mediated by higher cardiovascular risk factor levels in those with sleep-disordered breathing. The authors examined these relations in the Sleep Heart Health Study, a multiethnic cohort of 6,440 men and women over age 40 years conducted from October 1995 to February 1998 and characterized by home polysomnography. In 4,991 participants who were free of self-reported CVD at the time of the sleep study, moderate levels of sleep-disordered breathing were common, with a median Respiratory Disturbance Index (RDI) of 4.0 (interquartile range, 1.25-10.7). The level of RDI was associated cross-sectionally with age, body mass index, waist-to-hip ratio, hypertension, diabetes, and lipid levels. These relations were more pronounced in those under age 65 years than in those over age 65. Women under age 65 years with RDI in the higher quartiles were more obese than men with similar RDI. Although the pattern of associations was consistent with greater obesity in those with higher RDI, higher body mass index did not explain all of these associations. If sleep-disordered breathing is shown in future follow-up to increase the risk for incident CVD events, part of the risk is likely to be due to the higher cardiovascular risk factors in those with higher RDI.

%B Am J Epidemiol %V 154 %P 50-9 %8 2001 Jul 01 %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/11434366?dopt=Abstract %R 10.1093/aje/154.1.50 %0 Journal Article %J J Am Geriatr Soc %D 2001 %T Risk factors for hospitalized gastrointestinal bleeding among older persons. Cardiovascular Health Study Investigators. %A Kaplan, R C %A Heckbert, S R %A Koepsell, T D %A Furberg, C D %A Polak, J F %A Schoen, R E %A Psaty, B M %K Activities of Daily Living %K Age Distribution %K Aged %K Aged, 80 and over %K Anti-Inflammatory Agents, Non-Steroidal %K Anticoagulants %K Aspirin %K Cardiovascular Diseases %K Female %K Gastrointestinal Hemorrhage %K Hospitalization %K Humans %K Incidence %K Male %K Multivariate Analysis %K Predictive Value of Tests %K Proportional Hazards Models %K Prospective Studies %K Risk Factors %K Smoking %K United States %X

OBJECTIVES: We sought to estimate the incidence of hospitalization for upper and lower gastrointestinal bleeding among older persons and to identify independent risk factors.

DESIGN: Prospective cohort study.

SETTING: The Cardiovascular Health Study (CHS).

PARTICIPANTS: 5,888 noninstitutionalized men and women age 65 years or older in four U.S. communities enrolled in the CHS.

MEASUREMENTS: Gastrointestinal bleeding events during the period 1989 through 1998 were identified using hospital discharge diagnosis codes and confirmed by medical records review. Risk-factor information was collected in a standardized fashion at study baseline and annually during follow-up.

RESULTS: Among CHS participants (mean baseline age 73.3 years, 42% male), the incidence of hospitalized gastrointestinal bleeding was 6.8/1,000 person-years. In multivariate analyses, advanced age, male sex, unmarried status, cardiovascular disease, difficulty with daily activities, use of multiple medications, and use of oral anticoagulants were independent risk factors. Compared with nonsmokers, subjects who smoked more than half a pack per day had a multivariate-adjusted hazard ratio (HR) of 2.14 (95% confidence interval [CI] = 1.22-3.75) for upper gastrointestinal bleeding and a multivariate-adjusted HR of 0.21 (95% CI = 0.03-1.54) for lower gastrointestinal bleeding. Aspirin users did not have an elevated risk of upper gastrointestinal bleeding (HR = 0.76, 95% CI = 0.52-1.11), and users of other nonsteroidal anti-inflammatory drugs had a HR of 1.54 (95 % CI = 0.99-2.36). Low ankle-arm systolic blood pressure index was associated with higher risk of gastrointestinal bleeding among subjects with clinical cardiovascular disease but not among those without clinical cardiovascular disease.

CONCLUSION: This study identifies risk factors for gastrointestinal bleeding, such as disability, that may be amenable to modification. The findings will help clinicians to identify older persons who are at high risk for gastrointestinal bleeding.

%B J Am Geriatr Soc %V 49 %P 126-33 %8 2001 Feb %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/11207865?dopt=Abstract %R 10.1046/j.1532-5415.2001.49032.x %0 Journal Article %J J Clin Epidemiol %D 2001 %T The role of comorbidity in the assessment of intermittent claudication in older adults. %A Newman, A B %A Naydeck, B L %A Sutton-Tyrrell, K %A Polak, J F %A Kuller, L H %K Aged %K Angina Pectoris %K Arterial Occlusive Diseases %K Cerebrovascular Disorders %K Cohort Studies %K Comorbidity %K Diabetes Mellitus %K Female %K Humans %K Intermittent Claudication %K Leg %K Male %K Prevalence %K Sensitivity and Specificity %K Surveys and Questionnaires %X

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.

%B J Clin Epidemiol %V 54 %P 294-300 %8 2001 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/11223327?dopt=Abstract %R 10.1016/s0895-4356(00)00308-5 %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2002 %T Racial differences in coronary artery calcification in older adults. %A Newman, Anne B %A Naydeck, Barbara L %A Whittle, Jeff %A Sutton-Tyrrell, Kim %A Edmundowicz, Daniel %A Kuller, Lewis H %K Age Factors %K Aged %K Calcinosis %K Cohort Studies %K Coronary Artery Disease %K Female %K Humans %K Logistic Models %K Male %K Risk Factors %K Sex Factors %K Tomography, X-Ray Computed %X

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.

%B Arterioscler Thromb Vasc Biol %V 22 %P 424-30 %8 2002 Mar 01 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/11884285?dopt=Abstract %R 10.1161/hq0302.105357 %0 Journal Article %J Ann Epidemiol %D 2002 %T A regression model for longitudinal change in the presence of measurement error. %A Yanez, N David %A Kronmal, Richard A %A Shemanski, Lynn R %A Psaty, Bruce M %K Aged %K Bias %K Coronary Disease %K Humans %K Lipoproteins %K Models, Statistical %K Regression Analysis %K Risk Factors %X

PURPOSE: The analysis of change in measured variables has become quite popular in studies where data are collected repeatedly over time. The authors describe some of the potential pitfalls in the analysis of change when the variable for change is measured with error. They show that regression analysis is often biased, possibly leading to erroneous results.

METHODS: A simple method to correct for measurement error bias in regression models that model change is presented.

RESULTS AND CONCLUSIONS: The two examples illustrate how measurement error can adversely affect an analysis. The bias-corrected approach yields valid results.

%B Ann Epidemiol %V 12 %P 34-8 %8 2002 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/11750238?dopt=Abstract %R 10.1016/s1047-2797(01)00280-0 %0 Journal Article %J Stat Med %D 2002 %T Regression-based variable clustering for data reduction. %A McClelland, R L %A Kronmal, R A %K Aged %K Algorithms %K Cardiovascular Diseases %K Cluster Analysis %K Cognition %K Computer Simulation %K Humans %K Infarction %K Magnetic Resonance Imaging %K Models, Statistical %K Regression Analysis %X

In many studies it is of interest to cluster states, counties or other small regions in order to obtain improved estimates of disease rates or other summary measures, and a more parsimonious representation of the country as a whole. This may be the case if there are too many to summarize concisely, and/or many regions with a small number of cases. By merging the regions into larger geographic areas, we obtain more cases within each area (and hence lower standard errors for parameter estimates), as well as fewer areas to summarize in terms of disease rates. The resulting clusters should be such that regions within the same cluster are similar in terms of their disease rates. In this paper we present a clustering algorithm which uses data at the subject-specific level in order to cluster the original regions into a reduced set of larger areas. The proposed clustering algorithm expresses the clustering goals in terms of a regression framework. This formulation of the problem allows the regions to be clustered in terms of their association with the response, and confounding variables measured at the subject-specific level may be easily incorporated during the clustering process. Additionally, this framework allows estimation and testing of the association between the areas and the response. The statistical properties and performance of the algorithm were evaluated via simulation studies, and the results are promising. Additional simulations illustrate the importance of controlling for confounding variables during the clustering process, rather than after the clusters are determined. The algorithm is illustrated with data from the Cardiovascular Health Study. Although developed with a specific application in mind, the method is applicable to a wide range of problems.

%B Stat Med %V 21 %P 921-41 %8 2002 Mar 30 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/11870825?dopt=Abstract %R 10.1002/sim.1063 %0 Journal Article %J Br J Ophthalmol %D 2002 %T The relation of atherosclerotic cardiovascular disease to retinopathy in people with diabetes in the Cardiovascular Health Study. %A Klein, Ronald %A Marino, Emily K %A Kuller, Lewis H %A Polak, Joseph F %A Tracy, Russell P %A Gottdiener, John S %A Burke, Gregory L %A Hubbard, Larry D %A Boineau, Robin %K Age of Onset %K Aged %K Aged, 80 and over %K Arteriosclerosis %K Black People %K Blood Pressure %K Cohort Studies %K Diabetes Mellitus, Type 2 %K Diabetic Retinopathy %K Female %K Humans %K Longitudinal Studies %K Male %K Odds Ratio %K Prospective Studies %K Regression Analysis %K Risk Factors %K Time Factors %K White People %X

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.

%B Br J Ophthalmol %V 86 %P 84-90 %8 2002 Jan %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/11801510?dopt=Abstract %R 10.1136/bjo.86.1.84 %0 Journal Article %J Sleep %D 2002 %T The relationship between chronically disrupted sleep and healthcare use. %A Kapur, Vishesh K %A Redline, Susan %A Nieto, F Javier %A Young, Terry B %A Newman, Anne B %A Henderson, Jeffrey A %K Adult %K Chronic Disease %K Cohort Studies %K Community Health Services %K Cross-Sectional Studies %K Disorders of Excessive Somnolence %K Female %K Health Status %K Humans %K Male %K Middle Aged %K Patient Acceptance of Health Care %K Polysomnography %K Prevalence %K Severity of Illness Index %K Sleep Apnea, Obstructive %K Sleep Deprivation %X

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.

%B Sleep %V 25 %P 289-96 %8 2002 May 01 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/12003159?dopt=Abstract %0 Journal Article %J Arterioscler Thromb Vasc Biol %D 2002 %T Relationship between coronary artery calcification and other measures of subclinical cardiovascular disease in older adults. %A Newman, Anne B %A Naydeck, Barbara L %A Sutton-Tyrrell, Kim %A Edmundowicz, Daniel %A O'Leary, Daniel %A Kronmal, Richard %A Burke, Gregory L %A Kuller, Lewis H %K Aged %K Aged, 80 and over %K Calcinosis %K Cardiovascular Diseases %K Carotid Stenosis %K Cohort Studies %K Coronary Artery Disease %K Demography %K Female %K Humans %K Male %K Prevalence %K Risk Factors %K Sensitivity and Specificity %K Sex Factors %K Tomography, X-Ray Computed %K Tunica Intima %K Tunica Media %X

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.

%B Arterioscler Thromb Vasc Biol %V 22 %P 1674-9 %8 2002 Oct 01 %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/12377748?dopt=Abstract %R 10.1161/01.atv.0000033540.89672.24 %0 Journal Article %J Addiction Research and Theory %D 2002 %T Reproducibility of two approaches for assessing alcohol consumption among older adults. %A Crum, RM %A Puddey, I %A Gilbert, CG %A Fried, LP %K alcohol %K elderly %K measurement %K questionnaire %X Objectives: In this study, we hypothesized that there is greater disclosure in self reports of alcohol intake when details of quantity-frequency measures of alcohol consumption are ascertained in the context of a general health and life style questionnaire as compared to a directed interview on usual drinking habits. Methods: Data are from the 1993 to 1994 follow-up of the Washington County cohort of men and women 65 years and older, participating in the Cardiovascular Health Study. A total of 918 subjects completed a questionnaire evaluation of their usual alcohol consumption by two separate approaches: (1) alcohol intake was derived from responses to questions contained within a medical and personal history questionnaire; (2) the same questions were within a medical and personal history questionnaire. Results: The mean alcohol intake for the entire cohort, and for drinkers alone were almost identical when assessed by either questionnaire, with high correlation between the two estimates, irrespective of beverage type. There was 89% agreement classifying drinkers versus nondrinkers by both approaches, with the strength of the agreement good (k=0.76). This agreement became moderate if drinkers were further categorized into three levels of alcohol intake. Predictors of the differences in alcohol intake between the two questionnaires were explored by multiple regression. Differences were largest for those who stated that the reason they drank was because they were no longer working, and for those drinking on average more than 24g (greater than approximately 2 drinks) of alcohol daily. Discussion: Although agreement between the two approaches was generally comparable, some findings may indicate that older adults who are problem drinkers or drink heavily report lower consumption patterns when administered a more directed questionnaire specifically focusing on drinking behavior. These findings have implications in the design of studies measuring alcohol consumption among elderly persons with a relatively low background alcohol intake. %B Addiction Research and Theory %V 10 %P 385 %8 2002-01-01 %G eng %N 4 %& 373 %0 Journal Article %J Br J Ophthalmol %D 2002 %T Retinal microvascular abnormalities and blood pressure in older people: the Cardiovascular Health Study. %A Wong, T Y %A Hubbard, L D %A Klein, R %A Marino, E K %A Kronmal, R %A Sharrett, A R %A Siscovick, D S %A Burke, G %A Tielsch, J M %K Aged %K Aged, 80 and over %K Blood Pressure %K Cohort Studies %K Diabetic Retinopathy %K Eye %K Female %K Humans %K Male %K Microcirculation %K Prospective Studies %K Retina %K Retinal Diseases %X

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.

%B Br J Ophthalmol %V 86 %P 1007-13 %8 2002 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/12185128?dopt=Abstract %R 10.1136/bjo.86.9.1007 %0 Journal Article %J Sleep Breath %D 2003 %T Recruitment of healthy adults into a study of overnight sleep monitoring in the home: experience of the Sleep Heart Health Study. %A Lind, Bonnie K %A Goodwin, James L %A Hill, Joel G %A Ali, Tauqeer %A Redline, Susan %A Quan, Stuart F %K Adult %K Body Mass Index %K Cardiovascular Diseases %K Catchment Area, Health %K Circadian Rhythm %K Cohort Studies %K Disorders of Excessive Somnolence %K Health Status %K Home Care Services %K Humans %K Hypertension %K Patient Selection %K Polysomnography %K Prospective Studies %K Severity of Illness Index %K Sleep Apnea Syndromes %K Surveys and Questionnaires %K United States %X

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.

%B Sleep Breath %V 7 %P 13-24 %8 2003 Mar %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/12712393?dopt=Abstract %R 10.1007/s11325-003-0013-z %0 Journal Article %J Mov Disord %D 2003 %T Regional and racial differences in the prevalence of physician-diagnosed essential tremor in the United States. %A Louis, Elan D %A Fried, Linda P %A Fitzpatrick, Annette L %A Longstreth, William T %A Newman, Anne B %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Essential Tremor %K European Continental Ancestry Group %K Female %K Humans %K Male %K Physicians %K Prevalence %K United States %X

For reasons that are unclear, prevalence estimates of essential tremor (ET) differ considerably across the United States. Separate communities have never been sampled within the framework of the same study to substantiate these differences. We estimated the prevalence of physician-diagnosed ET in the elderly in four communities in the United States in whom the same screening questions were used, and examined whether this prevalence differed between Caucasians and African Americans. The Cardiovascular Health Study recruited a sample of Medicare beneficiaries >/=65 years of age from four communities in different regions of the United States. In 1998 to 1999, 3,494 participants (mean age, 80.0 years; range, 70-103 years) answered a 12-question screen for ET, including the question, "has a doctor diagnosed you as having familial tremor or benign essential tremor?" Fifty-four participants reported that a doctor had diagnosed them as having ET (1.5%; 95% confidence interval, [CI], 1.1-2.0%). Prevalence was similar across the four communities (1.1-2.0%). A larger proportion of Caucasians than African Americans reported a diagnosis of ET (1.7% vs. 0.4%; odds ratio = 4.9; 95% CI, 1.2-20.2; P = 0.028). In a logistic regression analysis, physician-diagnosed ET was associated with Caucasian ethnicity (P = 0.038) but not with age, gender, education, mental status or depression scores, income, smoking status, or alcohol consumption. When a standardized screening question was used, the proportion of participants with physician-diagnosed ET was similar across four communities, suggesting that the prevalence of this condition may be less variable than is often reported. Caucasians were five times more likely to have physician-diagnosed ET than were African Americans. This study does not provide an explanation for this difference, which deserves further study.

%B Mov Disord %V 18 %P 1035-40 %8 2003 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/14502671?dopt=Abstract %R 10.1002/mds.10492 %0 Journal Article %J J Clin Epidemiol %D 2003 %T The relation of dietary patterns to future survival, health, and cardiovascular events in older adults. %A Diehr, Paula %A Beresford, Shirley A A %K Aged %K Cardiovascular Diseases %K Cluster Analysis %K Diet %K Energy Intake %K Female %K Follow-Up Studies %K Health Status %K Humans %K Incidence %K Linear Models %K Male %K Nutritional Physiological Phenomena %K Survival Rate %X

BACKGROUND: There have been few long-term follow-up studies of older adults who follow different dietary patterns.

METHODS: We cluster-analyzed data on dietary fat, fiber, protein, carbohydrate, and calorie consumption from the U.S. Cardiovascular Health Study (mean age=73), and examined the relationship of the dietary clusters to outcomes 10 years later.

RESULTS: The five clusters were named "Healthy diet" (relatively high in fiber and carbohydrate and low in fat), "Unhealthy diet" (relatively high in protein and fat, relatively low in carbohydrates and fiber); "High Calorie," "Low Calorie," and "Low 4," which was distinguished by higher alcohol consumption. The clusters were strongly associated with demographic factors, health behaviors, and baseline health status. The Healthy diet cluster had the most years of life and years of healthy life, and the Unhealthy diet cluster had the fewest. The Low 4 cluster had the best cardiovascular outcomes. Differences were not usually large.

CONCLUSIONS: Older adults who followed the healthy eating pattern had somewhat longer and healthier lives, and the cluster with more alcohol consumption was associated with fewer cardiovascular events. The unhealthy eating pattern had the worst outcomes.

%B J Clin Epidemiol %V 56 %P 1224-35 %8 2003 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/14680674?dopt=Abstract %R 10.1016/s0895-4356(03)00202-6 %0 Journal Article %J Am J Kidney Dis %D 2003 %T Relationships between renovascular disease, blood pressure, and renal function in the elderly: a population-based study. %A Edwards, Matthew S %A Hansen, Kimberley J %A Craven, Timothy E %A Cherr, Gregory S %A Bleyer, Anthony J %A Burke, Gregory L %A Dean, Richard H %K Aged %K Blood Pressure %K Female %K Humans %K Hypertension %K Kidney %K Kidney Diseases %K Male %K Prospective Studies %K Ultrasonography, Doppler, Duplex %K Vascular Diseases %X

BACKGROUND: The purpose of this study is to examine the associations between renovascular disease (RVD) and cross-sectional measures of blood pressure and renal function among participants in the Cardiovascular Health Study (CHS).

METHODS: The CHS is a prospective cohort study of cardiovascular disease among elderly Americans. As part of an ancillary study, participants in the Forsyth County, NC, cohort of the CHS were invited to undergo renal duplex sonography (RDS) to define the presence or absence of RVD (defined as any focal peak systolic velocity > or = 1.8 milliseconds or the absence of a Doppler shifted signal from an imaged artery). Demographic, risk factor, blood pressure, and serum creatinine data were obtained at the time of RDS and from the annual CHS examination.

RESULTS: 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 successful RDS. RVD was present in 57 participants (6.8%). When examined according to the presence or absence of RVD, significant univariate differences were observed in the prevalence of clinical hypertension (72% versus 50%; P = 0.001), systolic blood pressure (145 versus 136 mm Hg; P = 0.001), and renal insufficiency (16% versus 8%; P = 0.041). Multivariate analyses showed significant and independent associations for the presence of RVD with increasing systolic blood pressure (P = 0.034), clinical hypertension (odds ratio, 2.68; 95% confidence interval, 1.44 to 4.99; P = 0.002), increasing serum creatinine level, and renal insufficiency (odds ratio, 2.21; 95% confidence interval, 1.02 to 4.79; P = 0.043). A significant interaction was observed between the presence of RVD and increasing systolic blood pressure in association with increasing serum creatinine levels (P = 0.041).

CONCLUSION: These results suggest important population-based associations between RVD and cross-sectional measures of blood pressure and renal function. Furthermore, the observed relationship between RVD and increasing serum creatinine level was influenced strongly by increasing blood pressure.

%B Am J Kidney Dis %V 41 %P 990-6 %8 2003 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/12722033?dopt=Abstract %R 10.1016/s0272-6386(03)00196-3 %0 Journal Article %J J Am Coll Cardiol %D 2003 %T Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals. %A Fried, Linda F %A Shlipak, Michael G %A Crump, Casey %A Bleyer, Anthony J %A Gottdiener, John S %A Kronmal, Richard A %A Kuller, Lewis H %A Newman, Anne B %K Aged %K Cardiovascular Diseases %K Confidence Intervals %K Creatinine %K Female %K Heart Failure %K Humans %K Intermittent Claudication %K Kidney Failure, Chronic %K Male %K Odds Ratio %K Predictive Value of Tests %K Survival Analysis %X

OBJECTIVES: This study was designed to evaluate the relationship between elevated creatinine levels and cardiovascular events.

BACKGROUND: End-stage renal disease is associated with high cardiovascular morbidity and mortality. The association of mild to moderate renal insufficiency with cardiovascular outcomes remains unclear.

METHODS: We analyzed data from the Cardiovascular Health Study, a prospective population-based study of subjects, aged >65 years, who had a serum creatinine measured at baseline (n = 5,808) and were followed for a median of 7.3 years. Proportional hazards models were used to examine the association of creatinine to all-cause mortality and incident cardiovascular mortality and morbidity. Renal insufficiency was defined as a creatinine level > or =1.5 mg/dl in men or > or =1.3 mg/dl in women.

RESULTS: An elevated creatinine level was present in 648 (11.2%) participants. Subjects with elevated creatinine had higher overall (76.7 vs. 29.5/1,000 years, p < 0.001) and cardiovascular (35.8 vs. 13.0/1,000 years, p < 0.001) mortality than those with normal creatinine levels. They were more likely to develop cardiovascular disease (54.0 vs. 31.8/1,000 years, p < 0.001), stroke (21.1 vs. 11.9/1,000 years, p < 0.001), congestive heart failure (38.7 vs. 17/1,000 years, p < 0.001), and symptomatic peripheral vascular disease (10.6 vs. 3.5/1,000 years, p < 0.001). After adjusting for cardiovascular risk factors and subclinical disease measures, elevated creatinine remained a significant predictor of all-cause and cardiovascular mortality, total cardiovascular disease (CVD), claudication, and congestive heart failure (CHF). A linear increase in risk was observed with increasing creatinine.

CONCLUSIONS: Elevated creatinine levels are common in older adults and are associated with increased risk of mortality, CVD, and CHF. The increased risk is apparent early in renal disease.

%B J Am Coll Cardiol %V 41 %P 1364-72 %8 2003 Apr 16 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/12706933?dopt=Abstract %R 10.1016/s0735-1097(03)00163-3 %0 Journal Article %J Neuroepidemiology %D 2003 %T Risk factors for dementia in the cardiovascular health cognition study. %A Kuller, Lewis H %A Lopez, Oscar L %A Newman, Anne %A Beauchamp, Norman J %A Burke, Greg %A Dulberg, Corinne %A Fitzpatrick, Annette %A Fried, Linda %A Haan, Mary N %K Aged %K Aged, 80 and over %K Apolipoproteins E %K Cardiovascular Diseases %K Cognition Disorders %K Dementia %K Female %K Genotype %K Humans %K Magnetic Resonance Imaging %K Male %K Odds Ratio %K Predictive Value of Tests %K Proportional Hazards Models %K Risk Factors %X

BACKGROUND: The Cardiovascular Health Cognition Study has evaluated the determinants of dementia among 3,608 participants that had a magnetic resonance imaging (MRI) of the brain in 1991 and were followed to 1998-1999.

METHODS: There were 480 incident dementia cases, 330 (69%) were classified as Alzheimer's disease (AD).

RESULTS: In univariate analysis, low scores on the Modified Mini-Mental State Examination (3MSE) and on the Digit Symbol Substitution Test as well as declines in scores over time prior to the development of dementia were significant predictors of dementia. A high ventricular grade on the MRI (atrophy) as well as high white matter grade, a number of brain infarcts on the MRI were all determinants of dementia. Apolipoprotein E epsilon4 (Apo(E-4)) was also a powerful predictor of dementia. In a multivariate Cox proportional hazards model controlling for race, gender and grade, the hazard ratios for age (1.1), 3MSE score (0.9), ventricular size (1.4), white matter grade (1.8), presence of large infarcts >3 mm (1.3) and Apo(E-4) (2.1) were significant predictors of dementia. The combination of an Apo(E-4) genotype, 3MSE score <90, > or =5 ventricular grade, > or =3 white matter grade at the time of the MRI were associated with a 17-fold increased risk (95% CI: 8.6-34.9) of dementia as compared to individuals with none of the above attributes.

CONCLUSIONS: Measures of cognition, Apo(E-4) and MRI of the brain are strong predictors of both dementia and of AD.

%B Neuroepidemiology %V 22 %P 13-22 %8 2003 Jan-Feb %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/12566949?dopt=Abstract %R 10.1159/000067109 %0 Journal Article %J Arch Neurol %D 2003 %T Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. %A Lopez, Oscar L %A Jagust, William J %A Dulberg, Corinne %A Becker, James T %A DeKosky, Steven T %A Fitzpatrick, Annette %A Breitner, John %A Lyketsos, Constantine %A Jones, Beverly %A Kawas, Claudia %A Carlson, Michelle %A Kuller, Lewis H %K Aged %K Apolipoprotein E4 %K Apolipoproteins E %K Brain %K Cardiovascular Diseases %K Cognition Disorders %K Cohort Studies %K Depressive Disorder %K Female %K Humans %K Logistic Models %K Longitudinal Studies %K Magnetic Resonance Imaging %K Male %K Mood Disorders %K Pennsylvania %K Population %K Risk Factors %X

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.

%B Arch Neurol %V 60 %P 1394-9 %8 2003 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/14568809?dopt=Abstract %R 10.1001/archneur.60.10.1394 %0 Journal Article %J Am Heart J %D 2004 %T Racial differences in endothelial function in postmenopausal women. %A Loehr, Laura R %A Espeland, Mark A %A Sutton-Tyrrell, Kim %A Burke, Gregory L %A Crouse, John R %A Herrington, David M %K African Continental Ancestry Group %K Aged %K Brachial Artery %K Cohort Studies %K Endothelium, Vascular %K European Continental Ancestry Group %K Female %K Humans %K Multivariate Analysis %K Postmenopause %K Risk Factors %K Vasodilation %X

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.

%B Am Heart J %V 148 %P 606-11 %8 2004 Oct %G eng %N 4 %1 https://www.ncbi.nlm.nih.gov/pubmed/15459590?dopt=Abstract %R 10.1016/j.ahj.2004.04.032 %0 Journal Article %J Am J Kidney Dis %D 2004 %T The relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: the cardiovascular health study. %A Barzilay, Joshua I %A Peterson, Do %A Cushman, Mary %A Heckbert, Susan R %A Cao, Jie J %A Blaum, Caroline %A Tracy, Russell P %A Klein, Ronald %A Herrington, David M %K Age Distribution %K Aged %K Aged, 80 and over %K Albuminuria %K Biomarkers %K Brachial Artery %K Comorbidity %K Coronary Disease %K Cross-Sectional Studies %K Diabetes Mellitus %K Female %K Humans %K Hypertension %K Inflammation %K Logistic Models %K Male %K Multivariate Analysis %K Odds Ratio %K Risk Factors %K Smoking %K Ultrasonography %X

BACKGROUND: Microalbuminuria is a risk factor for coronary heart disease (CHD). It occurs most commonly in the settings of diabetes and hypertension. The mechanisms by which it increases CHD risk are uncertain.

METHODS: We examined the cross-sectional association of microalbuminuria with a broad range of CHD risk factors in 3 groups of adults aged 65 years or older with and without microalbuminuria: those with (1) no diabetes or hypertension (n = 1,098), (2) hypertension only (n = 1,450), and (3) diabetes with or without hypertension (n = 465).

RESULTS: Three factors were related to microalbuminuria in all 3 groups: age, elevated systolic blood pressure, and markers of systemic inflammation. In patients with neither diabetes nor hypertension, increasing C-reactive protein levels were associated with microalbuminuria (odds ratio per 1-mg/L increase, 1.46; 95% confidence interval [CI], 1.15 to 1.84). Among those with diabetes, an increase in white blood cell (WBC) count was associated with microalbuminuria (odds ratio per 1,000-cell/mL increase, 2.57; 95% CI, 1.12 to 5.89). Among those with hypertension, an increase in WBC count (odds ratio per 1,000-cell/mL increase, 1.83; 95% CI, 1.04 to 3.23) and fibrinogen level (odds ratio per 10-mg/dL increase, 1.02; 95% CI, 1.00 to 1.05) were significantly associated with microalbuminuria. In all 3 groups, prevalent CHD was related to an elevated WBC count. In none of the 3 groups was brachial artery reactivity to ischemia, an in vivo marker of endothelial function, related to microalbuminuria.

CONCLUSION: Microalbuminuria is associated with age, systolic blood pressure, and markers of inflammation. These associations reflect potential mechanisms by which microalbuminuria is related to CHD risk.

%B Am J Kidney Dis %V 44 %P 25-34 %8 2004 Jul %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/15211434?dopt=Abstract %R 10.1053/j.ajkd.2004.03.022 %0 Journal Article %J J Clin Endocrinol Metab %D 2004 %T The relationship of fasting serum radioimmune insulin levels to incident coronary heart disease in an insulin-treated diabetic cohort. %A Kronmal, Richard A %A Barzilay, Joshua I %A Tracy, Russell P %A Savage, Peter J %A Orchard, Trevor J %A Burke, Gregory L %K Aged %K Cohort Studies %K Coronary Disease %K Diabetes Mellitus, Type 1 %K Fasting %K Female %K Follow-Up Studies %K Humans %K Hypoglycemic Agents %K Incidence %K Insulin %K Male %K Radioimmunoassay %K Risk Factors %X

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.

%B J Clin Endocrinol Metab %V 89 %P 2852-8 %8 2004 Jun %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/15181068?dopt=Abstract %R 10.1210/jc.2003-031822 %0 Journal Article %J Thorax %D 2004 %T Respiratory muscle strength and the risk of incident cardiovascular events. %A van der Palen, J %A Rea, T D %A Manolio, T A %A Lumley, T %A Newman, A B %A Tracy, R P %A Enright, P L %A Psaty, B M %K Cardiovascular Diseases %K Female %K Follow-Up Studies %K Forced Expiratory Volume %K Humans %K Male %K Maximal Voluntary Ventilation %K Prospective Studies %K Respiratory Muscles %K Risk Factors %K Vital Capacity %X

BACKGROUND: Maximal inspiratory pressure (MIP) is a measure of inspiratory muscle strength. The prognostic importance of MIP for cardiovascular events among elderly community dwelling individuals is unknown. Diminished forced vital capacity (FVC) is a risk factor for cardiovascular events which remains largely unexplained.

METHODS: MIP was measured at the baseline examination of the Cardiovascular Health Study. Participants had to be free of prevalent congestive heart failure (CHF), myocardial infarction (MI), and stroke.

RESULTS: Subjects in the lowest quintile of MIP had a 1.5-fold increased risk of MI (HR 1.48, 95% CI 1.07 to 2.06) and cardiovascular disease (CVD) death (HR 1.54, 95% CI 1.09 to 2.15) after adjustment for non-pulmonary function covariates. There was a potential inverse relationship with stroke (HR 1.36, 95% CI 0.97 to 1.90), but there was little evidence of an association between MIP and CHF (HR 1.22, 95% CI 0.93 to 1.60). The addition of FVC to models attenuated the HR associated with MIP only modestly; similarly, addition of MIP attenuated the HR associated with FVC only modestly.

CONCLUSIONS: A reduced MIP is an independent risk factor for MI and CVD death, and a suggestion of an increased risk for stroke. This association with MIP appeared to be mediated through mechanisms other than inflammation.

%B Thorax %V 59 %P 1063-7 %8 2004 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/15563706?dopt=Abstract %R 10.1136/thx.2004.021915 %0 Journal Article %J J Am Geriatr Soc %D 2004 %T Risk of congestive heart failure in an elderly population treated with peripheral alpha-1 antagonists. %A Bryson, Chris L %A Smith, Nicholas L %A Kuller, Lewis H %A Chaves, Paulo H M %A Manolio, Teri A %A Lewis, William %A Boyko, Edward J %A Furberg, Curt D %A Psaty, Bruce M %K Adrenergic alpha-Antagonists %K Aged %K Antihypertensive Agents %K Benzothiadiazines %K Blood Pressure %K Cohort Studies %K Diuretics %K Female %K Heart Failure %K Humans %K Hypertension %K Male %K Risk Factors %K Sodium Chloride Symporter Inhibitors %K United States %X

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.

%B J Am Geriatr Soc %V 52 %P 1648-54 %8 2004 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/15450040?dopt=Abstract %R 10.1111/j.1532-5415.2004.52456.x %0 Journal Article %J Am J Kidney Dis %D 2005 %T Renal duplex parameters, blood pressure, and renal function in elderly people. %A Pearce, Jeffrey D %A Edwards, Matthew S %A Craven, Timothy E %A English, William P %A Mondi, Matthew M %A Reavis, Scott W %A Hansen, Kimberley J %K African Americans %K Aged %K Aging %K Arteriosclerosis %K Blood Pressure %K Cardiovascular Diseases %K Cohort Studies %K Creatinine %K Cross-Sectional Studies %K Diastole %K Disease Progression %K European Continental Ancestry Group %K Female %K Humans %K Hypertension, Renovascular %K Kidney %K Kidney Diseases %K Kidney Function Tests %K Male %K Renal Artery %K Renal Artery Obstruction %K Renal Circulation %K Risk Factors %K Sampling Studies %K Systole %K Ultrasonography, Doppler, Duplex %K United States %X

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.

%B Am J Kidney Dis %V 45 %P 842-50 %8 2005 May %G eng %N 5 %1 https://www.ncbi.nlm.nih.gov/pubmed/15861349?dopt=Abstract %R 10.1053/j.ajkd.2005.01.028 %0 Journal Article %J Arch Intern Med %D 2005 %T Renovascular disease and the risk of adverse coronary events in the elderly: a prospective, population-based study. %A Edwards, Matthew S %A Craven, Timothy E %A Burke, Gregory L %A Dean, Richard H %A Hansen, Kimberley J %K Age Distribution %K Aged %K Aged, 80 and over %K Analysis of Variance %K Cohort Studies %K Comorbidity %K Coronary Disease %K Female %K Geriatric Assessment %K Heart Function Tests %K Humans %K Hypertension, Renovascular %K Incidence %K Kidney Function Tests %K Male %K Multivariate Analysis %K Probability %K Prognosis %K Prospective Studies %K Risk Assessment %K Severity of Illness Index %K Sex Distribution %K Survival Rate %K Ultrasonography, Doppler %K United States %X

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.

%B Arch Intern Med %V 165 %P 207-13 %8 2005 Jan 24 %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/15668368?dopt=Abstract %R 10.1001/archinte.165.2.207 %0 Journal Article %J Arch Intern Med %D 2005 %T Risk factors for declining ankle-brachial index in men and women 65 years or older: the Cardiovascular Health Study. %A Kennedy, Margaret %A Solomon, Cam %A Manolio, Teri A %A Criqui, Michael H %A Newman, Anne B %A Polak, Joseph F %A Burke, Gregory L %A Enright, Paul %A Cushman, Mary %K Aged %K Aged, 80 and over %K Ankle %K Brachial Artery %K Cardiovascular Diseases %K Female %K Humans %K Male %K Peripheral Vascular Diseases %K Risk Assessment %K Risk Factors %X

BACKGROUND: An ankle-brachial index (ABI) of less than 0.9 is a noninvasive measure of lower extremity arterial disease and a predictor of cardiovascular events. Little information is available on longitudinal change in ABI or on risk factors for declining ABI in a community-based population.

METHODS: To assess risk factors for ABI decline, we studied 5888 participants in the Cardiovascular Health Study cohort (men and women 65 years or older). We measured ABI in 1992-1993 and again in 1998-1999. At baseline, we excluded individuals with an ABI less than 0.9, ABI greater than 1.4, or confirmed symptomatic lower extremity arterial disease (n = 823). The group with ABI decline included 218 participants with decline greater than 0.15 and to 0.9 or less. The comparison group comprised the remaining 2071 participants with follow-up ABI.

RESULTS: The percentage of participants with ABI decline was 9.5% over 6 years of follow-up. The mean +/- SD decline was 0.33 +/- 0.12 in cases of ABI decline and 0.02 +/- 0.13 in non-cases. Independent predictors of ABI decline, reported as odds ratios, were age, 1.96 (95% confidence interval [CI], 1.42-2.71) for 75 to 84 years and 3.79 (95% CI, 1.36-10.5) for those older than 85 years compared with those younger than 75 years; current cigarette use, 1.74 (95% CI, 1.02-2.96); hypertension, 1.64 (95% CI, 1.18-2.28); diabetes, 1.77 (95% CI, 1.14-2.76); higher low-density lipoprotein cholesterol level, 1.60 (95% CI, 1.03-2.51), and lipid-lowering drug use 1.74 (95% CI, 1.05-2.89).

CONCLUSION: Worsening lower extremity arterial disease, assessed as ABI decline, occurred in 9.5% of this elderly cohort over 6 years and was associated with modifiable vascular disease risk factors.

%B Arch Intern Med %V 165 %P 1896-902 %8 2005 Sep 12 %G eng %N 16 %1 https://www.ncbi.nlm.nih.gov/pubmed/16157835?dopt=Abstract %R 10.1001/archinte.165.16.1896 %0 Journal Article %J Int J Epidemiol %D 2006 %T Regression dilution methods for meta-analysis: assessing long-term variability in plasma fibrinogen among 27,247 adults in 15 prospective studies. %A Wood, Angela M %A White, Ian %A Thompson, Simon G %A Lewington, Sarah %A Danesh, John %K Adult %K Age Factors %K Bias %K Cardiovascular Diseases %K Female %K Fibrinogen %K Humans %K Male %K Meta-Analysis as Topic %K Prospective Studies %K Regression Analysis %K Risk Factors %K Sex Factors %K Smoking %K Time Factors %X

BACKGROUND: Within-person variability in measured values of a risk factor can bias its association with disease. The extent of this regression dilution bias for plasma fibrinogen was investigated using repeat measurement data collected at varying time intervals on 27 247 adults in 15 prospective studies.

METHODS: Regression dilution ratios (RDRs) were estimated from a linear regression of repeat measurements on baseline values in each study and for each time interval, and pooled allowing for within- and between-study heterogeneity. RDRs were estimated both without and with adjustment for confounders, and factors were investigated that might influence the RDRs.

RESULTS: The unadjusted overall RDR was 0.51 (95% CI: 0.47, 0.55), which decreased to 0.46 (95% CI: 0.42, 0.49) after adjustment for age, sex and measured values of other established vascular risk factors. The RDR did not vary materially by assay method, age, sex or smoking status, but decreased at higher levels of baseline fibrinogen.

CONCLUSION: It is appropriate to use an RDR of 0.5 to correct approximately for regression dilution bias in plasma fibrinogen values; however, this correction factor may produce somewhat conservative hazard ratios in adjusted analyses, at higher fibrinogen concentrations and in follow-up beyond a decade. More generally, the methods described in this report have widespread applicability to quantifying regression dilution bias in repeatability data from multiple prospective studies.

%B Int J Epidemiol %V 35 %P 1570-8 %8 2006 Dec %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/17148467?dopt=Abstract %R 10.1093/ije/dyl233 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2007 %T A regions-of-interest volumetric analysis of mobility limitations in community-dwelling older adults. %A Rosano, Caterina %A Aizenstein, Howard J %A Studenski, Stephanie %A Newman, Anne B %K Aged %K Aged, 80 and over %K Aging %K Brain %K Female %K Gait %K Humans %K Magnetic Resonance Imaging %K Male %K Mobility Limitation %K Postural Balance %X

BACKGROUND: In community-dwelling older adults, greater mobility impairment is associated with greater burden of diffuse brain structural abnormalities, such as higher white matter hyperintensities. This study examined the association between gray matter volumes of regions related to motor control, gait, and balance and whether this association is independent of burden of white matter hyperintensities.

METHODS: A random sample of 327 participants of the Cardiovascular Health Study (78.3 +/- 4.1 years old, 57% women) contributed brain magnetic resonance imaging (MRI) and mobility data. A brain imaging automated method measured gray matter volume in cerebellum, basal ganglia, and prefrontal and parietal cortex in both hemispheres. Gait speed was measured while walking 15 feet at usual pace. Standing balance was assessed by timing tandem stance. Associations between each region's volume and gait speed or balance were measured before and after adjustment for demographics, head size, cardiovascular risk factors, and 0-9 grading scores of white matter hyperintensities.

RESULTS: Smaller left cerebellum and left prefrontal regions were associated with slower gait, independently of covariates and of white matter hyperintensities. Smaller right putamen, right posterior superior parietal cortex, and both left and right cerebellum were associated with balance difficulty, independently of covariates and white matter hyperintensities.

CONCLUSIONS: Smaller gray matter volumes in regions crucial for motor control are associated with slower gait and poorer balance, and the association appears to be independent of other diffuse brain abnormalities such as white matter hyperintensities.

%B J Gerontol A Biol Sci Med Sci %V 62 %P 1048-55 %8 2007 Sep %G eng %N 9 %1 https://www.ncbi.nlm.nih.gov/pubmed/17895446?dopt=Abstract %R 10.1093/gerona/62.9.1048 %0 Journal Article %J J Clin Sleep Med %D 2007 %T Relationship between reported and measured sleep times: the sleep heart health study (SHHS). %A Silva, Graciela E %A Goodwin, James L %A Sherrill, Duane L %A Arnold, Jean L %A Bootzin, Richard R %A Smith, Terry %A Walsleben, Joyce A %A Baldwin, Carol M %A Quan, Stuart F %K Adult %K Attitude to Health %K Female %K Health Status %K Humans %K Male %K Middle Aged %K Polysomnography %K Psychometrics %K Sleep Initiation and Maintenance Disorders %K Sleep Stages %K Surveys and Questionnaires %K Time Factors %K Wakefulness %X

STUDY OBJECTIVE: Subjective and objective assessments of sleep may be discrepant due to sleep misperception and measurement effects, the latter of which may change the quality and quantity of a person's usual sleep. This study compared sleep times from polysomnography (PSG) with self-reports of habitual sleep and sleep estimated on the morning after a PSG in adults.

DESIGN: Total sleep time and sleep onset latency obtained from unattended home PSGs were compared to sleep times obtained from a questionnaire completed before the PSG and a Morning Survey completed the morning after the PSG.

PARTICIPANTS: A total of 2,113 subjects who were > or = 40 years of age were included in this analysis.

MEASURES AND RESULTS: Subjects were 53% female, 75% Caucasian, and 38% obese. The mean habitual sleep time (HABTST), morning estimated sleep time (AMTST), and PSG total sleep times (PSGTST) were 422 min, 379 min, and 363 min, respectively. The mean habitual sleep onset latency, morning estimated sleep onset latency, and PSG sleep onset latency were 17.0 min, 21.8 min, and 16.9 min, respectively. Models adjusting for related demographic factors showed that HABTST and AMTST differ significantly from PSGTST by 61 and 18 minutes, respectively. Obese and higher educated people reported less sleep time than their counterparts. Similarly, small but significant differences were seen for sleep latency.

CONCLUSIONS: In a community population, self-reported total sleep times and sleep latencies are overestimated even on the morning following overnight PSG.

%B J Clin Sleep Med %V 3 %P 622-30 %8 2007 Oct 15 %G eng %N 6 %1 https://www.ncbi.nlm.nih.gov/pubmed/17993045?dopt=Abstract %0 Journal Article %J Diabet Med %D 2007 %T The relationship of heart rate and heart rate variability to non-diabetic fasting glucose levels and the metabolic syndrome: the Cardiovascular Health Study. %A Stein, P K %A Barzilay, J I %A Domitrovich, P P %A Chaves, P M %A Gottdiener, J S %A Heckbert, S R %A Kronmal, R A %K Aged %K Aged, 80 and over %K Arrhythmias, Cardiac %K Blood Glucose %K Fasting %K Female %K Glucose Intolerance %K Heart Rate %K Humans %K Male %K Metabolic Syndrome %K Risk Factors %X

BACKGROUND: Increased heart rate (HR) and diminished heart rate variability (HRV) are signs of early cardiovascular autonomic neuropathy. We tested the hypotheses that increased HR and diminished HRV are present in people: (i) with increased fasting glucose (FG) levels not in the range of diabetes mellitus (DM), and (ii) in people with the metabolic syndrome (MetS) independent of elevated FG levels.

METHODS: HR and HRV were determined in 1267 adults (mean age 72 years) who had Holter monitoring and FG measures: 536 had normal FG levels (NORM, FG 4.5-5.5 mmol/l), 363 had mildly impaired FG (IFG-1, FG 5.6-6.0 mmol/l), 182 had significantly impaired FG (IFG-2, FG 6.1-6.9 mmol/l) and 178 had DM (FG > 6.9 mmol/l or use of glucose-lowering agents/insulin). HR and HRV in NORM/IFG-1 was further compared by the number of components of the MetS and compared by the presence or absence of MetS in IFG-2/DM.

RESULTS: HRV indices were more impaired in IFG-2 and DM than in NORM or IFG-1. There were few differences in HRV indices between NORM and IFG-1 or between IFG-2 and DM. In NORM/IFG-1 participants, having > or = 2 components of the MetS was associated with a greater decrease in HRV compared with having no or one components. In IFG-2/DM participants, MetS was associated with decreased HRV compared with no MetS.

CONCLUSIONS: Increased HR and diminished HRV occur in the non-diabetic FG range. Diminished HRV is associated with the MetS, independent of FG levels. Both these results suggest that factors associated with increasing non-diabetic FG levels and the MetS play a role in the onset of cardiac autonomic impairment.

%B Diabet Med %V 24 %P 855-63 %8 2007 Aug %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/17403115?dopt=Abstract %R 10.1111/j.1464-5491.2007.02163.x %0 Journal Article %J Am J Kidney Dis %D 2007 %T Relationship of uric acid with progression of kidney disease. %A Chonchol, Michel %A Shlipak, Michael G %A Katz, Ronit %A Sarnak, Mark J %A Newman, Anne B %A Siscovick, David S %A Kestenbaum, Bryan %A Carney, Jan Kirk %A Fried, Linda F %K Aged %K Aged, 80 and over %K Cohort Studies %K Cross-Sectional Studies %K Disease Progression %K Female %K Glomerular Filtration Rate %K Humans %K Kidney Diseases %K Male %K Prospective Studies %K Uric Acid %X

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.

%B Am J Kidney Dis %V 50 %P 239-47 %8 2007 Aug %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/17660025?dopt=Abstract %R 10.1053/j.ajkd.2007.05.013 %0 Journal Article %J Stroke %D 2007 %T Retinal microvascular signs, cognitive function, and dementia in older persons: the Cardiovascular Health Study. %A Baker, Michelle L %A Marino Larsen, Emily K %A Kuller, Lewis H %A Klein, Ronald %A Klein, Barbara E K %A Siscovick, David S %A Bernick, Charles %A Manolio, Teri A %A Wong, Tien Yin %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Cognition %K Cross-Sectional Studies %K Dementia %K Female %K Humans %K Longitudinal Studies %K Male %K Microcirculation %K Neuropsychological Tests %K Retinal Vessels %K Risk Factors %X

BACKGROUND AND PURPOSE: Cerebral microvascular disease may be a risk factor for the development of dementia in elderly persons. We describe the association of retinal microvascular signs with cognitive function and dementia among older individuals.

METHODS: In the population-based Cardiovascular Health Study, 2211 persons aged 69 to 97 years at recruitment had retinal photography. Photographs were evaluated for retinopathy (eg, microaneurysms, retinal hemorrhages), focal arteriolar narrowing, arteriovenous nicking, and retinal arteriolar and venular caliber. Cognitive status was determined from the Digit-Symbol Substitution Test and Modified Mini-Mental State Examination. Participants were also further evaluated for the presence of dementia with detailed neuropsychological testing. Persons with a prior stroke or taking antipsychotic or antidepressant medications were excluded.

RESULTS: After adjusting for age, gender, race, field center, education level, internal carotid intima-media thickness, body mass index, hypertension, diabetes, and cigarette smoking status, persons with retinopathy had lower mean Digit-Symbol Substitution Test scores but not Modified Mini-Mental State Examination than those without retinopathy (39 versus 41, P=0.002). In hypertensive persons, retinopathy (multivariable-adjusted OR, 2.10; 95% CI, 1.04 to 4.24) and focal arteriolar narrowing (OR, 3.02; 95% CI, 1.51 to 6.02) were associated with dementia. These associations were not present in individuals without hypertension.

CONCLUSIONS: In older persons, our study shows a modest cross-sectional association between retinopathy signs with poorer cognitive function and, in persons with hypertension, with dementia. These data support a possible role of cerebral microvascular disease in the pathogenesis of impaired cognitive function and dementia in older hypertensive persons.

%B Stroke %V 38 %P 2041-7 %8 2007 Jul %G eng %N 7 %1 https://www.ncbi.nlm.nih.gov/pubmed/17525385?dopt=Abstract %R 10.1161/STROKEAHA.107.483586 %0 Journal Article %J Stroke %D 2007 %T Risk factors for intracerebral hemorrhage in a pooled prospective study. %A Sturgeon, Jared D %A Folsom, Aaron R %A Longstreth, W T %A Shahar, Eyal %A Rosamond, Wayne D %A Cushman, Mary %K African Americans %K Age Distribution %K Cerebral Hemorrhage %K Cholesterol, LDL %K Female %K Follow-Up Studies %K Humans %K Hypertension %K Incidence %K Male %K Middle Aged %K Multivariate Analysis %K Predictive Value of Tests %K Prevalence %K Prospective Studies %K Risk Factors %K Stroke %K Triglycerides %X

BACKGROUND AND PURPOSE: Few prospective studies have reported risk factors for intracerebral hemorrhage (ICH), and results are inconsistent. We studied risk factors for ICH in a pooled cohort of the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS).

METHODS: The ARIC cohort was recruited in 1987 to 1989 and involves 15 792 men and women, aged 45 to 64 years at baseline, sampled from 4 US communities. The CHS cohort was recruited in 1989 to 1993 and involves 5888 men and women, aged 65 or over at baseline, sampled from 4 US communities. Baseline measurements included many potential vascular risk factors. The cohorts were followed for incident stroke events.

RESULTS: Over 263 489 person-years of follow-up, 135 incident ICH events occurred. In a multivariable model, age, African-American ethnicity (versus Whites), and hypertension were positively associated with incident ICH, whereas low-density lipoprotein cholesterol and triglycerides were inversely related to incident ICH. Participants with systolic blood pressure >or=160 mm Hg or diastolic blood pressure >/=110 mm Hg had 5.55 (95% CI 3.07 to 10.0) times the rate of ICH as nonhypertensives. Sex, smoking, alcohol intake, body mass index, waist-to-hip ratio, waist circumference, and diabetes were not related to ICH.

CONCLUSIONS: In this pooled cohort the risk factors for ICH were older age, African-American ethnicity, hypertension, lower LDL-C, and lower triglycerides.

%B Stroke %V 38 %P 2718-25 %8 2007 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/17761915?dopt=Abstract %R 10.1161/STROKEAHA.107.487090 %0 Journal Article %J Arch Intern Med %D 2008 %T Rapid kidney function decline and mortality risk in older adults. %A Rifkin, Dena E %A Shlipak, Michael G %A Katz, Ronit %A Fried, Linda F %A Siscovick, David %A Chonchol, Michel %A Newman, Anne B %A Sarnak, Mark J %K Aged %K Cardiovascular Diseases %K Creatinine %K Cystatins %K Female %K Glomerular Filtration Rate %K Humans %K Kidney %K Male %K Mortality %X

BACKGROUND: Impaired kidney function is associated with increased mortality risk in older adults. It remains unknown, however, whether longitudinal declines in kidney function are independently associated with increased cardiovascular and all-cause mortality in older adults.

METHODS: The Cardiovascular Health Study evaluated a cohort of community-dwelling older adults enrolled from 1989 to 1993 in 4 US communities with follow-up through 2005. Among 4380 participants, the slope of annual decline in estimated glomerular filtration rate (eGFR) was estimated using both serum creatinine (eGFR(creat)) and cystatin C (eGFR(cys)) rates, which were measured at baseline, year 3, and year 7 of follow-up. Rapid decline in eGFR was defined as a loss greater than 3 mL/min/1.73 m(2) per year, and cardiovascular and all-cause mortality were assessed over a mean of 9.9 years of follow-up.

RESULTS: Mean (SD) levels of creatinine and cystatin C were 0.93 (0.30) mg/dL and 1.03 (0.25) mg/L, respectively; mean (SD) eGFR(creat) and eGFR(cys) were 79 (23) mL/min/1.73 m(2) and 79 (19) mL/min/1.73 m(2), respectively. Individuals with rapid decline measured by eGFR(creat) (n = 714; 16%) had increased risk of cardiovascular (adjusted hazard ratio [AHR], 1.70; 95% confidence interval [CI], 1.40-2.06) and all-cause (AHR, 1.73; 95% CI, 1.54-1.94) mortality. Individuals with rapid decline measured by eGFR(cys) (n = 1083; 25%) also had increased risk of cardiovascular (AHR, 1.53; 95% CI, 1.29-1.80) and all-cause (AHR, 1.53; 95% CI, 1.38-1.69) mortality. The association of rapid decline in eGFR with elevated mortality risk did not differ across subgroups based on baseline kidney function, age, sex, race, or prevalent coronary heart disease.

CONCLUSION: Rapid decline in eGFR is associated with an increased risk of cardiovascular and all-cause mortality in older adults, independent of baseline eGFR and other demographic variables.

%B Arch Intern Med %V 168 %P 2212-8 %8 2008 Nov 10 %G eng %N 20 %1 https://www.ncbi.nlm.nih.gov/pubmed/19001197?dopt=Abstract %R 10.1001/archinte.168.20.2212 %0 Journal Article %J Atherosclerosis %D 2008 %T Relation of sleep-disordered breathing to carotid plaque and intima-media thickness. %A Wattanakit, Keattiyoat %A Boland, Lori %A Punjabi, Naresh M %A Shahar, Eyal %K Aged %K Carotid Arteries %K Carotid Artery Diseases %K Female %K Humans %K Male %K Middle Aged %K Odds Ratio %K Risk Factors %K Sleep Apnea Syndromes %K Tunica Intima %K Tunica Media %K Ultrasonography %X

BACKGROUND: Sleep-disordered breathing (SDB) is associated with clinical cardiovascular disease (CVD), but its relation to subclinical atherosclerosis remains to be determined.

METHODS: We analyzed the cross-sectional associations of SDB, measured by the respiratory disturbance index (RDI), a hypoxemia index, and an arousal index, with carotid plaque and carotid intima-media thickness (IMT), measured by ultrasound. The sample included 985 participants in the Sleep Heart Health Study (mean age-62, median RDI-8.7) with no history of coronary heart disease and stroke, of whom 396 had evidence of a carotid plaque.

RESULTS: As compared with the first quartile of the RDI (0-1.2), the crude odds ratio for carotid plaque was 1.14, 1.27, and 1.48 for the second (1.3-4.1), third (4.2-10.7), and fourth (>10.7) quartile, respectively. After adjustment for CVD risk factors, the corresponding odds ratios were reduced (1.00, 1.04, 1.07, and 1.25). Similarly, the unadjusted mean carotid IMT increased with RDI, but adjusted means (mm) were similar (0.84, 0.85, 0.84, 0.85). Spline regression models did not show monotonicity of the dose-response functions at the right end of the RDI distribution. Neither the hypoxemia index nor the arousal index was associated with carotid plaque or carotid IMT.

CONCLUSION: The results of this study suggest that crude, positive associations between SDB and subclinical atherosclerosis can be attributed to confounding by CVD risk factors.

%B Atherosclerosis %V 197 %P 125-31 %8 2008 Mar %G eng %N 1 %1 https://www.ncbi.nlm.nih.gov/pubmed/17433330?dopt=Abstract %R 10.1016/j.atherosclerosis.2007.02.029 %0 Journal Article %J Atherosclerosis %D 2008 %T Relationship between brachial flow-mediated dilation and carotid intima-media thickness in an elderly cohort: the Cardiovascular Health Study. %A Yeboah, Joseph %A Burke, Gregory L %A Crouse, John R %A Herrington, David M %K Age Factors %K Aged %K Aged, 80 and over %K Brachial Artery %K Carotid Arteries %K Carotid Artery Diseases %K Cohort Studies %K Female %K Hemorheology %K Humans %K Male %K Tunica Intima %K Tunica Media %K Ultrasonography %K Vasodilation %X

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.

%B Atherosclerosis %V 197 %P 840-5 %8 2008 Apr %G eng %N 2 %1 https://www.ncbi.nlm.nih.gov/pubmed/17804000?dopt=Abstract %R 10.1016/j.atherosclerosis.2007.07.032 %0 Journal Article %J J Am Geriatr Soc %D 2008 %T The relationship between exercise and risk of venous thrombosis in elderly people. %A van Stralen, Karlijn J %A Doggen, Carine J M %A Lumley, Thomas %A Cushman, Mary %A Folsom, Aaron R %A Psaty, Bruce M %A Siscovick, David %A Rosendaal, Frits R %A Heckbert, Susan R %K Aged %K Aged, 80 and over %K Case-Control Studies %K Cohort Studies %K Energy Metabolism %K Exercise %K Female %K Humans %K Male %K Prevalence %K Risk Factors %K United States %K Venous Thrombosis %X

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.

%B J Am Geriatr Soc %V 56 %P 517-22 %8 2008 Mar %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/18179500?dopt=Abstract %R 10.1111/j.1532-5415.2007.01588.x %0 Journal Article %J Arch Phys Med Rehabil %D 2008 %T The reliability and validity of measures of gait variability in community-dwelling older adults. %A Brach, Jennifer S %A Perera, Subashan %A Studenski, Stephanie %A Newman, Anne B %K Activities of Daily Living %K Aged %K Cross-Sectional Studies %K Disability Evaluation %K Exercise %K Female %K Gait %K Health Status %K Humans %K Male %K Pennsylvania %K Rehabilitation %K Reproducibility of Results %X

OBJECTIVE: To examine the test-retest reliability and concurrent validity of variability of gait characteristics.

DESIGN: Cross-sectional study.

SETTING: Research laboratory.

PARTICIPANTS: Older adults (N=558) from the Cardiovascular Health Study.

INTERVENTIONS: Not applicable.

MAIN OUTCOME MEASURES: Gait characteristics were measured using a 4-m computerized walkway. SD determined from the steps recorded were used as the measures of variability. Intraclass correlation coefficients (ICC) were calculated to examine test-retest reliability of a 4-m walk and two 4-m walks. To establish concurrent validity, the measures of gait variability were compared across levels of health, functional status, and physical activity using independent t tests and analysis of variances.

RESULTS: Gait variability measures from the two 4-m walks demonstrated greater test-retest reliability than those from the single 4-m walk (ICC=.22-.48 and ICC=.40-.63, respectively). Greater step length and stance time variability were associated with poorer health, functional status and physical activity (P<.05).

CONCLUSIONS: Gait variability calculated from a limited number of steps has fair to good test-retest reliability and concurrent validity. Reliability of gait variability calculated from a greater number of steps should be assessed to determine if the consistency can be improved.

%B Arch Phys Med Rehabil %V 89 %P 2293-6 %8 2008 Dec %G eng %N 12 %1 https://www.ncbi.nlm.nih.gov/pubmed/19061741?dopt=Abstract %R 10.1016/j.apmr.2008.06.010 %0 Journal Article %J Am J Cardiol %D 2009 %T Race, gender, and mortality in adults > or =65 years of age with incident heart failure (from the Cardiovascular Health Study). %A Parashar, Susmita %A Katz, Ronit %A Smith, Nicholas L %A Arnold, Alice M %A Vaccarino, Viola %A Wenger, Nanette K %A Gottdiener, John S %K African Americans %K Age Factors %K Aged %K Aged, 80 and over %K Cohort Studies %K Continental Population Groups %K European Continental Ancestry Group %K Female %K Heart Failure %K Humans %K Incidence %K Male %K Proportional Hazards Models %K Sex Factors %K United States %X

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.

%B Am J Cardiol %V 103 %P 1120-7 %8 2009 Apr 15 %G eng %N 8 %1 https://www.ncbi.nlm.nih.gov/pubmed/19361600?dopt=Abstract %R 10.1016/j.amjcard.2008.12.043 %0 Journal Article %J J Am Soc Nephrol %D 2009 %T Rapid decline of kidney function increases cardiovascular risk in the elderly. %A Shlipak, Michael G %A Katz, Ronit %A Kestenbaum, Bryan %A Siscovick, David %A Fried, Linda %A Newman, Anne %A Rifkin, Dena %A Sarnak, Mark J %K Aged %K Aged, 80 and over %K Cardiovascular Diseases %K Creatinine %K Cystatin C %K Female %K Glomerular Filtration Rate %K Heart Failure %K Humans %K Longitudinal Studies %K Male %K Myocardial Infarction %K Peripheral Vascular Diseases %K Renal Insufficiency, Chronic %K Risk Factors %K Stroke %K Time Factors %K United States %X

Chronic kidney disease (CKD), defined at a specific time point, is an important risk factor for cardiovascular disease. Whether the rate of kidney function decline contributes additional cardiovascular risk is unknown. In the Cardiovascular Health Study, we compared the associations of changes in kidney function during the first 7 yr with the incidence of heart failure (HF), myocardial infarction (MI), stroke, and peripheral arterial disease (PAD) during the subsequent 8 yr. We defined a rapid decline in cystatin C-based estimated GFR as >3 ml/min per 1.73 m(2)/yr, on the basis of determination at baseline, year 3, and year 7. Among eligible participants, 1083 (24%) had rapid kidney decline. The incidence of each type of cardiovascular event was significantly higher among patients with rapid decline (all P < 0.001). After multivariate adjustment for demographics, cardiovascular disease risk factors, and baseline kidney function, rapid kidney function decline was significantly associated with HF (adjusted hazard ratio [HR] 1.32; 95% confidence interval [CI] 1.13 to 1.53), MI (HR 1.48; 95% CI 1.21 to 1.83), and PAD (HR 1.67; 95% CI 1.02 to 2.75) but not with stroke (HR 1.19; 95% CI 0.97 to 1.45). The association of rapid decline with each outcome did not differ by the presence or absence of CKD. In conclusion, declining kidney function associates with higher risk for HF, MI, and PAD among patients with or without CKD.

%B J Am Soc Nephrol %V 20 %P 2625-30 %8 2009 Dec %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/19892934?dopt=Abstract %R 10.1681/ASN.2009050546 %0 Journal Article %J Am J Nephrol %D 2009 %T Rate of kidney function decline in older adults: a comparison using creatinine and cystatin C. %A Shlipak, Michael G %A Katz, Ronit %A Kestenbaum, Bryan %A Fried, Linda F %A Newman, Anne B %A Siscovick, David S %A Stevens, Lesley %A Sarnak, Mark J %K Age Factors %K Aged %K Creatinine %K Cystatin C %K Disease Progression %K Female %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Diseases %K Male %K Risk Factors %X

BACKGROUND/AIMS: The aim of this study was to determine the decline in the estimated glomerular filtration rate (eGFR) in elderly persons and to compare estimates based on creatinine and cystatin C.

METHODS: In the Cardiovascular Health Study, GFR changes in an elderly cohort were estimated from serum creatinine and cystatin C measured at baseline, year 3 and year 7 in 4,380 participants (age 72 +/- 5 years at entry). Outcomes were mean eGFR decline, incident chronic kidney disease (CKD) and rapid decline in eGFR (annual loss >3 ml/min/1.73 m(2)).

RESULTS: Mean annual eGFR loss as estimated from creatinine was 0.4 +/- 3.6 ml/min/1.73 m(2), with 16% of the participants experiencing a rapid decline. Mean eGFR loss as estimated from cystatin C was 1.8 +/- 2.6, with 25% of the participants experiencing a rapid decline (p < 0.001 for both). Among participants without baseline CKD, incident CKD was detected at year 7 in 10% (n = 263) using creatinine and 19% (n = 544) using cystatin C (p < 0.001). Increasing age was the strongest predictor of rapid decline; adjusted odds ratios were 1.38 (1.16-1.65), 1.62 (1.31-1.99) and 2.96 (2.28-3.84) for participants aged 70-74, 75-79 and 80+ at baseline, compared with those aged 65-69.

CONCLUSION: In elderly persons, cystatin C estimated substantially larger declines in kidney function than creatinine did. Defining the optimal measurement of kidney function in elderly persons should be a high priority for future research.

%B Am J Nephrol %V 30 %P 171-8 %8 2009 %G eng %N 3 %1 https://www.ncbi.nlm.nih.gov/pubmed/19349699?dopt=Abstract %R 10.1159/000212381 %0 Journal Article %J J Thromb Haemost %D 2009 %T Replication of findings on the association of genetic variation in 24 hemostasis genes and risk of incident venous thrombosis. %A Smith, N L %A Wiggins, K L %A Reiner, A P %A Lange, L A %A Cushman, M %A Heckbert, S R %A Lumley, T %A Rice, K M %A Folsom, A R %A Psaty, B M %K Adolescent %K Adult %K Aged %K Aged, 80 and over %K Case-Control Studies %K Cohort Studies %K Female %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genetic Variation %K Haplotypes %K Hemostasis %K Humans %K Incidence %K Male %K Menopause %K Middle Aged %K Polymorphism, Single Nucleotide %K Reproducibility of Results %K Risk %K Thrombophilia %K Venous Thrombosis %K Young Adult %B J Thromb Haemost %V 7 %P 1743-6 %8 2009 Oct %G eng %N 10 %1 http://www.ncbi.nlm.nih.gov/pubmed/19682239?dopt=Abstract %R 10.1111/j.1538-7836.2009.03567.x %0 Journal Article %J Br J Haematol %D 2010 %T Reproductive history, hormone replacement, and incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology. %A Ohira, Tetsuya %A Folsom, Aaron R %A Cushman, Mary %A White, Richard H %A Hannan, Peter J %A Rosamond, Wayne D %A Heckbert, Susan R %K Age Factors %K Aged %K Epidemiologic Methods %K Estrogen Replacement Therapy %K Female %K Humans %K Male %K Middle Aged %K Parity %K Pregnancy %K Reproductive History %K United States %K Venous Thromboembolism %X

Numerous studies have established that hormone replacement therapy increases the risk of venous thromboembolism (VTE), but an association of endogenous oestrogen exposure with the incidence of VTE is not fully established. Using a prospective design combining the Atherosclerosis Risk in Communities and the Cardiovascular Health Study cohort, we studied the 12-year risk of VTE in relation to hormone replacement therapy use, age at menopause, parity number, and type of menopause in 8236 post-menopausal women. There were no significant associations of age at menopause, parity number, or type of menopause with incidence of VTE. Women currently using hormone replacement had a 1.6-times higher multivariate-adjusted rate ratio (RR) of VTE compared with those without hormone use in the time-dependent model (RR=1.60, 95% confidence interval [CI], 1.06-2.36; Population attributable fraction=6.7%, 95%CI, 1.0-10.3). When we excluded women with 1-year or more duration of hormone therapy at baseline, the association was stronger (RR=2.02, 95%CI, 1.31-3.12). The multivariate-adjusted RRs of VTE for current users tended to be higher in those with idiopathic VTE (RR=2.40, 95%CI, 1.40-4.12) than those with secondary VTE (RR=1.08, 95%CI, 0.63-1.85). Hormone replacement therapy is associated with increased risk of VTE, but reproductive history markers of endogenous oestrogen exposure were not associated with VTE.

%B Br J Haematol %V 149 %P 606-12 %8 2010 May %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/20230397?dopt=Abstract %R 10.1111/j.1365-2141.2010.08128.x %0 Journal Article %J Circ Heart Fail %D 2011 %T The relationship between serum markers of collagen turnover and cardiovascular outcome in the elderly: the Cardiovascular Health Study. %A Barasch, Eddy %A Gottdiener, John S %A Aurigemma, Gerard %A Kitzman, Dalane W %A Han, Jing %A Kop, Willem J %A Tracy, Russell P %K Aged %K Aged, 80 and over %K Aging %K Biomarkers %K Cardiovascular Diseases %K Case-Control Studies %K Cohort Studies %K Collagen %K Collagen Type I %K Female %K Follow-Up Studies %K Heart Failure %K Humans %K Incidence %K Male %K Peptide Fragments %K Peptides %K Predictive Value of Tests %K Procollagen %K Prospective Studies %K Stroke Volume %K Survival Rate %X

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.

%B Circ Heart Fail %V 4 %P 733-9 %8 2011 Nov %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21900186?dopt=Abstract %R 10.1161/CIRCHEARTFAILURE.111.962027 %0 Journal Article %J J Cardiovasc Electrophysiol %D 2011 %T Relationship of abnormal heart rate turbulence and elevated CRP to cardiac mortality in low, intermediate, and high-risk older adults. %A Stein, Phyllis K %A Barzilay, Joshua I %K Aged %K C-Reactive Protein %K Cardiovascular Diseases %K Comorbidity %K Electrocardiography, Ambulatory %K Female %K Humans %K Incidence %K Male %K Risk Assessment %K Risk Factors %K Statistics as Topic %K Survival Analysis %K Survival Rate %K United States %K Ventricular Premature Complexes %X

INTRODUCTION: We examined whether heart rate turbulence (HRT) and C-reactive protein (CRP) add to traditional risk factors for cardiac mortality in older adults at low, intermediate, and high risk.

METHODS AND RESULTS: One thousand two hundred and seventy-two individuals, age ≥ 65 years, with 24-hour Holter recordings were studied. HRT, which quantifies heart rate response to ventricular premature contractions, was categorized as: both turbulence onset (TO) and turbulence slope (TS) normal; TO abnormal; TS abnormal; or both abnormal. Independent risks for cardiac mortality associated with HRT or, for comparison, elevated CRP (>3.0 mg/L), were calculated using Cox regression analysis adjusted for traditional cardiovascular disease risk factors and stratified by the presence of no, isolated subclinical (i.e., intermediate risk) or clinical cardiovascular disease. Having TS + TO abnormal compared to both normal was associated with cardiac mortality in the low-risk group [HR 7.9, 95% confidence interval (CI) 2.8-22.5, (P < 0.001)]. In the high and intermediate risk groups, abnormal TS and TS + TO ([HR 2.2, 95% CI 1.5-4.0, P = 0.016] and [HR 2.7, 95% CI 1.2-5.9, P = 0.012]), respectively, were also significantly associated with cardiac mortality. In contrast, elevated CRP was associated with increased cardiac mortality risk only in low-risk individuals [HR 2.5, 95% CI 1.3-5.1, P = 0.009]. Among low risk, the c-statistic was 0.706 for the base model, 0.725 for the base model with CRP, and 0.767 for the base model with HRT.

CONCLUSIONS: Abnormal HRT independently adds to risk stratification of low, intermediate and high-risk individuals, but HRT and CRP appear to both add to stratification of those considered low risk.

%B J Cardiovasc Electrophysiol %V 22 %P 122-7 %8 2011 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/21134026?dopt=Abstract %R 10.1111/j.1540-8167.2010.01967.x %0 Journal Article %J Stroke %D 2011 %T Retinal microvascular signs and functional loss in older persons: the cardiovascular health study. %A Kim, Dae Hyun %A Newman, Anne B %A Hajjar, Ihab %A Strotmeyer, Elsa S %A Klein, Ronald %A Newton, Elizabeth %A Sarnak, Mark J %A Burke, Gregory L %A Lipsitz, Lewis A %K Aged %K Cardiovascular Diseases %K Depressive Disorder %K Frontal Lobe %K Humans %K Microcirculation %K Neuropsychological Tests %K Retinal Diseases %K Retinal Vessels %K Risk Factors %X

BACKGROUND AND PURPOSE: We hypothesized that retinal microvascular signs are associated with executive dysfunction, slow gait, and depressive mood, which are characteristic features of microvascular disease affecting frontal subcortical regions of the brain.

METHODS: In the Cardiovascular Health Study, 1744 participants (mean age, 78) free of stroke had retinal photographs and carotid ultrasound during the 1997 to 1998 visit. We examined the cross-sectional association of retinal signs with the digit-symbol substitution test (DSST) score, gait speed, the Center for Epidemiologic Studies-Depression score, and depressive mood, defined as Center for Epidemiologic Studies-Depression score >9 or antidepressant use.

RESULTS: After adjusting for potential confounders, retinal signs were associated with lower DSST score (generalized arteriolar narrowing and arteriovenous nicking), slower gait (retinopathy), and depressive mood (generalized arteriolar narrowing). A higher number of retinal signs was associated with lower DSST score (-0.76 and -2.79 points for 1 sign and ≥2 signs versus none; P<0.001) and slower gait (-0.009 and -0.083 m/s; P=0.047), but not with the square root of Center for Epidemiologic Studies-Depression score (0.079 and -0.208; P=0.072). In addition, coexistence of retinal signs (generalized arteriolar narrowing and arteriovenous nicking) and carotid atherosclerosis was associated with lower DSST score compared with either process alone (P for interaction <0.01). Notably, further adjustment for ventricular size, white matter disease, and infarcts on MRI did not attenuate the association.

CONCLUSIONS: Retinal signs are associated with executive dysfunction and slow gait, and possibly with depressive mood, suggesting a common process involving small vessels.

%B Stroke %V 42 %P 1589-95 %8 2011 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/21493913?dopt=Abstract %R 10.1161/STROKEAHA.110.605261 %0 Journal Article %J J Card Fail %D 2011 %T Risk factors for onset of disability among older persons newly diagnosed with heart failure: the Cardiovascular Health Study. %A Chaudhry, Sarwat I %A McAvay, Gail %A Ning, Yuming %A Allore, Heather G %A Newman, Anne B %A Gill, Thomas M %K Activities of Daily Living %K Age Factors %K Aged %K Aged, 80 and over %K Disability Evaluation %K Disabled Persons %K Female %K Health Status %K Heart Failure %K Humans %K Longitudinal Studies %K Male %K Risk Factors %X

BACKGROUND: As the heart failure population continues to age, disability is becoming an increasingly important issue. Our objective was to identify risk factors for the onset of disability in activities of daily living among older persons with heart failure.

METHODS: The study population included participants with newly diagnosed heart failure from the Cardiovascular Health Study, a longitudinal study of community-living, older persons. Data were collected through annual examinations. Cox regression modeling was used to examine associations between time-dependent predictors and onset of disability.

RESULTS: Of 461 participants newly diagnosed with heart failure (mean age 78.7 [SD 5.89]), 23% subsequently developed disability. The first year after heart failure diagnosis was the period of greatest risk for onset of disability (chi-square P value <.001). Factors that were independently associated with disability included: impaired gait speed (HR 2.29, 95% CI 1.34-3.90); impaired cognition (HR 1.87, 95% CI 1.14-3.05); and depressive symptoms (HR 1.72, 95% CI 1.04-2.83).

CONCLUSIONS: Onset of disability is a common occurrence among older persons newly diagnosed with heart failure. Risk factors for onset of disability in this population are potentially modifiable, and should be routinely assessed in an effort to reduce disability in this growing population.

%B J Card Fail %V 17 %P 764-70 %8 2011 Sep %G eng %N 9 %1 http://www.ncbi.nlm.nih.gov/pubmed/21872147?dopt=Abstract %R 10.1016/j.cardfail.2011.04.015 %0 Journal Article %J Neuroepidemiology %D 2011 %T The risk of Parkinson disease associated with urate in a community-based cohort of older adults. %A Jain, S %A Ton, T G %A Boudreau, R M %A Yang, M %A Thacker, E L %A Studenski, S %A Longstreth, W T %A Strotmeyer, E S %A Newman, A B %K Aged %K California %K Cohort Studies %K Female %K Humans %K Male %K Maryland %K North Carolina %K Parkinson Disease %K Pennsylvania %K Prospective Studies %K Risk Factors %K Sex Distribution %K Sex Factors %K Uric Acid %X

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.

%B Neuroepidemiology %V 36 %P 223-9 %8 2011 %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/21677446?dopt=Abstract %R 10.1159/000327748 %0 Journal Article %J Circulation %D 2012 %T 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. %A Feinstein, Matthew %A Ning, Hongyan %A Kang, Joseph %A Bertoni, Alain %A Carnethon, Mercedes %A Lloyd-Jones, Donald M %K African Continental Ancestry Group %K Age Factors %K Aged %K Aged, 80 and over %K Atherosclerosis %K Cardiovascular Diseases %K Cohort Studies %K Continental Population Groups %K Ethnic Groups %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Residence Characteristics %K Risk Factors %X

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.

%B Circulation %V 126 %P 50-9 %8 2012 Jul 03 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/22693351?dopt=Abstract %R 10.1161/CIRCULATIONAHA.111.057232 %0 Journal Article %J Arch Ophthalmol %D 2012 %T Retinal microvascular signs and disability in the Cardiovascular Health Study. %A Kim, Dae Hyun %A Chaves, Paulo H M %A Newman, Anne B %A Klein, Ronald %A Sarnak, Mark J %A Newton, Elizabeth %A Strotmeyer, Elsa S %A Burke, Gregory L %A Lipsitz, Lewis A %K Activities of Daily Living %K Aged %K Carotid Artery Diseases %K Cognition Disorders %K Diagnostic Techniques, Ophthalmological %K Disability Evaluation %K Follow-Up Studies %K Humans %K Hypertension %K Incidence %K Kaplan-Meier Estimate %K Microcirculation %K Predictive Value of Tests %K Prevalence %K Prognosis %K Prospective Studies %K Retinal Diseases %K Risk Factors %K Smoking %X

OBJECTIVE: To study the associations of retinal microvascular changes, which are associated with systemic conditions and cognitive decline, with disability in performing activities of daily living (ADL).

DESIGN: Prospective cohort study of 1487 community-dwelling participants in the Cardiovascular Health Study (mean age, 78 years) who were free of ADL disability and had available data on retinal signs and carotid intima-media thickness at the 1998-1999 visit. Main outcome measures were incident ADL disability, defined as self-reported difficulty in performing any ADL, by the presence of retinal signs and advanced carotid atherosclerosis, defined by carotid intima-media thickness in the 80th percentile or more or 25% or more stenosis, and potential mediation by cerebral microvascular disease on brain imaging or by executive dysfunction, slow gait, and depressive mood, which are symptoms of frontal subcortical dysfunction.

RESULTS: During the median follow-up of 3.1 years (maximum, 7.8 years), participants with 2 or more retinal signs had a higher rate of disability than those with fewer than 2 retinal signs (10.1% vs 7.1%; adjusted hazard ratio, 1.45; 95% confidence interval, 1.24-1.69; P < .001). There was no evidence of interaction by advanced carotid atherosclerosis (P > .10). The association seemed to be partially mediated by executive dysfunction, slow gait, and depressive symptoms but not by cerebral microvascular disease on brain imaging.

CONCLUSIONS: These results provide further support for the pathophysiologic and prognostic significance of microvascular disease in age-related disability. However, it remains to be determined how to best use retinal photography in clinical risk prediction.

%B Arch Ophthalmol %V 130 %P 350-6 %8 2012 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/22084159?dopt=Abstract %R 10.1001/archophthalmol.2011.360 %0 Journal Article %J Am J Kidney Dis %D 2012 %T The risk of infection-related hospitalization with decreased kidney function. %A Dalrymple, Lorien S %A Katz, Ronit %A Kestenbaum, Bryan %A de Boer, Ian H %A Fried, Linda %A Sarnak, Mark J %A Shlipak, Michael G %K Aged %K Cohort Studies %K Female %K Glomerular Filtration Rate %K Hospitalization %K Humans %K Infection %K Kidney %K Male %K Risk Factors %X

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.

%B Am J Kidney Dis %V 59 %P 356-63 %8 2012 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/21906862?dopt=Abstract %R 10.1053/j.ajkd.2011.07.012 %0 Journal Article %J Ann Neurol %D 2012 %T Risk of intraparenchymal hemorrhage with magnetic resonance imaging-defined leukoaraiosis and brain infarcts. %A Folsom, Aaron R %A Yatsuya, Hiroshi %A Mosley, Thomas H %A Psaty, Bruce M %A Longstreth, W T %K Cerebral Infarction %K Cohort Studies %K Female %K Humans %K Incidence %K Intracranial Hemorrhages %K Leukoaraiosis %K Magnetic Resonance Imaging %K Male %K Middle Aged %K Risk Factors %X

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.

%B Ann Neurol %V 71 %P 552-9 %8 2012 Apr %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/22522444?dopt=Abstract %R 10.1002/ana.22690 %0 Journal Article %J J Am Geriatr Soc %D 2013 %T Racial differences in the incidence of and risk factors for atrial fibrillation in older adults: the cardiovascular health study. %A Jensen, Paul N %A Thacker, Evan L %A Dublin, Sascha %A Psaty, Bruce M %A Heckbert, Susan R %K Aged %K Atrial Fibrillation %K Continental Population Groups %K Female %K Follow-Up Studies %K Humans %K Incidence %K Male %K Prevalence %K Risk Assessment %K Risk Factors %K Stroke %K United States %X

This study examined whether different associations between risk factors and atrial fibrillation (AF) according to race could explain the lower incidence of AF in blacks. Baseline risk factor information was obtained from interviews, clinical examinations, and echocardiography in 4,774 white and 911 black Cardiovascular Health Study participants aged 65 and older without a history of AF at baseline in 1989/90 or 1992/93. Incident AF was determined according to hospital discharge diagnosis or annual study electrocardiogram. Cox regression was used to assess associations between risk factors and race and incident AF. During a mean 11.2 years of follow-up, 1,403 whites and 182 blacks had incident AF. Associations between all examined risk factors were similar in both races, except left ventricular posterior wall thickness, which was more strongly associated with AF in blacks (per 0.2 cm, blacks: hazard ratio (HR) = 1.72, 95% confidence interval (CI) = 1.44-2.06; whites: HR = 1.30, 95% CI = 1.18-1.43). Overall, the relative risk of AF was 25% lower in blacks than whites after adjustment for age and sex (HR = 0.75, 95% CI = 0.64-0.87) and 45% lower after adjustment for all considered risk factors (HR = 0.55, 95% CI = 0.35-0.88). Different associations of the considered risk factors and incident AF by race do not explain the lower incidence of AF in blacks.

%B J Am Geriatr Soc %V 61 %P 276-80 %8 2013 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/23320758?dopt=Abstract %R 10.1111/jgs.12085 %0 Journal Article %J Am J Cardiol %D 2013 %T Relation of vitamin D and parathyroid hormone to cardiac biomarkers and to left ventricular mass (from the Cardiovascular Health Study). %A van Ballegooijen, Adriana J %A Visser, Marjolein %A Kestenbaum, Bryan %A Siscovick, David S %A de Boer, Ian H %A Gottdiener, John S %A deFilippi, Christopher R %A Brouwer, Ingeborg A %K Adult %K Aged %K Biomarkers %K Cardiovascular Diseases %K Echocardiography %K Electrocardiography %K Female %K Follow-Up Studies %K Heart Ventricles %K Humans %K Incidence %K Male %K Mass Spectrometry %K Middle Aged %K Parathyroid Hormone %K Prospective Studies %K United States %K Vitamin D %X

Vitamin D and parathyroid hormone (PTH) may affect cardiovascular health in patients with kidney disease and in the general population. The aim of this study was to investigate associations of serum 25-hydroxyvitamin D (25(OH)D) and PTH concentrations with a comprehensive set of biochemical, electrocardiographic, and echocardiographic measurements of cardiac structure and function in the Cardiovascular Health Study. A total of 2,312 subjects who were free of cardiovascular disease at baseline were studied. Serum 25(OH)D and intact PTH concentrations were measured using mass spectrometry and a 2-site immunoassay. Outcomes were N-terminal pro-B-type natriuretic peptide, cardiac troponin T, electrocardiographic measures of conduction, and echocardiographic measures of left ventricular mass and diastolic dysfunction. At baseline, subjects had a mean age of 73.9 ± 4.9 years, 69.7% were women, and 21% had chronic kidney disease (glomerular filtration rate <60 ml/min). Mean 25(OH)D was 25.2 ± 10.2 ng/ml, and median PTH was 51 pg/ml (range 39 to 65). After adjustment, 25(OH)D was not associated with any of the biochemical, conduction, or echocardiographic outcomes. Serum PTH levels ≥65 pg/ml were associated with greater N-terminal pro-B-type natriuretic peptide, cardiac troponin T, and left ventricular mass in patients with chronic kidney disease. The regression coefficients were: 120 pg/ml (95% confidence interval 36.1 to 204), 5.2 pg/ml (95% confidence interval 3.0 to 7.4), and 17 g (95% confidence interval 6.2 to 27.8) (p <0.001). In subjects with normal kidney function, PTH was not associated with the outcomes. In conclusion, in older adults with chronic kidney disease, PTH excess is associated with higher N-terminal pro-B-type natriuretic peptide, cardiac troponin T, and left ventricular mass. These findings suggest a role for PTH in cardiovascular health and the prevention of cardiac diseases.

%B Am J Cardiol %V 111 %P 418-24 %8 2013 Feb 01 %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/23168286?dopt=Abstract %R 10.1016/j.amjcard.2012.10.021 %0 Journal Article %J Hum Reprod %D 2013 %T Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study. %A Carty, C L %A Spencer, K L %A Setiawan, V W %A Fernandez-Rhodes, L %A Malinowski, J %A Buyske, S %A Young, A %A Jorgensen, N W %A Cheng, I %A Carlson, C S %A Brown-Gentry, K %A Goodloe, R %A Park, A %A Parikh, N I %A Henderson, B %A Le Marchand, L %A Wactawski-Wende, J %A Fornage, M %A Matise, T C %A Hindorff, L A %A Arnold, A M %A Haiman, C A %A Franceschini, N %A Peters, U %A Crawford, D C %K Age Factors %K Cross-Sectional Studies %K Female %K Genome-Wide Association Study %K Genotype %K Humans %K Menarche %K Menopause %K Polymorphism, Single Nucleotide %X

STUDY QUESTION: Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study?

SUMMARY ANSWER: We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry.

WHAT IS KNOWN ALREADY: Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations.

STUDY DESIGN, SIZE, DURATION: A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM.

MATERIALS, SETTING, METHODS: SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P < 0.01 for ANM analyses and P < 0.017 for AM analyses.

MAIN RESULTS AND THE ROLE OF CHANCE: We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends.

LIMITATIONS, REASONS FOR CAUTION: Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings.

WIDER IMPLICATIONS OF THE FINDINGS: The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research.

%B Hum Reprod %V 28 %P 1695-706 %8 2013 Jun %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23508249?dopt=Abstract %R 10.1093/humrep/det071 %0 Journal Article %J Circulation %D 2013 %T Resequencing and clinical associations of the 9p21.3 region: a comprehensive investigation in the Framingham heart study. %A Johnson, Andrew D %A Hwang, Shih-Jen %A Voorman, Arend %A Morrison, Alanna %A Peloso, Gina M %A Hsu, Yi-Hsiang %A Thanassoulis, George %A Newton-Cheh, Christopher %A Rogers, Ian S %A Hoffmann, Udo %A Freedman, Jane E %A Fox, Caroline S %A Psaty, Bruce M %A Boerwinkle, Eric %A Cupples, L Adrienne %A O'Donnell, Christopher J %K Calcinosis %K Chromosomes, Human, Pair 9 %K Coronary Artery Disease %K Cyclin-Dependent Kinase Inhibitor p15 %K Cyclin-Dependent Kinase Inhibitor p16 %K DNA Copy Number Variations %K Female %K Follow-Up Studies %K Genetic Predisposition to Disease %K Genotype %K Humans %K Longitudinal Studies %K Male %K Massachusetts %K Middle Aged %K Myocardial Infarction %K Phenotype %K Polymorphism, Single Nucleotide %K Risk Factors %K RNA, Long Noncoding %K Sequence Analysis, DNA %X

BACKGROUND: 9p21.3 is among the most strongly replicated regions for cardiovascular disease. There are few reports of sequencing the associated 9p21.3 interval. We set out to sequence the 9p21.3 region followed by a comprehensive study of genetic associations with clinical and subclinical cardiovascular disease and its risk factors, as well as with copy number variation and gene expression, in the Framingham Heart Study (FHS).

METHODS AND RESULTS: We sequenced 281 individuals (94 with myocardial infarction, 94 with high coronary artery calcium levels, and 93 control subjects free of elevated coronary artery calcium or myocardial infarction), followed by genotyping and association in >7000 additional FHS individuals. We assessed genetic associations with clinical and subclinical cardiovascular disease, risk factor phenotypes, and gene expression levels of the protein-coding genes CDKN2A and CDKN2B and the noncoding gene ANRIL in freshly harvested leukocytes and platelets. Within this large sample, we found strong associations of 9p21.3 variants with increased risk for myocardial infarction, higher coronary artery calcium levels, and larger abdominal aorta diameters and no evidence for association with traditional cardiovascular disease risk factors. No common protein-coding variation, variants in splice donor or acceptor sites, or copy number variation events were observed. By contrast, strong associations were observed between genetic variants and gene expression, particularly for a short isoform of ANRIL and for CDKN2B.

CONCLUSIONS: Our thorough genomic characterization of 9p21.3 suggests common variants likely account for observed disease associations and provides further support for the hypothesis that complex regulatory variation affecting ANRIL and CDKN2B gene expression may contribute to increased risk for clinically apparent and subclinical coronary artery disease and aortic disease.

%B Circulation %V 127 %P 799-810 %8 2013 Feb 19 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/23315372?dopt=Abstract %R 10.1161/CIRCULATIONAHA.112.111559 %0 Journal Article %J Exp Aging Res %D 2013 %T Results differ by applying distinctive multiple imputation approaches on the longitudinal cardiovascular health study data. %A Ning, Yuming %A McAvay, Gail %A Chaudhry, Sarwat I %A Arnold, Alice M %A Allore, Heather G %K Activities of Daily Living %K Aged %K Arthritis %K Cardiac Rehabilitation %K Cardiovascular Diseases %K Data Interpretation, Statistical %K Female %K Humans %K Longitudinal Studies %K Male %K Outcome Assessment (Health Care) %K Regression Analysis %K Social Support %X

UNLABELLED: BACKGROUND/STUDY CONTEXT: The objective of this study was to examine sequential and simultaneous approaches to multiple imputation of missing data in a longitudinal data set where losses due to death were common.

METHODS: Comparison of results from analyses and simulations of time to incident difficulty of activities of daily living (ADL) in the Cardiovascular Health Study when missing data were imputed simultaneously or sequentially.

RESULTS: Results differed with imputation methods. The largest proportional differences in 12 risk factor parameter estimates were heart failure by 106%, social support by 33%, and arthritis by 27%.

CONCLUSION: Decedents' final characteristics were influential on future imputations of those with missing values.

%B Exp Aging Res %V 39 %P 27-43 %8 2013 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/23316735?dopt=Abstract %R 10.1080/0361073X.2013.741968 %0 Journal Article %J J Am Coll Cardiol %D 2013 %T Risk factors for hospital admission among older persons with newly diagnosed heart failure: findings from the Cardiovascular Health Study. %A Chaudhry, Sarwat I %A McAvay, Gail %A Chen, Shu %A Whitson, Heather %A Newman, Anne B %A Krumholz, Harlan M %A Gill, Thomas M %K Age Factors %K Aged %K Aged, 80 and over %K Comorbidity %K Effect Modifier, Epidemiologic %K Female %K Geriatric Assessment %K Health Surveys %K Heart Failure %K Hospitalization %K Humans %K Longitudinal Studies %K Male %K Mental Competency %K Risk Assessment %K Risk Factors %K Severity of Illness Index %K Stroke Volume %K Time-to-Treatment %K United States %X

OBJECTIVES: This study sought to identify risk factors for the occurrence of all-cause hospital admissions among older persons after heart failure diagnosis, and to determine whether geriatric conditions would emerge as independent risk factors for admission when evaluated in the context of other relevant clinical data.

BACKGROUND: Efforts to reduce costs in heart failure have focused on hospital utilization, yet few studies have examined how geriatric conditions affect the long-term risk for hospital admission after heart failure diagnosis. With the aging of the population with heart failure, geriatric conditions such as slow gait and muscle weakness are becoming increasingly common.

METHODS: The study population included participants with a new diagnosis of heart failure in the Cardiovascular Health Study, a longitudinal study of community-living older persons. Data were collected through annual examinations and medical-record reviews. Geriatric conditions assessed were slow gait, muscle weakness (defined as weak grip), cognitive impairment, and depressive symptoms. Anderson-Gill regression modeling was used to determine the predictors of hospital admission after heart failure diagnosis.

RESULTS: Of the 758 participants with a new diagnosis of heart failure, the mean rate of hospital admission was 7.9 per 10 person-years (95% CI: 7.4 to 8.4). Independent risk factors for hospital admission included diabetes mellitus (HR: 1.36; 95% CI: 1.13 to 1.64), New York Heart Association functional class III or IV (HR: 1.32; 95% CI: 1.11 to 1.57), chronic kidney disease (HR: 1.32; 95% CI: 1.14 to 1.53), slow gait (HR: 1.28; 95% CI: 1.06 to 1.55), depressed ejection fraction (HR: 1.25; 95% CI: 1.04 to 1.51), depression (HR: 1.23; 95% CI: 1.05 to 1.45), and muscle weakness (HR: 1.19; 95% CI: 1.00 to 1.42).

CONCLUSIONS: Geriatric conditions are important, and potentially modifiable, risk factors for hospital admission in heart failure that should be routinely assessed at the time of heart failure diagnosis.

%B J Am Coll Cardiol %V 61 %P 635-42 %8 2013 Feb 12 %G eng %N 6 %1 http://www.ncbi.nlm.nih.gov/pubmed/23391194?dopt=Abstract %& 635 %R 10.1016/j.jacc.2012.11.027 %0 Journal Article %J Am J Epidemiol %D 2013 %T Risk factors for type 2 diabetes mellitus preceded by β-cell dysfunction, insulin resistance, or both in older adults: the Cardiovascular Health Study. %A Imamura, Fumiaki %A Mukamal, Kenneth J %A Meigs, James B %A Luchsinger, José A %A Ix, Joachim H %A Siscovick, David S %A Mozaffarian, Dariush %K Adiposity %K Age Factors %K Aged %K Aged, 80 and over %K Aging %K Alcohol Drinking %K Blood Pressure %K Cross-Sectional Studies %K Diabetes Mellitus, Type 2 %K Female %K Humans %K Incidence %K Insulin Resistance %K Insulin-Secreting Cells %K Lipids %K Male %K Prospective Studies %K Risk Factors %K Socioeconomic Factors %K United States %X

Insulin resistance (IR) and pancreatic β-cell dysfunction lead to type 2 diabetes mellitus (DM). We tested whether risk factors would differ for DM that was preceded predominantly by IR, β-cell dysfunction, or both among 4,384 older adults (mean age, 72.7 (standard deviation, 5.6) years) in the Cardiovascular Health Study, which was conducted in North Carolina, California, Maryland, and Pennsylvania (1989-2007). When evaluating established risk factors, we found older age, greater adiposity, higher systolic blood pressure, a lower high-density lipoprotein cholesterol level, a higher triglyceride level, and a lower alcohol intake to be independently associated with greater IR but, conversely, with better β-cell function (P < 0.001). The prospective associations between some risk factors and incident DM varied significantly depending on whether DM was preceded predominantly by IR, β-cell dysfunction, or both. For example, obesity and lower high-density lipoprotein cholesterol levels were positively associated with DM preceded predominantly by IR (hazard ratio (HR) = 5.02, 95% confidence interval (CI): 2.81, 9.00; and HR = 1.97, 95% CI: 1.32, 2.93, respectively), with a significant association with and an insignificant trend toward a lower risk of DM preceded predominantly by β-cell dysfunction (HR = 0.33, 95% CI: 0.14, 0.80; and HR = 0.78, 95% CI: 0.43, 1.39, respectively). In conclusion, among older adults, DM risk factors were differentially associated with DM preceded predominantly by IR or β-cell dysfunction. Biologic and clinical implications of putative subtypes of DM require further investigation.

%B Am J Epidemiol %V 177 %P 1418-29 %8 2013 Jun 15 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/23707958?dopt=Abstract %& 1418 %R 10.1093/aje/kws440 %0 Journal Article %J Eur J Epidemiol %D 2013 %T Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls. %A Simone, Benedetto %A De Stefano, Valerio %A Leoncini, Emanuele %A Zacho, Jeppe %A Martinelli, Ida %A Emmerich, Joseph %A Rossi, Elena %A Folsom, Aaron R %A Almawi, Wassim Y %A Scarabin, Pierre Y %A den Heijer, Martin %A Cushman, Mary %A Penco, Silvana %A Vaya, Amparo %A Angchaisuksiri, Pantep %A Okumus, Gulfer %A Gemmati, Donato %A Cima, Simona %A Akar, Nejat %A Oguzulgen, Kivilcim I %A Ducros, Véronique %A Lichy, Christoph %A Fernandez-Miranda, Consuelo %A Szczeklik, Andrzej %A Nieto, José A %A Torres, Jose Domingo %A Le Cam-Duchez, Véronique %A Ivanov, Petar %A Cantu-Brito, Carlos %A Shmeleva, Veronika M %A Stegnar, Mojka %A Ogunyemi, Dotun %A Eid, Suhair S %A Nicolotti, Nicola %A De Feo, Emma %A Ricciardi, Walter %A Boccia, Stefania %K Case-Control Studies %K Factor V %K Genetic Predisposition to Disease %K Humans %K Methylenetetrahydrofolate Reductase (NADPH2) %K Prothrombin %K Risk Factors %K Venous Thromboembolism %X

Genetic and environmental factors interact in determining the risk of venous thromboembolism (VTE). The risk associated with the polymorphic variants G1691A of factor V (Factor V Leiden, FVL), G20210A of prothrombin (PT20210A) and C677T of methylentetrahydrofolate reductase (C677T MTHFR) genes has been investigated in many studies. We performed a pooled analysis of case-control and cohort studies investigating in adults the association between each variant and VTE, published on Pubmed, Embase or Google through January 2010. Authors of eligible papers, were invited to provide all available individual data for the pooling. The Odds Ratio (OR) for first VTE associated with each variant, individually and combined with the others, were calculated with a random effect model, in heterozygotes and homozygotes (dominant model for FVL and PT20210A; recessive for C677T MTHFR). We analysed 31 databases, including 11,239 cases and 21,521 controls. No significant association with VTE was found for homozygous C677T MTHFR (OR: 1.38; 95 % confidence intervals [CI]: 0.98-1.93), whereas the risk was increased in carriers of either heterozygous FVL or PT20210 (OR = 4.22; 95 % CI: 3.35-5.32; and OR = 2.79;95 % CI: 2.25-3.46, respectively), in double heterozygotes (OR = 3.42; 95 %CI 1.64-7.13), and in homozygous FVL or PT20210A (OR = 11.45; 95 %CI: 6.79-19.29; and OR: 6.74 (CI 95 % 2.19-20.72), respectively). The stratified analyses showed a stronger effect of FVL on individuals ≤ 45 years (p value for interaction = 0.036) and of PT20210A in women using oral contraceptives (p-value for interaction = 0.045). In this large pooled analysis, inclusive of large studies like MEGA, no effect was found for C677T MTHFR on VTE; FVL and PT20210A were confirmed to be moderate risk factors. Notably, double carriers of the two genetic variants produced an impact on VTE risk significantly increased but weaker than previously thought.

%B Eur J Epidemiol %V 28 %P 621-47 %8 2013 Aug %G eng %N 8 %1 http://www.ncbi.nlm.nih.gov/pubmed/23900608?dopt=Abstract %R 10.1007/s10654-013-9825-8 %0 Journal Article %J Circulation %D 2014 %T Racial and regional differences in venous thromboembolism in the United States in 3 cohorts. %A Zakai, Neil A %A McClure, Leslie A %A Judd, Suzanne E %A Safford, Monika M %A Folsom, Aaron R %A Lutsey, Pamela L %A Cushman, Mary %K African Continental Ancestry Group %K Aged %K Cohort Studies %K European Continental Ancestry Group %K Female %K Humans %K Longitudinal Studies %K Male %K Middle Aged %K Prevalence %K Proportional Hazards Models %K Prospective Studies %K Residence Characteristics %K Risk Factors %K United States %K Venous Thromboembolism %X

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.

%B Circulation %V 129 %P 1502-9 %8 2014 Apr 08 %G eng %N 14 %1 http://www.ncbi.nlm.nih.gov/pubmed/24508826?dopt=Abstract %R 10.1161/CIRCULATIONAHA.113.006472 %0 Journal Article %J J Clin Endocrinol Metab %D 2014 %T Ratio of urine albumin to creatinine attenuates the association of dementia with hip fracture risk. %A Bůzková, Petra %A Barzilay, Joshua I %A Fink, Howard A %A Robbins, John A %A Cauley, Jane A %A Fitzpatrick, Annette L %K Aged %K Aged, 80 and over %K Albuminuria %K Creatinine %K Dementia %K Female %K Hip Fractures %K Humans %K Incidence %K Magnetic Resonance Imaging %K Male %K Mild Cognitive Impairment %K Neuropsychological Tests %K Prospective Studies %K Risk %X

CONTEXT: Microvascular disease is a leading cause of cognitive impairment. Approximately 50% of people with a hip fracture have cognitive impairment.

OBJECTIVE: We tested the hypothesis that microvascular diseases of the brain (lacunar infarcts and white matter disease [WMD]), kidney (albuminuria [≥ 30 mg/g creatinine] and albumin creatinine ratio [ACR]), and eye (retinal vascular disorders) attenuate the association of cognitive impairment with hip fracture risk.

SETTING: The Cardiovascular Health Cognition Study.

PATIENTS: Three thousand, one-hundred six participants (mean age, ∼ 79 y; 8.84 y median follow-up) with cognitive testing. Subsets received ACR testing (n=2389), brain magnetic resonance imaging scans (n = 2094), and retinal photography (n = 1098).

MAIN OUTCOME MEASURE: Incident hip fracture.

RESULTS: There were 488 participants (16%) with mild cognitive impairment (MCI) and 564 (18%) with dementia. There were 337 incident hip fractures, of which 19% occurred in participants with MCI and 26% in participants with dementia. Adjusted hazard ratios (HR) and 95% confidence interval for hip fracture in participants with MCI were 2.45 (1.67-3.61) and for dementia 2.35 (1.57-3.52). With doubling of ACR, the HR for fracture was attenuated in participants with dementia compared with participants with normal cognition [interaction HR 0.70 (0.55-0.91)]. No such effect was found in participants with MCI. Albuminuria, lacunar infarcts, WMD, and retinal vascular disease (RVD) did not modify the association of dementia or MCI with hip fracture risk.

CONCLUSIONS: ACR attenuates part of the risk of hip fracture in people with dementia, suggesting that these disorders share a common pathogenesis.

%B J Clin Endocrinol Metab %V 99 %P 4116-23 %8 2014 Nov %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/25148233?dopt=Abstract %R 10.1210/jc.2014-2409 %0 Journal Article %J Am J Prev Med %D 2014 %T Regular fish consumption and age-related brain gray matter loss. %A Raji, Cyrus A %A Erickson, Kirk I %A Lopez, Oscar L %A Kuller, Lewis H %A Gach, H Michael %A Thompson, Paul M %A Riverol, Mario %A Becker, James T %K Aged %K Aged, 80 and over %K Animals %K Brain %K Cross-Sectional Studies %K Diet %K Fatty Acids, Omega-3 %K Female %K Fishes %K Gray Matter %K Humans %K Life Style %K Magnetic Resonance Imaging %K Male %K Regression Analysis %K Surveys and Questionnaires %X

BACKGROUND: Brain health may be affected by modifiable lifestyle factors; consuming fish and antioxidative omega-3 fatty acids may reduce brain structural abnormality risk.

PURPOSE: To determine whether dietary fish consumption is related to brain structural integrity among cognitively normal elders.

METHODS: Data were analyzed from 260 cognitively normal individuals from the Cardiovascular Health Study with information on fish consumption from the National Cancer Institute Food Frequency Questionnaire and brain magnetic resonance imaging (MRI). The relationship between fish consumption data collected in 1989-1990 and brain structural MRI obtained in 1998-1999 was assessed using voxel-based morphometry in multiple regression analyses in 2012. Covariates were age, gender, race, education, white matter lesions, MRI-identified infarcts, waist-hip ratio, and physical activity as assessed by the number of city blocks walked in 1 week. Volumetric changes were further modeled with omega-3 fatty acid estimates to better understand the mechanistic link between fish consumption, brain health, and Alzheimer disease.

RESULTS: Weekly consumption of baked or broiled fish was positively associated with gray matter volumes in the hippocampus, precuneus, posterior cingulate, and orbital frontal cortex even after adjusting for covariates. These results did not change when including omega-3 fatty acid estimates in the analysis.

CONCLUSIONS: Dietary consumption of baked or broiled fish is related to larger gray matter volumes independent of omega-3 fatty acid content. These findings suggest that a confluence of lifestyle factors influence brain health, adding to the growing body of evidence that prevention strategies for late-life brain health need to begin decades earlier.

%B Am J Prev Med %V 47 %P 444-51 %8 2014 Oct %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/25084680?dopt=Abstract %R 10.1016/j.amepre.2014.05.037 %0 Journal Article %J Am J Cardiol %D 2014 %T Relations of plasma total and high-molecular-weight adiponectin to new-onset heart failure in adults ≥65 years of age (from the Cardiovascular Health study). %A Karas, Maria G %A Benkeser, David %A Arnold, Alice M %A Bartz, Traci M %A Djoussé, Luc %A Mukamal, Kenneth J %A Ix, Joachim H %A Zieman, Susan J %A Siscovick, David S %A Tracy, Russell P %A Mantzoros, Christos S %A Gottdiener, John S %A deFilippi, Christopher R %A Kizer, Jorge R %K Adiponectin %K Age of Onset %K Aged %K Biomarkers %K Cross-Sectional Studies %K Echocardiography, Doppler %K Enzyme-Linked Immunosorbent Assay %K Female %K Follow-Up Studies %K Heart Failure %K Humans %K Incidence %K Male %K Prognosis %K Prospective Studies %K Recurrence %K Severity of Illness Index %K United States %K Ventricular Function, Left %X

Adiponectin exhibits cardioprotective properties in experimental studies, but elevated levels have been linked to increased mortality in older adults and patients with chronic heart failure (HF). The adipokine's association with new-onset HF remains less well defined. The aim of this study was to investigate the associations of total and high-molecular weight (HMW) adiponectin with incident HF (n = 780) and, in a subset, echocardiographic parameters in a community-based cohort of adults aged ≥65 years. Total and HMW adiponectin were measured in 3,228 subjects without prevalent HF, atrial fibrillation or CVD. The relations of total and HMW adiponectin with HF were nonlinear, with significant associations observed only for concentrations greater than the median (12.4 and 6.2 mg/L, respectively). After adjustment for potential confounders, the hazard ratios per SD increment in total adiponectin were 0.93 (95% confidence interval 0.72 to 1.21) for concentrations less than the median and 1.25 (95% confidence interval 1.14 to 1.38) higher than the median. There was a suggestion of effect modification by body mass index, whereby the association appeared strongest in participants with lower body mass indexes. Consistent with the HF findings, higher adiponectin tended to be associated with left ventricular systolic dysfunction and left atrial enlargement. Results were similar for HMW adiponectin. In conclusion, total and HMW adiponectin showed comparable relations with incident HF in this older cohort, with a threshold effect of increasing risk occurring at their median concentrations. High levels of adiponectin may mark or mediate age-related processes that lead to HF in older adults.

%B Am J Cardiol %V 113 %P 328-34 %8 2014 Jan 15 %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24169012?dopt=Abstract %R 10.1016/j.amjcard.2013.09.027 %0 Journal Article %J Kidney Int %D 2014 %T Relative risks of chronic kidney disease for mortality and end-stage renal disease across races are similar. %A Wen, Chi Pang %A Matsushita, Kunihiro %A Coresh, Josef %A Iseki, Kunitoshi %A Islam, Muhammad %A Katz, Ronit %A McClellan, William %A Peralta, Carmen A %A Wang, Haiyan %A de Zeeuw, Dick %A Astor, Brad C %A Gansevoort, Ron T %A Levey, Andrew S %A Levin, Adeera %K Adult %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Albuminuria %K Asian Continental Ancestry Group %K Cardiovascular Diseases %K Cohort Studies %K Creatinine %K European Continental Ancestry Group %K Female %K Glomerular Filtration Rate %K Humans %K Kidney Failure, Chronic %K Male %K Middle Aged %K Odds Ratio %K Renal Insufficiency, Chronic %K Risk Factors %X

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.

%B Kidney Int %V 86 %P 819-27 %8 2014 Oct %G eng %N 4 %1 http://www.ncbi.nlm.nih.gov/pubmed/24522492?dopt=Abstract %R 10.1038/ki.2013.553 %0 Journal Article %J J Environ Public Health %D 2014 %T Residential relocation by older adults in response to incident cardiovascular health events: a case-crossover analysis. %A Lovasi, Gina S %A Richardson, John M %A Rodriguez, Carlos J %A Kop, Willem J %A Ahmed, Ali %A Brown, Arleen F %A Greenlee, Heather %A Siscovick, David S %K Aged %K Cardiovascular Diseases %K Cross-Over Studies %K Female %K Humans %K Incidence %K Life Change Events %K Logistic Models %K Longitudinal Studies %K Male %K Prospective Studies %K Residence Characteristics %K United States %X

OBJECTIVE: We use a case-crossover analysis to explore the association between incident cardiovascular events and residential relocation to a new home address.

METHODS: We conducted an ambidirectional case-crossover analysis to explore the association between incident cardiovascular events and residential relocation to a new address using data from the Cardiovascular Health Study (CHS), a community-based prospective cohort study of 5,888 older adults from four U.S. sites beginning in 1989. Relocation was assessed twice a year during follow-up. Event occurrences were classified as present or absent for the period preceding the first reported move, as compared with an equal length of time immediately prior to and following this period.

RESULTS: Older adults (65+) that experience incident cardiovascular disease had an increased probability of reporting a change of residence during the following year (OR 1.6, 95% confidence interval (CI) = 1.2-2.1). Clinical conditions associated with relocation included stroke (OR: 2.0, 95% CI: 1.2-3.3), angina (OR: 1.6, 95% CI: 1.0-2.6), and congestive heart failure (OR: 1.5, 95% CI: 1.0-2.1).

CONCLUSIONS: Major incident cardiovascular disease may increase the probability of residential relocation in older adults. Case-crossover analyses represent an opportunity to investigate triggering events, but finer temporal resolution would be crucial for future research on residential relocations.

%B J Environ Public Health %V 2014 %P 951971 %8 2014 %G eng %1 http://www.ncbi.nlm.nih.gov/pubmed/24782900?dopt=Abstract %R 10.1155/2014/951971 %0 Journal Article %J Atherosclerosis %D 2014 %T Risk factors for cardiovascular disease across the spectrum of older age: the Cardiovascular Health Study. %A Odden, Michelle C %A Shlipak, Michael G %A Whitson, Heather E %A Katz, Ronit %A Kearney, Patricia M %A deFilippi, Chris %A Shastri, Shani %A Sarnak, Mark J %A Siscovick, David S %A Cushman, Mary %A Psaty, Bruce M %A Newman, Anne B %K Aged %K Aged, 80 and over %K Blood Pressure %K C-Reactive Protein %K Cardiovascular Diseases %K Cholesterol, HDL %K Cholesterol, LDL %K Diabetes Complications %K Diabetes Mellitus %K Female %K Humans %K Inflammation %K Kidney %K Kidney Diseases %K Lipids %K Male %K Natriuretic Peptide, Brain %K Obesity %K Peptide Fragments %K Risk Factors %X

OBJECTIVE: The associations of some risk factors with cardiovascular disease (CVD) are attenuated in older age; whereas others appear robust. The present study aimed to compare CVD risk factors across older age.

METHODS: Participants (n = 4883) in the Cardiovascular Health Study free of prevalent CVD, were stratified into three age groups: 65-74, 75-84, 85+ years. Traditional risk factors included systolic blood pressure (BP), LDL-cholesterol, HDL-cholesterol, obesity, and diabetes. Novel risk factors included kidney function, C-reactive protein (CRP), and N-terminal pro-B-type natriuretic peptide (NT pro-BNP).

RESULTS: There were 1498 composite CVD events (stroke, myocardial infarction, and cardiovascular death) over 5 years. The associations of high systolic BP and diabetes appeared strongest, though both were attenuated with age (p-values for interaction = 0.01 and 0.002, respectively). The demographic-adjusted hazard ratios (HR) for elevated systolic BP were 1.79 (95% confidence interval: 1.49, 2.15), 1.59 (1.37, 1.85) and 1.10 (0.86, 1.41) in participants aged 65-74, 75-84, 85+, and for diabetes, 2.36 (1.89, 2.95), 1.55 (1.27, 1.89), 1.51 (1.10, 2.09). The novel risk factors had consistent associations with the outcome across the age spectrum; low kidney function: 1.69 (1.31, 2.19), 1.61 (1.36, 1.90), and 1.57 (1.16, 2.14) for 65-74, 75-84, and 85+ years, respectively; elevated CRP: 1.54 (1.28, 1.87), 1.33 (1.13, 1.55), and 1.51 (1.15, 1.97); elevated NT pro-BNP: 2.67 (1.96, 3.64), 2.71 (2.25, 3.27), and 2.18 (1.43, 3.45).

CONCLUSIONS: The associations of most traditional risk factors with CVD were minimal in the oldest old, whereas diabetes, eGFR, CRP, and NT pro-BNP were associated with CVD across older age.

%B Atherosclerosis %V 237 %P 336-42 %8 2014 Nov %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25303772?dopt=Abstract %R 10.1016/j.atherosclerosis.2014.09.012 %0 Journal Article %J Genet Epidemiol %D 2014 %T A robust method for genome-wide association meta-analysis with the application to circulating insulin-like growth factor I concentrations. %A Wang, Tao %A Zhou, Baiyu %A Guo, Tingwei %A Bidlingmaier, Martin %A Wallaschofski, Henri %A Teumer, Alexander %A Vasan, Ramachandran S %A Kaplan, Robert C %K Computer Simulation %K Genetic Linkage %K Genome %K Genome-Wide Association Study %K Humans %K Insulin-Like Growth Factor I %K Meta-Analysis as Topic %K Models, Genetic %K Polymorphism, Single Nucleotide %K Sample Size %X

Genome-wide association studies (GWAS) offer an excellent opportunity to identify the genetic variants underlying complex human diseases. Successful utilization of this approach requires a large sample size to identify single nucleotide polymorphisms (SNPs) with subtle effects. Meta-analysis is a cost-efficient means to achieve large sample size by combining data from multiple independent GWAS; however, results from studies performed on different populations can be variable due to various reasons, including varied linkage equilibrium structures as well as gene-gene and gene-environment interactions. Nevertheless, one should expect effects of the SNP are more similar between similar populations than those between populations with quite different genetic and environmental backgrounds. Prior information on populations of GWAS is often not considered in current meta-analysis methods, rendering such analyses less optimal for the detecting association. This article describes a test that improves meta-analysis to incorporate variable heterogeneity among populations. The proposed method is remarkably simple in computation and hence can be performed in a rapid fashion in the setting of GWAS. Simulation results demonstrate the validity and higher power of the proposed method over conventional methods in the presence of heterogeneity. As a demonstration, we applied the test to real GWAS data to identify SNPs associated with circulating insulin-like growth factor I concentrations.

%B Genet Epidemiol %V 38 %P 162-71 %8 2014 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/24446417?dopt=Abstract %R 10.1002/gepi.21766 %0 Journal Article %J PLoS One %D 2015 %T Race/Ethnic Differences in the Associations of the Framingham Risk Factors with Carotid IMT and Cardiovascular Events. %A Gijsberts, Crystel M %A Groenewegen, Karlijn A %A Hoefer, Imo E %A Eijkemans, Marinus J C %A Asselbergs, Folkert W %A Anderson, Todd J %A Britton, Annie R %A Dekker, Jacqueline M %A Engström, Gunnar %A Evans, Greg W %A de Graaf, Jacqueline %A Grobbee, Diederick E %A Hedblad, Bo %A Holewijn, Suzanne %A Ikeda, Ai %A Kitagawa, Kazuo %A Kitamura, Akihiko %A de Kleijn, Dominique P V %A Lonn, Eva M %A Lorenz, Matthias W %A Mathiesen, Ellisiv B %A Nijpels, Giel %A Okazaki, Shuhei %A O'Leary, Daniel H %A Pasterkamp, Gerard %A Peters, Sanne A E %A Polak, Joseph F %A Price, Jacqueline F %A Robertson, Christine %A Rembold, Christopher M %A Rosvall, Maria %A Rundek, Tatjana %A Salonen, Jukka T %A Sitzer, Matthias %A Stehouwer, Coen D A %A Bots, Michiel L %A den Ruijter, Hester M %K Adult %K Age Distribution %K Aged %K Carotid Artery Diseases %K Carotid Intima-Media Thickness %K Cholesterol, HDL %K Cholesterol, LDL %K Comorbidity %K Continental Population Groups %K Diabetes Mellitus %K Dyslipidemias %K Ethnic Groups %K Female %K Follow-Up Studies %K Global Health %K Humans %K Hypertension %K Incidence %K Linear Models %K Male %K Middle Aged %K Myocardial Infarction %K Prevalence %K Proportional Hazards Models %K Risk Factors %K Smoking %K Stroke %X

BACKGROUND: Clinical manifestations and outcomes of atherosclerotic disease differ between ethnic groups. In addition, the prevalence of risk factors is substantially different. Primary prevention programs are based on data derived from almost exclusively White people. We investigated how race/ethnic differences modify the associations of established risk factors with atherosclerosis and cardiovascular events.

METHODS: We used data from an ongoing individual participant meta-analysis involving 17 population-based cohorts worldwide. We selected 60,211 participants without cardiovascular disease at baseline with available data on ethnicity (White, Black, Asian or Hispanic). We generated a multivariable linear regression model containing risk factors and ethnicity predicting mean common carotid intima-media thickness (CIMT) and a multivariable Cox regression model predicting myocardial infarction or stroke. For each risk factor we assessed how the association with the preclinical and clinical measures of cardiovascular atherosclerotic disease was affected by ethnicity.

RESULTS: Ethnicity appeared to significantly modify the associations between risk factors and CIMT and cardiovascular events. The association between age and CIMT was weaker in Blacks and Hispanics. Systolic blood pressure associated more strongly with CIMT in Asians. HDL cholesterol and smoking associated less with CIMT in Blacks. Furthermore, the association of age and total cholesterol levels with the occurrence of cardiovascular events differed between Blacks and Whites.

CONCLUSION: The magnitude of associations between risk factors and the presence of atherosclerotic disease differs between race/ethnic groups. These subtle, yet significant differences provide insight in the etiology of cardiovascular disease among race/ethnic groups. These insights aid the race/ethnic-specific implementation of primary prevention.

%B PLoS One %V 10 %P e0132321 %8 2015 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/26134404?dopt=Abstract %R 10.1371/journal.pone.0132321 %0 Journal Article %J JAMA Neurol %D 2015 %T Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project. %A Auer, Paul L %A Nalls, Mike %A Meschia, James F %A Worrall, Bradford B %A Longstreth, W T %A Seshadri, Sudha %A Kooperberg, Charles %A Burger, Kathleen M %A Carlson, Christopher S %A Carty, Cara L %A Chen, Wei-Min %A Cupples, L Adrienne %A DeStefano, Anita L %A Fornage, Myriam %A Hardy, John %A Hsu, Li %A Jackson, Rebecca D %A Jarvik, Gail P %A Kim, Daniel S %A Lakshminarayan, Kamakshi %A Lange, Leslie A %A Manichaikul, Ani %A Quinlan, Aaron R %A Singleton, Andrew B %A Thornton, Timothy A %A Nickerson, Deborah A %A Peters, Ulrike %A Rich, Stephen S %K Aged %K Brain Ischemia %K Exome %K Female %K Genetic Predisposition to Disease %K Genetic Variation %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Muscle Proteins %K National Heart, Lung, and Blood Institute (U.S.) %K Nuclear Proteins %K Open Reading Frames %K Palmitoyl-CoA Hydrolase %K Stroke %K United States %X

IMPORTANCE: Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.

OBJECTIVE: To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome.

DESIGN, SETTING, AND PARTICIPANTS: The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013.

MAIN OUTCOMES AND MEASURES: Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).

RESULTS: We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).

CONCLUSIONS AND RELEVANCE: Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.

%B JAMA Neurol %V 72 %P 781-8 %8 2015 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/25961151?dopt=Abstract %R 10.1001/jamaneurol.2015.0582 %0 Journal Article %J Blood %D 2015 %T Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. %A Huffman, Jennifer E %A de Vries, Paul S %A Morrison, Alanna C %A Sabater-Lleal, Maria %A Kacprowski, Tim %A Auer, Paul L %A Brody, Jennifer A %A Chasman, Daniel I %A Chen, Ming-Huei %A Guo, Xiuqing %A Lin, Li-An %A Marioni, Riccardo E %A Müller-Nurasyid, Martina %A Yanek, Lisa R %A Pankratz, Nathan %A Grove, Megan L %A de Maat, Moniek P M %A Cushman, Mary %A Wiggins, Kerri L %A Qi, Lihong %A Sennblad, Bengt %A Harris, Sarah E %A Polasek, Ozren %A Riess, Helene %A Rivadeneira, Fernando %A Rose, Lynda M %A Goel, Anuj %A Taylor, Kent D %A Teumer, Alexander %A Uitterlinden, André G %A Vaidya, Dhananjay %A Yao, Jie %A Tang, Weihong %A Levy, Daniel %A Waldenberger, Melanie %A Becker, Diane M %A Folsom, Aaron R %A Giulianini, Franco %A Greinacher, Andreas %A Hofman, Albert %A Huang, Chiang-Ching %A Kooperberg, Charles %A Silveira, Angela %A Starr, John M %A Strauch, Konstantin %A Strawbridge, Rona J %A Wright, Alan F %A McKnight, Barbara %A Franco, Oscar H %A Zakai, Neil %A Mathias, Rasika A %A Psaty, Bruce M %A Ridker, Paul M %A Tofler, Geoffrey H %A Völker, Uwe %A Watkins, Hugh %A Fornage, Myriam %A Hamsten, Anders %A Deary, Ian J %A Boerwinkle, Eric %A Koenig, Wolfgang %A Rotter, Jerome I %A Hayward, Caroline %A Dehghan, Abbas %A Reiner, Alex P %A O'Donnell, Christopher J %A Smith, Nicholas L %K Cohort Studies %K Factor VII %K Factor VIII %K Fibrinogen %K Gene Frequency %K Genetic Association Studies %K Genetic Variation %K Humans %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Potassium Channels %K von Willebrand Factor %X

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.

%B Blood %V 126 %P e19-29 %8 2015 Sep 10 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/26105150?dopt=Abstract %R 10.1182/blood-2015-02-624551 %0 Journal Article %J J Alzheimers Dis %D 2015 %T Relationship between Systemic and Cerebral Vascular Disease and Brain Structure Integrity in Normal Elderly Individuals. %A Riverol, Mario %A Becker, James T %A Lopez, Oscar L %A Raji, Cyrus A %A Thompson, Paul M %A Carmichael, Owen T %A Gach, H Michael %A Longstreth, William T %A Fried, Linda %A Tracy, Russell P %A Kuller, Lewis H %K Aged %K Aged, 80 and over %K Analysis of Variance %K Brain %K Cerebrovascular Disorders %K Female %K Humans %K Image Processing, Computer-Assisted %K Logistic Models %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Peripheral Vascular Diseases %K Predictive Value of Tests %K Retrospective Studies %K White Matter %X

Cerebral white matter lesions (WMLs) are considered a reflection of cerebral and systemic small vessel disease (SVD), and are associated with reductions in brain volume. Like the brain, the kidney is also sensitive to factors that affect vasculature. Glomerular dysfunction due to renal vascular damage can be measured with different biochemical parameters, such as creatinine or cystatin C, although cystatin C is considered to be more accurate than creatinine in the elderly. The purpose of the study was to determine whether manifestations of SVD in the kidney can predict SVD-based damage to the brain. We examined the relationship between glomerular dysfunction as a measure of SVD on WMLs, gray matter (GM) volume, and cognition in 735 cognitively normal participants from the Cardiovascular Health Study Cognition Study. The multivariate analyses controlled for demographic characteristics, hypertension, heart disease, diabetes, Apolipoprotein 4 allele, C reactive protein, lipids, physical activity, smoking, and body mass index (BMI). Elevated cystatin C levels were associated with lower neuropsychological test scores, the presence of MRI-identified brain infarcts, the severity of WMLs, and GM atrophy five years later. In adjusted models, GM volume was significantly associated with cystatin-C only until BMI and severity of WMLs were added to the model, meaning that the effect of SVD on GM volume is mediated by these two variables. These findings suggest that age-related SVD is a process that leads to altered brain structure, and creates a vulnerability state for cognitive decline.

%B J Alzheimers Dis %V 44 %P 319-28 %8 2015 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25213770?dopt=Abstract %R 10.3233/JAD-141077 %0 Journal Article %J J Am Heart Assoc %D 2015 %T Resting heart rate and risk of incident heart failure: three prospective cohort studies and a systematic meta-analysis. %A Khan, Hassan %A Kunutsor, Setor %A Kalogeropoulos, Andreas P %A Georgiopoulou, Vasiliki V %A Newman, Anne B %A Harris, Tamara B %A Bibbins-Domingo, Kirsten %A Kauhanen, Jussi %A Gheorghiade, Mihai %A Fonarow, Gregg C %A Kritchevsky, Stephen B %A Laukkanen, Jari A %A Butler, Javed %K Age Distribution %K Aged %K Aged, 80 and over %K Aging %K Cohort Studies %K Female %K Heart Failure %K Heart Rate %K Humans %K Incidence %K Japan %K Male %K Predictive Value of Tests %K Prospective Studies %K Rest %K Risk Assessment %K Severity of Illness Index %K Sex Distribution %K Survival Rate %X

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.

%B J Am Heart Assoc %V 4 %P e001364 %8 2015 Jan %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/25589535?dopt=Abstract %R 10.1161/JAHA.114.001364 %0 Journal Article %J Circ Cardiovasc Genet %D 2016 %T Rare Exome Sequence Variants in CLCN6 Reduce Blood Pressure Levels and Hypertension Risk. %A Yu, Bing %A Pulit, Sara L %A Hwang, Shih-Jen %A Brody, Jennifer A %A Amin, Najaf %A Auer, Paul L %A Bis, Joshua C %A Boerwinkle, Eric %A Burke, Gregory L %A Chakravarti, Aravinda %A Correa, Adolfo %A Dreisbach, Albert W %A Franco, Oscar H %A Ehret, Georg B %A Franceschini, Nora %A Hofman, Albert %A Lin, Dan-Yu %A Metcalf, Ginger A %A Musani, Solomon K %A Muzny, Donna %A Palmas, Walter %A Raffel, Leslie %A Reiner, Alex %A Rice, Ken %A Rotter, Jerome I %A Veeraraghavan, Narayanan %A Fox, Ervin %A Guo, Xiuqing %A North, Kari E %A Gibbs, Richard A %A van Duijn, Cornelia M %A Psaty, Bruce M %A Levy, Daniel %A Newton-Cheh, Christopher %A Morrison, Alanna C %X

BACKGROUND: Rare genetic variants influence blood pressure (BP).

METHODS AND RESULTS: Whole-exome sequencing was performed on DNA samples from 17 956 individuals of European ancestry and African ancestry (14 497, first-stage discovery and 3459, second-stage discovery) to examine the effect of rare variants on hypertension and 4 BP traits: systolic BP, diastolic BP, pulse pressure, and mean arterial pressure. Tests of ≈170 000 common variants (minor allele frequency, ≥1%; statistical significance, P≤2.9×10(-7)) and gene-based tests of rare variants (minor allele frequency, <1%; ≈17 000 genes; statistical significance, P≤1.5×10(-6)) were evaluated for each trait and ancestry, followed by multiethnic meta-analyses. In the first-stage discovery, rare coding variants (splicing, stop-gain, stop-loss, nonsynonymous variants, or indels) in CLCN6 were associated with lower diastolic BP (cumulative minor allele frequency, 1.3%; β=-3.20; P=4.1×10(-6)) and were independent of a nearby common variant (rs17367504) previously associated with BP. CLCN6 rare variants were also associated with lower systolic BP (β=-4.11; P=2.8×10(-4)), mean arterial pressure (β=-3.50; P=8.9×10(-6)), and reduced hypertension risk (odds ratio, 0.72; P=0.017). Meta-analysis of the 2-stage discovery samples showed that CLCN6 was associated with lower diastolic BP at exome-wide significance (cumulative minor allele frequency, 1.1%; β=-3.30; P=5.0×10(-7)).

CONCLUSIONS: These findings implicate the effect of rare coding variants in CLCN6 in BP variation and offer new insights into BP regulation.

%B Circ Cardiovasc Genet %V 9 %P 64-70 %8 2016 Feb %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/26658788?dopt=Abstract %R 10.1161/CIRCGENETICS.115.001215 %0 Journal Article %J PLoS Genet %D 2016 %T Rare Functional Variant in TM2D3 is Associated with Late-Onset Alzheimer's Disease. %A Jakobsdottir, Johanna %A van der Lee, Sven J %A Bis, Joshua C %A Chouraki, Vincent %A Li-Kroeger, David %A Yamamoto, Shinya %A Grove, Megan L %A Naj, Adam %A Vronskaya, Maria %A Salazar, Jose L %A DeStefano, Anita L %A Brody, Jennifer A %A Smith, Albert V %A Amin, Najaf %A Sims, Rebecca %A Ibrahim-Verbaas, Carla A %A Choi, Seung-Hoan %A Satizabal, Claudia L %A Lopez, Oscar L %A Beiser, Alexa %A Ikram, M Arfan %A Garcia, Melissa E %A Hayward, Caroline %A Varga, Tibor V %A Ripatti, Samuli %A Franks, Paul W %A Hallmans, Göran %A Rolandsson, Olov %A Jansson, Jan-Håkon %A Porteous, David J %A Salomaa, Veikko %A Eiriksdottir, Gudny %A Rice, Kenneth M %A Bellen, Hugo J %A Levy, Daniel %A Uitterlinden, André G %A Emilsson, Valur %A Rotter, Jerome I %A Aspelund, Thor %A O'Donnell, Christopher J %A Fitzpatrick, Annette L %A Launer, Lenore J %A Hofman, Albert %A Wang, Li-San %A Williams, Julie %A Schellenberg, Gerard D %A Boerwinkle, Eric %A Psaty, Bruce M %A Seshadri, Sudha %A Shulman, Joshua M %A Gudnason, Vilmundur %A van Duijn, Cornelia M %X

We performed an exome-wide association analysis in 1393 late-onset Alzheimer's disease (LOAD) cases and 8141 controls from the CHARGE consortium. We found that a rare variant (P155L) in TM2D3 was enriched in Icelanders (~0.5% versus <0.05% in other European populations). In 433 LOAD cases and 3903 controls from the Icelandic AGES sub-study, P155L was associated with increased risk and earlier onset of LOAD [odds ratio (95% CI) = 7.5 (3.5-15.9), p = 6.6x10-9]. Mutation in the Drosophila TM2D3 homolog, almondex, causes a phenotype similar to loss of Notch/Presenilin signaling. Human TM2D3 is capable of rescuing these phenotypes, but this activity is abolished by P155L, establishing it as a functionally damaging allele. Our results establish a rare TM2D3 variant in association with LOAD susceptibility, and together with prior work suggests possible links to the β-amyloid cascade.

%B PLoS Genet %V 12 %P e1006327 %8 2016 Oct %G eng %N 10 %R 10.1371/journal.pgen.1006327 %0 Journal Article %J Mol Psychiatry %D 2016 %T Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans. %A Olfson, E %A Saccone, N L %A Johnson, E O %A Chen, L-S %A Culverhouse, R %A Doheny, K %A Foltz, S M %A Fox, L %A Gogarten, S M %A Hartz, S %A Hetrick, K %A Laurie, C C %A Marosy, B %A Amin, N %A Arnett, D %A Barr, R G %A Bartz, T M %A Bertelsen, S %A Borecki, I B %A Brown, M R %A Chasman, D I %A van Duijn, C M %A Feitosa, M F %A Fox, E R %A Franceschini, N %A Franco, O H %A Grove, M L %A Guo, X %A Hofman, A %A Kardia, S L R %A Morrison, A C %A Musani, S K %A Psaty, B M %A Rao, D C %A Reiner, A P %A Rice, K %A Ridker, P M %A Rose, L M %A Schick, U M %A Schwander, K %A Uitterlinden, A G %A Vojinovic, D %A Wang, J-C %A Ware, E B %A Wilson, G %A Yao, J %A Zhao, W %A Breslau, N %A Hatsukami, D %A Stitzel, J A %A Rice, J %A Goate, A %A Bierut, L J %X

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine-dependent cases (Fagerström Test for Nicotine Dependence score⩾4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (minor allele frequency (MAF)⩾0.05), aggregate low frequency variants (0.05>MAF⩾0.005) and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180 × coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: odds ratio (OR)=1.3, P=3.5 × 10(-11); African ancestry: OR=1.3, P=0.01) and demonstrated that three low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, P=0.005; African ancestry: OR=1.4, P=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, P=0.01) and in the same risk direction in African Americans (OR=1.5, P=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence the risk for smoking-related diseases such as lung cancer.

%B Mol Psychiatry %V 21 %P 601-7 %8 2016 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/26239294?dopt=Abstract %R 10.1038/mp.2015.105 %0 Journal Article %J Blood Coagul Fibrinolysis %D 2016 %T Relation of coagulation factor XI with incident coronary heart disease and stroke: the Cardiovascular Health Study. %A Appiah, Duke %A Fashanu, Oluwaseun E %A Heckbert, Susa R %A Cushman, Mary %A Psaty, Bruce M %A Folsom, Aaron R %X

The role of coagulation factor XI (FXI) in the cause of arterial thrombotic events remains uncertain. We examined the association of FXI with incident coronary heart disease (CHD), ischemic stroke, and hemorrhagic stroke. Data were from 3394 adults (mean age: 74.5 years) enrolled in the Cardiovascular Health Study who had FXI antigen from plasma samples drawn in 1992-1993 and were followed for cardiovascular events until 30 June 2013. Approximately 63% of participants were women and 17% were black. FXI levels were higher in blacks and women, showed positive associations with high-density lipoprotein and total cholesterol, BMI and diabetes, and negative associations with age and alcohol intake. During median follow-up of 13 years, we identified 1232 incident CHD, 473 ischemic stroke, and 84 hemorrhagic stroke events. In multivariable Cox models adjusted for traditional cardiovascular disease risk factors, the hazard ratio per one SD (32.2 mg/dl) increment of FXI was 1.02 (95% confidence interval: 0.96-1.08) for CHD; 0.94 (0.85-1.04) for ischemic stroke, and 0.85 (0.65-1.10) for hemorrhagic stroke. In this prospective cohort of elderly adults, there was no statistically significant association of higher FXI levels with incident CHD and stroke.

%B Blood Coagul Fibrinolysis %8 2016 Dec 22 %G eng %R 10.1097/MBC.0000000000000616 %0 Journal Article %J J Gerontol A Biol Sci Med Sci %D 2016 %T Relations of Postload and Fasting Glucose With Incident Cardiovascular Disease and Mortality Late in Life: The Cardiovascular Health Study. %A Brutsaert, Erika F %A Shitole, Sanyog %A Biggs, Mary Lou %A Mukamal, Kenneth J %A deBoer, Ian H %A Thacker, Evan L %A Barzilay, Joshua I %A Djoussé, Luc %A Ix, Joachim H %A Smith, Nicholas L %A Kaplan, Robert C %A Siscovick, David S %A Psaty, Bruce M %A Kizer, Jorge R %K Aged %K Aging %K Blood Glucose %K Cardiovascular Diseases %K Fasting %K Female %K Follow-Up Studies %K Glucose %K Glucose Tolerance Test %K Health Surveys %K Humans %K Incidence %K Male %K Proportional Hazards Models %K Prospective Studies %K Risk Assessment %K Risk Factors %K Survival Rate %K United States %X

BACKGROUND: Older adults have a high prevalence of postload hyperglycemia. Postload glucose has shown more robust associations with cardiovascular disease (CVD) and death than fasting glucose, but data in the oldest old are sparse.

METHODS: Fasting and 2-hour postload glucose were measured in community-dwelling older adults, mean age 78, at the 1996-1997 follow-up visit of the Cardiovascular Health Study. We evaluated their associations with atherosclerotic CVD (ASCVD) and mortality using standard Cox regression and competing-risks analyses and assessed improvement in prediction-model discrimination with the c-statistic.

RESULTS: Among 2,394 participants without treated diabetes and available data on glycemic measures, there were 579 ASCVD events and 1,698 deaths during median follow-up of 11.2 years. In fully adjusted models, both fasting and 2-hour glucose were associated with ASCVD (HR per SD, 1.13 [1.03-1.25] and 1.17 [1.07-1.28], respectively) and all-cause mortality (HR 1.12 [1.07-1.18] and 1.14 [1.08-1.20]). After mutual adjustment, however, the associations for fasting glucose with both outcomes were abolished, but those for postload glucose were largely unchanged. Consistent findings were observed for ASCVD in competing-risks models.

CONCLUSION: In adults surviving to advanced old age, postload glucose was associated with ASCVD and mortality independently of fasting glucose, but fasting glucose was not associated with these outcomes independently of postload glucose. These findings affirm the robust association of postload glucose with ASCVD and death late in life.

%B J Gerontol A Biol Sci Med Sci %V 71 %P 370-7 %8 2016 Mar %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/26314953?dopt=Abstract %R 10.1093/gerona/glv106 %0 Journal Article %J Cerebrovasc Dis Extra %D 2016 %T Risk Factors for Incident Carotid Artery Revascularization among Older Adults: The Cardiovascular Health Study. %A Garg, Parveen K %A Koh, Willam J H %A Delaney, Joseph A %A Halm, Ethan A %A Hirsch, Calvin H %A Longstreth, William T %A Mukamal, Kenneth J %A Kucharska-Newton, Anna %A Polak, Joseph F %A Curtis, Lesley %X

BACKGROUND: Population-based risk factors for carotid artery revascularization are not known. We investigated the association between demographic and clinical characteristics and incident carotid artery revascularization in a cohort of older adults.

METHODS: Among Cardiovascular Health Study participants, a population-based cohort of 5,888 adults aged 65 years or older enrolled in two waves (1989-1990 and 1992-1993), 5,107 participants without a prior history of carotid endarterectomy (CEA) or cerebrovascular disease had a carotid ultrasound at baseline and were included in these analyses. Cox proportional hazards multivariable analysis was used to determine independent risk factors for incident carotid artery revascularization.

RESULTS: Over a mean follow-up of 13.5 years, 141 participants underwent carotid artery revascularization, 97% were CEA. Baseline degree of stenosis and incident ischemic cerebral events occurring during follow-up were the strongest predictors of incident revascularization. After adjustment for these, factors independently associated with an increased risk of incident revascularization were: hypertension (HR 1.53; 95% CI: 1.05-2.23), peripheral arterial disease (HR 2.57; 95% CI: 1.34-4.93), and low-density lipoprotein cholesterol (HR 1.23 per standard deviation [SD] increment [35.4 mg/dL]; 95% CI: 1.04-1.46). Factors independently associated with a lower risk of incident revascularization were: female gender (HR 0.51; 95% CI: 0.34-0.77) and older age (HR 0.69 per SD increment [5.5 years]; 95% CI: 0.56-0.86).

CONCLUSIONS: Even after accounting for carotid stenosis and incident cerebral ischemic events, carotid revascularization is related to age, gender, and cardiovascular risk factors. Further study of these demographic disparities and the role of risk factor control is warranted.

%B Cerebrovasc Dis Extra %V 6 %P 129-139 %8 2016 Nov 16 %G eng %N 3 %R 10.1159/000452426 %0 Journal Article %J Alzheimers Dement %D 2016 %T Risk of dementia and death in the long-term follow-up of the Pittsburgh Cardiovascular Health Study-Cognition Study. %A Kuller, Lewis H %A Lopez, Oscar L %A Becker, James T %A Chang, Yuefang %A Newman, Anne B %K African Continental Ancestry Group %K Aged %K Aged, 80 and over %K Apolipoprotein E4 %K Brain %K Cardiovascular Diseases %K Cognition %K Dementia %K European Continental Ancestry Group %K Female %K Follow-Up Studies %K Humans %K Magnetic Resonance Imaging %K Male %K Neuropsychological Tests %K Pennsylvania %K Risk Factors %K Walking %X

INTRODUCTION: Increasing life expectancy has resulted in a larger population of older individuals at risk of dementia.

METHODS: The Cardiovascular Health Study-Cognition Study followed 532 participants from 1998-99 (mean age 79) to 2013 (mean age 93) for death and dementia.

RESULTS: Risk of death was determined by extent of coronary artery calcium, high-sensitivity cardiac troponin, brain natriuretic peptide, and white matter grade. Significant predictors of dementia were age, apolipoprotein-E4, vocabulary raw score, hippocampal volume, ventricular size, cognitive performance, and number of blocks walked. By 2013, 160 of 532 were alive, including 19 cognitively normal. Those with normal cognition had higher grade education, better cognition test scores, greater hippocampal volume, faster gait speed, and number of blocks walked as compared with survivors who were demented.

DISCUSSION: Few survived free of dementia and disability. Prevention and delay of cognitive decline for this older population is an imperative.

%B Alzheimers Dement %V 12 %P 170-83 %8 2016 Feb %G eng %N 2 %1 http://www.ncbi.nlm.nih.gov/pubmed/26519786?dopt=Abstract %R 10.1016/j.jalz.2015.08.165 %0 Journal Article %J Pharmacogenomics %D 2016 %T Rooted in risk: genetic predisposition for low-density lipoprotein cholesterol level associates with diminished low-density lipoprotein cholesterol response to statin treatment. %A Smit, Roelof Aj %A Postmus, Iris %A Trompet, Stella %A Barnes, Michael R %A Warren, Helen %A Arsenault, Benoit J %A Chasman, Daniel I %A Cupples, L Adrienne %A Hitman, Graham A %A Krauss, Ronald M %A Li, Xiaohui %A Psaty, Bruce M %A Stein, Charles M %A Rotter, Jerome I %A Jukema, J Wouter %K Cholesterol, LDL %K Genetic Predisposition to Disease %K Humans %K Hydroxymethylglutaryl-CoA Reductase Inhibitors %K Pharmacogenetics %K Polymorphism, Single Nucleotide %K Triglycerides %X

AIMS: To utilize previously reported lead SNPs for low-density lipoprotein cholesterol (LDL-c) levels to find additional loci of importance to statin response, and examine whether genetic predisposition to LDL-c levels associates with differential statin response.

METHODS: We investigated effects on statin response of 59 LDL-c SNPs, by combining summary level statistics from the Global Lipids Genetics and Genomic Investigation of Statin Therapy consortia.

RESULTS: Lead SNPs for APOE, SORT1 and NPC1L1 were associated with a decreased LDL-c response to statin treatment, as was overall genetic predisposition for increased LDL-c levels as quantified with 59 SNPs, with a 5.4% smaller statin response per standard deviation increase in genetically raised LDL-c levels.

CONCLUSION: Genetic predisposition for increased LDL-c level may decrease efficacy of statin therapy.

%B Pharmacogenomics %V 17 %P 1621-1628 %8 2016 10 %G eng %N 15 %R 10.2217/pgs-2016-0091 %0 Journal Article %J Nat Genet %D 2017 %T Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease. %A Sims, Rebecca %A van der Lee, Sven J %A Naj, Adam C %A Bellenguez, Céline %A Badarinarayan, Nandini %A Jakobsdottir, Johanna %A Kunkle, Brian W %A Boland, Anne %A Raybould, Rachel %A Bis, Joshua C %A Martin, Eden R %A Grenier-Boley, Benjamin %A Heilmann-Heimbach, Stefanie %A Chouraki, Vincent %A Kuzma, Amanda B %A Sleegers, Kristel %A Vronskaya, Maria %A Ruiz, Agustin %A Graham, Robert R %A Olaso, Robert %A Hoffmann, Per %A Grove, Megan L %A Vardarajan, Badri N %A Hiltunen, Mikko %A Nöthen, Markus M %A White, Charles C %A Hamilton-Nelson, Kara L %A Epelbaum, Jacques %A Maier, Wolfgang %A Choi, Seung-Hoan %A Beecham, Gary W %A Dulary, Cécile %A Herms, Stefan %A Smith, Albert V %A Funk, Cory C %A Derbois, Céline %A Forstner, Andreas J %A Ahmad, Shahzad %A Li, Hongdong %A Bacq, Delphine %A Harold, Denise %A Satizabal, Claudia L %A Valladares, Otto %A Squassina, Alessio %A Thomas, Rhodri %A Brody, Jennifer A %A Qu, Liming %A Sánchez-Juan, Pascual %A Morgan, Taniesha %A Wolters, Frank J %A Zhao, Yi %A Garcia, Florentino Sanchez %A Denning, Nicola %A Fornage, Myriam %A Malamon, John %A Naranjo, Maria Candida Deniz %A Majounie, Elisa %A Mosley, Thomas H %A Dombroski, Beth %A Wallon, David %A Lupton, Michelle K %A Dupuis, Josée %A Whitehead, Patrice %A Fratiglioni, Laura %A Medway, Christopher %A Jian, Xueqiu %A Mukherjee, Shubhabrata %A Keller, Lina %A Brown, Kristelle %A Lin, Honghuang %A Cantwell, Laura B %A Panza, Francesco %A McGuinness, Bernadette %A Moreno-Grau, Sonia %A Burgess, Jeremy D %A Solfrizzi, Vincenzo %A Proitsi, Petra %A Adams, Hieab H %A Allen, Mariet %A Seripa, Davide %A Pastor, Pau %A Cupples, L Adrienne %A Price, Nathan D %A Hannequin, Didier %A Frank-García, Ana %A Levy, Daniel %A Chakrabarty, Paramita %A Caffarra, Paolo %A Giegling, Ina %A Beiser, Alexa S %A Giedraitis, Vilmantas %A Hampel, Harald %A Garcia, Melissa E %A Wang, Xue %A Lannfelt, Lars %A Mecocci, Patrizia %A Eiriksdottir, Gudny %A Crane, Paul K %A Pasquier, Florence %A Boccardi, Virginia %A Henández, Isabel %A Barber, Robert C %A Scherer, Martin %A Tarraga, Lluis %A Adams, Perrie M %A Leber, Markus %A Chen, Yuning %A Albert, Marilyn S %A Riedel-Heller, Steffi %A Emilsson, Valur %A Beekly, Duane %A Braae, Anne %A Schmidt, Reinhold %A Blacker, Deborah %A Masullo, Carlo %A Schmidt, Helena %A Doody, Rachelle S %A Spalletta, Gianfranco %A Jr, W T Longstreth %A Fairchild, Thomas J %A Bossù, Paola %A Lopez, Oscar L %A Frosch, Matthew P %A Sacchinelli, Eleonora %A Ghetti, Bernardino %A Yang, Qiong %A Huebinger, Ryan M %A Jessen, Frank %A Li, Shuo %A Kamboh, M Ilyas %A Morris, John %A Sotolongo-Grau, Oscar %A Katz, Mindy J %A Corcoran, Chris %A Dunstan, Melanie %A Braddel, Amy %A Thomas, Charlene %A Meggy, Alun %A Marshall, Rachel %A Gerrish, Amy %A Chapman, Jade %A Aguilar, Miquel %A Taylor, Sarah %A Hill, Matt %A Fairén, Mònica Díez %A Hodges, Angela %A Vellas, Bruno %A Soininen, Hilkka %A Kloszewska, Iwona %A Daniilidou, Makrina %A Uphill, James %A Patel, Yogen %A Hughes, Joseph T %A Lord, Jenny %A Turton, James %A Hartmann, Annette M %A Cecchetti, Roberta %A Fenoglio, Chiara %A Serpente, Maria %A Arcaro, Marina %A Caltagirone, Carlo %A Orfei, Maria Donata %A Ciaramella, Antonio %A Pichler, Sabrina %A Mayhaus, Manuel %A Gu, Wei %A Lleo, Alberto %A Fortea, Juan %A Blesa, Rafael %A Barber, Imelda S %A Brookes, Keeley %A Cupidi, Chiara %A Maletta, Raffaele Giovanni %A Carrell, David %A Sorbi, Sandro %A Moebus, Susanne %A Urbano, Maria %A Pilotto, Alberto %A Kornhuber, Johannes %A Bosco, Paolo %A Todd, Stephen %A Craig, David %A Johnston, Janet %A Gill, Michael %A Lawlor, Brian %A Lynch, Aoibhinn %A Fox, Nick C %A Hardy, John %A Albin, Roger L %A Apostolova, Liana G %A Arnold, Steven E %A Asthana, Sanjay %A Atwood, Craig S %A Baldwin, Clinton T %A Barnes, Lisa L %A Barral, Sandra %A Beach, Thomas G %A Becker, James T %A Bigio, Eileen H %A Bird, Thomas D %A Boeve, Bradley F %A Bowen, James D %A Boxer, Adam %A Burke, James R %A Burns, Jeffrey M %A Buxbaum, Joseph D %A Cairns, Nigel J %A Cao, Chuanhai %A Carlson, Chris S %A Carlsson, Cynthia M %A Carney, Regina M %A Carrasquillo, Minerva M %A Carroll, Steven L %A Diaz, Carolina Ceballos %A Chui, Helena C %A Clark, David G %A Cribbs, David H %A Crocco, Elizabeth A %A DeCarli, Charles %A Dick, Malcolm %A Duara, Ranjan %A Evans, Denis A %A Faber, Kelley M %A Fallon, Kenneth B %A Fardo, David W %A Farlow, Martin R %A Ferris, Steven %A Foroud, Tatiana M %A Galasko, Douglas R %A Gearing, Marla %A Geschwind, Daniel H %A Gilbert, John R %A Graff-Radford, Neill R %A Green, Robert C %A Growdon, John H %A Hamilton, Ronald L %A Harrell, Lindy E %A Honig, Lawrence S %A Huentelman, Matthew J %A Hulette, Christine M %A Hyman, Bradley T %A Jarvik, Gail P %A Abner, Erin %A Jin, Lee-Way %A Jun, Gyungah %A Karydas, Anna %A Kaye, Jeffrey A %A Kim, Ronald %A Kowall, Neil W %A Kramer, Joel H %A LaFerla, Frank M %A Lah, James J %A Leverenz, James B %A Levey, Allan I %A Li, Ge %A Lieberman, Andrew P %A Lunetta, Kathryn L %A Lyketsos, Constantine G %A Marson, Daniel C %A Martiniuk, Frank %A Mash, Deborah C %A Masliah, Eliezer %A McCormick, Wayne C %A McCurry, Susan M %A McDavid, Andrew N %A McKee, Ann C %A Mesulam, Marsel %A Miller, Bruce L %A Miller, Carol A %A Miller, Joshua W %A Morris, John C %A Murrell, Jill R %A Myers, Amanda J %A O'Bryant, Sid %A Olichney, John M %A Pankratz, Vernon S %A Parisi, Joseph E %A Paulson, Henry L %A Perry, William %A Peskind, Elaine %A Pierce, Aimee %A Poon, Wayne W %A Potter, Huntington %A Quinn, Joseph F %A Raj, Ashok %A Raskind, Murray %A Reisberg, Barry %A Reitz, Christiane %A Ringman, John M %A Roberson, Erik D %A Rogaeva, Ekaterina %A Rosen, Howard J %A Rosenberg, Roger N %A Sager, Mark A %A Saykin, Andrew J %A Schneider, Julie A %A Schneider, Lon S %A Seeley, William W %A Smith, Amanda G %A Sonnen, Joshua A %A Spina, Salvatore %A Stern, Robert A %A Swerdlow, Russell H %A Tanzi, Rudolph E %A Thornton-Wells, Tricia A %A Trojanowski, John Q %A Troncoso, Juan C %A Van Deerlin, Vivianna M %A Van Eldik, Linda J %A Vinters, Harry V %A Vonsattel, Jean Paul %A Weintraub, Sandra %A Welsh-Bohmer, Kathleen A %A Wilhelmsen, Kirk C %A Williamson, Jennifer %A Wingo, Thomas S %A Woltjer, Randall L %A Wright, Clinton B %A Yu, Chang-En %A Yu, Lei %A Garzia, Fabienne %A Golamaully, Feroze %A Septier, Gislain %A Engelborghs, Sebastien %A Vandenberghe, Rik %A De Deyn, Peter P %A Fernadez, Carmen Muñoz %A Benito, Yoland Aladro %A Thonberg, Håkan %A Forsell, Charlotte %A Lilius, Lena %A Kinhult-Ståhlbom, Anne %A Kilander, Lena %A Brundin, RoseMarie %A Concari, Letizia %A Helisalmi, Seppo %A Koivisto, Anne Maria %A Haapasalo, Annakaisa %A Dermecourt, Vincent %A Fiévet, Nathalie %A Hanon, Olivier %A Dufouil, Carole %A Brice, Alexis %A Ritchie, Karen %A Dubois, Bruno %A Himali, Jayanadra J %A Keene, C Dirk %A Tschanz, JoAnn %A Fitzpatrick, Annette L %A Kukull, Walter A %A Norton, Maria %A Aspelund, Thor %A Larson, Eric B %A Munger, Ron %A Rotter, Jerome I %A Lipton, Richard B %A Bullido, María J %A Hofman, Albert %A Montine, Thomas J %A Coto, Eliecer %A Boerwinkle, Eric %A Petersen, Ronald C %A Alvarez, Victoria %A Rivadeneira, Fernando %A Reiman, Eric M %A Gallo, Maura %A O'Donnell, Christopher J %A Reisch, Joan S %A Bruni, Amalia Cecilia %A Royall, Donald R %A Dichgans, Martin %A Sano, Mary %A Galimberti, Daniela %A St George-Hyslop, Peter %A Scarpini, Elio %A Tsuang, Debby W %A Mancuso, Michelangelo %A Bonuccelli, Ubaldo %A Winslow, Ashley R %A Daniele, Antonio %A Wu, Chuang-Kuo %A Peters, Oliver %A Nacmias, Benedetta %A Riemenschneider, Matthias %A Heun, Reinhard %A Brayne, Carol %A Rubinsztein, David C %A Bras, Jose %A Guerreiro, Rita %A Al-Chalabi, Ammar %A Shaw, Christopher E %A Collinge, John %A Mann, David %A Tsolaki, Magda %A Clarimon, Jordi %A Sussams, Rebecca %A Lovestone, Simon %A O'Donovan, Michael C %A Owen, Michael J %A Behrens, Timothy W %A Mead, Simon %A Goate, Alison M %A Uitterlinden, André G %A Holmes, Clive %A Cruchaga, Carlos %A Ingelsson, Martin %A Bennett, David A %A Powell, John %A Golde, Todd E %A Graff, Caroline %A De Jager, Philip L %A Morgan, Kevin %A Ertekin-Taner, Nilufer %A Combarros, Onofre %A Psaty, Bruce M %A Passmore, Peter %A Younkin, Steven G %A Berr, Claudine %A Gudnason, Vilmundur %A Rujescu, Dan %A Dickson, Dennis W %A Dartigues, Jean-François %A DeStefano, Anita L %A Ortega-Cubero, Sara %A Hakonarson, Hakon %A Campion, Dominique %A Boada, Merce %A Kauwe, John Keoni %A Farrer, Lindsay A %A Van Broeckhoven, Christine %A Ikram, M Arfan %A Jones, Lesley %A Haines, Jonathan L %A Tzourio, Christophe %A Launer, Lenore J %A Escott-Price, Valentina %A Mayeux, Richard %A Deleuze, Jean-Francois %A Amin, Najaf %A Holmans, Peter A %A Pericak-Vance, Margaret A %A Amouyel, Philippe %A van Duijn, Cornelia M %A Ramirez, Alfredo %A Wang, Li-San %A Lambert, Jean-Charles %A Seshadri, Sudha %A Williams, Julie %A Schellenberg, Gerard D %K Adaptor Proteins, Signal Transducing %K Alzheimer Disease %K Amino Acid Sequence %K Case-Control Studies %K Exome %K Gene Expression Profiling %K Gene Frequency %K Genetic Predisposition to Disease %K Genotype %K Humans %K Immunity, Innate %K Linkage Disequilibrium %K Membrane Glycoproteins %K Microglia %K Odds Ratio %K Phospholipase C gamma %K Polymorphism, Single Nucleotide %K Protein Interaction Maps %K Receptors, Immunologic %K Sequence Homology, Amino Acid %X

We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P < 1 × 10-4) in 35,962 independent samples using de novo genotyping and imputed genotypes. In stage 3, we used an additional 14,997 samples to test the most significant stage 2 associations (P < 5 × 10-8) using imputed genotypes. We observed three new genome-wide significant nonsynonymous variants associated with Alzheimer's disease: a protective variant in PLCG2 (rs72824905: p.Pro522Arg, P = 5.38 × 10-10, odds ratio (OR) = 0.68, minor allele frequency (MAF)cases = 0.0059, MAFcontrols = 0.0093), a risk variant in ABI3 (rs616338: p.Ser209Phe, P = 4.56 × 10-10, OR = 1.43, MAFcases = 0.011, MAFcontrols = 0.008), and a new genome-wide significant variant in TREM2 (rs143332484: p.Arg62His, P = 1.55 × 10-14, OR = 1.67, MAFcases = 0.0143, MAFcontrols = 0.0089), a known susceptibility gene for Alzheimer's disease. These protein-altering changes are in genes highly expressed in microglia and highlight an immune-related protein-protein interaction network enriched for previously identified risk genes in Alzheimer's disease. These genetic findings provide additional evidence that the microglia-mediated innate immune response contributes directly to the development of Alzheimer's disease.

%B Nat Genet %V 49 %P 1373-1384 %8 2017 Sep %G eng %N 9 %R 10.1038/ng.3916 %0 Journal Article %J PLoS Genet %D 2017 %T Rare coding variants pinpoint genes that control human hematological traits. %A Mousas, Abdou %A Ntritsos, Georgios %A Chen, Ming-Huei %A Song, Ci %A Huffman, Jennifer E %A Tzoulaki, Ioanna %A Elliott, Paul %A Psaty, Bruce M %A Auer, Paul L %A Johnson, Andrew D %A Evangelou, Evangelos %A Lettre, Guillaume %A Reiner, Alexander P %K Asthma %K Databases, Genetic %K Endometriosis %K Female %K Fibrin Fibrinogen Degradation Products %K Gene Frequency %K Genetic Loci %K Genome, Human %K Genome-Wide Association Study %K Humans %K Interleukin-33 %K Linear Models %K Logistic Models %K Male %K Mutation, Missense %K Phenotype %K Plasminogen %K Platelet Count %K Polymorphism, Single Nucleotide %K Principal Component Analysis %K Protein Splicing %K Rhinitis, Allergic %K Sequence Analysis, DNA %X

The identification of rare coding or splice site variants remains the most straightforward strategy to link genes with human phenotypes. Here, we analyzed the association between 137,086 rare (minor allele frequency (MAF) <1%) coding or splice site variants and 15 hematological traits in up to 308,572 participants. We found 56 such rare coding or splice site variants at P<5x10-8, including 31 that are associated with a blood-cell phenotype for the first time. All but one of these 31 new independent variants map to loci previously implicated in hematopoiesis by genome-wide association studies (GWAS). This includes a rare splice acceptor variant (rs146597587, MAF = 0.5%) in interleukin 33 (IL33) associated with reduced eosinophil count (P = 2.4x10-23), and lower risk of asthma (P = 2.6x10-7, odds ratio [95% confidence interval] = 0.56 [0.45-0.70]) and allergic rhinitis (P = 4.2x10-4, odds ratio = 0.55 [0.39-0.76]). The single new locus identified in our study is defined by a rare p.Arg172Gly missense variant (rs145535174, MAF = 0.05%) in plasminogen (PLG) associated with increased platelet count (P = 6.8x10-9), and decreased D-dimer concentration (P = 0.018) and platelet reactivity (P<0.03). Finally, our results indicate that searching for rare coding or splice site variants in very large sample sizes can help prioritize causal genes at many GWAS loci associated with complex human diseases and traits.

%B PLoS Genet %V 13 %P e1006925 %8 2017 Aug %G eng %N 8 %R 10.1371/journal.pgen.1006925 %0 Journal Article %J Clin J Am Soc Nephrol %D 2017 %T The Relation of Serum Potassium Concentration with Cardiovascular Events and Mortality in Community-Living Individuals. %A Hughes-Austin, Jan M %A Rifkin, Dena E %A Beben, Tomasz %A Katz, Ronit %A Sarnak, Mark J %A Deo, Rajat %A Hoofnagle, Andrew N %A Homma, Shunichi %A Siscovick, David S %A Sotoodehnia, Nona %A Psaty, Bruce M %A de Boer, Ian H %A Kestenbaum, Bryan %A Shlipak, Michael G %A Ix, Joachim H %X

BACKGROUND AND OBJECTIVES: Hyperkalemia is associated with adverse outcomes in patients with CKD and in hospitalized patients with acute medical conditions. Little is known regarding hyperkalemia, cardiovascular disease (CVD), and mortality in community-living populations. In a pooled analysis of two large observational cohorts, we investigated associations between serum potassium concentrations and CVD events and mortality, and whether potassium-altering medications and eGFR<60 ml/min per 1.73 m(2) modified these associations.

DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Among 9651 individuals from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Cardiovascular Health Study (CHS), who were free of CVD at baseline (2000-2002 in the MESA and 1989-1993 in the CHS), we investigated associations between serum potassium categories (<3.5, 3.5-3.9, 4.0-4.4, 4.5-4.9, and ≥5.0 mEq/L) and CVD events, mortality, and mortality subtypes (CVD versus non-CVD) using Cox proportional hazards models, adjusting for demographics, time-varying eGFR, traditional CVD risk factors, and use of potassium-altering medications.

RESULTS: Compared with serum potassium concentrations between 4.0 and 4.4 mEq/L, those with concentrations ≥5.0 mEq/L were at higher risk for all-cause mortality (hazard ratio, 1.41; 95% confidence interval, 1.12 to 1.76), CVD death (hazard ratio, 1.50; 95% confidence interval, 1.00 to 2.26), and non-CVD death (hazard ratio, 1.40; 95% confidence interval, 1.07 to 1.83) in fully adjusted models. Associations of serum potassium with these end points differed among diuretic users (Pinteraction<0.02 for all), such that participants who had serum potassium ≥5.0 mEq/L and were concurrently using diuretics were at higher risk of each end point compared with those not using diuretics.

CONCLUSIONS: Serum potassium concentration ≥5.0 mEq/L was associated with all-cause mortality, CVD death, and non-CVD death in community-living individuals; associations were stronger in diuretic users. Whether maintenance of potassium within the normal range may improve clinical outcomes requires future study.

%B Clin J Am Soc Nephrol %V 12 %P 245-252 %8 2017 Feb 07 %G eng %N 2 %R 10.2215/CJN.06290616 %0 Journal Article %J Am J Cardiol %D 2017 %T Relation of the Myocardial Contraction Fraction, as Calculated from M-Mode Echocardiography, With Incident Heart Failure, Atherosclerotic Cardiovascular Disease and Mortality (Results from the Cardiovascular Health Study). %A Maurer, Mathew S %A Koh, William J H %A Bartz, Traci M %A Vullaganti, Sirish %A Barasch, Eddy %A Gardin, Julius M %A Gottdiener, John S %A Psaty, Bruce M %A Kizer, Jorge R %X

We evaluated the association between 2-dimensional (2D) echocardiography (echo)-determined myocardial contraction fraction (MCF) and adverse cardiovascular outcomes including incident heart failure (HF), atherosclerotic cardiovascular disease (ASCVD), and mortality. The MCF, the ratio of left ventricular (LV) stroke volume (SV) to myocardial volume (MV), is a volumetric measure of myocardial shortening that can distinguish pathologic from physiological hypertrophy. Using 2D echo-guided M-mode data from the Cardiovascular Health Study, we calculated MCF in subjects with LV ejection fraction (EF) ≥55% and used Cox models to evaluate its association with incident HF, ASCVD, and all-cause mortality after adjusting for clinical and echo parameters. We assessed whether log2(SV) and log2(MV) were consistent with the expected 1:-1 ratio used in the definition of MCF. Among 2,147 participants (age 72 ± 5 years), average MCF was 59 ± 13%. After controlling for clinical and echo variables, each 10% absolute increment in MCF was associated with lower risk of HF (hazard ratio [HR] 0.88; 95% confidence interval [CI] 0.82, 0.94), ASCVD (HR 0.90; 95% CI 0.85, 0.95), and death (HR 0.93; 95% CI 0.89, 0.97). Moreover, the MCF was still significantly associated with ASCVD and mortality, but not HF, after adjustment for percent-predicted LV mass. Significant departure from the 1:-1 ratio was not observed for ASCVD or death, but did occur for HF, driven by a stronger association for MV than SV. In conclusion, among older adults without CVD or low LV ejection fraction, 2D echo-guided M-mode-derived MCF was independently associated with lower risk of adverse cardiovascular outcomes, but this ratiometric index may not capture the full relation that is apparent when its components are modeled separately in the case of HF.

%B Am J Cardiol %V 119 %P 923-928 %8 2017 Mar 15 %G eng %N 6 %R 10.1016/j.amjcard.2016.11.048 %0 Journal Article %J J Am Coll Cardiol %D 2017 %T Relationship Between Physical Activity, Body Mass Index, and Risk of Heart Failure. %A Pandey, Ambarish %A LaMonte, Michael %A Klein, Liviu %A Ayers, Colby %A Psaty, Bruce M %A Eaton, Charles B %A Allen, Norrina B %A de Lemos, James A %A Carnethon, Mercedes %A Greenland, Philip %A Berry, Jarett D %X

BACKGROUND: Lower leisure-time physical activity (LTPA) and higher body mass index (BMI) are independently associated with risk of heart failure (HF). However, it is unclear if this relationship is consistent for both heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF).

OBJECTIVES: This study sought to quantify dose-response associations between LTPA, BMI, and the risk of different HF subtypes.

METHODS: Individual-level data from 3 cohort studies (WHI [Women's Health Initiative], MESA [Multi-Ethnic Study of Atherosclerosis], and CHS [Cardiovascular Health Study]) were pooled and participants were stratified into guideline-recommended categories of LTPA and BMI. Associations between LTPA, BMI, and risk of overall HF, HFpEF (ejection fraction ≥45%), and HFrEF (ejection fraction <45%) were assessed by using multivariable adjusted Cox models and restricted cubic splines.

RESULTS: The study included 51,451 participants with 3,180 HF events (1,252 HFpEF, 914 HFrEF, and 1,014 unclassified HF). In the adjusted analysis, there was a dose-dependent association between higher LTPA levels, lower BMI, and overall HF risk. Among HF subtypes, LTPA in any dose range was not associated with HFrEF risk. In contrast, lower levels of LTPA (<500 MET-min/week) were not associated with HFpEF risk, and dose-dependent associations with lower HFpEF risk were observed at higher levels. Compared with no LTPA, higher than twice the guideline-recommended minimum LTPA levels (>1,000 MET-min/week) were associated with an 19% lower risk of HFpEF (hazard ratio: 0.81; 95% confidence interval: 0.68 to 0.97). The dose-response relationship for BMI with HFpEF risk was also more consistent than with HFrEF risk, such that increasing BMI above the normal range (≥25 kg/m(2)) was associated with a greater increase in risk of HFpEF than HFrEF.

CONCLUSIONS: Our study findings show strong, dose-dependent associations between LTPA levels, BMI, and risk of overall HF. Among HF subtypes, higher LTPA levels and lower BMI were more consistently associated with lower risk of HFpEF compared with HFrEF.

%B J Am Coll Cardiol %V 69 %P 1129-1142 %8 2017 Mar 07 %G eng %N 9 %R 10.1016/j.jacc.2016.11.081 %0 Journal Article %J Arch Osteoporos %D 2017 %T Relationship of bone mineral density with valvular and annular calcification in community-dwelling older people: The Cardiovascular Health Study. %A Massera, Daniele %A Xu, Shuo %A Bartz, Traci M %A Bortnick, Anna E %A Ix, Joachim H %A Chonchol, Michel %A Owens, David S %A Barasch, Eddy %A Gardin, Julius M %A Gottdiener, John S %A Robbins, John R %A Siscovick, David S %A Kizer, Jorge R %X

Associations between bone mineral density and aortic valvular, aortic annular, and mitral annular calcification were investigated in a cross-sectional analysis of a population-based cohort of 1497 older adults. Although there was no association between continuous bone mineral density and outcomes, a significant association between osteoporosis and aortic valvular calcification in men was found.

INTRODUCTION: The process of cardiac calcification bears a resemblance to skeletal bone metabolism and its regulation. Experimental studies suggest that bone mineral density (BMD) and valvular calcification may be reciprocally related, but epidemiologic data are sparse.

METHODS: We tested the hypothesis that BMD of the total hip and femoral neck measured by dual-energy X-ray absorptiometry (DXA) is inversely associated with prevalence of three echocardiographic measures of cardiac calcification in a cross-sectional analysis of 1497 older adults from the Cardiovascular Health Study. The adjusted association of BMD with aortic valve calcification (AVC), aortic annular calcification (AAC), and mitral annular calcification (MAC) was assessed with relative risk (RR) regression.

RESULTS: Mean (SD) age was 76.2 (4.8) years; 58% were women. Cardiac calcification was highly prevalent in women and men: AVC, 59.5 and 71.0%; AAC 45.1 and 46.7%; MAC 42.8 and 39.5%, respectively. After limited and full adjustment for potential confounders, no statistically significant associations were detected between continuous BMD at either site and the three measures of calcification. Assessment of WHO BMD categories revealed a significant association between osteoporosis at the total hip and AVC in men (adjusted RR compared with normal BMD = 1.24 (1.01-1.53)). In graded sensitivity analyses, there were apparent inverse associations between femoral neck BMD and AVC with stenosis in men, and femoral neck BMD and moderate/severe MAC in women, but these were not significant.

CONCLUSION: These findings support further investigation of the sex-specific relationships between low BMD and cardiac calcification, and whether processes linking the two could be targeted for therapeutic ends.

%B Arch Osteoporos %V 12 %P 52 %8 2017 Dec %G eng %N 1 %R 10.1007/s11657-017-0347-y %0 Journal Article %J Am J Epidemiol %D 2017 %T REPEATED MEASUREMENTS OF BLOOD PRESSURE AND CHOLESTEROL IMPROVES CARDIOVASCULAR DISEASE RISK PREDICTION: AN INDIVIDUAL-PARTICIPANT-DATA META-ANALYSIS. %A Paige, Ellie %A Barrett, Jessica %A Pennells, Lisa %A Sweeting, Michael %A Willeit, Peter %A Di Angelantonio, Emanuele %A Gudnason, Vilmundur %A Nordestgaard, Børge G %A Psaty, Bruce M %A Goldbourt, Uri %A Best, Lyle G %A Assmann, Gerd %A Salonen, Jukka T %A Nietert, Paul J %A Verschuren, Wm Monique %A Brunner, Eric J %A Kronmal, Richard A %A Salomaa, Veikko %A Bakker, Stephan Jl %A Dagenais, Gilles R %A Sato, Shinichi %A Jansson, Jan-Håkan %A Willeit, Johann %A Onat, Altan %A de la Cámara, Agustin Gómez %A Roussel, Ronan %A Völzke, Henry %A Dankner, Rachel %A Tipping, Robert W %A Meade, Tom W %A Donfrancesco, Chiara %A Kuller, Lewis H %A Peters, Annette %A Gallacher, John %A Kromhout, Daan %A Iso, Hiroyasu %A Knuiman, Matthew %A Casiglia, Edoardo %A Kavousi, Maryam %A Palmieri, Luigi %A Sundström, Johan %A Davis, Barry R %A Njølstad, Inger %A Couper, David %A Danesh, John %A Thompson, Simon G %A Wood, Angela %X

The added value of incorporating information from repeated measurements of blood pressure and cholesterol for cardiovascular disease (CVD) risk prediction has not been rigorously assessed. We used data from the Emerging Risk Factors Collaboration on 191,445 adults (38 cohorts from across 17 countries with data from 1962-2014) with > 1 million measurements of systolic blood pressure, total cholesterol and high-density lipoprotein cholesterol; over a median 12 years of follow-up, 21,170 CVD events occurred. Risk prediction models using cumulative means of repeated measurements and summary measures from longitudinal modelling of the repeated measurements were compared to models using measurements from a single time point. Risk discrimination (C-index) and net reclassification were calculated, and changes in C-indices were meta-analysed across studies. Compared to the single time point model, the cumulative means and the longitudinal models increased the C-index by 0.0040 (95% CI: 0.0023, 0.0057) and 0.0023 (0.0005, 0.0042), respectively. Reclassification was also improved in both models; compared to the single time point model, overall net reclassification improvements were 0.0369 (0.0303, 0.0436) for the cumulative means model and 0.0177 (0.0110, 0.0243) for the longitudinal model. In conclusion, incorporating repeated measurements of blood pressure and cholesterol into CVD risk prediction models slightly improves risk prediction.

%B Am J Epidemiol %8 2017 May 26 %G eng %R 10.1093/aje/kwx149 %0 Journal Article %J J Aging Health %D 2017 %T Role of Late-Life Depression in the Association of Subclinical Cardiovascular Disease With All-Cause Mortality: Cardiovascular Health Study. %A Armstrong, Nicole M %A Carlson, Michelle C %A Xue, Qian-Li %A Schrack, Jennifer %A Carnethon, Mercedes R %A Chaves, Paulo H M %A Gross, Alden L %X

OBJECTIVES: To evaluate whether late-life depression mediates the association of subclinical cardiovascular disease (CVD) with all-cause mortality.

METHOD: Using data from 3,473 Cardiovascular Health Study participants, the Cox proportional hazards model was used to examine the direct and indirect (via late-life depression) effects of the association between baseline subclinical CVD and all-cause mortality with weights derived from multivariable logistic regression of late-life depression on subclinical CVD.

RESULTS: Subclinical CVD led to a higher risk of all-cause mortality (hazard ratio [HR] = 1.51, 95% confidence interval, [CI] = [1.42, 1.94]). Total effect of subclinical CVD on all-cause mortality was decomposed into direct (HR = 1.41, 95% CI = [1.37, 1.58]) and indirect (HR = 1.07, 95% CI = [1.01, 1.23]) effects; 16.3% of the total effect of subclinical CVD on all-cause mortality was mediated by late-life depression.

DISCUSSION: Late-life depression accounts for little, if any, of the association between subclinical CVD, a risk factor of all-cause mortality, and all-cause mortality.

%B J Aging Health %P 898264317744921 %8 2017 Nov 01 %G eng %R 10.1177/0898264317744921 %0 Journal Article %J Hum Genet %D 2018 %T Rare loss of function variants in candidate genes and risk of colorectal cancer. %A Rosenthal, Elisabeth A %A Shirts, Brian H %A Amendola, Laura M %A Horike-Pyne, Martha %A Robertson, Peggy D %A Hisama, Fuki M %A Bennett, Robin L %A Dorschner, Michael O %A Nickerson, Deborah A %A Stanaway, Ian B %A Nassir, Rami %A Vickers, Kathy T %A Li, Christopher %A Grady, William M %A Peters, Ulrike %A Jarvik, Gail P %X

Although ~ 25% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR = 1.9, p = 0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p = 0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p = 0.0001), BRCA2 (p = 0.01) and BRIP1 (p = 0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P.

%B Hum Genet %8 2018 Sep 28 %G eng %R 10.1007/s00439-018-1938-4 %0 Journal Article %J Nat Genet %D 2018 %T Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. %A Mahajan, Anubha %A Wessel, Jennifer %A Willems, Sara M %A Zhao, Wei %A Robertson, Neil R %A Chu, Audrey Y %A Gan, Wei %A Kitajima, Hidetoshi %A Taliun, Daniel %A Rayner, N William %A Guo, Xiuqing %A Lu, Yingchang %A Li, Man %A Jensen, Richard A %A Hu, Yao %A Huo, Shaofeng %A Lohman, Kurt K %A Zhang, Weihua %A Cook, James P %A Prins, Bram Peter %A Flannick, Jason %A Grarup, Niels %A Trubetskoy, Vassily Vladimirovich %A Kravic, Jasmina %A Kim, Young Jin %A Rybin, Denis V %A Yaghootkar, Hanieh %A Müller-Nurasyid, Martina %A Meidtner, Karina %A Li-Gao, Ruifang %A Varga, Tibor V %A Marten, Jonathan %A Li, Jin %A Smith, Albert Vernon %A An, Ping %A Ligthart, Symen %A Gustafsson, Stefan %A Malerba, Giovanni %A Demirkan, Ayse %A Tajes, Juan Fernandez %A Steinthorsdottir, Valgerdur %A Wuttke, Matthias %A Lecoeur, Cécile %A Preuss, Michael %A Bielak, Lawrence F %A Graff, Marielisa %A Highland, Heather M %A Justice, Anne E %A Liu, Dajiang J %A Marouli, Eirini %A Peloso, Gina Marie %A Warren, Helen R %A Afaq, Saima %A Afzal, Shoaib %A Ahlqvist, Emma %A Almgren, Peter %A Amin, Najaf %A Bang, Lia B %A Bertoni, Alain G %A Bombieri, Cristina %A Bork-Jensen, Jette %A Brandslund, Ivan %A Brody, Jennifer A %A Burtt, Noel P %A Canouil, Mickaël %A Chen, Yii-Der Ida %A Cho, Yoon Shin %A Christensen, Cramer %A Eastwood, Sophie V %A Eckardt, Kai-Uwe %A Fischer, Krista %A Gambaro, Giovanni %A Giedraitis, Vilmantas %A Grove, Megan L %A de Haan, Hugoline G %A Hackinger, Sophie %A Hai, Yang %A Han, Sohee %A Tybjærg-Hansen, Anne %A Hivert, Marie-France %A Isomaa, Bo %A Jäger, Susanne %A Jørgensen, Marit E %A Jørgensen, Torben %A Käräjämäki, AnneMari %A Kim, Bong-Jo %A Kim, Sung Soo %A Koistinen, Heikki A %A Kovacs, Peter %A Kriebel, Jennifer %A Kronenberg, Florian %A Läll, Kristi %A Lange, Leslie A %A Lee, Jung-Jin %A Lehne, Benjamin %A Li, Huaixing %A Lin, Keng-Hung %A Linneberg, Allan %A Liu, Ching-Ti %A Liu, Jun %A Loh, Marie %A Mägi, Reedik %A Mamakou, Vasiliki %A McKean-Cowdin, Roberta %A Nadkarni, Girish %A Neville, Matt %A Nielsen, Sune F %A Ntalla, Ioanna %A Peyser, Patricia A %A Rathmann, Wolfgang %A Rice, Kenneth %A Rich, Stephen S %A Rode, Line %A Rolandsson, Olov %A Schönherr, Sebastian %A Selvin, Elizabeth %A Small, Kerrin S %A Stančáková, Alena %A Surendran, Praveen %A Taylor, Kent D %A Teslovich, Tanya M %A Thorand, Barbara %A Thorleifsson, Gudmar %A Tin, Adrienne %A Tönjes, Anke %A Varbo, Anette %A Witte, Daniel R %A Wood, Andrew R %A Yajnik, Pranav %A Yao, Jie %A Yengo, Loic %A Young, Robin %A Amouyel, Philippe %A Boeing, Heiner %A Boerwinkle, Eric %A Bottinger, Erwin P %A Chowdhury, Rajiv %A Collins, Francis S %A Dedoussis, George %A Dehghan, Abbas %A Deloukas, Panos %A Ferrario, Marco M %A Ferrieres, Jean %A Florez, Jose C %A Frossard, Philippe %A Gudnason, Vilmundur %A Harris, Tamara B %A Heckbert, Susan R %A Howson, Joanna M M %A Ingelsson, Martin %A Kathiresan, Sekar %A Kee, Frank %A Kuusisto, Johanna %A Langenberg, Claudia %A Launer, Lenore J %A Lindgren, Cecilia M %A Männistö, Satu %A Meitinger, Thomas %A Melander, Olle %A Mohlke, Karen L %A Moitry, Marie %A Morris, Andrew D %A Murray, Alison D %A de Mutsert, Renée %A Orho-Melander, Marju %A Owen, Katharine R %A Perola, Markus %A Peters, Annette %A Province, Michael A %A Rasheed, Asif %A Ridker, Paul M %A Rivadineira, Fernando %A Rosendaal, Frits R %A Rosengren, Anders H %A Salomaa, Veikko %A Sheu, Wayne H-H %A Sladek, Rob %A Smith, Blair H %A Strauch, Konstantin %A Uitterlinden, André G %A Varma, Rohit %A Willer, Cristen J %A Blüher, Matthias %A Butterworth, Adam S %A Chambers, John Campbell %A Chasman, Daniel I %A Danesh, John %A van Duijn, Cornelia %A Dupuis, Josée %A Franco, Oscar H %A Franks, Paul W %A Froguel, Philippe %A Grallert, Harald %A Groop, Leif %A Han, Bok-Ghee %A Hansen, Torben %A Hattersley, Andrew T %A Hayward, Caroline %A Ingelsson, Erik %A Kardia, Sharon L R %A Karpe, Fredrik %A Kooner, Jaspal Singh %A Köttgen, Anna %A Kuulasmaa, Kari %A Laakso, Markku %A Lin, Xu %A Lind, Lars %A Liu, Yongmei %A Loos, Ruth J F %A Marchini, Jonathan %A Metspalu, Andres %A Mook-Kanamori, Dennis %A Nordestgaard, Børge G %A Palmer, Colin N A %A Pankow, James S %A Pedersen, Oluf %A Psaty, Bruce M %A Rauramaa, Rainer %A Sattar, Naveed %A Schulze, Matthias B %A Soranzo, Nicole %A Spector, Timothy D %A Stefansson, Kari %A Stumvoll, Michael %A Thorsteinsdottir, Unnur %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Wareham, Nicholas J %A Wilson, James G %A Zeggini, Eleftheria %A Scott, Robert A %A Barroso, Inês %A Frayling, Timothy M %A Goodarzi, Mark O %A Meigs, James B %A Boehnke, Michael %A Saleheen, Danish %A Morris, Andrew P %A Rotter, Jerome I %A McCarthy, Mark I %X

We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.

%B Nat Genet %V 50 %P 559-571 %8 2018 Apr %G eng %N 4 %R 10.1038/s41588-018-0084-1 %0 Journal Article %J J Clin Endocrinol Metab %D 2018 %T The relation between thyroid function and anemia: a pooled analysis of individual participant data. %A Wopereis, Daisy M %A Du Puy, Robert S %A van Heemst, Diana %A Walsh, John P %A Bremner, Alexandra %A Bakker, Stephan J L %A Bauer, Douglas C %A Cappola, Anne R %A Ceresini, Graziano %A Degryse, Jean %A Dullaart, Robin P F %A Feller, Martin %A Ferrucci, Luigi %A Floriani, Carmen %A Franco, Oscar H %A Iacoviello, Massimo %A Iervasi, Georgio %A Imaizumi, Misa %A Jukema, J Wouter %A Khaw, Kay-Tee %A Luben, Robert N %A Molinaro, Sabrina %A Nauck, Matthias %A Patel, Kushang V %A Peeters, Robin P %A Psaty, Bruce M %A Razvi, Salman %A Schindhelm, Roger K %A van Schoor, Natasja M %A Stott, David J %A Vaes, Bert %A Vanderpump, Mark P J %A Völzke, Henry %A Westendorp, Rudi G J %A Rodondi, Nicolas %A Cobbaert, Christa M %A Gussekloo, Jacobijn %A den Elzen, Wendy P J %X

Context: Anemia and thyroid dysfunction often co-occur and both increase with age. Human data on the relationship between thyroid disease and anemia are scarce.

Objective: To investigate the cross-sectional and longitudinal associations between clinical thyroid status and anemia.

Design: Individual participant data meta-analysis.

Setting: Sixteen cohorts participating in the Thyroid Studies Collaboration (n=42 162).

Main outcome measures: Primary outcome measure was anemia (hemoglobin <130 g/L in men and <120 g/L in women).

Results: Cross-sectionally, participants with abnormal thyroid status had an increased risk of having anemia compared with euthyroid participants (overt hypothyroidism, pooled odds ratio 1.84 [95% CI: 1.35-2.50], subclinical hypothyroidism 1.21 [1.02-1.43], subclinical hyperthyroidism 1.27 [1.03-1.57], overt hyperthyroidism 1.69 [1.00-2.87]). Hemoglobin levels were lower in all groups compared to participants with euthyroidism. In the longitudinal analyses (n=25,466 from 14 cohorts), the pooled hazard ratio for the risk of development of anemia was 1.38 [95% CI: 0.86-2.20] for overt hypothyroidism, 1.18 [1.00-1.38] for subclinical hypothyroidism, 1.15 [0.94-1.42] for subclinical hyperthyroidism and 1.47 [0.91-2.38] for overt hyperthyroidism. Sensitivity analyses excluding thyroid medication or high levels of C-reactive protein yielded similar results. No differences in mean annual change in hemoglobin levels were observed between the thyroid hormone status groups.

Conclusion: Higher odds of having anemia were observed in both participants with hypothyroid function and hyperthyroid function. In addition, reduced thyroid function at baseline showed a trend of increased risk of developing anemia during follow-up. It remains to be assessed in a randomized controlled trial whether treatment is effective in reducing anemia.

%B J Clin Endocrinol Metab %8 2018 Aug 02 %G eng %R 10.1210/jc.2018-00481 %0 Journal Article %J Am J Kidney Dis %D 2018 %T Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium. %A Inker, Lesley A %A Grams, Morgan E %A Levey, Andrew S %A Coresh, Josef %A Cirillo, Massimo %A Collins, John F %A Gansevoort, Ron T %A Gutierrez, Orlando M %A Hamano, Takayuki %A Heine, Gunnar H %A Ishikawa, Shizukiyo %A Jee, Sun Ha %A Kronenberg, Florian %A Landray, Martin J %A Miura, Katsuyuki %A Nadkarni, Girish N %A Peralta, Carmen A %A Rothenbacher, Dietrich %A Schaeffner, Elke %A Sedaghat, Sanaz %A Shlipak, Michael G %A Zhang, Luxia %A van Zuilen, Arjan D %A Hallan, Stein I %A Kovesdy, Csaba P %A Woodward, Mark %A Levin, Adeera %X

RATIONALE & OBJECTIVE: Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework.

STUDY DESIGN: Cross-sectional individual participant-level analyses in a global consortium.

SETTING & STUDY POPULATIONS: 17 CKD and 38 general population and high-risk cohorts.

SELECTION CRITERIA FOR STUDIES: Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension.

DATA EXTRACTION: Data were obtained and analyzed between July 2015 and January 2018.

ANALYTICAL APPROACH: We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses.

RESULTS: The CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g).

LIMITATIONS: Variations in study era, health care delivery system, typical diet, and laboratory assays.

CONCLUSIONS: Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD.

%B Am J Kidney Dis %8 2018 Oct 19 %G eng %R 10.1053/j.ajkd.2018.08.013 %0 Journal Article %J J Am Heart Assoc %D 2018 %T Reversal of Aging-Induced Increases in Aortic Stiffness by Targeting Cytoskeletal Protein-Protein Interfaces. %A Nicholson, Christopher J %A Singh, Kuldeep %A Saphirstein, Robert J %A Gao, Yuan Z %A Li, Qian %A Chiu, Joanna G %A Leavis, Paul %A Verwoert, Germaine C %A Mitchell, G F %A Porter, Tyrone %A Morgan, Kathleen G %X

BACKGROUND: The proximal aorta normally functions as a critical shock absorber that protects small downstream vessels from damage by pressure and flow pulsatility generated by the heart during systole. This shock absorber function is impaired with age because of aortic stiffening.

METHODS AND RESULTS: We examined the contribution of common genetic variation to aortic stiffness in humans by interrogating results from the AortaGen Consortium genome-wide association study of carotid-femoral pulse wave velocity. Common genetic variation in the N-WASP () locus is associated with carotid-femoral pulse wave velocity (rs600420, =0.0051). Thus, we tested the hypothesis that decoy proteins designed to disrupt the interaction of cytoskeletal proteins such as N-WASP with its binding partners in the vascular smooth muscle cytoskeleton could decrease ex vivo stiffness of aortas from a mouse model of aging. A synthetic decoy peptide construct of N-WASP significantly reduced activated stiffness in ex vivo aortas of aged mice. Two other cytoskeletal constructs targeted to VASP and talin-vinculin interfaces similarly decreased aging-induced ex vivo active stiffness by on-target specific actions. Furthermore, packaging these decoy peptides into microbubbles enables the peptides to be ultrasound-targeted to the wall of the proximal aorta to attenuate ex vivo active stiffness.

CONCLUSIONS: We conclude that decoy peptides targeted to vascular smooth muscle cytoskeletal protein-protein interfaces and microbubble packaged can decrease aortic stiffness ex vivo. Our results provide proof of concept at the ex vivo level that decoy peptides targeted to cytoskeletal protein-protein interfaces may lead to substantive dynamic modulation of aortic stiffness.

%B J Am Heart Assoc %V 7 %8 2018 Jul 18 %G eng %N 15 %R 10.1161/JAHA.118.008926 %0 Journal Article %J Lancet %D 2018 %T Risk thresholds for alcohol consumption: combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies. %A Wood, Angela M %A Kaptoge, Stephen %A Butterworth, Adam S %A Willeit, Peter %A Warnakula, Samantha %A Bolton, Thomas %A Paige, Ellie %A Paul, Dirk S %A Sweeting, Michael %A Burgess, Stephen %A Bell, Steven %A Astle, William %A Stevens, David %A Koulman, Albert %A Selmer, Randi M %A Verschuren, W M Monique %A Sato, Shinichi %A Njølstad, Inger %A Woodward, Mark %A Salomaa, Veikko %A Nordestgaard, Børge G %A Yeap, Bu B %A Fletcher, Astrid %A Melander, Olle %A Kuller, Lewis H %A Balkau, Beverley %A Marmot, Michael %A Koenig, Wolfgang %A Casiglia, Edoardo %A Cooper, Cyrus %A Arndt, Volker %A Franco, Oscar H %A Wennberg, Patrik %A Gallacher, John %A de la Cámara, Agustin Gómez %A Völzke, Henry %A Dahm, Christina C %A Dale, Caroline E %A Bergmann, Manuela M %A Crespo, Carlos J %A van der Schouw, Yvonne T %A Kaaks, Rudolf %A Simons, Leon A %A Lagiou, Pagona %A Schoufour, Josje D %A Boer, Jolanda M A %A Key, Timothy J %A Rodriguez, Beatriz %A Moreno-Iribas, Conchi %A Davidson, Karina W %A Taylor, James O %A Sacerdote, Carlotta %A Wallace, Robert B %A Quiros, J Ramon %A Tumino, Rosario %A Blazer, Dan G %A Linneberg, Allan %A Daimon, Makoto %A Panico, Salvatore %A Howard, Barbara %A Skeie, Guri %A Strandberg, Timo %A Weiderpass, Elisabete %A Nietert, Paul J %A Psaty, Bruce M %A Kromhout, Daan %A Salamanca-Fernandez, Elena %A Kiechl, Stefan %A Krumholz, Harlan M %A Grioni, Sara %A Palli, Domenico %A Huerta, José M %A Price, Jackie %A Sundström, Johan %A Arriola, Larraitz %A Arima, Hisatomi %A Travis, Ruth C %A Panagiotakos, Demosthenes B %A Karakatsani, Anna %A Trichopoulou, Antonia %A Kühn, Tilman %A Grobbee, Diederick E %A Barrett-Connor, Elizabeth %A van Schoor, Natasja %A Boeing, Heiner %A Overvad, Kim %A Kauhanen, Jussi %A Wareham, Nick %A Langenberg, Claudia %A Forouhi, Nita %A Wennberg, Maria %A Després, Jean-Pierre %A Cushman, Mary %A Cooper, Jackie A %A Rodriguez, Carlos J %A Sakurai, Masaru %A Shaw, Jonathan E %A Knuiman, Matthew %A Voortman, Trudy %A Meisinger, Christa %A Tjønneland, Anne %A Brenner, Hermann %A Palmieri, Luigi %A Dallongeville, Jean %A Brunner, Eric J %A Assmann, Gerd %A Trevisan, Maurizio %A Gillum, Richard F %A Ford, Ian %A Sattar, Naveed %A Lazo, Mariana %A Thompson, Simon G %A Ferrari, Pietro %A Leon, David A %A Smith, George Davey %A Peto, Richard %A Jackson, Rod %A Banks, Emily %A Di Angelantonio, Emanuele %A Danesh, John %X

BACKGROUND: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.

METHODS: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies.

FINDINGS: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively.

INTERPRETATION: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.

FUNDING: UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

%B Lancet %V 391 %P 1513-1523 %8 2018 04 14 %G eng %N 10129 %R 10.1016/S0140-6736(18)30134-X %0 Journal Article %J Alzheimers Dement %D 2019 %T A rare missense variant of CASP7 is associated with familial late-onset Alzheimer's disease. %A Zhang, Xiaoling %A Zhu, Congcong %A Beecham, Gary %A Vardarajan, Badri N %A Ma, Yiyi %A Lancour, Daniel %A Farrell, John J %A Chung, Jaeyoon %A Mayeux, Richard %A Haines, Jonathan L %A Schellenberg, Gerard D %A Pericak-Vance, Margaret A %A Lunetta, Kathryn L %A Farrer, Lindsay A %X

INTRODUCTION: The genetic architecture of Alzheimer's disease (AD) is only partially understood.

METHODS: We conducted an association study for AD using whole sequence data from 507 genetically enriched AD cases (i.e., cases having close relatives affected by AD) and 4917 cognitively healthy controls of European ancestry (EA) and 172 enriched cases and 179 controls of Caribbean Hispanic ancestry. Confirmation of top findings from stage 1 was sought in two family-based genome-wide association study data sets and in a whole genome-sequencing data set comprising members from 42 EA and 115 Caribbean Hispanic families.

RESULTS: We identified associations in EAs with variants in 12 novel loci. The most robust finding is a rare CASP7 missense variant (rs116437863; P = 2.44 × 10) which improved when combined with results from stage 2 data sets (P = 1.92 × 10).

DISCUSSION: Our study demonstrated that an enriched case design can strengthen genetic signals, thus allowing detection of associations that would otherwise be missed in a traditional case-control study.

%B Alzheimers Dement %8 2019 Jan 03 %G eng %R 10.1016/j.jalz.2018.10.005 %0 Journal Article %J Am J Kidney Dis %D 2019 %T {Relationship of Estimated GFR and Albuminuria to Concurrent Laboratory Abnormalities: An Individual Participant Data Meta-analysis in a Global Consortium %A Inker, L. A. %A Grams, M. E. %A Levey, A. S. %A Coresh, J. %A Cirillo, M. %A Collins, J. F. %A Gansevoort, R. T. %A Gutierrez, O. M. %A Hamano, T. %A Heine, G. H. %A Ishikawa, S. %A Jee, S. H. %A Kronenberg, F. %A Landray, M. J. %A Miura, K. %A Nadkarni, G. N. %A Peralta, C. A. %A Rothenbacher, D. %A Schaeffner, E. %A Sedaghat, S. %A Shlipak, M. G. %A Zhang, L. %A van Zuilen, A. D. %A Hallan, S. I. %A Kovesdy, C. P. %A Woodward, M. %A Levin, A. %A Astor, B. %A Appel, L. %A Greene, T. %A Chen, T. %A Chalmers, J. %A Woodward, M. %A Arima, H. %A Perkovic, V. %A Yatsuya, H. %A Tamakoshi, K. %A Li, Y. %A Hirakawa, Y. %A Coresh, J. %A Matsushita, K. %A Grams, M. %A Sang, Y. %A Polkinghorne, K. %A Chadban, S. %A Atkins, R. %A Levin, A. %A Djurdjev, O. %A Zhang, L. %A Liu, L. %A Zhao, M. %A Wang, F. %A Wang, J. %A Schaeffner, E. %A Ebert, N. %A Martus, P. %A Levin, A. %A Djurdjev, O. %A Tang, M. %A Heine, G. %A Emrich, I. %A Seiler, S. %A Zawada, A. %A Nally, J. %A Navaneethan, S. %A Schold, J. %A Zhang, L. %A Zhao, M. %A Wang, F. %A Wang, J. %A Shlipak, M. %A Sarnak, M. %A Katz, R. %A Hiramoto, J. %A Iso, H. %A Yamagishi, K. %A Umesawa, M. %A Muraki, I. %A Fukagawa, M. %A Maruyama, S. %A Hamano, T. %A Hasegawa, T. %A Fujii, N. %A Wheeler, D. %A Emberson, J. %A Townend, J. %A Landray, M. %A Brenner, H. %A Sch?ttker, B. %A Saum, K. U. %A Rothenbacher, D. %A Fox, C. %A Hwang, S. J. %A K?ttgen, A. %A Kronenberg, F. %A Schneider, M. P. %A Eckardt, K. U. %A Green, J. %A Kirchner, H. L. %A Chang, A. R. %A Ho, K. %A Ito, S. %A Miyazaki, M. %A Nakayama, M. %A Yamada, G. %A Cirillo, M. %A Irie, F. %A Sairenchi, T. %A Ishikawa, S. %A Yano, Y. %A Kotani, K. %A Nakamura, T. %A Jee, S. H. %A Kimm, H. %A Mok, Y. %A Chodick, G. %A Shalev, V. %A Wetzels, J. F. M. %A Blankestijn, P. J. %A van Zuilen, A. D. %A van den Brand, J. %A Sarnak, M. %A Inker, L. %A Peralta, C. %A Hiramoto, J. %A Katz, R. %A Sarnak, M. %A Kronenberg, F. %A Kollerits, B. %A Ritz, E. %A Nitsch, D. %A Roderick, P. %A Fletcher, A. %A Bottinger, E. %A Nadkarni, G. N. %A Ellis, S. B. %A Nadukuru, R. %A Sang, Y. %A Ueshima, H. %A Okayama, A. %A Miura, K. %A Tanaka, S. %A Ueshima, H. %A Okamura, T. %A Miura, K. %A Tanaka, S. %A Miura, K. %A Okayama, A. %A Kadota, A. %A Tanaka, S. %A Kenealy, T. %A Elley, C. R. %A Collins, J. F. %A Drury, P. L. %A Ohkubo, T. %A Asayama, K. %A Metoki, H. %A Kikuya, M. %A Nakayama, M. %A Nelson, R. G. %A Knowler, W. C. %A Gansevoort, R. T. %A Bakker, S. J. %A Hak, E. %A Heerspink, H. J. L. %A Brunskill, N. %A Major, R. %A Shepherd, D. %A Medcalf, J. %A Jassal, S. K. %A Bergstrom, J. %A Ix, J. H. %A Barrett-Connor, E. %A Kovesdy, C. %A Kalantar-Zadeh, K. %A Sumida, K. %A Gutierrez, O. M. %A Muntner, P. %A Warnock, D. %A McClellan, W. %A Heerspink, H. J. L. %A de Zeeuw, D. %A Brenner, B. %A Sedaghat, S. %A Ikram, M. A. %A Hoorn, E. J. %A Dehghan, A. %A Carrero, J. J. %A Gasparini, A. %A Wettermark, B. %A Elinder, C. G. %A Wong, T. Y. %A Sabanayagam, C. %A Cheng, C. Y. %A Visseren, F. L. J. %A Evans, M. %A Segelmark, M. %A Stendahl, M. %A Sch?n, S. %A Tangri, N. %A Sud, M. %A Naimark, D. %A Wen, C. P. %A Tsao, C. K. %A Tsai, M. K. %A Chen, C. H. %A Konta, T. %A Hirayama, A. %A Ichikawa, K. %A Lannfelt, L. %A Larsson, A. %A ?rnl?v, J. %A Bilo, H. J. G. %A Landman, G. W. D. %A van Hateren, K. J. J. %A Kleefstra, N. %A Coresh Chair, J. %A Gansevoort, R. T. %A Grams, M. E. %A Hallan, S. %A Kovesdy, C. P. %A Levey, A. S. %A Matsushita, K. %A Shalev, V. %A Woodward, M. %A Ballew, S. H. %A Chen, J. %A Coresh, J. %A Grams, M. E. %A Kwak, L. %A Matsushita, K. %A Sang, Y. %A Surapaneni, A. %A Woodward, M. %X Chronic kidney disease (CKD) is complicated by abnormalities that reflect disruption in filtration, tubular, and endocrine functions of the kidney. Our aim was to explore the relationship of specific laboratory result abnormalities and hypertension with the estimated glomerular filtration rate (eGFR) and albuminuria CKD staging framework.\ Cross-sectional individual participant-level analyses in a global consortium.\ 17 CKD and 38 general population and high-risk cohorts.\ Cohorts in the CKD Prognosis Consortium with data for eGFR and albuminuria, as well as a measurement of hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, or calcium, or hypertension.\ Data were obtained and analyzed between July 2015 and January 2018.\ We modeled the association of eGFR and albuminuria with hemoglobin, bicarbonate, phosphorus, parathyroid hormone, potassium, and calcium values using linear regression and with hypertension and categorical definitions of each abnormality using logistic regression. Results were pooled using random-effects meta-analyses.\ The CKD cohorts (n=254,666 participants) were 27% women and 10% black, with a mean age of 69 (SD, 12) years. The general population/high-risk cohorts (n=1,758,334) were 50% women and 2% black, with a mean age of 50 (16) years. There was a strong graded association between lower eGFR and all laboratory result abnormalities (ORs ranging from 3.27 [95% CI, 2.68-3.97] to 8.91 [95% CI, 7.22-10.99] comparing eGFRs of 15 to 29 with eGFRs of 45 to 59mL/min/1.73m2), whereas albuminuria had equivocal or weak associations with abnormalities (ORs ranging from 0.77 [95% CI, 0.60-0.99] to 1.92 [95% CI, 1.65-2.24] comparing urinary albumin-creatinine ratio > 300 vs < 30mg/g).\ Variations in study era, health care delivery system, typical diet, and laboratory assays.\ Lower eGFR was strongly associated with higher odds of multiple laboratory result abnormalities. Knowledge of risk associations might help guide management in the heterogeneous group of patients with CKD. %B Am J Kidney Dis %V 73 %P 206–217 %8 02 %G eng %0 Journal Article %J J Hypertens %D 2019 %T The role of functional status on the relationship between blood pressure and cognitive decline: the Cardiovascular Health Study. %A Miller, Lindsay M %A Peralta, Carmen A %A Fitzpatrick, Annette L %A Wu, Chenkai %A Psaty, Bruce M %A Newman, Anne B %A Odden, Michelle C %X

OBJECTIVE: To examine whether self-reported functional status modified the association between blood pressure (BP) and cognitive decline among older adults.

METHODS: The study included 2097 US adults aged 75 years and older from the Cardiovascular Health Study, followed for up to 6 years. Functional status was ascertained by self-reported limitation in activities of daily living (ADL; none vs. any). Cognitive function was assessed by the Modified Mini Mental State Exam (3MSE). We used linear mixed models to examine whether the presence of at least one ADL limitation modified the association between BP and cognitive decline. Potential confounders included demographics, physiologic measures, antihypertensive medication use and apolipoprotein E ε4 allele. We conducted stratified analyses for significant interactions between BP and ADL.

RESULTS: The association between BP and change in 3MSE differed by baseline ADL limitation. Among participants without ADL limitation, elevated systolic BP (≥140 mmHg) was associated with a 0.15 decrease (95% CI -0.24 to -0.07); P value for interaction less than 0.001, whereas in those with an ADL limitation, elevated systolic BP was independently associated with a 0.30 increase in 3MSE scores per year (95% CI 0.06-0.55). Elevated diastolic BP (≥80 mmHg) was associated with an increase in cognitive function in both groups, although the increase was greater in those with ADL limitation (0.47 points per year vs. 0.18 points per year, P value for interaction = 0.01).

CONCLUSION: Elevated BP appears to be associated with a decrease in cognitive scores among functioning older adults, and modest improvements in cognitive function among poorly functioning elders.

%B J Hypertens %8 2019 May 01 %G eng %R 10.1097/HJH.0000000000002102 %0 Journal Article %J J Hypertens %D 2019 %T The role of functional status on the relationship between blood pressure and cognitive decline: the Cardiovascular Health Study. %A O'Rourke, Michael F %A Adji, Audrey %B J Hypertens %V 37 %P 2500-2501 %8 2019 Dec %G eng %N 12 %R 10.1097/HJH.0000000000002263 %0 Journal Article %J Am J Cardiol %D 2020 %T Relation of Biomarkers of Cardiac Injury, Stress, and Fibrosis With Cardiac Mechanics in Patients ≥ 65 Years of Age. %A Gottdiener, John S %A Seliger, Stephen %A DeFilippi, Christopher %A Christenson, Robert %A Baldridge, Abigail S %A Kizer, Jorge R %A Psaty, Bruce M %A Shah, Sanjiv J %X

High sensitivity cardiac troponin T (hscTnT), soluble ST2 (sST2), N-terminal B-type natriuretic peptide (NT-proBNP), and galectin-3 are biomarkers of cardiac injury, stress, myocardial stretch, and fibrosis. Elevated levels are associated with poor outcomes. However, their association with cardiac mechanics in older persons is unknown. Associations between these biomarkers and cardiac mechanics derived from speckle tracking echocardiography, including left ventricular longitudinal strain (LVLS), early diastolic strain, and left atrial reservoir strain (LARS) were evaluated using standardized beta coefficients () in a cross sectional analysis with cardiac biomarkers in older patients without cardiovascular disease, low ejection fraction, or wall motion abnormalities. Biomarker associations with strain were attenuated by demographics and risk factors. In adjusted models, LVLS was associated with continuous measures of hscTnT (β-0.06, p = 0.020), sST2 (β -0.05, p = 0.024) and NT-proBNP (β -0.06, p = 0.007). "High" levels (i.e., greater than prognostic cutpoint) of hscTnT (>13 ng/ml), sST2 (>35 ng/ml), and NT-proBNP (>190 pg/ml) were also associated with worse LVLS. In risk factor adjusted models, LARS was associated with hscTnT (β -0.08, p = 0.003) and NT-proBNP (β-0.18, p <0.0001). High hscTnT (>13 ng/ml) and high NT-proBNP (>190 pg/ml) were also both associated with worse LARS. Gal-3 was not associated with any strain measure. In conclusion, in persons ≥ 65 years of age, without cardiovascular disease, low ejection fraction, or wall motion abnormalities, hscTnT, sST2, and NT-proBNP are associated with worse LVLS. HscTnT and NT-proBNP are associated with worse LARS. In conclusion, these subclinical increases in blood biomarkers, and their associations with subtle diastolic and systolic dysfunction, may represent pre-clinical heart failure.

%B Am J Cardiol %8 2020 Sep 16 %G eng %R 10.1016/j.amjcard.2020.09.013 %0 Journal Article %J Circ Genom Precis Med %D 2020 %T Role of Rare and Low-Frequency Variants in Gene-Alcohol Interactions on Plasma Lipid Levels. %A Wang, Zhe %A Chen, Han %A Bartz, Traci M %A Bielak, Lawrence F %A Chasman, Daniel I %A Feitosa, Mary F %A Franceschini, Nora %A Guo, Xiuqing %A Lim, Elise %A Noordam, Raymond %A Richard, Melissa A %A Wang, Heming %A Cade, Brian %A Cupples, L Adrienne %A de Vries, Paul S %A Giulanini, Franco %A Lee, Jiwon %A Lemaitre, Rozenn N %A Martin, Lisa W %A Reiner, Alex P %A Rich, Stephen S %A Schreiner, Pamela J %A Sidney, Stephen %A Sitlani, Colleen M %A Smith, Jennifer A %A Willems van Dijk, Ko %A Yao, Jie %A Zhao, Wei %A Fornage, Myriam %A Kardia, Sharon L R %A Kooperberg, Charles %A Liu, Ching-Ti %A Mook-Kanamori, Dennis O %A Province, Michael A %A Psaty, Bruce M %A Redline, Susan %A Ridker, Paul M %A Rotter, Jerome I %A Boerwinkle, Eric %A Morrison, Alanna C %X

BACKGROUND: Alcohol intake influences plasma lipid levels, and such effects may be moderated by genetic variants. We aimed to characterize the role of aggregated rare and low-frequency protein-coding variants in gene by alcohol consumption interactions associated with fasting plasma lipid levels.

METHODS: In the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, fasting plasma triglycerides and high- and low-density lipoprotein cholesterol were measured in 34 153 individuals with European ancestry from 5 discovery studies and 32 277 individuals from 6 replication studies. Rare and low-frequency functional protein-coding variants (minor allele frequency, ≤5%) measured by an exome array were aggregated by genes and evaluated by a gene-environment interaction test and a joint test of genetic main and gene-environment interaction effects. Two dichotomous self-reported alcohol consumption variables, current drinker, defined as any recurrent drinking behavior, and regular drinker, defined as the subset of current drinkers who consume at least 2 drinks per week, were considered.

RESULTS: We discovered and replicated 21 gene-lipid associations at 13 known lipid loci through the joint test. Eight loci (, , , , , , , and ) remained significant after conditioning on the common index single-nucleotide polymorphism identified by previous genome-wide association studies, suggesting an independent role for rare and low-frequency variants at these loci. One significant gene-alcohol interaction on triglycerides in a novel locus was significantly discovered (=6.65×10 for the interaction test) and replicated at nominal significance level (=0.013) in .

CONCLUSIONS: In conclusion, this study applied new gene-based statistical approaches and suggested that rare and low-frequency genetic variants interacted with alcohol consumption on lipid levels.

%B Circ Genom Precis Med %V 13 %P e002772 %8 2020 Aug %G eng %N 4 %R 10.1161/CIRCGEN.119.002772 %0 Journal Article %J Sci Rep %D 2021 %T {Rare and low-frequency exonic variants and gene-by-smoking interactions in pulmonary function %A Yang, T. %A Jackson, V. E. %A Smith, A. V. %A Chen, H. %A Bartz, T. M. %A Sitlani, C. M. %A Psaty, B. M. %A Gharib, S. A. %A O'Connor, G. T. %A Dupuis, J. %A Xu, J. %A Lohman, K. %A Liu, Y. %A Kritchevsky, S. B. %A Cassano, P. A. %A Flexeder, C. %A Gieger, C. %A Karrasch, S. %A Peters, A. %A Schulz, H. %A Harris, S. E. %A Starr, J. M. %A Deary, I. J. %A Manichaikul, A. %A Oelsner, E. C. %A Barr, R. G. %A Taylor, K. D. %A Rich, S. S. %A Bonten, T. N. %A Mook-Kanamori, D. O. %A Noordam, R. %A Li-Gao, R. %A Jarvelin, M. R. %A Wielscher, M. %A Terzikhan, N. %A Lahousse, L. %A Brusselle, G. %A Weiss, S. %A Ewert, R. %A Gläser, S. %A Homuth, G. %A Shrine, N. %A Hall, I. P. %A Tobin, M. %A London, S. J. %A Wei, P. %A Morrison, A. C. %X . This study investigates the utility of assessing gene-by-smoking interactions and underscores their effects on potential pulmonary function. %B Sci Rep %V 11 %P 19365 %8 09 %G eng %0 Journal Article %J Circ Genom Precis Med %D 2021 %T {Rare Coding Variants Associated With Electrocardiographic Intervals Identify Monogenic Arrhythmia Susceptibility Genes: A Multi-Ancestry Analysis %A Choi, S. H. %A Jurgens, S. J. %A Haggerty, C. M. %A Hall, A. W. %A Halford, J. L. %A Morrill, V. N. %A Weng, L. C. %A Lagerman, B. %A Mirshahi, T. %A Pettinger, M. %A Guo, X. %A Lin, H. J. %A Alonso, A. %A Soliman, E. Z. %A Kornej, J. %A Lin, H. %A Moscati, A. %A Nadkarni, G. N. %A Brody, J. A. %A Wiggins, K. L. %A Cade, B. E. %A Lee, J. %A Austin-Tse, C. %A Blackwell, T. %A Chaffin, M. D. %A Lee, C. J. %A Rehm, H. L. %A Roselli, C. %A Redline, S. %A Mitchell, B. D. %A Sotoodehnia, N. %A Psaty, B. M. %A Heckbert, S. R. %A Loos, R. J. F. %A Vasan, R. S. %A Benjamin, E. J. %A Correa, A. %A Boerwinkle, E. %A Arking, D. E. %A Rotter, J. I. %A Rich, S. S. %A Whitsel, E. A. %A Perez, M. %A Kooperberg, C. %A Fornwalt, B. K. %A Lunetta, K. L. %A Ellinor, P. T. %A Lubitz, S. A. %X Alterations in electrocardiographic (ECG) intervals are well-known markers for arrhythmia and sudden cardiac death (SCD) risk. While the genetics of arrhythmia syndromes have been studied, relations between electrocardiographic intervals and rare genetic variation at a population level are poorly understood.\ Using a discovery sample of 29 000 individuals with whole-genome sequencing from Trans-Omics in Precision Medicine and replication in nearly 100 000 with whole-exome sequencing from the UK Biobank and MyCode, we examined associations between low-frequency and rare coding variants with 5 routinely measured electrocardiographic traits (RR, P-wave, PR, and QRS intervals and corrected QT interval).\ ), a marker of SCD risk. Incomplete penetrance of such deleterious variation was common as over 70% of carriers had normal electrocardiographic intervals.\ Our findings indicate that large-scale high-depth sequence data and electrocardiographic analysis identifies monogenic arrhythmia susceptibility genes and rare variants with large effects. Known pathogenic variation in conventional arrhythmia and SCD genes exhibited incomplete penetrance and accounted for only a small fraction of marked electrocardiographic interval prolongation. %B Circ Genom Precis Med %V 14 %P e003300 %8 Aug %G eng %0 Journal Article %J PLoS Genet %D 2021 %T Rare variants in the endocytic pathway are associated with Alzheimer's disease, its related phenotypes, and functional consequences. %A Zhan, Lingyu %A Li, Jiajin %A Jew, Brandon %A Sul, Jae Hoon %K Alzheimer Disease %K Endocytosis %K Genome-Wide Association Study %K Humans %K Phenotype %K Polymorphism, Single Nucleotide %K Whole Genome Sequencing %X

Late-onset Alzheimer's disease (LOAD) is the most common type of dementia causing irreversible brain damage to the elderly and presents a major public health challenge. Clinical research and genome-wide association studies have suggested a potential contribution of the endocytic pathway to AD, with an emphasis on common loci. However, the contribution of rare variants in this pathway to AD has not been thoroughly investigated. In this study, we focused on the effect of rare variants on AD by first applying a rare-variant gene-set burden analysis using genes in the endocytic pathway on over 3,000 individuals with European ancestry from three large whole-genome sequencing (WGS) studies. We identified significant associations of rare-variant burden within the endocytic pathway with AD, which were successfully replicated in independent datasets. We further demonstrated that this endocytic rare-variant enrichment is associated with neurofibrillary tangles (NFTs) and age-related phenotypes, increasing the risk of obtaining severer brain damage, earlier age-at-onset, and earlier age-of-death. Next, by aggregating rare variants within each gene, we sought to identify single endocytic genes associated with AD and NFTs. Careful examination using NFTs revealed one significantly associated gene, ANKRD13D. To identify functional associations, we integrated bulk RNA-Seq data from over 600 brain tissues and found two endocytic expression genes (eGenes), HLA-A and SLC26A7, that displayed significant influences on their gene expressions. Differential expressions between AD patients and controls of these three identified genes were further examined by incorporating scRNA-Seq data from 48 post-mortem brain samples and demonstrated distinct expression patterns across cell types. Taken together, our results demonstrated strong rare-variant effect in the endocytic pathway on AD risk and progression and functional effect of gene expression alteration in both bulk and single-cell resolution, which may bring more insight and serve as valuable resources for future AD genetic studies, clinical research, and therapeutic targeting.

%B PLoS Genet %V 17 %P e1009772 %8 2021 09 %G eng %N 9 %R 10.1371/journal.pgen.1009772 %0 Journal Article %J Am J Hum Genet %D 2022 %T Rare coding variants in 35 genes associate with circulating lipid levels-A multi-ancestry analysis of 170,000 exomes. %A Hindy, George %A Dornbos, Peter %A Chaffin, Mark D %A Liu, Dajiang J %A Wang, Minxian %A Selvaraj, Margaret Sunitha %A Zhang, David %A Park, Joseph %A Aguilar-Salinas, Carlos A %A Antonacci-Fulton, Lucinda %A Ardissino, Diego %A Arnett, Donna K %A Aslibekyan, Stella %A Atzmon, Gil %A Ballantyne, Christie M %A Barajas-Olmos, Francisco %A Barzilai, Nir %A Becker, Lewis C %A Bielak, Lawrence F %A Bis, Joshua C %A Blangero, John %A Boerwinkle, Eric %A Bonnycastle, Lori L %A Bottinger, Erwin %A Bowden, Donald W %A Bown, Matthew J %A Brody, Jennifer A %A Broome, Jai G %A Burtt, Noel P %A Cade, Brian E %A Centeno-Cruz, Federico %A Chan, Edmund %A Chang, Yi-Cheng %A Chen, Yii-der I %A Cheng, Ching-Yu %A Choi, Won Jung %A Chowdhury, Rajiv %A Contreras-Cubas, Cecilia %A Córdova, Emilio J %A Correa, Adolfo %A Cupples, L Adrienne %A Curran, Joanne E %A Danesh, John %A de Vries, Paul S %A DeFronzo, Ralph A %A Doddapaneni, Harsha %A Duggirala, Ravindranath %A Dutcher, Susan K %A Ellinor, Patrick T %A Emery, Leslie S %A Florez, Jose C %A Fornage, Myriam %A Freedman, Barry I %A Fuster, Valentin %A Garay-Sevilla, Ma Eugenia %A García-Ortiz, Humberto %A Germer, Soren %A Gibbs, Richard A %A Gieger, Christian %A Glaser, Benjamin %A Gonzalez, Clicerio %A Gonzalez-Villalpando, Maria Elena %A Graff, Mariaelisa %A Graham, Sarah E %A Grarup, Niels %A Groop, Leif C %A Guo, Xiuqing %A Gupta, Namrata %A Han, Sohee %A Hanis, Craig L %A Hansen, Torben %A He, Jiang %A Heard-Costa, Nancy L %A Hung, Yi-Jen %A Hwang, Mi Yeong %A Irvin, Marguerite R %A Islas-Andrade, Sergio %A Jarvik, Gail P %A Kang, Hyun Min %A Kardia, Sharon L R %A Kelly, Tanika %A Kenny, Eimear E %A Khan, Alyna T %A Kim, Bong-Jo %A Kim, Ryan W %A Kim, Young Jin %A Koistinen, Heikki A %A Kooperberg, Charles %A Kuusisto, Johanna %A Kwak, Soo Heon %A Laakso, Markku %A Lange, Leslie A %A Lee, Jiwon %A Lee, Juyoung %A Lee, Seonwook %A Lehman, Donna M %A Lemaitre, Rozenn N %A Linneberg, Allan %A Liu, Jianjun %A Loos, Ruth J F %A Lubitz, Steven A %A Lyssenko, Valeriya %A Ma, Ronald C W %A Martin, Lisa Warsinger %A Martínez-Hernández, Angélica %A Mathias, Rasika A %A McGarvey, Stephen T %A McPherson, Ruth %A Meigs, James B %A Meitinger, Thomas %A Melander, Olle %A Mendoza-Caamal, Elvia %A Metcalf, Ginger A %A Mi, Xuenan %A Mohlke, Karen L %A Montasser, May E %A Moon, Jee-Young %A Moreno-Macias, Hortensia %A Morrison, Alanna C %A Muzny, Donna M %A Nelson, Sarah C %A Nilsson, Peter M %A O'Connell, Jeffrey R %A Orho-Melander, Marju %A Orozco, Lorena %A Palmer, Colin N A %A Palmer, Nicholette D %A Park, Cheol Joo %A Park, Kyong Soo %A Pedersen, Oluf %A Peralta, Juan M %A Peyser, Patricia A %A Post, Wendy S %A Preuss, Michael %A Psaty, Bruce M %A Qi, Qibin %A Rao, D C %A Redline, Susan %A Reiner, Alexander P %A Revilla-Monsalve, Cristina %A Rich, Stephen S %A Samani, Nilesh %A Schunkert, Heribert %A Schurmann, Claudia %A Seo, Daekwan %A Seo, Jeong-Sun %A Sim, Xueling %A Sladek, Rob %A Small, Kerrin S %A So, Wing Yee %A Stilp, Adrienne M %A Tai, E Shyong %A Tam, Claudia H T %A Taylor, Kent D %A Teo, Yik Ying %A Thameem, Farook %A Tomlinson, Brian %A Tsai, Michael Y %A Tuomi, Tiinamaija %A Tuomilehto, Jaakko %A Tusié-Luna, Teresa %A Udler, Miriam S %A van Dam, Rob M %A Vasan, Ramachandran S %A Viaud Martinez, Karine A %A Wang, Fei Fei %A Wang, Xuzhi %A Watkins, Hugh %A Weeks, Daniel E %A Wilson, James G %A Witte, Daniel R %A Wong, Tien-Yin %A Yanek, Lisa R %A Kathiresan, Sekar %A Rader, Daniel J %A Rotter, Jerome I %A Boehnke, Michael %A McCarthy, Mark I %A Willer, Cristen J %A Natarajan, Pradeep %A Flannick, Jason A %A Khera, Amit V %A Peloso, Gina M %K Alleles %K Blood Glucose %K Case-Control Studies %K Computational Biology %K Databases, Genetic %K Diabetes Mellitus, Type 2 %K Exome %K Genetic Predisposition to Disease %K Genetic Variation %K Genetics, Population %K Genome-Wide Association Study %K Humans %K Lipid Metabolism %K Lipids %K Liver %K Molecular Sequence Annotation %K Multifactorial Inheritance %K Open Reading Frames %K Phenotype %K Polymorphism, Single Nucleotide %X

Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels.

%B Am J Hum Genet %V 109 %P 81-96 %8 2022 01 06 %G eng %N 1 %R 10.1016/j.ajhg.2021.11.021 %0 Journal Article %J Nat Hum Behav %D 2022 %T Rare genetic variants explain missing heritability in smoking. %A Jang, Seon-Kyeong %A Evans, Luke %A Fialkowski, Allison %A Arnett, Donna K %A Ashley-Koch, Allison E %A Barnes, Kathleen C %A Becker, Diane M %A Bis, Joshua C %A Blangero, John %A Bleecker, Eugene R %A Boorgula, Meher Preethi %A Bowden, Donald W %A Brody, Jennifer A %A Cade, Brian E %A Jenkins, Brenda W Campbell %A Carson, April P %A Chavan, Sameer %A Cupples, L Adrienne %A Custer, Brian %A Damrauer, Scott M %A David, Sean P %A de Andrade, Mariza %A Dinardo, Carla L %A Fingerlin, Tasha E %A Fornage, Myriam %A Freedman, Barry I %A Garrett, Melanie E %A Gharib, Sina A %A Glahn, David C %A Haessler, Jeffrey %A Heckbert, Susan R %A Hokanson, John E %A Hou, Lifang %A Hwang, Shih-Jen %A Hyman, Matthew C %A Judy, Renae %A Justice, Anne E %A Kaplan, Robert C %A Kardia, Sharon L R %A Kelly, Shannon %A Kim, Wonji %A Kooperberg, Charles %A Levy, Daniel %A Lloyd-Jones, Donald M %A Loos, Ruth J F %A Manichaikul, Ani W %A Gladwin, Mark T %A Martin, Lisa Warsinger %A Nouraie, Mehdi %A Melander, Olle %A Meyers, Deborah A %A Montgomery, Courtney G %A North, Kari E %A Oelsner, Elizabeth C %A Palmer, Nicholette D %A Payton, Marinelle %A Peljto, Anna L %A Peyser, Patricia A %A Preuss, Michael %A Psaty, Bruce M %A Qiao, Dandi %A Rader, Daniel J %A Rafaels, Nicholas %A Redline, Susan %A Reed, Robert M %A Reiner, Alexander P %A Rich, Stephen S %A Rotter, Jerome I %A Schwartz, David A %A Shadyab, Aladdin H %A Silverman, Edwin K %A Smith, Nicholas L %A Smith, J Gustav %A Smith, Albert V %A Smith, Jennifer A %A Tang, Weihong %A Taylor, Kent D %A Telen, Marilyn J %A Vasan, Ramachandran S %A Gordeuk, Victor R %A Wang, Zhe %A Wiggins, Kerri L %A Yanek, Lisa R %A Yang, Ivana V %A Young, Kendra A %A Young, Kristin L %A Zhang, Yingze %A Liu, Dajiang J %A Keller, Matthew C %A Vrieze, Scott %X

Common genetic variants explain less variation in complex phenotypes than inferred from family-based studies, and there is a debate on the source of this 'missing heritability'. We investigated the contribution of rare genetic variants to tobacco use with whole-genome sequences from up to 26,257 unrelated individuals of European ancestries and 11,743 individuals of African ancestries. Across four smoking traits, single-nucleotide-polymorphism-based heritability ([Formula: see text]) was estimated from 0.13 to 0.28 (s.e., 0.10-0.13) in European ancestries, with 35-74% of it attributable to rare variants with minor allele frequencies between 0.01% and 1%. These heritability estimates are 1.5-4 times higher than past estimates based on common variants alone and accounted for 60% to 100% of our pedigree-based estimates of narrow-sense heritability ([Formula: see text], 0.18-0.34). In the African ancestry samples, [Formula: see text] was estimated from 0.03 to 0.33 (s.e., 0.09-0.14) across the four smoking traits. These results suggest that rare variants are important contributors to the heritability of smoking.

%B Nat Hum Behav %8 2022 Aug 04 %G eng %R 10.1038/s41562-022-01408-5 %0 Journal Article %J Am J Cardiol %D 2022 %T Relation of Cigarette Smoking and Heart Failure in Adults ≥65 Years of Age (From the Cardiovascular Health Study). %A Gottdiener, John S %A Bůzková, Petra %A Kahn, Peter A %A DeFilippi, Christopher %A Shah, Sanjiv %A Barasch, Eddy %A Kizer, Jorge R %A Psaty, Bruce %A Gardin, Julius M %X

Cigarette smoking is associated with adverse cardiac outcomes, including incident heart failure (HF). However, key components of potential pathways from smoking to HF have not been evaluated in older adults. In a community-based study, we studied cross-sectional associations of smoking with blood and imaging biomarkers reflecting mechanisms of cardiac disease. Serial nested, multivariable Cox models were used to determine associations of smoking with HF, and to assess the influence of biochemical and functional (cardiac strain) phenotypes on these associations. Compared with never smokers, smokers had higher levels of inflammation (C-reactive protein and interleukin-6), cardiomyocyte injury (cardiac troponin T [hscTnT]), myocardial "stress"/fibrosis (soluble suppression of tumorigenicity 2 [sST2], galectin 3), and worse left ventricle systolic and diastolic function. In models adjusting for age, gender, and race (DEMO) and for clinical factors potentially in the causal pathway (CLIN), smoking exposures were associated with C-reactive protein and interleukin-6, sST2, hscTnT, and with N-terminal pro-brain natriuretic protein (in Whites). In DEMO adjusted models, the cumulative burden of smoking was associated with worse left ventricle systolic strain. Current smoking and former smoking were associated with HF in DEMO models (hazard ratio 1.41, 95% confidence interval 1.22 to 1.64 and hazard ratio 1.14, 95% confidence interval 1.03 to 1.25, respectively), and with current smoking after CLIN adjustment. Adjustment for time-varying myocardial infarction, inflammation, cardiac strain, hscTnT, sST2, and galectin 3 did not materially alter the associations. Smoking was associated with HF with preserved and decreased ejection fraction. In conclusion, in older adults, smoking is associated with multiple blood and imaging biomarker measures of pathophysiology previously linked to HF, and to incident HF even after adjustment for clinical intermediates.

%B Am J Cardiol %8 2022 Jan 16 %G eng %R 10.1016/j.amjcard.2021.12.021 %0 Journal Article %J Alzheimers Dement %D 2022 %T {Replication study of AD-associated rare variants %A Neupane, A. %A Lenny, B. %A Budde, J. P. %A Wang, F. %A Norton, J. %A Morris, J. C. %A Cruchaga, C. %A Fernández, M. V. %B Alzheimers Dement %V 18 %P 858–862 %8 Apr %G eng %0 Journal Article %J medRxiv %D 2023 %T Rare variants in long non-coding RNAs are associated with blood lipid levels in the TOPMed Whole Genome Sequencing Study. %A Wang, Yuxuan %A Selvaraj, Margaret Sunitha %A Li, Xihao %A Li, Zilin %A Holdcraft, Jacob A %A Arnett, Donna K %A Bis, Joshua C %A Blangero, John %A Boerwinkle, Eric %A Bowden, Donald W %A Cade, Brian E %A Carlson, Jenna C %A Carson, April P %A Chen, Yii-Der Ida %A Curran, Joanne E %A de Vries, Paul S %A Dutcher, Susan K %A Ellinor, Patrick T %A Floyd, James S %A Fornage, Myriam %A Freedman, Barry I %A Gabriel, Stacey %A Germer, Soren %A Gibbs, Richard A %A Guo, Xiuqing %A He, Jiang %A Heard-Costa, Nancy %A Hildalgo, Bertha %A Hou, Lifang %A Irvin, Marguerite R %A Joehanes, Roby %A Kaplan, Robert C %A Kardia, Sharon Lr %A Kelly, Tanika N %A Kim, Ryan %A Kooperberg, Charles %A Kral, Brian G %A Levy, Daniel %A Li, Changwei %A Liu, Chunyu %A Lloyd-Jone, Don %A Loos, Ruth Jf %A Mahaney, Michael C %A Martin, Lisa W %A Mathias, Rasika A %A Minster, Ryan L %A Mitchell, Braxton D %A Montasser, May E %A Morrison, Alanna C %A Murabito, Joanne M %A Naseri, Take %A O'Connell, Jeffrey R %A Palmer, Nicholette D %A Preuss, Michael H %A Psaty, Bruce M %A Raffield, Laura M %A Rao, Dabeeru C %A Redline, Susan %A Reiner, Alexander P %A Rich, Stephen S %A Ruepena, Muagututi'a Sefuiva %A Sheu, Wayne H-H %A Smith, Jennifer A %A Smith, Albert %A Tiwari, Hemant K %A Tsai, Michael Y %A Viaud-Martinez, Karine A %A Wang, Zhe %A Yanek, Lisa R %A Zhao, Wei %A Rotter, Jerome I %A Lin, Xihong %A Natarajan, Pradeep %A Peloso, Gina M %X

Long non-coding RNAs (lncRNAs) are known to perform important regulatory functions. Large-scale whole genome sequencing (WGS) studies and new statistical methods for variant set tests now provide an opportunity to assess the associations between rare variants in lncRNA genes and complex traits across the genome. In this study, we used high-coverage WGS from 66,329 participants of diverse ancestries with blood lipid levels (LDL-C, HDL-C, TC, and TG) in the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program to investigate the role of lncRNAs in lipid variability. We aggregated rare variants for 165,375 lncRNA genes based on their genomic locations and conducted rare variant aggregate association tests using the STAAR (variant-Set Test for Association using Annotation infoRmation) framework. We performed STAAR conditional analysis adjusting for common variants in known lipid GWAS loci and rare coding variants in nearby protein coding genes. Our analyses revealed 83 rare lncRNA variant sets significantly associated with blood lipid levels, all of which were located in known lipid GWAS loci (in a ±500 kb window of a Global Lipids Genetics Consortium index variant). Notably, 61 out of 83 signals (73%) were conditionally independent of common regulatory variations and rare protein coding variations at the same loci. We replicated 34 out of 61 (56%) conditionally independent associations using the independent UK Biobank WGS data. Our results expand the genetic architecture of blood lipids to rare variants in lncRNA, implicating new therapeutic opportunities.

%B medRxiv %8 2023 Jun 29 %G eng %R 10.1101/2023.06.28.23291966 %0 Journal Article %J Circulation %D 2024 %T Role of Polyunsaturated Fat in Modifying Cardiovascular Risk Associated With Family History of Cardiovascular Disease: Pooled De Novo Results From 15 Observational Studies. %A Laguzzi, Federica %A Åkesson, Agneta %A Marklund, Matti %A Qian, Frank %A Gigante, Bruna %A Bartz, Traci M %A Bassett, Julie K %A Birukov, Anna %A Campos, Hannia %A Hirakawa, Yoichiro %A Imamura, Fumiaki %A Jäger, Susanne %A Lankinen, Maria %A Murphy, Rachel A %A Senn, Mackenzie %A Tanaka, Toshiko %A Tintle, Nathan %A Virtanen, Jyrki K %A Yamagishi, Kazumasa %A Allison, Matthew %A Brouwer, Ingeborg A %A de Faire, Ulf %A Eiriksdottir, Gudny %A Ferrucci, Luigi %A Forouhi, Nita G %A Geleijnse, Johanna M %A Hodge, Allison M %A Kimura, Hitomi %A Laakso, Markku %A Riserus, Ulf %A van Westing, Anniek C %A Bandinelli, Stefania %A Baylin, Ana %A Giles, Graham G %A Gudnason, Vilmundur %A Iso, Hiroyasu %A Lemaitre, Rozenn N %A Ninomiya, Toshiharu %A Post, Wendy S %A Psaty, Bruce M %A Salonen, Jukka T %A Schulze, Matthias B %A Tsai, Michael Y %A Uusitupa, Matti %A Wareham, Nicholas J %A Oh, Seung-Won %A Wood, Alexis C %A Harris, William S %A Siscovick, David %A Mozaffarian, Dariush %A Leander, Karin %K Animals %K Biomarkers %K Cardiovascular Diseases %K Docosahexaenoic Acids %K Fatty Acids, Omega-3 %K Risk Factors %X

BACKGROUND: It is unknown whether dietary intake of polyunsaturated fatty acids (PUFA) modifies the cardiovascular disease (CVD) risk associated with a family history of CVD. We assessed interactions between biomarkers of low PUFA intake and a family history in relation to long-term CVD risk in a large consortium.

METHODS: Blood and tissue PUFA data from 40 885 CVD-free adults were assessed. PUFA levels ≤25th percentile were considered to reflect low intake of linoleic, alpha-linolenic, and eicosapentaenoic/docosahexaenoic acids (EPA/DHA). Family history was defined as having ≥1 first-degree relative who experienced a CVD event. Relative risks with 95% CI of CVD were estimated using Cox regression and meta-analyzed. Interactions were assessed by analyzing product terms and calculating relative excess risk due to interaction.

RESULTS: After multivariable adjustments, a significant interaction between low EPA/DHA and family history was observed (product term pooled RR, 1.09 [95% CI, 1.02-1.16]; =0.01). The pooled relative risk of CVD associated with the combined exposure to low EPA/DHA, and family history was 1.41 (95% CI, 1.30-1.54), whereas it was 1.25 (95% CI, 1.16-1.33) for family history alone and 1.06 (95% CI, 0.98-1.14) for EPA/DHA alone, compared with those with neither exposure. The relative excess risk due to interaction results indicated no interactions.

CONCLUSIONS: A significant interaction between biomarkers of low EPA/DHA intake, but not the other PUFA, and a family history was observed. This novel finding might suggest a need to emphasize the benefit of consuming oily fish for individuals with a family history of CVD.

%B Circulation %V 149 %P 305-316 %8 2024 Jan 23 %G eng %N 4 %R 10.1161/CIRCULATIONAHA.123.065530