@article {1082, title = {Use of sonography to evaluate carotid atherosclerosis in the elderly. The Cardiovascular Health Study. CHS Collaborative Research Group.}, journal = {Stroke}, volume = {22}, year = {1991}, month = {1991 Sep}, pages = {1155-63}, abstract = {

Carotid sonography is being performed on more than 5,000 participants in the Cardiovascular Health Study, a prospective, multicenter study of cardiovascular disease in men and women aged 65 years and older. The sonographic methods used to examine and measure the extracranial carotid arteries are described. Initial validation studies were performed on 61 subjects with a mean age of 68.6 years. Analysis of within- and between-sonographer differences and between-reader differences were performed for selected variables. In general, the mean absolute differences for within- and between-sonographer comparisons were small, with even less variability between readers. Variability was less for the common carotid artery than for the internal carotid artery. These data suggest that carotid sonography is a reliable and reproducible method for use in the study of carotid atherosclerosis in population studies.

}, keywords = {Age Factors, Aged, Arteriosclerosis, Carotid Arteries, Carotid Artery Diseases, Carotid Artery, Internal, Female, Humans, Image Interpretation, Computer-Assisted, Image Processing, Computer-Assisted, Male, Prospective Studies, Ultrasonography}, issn = {0039-2499}, doi = {10.1161/01.str.22.9.1155}, author = {O{\textquoteright}Leary, D H and Polak, J F and Wolfson, S K and Bond, M G and Bommer, W and Sheth, S and Psaty, B M and Sharrett, A R and Manolio, T A} } @article {848, title = {Assessing the use of medications in the elderly: methods and initial experience in the Cardiovascular Health Study. The Cardiovascular Health Study Collaborative Research Group.}, journal = {J Clin Epidemiol}, volume = {45}, year = {1992}, month = {1992 Jun}, pages = {683-92}, abstract = {

The Cardiovascular Health Study (CHS), a cohort study of risk factors for coronary heart disease and stroke, recruited 5201 community-dwelling adults aged 65 years or older. To assess the prevalence of medication use at baseline, we used the method of medication inventory and transcribed information about drug names and doses from prescription bottles. Using a specially-written computer program, persons without a knowledge of drug nomenclature coded 10,511 (89\%) of the 11,846 medicines entered. We compared the results of the medication inventory and answers to questions on specific medications for reliability and validity. The use of beta-blockers and beta-agonists assessed by the method of medication inventory, but not by the method of directed recall, was associated with a significant effect on mean heart rate. Among 5197 participants with medication data, 76.1\% were taking at least one medicine, and the mean number of drugs per person was 2.28. Among those with a reported history of high blood pressure, participants with cardiovascular disease (CVD) were more likely to be treated, and they were more likely to be taking beta-blockers and calcium-channel blockers than those without CVD. Daily aspirin use was also more common among those with CVD (30.5\% of women and 43.2\% of men) than among those without CVD (14.0\% of women and 14.0\% of men). The prevalence of post-menopausal estrogen use differed significantly among the four clinical centers (range = 5.5\%-22.5\% of women). We conclude that this method of assessing medications was easy to use and provided estimates of exposure to drugs that may affect risk of cardiovascular disease.

}, keywords = {Aged, Aged, 80 and over, Cerebrovascular Disorders, Coronary Disease, Data Collection, Drug Utilization, Female, Humans, Male, Prospective Studies, Risk Factors, United States}, issn = {0895-4356}, doi = {10.1016/0895-4356(92)90143-b}, author = {Psaty, B M and Lee, M and Savage, P J and Rutan, G H and German, P S and Lyles, M} } @article {747, title = {The distribution of coagulation factors VII and VIII and fibrinogen in adults over 65 years. Results from the Cardiovascular Health Study.}, journal = {Ann Epidemiol}, volume = {2}, year = {1992}, month = {1992 Jul}, pages = {509-19}, abstract = {

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

}, keywords = {African Continental Ancestry Group, Age Factors, Aged, Cardiovascular Diseases, Cohort Studies, Factor VII, Factor VIII, Female, Fibrinogen, Humans, Male, Middle Aged, Risk Factors}, issn = {1047-2797}, doi = {10.1016/1047-2797(92)90100-5}, author = {Tracy, R P and Bovill, E G and Fried, L P and Heiss, G and Lee, M H and Polak, J F and Psaty, B M and Savage, P J} } @article {748, title = {Isolated systolic hypertension and subclinical cardiovascular disease in the elderly. Initial findings from the Cardiovascular Health Study.}, journal = {JAMA}, volume = {268}, year = {1992}, month = {1992 Sep 09}, pages = {1287-91}, abstract = {

OBJECTIVE: To assess the association between isolated systolic hypertension (ISH) and subclinical disease in adults aged 65 years and above.

DESIGN: Medicare eligibility lists were used to obtain a representative sample of 5201 community-dwelling elderly persons for the Cardiovascular Health Study, a National Heart, Lung, and Blood Institute--sponsored cohort study of risk factors for coronary heart disease and stroke. In this cross-sectional analysis of baseline data, we excluded 3012 participants who were receiving antihypertensive medications, had clinical cardiovascular disease, or had a diastolic blood pressure of at least 90 mm Hg.

MAIN OUTCOME MEASURES: For electrocardiogram: myocardial infarction, left ventricular hypertrophy, and left ventricular mass as measures of myocardial damage and strain; for echocardiography: left ventricular mass, fractional shortening, and Doppler flow velocities as measures of cardiac systolic and diastolic function; and for carotid sonography: carotid arterial intima-media thickness as a measure of atherosclerosis.

RESULTS: Among the 2189 men and women in this analysis, 195 (9\%) had ISH (systolic blood pressure, greater than or equal to 160 mm Hg) and 596 (23\%) had borderline ISH (systolic blood pressure, 140 to 159 mm Hg). Systolic blood pressure was associated with myocardial infarction by electrocardiogram (P = .02). Borderline and definite ISH were strongly associated with left ventricular mass (P less than .001). While there was little association with cardiac systolic function, borderline and definite ISH were associated with cardiac diastolic function (P less than .001). Isolated systolic hypertension was also strongly associated with increased intima-media thickness of the carotid artery (P less than .001).

CONCLUSIONS: While cohort analyses of future repeated measures will provide a better assessment of risk, both borderline and definite ISH were strongly related to a variety of measures of subclinical disease in elderly men and women.

}, keywords = {Aged, Aged, 80 and over, Cardiomegaly, Cardiovascular Diseases, Carotid Artery Diseases, Cerebrovascular Disorders, Coronary Disease, Cross-Sectional Studies, Echocardiography, Electrocardiography, Female, Humans, Hypertension, Male, Myocardial Infarction, Prospective Studies, Risk Factors, Systole}, issn = {0098-7484}, author = {Psaty, B M and Furberg, C D and Kuller, L H and Borhani, N O and Rautaharju, P M and O{\textquoteright}Leary, D H and Bild, D E and Robbins, J and Fried, L P and Reid, C} } @article {835, title = {Major electrocardiographic abnormalities in persons aged 65 years and older (the Cardiovascular Health Study). Cardiovascular Health Study Collaborative Research Group.}, journal = {Am J Cardiol}, volume = {69}, year = {1992}, month = {1992 May 15}, pages = {1329-35}, abstract = {

Electrocardiographic abnormalities are often found in older patients, but their prevalence in free-living elderly populations is not well-defined. In addition, the clinical significance of many of these abnormalities is uncertain. The prevalence of major electrocardiographic abnormalities was determined in 5,150 adults aged greater than or equal to 65 years from the Cardiovascular Health Study--a study of risk factors for stroke and coronary heart disease in the elderly. Ventricular conduction defects, major Q/QS waves, left ventricular hypertrophy, isolated major ST-T-wave abnormalities, atrial fibrillation and first-degree atrioventricular block were collectively categorized as major electrocardiographic abnormalities. Prevalence of any major electrocardiographic abnormality was 29\% in the entire cohort, 19\% among 2,413 participants who reported no history of coronary artery disease or systemic hypertension, and 37\% among 2,737 participants with a history of coronary artery disease or hypertension. Prevalence of major electrocardiographic abnormalities was higher in men than in women regardless of history, and tended to increase with age. Major Q/QS waves were found in 5.2\%, and more than half were in those who did not report a previous myocardial infarction. Major electrocardiographic abnormalities are common in elderly men and women irrespective of the history of heart disease.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Arrhythmias, Cardiac, Chi-Square Distribution, Electrocardiography, Female, Heart Diseases, Humans, Logistic Models, Male, Prevalence, Risk Factors, Sex Factors, United States}, issn = {0002-9149}, doi = {10.1016/0002-9149(92)91231-r}, author = {Furberg, C D and Manolio, T A and Psaty, B M and Bild, D E and Borhani, N O and Newman, A and Tabatznik, B and Rautaharju, P M} } @article {1435, title = {Associations of postmenopausal estrogen use with cardiovascular disease and its risk factors in older women. The CHS Collaborative Research Group.}, journal = {Circulation}, volume = {88}, year = {1993}, month = {1993 Nov}, pages = {2163-71}, abstract = {

BACKGROUND: Postmenopausal estrogen replacement therapy has been associated with favorable levels of cardiovascular disease risk factors, but these associations and the relations between estrogen use and subclinical disease have not been examined in large samples of older women.

METHODS AND RESULTS: Present and past estrogen use was ascertained in 2955 women > or = 65 years old in the Cardiovascular Health Study, a study of risk factors for coronary heart disease and stroke in the elderly. Present estrogen use was reported by 12\% of these women and past use by an additional 26.5\%. Estrogen use (past or present) was strongly associated with lower low-density lipoprotein cholesterol, fibrinogen, glucose, insulin, obesity, and age and higher high-density lipoprotein cholesterol and socioeconomic status (all P < .0001). Estrogen users also had lower levels of subclinical disease as measured by carotid intimal-medial thickness, carotid stenosis grade, ECG left ventricular mass, and Doppler mitral peak flow velocities (each P < .02). Relations were similar in younger and older women (65 to 74 versus > or = 75 years) and smokers and nonsmokers and were unchanged after women with poor medication compliance were excluded. After adjustment for other factors, estrogen use was associated with decreased carotid wall thickness, although this association was of borderline significance after further adjustment for lipids.

CONCLUSIONS: Postmenopausal estrogen use in this sample of older women was associated with favorable cardiovascular disease risk factor profiles and with lower measures of subclinical disease. These findings suggest that postmenopausal estrogen use may be associated with lower risk of cardiovascular disease in women well into the eighth decade of life.

}, keywords = {Aged, Aging, Cardiovascular Diseases, Carotid Arteries, Carotid Stenosis, Electrocardiography, Estrogen Replacement Therapy, Female, Heart, Heart Ventricles, Humans, Patient Compliance, Risk Factors, Smoking, Ultrasonography}, issn = {0009-7322}, author = {Manolio, T A and Furberg, C D and Shemanski, L and Psaty, B M and O{\textquoteright}Leary, D H and Tracy, R P and Bush, T L} } @article {1446, title = {Prevalence of cardiovascular diseases among older adults. The Cardiovascular Health Study.}, journal = {Am J Epidemiol}, volume = {137}, year = {1993}, month = {1993 Feb 01}, pages = {311-7}, abstract = {

The Cardiovascular Health Study is a population-based longitudinal study of 5,201 adults aged 65 years and older. Prevalences of myocardial infarction, angina pectoris, congestive heart failure, peripheral artery disease, stroke, and transient ischemic attack were ascertained between June 1989 and May 1990 in participants recruited from Forsyth County, North Carolina; Washington County, Maryland; Sacramento County, California; and Pittsburgh, Pennsylvania. A medical history was taken to obtain self-reports of prevalent disease. For all participants, use of nitrates was ascertained to document angina, electrocardiograms were used to document prevalent myocardial infarction, and ankle-arm blood pressure studies were used to document peripheral artery disease. Self-reports of disease that were not confirmed by examination findings were further investigated by examination of medical records. Reported disease that was confirmed by examination findings or by medical records was classified as "definite." Disease that was documented by examination, but not reported by the participant, was classified as "unreported." The prevalence rates of definite myocardial infarction and angina were 11\% and 15\%, respectively, among men aged 65-69 years, 18\% and 17\% among men aged 80-84 years, 4\% and 8\% among women aged 65-69 years, and 3\% and 13\% among women aged 80-84 years. Twenty-three percent of men and 38\% of women with electrocardiographic evidence of myocardial infarction did not report it. These results suggest that prevalent disease estimates based only on self-report may underestimate the prevalence of cardiovascular diseases in older Americans.

}, keywords = {Age Factors, Aged, Aged, 80 and over, Bias, California, Cardiovascular Diseases, Electrocardiography, Female, Health Surveys, Humans, Longitudinal Studies, Male, Maryland, Mass Screening, North Carolina, Pennsylvania, Population Surveillance, Prevalence, Reproducibility of Results}, issn = {0002-9262}, author = {Mittelmark, M B and Psaty, B M and Rautaharju, P M and Fried, L P and Borhani, N O and Tracy, R P and Gardin, J M and O{\textquoteright}Leary, D H} } @article {1429, title = {Temporal patterns of antihypertensive medication use among elderly patients. The Cardiovascular Health Study.}, journal = {JAMA}, volume = {270}, year = {1993}, month = {1993 Oct 20}, pages = {1837-41}, abstract = {

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

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

INTERVENTIONS: None.

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

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

}, keywords = {Adrenergic beta-Antagonists, Aged, Analysis of Variance, Angiotensin-Converting Enzyme Inhibitors, Antihypertensive Agents, Calcium Channel Blockers, Cohort Studies, Diuretics, Drug Utilization, Female, Follow-Up Studies, Humans, Hypertension, Linear Models, Logistic Models, Male, Medicare, Practice Patterns, Physicians{\textquoteright}, Recurrence, United States, Vasodilator Agents}, issn = {0098-7484}, author = {Psaty, B M and Savage, P J and Tell, G S and Polak, J F and Hirsch, C H and Gardin, J M and McDonald, R H} } @article {1433, title = {Correlates of QT prolongation in older adults (the Cardiovascular Health Study). Cardiovascular Health Study Collaborative Research Group.}, journal = {Am J Cardiol}, volume = {73}, year = {1994}, month = {1994 May 15}, pages = {999-1002}, keywords = {Aged, Aged, 80 and over, Female, Humans, Logistic Models, Long QT Syndrome, Longitudinal Studies, Male, Sex Factors}, issn = {0002-9149}, author = {Rautaharju, P M and Manolio, T A and Psaty, B M and Borhani, N O and Furberg, C D} } @article {1427, title = {Prevalence of atrial fibrillation in elderly subjects (the Cardiovascular Health Study).}, journal = {Am J Cardiol}, volume = {74}, year = {1994}, month = {1994 Aug 01}, pages = {236-41}, abstract = {

Atrial fibrillation (AF) is a common arrhythmia in elderly persons and a common cause of embolic stroke. Most studies of the prevalence and correlates of AF have used selected, hospital-based populations. The Cardiovascular Health Study is a population-based, longitudinal study of risk factors for coronary artery disease and stroke in 5,201 men and women aged > or = 65 years. AF was diagnosed in 4.8\% of women and in 6.2\% of men at the baseline examination, and prevalence was strongly associated with advanced age in women. Prevalence of AF was 9.1\% in men and women with clinical cardiovascular disease, 4.6\% in patients with evidence of subclinical but no clinical cardiovascular disease, and only 1.6\% in subjects with neither clinical nor subclinical cardiovascular disease. A history of congestive heart failure, valvular heart disease and stroke, echocardiographic evidence of enlarged left atrial dimension, abnormal mitral or aortic valve function, treated systemic hypertension, and advanced age were independently associated with the prevalence of AF. The low prevalence of AF in the absence of clinical and subclinical cardiovascular disease calls into question the existence and clinical usefulness of the concept of so-called "lone atrial fibrillation" in the elderly.

}, keywords = {Aged, Aged, 80 and over, Anti-Arrhythmia Agents, Anticoagulants, Atrial Fibrillation, Blood Glucose, Cardiovascular Diseases, Chi-Square Distribution, Coronary Disease, Electrocardiography, Female, Humans, Male, Prevalence, Regression Analysis, Sampling Studies}, issn = {0002-9149}, author = {Furberg, C D and Psaty, B M and Manolio, T A and Gardin, J M and Smith, V E and Rautaharju, P M} } @article {1414, title = {Black-white differences in subclinical cardiovascular disease among older adults: the Cardiovascular Health Study. CHS Collaborative Research Group.}, journal = {J Clin Epidemiol}, volume = {48}, year = {1995}, month = {1995 Sep}, pages = {1141-52}, abstract = {

Cardiovascular and all-cause mortality are higher in black than white Americans, but racial differences in clinical and subclinical cardiovascular disease (CVD) have not been examined in older adults. Clinical and subclinical CVD and its risk factors were compared in 4926 white and 244 black men and women aged 65 years and older. Black participants had lower socioeconomic status and generally higher prevalences of CVD and its risk factors, except for adverse lipid profiles. Common carotid wall thickness was greater in black than white women, and ankle-arm blood pressure ratios were lower in black women and men (p < 0.01). After adjustment for CVD risk factors, common carotid walls were significantly thicker and ankle-arm ratios were lower in blacks than whites of both sexes, while internal carotid walls were significantly thinner in black women. Racial differences in clinical and subclinical CVD in older adults are similar to those reported in younger populations and do not appear to be explained by CVD risk factors.

}, keywords = {African Continental Ancestry Group, Aged, Cardiovascular Diseases, Carotid Arteries, European Continental Ancestry Group, Female, Geriatric Assessment, Humans, Male, Multivariate Analysis, Prevalence, Regression Analysis, Risk Factors, Sex Factors}, issn = {0895-4356}, author = {Manolio, T A and Burke, G L and Psaty, B M and Newman, A B and Haan, M and Powe, N and Tracy, R P and O{\textquoteright}Leary, D H} } @article {1449, title = {Methods of assessing prevalent cardiovascular disease in the Cardiovascular Health Study.}, journal = {Ann Epidemiol}, volume = {5}, year = {1995}, month = {1995 Jul}, pages = {270-7}, abstract = {

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

}, keywords = {Aged, Cerebrovascular Disorders, Cohort Studies, Coronary Disease, Electrocardiography, Epidemiologic Methods, False Negative Reactions, Female, Humans, Male, Population Surveillance, Prevalence, Prospective Studies, Reproducibility of Results, Risk Factors, Self Disclosure, United States}, issn = {1047-2797}, author = {Psaty, B M and Kuller, L H and Bild, D and Burke, G L and Kittner, S J and Mittelmark, M and Price, T R and Rautaharju, P M and Robbins, J} } @article {1415, title = {Subclinical disease as an independent risk factor for cardiovascular disease.}, journal = {Circulation}, volume = {92}, year = {1995}, month = {1995 Aug 15}, pages = {720-6}, abstract = {

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

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

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

}, keywords = {Aged, Cardiovascular Diseases, Cohort Studies, Coronary Disease, Female, Humans, Incidence, Longitudinal Studies, Male, Myocardial Infarction, Odds Ratio, Reference Values, Risk Factors}, issn = {0009-7322}, author = {Kuller, L H and Shemanski, L and Psaty, B M and Borhani, N O and Gardin, J and Haan, M N and O{\textquoteright}Leary, D H and Savage, P J and Tell, G S and Tracy, R} } @article {1450, title = {Surveillance and ascertainment of cardiovascular events. The Cardiovascular Health Study.}, journal = {Ann Epidemiol}, volume = {5}, year = {1995}, month = {1995 Jul}, pages = {278-85}, abstract = {

While previous prospective multicenter studies have conducted cardiovascular disease surveillance, few have detailed the techniques relating to the ascertainment of and data collection for events. The Cardiovascular Health Study (CHS) is a population-based study of coronary heart disease and stroke in older adults. This article summarizes the CHS events protocol and describes the methods of surveillance and ascertainment of hospitalized and nonhospitalized events, the use of medical records and other support documents, organizational issues at the field center level, and the classification of events through an adjudication process. We present data on incidence and mortality, the classification of adjudicated events, and the agreement between classification by the Events Subcommittee and the medical records diagnostic codes. The CHS techniques are a successful model for complete ascertainment, investigation, and documentation of events in an older cohort.

}, keywords = {Aged, Cerebrovascular Disorders, Coronary Disease, Epidemiologic Methods, Female, Hospitalization, Humans, Incidence, Longitudinal Studies, Male, Population Surveillance, Quality Control, United States}, issn = {1047-2797}, author = {Ives, D G and Fitzpatrick, A L and Bild, D E and Psaty, B M and Kuller, L H and Crowley, P M and Cruise, R G and Theroux, S} } @article {1418, title = {Temporal patterns of antihypertensive medication use among older adults, 1989 through 1992. An effect of the major clinical trials on clinical practice?}, journal = {JAMA}, volume = {273}, year = {1995}, month = {1995 May 10}, pages = {1436-8}, abstract = {

OBJECTIVE: To describe the changing patterns of antihypertensive medication use in the years immediately before and after the publication of the results of three major clinical trials of the treatment of hypertension in older adults.

DESIGN: In this cohort study, adults 65 years or older were examined annually on four occasions between June 1989 and May 1992, and the use of antihypertensive medications was assessed by inventory at each visit. The four visits defined the boundaries of three study periods. For each study period, participants receiving antihypertensive therapy were either continuous users (n = 1667, 1643, and 1605, respectively) or starters (n = 157, 142, 120) of hypertensive therapy. The large clinical trials that convincingly proved the efficacy and safety of low-dose diuretic therapy in older adults were published during the latter parts of period 2 and the early parts of period 3.

RESULTS: Among starters, the proportion initiating therapy on diuretics increased from 35.9\% in period 2 to 47.5\% in period 3, significantly so among women (P = .04). The proportions initiating other drugs displayed no significant trends. Among continuous users, the use of diuretics, beta-blockers, and vasodilators generally decreased over the 3-year period, while the use of calcium channel blockers and angiotensin-converting enzyme inhibitors increased significantly in each of the three periods (P < .05). The decline of 2.7\% in the prevalence of diuretic use in period 1 abated during period 2 (1.8\% decline), and it slowed significantly (P = .03) to almost a complete halt during period 3 (0.2\% decline). The rate of increase in the use of calcium channel blockers slowed significantly (P = .01) between period 1 (+6.7\%) and period 3 (+2.8\%).

CONCLUSIONS: Although other factors such as cost may have been important, the temporal trends in antihypertensive drug therapy coincided in time with and may have reflected in part the influence of the major clinical trials on the patterns of clinical practice.

}, keywords = {Aged, Antihypertensive Agents, Clinical Trials as Topic, Data Interpretation, Statistical, Drug Utilization Review, Female, Humans, Hypertension, Male, Practice Patterns, Physicians{\textquoteright}, United States}, issn = {0098-7484}, author = {Psaty, B M and Koepsell, T D and Yanez, N D and Smith, N L and Manolio, T A and Heckbert, S R and Borhani, N O and Gardin, J M and Gottdiener, J S and Rutan, G H} } @article {1457, title = {Association of fibrinogen and coagulation factors VII and VIII with cardiovascular risk factors in the elderly: the Cardiovascular Health Study. Cardiovascular Health Study Investigators.}, journal = {Am J Epidemiol}, volume = {143}, year = {1996}, month = {1996 Apr 01}, pages = {665-76}, abstract = {

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

}, keywords = {Age Distribution, Aged, Aged, 80 and over, Analysis of Variance, Cardiovascular Diseases, Cohort Studies, Factor VII, Factor VIII, Female, Fibrinogen, Humans, Linear Models, Logistic Models, Male, Prevalence, Risk Factors, Sex Distribution, United States}, issn = {0002-9262}, author = {Cushman, M and Yanez, D and Psaty, B M and Fried, L P and Heiss, G and Lee, M and Polak, J F and Savage, P J and Tracy, R P} } @article {1464, title = {Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {16}, year = {1996}, month = {1996 Sep}, pages = {1163-9}, abstract = {

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

}, keywords = {Aged, Biomarkers, Cardiovascular Diseases, Cohort Studies, Female, Hemostasis, Humans, Male, Risk Factors, Thrombin}, issn = {1079-5642}, author = {Cushman, M and Psaty, B M and Macy, E and Bovill, E G and Cornell, E S and Kuller, L H and Tracy, R P} } @article {1465, title = {Current estrogen-progestin and estrogen replacement therapy in elderly women: association with carotid atherosclerosis. CHS Collaborative Research Group. Cardiovascular Health Study.}, journal = {Ann Epidemiol}, volume = {6}, year = {1996}, month = {1996 Jul}, pages = {314-23}, abstract = {

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

}, keywords = {Aged, Arteriosclerosis, Carotid Arteries, Carotid Stenosis, Cohort Studies, Confidence Intervals, Cross-Sectional Studies, Databases, Factual, Drug Therapy, Combination, Estrogen Replacement Therapy, Estrogens, Female, Health Status Indicators, Humans, Odds Ratio, Progestins, Reproductive History, Ultrasonography, United States, Women{\textquoteright}s Health}, issn = {1047-2797}, author = {Jonas, H A and Kronmal, R A and Psaty, B M and Manolio, T A and Meilahn, E N and Tell, G S and Tracy, R P and Robbins, J A and Anton-Culver, H} } @article {1491, title = {The association of antihypertensive agents with MRI white matter findings and with Modified Mini-Mental State Examination in older adults.}, journal = {J Am Geriatr Soc}, volume = {45}, year = {1997}, month = {1997 Dec}, pages = {1423-33}, abstract = {

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

DESIGN: Cross-sectional study.

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

PARTICIPANTS: 1268 men and women with pharmacologically treated hypertension.

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

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

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

}, keywords = {Adrenergic beta-Antagonists, Aged, Aged, 80 and over, Antihypertensive Agents, Brain, Calcium Channel Blockers, Cognition, Cohort Studies, Cross-Sectional Studies, Diuretics, Female, Geriatric Assessment, Humans, Magnetic Resonance Imaging, Male, Risk Factors}, issn = {0002-8614}, author = {Heckbert, S R and Longstreth, W T and Psaty, B M and Murros, K E and Smith, N L and Newman, A B and Williamson, J D and Bernick, C and Furberg, C D} } @article {1493, title = {The association of antihypertensive medication with serum creatinine changes in older adults.}, journal = {Am J Hypertens}, volume = {10}, year = {1997}, month = {1997 Dec}, pages = {1368-77}, abstract = {

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

}, keywords = {Aged, Antihypertensive Agents, Cohort Studies, Creatinine, Female, Humans, Male}, issn = {0895-7061}, author = {Smith, N L and Psaty, B M and Heckbert, S R and Lemaitre, R N and Kates, D M and Rutan, G H and Bleyer, A} } @article {1488, title = {Incidence of and risk factors for atrial fibrillation in older adults.}, journal = {Circulation}, volume = {96}, year = {1997}, month = {1997 Oct 07}, pages = {2455-61}, abstract = {

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

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

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

}, keywords = {Adult, Aged, Atrial Fibrillation, Blood Glucose, Blood Pressure, Cerebrovascular Disorders, Cohort Studies, Coronary Disease, Electrocardiography, Female, Follow-Up Studies, Hospital Records, Humans, Incidence, Male, Prospective Studies, Risk Factors, United States}, issn = {0009-7322}, author = {Psaty, B M and Manolio, T A and Kuller, L H and Kronmal, R A and Cushman, M and Fried, L P and White, R and Furberg, C D and Rautaharju, P M} } @article {1490, title = {Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {17}, year = {1997}, month = {1997 Oct}, pages = {2167-76}, abstract = {

Blood levels of C-reactive protein (CRP), a marker of inflammation, are related to cardiovascular disease risk. To determine cross-sectional correlates in the elderly, we measured CRP in 400 men and women older than 65 years and free of clinical cardiovascular disease at baseline as part of the Cardiovascular Health Study. Only 2\% of the values were greater than 10 mg/L, the cut-point usually used to identify inflammation. CRP levels appeared tightly regulated, since there were strong bivariate correlations between CRP and the following: inflammation-sensitive proteins such as fibrinogen (r = .52); measures of fibrinolysis such as plasmin-antiplasmin complex (r = .23); pack-years of smoking (r = .30); and body mass index (r = .24; all P values < or = .001). The association with pack-years was independent of the length of time since cessation of smoking. CRP levels were also associated with coagulation factors VIIc, IXc, and Xc; HDL cholesterol (negative) and triglyceride; diabetes status; diuretic use; ECG abnormalities; and level of exercise. Because of effect modification, two multiple linear regression prediction models were developed for CRP, one each for never smokers and ever smokers. An a priori physiologic model was used to guide these analyses, which disallowed the use of other inflammation-sensitive variables such as fibrinogen. In never smokers, the independent predictors were body mass index (+), diabetes status (+), plasmin-antiplasmin complex (+), and the presence of ECG abnormalities (+); this model predicted 15\% of the CRP population variance. In ever smokers, the predictors were body mass index (+), plasmin-antiplasmin complex (+), pack-years of smoking (+), HDL cholesterol (-), and ankle-arm blood pressure index (-); this model predicted 42\% of the population variance. We conclude that levels of CRP in the healthy elderly are tightly regulated and reflect lifetime exposure to smoking as well as level of obesity, ongoing level of fibrinolysis, diabetes status, and level of subclinical atherothrombotic disease. Moreover, exposure to smoking affects the relation of CRP to these other factors.

}, keywords = {Aged, Body Mass Index, C-Reactive Protein, Cardiovascular Diseases, Female, Humans, Male, Multivariate Analysis, Risk Factors, Smoking}, issn = {1079-5642}, author = {Tracy, R P and Psaty, B M and Macy, E and Bovill, E G and Cushman, M and Cornell, E S and Kuller, L H} } @article {1484, title = {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.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {17}, year = {1997}, month = {1997 Jun}, pages = {1121-7}, abstract = {

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.

}, keywords = {Aged, Aging, C-Reactive Protein, Cardiovascular Diseases, Case-Control Studies, Female, Humans, Male, Prospective Studies, Sex Factors}, issn = {1079-5642}, author = {Tracy, R P and Lemaitre, R N and Psaty, B M and Ives, D G and Evans, R W and Cushman, M and Meilahn, E N and Kuller, L H} } @article {1503, title = {Correlates and prevalence of benzodiazepine use in community-dwelling elderly.}, journal = {J Gen Intern Med}, volume = {13}, year = {1998}, month = {1998 Apr}, pages = {243-50}, abstract = {

OBJECTIVE: To describe the prevalence of benzodiazepine use, sociodemographic and physical health factors associated with use, dosages taken, and directions for use among individuals aged 65 years and older.

DESIGN: Cross-sectional analysis of baseline data from the community-based, prospective observational Cardiovascular Health Study.

PATIENTS/PARTICIPANTS: Medicare eligibility lists from four U.S. communities were used to recruit a representative sample of 5,201 community-dwelling elderly, of which 5,181 participants met all study criteria.

MEASUREMENTS AND MAIN RESULTS: Among participants, 511 (9.9\%) were taking at least one benzodiazepine, primarily anxiolytics (73\%). Benzodiazepines were often prescribed to be taken pro re nata (PRN "as needed"), and 36.5\% of prescriptions with instructions to be taken regularly were taken at a dose lower than prescribed. Reported over-the-counter (OTC) sleep aid medication use was 39.2\% in benzodiazepine users and 3.3\% in nonusers. In a multivariate logistic model, the significant independent correlates of benzodiazepine use were being white (odds ratio [OR] 1.9; 95\% confidence interval [CI] 1.0, 3.4), female (OR 1.7; CI 1.4, 2.2), and living in Forsyth County, North Carolina, or Washington County, Maryland, compared with living in Sacramento County, California, or Allegheny County, Pennsylvania (OR 2.3; CI 1.4, 2.2); having coronary heart disease (OR 1.6; CI 1.2, 2.1), health status reported as poor or fair (OR 1.8; CI 1.4, 2.3), self-reported diagnosis of nervous or emotional disorder (OR 6.7; CI 5.1, 8.7), and reporting use of an OTC sleep aid medication (OR 18.7; CI 14.1, 24.7).

CONCLUSIONS: One in 10 participants reported taking a benzodiazepine, most frequently an anxiolytic, often at a lower dose than prescribed and usually PRN. The high prevalence of OTC sleep aid medication and benzodiazepine use may place the patient at increased risk of psychomotor impairment. Physicians should assess OTC sleep aid medication use when prescribing benzodiazepines.

}, keywords = {Aged, Aged, 80 and over, Benzodiazepines, Cross-Sectional Studies, Drug Utilization, Female, Humans, Male, Practice Patterns, Physicians{\textquoteright}, Socioeconomic Factors}, issn = {0884-8734}, author = {Gleason, P P and Schulz, R and Smith, N L and Newsom, J T and Kroboth, P D and Kroboth, F J and Psaty, B M} } @article {1570, title = {Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort.}, journal = {Thromb Haemost}, volume = {80}, year = {1998}, month = {1998 Jul}, pages = {134-9}, abstract = {

The majority of fatal acute myocardial infarctions occur in the elderly. Since these events are predominantly thrombotic, we studied the cross-sectional associations of the anticoagulant proteins Antithrombin, Protein C, Protein S. and Tissue Factor Pathway Inhibitor (TFPI) in a subgroup (n = 400) of the Cardiovascular Health Study (a study of healthy men and women > or = 65 years) free of clinical cardiovascular disease (CVD). We did not observe any strong age-associated trends, although Protein C was lower in older women (p < or = 0.001), and TFPI was higher in older men (p < or = 0.01). The inhibitors were highly intercorrelated, and were associated with increased levels of inflammation-sensitive proteins (e.g., fibrinogen. plasminogen), lipids (especially total and LDL-cholesterol), and coagulation factors, such as Factors VIIc, IXc, and Xc. None was associated with the procoagulant markers Prothrombin Fragment F1-2 or Fibrinopeptide A. Only TFPI was associated with subclinical atherosclerosis: ankle-arm index and internal carotid artery stenosis, p trend < or = 0.01; and carotid wall thickness, p trend < or = 0.05. In multivariate analysis the independent predictors of TFPI were levels of fibrinogen; the fibrinolytic marker plasmin-antiplasmin complex; LDL-cholesterol; and carotid wall thickness (R2 for the model = 0.35). In summary, the inhibitors did not appear to increase with age, and were predominantly associated with inflammation markers and lipids. Since markers of thrombin production do increase with age, we hypothesize that an age-related hemostatic imbalance may ensue, with associated increased thrombotic risk. Only TFPI was associated with subclinical CVD, suggesting that it may more closely reflect endothelial damage.

}, keywords = {Aged, Aged, 80 and over, Analysis of Variance, Anticoagulants, Antithrombin III, Biomarkers, Cross-Sectional Studies, Disease Susceptibility, Female, Humans, Lipoproteins, Male, Prevalence, Protein C, Protein S, Reference Values, Risk Factors, Thrombosis}, issn = {0340-6245}, author = {Sakkinen, P A and Cushman, M and Psaty, B M and Kuller, L H and Bajaj, S P and Sabharwal, A K and Boineau, R and Macy, E and Tracy, R P} } @article {1515, title = {Diabetes in older adults: comparison of 1997 American Diabetes Association classification of diabetes mellitus with 1985 WHO classification.}, journal = {Lancet}, volume = {352}, year = {1998}, month = {1998 Sep 26}, pages = {1012-5}, abstract = {

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

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

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

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

}, keywords = {African Americans, Aged, Aged, 80 and over, Cohort Studies, Diabetes Mellitus, Female, Glucose Tolerance Test, Humans, Male, Prevalence, Societies, Medical, World Health Organization}, issn = {0140-6736}, doi = {10.1016/S0140-6736(98)04055-0}, author = {Wahl, P W and Savage, P J and Psaty, B M and Orchard, T J and Robbins, J A and Tracy, R P} } @article {1508, title = {Factor V Leiden is not a risk factor for arterial vascular disease in the elderly: results from the Cardiovascular Health Study.}, journal = {Thromb Haemost}, volume = {79}, year = {1998}, month = {1998 May}, pages = {912-5}, abstract = {

Coagulation factor V Leiden is a risk marker for venous thrombosis. For arterial thrombosis no large study to date has included population-based elderly patients. The Cardiovascular Health Study is a longitudinal study of 5,201 men and women over age 65. With 3.4-year follow-up, we studied 373 incident cases of myocardial infarction (MI), angina, stroke. or transient ischemic attack (TIA), and 482 controls. The odds ratios for each event with heterozygous factor V Leiden were: MI, 0.46 (95\% CI 0.17 to 1.25); angina, 1.0 (95\% CI 0.45 to 2.23); stroke, 0.77 (95\% CI 0.35 to 1.70): TIA, 1.33 (95\% CI 0.5 to 3.55); any outcome, 0.83 (95\% CI 0.48 to 1.44). Adjustment for cardiovascular risk factors did not change relationships. In older adults factor V Leiden is not a risk factor for future arterial thrombosis.

}, keywords = {Adult, Age Factors, Aged, Arteries, Factor V, Female, Humans, Male, Middle Aged, Mutation, Risk Factors, Thrombosis}, issn = {0340-6245}, author = {Cushman, M and Rosendaal, F R and Psaty, B M and Cook, E F and Valliere, J and Kuller, L H and Tracy, R P} } @article {1507, title = {Temporal patterns in the medical treatment of congestive heart failure with angiotensin-converting enzyme inhibitors in older adults, 1989 through 1995.}, journal = {Arch Intern Med}, volume = {158}, year = {1998}, month = {1998 May 25}, pages = {1074-80}, abstract = {

BACKGROUND: Evidence from clinical trials in the past decade has consistently shown that angiotensin-converting enzyme (ACE) inhibitors reduce morbidity and mortality in patients with congestive heart failure (CHF). The extent to which clinical practice has adopted ACE inhibitor therapy is unknown.

METHODS: The Cardiovascular Health Study is a prospective observational study of 5201 community-dwelling adults aged 65 years and older. Prevalent CHF cases were identified on study entry (from June 10, 1989, through May 31, 1990) and incident CHF cases were identified throughout 5 years of follow-up. Medication data were collected from annual medication inventories. The percentage of patients with CHF using ACE inhibitors was calculated at each annual examination. Temporal trends in CHF treatment with ACE inhibitors between June 10, 1989, through May 31, 1990, and June 1, 1994, through May 31, 1995, were analyzed.

RESULTS: Use of ACE inhibitors to treat CHF increased slightly over time among prevalent cases at each annual examination: 26\% of prevalent CHF cases were treated in 1989-1990 compared with 36\% of prevalent cases in 1994-1995. This 10\% increase was statistically significant (P<.01). Participants with low ejection fractions were 2 times more likely to be treated with ACE inhibitors than were those with normal ejection fraction and this tendency did not change over time. Among cases newly diagnosed in the year before the 1990-1991 examination, 42\% were using ACE inhibitors; among those newly diagnosed in the year before 1994-1995, 40\% were using ACE inhibitors. This 2\% decrease was not statistically significant (P=.68).

CONCLUSION: These findings suggest that, while the medical management of CHF with ACE inhibitors has increased modestly over time in prevalent cases, these drugs may still be underused, especially among incident cases.

}, keywords = {Aged, Angiotensin-Converting Enzyme Inhibitors, Drug Utilization, Female, Heart Failure, Humans, Logistic Models, Male, Stroke Volume, Treatment Outcome, United States}, issn = {0003-9926}, author = {Smith, N L and Psaty, B M and Pitt, B and Garg, R and Gottdiener, J S and Heckbert, S R} } @article {1513, title = {Time trends in the use of cholesterol-lowering agents in older adults: the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {158}, year = {1998}, month = {1998 Sep 14}, pages = {1761-8}, abstract = {

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

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

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

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

}, keywords = {Aged, Anticholesteremic Agents, Cholesterol, LDL, Cohort Studies, Female, Humans, Hypercholesterolemia, Male, Prevalence, Risk Factors, United States}, issn = {0003-9926}, author = {Lemaitre, R N and Furberg, C D and Newman, A B and Hulley, S B and Gordon, D J and Gottdiener, J S and McDonald, R H and Psaty, B M} } @article {591, title = {Antidiabetic treatment trends in a cohort of elderly people with diabetes. The cardiovascular health study, 1989-1997.}, journal = {Diabetes Care}, volume = {22}, year = {1999}, month = {1999 May}, pages = {736-42}, abstract = {

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

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

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

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

}, keywords = {Aged, Blood Glucose, Cardiovascular Diseases, Cohort Studies, Diabetes Mellitus, Drug Therapy, Female, Follow-Up Studies, Humans, Hypoglycemic Agents, Insulin, Male, Prospective Studies, Risk Factors, Time Factors, United States}, issn = {0149-5992}, doi = {10.2337/diacare.22.5.736}, author = {Smith, N L and Heckbert, S R and Bittner, V A and Savage, P J and Barzilay, J I and Dobs, A S and Psaty, B M} } @article {584, title = {Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {19}, year = {1999}, month = {1999 Mar}, pages = {493-8}, abstract = {

Coagulation factor levels predict arterial thrombosis in epidemiological studies, but studies of older persons are needed. We studied 3 plasma antigenic markers of fibrinolysis, viz, plasminogen activator inhibitor-1 (PAI-1), fibrin fragment D-dimer, and plasmin-antiplasmin complex (PAP) for the prediction of arterial thrombosis in healthy elderly persons over age 65. The study was a nested case-control study in the Cardiovascular Health Study cohort of 5201 men and women >/=65 years of age who were enrolled from 1989 to 1990. Cases were 146 participants without baseline clinical vascular disease who developed myocardial infarction, angina, or coronary death during a follow-up of 2.4 years. Controls remained free of cardiovascular events and were matched 1:1 to cases with respect to sex, duration of follow-up, and baseline subclinical vascular disease status. With increasing quartile of D-dimer and PAP levels but not of PAI-1, there was an independent increased risk of myocardial infarction or coronary death, but not of angina. The relative risk for D-dimer above versus below the median value (>/=120 microg/L) was 2.5 (95\% confidence interval, 1.1 to 5.9) and for PAP above the median (>/=5.25 nmol/L), 3.1 (1.3 to 7.7). Risks were independent of C-reactive protein and fibrinogen concentrations. There were no differences in risk by sex or presence of baseline subclinical disease. D-dimer and PAP, but not PAI-1, predicted future myocardial infarction in men and women over age 65. Relationships were independent of other risk factors, including inflammation markers. Results indicate a major role for these markers in identifying a high risk of arterial disease in this age group.

}, keywords = {Age Factors, Aged, Angina Pectoris, Biomarkers, Female, Fibrin Fibrinogen Degradation Products, Fibrinolysin, Fibrinolysis, Follow-Up Studies, Heart Arrest, Humans, Male, Myocardial Infarction, Plasminogen Activator Inhibitor 1, Risk Factors}, issn = {1079-5642}, doi = {10.1161/01.atv.19.3.493}, author = {Cushman, M and Lemaitre, R N and Kuller, L H and Psaty, B M and Macy, E M and Sharrett, A R and Tracy, R P} } @article {588, title = {Hormone replacement therapy, inflammation, and hemostasis in elderly women.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {19}, year = {1999}, month = {1999 Apr}, pages = {893-9}, abstract = {

Lipid-lowering by postmenopausal hormone therapy (HRT) explains only partly the assumed coronary risk reduction associated with therapy. To explore other possible mechanisms, we studied associations of HRT use with inflammation and hemostasis risk markers in women >/=65 years of age. Subjects were selected from 3393 participants in the fourth year examination of the Cardiovascular Health Study, an observational study of vascular disease risk factors. After excluding women with vascular disease, we compared levels of inflammation and hemostasis variables in the 230 women using unopposed estrogen and 60 using estrogen/progestin, with those of 196 nonusers selected as controls. Compared with nonusers, unopposed estrogen use was associated with 59\% higher mean C-reactive protein (P<0.001), but with modestly lower levels of other inflammation indicators, fibrinogen, and alpha-1 acid glycoprotein (P<0.001). Factor VIIc was 16\% higher among estrogen users (P<0.001), but this was not associated with higher thrombin production (prothrombin fragment 1-2), or increased fibrin breakdown (D-dimer). Concentration of plasminogen activator inhibitor-1 was 50\% lower in both using groups (P<0.001) compared with nonusers, and this was associated with higher plasmin-antiplasmin complex: 8\% higher in estrogen and 18\% higher in estrogen/progestin users (P<0. 05). Relationships between the markers and hormone use were less pronounced in estrogen/progestin users, with no association for C-reactive protein except in women in upper 2 tertiles of body mass index (P for interaction, 0.02). The direction and strength of the associations of HRT use with inflammation markers differed depending on the protein, so it is not clear whether HRT confers coronary risk reduction through an inflammation-sensitive mechanism. Associations with hemostasis markers indicated no association with evidence of procoagulation and a possible association with increased fibrinolytic activity.

}, keywords = {Aged, Biomarkers, Case-Control Studies, Cross-Sectional Studies, Estrogens, Female, Hemostasis, Hormone Replacement Therapy, Humans, Inflammation, Progestins, Random Allocation, United Kingdom, United States}, issn = {1079-5642}, doi = {10.1161/01.atv.19.4.893}, author = {Cushman, M and Meilahn, E N and Psaty, B M and Kuller, L H and Dobs, A S and Tracy, R P} } @article {585, title = {Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women.}, journal = {Arterioscler Thromb Vasc Biol}, volume = {19}, year = {1999}, month = {1999 Mar}, pages = {499-504}, abstract = {

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, }, keywords = {Aged, Aged, 80 and over, alpha-2-Antiplasmin, Antifibrinolytic Agents, Asian Continental Ancestry Group, Cohort Studies, Coronary Disease, Diabetes Mellitus, Type 2, European Continental Ancestry Group, Female, Fibrinolysin, Fibrinolysis, Humans, Insulin Resistance, Male, Multivariate Analysis, Myocardial Infarction, Plasminogen Activator Inhibitor 1, Risk Factors}, issn = {1079-5642}, doi = {10.1161/01.atv.19.3.499}, author = {Sakkinen, P A and Cushman, M and Psaty, B M and Rodriguez, B and Boineau, R and Kuller, L H and Tracy, R P} } @article {599, title = {Temporal trends in the use of anticoagulants among older adults with atrial fibrillation.}, journal = {Arch Intern Med}, volume = {159}, year = {1999}, month = {1999 Jul 26}, pages = {1574-8}, abstract = {

BACKGROUND: Several recent randomized clinical trials have demonstrated that warfarin sodium treatment, and to a lesser extent aspirin, reduces risk of stroke and death compared with placebo in persons with atrial fibrillation. Insufficient documentation exists on the extent to which the use of these therapies following trial publications has continued to increase in the elderly with atrial fibrillation.

METHODS: We used data from the Cardiovascular Health Study, a study of 5888 community-dwelling adults aged 65 years or older, to determine the prevalence of warfarin and aspirin use in persons with electrocardiogram-identified atrial fibrillation. Electrocardiogram examinations were conducted at baseline from 1989 through 1990, and at 6 subsequent annual examinations through 1995-1996. Medication data were collected by inventory methods at each examination. Temporal change in use of anticoagulants was analyzed by comparing percentage use in 1990 to use in each year through 1996.

RESULTS: The use of warfarin increased 4-fold from 13\% in 1990 to 50\% in 1996 among participants with prevalent atrial fibrillation (P<.001). Daily use of aspirin did not increase over time. Participants younger than 80 years were 4 times more likely to use warfarin in 1996 (P<.001) than those 80 years and older. Use of aspirin did not vary significantly with age.

CONCLUSIONS: Warfarin use in community-dwelling elderly persons with electrocardiogram-documented atrial fibrillation increased steadily following the first publication of its treatment benefit, reaching 50\% by 1996. In contrast, use of aspirin was unchanged during this same period. Continued efforts to promote appropriate anticoagulation therapy to physicians and their patients may still be needed.

}, keywords = {Aged, Anticoagulants, Aspirin, Atrial Fibrillation, Cerebrovascular Disorders, Drug Therapy, Electrocardiography, Female, Humans, Incidence, Male, Prevalence, Treatment Outcome, Warfarin}, issn = {0003-9926}, doi = {10.1001/archinte.159.14.1574}, author = {Smith, N L and Psaty, B M and Furberg, C D and White, R and Lima, J A and Newman, A B and Manolio, T A} } @article {593, title = {Traditional risk factors and subclinical disease measures as predictors of first myocardial infarction in older adults: the Cardiovascular Health Study.}, journal = {Arch Intern Med}, volume = {159}, year = {1999}, month = {1999 Jun 28}, pages = {1339-47}, abstract = {

BACKGROUND: Risk factors for myocardial infarction (MI) have not been well characterized in older adults, and in estimating risk, we sought to assess the individual and joint contributions made by both traditional risk factors and measures of subclinical disease.

METHODS: In the Cardiovascular Health Study, we recruited 5888 adults aged 65 years and older from 4 US centers. At baseline in 1989-1990, participants underwent an extensive examination that included traditional risk factors such as blood pressure and fasting glucose level and measures of subclinical disease as assessed by electrocardiography, carotid ultrasonography, echocardiography, pulmonary function, and ankle-arm index. Participants were followed up with semiannual contacts, and all cardiovascular events were classified by the Morbidity and Mortality Committee. The main analytic technique was the Cox proportional hazards model.

RESULTS: At baseline, 1967 men and 2979 women had no history of an MI. After follow-up for an average of 4.8 years, there were 302 coronary events, which included 263 patients with MI and 39 with definite fatal coronary disease. The incidence was higher in men (20.7 per 1000 person-years) than women (7.9 per 1000 person-years). In all subjects, the incidence was strongly associated with age, increasing from 7.8 per 1000 person-years in subjects aged 65 to 69 years to 25.6 per 1000 person-years in subjects aged 85 years and older. Glucose level and systolic blood pressure were associated with the incidence of MI, but smoking and lipid measures were not. After adjustment for age and sex, the significant subclinical disease predictors of MI were borderline or abnormal ejection fraction by echocardiography, high levels of intimal-medial thickness of the internal carotid artery, and a low ankle-arm index. Forced vital capacity and electrocardiographic left ventricular mass did not enter the stepwise model. Excluding subjects with clinical cardiovascular diseases such as prior angina or congestive heart failure at baseline had little effect on these results. Risk factors were generally similar in men and women.

CONCLUSIONS: After follow-up of 4.8 years, systolic blood pressure, fasting glucose level, and selected subclinical disease measures were important predictors of the incidence of MI in older adults. Uncontrolled high blood pressure may explain about one quarter of the coronary events in this population.

}, keywords = {Age Distribution, Aged, Female, Follow-Up Studies, Humans, Incidence, Male, Multivariate Analysis, Myocardial Infarction, Predictive Value of Tests, Proportional Hazards Models, Risk, Risk Factors, Sex Distribution}, issn = {0003-9926}, doi = {10.1001/archinte.159.12.1339}, author = {Psaty, B M and Furberg, C D and Kuller, L H and Bild, D E and Rautaharju, P M and Polak, J F and Bovill, E and Gottdiener, J S} } @article {625, title = {Chlamydia pneumoniae, herpes simplex virus type 1, and cytomegalovirus and incident myocardial infarction and coronary heart disease death in older adults : the Cardiovascular Health Study.}, journal = {Circulation}, volume = {102}, year = {2000}, month = {2000 Nov 07}, pages = {2335-40}, abstract = {

BACKGROUND: Whether serological evidence of prior infection with Chlamydia pneumoniae, herpes simplex virus type 1 (HSV-1), and cytomegalovirus (CMV) is associated with myocardial infarction (MI) and coronary heart disease (CHD) death remains a source of controversy.

METHODS AND RESULTS: We conducted a nested case-control study among participants in the Cardiovascular Health Study, a cohort study of persons aged >/=65 years. Cases experienced an incident MI and CHD death (n=213). Control subjects were matched to cases by age, sex, clinic, year of enrollment, and month of blood draw (n=405). Serum was analyzed for IgG antibodies to C pneumoniae, HSV-1, and CMV. After adjustment for other risk factors, the risk of MI and CHD death was associated with the presence of IgG antibodies to HSV-1 (odds ratio [OR] 2.0, 95\% CI 1.1 to 3.6) but was not associated with the presence of IgG antibodies to either C pneumoniae (OR 1.1, 95\% CI 0.7 to 1.8) or CMV (OR 1.2, 95\% CI 0.7 to 1.9). Although there was little association with low to moderate C pneumoniae antibody titers (

CONCLUSIONS: Among older adults, the presence of IgG antibodies to HSV-1 was associated with a 2-fold increase in the risk of incident MI and CHD death. For C pneumoniae, only high-titer IgG antibodies were associated with an increased risk of MI and CHD death. The presence of IgG antibodies to CMV was not associated with risk among the elderly.

}, keywords = {Adult, Age Factors, Aged, Antibodies, Bacterial, Antibodies, Viral, Case-Control Studies, Chlamydophila pneumoniae, Coronary Disease, Cytomegalovirus, Female, Herpesvirus 1, Human, HIV Antibodies, Humans, Immunoglobulin G, Male, Myocardial Infarction, Risk Factors}, issn = {1524-4539}, doi = {10.1161/01.cir.102.19.2335}, author = {Siscovick, D S and Schwartz, S M and Corey, L and Grayston, J T and Ashley, R and Wang, S P and Psaty, B M and Tracy, R P and Kuller, L H and Kronmal, R A} } @article {647, title = {Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study.}, journal = {Arch Intern Med}, volume = {161}, year = {2001}, month = {2001 May 14}, pages = {1183-92}, abstract = {

BACKGROUND: Recent reports have drawn attention to the importance of pulse pressure as a predictor of cardiovascular events. Pulse pressure is used neither by clinicians nor by guidelines to define treatable levels of blood pressure.

METHODS: In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline in 1989-1990, participants underwent an extensive examination, and all subsequent cardiovascular events were ascertained and classified.

RESULTS: At baseline, 1961 men and 2941 women were at risk for an incident myocardial infarction or stroke. During follow-up that averaged 6.7 years, 572 subjects had a coronary event, 385 had a stroke, and 896 died. After adjustment for potential confounders, systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure were directly associated with the risk of incident myocardial infarction and stroke. Only SBP was associated with total mortality. Importantly, SBP was a better predictor of cardiovascular events than DBP or pulse pressure. In the adjusted model for myocardial infarction, a 1-SD change in SBP, DBP, and pulse pressure was associated with hazard ratios (95\% confidence intervals) of 1.24 (1.15-1.35), 1.13 (1.04-1.22), and 1.21 (1.12-1.31), respectively; and adding pulse pressure or DBP to the model did not improve the fit. For stroke, the hazard ratios (95\% confidence intervals) were 1.34 (1.21-1.47) with SBP, 1.29 (1.17-1.42) with DBP, and 1.21 (1.10-1.34) with pulse pressure. The association between blood pressure level and cardiovascular disease risk was generally linear; specifically, there was no evidence of a J-shaped relationship. In those with treated hypertension, the hazard ratios for the association of SBP with the risks for myocardial infarction and stroke were less pronounced than in those without treated hypertension.

CONCLUSION: In this population-based study of older adults, although all measures of blood pressure were strongly and directly related to the risk of coronary and cerebrovascular events, SBP was the best single predictor of cardiovascular events.

}, keywords = {Aged, Blood Pressure, Female, Humans, Male, Myocardial Infarction, Prognosis, Proportional Hazards Models, Prospective Studies, Risk Factors, Stroke, Survival Rate, United States}, issn = {0003-9926}, doi = {10.1001/archinte.161.9.1183}, author = {Psaty, B M and Furberg, C D and Kuller, L H and Cushman, M and Savage, P J and Levine, D and O{\textquoteright}Leary, D H and Bryan, R N and Anderson, M and Lumley, T} } @article {659, title = {Post-menopausal hormone therapy and concentrations of protein C and antithrombin in elderly women.}, journal = {Br J Haematol}, volume = {114}, year = {2001}, month = {2001 Jul}, pages = {162-8}, abstract = {

The effects of post-menopausal hormone therapy (HRT) on blood coagulation in elderly women are not well defined. We studied associations of HRT use with levels of natural anticoagulant proteins in a cross-sectional study of 3393 women > or = 65 years of age participating in the Cardiovascular Health Study. Protein C antigen and antithrombin were measured in all users (n = 230 unopposed oestrogen; 60 oestrogen/progestin) and a comparison group of 196 age- and race-matched non-users. Compared with non-users, oestrogen use was associated with higher protein C (4.80 vs. 4.30 microg/ml, P < 0.01). Results were similar for oestrogen/progestin (P > 0.05). In both user groups, antithrombin was lower than in non-users (109\% for each vs. 115\% in non-users, P < 0.001). Adjustment for factors related to prescription of HRT and to anticoagulant protein levels had little impact on the results. For antithrombin, associations with HRT were larger for thinner Caucasian women and black women. Venous thrombosis from HRT may be mediated partly by alterations in antithrombin, but not protein C concentrations. This study extends previous observations to older women, the group at highest risk of venous thromboembolism. Studies of HRT-induced alterations in anticoagulant function in relation to the occurrence of thrombosis with HRT are required.

}, keywords = {Aged, Antithrombins, Black People, Body Mass Index, Cross-Sectional Studies, Estrogen Replacement Therapy, Female, Humans, Logistic Models, Postmenopause, Progestins, Protein C, Risk Factors, Venous Thrombosis, White People}, issn = {0007-1048}, doi = {10.1046/j.1365-2141.2001.02911.x}, author = {Cushman, M and Psaty, B M and Meilahn, E N and Dobs, A S and Kuller, L H} } @article {635, title = {Risk factors for hospitalized gastrointestinal bleeding among older persons. Cardiovascular Health Study Investigators.}, journal = {J Am Geriatr Soc}, volume = {49}, year = {2001}, month = {2001 Feb}, pages = {126-33}, abstract = {

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.

}, keywords = {Activities of Daily Living, Age Distribution, Aged, Aged, 80 and over, Anti-Inflammatory Agents, Non-Steroidal, Anticoagulants, Aspirin, Cardiovascular Diseases, Female, Gastrointestinal Hemorrhage, Hospitalization, Humans, Incidence, Male, Multivariate Analysis, Predictive Value of Tests, Proportional Hazards Models, Prospective Studies, Risk Factors, Smoking, United States}, issn = {0002-8614}, doi = {10.1046/j.1532-5415.2001.49032.x}, author = {Kaplan, R C and Heckbert, S R and Koepsell, T D and Furberg, C D and Polak, J F and Schoen, R E and Psaty, B M} } @article {811, title = {Respiratory muscle strength and the risk of incident cardiovascular events.}, journal = {Thorax}, volume = {59}, year = {2004}, month = {2004 Dec}, pages = {1063-7}, abstract = {

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.

}, keywords = {Cardiovascular Diseases, Female, Follow-Up Studies, Forced Expiratory Volume, Humans, Male, Maximal Voluntary Ventilation, Prospective Studies, Respiratory Muscles, Risk Factors, Vital Capacity}, issn = {0040-6376}, doi = {10.1136/thx.2004.021915}, author = {van der Palen, J and Rea, T D and Manolio, T A and Lumley, T and Newman, A B and Tracy, R P and Enright, P L and Psaty, B M} } @article {860, title = {Vascular events, mortality, and preventive therapy following ischemic stroke in the elderly.}, journal = {Neurology}, volume = {65}, year = {2005}, month = {2005 Sep 27}, pages = {835-42}, abstract = {

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

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

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

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

}, keywords = {Age Factors, Aged, Aged, 80 and over, Aging, Anticoagulants, Antihypertensive Agents, Brain Ischemia, Cohort Studies, Comorbidity, Coronary Artery Disease, Drug Utilization, Female, Humans, Hyperlipidemias, Hypertension, Hypolipidemic Agents, Male, Mortality, Prospective Studies, Recurrence, Sex Factors, Stroke, Treatment Outcome}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000176058.09848.bb}, author = {Kaplan, R C and Tirschwell, D L and Longstreth, W T and Manolio, T A and Heckbert, S R and Lefkowitz, D and El-Saed, A and Psaty, B M} } @article {880, title = {Soluble intracellular adhesion molecule-1 is associated with cardiovascular disease risk and mortality in older adults.}, journal = {J Thromb Haemost}, volume = {4}, year = {2006}, month = {2006 Jan}, pages = {107-13}, abstract = {

BACKGROUND: Intracellular adhesion molecule-1 (ICAM-1) regulates leukocyte-endothelial attachment, a process crucial to atherosclerosis. Circulating soluble ICAM-1 (sICAM-1) may serve as a marker of cardiovascular disease (CVD) progression.

OBJECTIVES: We examined the association of sICAM-1 with measures of subclinical CVD and risk of incident CVD events and death in older men and women (age > or = 65 years) from the Cardiovascular Health Study.

METHODS: Selected participants were free of clinical CVD at baseline. Non-exclusive incident case groups were angina (n = 534), myocardial infarction (n = 304), stroke (n = 327), and death (n = 842; CVD death = 310). A total 643 subjects were free of events during follow-up.

RESULTS: sICAM-1 was positively associated with C-reactive protein, interleukin-6 and fibrinogen and measures of subclinical CVD in these older men and women. In Cox regression models adjusted for age, gender, and race, increasing levels of sICAM-1 were associated with increased risk of all cause mortality in men and women. Hazard ratios (95\% confidence intervals) for a one standard deviation increase in sICAM-1 (89.7 ng mL(-1)) were 1.3 (1.1-1.4) in men and 1.2 (1.1-1.3) in women. sICAM-1 was associated with increased risk of CVD death in women (1.2; 1.0-1.5), but not men (1.1; 0.9-1.3). There were no associations of sICAM-1 with non-fatal CVD events.

CONCLUSIONS: While sICAM-1 was associated with death in older men and women, there was a more marked association between sICAM-1 and CVD death in women.

}, keywords = {Aged, Aged, 80 and over, Angina Pectoris, Biomarkers, Cardiovascular Diseases, Female, Humans, Incidence, Intercellular Adhesion Molecule-1, Male, Mortality, Myocardial Infarction, Regression Analysis, Risk Factors, Sex Factors, Solubility, Stroke}, issn = {1538-7933}, doi = {10.1111/j.1538-7836.2005.01678.x}, author = {Jenny, N S and Arnold, A M and Kuller, L H and Sharrett, A R and Fried, L P and Psaty, B M and Tracy, R P} } @article {950, title = {Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study.}, journal = {J Thromb Haemost}, volume = {5}, year = {2007}, month = {2007 Jun}, pages = {1128-35}, abstract = {

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

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

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

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

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

}, keywords = {Aged, Aging, Biomarkers, C-Reactive Protein, Cardiovascular Diseases, Cholesterol, Cohort Studies, Factor VIII, Female, Fibrinogen, Hemostasis, Homocysteine, Humans, Inflammation Mediators, Interleukin-6, Leukocyte Count, Lipoprotein(a), Male, Prospective Studies, Risk Factors}, issn = {1538-7933}, doi = {10.1111/j.1538-7836.2007.02528.x}, author = {Zakai, N A and Katz, R and Jenny, N S and Psaty, B M and Reiner, A P and Schwartz, S M and Cushman, M} } @article {1034, title = {No advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies.}, journal = {Neurology}, volume = {70}, year = {2008}, month = {2008 Jun 10}, pages = {2291-8}, abstract = {

INTRODUCTION: Observational studies show reduced incidence of Alzheimer dementia (AD) in users of nonsteroidal anti-inflammatory drugs (NSAIDs). One hypothesis holds that the subset of NSAIDs known as selective A beta(42)-lowering agents (SALAs) is responsible for this apparent reduction in AD risk.

METHODS: We pooled individual-level data from six prospective studies to obtain a sufficient sample to examine AD risk in users of SALA vs non-SALA NSAIDs.

RESULTS: Of 13,499 initially dementia-free participants (70,863 person-years), 820 developed incident AD. Users of NSAIDs (29.6\%) showed reduced risk of AD (adjusted hazard ratio [aHR] 0.77, 95\% CI 0.65-0.91). The point estimates were similar for SALAs (aHR 0.87, CI 0.72-1.04) and non-SALAs (aHR 0.75, CI 0.56-1.01). Because 573 NSAID users (14.5\%) reported taking both a SALA and non-SALA, we examined their use alone and in combination. Resulting aHRs were 0.82 (CI 0.67-0.99) for SALA only, 0.60 (CI 0.40-0.90) for non-SALA only, and 0.87 (CI 0.57-1.33) for both NSAIDs (Wald test for differences, p = 0.32). The 40.7\% of participants who used aspirin also showed reduced risk of AD, even when they used no other NSAIDs (aHR 0.78, CI 0.66-0.92). By contrast, there was no association with use of acetaminophen (aHR 0.93, CI 0.76-1.13).

CONCLUSIONS: In this pooled dataset, nonsteroidal anti-inflammatory drug (NSAID) use reduced the risk of Alzheimer dementia (AD). However, there was no apparent advantage in AD risk reduction for the subset of NSAIDs shown to selectively lower A beta(42), suggesting that all conventional NSAIDs including aspirin have a similar protective effect in humans.

}, keywords = {Acetaminophen, Adolescent, Adult, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Analgesics, Non-Narcotic, Anti-Inflammatory Agents, Non-Steroidal, Aspirin, Cohort Studies, Female, Humans, Male, Middle Aged, Neuroprotective Agents, Peptide Fragments, Proportional Hazards Models, Prospective Studies, Risk Factors}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000313933.17796.f6}, author = {Szekely, C A and Green, R C and Breitner, J C S and {\O}stbye, T and Beiser, A S and Corrada, M M and Dodge, H H and Ganguli, M and Kawas, C H and Kuller, L H and Psaty, B M and Resnick, S M and Wolf, P A and Zonderman, A B and Welsh-Bohmer, K A and Zandi, P P} } @article {998, title = {NSAID use and dementia risk in the Cardiovascular Health Study: role of APOE and NSAID type.}, journal = {Neurology}, volume = {70}, year = {2008}, month = {2008 Jan 01}, pages = {17-24}, abstract = {

BACKGROUND: Epidemiologic and laboratory studies suggest that nonsteroidal antiinflammatory drugs (NSAIDs) reduce risk of Alzheimer disease (AD). We therefore investigated the association between use of NSAIDs, aspirin, and the non-NSAID analgesic acetaminophen with incidence of dementia and AD.

METHODS: Participants in the Cardiovascular Health Cognition Study included 3,229 individuals aged 65 or older, free of dementia at baseline, with information on medication use. We used Cox proportional hazards regression to estimate the association of medication use with incident all-cause dementia, AD, and vascular dementia (VaD). Additional analyses considered the NSAID-AD relationship as a function of age, presence of at least one epsilon 4 allele at APOE, race, and individual NSAIDs{\textquoteright} reported ability to reduce production of the amyloid-beta peptide variant A beta(42).

RESULTS: Use of NSAIDs was associated with a lower risk of dementia (adjusted hazard ratio or aHR 0.76, 95\% CI or CI 0.60-0.96) and, in particular, AD (aHR 0.63, CI 0.45-0.88), but not VaD (aHR 0.92, CI 0.65-1.28). No similar trends were observed with acetaminophen (aHR 0.99, CI 0.79-1.24). Closer examination suggested AD risk reduction with NSAIDs only in participants having an APOE epsilon 4 allele (aHR 0.34, CI 0.18-0.65; aHR for others 0.88, CI 0.59-1.32). There was no advantage in AD risk reduction with NSAIDs reported to selectively reduce A beta(42).

CONCLUSIONS: Results were consistent with previous cohort studies showing reduced risk of AD in NSAID users, but this association was found only in those with an APOE epsilon 4 allele, and there was no advantage for A beta(42)-lowering NSAIDs.

}, keywords = {Aged, Aged, 80 and over, Alzheimer Disease, Anti-Inflammatory Agents, Non-Steroidal, Apolipoproteins E, Cardiovascular System, Dementia, Female, Humans, Incidence, Male, Proportional Hazards Models, Prospective Studies, Risk Factors}, issn = {1526-632X}, doi = {10.1212/01.wnl.0000284596.95156.48}, author = {Szekely, C A and Breitner, J C S and Fitzpatrick, A L and Rea, T D and Psaty, B M and Kuller, L H and Zandi, P P} } @article {1068, title = {Platelet count and the risk for thrombosis and death in the elderly.}, journal = {J Thromb Haemost}, volume = {7}, year = {2009}, month = {2009 Mar}, pages = {399-405}, abstract = {

AIM: Our aim was to examine the association between platelet count and the incidence of myocardial infarction, ischemic stroke, hemorrhagic stroke, venous thrombosis, and mortality.

METHODS AND RESULTS: Platelet count was measured at baseline in 1989-1990 and at 3 years follow-up, or at baseline (for a newly recruited group) in 1992-1993 in 5766 community-dwelling individuals aged 65 years and older (mean age at baseline, 73 years). During 12-15 years of follow-up, there were 821 incident myocardial infarctions, 807 ischemic strokes, 161 hemorrhagic strokes, 159 venous thrombotic events, and 3413 participants died. Platelet count was not associated with the occurrence of myocardial infarction, ischemic or hemorrhagic stroke, venous thrombosis, or cardiovascular mortality. Non-cardiovascular mortality was higher among both participants with low and with high platelet count. Adjusted non-cardiovascular mortality rates for platelet counts below 100, 100-199, 300-399, and above 400 x 10(9) L(-1) relative to the reference mortality rate in participants with platelet count values between 200 and 299 x 10(9) L(-1) were 1.89 (1.21-2.96), 1.08 (0.98-1.20), 1.20 (1.06-1.37), and 1.47 (1.14-1.90), respectively.

CONCLUSION: Platelet counts were not associated with vascular outcomes but low and high platelet counts were associated with non-cardiovascular mortality, including cancer mortality.

}, keywords = {Aged, Aged, 80 and over, Cause of Death, Cerebral Hemorrhage, Female, Humans, Male, Myocardial Infarction, Platelet Count, Risk, Stroke, Survival Analysis, Thrombosis, Venous Thrombosis}, issn = {1538-7836}, doi = {10.1111/j.1538-7836.2008.03267.x}, author = {van der Bom, J G and Heckbert, S R and Lumley, T and Holmes, C E and Cushman, M and Folsom, A R and Rosendaal, F R and Psaty, B M} } @article {1121, title = {Replication of findings on the association of genetic variation in 24 hemostasis genes and risk of incident venous thrombosis.}, journal = {J Thromb Haemost}, volume = {7}, year = {2009}, month = {2009 Oct}, pages = {1743-6}, keywords = {Adolescent, Adult, Aged, Aged, 80 and over, Case-Control Studies, Cohort Studies, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Haplotypes, Hemostasis, Humans, Incidence, Male, Menopause, Middle Aged, Polymorphism, Single Nucleotide, Reproducibility of Results, Risk, Thrombophilia, Venous Thrombosis, Young Adult}, issn = {1538-7836}, doi = {10.1111/j.1538-7836.2009.03567.x}, author = {Smith, N L and Wiggins, K L and Reiner, A P and Lange, L A and Cushman, M and Heckbert, S R and Lumley, T and Rice, K M and Folsom, A R and Psaty, B M} } @article {1079, title = {Systematically missing confounders in individual participant data meta-analysis of observational cohort studies.}, journal = {Stat Med}, volume = {28}, year = {2009}, month = {2009 Apr 15}, pages = {1218-37}, abstract = {

One difficulty in performing meta-analyses of observational cohort studies is that the availability of confounders may vary between cohorts, so that some cohorts provide fully adjusted analyses while others only provide partially adjusted analyses. Commonly, analyses of the association between an exposure and disease either are restricted to cohorts with full confounder information, or use all cohorts but do not fully adjust for confounding. We propose using a bivariate random-effects meta-analysis model to use information from all available cohorts while still adjusting for all the potential confounders. Our method uses both the fully adjusted and the partially adjusted estimated effects in the cohorts with full confounder information, together with an estimate of their within-cohort correlation. The method is applied to estimate the association between fibrinogen level and coronary heart disease incidence using data from 154,012 participants in 31 cohorts

}, keywords = {Cohort Studies, Computer Simulation, Coronary Disease, Data Interpretation, Statistical, Female, Fibrinogen, Humans, Male, Meta-Analysis as Topic, Models, Statistical}, issn = {0277-6715}, doi = {10.1002/sim.3540}, author = {Jackson, Dan and White, Ian and Kostis, J B and Wilson, A C and Folsom, A R and Wu, K and Chambless, L and Benderly, M and Goldbourt, U and Willeit, J and Kiechl, S and Yarnell, J W G and Sweetnam, P M and Elwood, P C and Cushman, M and Psaty, B M and Tracy, R P and Tybjaerg-Hansen, A and Haverkate, F and de Maat, M P M and Thompson, S G and Fowkes, F G R and Lee, A J and Smith, F B and Salomaa, V and Harald, K and Rasi, V and Vahtera, E and Jousilahti, P and D{\textquoteright}Agostino, R and Kannel, W B and Wilson, P W F and Tofler, G and Levy, D and Marchioli, R and Valagussa, F and Rosengren, A and Wilhelmsen, L and Lappas, G and Eriksson, H and Cremer, P and Nagel, D and Curb, J D and Rodriguez, B and Yano, K and Salonen, J T and Nyyss{\"o}nen, K and Tuomainen, T-P and Hedblad, B and Engstrom, G and Berglund, G and Loewel, H and Koenig, W and Hense, H W and Meade, T W and Cooper, J A and De Stavola, B and Knottenbelt, C and Miller, G J and Cooper, J A and Bauer, K A and Rosenberg, R D and Sato, S and Kitamura, A and Naito, Y and Iso, H and Salomaa, V and Harald, K and Rasi, V and Vahtera, E and Jousilahti, P and Palosuo, T and Ducimetiere, P and Amouyel, P and Arveiler, D and Evans, A E and Ferrieres, J and Juhan-Vague, I and Bingham, A and Schulte, H and Assmann, G and Cantin, B and Lamarche, B and Despr{\'e}s, J-P and Dagenais, G R and Tunstall-Pedoe, H and Lowe, G D O and Woodward, M and Ben-Shlomo, Y and Davey Smith, G and Palmieri, V and Yeh, J L and Meade, T W and Rudnicka, A and Brennan, P and Knottenbelt, C and Cooper, J A and Ridker, P and Rodeghiero, F and Tosetto, A and Shepherd, J and Lowe, G D O and Ford, I and Robertson, M and Brunner, E and Shipley, M and Feskens, E J M and Di Angelantonio, E and Kaptoge, S and Lewington, S and Lowe, G D O and Sarwar, N and Thompson, S G and Walker, M and Watson, S and White, I R and Wood, A M and Danesh, J} } @article {6804, title = {Genome-wide meta-analyses of smoking behaviors in African Americans.}, journal = {Transl Psychiatry}, volume = {2}, year = {2012}, month = {2012}, pages = {e119}, abstract = {

The identification and exploration of genetic loci that influence smoking behaviors have been conducted primarily in populations of the European ancestry. Here we report results of the first genome-wide association study meta-analysis of smoking behavior in African Americans in the Study of Tobacco in Minority Populations Genetics Consortium (n = 32,389). We identified one non-coding single-nucleotide polymorphism (SNP; rs2036527[A]) on chromosome 15q25.1 associated with smoking quantity (cigarettes per day), which exceeded genome-wide significance (β = 0.040, s.e. = 0.007, P = 1.84 {\texttimes} 10(-8)). This variant is present in the 5{\textquoteright}-distal enhancer region of the CHRNA5 gene and defines the primary index signal reported in studies of the European ancestry. No other SNP reached genome-wide significance for smoking initiation (SI, ever vs never smoking), age of SI, or smoking cessation (SC, former vs current smoking). Informative associations that approached genome-wide significance included three modestly correlated variants, at 15q25.1 within PSMA4, CHRNA5 and CHRNA3 for smoking quantity, which are associated with a second signal previously reported in studies in European ancestry populations, and a signal represented by three SNPs in the SPOCK2 gene on chr10q22.1. The association at 15q25.1 confirms this region as an important susceptibility locus for smoking quantity in men and women of African ancestry. Larger studies will be needed to validate the suggestive loci that did not reach genome-wide significance and further elucidate the contribution of genetic variation to disparities in cigarette consumption, SC and smoking-attributable disease between African Americans and European Americans.

}, keywords = {Adult, African Americans, Aged, Chromosomes, Human, Pair 10, Chromosomes, Human, Pair 15, Female, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Nerve Tissue Proteins, Phenotype, Polymorphism, Single Nucleotide, Proteoglycans, Receptors, Nicotinic, Smoking, Statistics as Topic}, issn = {2158-3188}, doi = {10.1038/tp.2012.41}, author = {David, S P and Hamidovic, A and Chen, G K and Bergen, A W and Wessel, J and Kasberger, J L and Brown, W M and Petruzella, S and Thacker, E L and Kim, Y and Nalls, M A and Tranah, G J and Sung, Y J and Ambrosone, C B and Arnett, D and Bandera, E V and Becker, D M and Becker, L and Berndt, S I and Bernstein, L and Blot, W J and Broeckel, U and Buxbaum, S G and Caporaso, N and Casey, G and Chanock, S J and Deming, S L and Diver, W R and Eaton, C B and Evans, D S and Evans, M K and Fornage, M and Franceschini, N and Harris, T B and Henderson, B E and Hernandez, D G and Hitsman, B and Hu, J J and Hunt, S C and Ingles, S A and John, E M and Kittles, R and Kolb, S and Kolonel, L N and Le Marchand, L and Liu, Y and Lohman, K K and McKnight, B and Millikan, R C and Murphy, A and Neslund-Dudas, C and Nyante, S and Press, M and Psaty, B M and Rao, D C and Redline, S and Rodriguez-Gil, J L and Rybicki, B A and Signorello, L B and Singleton, A B and Smoller, J and Snively, B and Spring, B and Stanford, J L and Strom, S S and Swan, G E and Taylor, K D and Thun, M J and Wilson, A F and Witte, J S and Yamamura, Y and Yanek, L R and Yu, K and Zheng, W and Ziegler, R G and Zonderman, A B and Jorgenson, E and Haiman, C A and Furberg, H} } @article {1549, title = {A screening study of drug-drug interactions in cerivastatin users: an adverse effect of clopidogrel.}, journal = {Clin Pharmacol Ther}, volume = {91}, year = {2012}, month = {2012 May}, pages = {896-904}, abstract = {

An analysis of a case-control study of rhabdomyolysis was conducted to screen for previously unrecognized cytochrome P450 enzyme (CYP) 2C8 inhibitors that may cause other clinically important drug-drug interactions. Medication use in cases of rhabdomyolysis using cerivastatin (n = 72) was compared with that in controls using atorvastatin (n = 287) for the period 1998-2001. The use of clopidogrel was strongly associated with rhabdomyolysis (odds ratio (OR) 29.6; 95\% confidence interval (CI), 6.1-143). In a replication effort that used the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), it was found that clopidogrel was used more commonly in patients with rhabdomyolysis receiving cerivastatin (17\%) than in those receiving atorvastatin (0\%, OR infinity; 95\% CI = 5.2-infinity). Several medications were tested in vitro for their potential to cause drug-drug interactions. Clopidogrel, rosiglitazone, and montelukast were the most potent inhibitors of cerivastatin metabolism. Clopidogrel and its metabolites also inhibited cerivastatin metabolism in human hepatocytes. These epidemiological and in vitro findings suggest that clopidogrel may cause clinically important, dose-dependent drug-drug interactions with other medications metabolized by CYP2C8.

}, keywords = {Adverse Drug Reaction Reporting Systems, Aged, Aged, 80 and over, Aryl Hydrocarbon Hydroxylases, Case-Control Studies, Cytochrome P-450 CYP2C8, Cytochrome P-450 CYP3A, Cytochrome P-450 CYP3A Inhibitors, Drug Interactions, Female, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Male, Platelet Aggregation Inhibitors, Pyridines, Rhabdomyolysis, Ticlopidine}, issn = {1532-6535}, doi = {10.1038/clpt.2011.295}, author = {Floyd, J S and Kaspera, R and Marciante, K D and Weiss, N S and Heckbert, S R and Lumley, T and Wiggins, K L and Tamraz, B and Kwok, P-Y and Totah, R A and Psaty, B M} } @article {6063, title = {Common genetic variation near the connexin-43 gene is associated with resting heart rate in African Americans: a genome-wide association study of 13,372 participants.}, journal = {Heart Rhythm}, volume = {10}, year = {2013}, month = {2013 Mar}, pages = {401-8}, abstract = {

BACKGROUND: Genome-wide association studies have identified several genetic loci associated with variation in resting heart rate in European and Asian populations. No study has evaluated genetic variants associated with heart rate in African Americans.

OBJECTIVE: To identify novel genetic variants associated with resting heart rate in African Americans.

METHODS: Ten cohort studies participating in the Candidate-gene Association Resource and Continental Origins and Genetic Epidemiology Network consortia performed genome-wide genotyping of single nucleotide polymorphisms (SNPs) and imputed 2,954,965 SNPs using HapMap YRI and CEU panels in 13,372 participants of African ancestry. Each study measured the RR interval (ms) from 10-second resting 12-lead electrocardiograms and estimated RR-SNP associations using covariate-adjusted linear regression. Random-effects meta-analysis was used to combine cohort-specific measures of association and identify genome-wide significant loci (P<=2.5{\texttimes}10(-8)).

RESULTS: Fourteen SNPs on chromosome 6q22 exceeded the genome-wide significance threshold. The most significant association was for rs9320841 (+13 ms per minor allele; P = 4.98{\texttimes}10(-15)). This SNP was approximately 350 kb downstream of GJA1, a locus previously identified as harboring SNPs associated with heart rate in Europeans. Adjustment for rs9320841 also attenuated the association between the remaining 13 SNPs in this region and heart rate. In addition, SNPs in MYH6, which have been identified in European genome-wide association study, were associated with similar changes in the resting heart rate as this population of African Americans.

CONCLUSIONS: An intergenic region downstream of GJA1 (the gene encoding connexin 43, the major protein of the human myocardial gap junction) and an intragenic region within MYH6 are associated with variation in resting heart rate in African Americans as well as in populations of European and Asian origin.

}, keywords = {Adult, African Americans, Aged, Arrhythmias, Cardiac, Connexin 43, Electrocardiography, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Heart Rate, Humans, Male, Meta-Analysis as Topic, Middle Aged, Polymorphism, Single Nucleotide, Rest, United States}, issn = {1556-3871}, doi = {10.1016/j.hrthm.2012.11.014}, author = {Deo, R and Nalls, M A and Avery, C L and Smith, J G and Evans, D S and Keller, M F and Butler, A M and Buxbaum, S G and Li, G and Miguel Quibrera, P and Smith, E N and Tanaka, T and Akylbekova, E L and Alonso, A and Arking, D E and Benjamin, E J and Berenson, G S and Bis, J C and Chen, L Y and Chen, W and Cummings, S R and Ellinor, P T and Evans, M K and Ferrucci, L and Fox, E R and Heckbert, S R and Heiss, G and Hsueh, W C and Kerr, K F and Limacher, M C and Liu, Y and Lubitz, S A and Magnani, J W and Mehra, R and Marcus, G M and Murray, S S and Newman, A B and Njajou, O and North, K E and Paltoo, D N and Psaty, B M and Redline, S S and Reiner, A P and Robinson, J G and Rotter, J I and Samdarshi, T E and Schnabel, R B and Schork, N J and Singleton, A B and Siscovick, D and Soliman, E Z and Sotoodehnia, N and Srinivasan, S R and Taylor, H A and Trevisan, M and Zhang, Z and Zonderman, A B and Newton-Cheh, C and Whitsel, E A} } @article {6156, title = {Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer{\textquoteright}s disease.}, journal = {Nat Genet}, volume = {45}, year = {2013}, month = {2013 Dec}, pages = {1452-8}, abstract = {

Eleven susceptibility loci for late-onset Alzheimer{\textquoteright}s disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer{\textquoteright}s disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer{\textquoteright}s disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 {\texttimes} 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer{\textquoteright}s disease.

}, keywords = {Age of Onset, Aged, Aged, 80 and over, Alzheimer Disease, Case-Control Studies, Cohort Studies, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {1546-1718}, doi = {10.1038/ng.2802}, author = {Lambert, J C and Ibrahim-Verbaas, C A and Harold, D and Naj, A C and Sims, R and Bellenguez, C and DeStafano, A L and Bis, J C and Beecham, G W and Grenier-Boley, B and Russo, G and Thorton-Wells, T A and Jones, N and Smith, A V and Chouraki, V and Thomas, C and Ikram, M A and Zelenika, D and Vardarajan, B N and Kamatani, Y and Lin, C F and Gerrish, A and Schmidt, H and Kunkle, B and Dunstan, M L and Ruiz, A and Bihoreau, M T and Choi, S H and Reitz, C and Pasquier, F and Cruchaga, C and Craig, D and Amin, N and Berr, C and Lopez, O L and De Jager, P L and Deramecourt, V and Johnston, J A and Evans, D and Lovestone, S and Letenneur, L and Mor{\'o}n, F J and Rubinsztein, D C and Eiriksdottir, G and Sleegers, K and Goate, A M and Fi{\'e}vet, N and Huentelman, M W and Gill, M and Brown, K and Kamboh, M I and Keller, L and Barberger-Gateau, P and McGuiness, B and Larson, E B and Green, R and Myers, A J and Dufouil, C and Todd, S and Wallon, D and Love, S and Rogaeva, E and Gallacher, J and St George-Hyslop, P and Clarimon, J and Lleo, A and Bayer, A and Tsuang, D W and Yu, L and Tsolaki, M and Boss{\`u}, P and Spalletta, G and Proitsi, P and Collinge, J and Sorbi, S and Sanchez-Garcia, F and Fox, N C and Hardy, J and Deniz Naranjo, M C and Bosco, P and Clarke, R and Brayne, C and Galimberti, D and Mancuso, M and Matthews, F and Moebus, S and Mecocci, P and Del Zompo, M and Maier, W and Hampel, H and Pilotto, A and Bullido, M and Panza, F and Caffarra, P and Nacmias, B and Gilbert, J R and Mayhaus, M and Lannefelt, L and Hakonarson, H and Pichler, S and Carrasquillo, M M and Ingelsson, M and Beekly, D and Alvarez, V and Zou, F and Valladares, O and Younkin, S G and Coto, E and Hamilton-Nelson, K L and Gu, W and Razquin, C and Pastor, P and Mateo, I and Owen, M J and Faber, K M and Jonsson, P V and Combarros, O and O{\textquoteright}Donovan, M C and Cantwell, L B and Soininen, H and Blacker, D and Mead, S and Mosley, T H and Bennett, D A and Harris, T B and Fratiglioni, L and Holmes, C and de Bruijn, R F and Passmore, P and Montine, T J and Bettens, K and Rotter, J I and Brice, A and Morgan, K and Foroud, T M and Kukull, W A and Hannequin, D and Powell, J F and Nalls, M A and Ritchie, K and Lunetta, K L and Kauwe, J S and Boerwinkle, E and Riemenschneider, M and Boada, M and Hiltuenen, M and Martin, E R and Schmidt, R and Rujescu, D and Wang, L S and Dartigues, J F and Mayeux, R and Tzourio, C and Hofman, A and N{\"o}then, M M and Graff, C and Psaty, B M and Jones, L and Haines, J L and Holmans, P A and Lathrop, M and Pericak-Vance, M A and Launer, L J and Farrer, L A and van Duijn, C M and Van Broeckhoven, C and Moskvina, V and Seshadri, S and Williams, J and Schellenberg, G D and Amouyel, P} } @article {6133, title = {Novel gene variants predict serum levels of the cytokines IL-18 and IL-1ra in older adults.}, journal = {Cytokine}, volume = {65}, year = {2014}, month = {2014 Jan}, pages = {10-6}, abstract = {

Activation of inflammatory pathways measured by serum inflammatory markers such as interleukin-18 (IL-18) and interleukin-1 receptor antagonist (IL-1ra) is strongly associated with the progression of chronic disease states in older adults. Given that these serum cytokine levels are in part a heritable trait, genetic variation may predict increased serum levels. Using the Cardiovascular Health Study and InCHIANTI cohorts, a genome-wide association study was performed to identify genetic variants that influence IL-18 and IL-1ra serum levels among older adults. Multiple linear regression models characterized the association between each SNP and log-transformed cytokine values. Tests for multiple independent signals within statistically significant loci were performed using haplotype analysis and regression models conditional on lead SNP in each region. Multiple SNPs were associated with these cytokines with genome-wide significance, including SNPs in the IL-18-BCO gene region of chromosome 2 for IL-18 (top SNP rs2250417, P=1.9{\texttimes}10(-32)) and in the IL-1 gene family region of chromosome 2 for IL-1ra (rs6743376, P=2.3{\texttimes}10(-26)). Haplotype tests and conditional linear regression models showed evidence of multiple independent signals in these regions. Serum IL-18 levels were also associated with a region on chromosome 2 containing the NLRC4 gene (rs12989936, P=2.7{\texttimes}10(-19)). These data characterize multiple robust genetic signals that influence IL-18 and IL-1ra cytokine production. In particular, the signal for serum IL-18 located on chromosome two is novel and potentially important in inflammasome triggered chronic activation of inflammation in older adults. Replication in independent cohorts is an important next step, as well as molecular studies to better understand the role of NLRC4.

}, keywords = {Aged, Aged, 80 and over, Calcium-Binding Proteins, CARD Signaling Adaptor Proteins, Chromosomes, Human, Pair 2, Female, Genetic Variation, Genome-Wide Association Study, Genotype, Haplotypes, Humans, Inflammation, Interleukin 1 Receptor Antagonist Protein, Interleukin-18, Male, Polymorphism, Single Nucleotide}, issn = {1096-0023}, doi = {10.1016/j.cyto.2013.10.002}, author = {Matteini, A M and Li, J and Lange, E M and Tanaka, T and Lange, L A and Tracy, R P and Wang, Y and Biggs, M L and Arking, D E and Fallin, M D and Chakravarti, A and Psaty, B M and Bandinelli, S and Ferrucci, L and Reiner, A P and Walston, J D} } @article {6851, title = {Association of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study.}, journal = {Respir Res}, volume = {16}, year = {2015}, month = {2015}, pages = {81}, abstract = {

BACKGROUND: Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults.

METHODS: We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts.

RESULTS: We found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P=0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P=0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene-based P<0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P=0.09).

CONCLUSIONS: Serum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies.

}, keywords = {Adult, Aged, Cohort Studies, Cross-Sectional Studies, DNA-Binding Proteins, Female, Genetic Variation, Humans, Longitudinal Studies, Male, Massachusetts, Metabolic Networks and Pathways, Middle Aged, Nuclear Proteins, Polymorphism, Single Nucleotide, Vitamin D}, issn = {1465-993X}, doi = {10.1186/s12931-015-0238-y}, author = {Hansen, J G and Gao, W and Dupuis, J and O{\textquoteright}Connor, G T and Tang, W and Kowgier, M and Sood, A and Gharib, S A and Palmer, L J and Fornage, M and Heckbert, S R and Psaty, B M and Booth, S L and Cassano, Patricia A} } @article {6816, title = {Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).}, journal = {Mol Psychiatry}, volume = {20}, year = {2015}, month = {2015 Feb}, pages = {183-92}, abstract = {

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 {\texttimes} 10(-9), MIR2113; rs17522122, P=2.55 {\texttimes} 10(-8), AKAP6; rs10119, P=5.67 {\texttimes} 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 {\texttimes} 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29\% (s.e.=5\%) and 28\% (s.e.=7\%), respectively. Using polygenic prediction analysis, ~1.2\% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 {\texttimes} 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer{\textquoteright}s disease: TOMM40, APOE, ABCG1 and MEF2C.

}, keywords = {Aged, Aged, 80 and over, Atherosclerosis, Cognition, Cognition Disorders, Cohort Studies, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, HMGN1 Protein, Humans, Male, Middle Aged, Neuropsychological Tests, Phenotype, Polymorphism, Single Nucleotide, Scotland}, issn = {1476-5578}, doi = {10.1038/mp.2014.188}, author = {Davies, G and Armstrong, N and Bis, J C and Bressler, J and Chouraki, V and Giddaluru, S and Hofer, E and Ibrahim-Verbaas, C A and Kirin, M and Lahti, J and van der Lee, S J and Le Hellard, S and Liu, T and Marioni, R E and Oldmeadow, C and Postmus, I and Smith, A V and Smith, J A and Thalamuthu, A and Thomson, R and Vitart, V and Wang, J and Yu, L and Zgaga, L and Zhao, W and Boxall, R and Harris, S E and Hill, W D and Liewald, D C and Luciano, M and Adams, H and Ames, D and Amin, N and Amouyel, P and Assareh, A A and Au, R and Becker, J T and Beiser, A and Berr, C and Bertram, L and Boerwinkle, E and Buckley, B M and Campbell, H and Corley, J and De Jager, P L and Dufouil, C and Eriksson, J G and Espeseth, T and Faul, J D and Ford, I and Gottesman, R F and Griswold, M E and Gudnason, V and Harris, T B and Heiss, G and Hofman, A and Holliday, E G and Huffman, J and Kardia, S L R and Kochan, N and Knopman, D S and Kwok, J B and Lambert, J-C and Lee, T and Li, G and Li, S-C and Loitfelder, M and Lopez, O L and Lundervold, A J and Lundqvist, A and Mather, K A and Mirza, S S and Nyberg, L and Oostra, B A and Palotie, A and Papenberg, G and Pattie, A and Petrovic, K and Polasek, O and Psaty, B M and Redmond, P and Reppermund, S and Rotter, J I and Schmidt, H and Schuur, M and Schofield, P W and Scott, R J and Steen, V M and Stott, D J and van Swieten, J C and Taylor, K D and Trollor, J and Trompet, S and Uitterlinden, A G and Weinstein, G and Widen, E and Windham, B G and Jukema, J W and Wright, A F and Wright, M J and Yang, Q and Amieva, H and Attia, J R and Bennett, D A and Brodaty, H and de Craen, A J M and Hayward, C and Ikram, M A and Lindenberger, U and Nilsson, L-G and Porteous, D J and R{\"a}ikk{\"o}nen, K and Reinvang, I and Rudan, I and Sachdev, P S and Schmidt, R and Schofield, P R and Srikanth, V and Starr, J M and Turner, S T and Weir, D R and Wilson, J F and van Duijn, C and Launer, L and Fitzpatrick, A L and Seshadri, S and Mosley, T H and Deary, I J} } @article {6566, title = {Novel loci associated with usual sleep duration: the CHARGE Consortium Genome-Wide Association Study.}, journal = {Mol Psychiatry}, volume = {20}, year = {2015}, month = {2015 Oct}, pages = {1232-9}, abstract = {

Usual sleep duration is a heritable trait correlated with psychiatric morbidity, cardiometabolic disease and mortality, although little is known about the genetic variants influencing this trait. A genome-wide association study (GWAS) of usual sleep duration was conducted using 18 population-based cohorts totaling 47 180 individuals of European ancestry. Genome-wide significant association was identified at two loci. The strongest is located on chromosome 2, in an intergenic region 35- to 80-kb upstream from the thyroid-specific transcription factor PAX8 (lowest P=1.1 {\texttimes} 10(-9)). This finding was replicated in an African-American sample of 4771 individuals (lowest P=9.3 {\texttimes} 10(-4)). The strongest combined association was at rs1823125 (P=1.5 {\texttimes} 10(-10), minor allele frequency 0.26 in the discovery sample, 0.12 in the replication sample), with each copy of the minor allele associated with a sleep duration 3.1 min longer per night. The alleles associated with longer sleep duration were associated in previous GWAS with a more favorable metabolic profile and a lower risk of attention deficit hyperactivity disorder. Understanding the mechanisms underlying these associations may help elucidate biological mechanisms influencing sleep duration and its association with psychiatric, metabolic and cardiovascular disease.

}, keywords = {Adult, African Americans, Aged, Dyssomnias, European Continental Ancestry Group, Female, Genetic Association Studies, Genome-Wide Association Study, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Self Report, Sleep}, issn = {1476-5578}, doi = {10.1038/mp.2014.133}, author = {Gottlieb, D J and Hek, K and Chen, T-H and Watson, N F and Eiriksdottir, G and Byrne, E M and Cornelis, M and Warby, S C and Bandinelli, S and Cherkas, L and Evans, D S and Grabe, H J and Lahti, J and Li, M and Lehtim{\"a}ki, T and Lumley, T and Marciante, K D and P{\'e}russe, L and Psaty, B M and Robbins, J and Tranah, G J and Vink, J M and Wilk, J B and Stafford, J M and Bellis, C and Biffar, R and Bouchard, C and Cade, B and Curhan, G C and Eriksson, J G and Ewert, R and Ferrucci, L and F{\"u}l{\"o}p, T and Gehrman, P R and Goodloe, R and Harris, T B and Heath, A C and Hernandez, D and Hofman, A and Hottenga, J-J and Hunter, D J and Jensen, M K and Johnson, A D and K{\"a}h{\"o}nen, M and Kao, L and Kraft, P and Larkin, E K and Lauderdale, D S and Luik, A I and Medici, M and Montgomery, G W and Palotie, A and Patel, S R and Pistis, G and Porcu, E and Quaye, L and Raitakari, O and Redline, S and Rimm, E B and Rotter, J I and Smith, A V and Spector, T D and Teumer, A and Uitterlinden, A G and Vohl, M-C and Widen, E and Willemsen, G and Young, T and Zhang, X and Liu, Y and Blangero, J and Boomsma, D I and Gudnason, V and Hu, F and Mangino, M and Martin, N G and O{\textquoteright}Connor, G T and Stone, K L and Tanaka, T and Viikari, J and Gharib, S A and Punjabi, N M and R{\"a}ikk{\"o}nen, K and V{\"o}lzke, H and Mignot, E and Tiemeier, H} }