Respondent Burden in Studies of the Elderly: Experience from the Cardiovascular Health Study (CHS) - Manolio, TA; Hermanson, B; Hill, J; Meyer, M; Cruise, G; Anton-Culver, H (ACC, 1992)
ACC Workshop entitled "Inclusion of Elderly Individuals in Clinical Trials" September 15-16, 1992
Keywords: Health; respondent burden

Serum fructosamine as a screening test for diabetes in the elderly: a pilot study. - Cefalu, W T; Ettinger, W H; Bell-Farrow, A D; Rushing, J T (J Am Geriatr Soc, 1993)
OBJECTIVE: To determine the value of serum glycated protein, measured as serum fructosamine, as a screening test for diabetes in the elderly. DESIGN: Cross-sectional pilot study. SETTING: Ambulatory research clinic in university setting. PATIENTS: One hundred fifty-seven consecutive community-dwelling participants in the Cardiovascular Health Study, average age 71.8 + 5 (mean +/- SD, range 65-88 years). MEASUREMENTS: Serum fructosamine levels (first and second generation assay) were obtained. All subjects who did not have a diagnosis of diabetes were given a 75-g glucose tolerance test (GTT). RESULTS: Twenty-six subjects (17%) (10 previously diagnosed, 16 undiagnosed and asymptomatic) had diabetes mellitus, and 38 subjects (24%) had impaired glucose tolerance by history or by the GTT (WHO criteria). Only the 16 asymptomatic diabetics were included in the analysis for the pilot study. There was a significant difference in the fasting fructosamine level between non-diabetics and asymptomatic diabetics for the first generation (2.06 +/- .21 vs 2.53 +/- .49 mMol/L, P < 0.0015) and second generation assay (221 +/- 27 vs 269 +/- 48 mMol/L, P < 0.0012). Receiver operator curves were constructed to evaluate the test characteristics of serum fructosamine. Using a point of > or = 2.3 mMol/L for the first-generation assay, the sensitivity to detect asymptomatic diabetes was 75%, specificity 83%, and positive predictive value 35%. To detect both diabetes and impaired glucose tolerance using a cutpoint of > or = 2.3 mMol/L, the sensitivity was 24%, specificity 95%, and positive predictive value 68%. Employing a cut point of 250 muMol/L for the second generation assay, the sensitivity to detect diabetes was 81%, specificity 87%, and positive predictive value 43%. However, to detect diabetes and glucose intolerance using the second generation assay, the sensitivity was 39% and specificity was 86%. CONCLUSION: This study demonstrated that a single measurement of either first or second generation fructosamine showed promise as a screening test for diabetes, but not impaired glucose tolerance, in older people.
Keywords: Aged; Diabetes Mellitus; Female; Fructosamine; Glucose Tolerance Test; Hexosamines; Humans; Insulin; Male; Pilot Projects; Predictive Value of Tests; Sensitivity and Specificity

Laboratory methods and quality assurance in the Cardiovascular Health Study. - Cushman, M; Cornell, E S; Howard, P R; Bovill, E G; Tracy, R P (Clin Chem, 1995)
The Cardiovascular Health Study is an observational cohort study of risk factors for cardiovascular disease in 5201 participants, ages > or = 65 years. We report the methods and quality-assurance results for blood procurement, processing, shipping, storage, and sample analysis used during the first examination period (May 1989-June 1990). The most frequent difficulty in phlebotomy and processing was the requirement of more than one venipuncture (in 2.6% of the participants). The CVs for control materials ranged from 0.93% for glucose to 10.7% for insulin; most were < 4%. In addition to standard quality-assurance methods, we applied two other methods: technical error calculation for replicates, and weighted linear regression to assess time trend in results of control materials. After outliers were excluded, technical error values ranged from 1.7 for uric acid to 18.8 for insulin. Factor VII and factor VIII had slight trends over the 12-month analysis period. Results of quality-assurance analyses used to resolve problems were successful, thereby improving the second laboratory examination.
Keywords: Aged; Blood Glucose; Blood Specimen Collection; Cardiovascular Diseases; Chemistry, Clinical; Factor VII; Factor VIII; Fibrinogen; Humans; Insulin; Quality Control; Regression Analysis; Triglycerides

Surveillance and ascertainment of cardiovascular events. The Cardiovascular Health Study. - Ives, D G; Fitzpatrick, A L; Bild, D E; Psaty, B M; Kuller, L H; Crowley, P M; Cruise, R G; Theroux, S (Ann Epidemiol, 1995)
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

Association of fibrinogen and coagulation factors VII and VIII with cardiovascular risk factors in the elderly: the Cardiovascular Health Study. Cardiovascular Health Study Investigators. - Cushman, M; Yanez, D; Psaty, B M; Fried, L P; Heiss, G; Lee, M; Polak, J F; Savage, P J; Tracy, R P (Am J Epidemiol, 1996)
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

Correlates of thrombin markers in an elderly cohort free of clinical cardiovascular disease. - Cushman, M; Psaty, B M; Macy, E; Bovill, E G; Cornell, E S; Kuller, L H; Tracy, R P (Arterioscler Thromb Vasc Biol, 1996)
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

Picture-sort method for administering a food frequency questionnaire to older adults. - Kumanyika, S; Tell, G S; Fried, L; Martel, J K; Chinchilli, V M (J Am Diet Assoc, 1996)
OBJECTIVE: To assess the validity of a picture-sort approach to administering the National Cancer Institute food frequency questionnaire to older adults. DESIGN: A picture-sort interview was conducted in each respondent's home. After the picture sort, a 24-hour recall interview was administered on the same occasion. Five additional in-home recall interviews were subsequently conducted at approximately 1-month intervals. SUBJECTS/SETTING: Forty-seven female and 49 male volunteers aged 66 to 100 years were recruited from among Cardiovascular Health Study participants from Maryland and North Carolina. MAIN OUTCOME MEASURES: Estimates from the picture sort and the recall for intakes of macronutrients, cholesterol, fiber, and selected vitamins and minerals exclusive of supplements. STATISTICAL ANALYSES: Comparison of means estimated by the two methods and correlation analyses were used. Correlations were adjusted under varied assumptions about the nature of the information contained in the six 24-hour recalls relative to respondents' usual intakes. RESULTS: After correction for attenuation, Pearson correlation coefficients for macronutrients ranged from .41 for protein to .74 for saturated fat and cholesterol. For vitamins and minerals, correlations ranged from .26 for beta carotene to .62 for calcium. APPLICATIONS: Picture-sort estimates of mean nutrient intakes were comparable with estimates based on 24-hour recalls, and correlations with reference data were similar to those reported in the literature for conventionally administered food frequency questionnaires. This dietary assessment method may, therefore, offer a way to simplify or structure responses to improve ease of administration and increase respondents' liking for the interview without loss of data quality.
Keywords: Aged; Aged, 80 and over; Audiovisual Aids; Data Interpretation, Statistical; Diet Records; Eating; Female; Humans; Interviews as Topic; Male; Mental Recall; Surveys and Questionnaires

Dietary assessment using a picture-sort approach. - Kumanyika, S K; Tell, G S; Shemanski, L; Martel, J; Chinchilli, V M (Am J Clin Nutr, 1997)
Food-frequency questionnaires are usually administered as a list of foods to be checked off by the respondent or interviewer. Techniques in which participants sort into categories cards on which names or pictures of foods are printed can also be used to assess food intake. Food-frequency scores were obtained from a five-category picture sort administered to 4643 men and women aged > or = 65 y in the Cardiovascular Health Study (CHS). This one-step (qualitative) assessment yielded significant associations in expected directions between frequency scores and sex, age, race or ethnicity, body mass index, and use of a special diet. In the two-step (semiquantitative) version of this instrument, an interviewer documented specific frequencies and portion-size information for the foods in each sorting category. A substudy of the two-step version with 96 CHS participants indicated relative validity similar to that of conventionally administered food-frequency questionnaires. The one-step version may be broadly applicable to situations in which general food-pattern data can be informative and cost and time limitations are great. When it is feasible, the two-step picture sort may offer certain methodologic advantages because respondents have a chance to change their responses and the format may simplify the cognitive-response task. Sorting or picture-sort procedures deserve systematic attention in research on dietary assessment methods.
Keywords: Aged; Audiovisual Aids; Diet; Female; Food; Humans; Male; Nutrition Assessment; Surveys and Questionnaires

Incidence of and risk factors for atrial fibrillation in older adults. - Psaty, B M; Manolio, T A; Kuller, L H; Kronmal, R A; Cushman, M; Fried, L P; White, R; Furberg, C D; Rautaharju, P M (Circulation, 1997)
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

Knowledge of risk among patients at increased risk for stroke. - Samsa, G P; Cohen, S J; Goldstein, L B; Bonito, A J; Duncan, P W; Enarson, C; DeFriese, G H; Horner, R D; Matchar, D B (Stroke, 1997)
BACKGROUND AND PURPOSE: Patients who recognize their increased risk for stroke are more likely to engage in (and comply with) stroke prevention practices than those who do not. We describe perceived risk of stroke among a nationally diverse sample of patients at increased risk for stroke and determine whether patients' knowledge of their stroke risk varied according to patients' demographic and clinical characteristics. METHODS: Respondents were recruited from the Academic Medical Center Consortium (n = 621, five academic medical centers, inpatients of varying age); the Cardiovascular Health Study (n = 321, population-based sample of persons aged 65+ years); and United HealthCare (n = 319, five health plans, inpatients and outpatients typically younger than 65 years). The primary outcome was awareness of being at risk for stroke. RESULTS: Only 41% of respondents were aware of their increased risk for stroke (including less than one half of patients with previous minor stroke). Approximately 74% of patients who recalled being told of their increased stroke risk by a physician acknowledged this risk in comparison with 28% of patients who did not recall being informed by a physician. Younger patients, depressed patients, those in poor current health, and those with a history of TIA were most likely to be aware of their stroke risk. CONCLUSIONS: Over one half of patients at increased risk of stroke are unaware of their risk. Healthcare providers play a crucial role in communicating information about risk, and successful communication encourages adoption of stroke prevention practices. Educational messages should be targeted toward patients least likely to be aware of their risk.
Keywords: Adult; Aged; Aged, 80 and over; Awareness; Cerebrovascular Disorders; Female; Humans; Knowledge; Male; Middle Aged; Multivariate Analysis; Risk Factors

Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects. - Tracy, R P; Psaty, B M; Macy, E; Bovill, E G; Cushman, M; Cornell, E S; Kuller, L H (Arterioscler Thromb Vasc Biol, 1997)
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

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. - Tracy, R P; Lemaitre, R N; Psaty, B M; Ives, D G; Evans, R W; Cushman, M; Meilahn, E N; Kuller, L H (Arterioscler Thromb Vasc Biol, 1997)
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

Correlates of antithrombin, protein C, protein S, and TFPI in a healthy elderly cohort. - Sakkinen, P A; Cushman, M; Psaty, B M; Kuller, L H; Bajaj, S P; Sabharwal, A K; Boineau, R; Macy, E; Tracy, R P (Thromb Haemost, 1998)
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

Differences in prevalence of and risk factors for subclinical vascular disease among black and white participants in the Cardiovascular Health Study. - Kuller, L; Fisher, L; McClelland, R; Fried, L; Cushman, M; Jackson, S; Manolio, T (Arterioscler Thromb Vasc Biol, 1998)
A composite measure of subclinical vascular disease has been developed in the Cardiovascular Health Study (CHS). In previous reports, we measured the prevalence of subclinical disease among the original 5201 participants in the CHS, the relationship of risk factors to subclinical disease, and the association of subclinical disease to clinical coronary heart disease. In 1992 to 1993 (year 4 of the study), a larger cohort of 424 black women and 248 black men was added to the study. In this study, we have compared the prevalence of subclinical disease among blacks and whites in the CHS and the association with cardiovascular risk factors. The prevalence of subclinical disease for all participants (aged > or =65 years) was 41.3% for white women, 39.7% for black women, 41.9% for white men, and 43.7% for black men. The prevalence increased with age. The risk factor associations for subclinical disease were similar among blacks and whites. In multivariate analysis, age, systolic blood pressure, LDL cholesterol, smoking, and family history of myocardial infarction were independently associated with subclinical disease among both black and white women, while for white men, systolic blood pressure, use of antihypertensive medication, smoking, body mass index, and diastolic blood pressure (inverse) were related to subclinical disease. In black men, blood triglyceride level, use of antihypertensive medications, and family history of myocardial infarction (inverse) were associated with subclinical disease.
Keywords: African Americans; Aged; Cardiovascular Physiological Phenomena; Cohort Studies; European Continental Ancestry Group; Female; Health Status; Humans; Male; Multivariate Analysis; Prevalence; Regression Analysis; Risk Factors; Vascular Diseases

Factor V Leiden is not a risk factor for arterial vascular disease in the elderly: results from the Cardiovascular Health Study. - Cushman, M; Rosendaal, F R; Psaty, B M; Cook, E F; Valliere, J; Kuller, L H; Tracy, R P (Thromb Haemost, 1998)
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

High body fatness, but not low fat-free mass, predicts disability in older men and women: the Cardiovascular Health Study. - Visser, M; Langlois, J; Guralnik, J M; Cauley, J A; Kronmal, R A; Robbins, J; Williamson, J D; Harris, T B (Am J Clin Nutr, 1998)
Using data from the Cardiovascular Health Study, we studied the relation between body composition (fat mass and fat-free mass, assessed by bioelectrical impedance) and self-reported, mobility-related disability (difficulty walking or stair climbing) in 2714 women and 2095 men aged 65-100 y. In a cross-sectional analysis at baseline (1989-1990), disability was reported by 26.5% of the women and 16.9% of the men. A positive association was observed between fat mass and disability. The odds ratio for disability in the highest quintile of fat mass was 3.04 (95% CI: 2.18, 4.25) for women and 2.77 (95% CI: 1.82, 4.23) for men compared with those in the lowest quintile. Low fat-free mass was not associated with a higher prevalence of disability. In a longitudinal analysis among persons not reporting disability at baseline, 20.3% of the women and 14.8% of the men reported disability 3 y later. Fat mass at baseline was predictive of disability 3 y later, with odds ratios of 2.83 (95% CI: 1.80, 4.46) for women and 1.72 (95% CI: 1.03, 2.85) for men in the highest quintile of fat. The increased risk was not explained by age, physical activity, chronic disease, or other potential confounders. Low fat-free mass was not predictive of disability. The results showed that high body fatness is an independent predictor of mobility-related disability in older men and women. These findings suggest that high body fatness in old age should be avoided to decrease the risk of disability.
Keywords: Adipose Tissue; Aged; Aged, 80 and over; Body Composition; Cross-Sectional Studies; Disability Evaluation; Female; Geriatric Assessment; Health Surveys; Humans; Male; Obesity; Predictive Value of Tests; Walking

Sex differences in brain aging: a quantitative magnetic resonance imaging study. - Coffey, C E; Lucke, J F; Saxton, J A; Ratcliff, G; Unitas, L J; Billig, B; Bryan, R N (Arch Neurol, 1998)
BACKGROUND: Little is known about the effect of sex on age-related changes in brain structure. METHODS: Quantitative magnetic resonance imaging of the brain was performed in 330 elderly (age range, 66-96 years) volunteers living independently in the community, all of whom were participants in the Cardiovascular Health Study. Blinded measurements of global and regional brain size were made from T1-weighted axial images by means of computer-assisted edge detection and trace methods. High measurement reliabilities were obtained. RESULTS: Age-specific changes in brain size were significantly greater in men than women for the peripheral (sulcal) cerebrospinal fluid volume, the lateral (sylvian) fissure cerebrospinal fluid volume, and the parieto-occipital region area. Main effects of age were observed for all the remaining brain regions examined (cerebral hemisphere volume, frontal region area, temporoparietal region area, lateral ventricular volume, and third ventricle volume), but these effects were similar in men and women. Asymmetries in brain structures were not affected by aging in either sex. CONCLUSIONS: Our results are generally consistent with the few published studies on sex differences in brain aging and suggest that, for at least some structures, aging effects may be more apparent in men than women. The neurobiological bases and functional correlates of these sex differences require further investigation.
Keywords: Age Distribution; Aged; Aged, 80 and over; Aging; Atrophy; Brain; Cerebrospinal Fluid; Diagnosis, Computer-Assisted; Female; Health Status; Humans; Magnetic Resonance Imaging; Male; Regression Analysis; Sex Characteristics; Sex Distribution

Analytical and biologic variability in measures of hemostasis, fibrinolysis, and inflammation: assessment and implications for epidemiology. - Sakkinen, P A; Macy, E M; Callas, P W; Cornell, E S; Hayes, T E; Kuller, L H; Tracy, R P (Am J Epidemiol, 1999)
An increasing number of cardiovascular epidemiologic studies are measuring non-traditional risk markers of disease, most of which do not have established biovariability characteristics. When biovariability data have been reported, they usually represent a short time period, and, in any case, there is little consensus on how the information should be used. The authors performed a long-term (6-month) repeated measures study on 26 healthy individuals, and, using a nested analysis of variance (ANOVA) approach, report on the analytical (CVA), intraindividual (CVI), and between individual (CVG) variability of 12 procoagulant, fibrinolysis, and inflammation assays, including total cholesterol for comparison. The results suggest acceptable analytical variability (CVA < or = 1/2 CVI) for all assays. However, there was a large range of intraindividual variation as a proportion of total variance (2-78%), and adjusting for intraindividual and between individual variation in bivariate correlations increased the observed correlation by more than 30 percent for three of these assays. Overall, the assays showed a significant increase in intraindividual variation over 6 months (p < 0.05). While these findings suggest that most of these assays have biovariability characteristics similar to cholesterol, there is variation among assays. Some assays may be better suited to epidemiologic studies, and knowledge of an assay's biovariability data may be useful in interpreting simple statistics, and in designing multivariate models.
Keywords: Adult; Aged; Analysis of Variance; Cardiovascular Diseases; Cholesterol; Epidemiology; Female; Fibrinolysis; Hemostasis; Humans; Inflammation; Male; Middle Aged; Models, Statistical; Multivariate Analysis; Risk Factors

Ankle-arm index as a predictor of cardiovascular disease and mortality in the Cardiovascular Health Study. The Cardiovascular Health Study Group. - Newman, A B; Shemanski, L; Manolio, T A; Cushman, M; Mittelmark, M; Polak, J F; Powe, N R; Siscovick, D (Arterioscler Thromb Vasc Biol, 1999)
Peripheral arterial disease (PAD) in the legs, measured noninvasively by the ankle-arm index (AAI) is associated with clinically manifest cardiovascular disease (CVD) and its risk factors. To determine risk of total mortality, coronary heart disease, or stroke mortality and incident versus recurrent CVD associated with a low AAI, we examined the relationship of the AAI to subsequent CVD events in 5888 older adults with and without CVD. The AAI was measured in 5888 participants >/=65 years old at the baseline examination of the Cardiovascular Health Study. All participants had a detailed assessment of prevalent CVD and were contacted every 6 months for total mortality and CVD events (including CVD mortality, fatal and nonfatal myocardial infarction, congestive heart failure, angina, stroke, and hospitalized PAD). The crude mortality rate at 6 years was highest (32.3%) in those participants with prevalent CVD and a low AAI (P<0.9), and it was lowest in those with neither of these findings (8.7%, P<0.01). Similar patterns emerged from analysis of recurrent CVD and incident CVD. The risk for incident congestive heart failure (relative risk [RR]=1.61) and for total mortality (RR=1.62) in those without CVD at baseline but with a low AAI remained significantly elevated after adjustment for cardiovascular risk factors. Hospitalized PAD events occurred months to years after the AAI was measured, with an adjusted RR of 5.55 (95% CI, 3.08 to 9.98) in those at risk for incident events. A statistically significant decline in survival was seen at each 0.1 decrement in the AAI. An AAI of <0.9 is an independent risk factor for incident CVD, recurrent CVD, and mortality in this group of older adults in the Cardiovascular Health Study.
Keywords: Age Distribution; Aged; Aged, 80 and over; Ankle; Arm; Blood Pressure Determination; Cardiovascular Diseases; Cohort Studies; Female; Humans; Hypertension; Male; Predictive Value of Tests; Risk Factors; Sex Distribution; Survival Analysis

Cardiovascular disease in older adults with glucose disorders: comparison of American Diabetes Association criteria for diabetes mellitus with WHO criteria. - Barzilay, J I; Spiekerman, C F; Wahl, P W; Kuller, L H; Cushman, M; Furberg, C D; Dobs, A; Polak, J F; Savage, P J (Lancet, 1999)
BACKGROUND: The new fasting American Diabetes Association (ADA) criteria for the diagnosis of diabetes mellitus rely mainly on fasting blood glucose concentrations and use a lower cut-off value for diagnosis than the WHO criteria. We aimed to assess the sensitivity of these criteria for the detection of cardiovascular disease, the main complication of diabetes mellitus in the elderly. METHODS: We did a cross-sectional and prospective analysis of 4515 participants of the Cardiovascular Health Study, an 8 year longitudinal study designed to identify factors related to the onset and course of cardiovascular disease in adults aged at least 65 years. We calculated the prevalence and incidence of cardiovascular disease for the ADA and WHO criteria. FINDINGS: There was a higher prevalence of cardiovascular disease among individuals with impaired glucose or newly diagnosed diabetes by both criteria than among those with normal glucose concentrations. However, because fewer individuals had abnormal glucose states by the fasting ADA criteria (22.3%) than by the WHO criteria (46.8%), the number of cases of cardiovascular disease attributable to abnormal glucose states was a third of that attributable by the WHO criteria (53 vs 159 cases per 10,000). For the two sets of criteria, the relative risk for incident cardiovascular disease (mean follow-up 5.9 years) was higher in individuals with impaired glucose and newly diagnosed diabetes than in those with normal glucose. Individuals classified as normal by the fasting ADA criteria had a higher absolute number of incident events (455 of 581 events) than those classified as normal by the WHO criteria (269 of 581 events). Fasting ADA criteria were therefore less sensitive than the WHO criteria for predicting cardiovascular disease among individuals with abnormal glucose (sensitivity, 28% vs 54%). INTERPRETATION: The new fasting ADA criteria seem to be less predictive than the WHO criteria for the burden of cardiovascular disease associated with abnormal glucose in the elderly.
Keywords: Age Factors; Aged; Blood Glucose; Cardiovascular Diseases; Cross-Sectional Studies; Diabetes Complications; Diabetes Mellitus; Fasting; Female; Glucose Intolerance; Humans; Longitudinal Studies; Male; Prospective Studies; Risk Factors; Sensitivity and Specificity; Societies, Medical; United States; World Health Organization

Fibrinolytic activation markers predict myocardial infarction in the elderly. The Cardiovascular Health Study. - Cushman, M; Lemaitre, R N; Kuller, L H; Psaty, B M; Macy, E M; Sharrett, A R; Tracy, R P (Arterioscler Thromb Vasc Biol, 1999)
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

Hormone replacement therapy, inflammation, and hemostasis in elderly women. - Cushman, M; Meilahn, E N; Psaty, B M; Kuller, L H; Dobs, A S; Tracy, R P (Arterioscler Thromb Vasc Biol, 1999)
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

Increased blood glucose and insulin, body size, and incident colorectal cancer. - Schoen, R E; Tangen, C M; Kuller, L H; Burke, G L; Cushman, M; Tracy, R P; Dobs, A; Savage, P J (J Natl Cancer Inst, 1999)
BACKGROUND: Abdominal obesity--an elevated level of visceral adipose tissue--has been linked to colorectal cancer. Furthermore, elevated levels of visceral adipose tissue have been associated with hyperinsulinemia, and insulin is a growth factor in the colon. We assessed whether waist circumference, a surrogate measure of visceral adipose tissue, and metabolic parameters associated with visceral adipose tissue were related to colorectal cancer. METHODS: In the Cardiovascular Health Study cohort, we examined the relationship of baseline measurements of body size, glucose, insulin, and lipoproteins to incident colorectal cancer. All P values are two-sided. RESULTS: Among 5849 participants, 102 incident cases of colorectal cancer were identified. Individuals in the highest quartile of fasting glucose had a nearly twofold increased risk of colorectal cancer (relative risk [RR] = 1.8; 95% confidence interval [CI] = 1.0-3.1), and the linear trend RR (LT RR = 1.2; 95% CI = 1.0-1.5) for fasting glucose level was statistically significant (P =. 02). Glucose and insulin levels 2 hours after oral glucose challenge also exhibited statistically significant associations with colorectal cancer (2-hour glucose levels: RR = 2.4 [95% CI = 1.2-4. 7]/LT RR = 1.3 [95% CI = 1.0-1.6; P =.02]; 2-hour insulin levels: RR = 2.0 [95% CI = 1.0-3.8]/LT RR = 1.2 [95% CI = 1.0-1.5; P =.04]). Analysis of fasting insulin levels suggested a threshold effect, with values above the median associated with colorectal cancer (RR = 1.6; 95% CI = 1.1-2.4; P =.02). Higher levels of waist circumference were also statistically significantly associated with colorectal cancer (RR = 1.9; 95% CI = 1.1-3.3; P =.02). CONCLUSIONS: These data provide, to our knowledge, the first direct evidence of an association between elevated visceral adipose tissue level, its associated metabolic effects, and colorectal cancer.
Keywords: Adipose Tissue; Aged; Blood Glucose; Body Constitution; Cholesterol, HDL; Colorectal Neoplasms; Female; Humans; Incidence; Insulin; Male; Prospective Studies; Risk; Triglycerides; Viscera

Relation of education to brain size in normal aging: implications for the reserve hypothesis. - Coffey, C E; Saxton, J A; Ratcliff, G; Bryan, R N; Lucke, J F (Neurology, 1999)
OBJECTIVE: To examine the relations between education and age-related changes in brain structure in a nonclinical sample of elderly adults. BACKGROUND: Education may protect against cognitive decline in late life--an observation that has led to the "reserve" hypothesis of brain aging. Little is known, however, about the effect of education on age-related changes in brain structure. METHODS: Quantitative MRI of the brain was performed in 320 elderly volunteers (age range, 66 to 90 years) living independently in the community (Mini-Mental State Examination scores > or =24), all of whom were participants in the Cardiovascular Health Study. Blinded measurements of global and regional brain size were made from T1-weighted axial images using computer-assisted edge detection and trace methodology. High measurement reliabilities were obtained. RESULTS: Regression analyses (adjusting for the effects of intracranial size, sex, age, age-by-sex interactions, and potential confounders) revealed significant main effects of education on peripheral (sulcal) CSF volume-a marker of cortical atrophy. Each year of education was associated with an increase in peripheral CSF volume of 1.77 mL (p<0.03). As reported previously, main effects of age (but not education) were observed for all of the remaining brain regions examined, including cerebral hemisphere volume, frontal region area, temporoparietal region area, parieto-occipital region area, lateral (Sylvian) fissure volume, lateral ventricular volume, and third ventricle volume. CONCLUSIONS: The authors' findings demonstrate a relation between education and age-related cortical atrophy in a nonclinical sample of elderly persons, and are consistent with the reserve hypothesis as well as with a small number of brain imaging studies in patients with dementia. The neurobiological basis and functional correlates of this education effect require additional investigation.
Keywords: Aged; Aged, 80 and over; Atrophy; Brain; Cerebral Cortex; Cerebrospinal Fluid; Educational Status; Female; Functional Laterality; Health Status; Humans; Magnetic Resonance Imaging; Male; Mental Status Schedule; Regression Analysis; Sex Characteristics

Relationship of plasmin generation to cardiovascular disease risk factors in elderly men and women. - Sakkinen, P A; Cushman, M; Psaty, B M; Rodriguez, B; Boineau, R; Kuller, L H; Tracy, R P (Arterioscler Thromb Vasc Biol, 1999)
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, </=0.001). PAP was negatively related to factors associated with the insulin resistance syndrome (IRS) (eg, fasting insulin, r=-0.26; body mass index, r=-0.26), possibly reflecting an association with plasminogen activator inhibitor-1 (r=-0.29). Although our study did not have sufficient power to detect a significant interaction, PAP and AAI appeared to be more weakly associated in subjects with more manifestations of the IRS: PAP appeared more strongly associated with AAI in the subgroup with 0 or 1 metabolic disorders (P</=0.001; slope estimate, -0.14) compared with the subgroup with 2 or more metabolic disorders (P=0.10; slope estimate, -0.08) and in those with non-insulin-dependent diabetes mellitus (P=0.46; slope estimate, -0.04). Although PAP reflects reactive fibrinolysis and is associated with subclinical atherosclerosis, this relationship may be weaker in populations with characteristics of the IRS, possibly reflecting the inhibitory effects of plasminogen activator inhibitor-1 on PAP. Decreased fibrinolysis in the presence of subclinical disease in subjects with hyperinsulinemia or glucose intolerance is consistent with the premise that depressed plasmin generation may enhance the progression of atherosclerosis in these people.
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

The reliability of medication inventory methods compared to serum levels of cardiovascular drugs in the elderly. - Smith, N L; Psaty, B M; Heckbert, S R; Tracy, R P; Cornell, E S (J Clin Epidemiol, 1999)
Medication inventory is more reliable than self-report in assessing prescription drug use in elderly populations. It is not known how strongly medication inventory reflects actual medication use as measured by serum drug levels. In the Cardiovascular Health Study, medication data were collected annually by study interviewers from medication containers brought to the clinic visit. At the fourth clinic visit, venipuncture was performed under 12-hour fasting conditions. Participants were told to take medications as usual. Based on medication inventory results, we randomly selected 55 users and 55 non-users of four cardiovascular drugs: aspirin, propranolol, hydrochlorothiazide, and digoxin. All 110 blood samples for each of the four drugs were analyzed; cut points were based on detectable levels given laboratory limitations. Kappa statistics (K) tested degree of agreement between medication inventory findings and serum detection. Assays were completed on 400 samples (91%). Agreement for aspirin (n=102) was poor: K=0.16 (95% CI: 0.0-0.32). Agreement for propranolol (n = 98) was fair: K=0.43 (95% CI: 0.27-0.59). Agreement for hydrochlorothiazide (n=100) was good: K=0.62 (95% CI: 0.53-0.91). Agreement for digoxin (n=100) was excellent: K=0.94 (95% CI: 0.74-1.0). For four all drugs, lack of agreement was confined primarily to participants who reported use but did not have detectable levels. Excluding aspirin users, only one non-user (0.7%) had drug detected in serum. The medication inventory is a reasonably sensitive and a fairly reliable method for ascertaining non-aspirin cardiovascular drug use in the elderly even though this method may overestimate use as assessed by serum level.
Keywords: Aged; Aspirin; Cardiovascular Agents; Digoxin; Humans; Hydrochlorothiazide; Patient Compliance; Propranolol; Reproducibility of Results

Stroke risk in an elderly population with atrial fibrillation. - Feinberg, W M; Kronmal, R A; Newman, A B; Kraut, M A; Bovill, E G; Cooper, L; Hart, R G (J Gen Intern Med, 1999)
Patients with nonvalvular atrial fibrillation (AF) have an increased risk of stroke, but the absolute rate of stroke varies widely depending on coexistent vascular disease. We assessed the stroke rate and predictive value of two published schemes for stroke risk stratification in a population-derived cohort of 259 elderly people with nonvalvular AF followed for a median of 5.3 years. The rate of ischemic stroke was 2.8% per year (95% confidence interval [CI] 1.9, 3.9). Thirty-one percent were predicted to be at low risk, and their stroke rate was 1.7% per year (95% CI 0.6, 3.8). Many people with AF in this population-derived cohort had relatively low rates of stroke. Further studies to reliably stratify stroke risk in patients with AF are needed.
Keywords: Aged; Atrial Fibrillation; Cerebrovascular Disorders; Cohort Studies; Humans; Male; Poisson Distribution; Proportional Hazards Models; Risk Factors

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. - Siscovick, D S; Schwartz, S M; Corey, L; Grayston, J T; Ashley, R; Wang, S P; Psaty, B M; Tracy, R P; Kuller, L H; Kronmal, R A (Circulation, 2000)
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 (</=1:512), high-titer (1:1024) C pneumoniae antibody was associated with an increased risk (OR 2.2, 95% CI 1.1 to 4.4). 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

Clustering of procoagulation, inflammation, and fibrinolysis variables with metabolic factors in insulin resistance syndrome. - Sakkinen, P A; Wahl, P; Cushman, M; Lewis, M R; Tracy, R P (Am J Epidemiol, 2000)
The known metabolic cardiovascular disease risk factors associated with insulin resistance syndrome (IRS) do not adequately explain the excess cardiovascular disease risk attributed to this syndrome, and abnormalities in hemostatic variables may contribute to this excess risk. Using data from 322 nondiabetic elderly men and women (aged 65-100 years) participating in the Cardiovascular Health Study during 1989-1990, the authors performed factor analysis on 10 metabolic risk factors associated with IRS and 11 procoagulation, inflammation, and fibrinolysis variables to examine the clustering of the metabolic and hemostatic risk markers. Factor analysis of the metabolic variables confirmed four uncorrelated factors: body mass, insulin/glucose, lipids, and blood pressure. Adding the hemostatic variables yielded three new factors interpreted as inflammation, vitamin K-dependent proteins, and procoagulant activity. Plasminogen activator inhibitor-1 clustered with the body mass factor, supporting the hypothesis that obesity is related to impaired fibrinolysis. Fibrinogen clustered with the inflammation summary factor rather than procoagulant activity, supporting the position that fibrinogen principally reflects underlying inflammation rather than procoagulant potential. The authors conclude that should hemostatic variables be shown to contribute to IRS-related cardiovascular disease, apart from plasminogen activator inhibitor-1, they may do so independently of the established metabolic abnormalities.
Keywords: Aged; Aged, 80 and over; Antigens; Blood Coagulation; Cardiovascular Diseases; Cluster Analysis; Factor Analysis, Statistical; Factor VII; Female; Fibrinogen; Fibrinolysis; Humans; Inflammation; Insulin Resistance; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Risk Factors

Depressive symptoms and risks of coronary heart disease and mortality in elderly Americans. Cardiovascular Health Study Collaborative Research Group. - Ariyo, A A; Haan, M; Tangen, C M; Rutledge, J C; Cushman, M; Dobs, A; Furberg, C D (Circulation, 2000)
BACKGROUND: Several epidemiological studies have associated depressive symptoms with cardiovascular disease. We investigated whether depressive symptoms constituted a risk for coronary heart disease (CHD) and total mortality among an apparently healthy elderly cohort. METHODS AND RESULTS: In a prospective cohort of 5888 elderly Americans (>/=65 years) who were enrolled in the Cardiovascular Health Study, 4493 participants who were free of cardiovascular disease at baseline provided annual information on their depressive status, which was assessed using the Depression Scale of the Center for Epidemiological Studies. These 4493 subjects were followed for 6 years for the development of CHD and mortality. The cumulative mean depression score was assessed for each participant up to the time of event (maximum 6-year follow-up). Using time-dependent, proportional-hazards models, the unadjusted hazard ratio associated with every 5-unit increase in mean depression score for the development of CHD was 1.15 (P:=0.006); the ratio for all-cause mortality was 1.29 (P:<0.0001). In multivariate analyses adjusted for age, race, sex, education, diabetes, hypertension, cigarette smoking, total cholesterol, triglyceride level, congestive heart failure, and physical inactivity, the hazard ratio for CHD was 1.15 (P:=0.006) and that for all-cause mortality was 1.16 (P:=0.006). Among participants with the highest cumulative mean depression scores, the risk of CHD increased by 40% and risk of death by 60% compared with those who had the lowest mean scores. CONCLUSIONS: Among elderly Americans, depressive symptoms constitute an independent risk factor for the development of CHD and total mortality.
Keywords: Aged; Aged, 80 and over; Cohort Studies; Coronary Disease; Depression; Female; Humans; Male; Prospective Studies; Risk Factors; United States

Estrogen replacement therapy and MRI-demonstrated cerebral infarcts, white matter changes, and brain atrophy in older women: the Cardiovascular Health Study. - Luoto, R; Manolio, T; Meilahn, E; Bhadelia, R; Furberg, C; Cooper, L; Kraut, M (J Am Geriatr Soc, 2000)
OBJECTIVE: We studied the relationship between the use of estrogen replacement therapy (ERT) and cerebral magnetic resonance imaging (MRI) abnormalities among older women. DESIGN: A population-based prospective study (Cardiovascular Health Study). SETTING: Four regions in the United States. PARTICIPANTS: A total of 2133 (62.9% of the eligible) women aged 65 to 95 years (mean age 74.8), on whom MRI was performed in 1992-1994. MEASUREMENTS: Presence of global brain atrophy, white matter changes, small infarct-like lesion (ILL) (<3 mm), MRI infarcts (> or =3 mm, mostly small and asymptomatic), and cognitive function as measured by Mini-Mental State Exam (MMSE), and by ERT use (current/past/never), adjusted for a number of socioeconomic, lifestyle, and reproductive covariates. RESULTS: Current use of ERT was reported by 15% and past use by another 23% of participants; 35% of all women had MRI infarcts. The prevalence of MRI infarcts did not differ in current or past users from those who had never used ERT (nonusers). Bifrontal distance, the largest distance between frontal horns, and the size of ventricles were larger among current ERT users compared to past users or nonusers (P (trend) = .01), adjusted for all other covariates, but no dose-response relationship to current or past ERT use was found. Duration of estrogen use was not associated with any atrophy measure. Cortical atrophy measure, sulcal widening, or white matter disease did not differ significantly by ERT use or duration of use. Central measures of atrophy, bifrontal distance, and ventricular size were significantly associated with cognition as measured by MMSE. CONCLUSIONS: Current ERT users had much more clinically significant central atrophy than nonusers, but the implications remained unclear.
Keywords: Aged; Aged, 80 and over; Atrophy; Brain; Brain Infarction; Estrogen Replacement Therapy; Female; Humans; Intelligence Tests; Life Style; Magnetic Resonance Imaging; Population Surveillance; Prevalence; Prospective Studies; Social Class; United States

Normative data on the Boston Naming Test and two equivalent 30-item short forms. - Saxton, J; Ratcliff, G; Munro, C A; Coffey, E C; Becker, J T; Fried, L; Kuller, L (Clin Neuropsychol, 2000)
Because of the significance of the Boston Naming Test (BNT) in the differential diagnosis of the dementias, especially Alzheimer's disease, adequate norms from community-dwelling elderly individuals are essential. The present study describes the development of two new empirically derived equivalent short forms (30 items each) of the test. Normative data for the total BNT and the two equivalent 30-item halves based on item difficulty are presented using the performance of 314 community-dwelling individuals aged 65 and over. Age and education norms are presented using an overlapping midpoint interval strategy.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Female; Humans; Male; Neuropsychological Tests; Population Surveillance; Reference Values

Alcohol consumption and subclinical findings on magnetic resonance imaging of the brain in older adults: the cardiovascular health study. - Mukamal, K J; Longstreth, W T; Mittleman, M A; Crum, R M; Siscovick, D S (Stroke, 2001)
BACKGROUND AND PURPOSE: Subclinical findings on MRI of the brain are associated with poorer cognitive and neurological function among older adults. We sought to determine how alcohol consumption is related to these findings. METHODS: As part of the Cardiovascular Health Study, 3660 adults aged 65 years and older underwent MRI of the brain from 1992 to 1994. We excluded 284 participants with a confirmed history of cerebrovascular disease. We assessed self-reported intake of beer, wine, and liquor at the annual clinic visit closest to the date of the MRI and grouped participants into 6 categories: abstainers, former drinkers, <1 drink weekly, 1 to <7 drinks weekly, 7 to <15 drinks weekly, and >/=15 drinks weekly. Neuroradiologists assessed white matter grade, infarcts, ventricular size, and sulcal size in a standardized and blinded manner. We used multivariate regression to control for sociodemographic and clinical characteristics. RESULTS: We found a U-shaped relationship between alcohol consumption and white matter abnormalities. Compared with abstainers, individuals consuming 1 to <7 drinks had an OR of 0.68, and those consuming >/=15 drinks weekly had an OR of 0.95 (p for quadratic term=0.01). Heavier alcohol consumption was associated with a lower prevalence of infarcts (OR for >/=15 drinks weekly relative to abstainers 0.59; P for trend=0.004), but larger ventricular size (OR for >/=15 drinks weekly relative to abstainers 1.32; P for trend=0.006) and sulcal size (OR for >/=15 drinks weekly relative to abstainers 1.53; P for trend=0.007). CONCLUSIONS: Moderate alcohol consumption is associated with a lower prevalence of white matter abnormalities and infarcts, thought to be of vascular origin, but with a dose-dependent higher prevalence of brain atrophy on MRI among older adults. The extent to which these competing associations influence overall brain function will require further study.
Keywords: Aged; Aging; Alcohol Drinking; Atrophy; Brain; Brain Diseases; Cerebral Infarction; Comorbidity; Demography; Female; Health Surveys; Humans; Logistic Models; Longitudinal Studies; Magnetic Resonance Imaging; Male; Nerve Fibers, Myelinated; Odds Ratio; Prospective Studies; Sensitivity and Specificity; United States

Association between blood pressure level and the risk of myocardial infarction, stroke, and total mortality: the cardiovascular health study. - Psaty, B M; Furberg, C D; Kuller, L H; Cushman, M; Savage, P J; Levine, D; O'Leary, D H; Bryan, R N; Anderson, M; Lumley, T (Arch Intern Med, 2001)
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

Association between physical activity and markers of inflammation in a healthy elderly population. - Geffken, D F; Cushman, M; Burke, G L; Polak, J F; Sakkinen, P A; Tracy, R P (Am J Epidemiol, 2001)
Higher levels of physical activity are associated with lower risk of cardiovascular disease. There is growing evidence that the development of the atherosclerotic plaque is associated with inflammation. In this study, the authors investigated the cross-sectional association between physical activity and markers of inflammation in a healthy elderly population. Data obtained in 1989-1990 and 1992-1993 from the Cardiovascular Health Study, a cohort of 5,888 men and women aged >/=65 years, were analyzed. Concentrations of the inflammation markers-C-reactive protein, fibrinogen, Factor VIII activity, white blood cells, and albumin-were compared cross-sectionally by quartile of self-reported physical activity. Compared with persons in the lowest quartile, those in the highest quartile of physical activity had 19%, 6%, 4%, and 3% lower concentrations of C-reactive protein, white blood cells, fibrinogen, and Factor VIII activity, respectively, after adjustment for gender, the presence of cardiovascular disease, age, race, smoking, body mass index, diabetes, and hypertension. Multivariate regression models suggested that the association of higher levels of physical activity with lower levels of inflammation markers may be mediated by body mass index and glucose. There was no association between physical activity and albumin. Higher levels of physical activity were associated with lower concentrations of four out of five inflammation markers in this elderly cohort. These data suggest that increased exercise is associated with reduced inflammation. Prospective studies will be required for verification of these findings.
Keywords: Aged; Analysis of Variance; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Factor VIII; Female; Fibrinogen; Humans; Inflammation; Leukocyte Count; Male; Physical Exertion; Sex Factors; Smoking

The association of bone mineral density and depression in an older population. - Robbins, J; Hirsch, C; Whitmer, R; Cauley, J; Harris, T (J Am Geriatr Soc, 2001)
OBJECTIVE: To evaluate the association between bone mineral density (BMD) and measurements of depression in an older population. DESIGN: Population-based, cross-sectional study. SETTING: Study subjects were participants in the Cardiovascular Health Study (CHS), a longitudinal, long-term, follow-up study, at the University of California Davis (Sacramento, California) and the University of Pittsburgh (Pittsburgh, Pennsylvania) clinical centers. PARTICIPANTS: A random sample of 1,566 Medicare enrollees age 65 and older enrolled in the CHS. MEASUREMENTS: Total hip BMD, measured using dual energy x-ray absorptiometry (DEXA), after adjustment for multiple covariates, was compared with depression evaluated with the Center for Epidemiological Studies 10-item Depression Scale (CES-Dm). Risk factors for osteoporosis were compared in depressed and nondepressed participants. Potential correlates were entered into a regression model. Depression scores were compared in normal, osteopenic, and osteoporotic individuals. RESULTS: Sixteen percent of participants were clinically depressed; 9% had BMDs in the osteoporotic range. Mean BMD was 40 mg/cm2 lower in those with clinical depression. High CES-Dm scores were associated with lower BMD (P < .001) when adjusted for body mass index (BMI), age, kilocalories of activity, estrogen use, gender, race, smoking and drinking. When stratified by race, this remained true for all Caucasians (P < .01), all African Americans (P < .05), and when stratified by race and gender the association remained only for all Caucasian women (P < .001). In women and Caucasian men there was an increase in depression scores among individuals with osteoporotic-range BMDs. CONCLUSIONS: A significant association was found between BMD and depressive symptoms after adjustment for osteoporosis risk factors. In Caucasians, depressive symptoms were associated with both osteoporotic and osteopenic levels of BMD. Causality cannot be ascribed, with only one measurement of BMD. We postulate that there may be an unmeasured third factor, such as an endogenous steroid, that is responsible for both low BMD and depression.
Keywords: Absorptiometry, Photon; Aged; Analysis of Variance; Black People; Body Mass Index; Bone Density; Bone Diseases, Metabolic; California; Cross-Sectional Studies; Depression; Energy Metabolism; Exercise; Female; Follow-Up Studies; Fractures, Bone; Humans; Linear Models; Male; Osteoporosis; Pennsylvania; Population Surveillance; Psychiatric Status Rating Scales; Radionuclide Imaging; Risk Factors; Sex Distribution; Single-Blind Method; White People

Associations of subclinical cardiovascular disease with frailty. - Newman, A B; Gottdiener, J S; McBurnie, M A; Hirsch, C H; Kop, W J; Tracy, R; Walston, J D; Fried, L P (J Gerontol A Biol Sci Med Sci, 2001)
BACKGROUND: Frail health in old age has been conceptualized as a loss of physiologic reserve associated with loss of lean mass, neuroendocrine dysregulation, and immune dysfunction. Little work has been done to define frailty and describe the underlying pathophysiology. METHODS: Frailty status was defined in participants of the Cardiovascular Health Study (CHS), a cohort of 5,201 community-dwelling older adults, based on the presence of three out of five clinical criteria. The five criteria included self-reported weight loss, low grip strength, low energy, slow gait speed, and low physical activity. We examined the spectrum of clinical and subclinical cardiovascular disease in those who were frail (3/5 criteria) or of intermediate frailty status (1 or 2/5 criteria), compared to those who were not frail (0/5). We hypothesized that the severity of frailty would be related to a higher prevalence of reported cardiovascular disease (CVD), as well as to a greater extent of CVD, measured by noninvasive testing. RESULTS: Of 4,735 eligible participants, 2,289 (48%) were not frail, 299 (6%) were frail, and 2.147 (45%) were of intermediate frailty status. Those who were frail were older (77.2 yrs) compared to those who were not frail (71.5 yrs) or intermediate (73.4 yrs) (p < .001). Frailty status was associated with clinical CVD and most strongly with congestive heart failure (odds ratio [OR] = 7.51 (95% confidence interval [CI] = 4.66-12.12). In those without a history of a CVD event (n = 1.259), frailty was associated with many noninvasive measures of CVD. Those with carotid stenosis >75% (adjusted OR = 3.41), ankle-arm index <0.8 (adjusted OR = 3.17) or 0.8-0.9 (adjusted OR = 2.01), major electrocardiography (ECG) abnormalities (adjusted OR = 1.58), greater left ventricular (LV) mass by echocardiography (adjusted OR = 1.16), and higher degree of infarct-like lesions in the brain (adjusted OR = 1.71), were more likely to be frail compared to those who were not frail. The overall associations of each of these noninvasive measures of CVD with frailty level were significant (all p < .05). CONCLUSIONS: Cardiovascular disease was associated with an increased likelihood of frail health. In those with no history of CVD, the extent of underlying cardiovascular disease measured by carotid ultrasound and ankle-arm index, LV hypertrophy by ECG and echocardiography, was related to frailty. Infarct-like lesions in the brain on magnet resonance imaging were related to frailty as well.
Keywords: Aged; Ankle; Arm; Black or African American; Blood Pressure; Brain; Cardiovascular Diseases; Carotid Artery Diseases; Cerebral Infarction; Cerebrovascular Disorders; Cohort Studies; Echocardiography; Electrocardiography; Frail Elderly; Health Status; Heart Failure; Humans; Magnetic Resonance Imaging; United States; Vascular Diseases

Brachial flow-mediated vasodilator responses in population-based research: methods, reproducibility and effects of age, gender and baseline diameter. - Herrington, D M; Fan, L; Drum, M; Riley, W A; Pusser, B E; Crouse, J R; Burke, G L; McBurnie, M A; Morgan, T M; Espeland, M A (J Cardiovasc Risk, 2001)
BACKGROUND: Brachial artery ultrasound has been proposed as an inexpensive, accurate way to assess cardiovascular risk in populations. However, analysis and interpretation of these data are not uniform. METHODS: We analysed the relationship between relative and absolute changes in brachial artery diameter in response to flow-mediated dilation and age, gender and baseline diameter among 4,040 ultrasound examinations from subjects aged 14 to 98 years. RESULTS: Reproducibility studies demonstrated intra- and interreader and intrasubject correlations from 0.67 to 0.84 for repeated measures of per cent change in diameter. Per cent change in diameter after flow stimulus was 3.58 +/- 0.10% (mean +/- standard deviation). Corresponding values for baseline diameter and absolute change in diameter were 4.43 +/- 0.87 mm and 0.15 +/- 0.01 mm, respectively. Baseline diameter and its variance were inversely related to per cent change in diameter (P< 0.001). In contrast, absolute change in diameter was more uniform throughout the range of baseline diameters. Baseline diameter was directly related, and per cent change in diameter inversely related, to age (P < 0.001 for all three measures). Time to maximum vasodilator response increased with age (P < 0.001). Women (n=2,315) had significantly larger per cent change in diameter than men (n=1,725) (P < 0.001). However, after adjustment for age and baseline diameter, per cent and absolute change were 5% smaller in women than men (P < 0.05 for both). In multivariate analysis, age was overwhelmingly the most important determinant of absolute change in diameter (P < 0.001). CONCLUSIONS: Automated analysis of brachial flow-mediated vasodilator responses is both feasible and reproducible in large-scale clinical and population-based research.
Keywords: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Blood Circulation; Brachial Artery; Female; Humans; Male; Middle Aged; Observer Variation; Population Surveillance; Reproducibility of Results; Sex Factors; Vasodilation; Vasodilator Agents

Cluster analysis and patterns of findings on cranial magnetic resonance imaging of the elderly: the Cardiovascular Health Study. - Longstreth, W T; Diehr, P; Manolio, T A; Beauchamp, N J; Jungreis, C A; Lefkowitz, D (Arch Neurol, 2001)
OBJECTIVE: To characterize patterns of findings on cranial magnetic resonance imaging (MRI) of the elderly using a statistical technique called cluster analysis. SUBJECTS AND METHODS: The Cardiovascular Health Study is a population-based, longitudinal study of 5888 people 65 years and older. Of these, 3230 underwent cranial MRI scans, which were coded for presence of infarcts and grades for white matter, ventricles, and sulci. Cluster analysis separated participants into 5 clusters based solely on patterns of MRI findings. Participants comprising each cluster were contrasted with respect to cardiovascular risk factors and clinical manifestations. RESULTS: One cluster was low on all the MRI findings (normal) and another was high on all of them (complex infarcts). Another cluster had evidence for infarcts alone (simple infarcts), whereas the last 2 clusters lacked infarcts, one having enlarged ventricles and sulci (atrophy) and the other having prominent white matter changes and enlarged ventricles (leukoaraiosis). Factors that distinguished these clusters in a discriminant analysis were age, sex, several measures of hypertension, internal carotid artery wall thickness, smoking, and prevalent claudication before the MRI. The atrophy group had the highest percentage of men and the normal group had the lowest. Cognitive and motor performance also differed across clusters, with the atrophy cluster performing better than may have been expected. CONCLUSIONS: These MRI patterns identified participants with different vascular disease risk factors and clinical manifestations. Results of these exploratory analyses warrant consideration in other populations of elderly people. Such patterns may provide clues about the pathophysiology of structural brain changes in the elderly.
Keywords: Aged; Brain; Cerebral Infarction; Cerebrovascular Disorders; Cluster Analysis; Cohort Studies; Discriminant Analysis; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Risk Factors

Correlates of peak expiratory flow lability in elderly persons. - Enright, P L; McClelland, R L; Buist, A S; Lebowitz, M D (Chest, 2001)
OBJECTIVE: To determine the correlates of the lability of peak expiratory flow (PEF) in the elderly. METHODS: A community sample of 4,581 persons > or = 65 years old from the Cardiovascular Health Study completed an asthma questionnaire and underwent spirometry. During a follow-up examination of the cohort, 1,836 persons agreed to measure PEF at home twice daily for 2 weeks, and 90% successfully obtained at least 4 days of valid measurements. PEF lability was calculated as the highest daily (PEF maximum - PEF minimum)/mean PEF. RESULTS: Mean PEF measured at home was accurate when compared to PEF determined by spirometry in the clinic. Mean PEF lability was 18% in those with current asthma (n = 165) vs 12% in healthy nonsmokers (upper limit of normal, 29%). Approximately 26% of those with asthma and 14% of the other participants had abnormally high PEF lability (> 29%). After excluding participants with asthma, other independent predictors of high PEF lability included black race, current and former smoking, airway obstruction on spirometry, daytime sleepiness, recent wheezing, chronic cough, emphysema, and wheezing from lying in a supine position. Despite having a lower mean PEF, those reporting congestive heart failure (n = 82) did not have significantly higher PEF lability. CONCLUSIONS: Measurement of PEF lability at home is highly successful in elderly persons. PEF lability > or = 30% is abnormal in the elderly and is associated with asthma.
Keywords: Aged; Aged, 80 and over; Aging; Asthma; Female; Heart Failure; Humans; Male; Monitoring, Ambulatory; Peak Expiratory Flow Rate; Predictive Value of Tests; Pulmonary Disease, Chronic Obstructive; Reference Values; Rhinitis, Allergic, Seasonal; Risk Factors; Signal Processing, Computer-Assisted; Spirometry

Estrogen replacement and brachial artery flow-mediated vasodilation in older women. - Herrington, D M; Espeland, M A; Crouse, J R; Robertson, J; Riley, W A; McBurnie, M A; Burke, G L (Arterioscler Thromb Vasc Biol, 2001)
It remains unclear whether estrogen therapy (with or without progestin) improves endothelial function in older postmenopausal women with or at risk for coronary heart disease. To address this issue, we analyzed brachial artery flow-mediated vasodilation in the Cardiovascular Health Study, a longitudinal study of cardiovascular risk factors in subjects over 65 years of age. At the tenth annual Cardiovascular Health Study examination, 1662 women returned for follow-up. Eighteen percent (n=291) were current users of estrogen replacement, most of whom (75.9%, n=221) took unopposed estrogen. Brachial artery ultrasound examinations measuring vasodilation in response to a flow stimulus (hyperemia) were performed on 1636 women. There were no statistical differences in brachial flow-mediated vasodilator responses between users and nonusers, even after adjustment for potential confounders. Absence of an effect was most notable in women over 80 years old and in those with established cardiovascular disease. However, among women without clinical or subclinical cardiovascular disease or its risk factors, there was a significant association between hormone replacement therapy use and flow-mediated vasodilator responses (P=0.01). Among older postmenopausal women, favorable vascular effects of estrogen may be limited to those who have not yet developed atherosclerotic vascular disease. These data emphasize the importance of ongoing efforts to determine the role of hormone replacement therapy for primary prevention of cardiovascular disease.
Keywords: Aged; Aged, 80 and over; Analysis of Variance; Brachial Artery; Cardiovascular Diseases; Drug Therapy, Combination; Estrogen Replacement Therapy; Estrogens; Female; Humans; Longitudinal Studies; Progestins; Risk Factors; Ultrasonography; Vasodilation

Factors associated with healthy aging: the cardiovascular health study. - Burke, G L; Arnold, A M; Bild, D E; Cushman, M; Fried, L P; Newman, A; Nunn, C; Robbins, J (J Am Geriatr Soc, 2001)
OBJECTIVES: To identify factors associated with remaining healthy in older adults. DESIGN: Longitudinal cohort study. SETTING: Data were collected at the four Cardiovascular Health Study field centers. PARTICIPANTS: 5,888 participants age 65 years and older in the Cardiovascular Health Study. MEASUREMENTS: Presence of chronic disease was assessed at baseline and over a maximum 7-year follow-up period. Participants who were free of chronic disease (no cardiovascular disease (CVD), chronic obstructive pulmonary disease, or self-reported cancer, except nonmelanoma skin cancer) at the baseline examination were then monitored for the onset of incident cancer, cardiovascular disease, and fatal outcomes. RESULTS: A high proportion of these older adults was healthy at the initial examination and remained healthy over the follow-up period. Numerous behavioral factors were associated with continued health, including physical activity, refraining from cigarette smoking, wine consumption (women), higher educational status, and lower waist circumference. A number of CVD risk factors and subclinical disease measures were associated with continued health, including higher high-density lipoprotein (HDL) cholesterol, lack of diabetes, thinner common carotid intimal nmedial thickness, lower blood pressure, lower C-reactive protein, and higher ankle-arm blood pressure ratio. Among the behavioral factors, exercise, not smoking, and not taking aspirin remained significant predictors of health even after controlling for CVD risk factors and subclinical disease in older adults. CONCLUSIONS: These data suggest that a number of modifiable behavioral factors (physical activity, smoking, and obesity) and cardiovascular risk factors (diabetes, HDL cholesterol, and blood pressure) are associated with maintenance of good health in older adults.
Keywords: Aged; Aged, 80 and over; Aging; Cardiovascular Diseases; Cohort Studies; Diet; Exercise; Female; Health Status; Humans; Incidence; Life Style; Longitudinal Studies; Lung Diseases, Obstructive; Male; Neoplasms; Probability; Reference Values; Risk Factors; Sex Distribution; Socioeconomic Factors; Survival Rate; United States

Frailty in older adults: evidence for a phenotype. - Fried, L P; Tangen, C M; Walston, J; Newman, A B; Hirsch, C; Gottdiener, J; Seeman, T; Tracy, R; Kop, W J; Burke, G; McBurnie, M A (J Gerontol A Biol Sci Med Sci, 2001)
BACKGROUND: Frailty is considered highly prevalent in old age and to confer high risk for falls, disability, hospitalization, and mortality. Frailty has been considered synonymous with disability, comorbidity, and other characteristics, but it is recognized that it may have a biologic basis and be a distinct clinical syndrome. A standardized definition has not yet been established. METHODS: To develop and operationalize a phenotype of frailty in older adults and assess concurrent and predictive validity, the study used data from the Cardiovascular Health Study. Participants were 5,317 men and women 65 years and older (4,735 from an original cohort recruited in 1989-90 and 582 from an African American cohort recruited in 1992-93). Both cohorts received almost identical baseline evaluations and 7 and 4 years of follow-up, respectively, with annual examinations and surveillance for outcomes including incident disease, hospitalization, falls, disability, and mortality. RESULTS: Frailty was defined as a clinical syndrome in which three or more of the following criteria were present: unintentional weight loss (10 lbs in past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity. The overall prevalence of frailty in this community-dwelling population was 6.9%; it increased with age and was greater in women than men. Four-year incidence was 7.2%. Frailty was associated with being African American, having lower education and income, poorer health, and having higher rates of comorbid chronic diseases and disability. There was overlap, but not concordance, in the cooccurrence of frailty, comorbidity, and disability. This frailty phenotype was independently predictive (over 3 years) of incident falls, worsening mobility or ADL disability, hospitalization, and death, with hazard ratios ranging from 1.82 to 4.46, unadjusted, and 1.29-2.24, adjusted for a number of health, disease, and social characteristics predictive of 5-year mortality. Intermediate frailty status, as indicated by the presence of one or two criteria, showed intermediate risk of these outcomes as well as increased risk of becoming frail over 3-4 years of follow-up (odds ratios for incident frailty = 4.51 unadjusted and 2.63 adjusted for covariates, compared to those with no frailty criteria at baseline). CONCLUSIONS: This study provides a potential standardized definition for frailty in community-dwelling older adults and offers concurrent and predictive validity for the definition. It also finds that there is an intermediate stage identifying those at high risk of frailty. Finally, it provides evidence that frailty is not synonymous with either comorbidity or disability, but comorbidity is an etiologic risk factor for, and disability is an outcome of, frailty. This provides a potential basis for clinical assessment for those who are frail or at risk, and for future research to develop interventions for frailty based on a standardized ascertainment of frailty.
Keywords: Aged; Aged, 80 and over; Cohort Studies; Disabled Persons; Fatigue; Female; Frail Elderly; Humans; Incidence; Male; Muscle Weakness; Phenotype; Prevalence; Sex Distribution; United States; Weight Loss

Frequency and predictors of stroke death in 5,888 participants in the Cardiovascular Health Study. - Longstreth, W T; Bernick, C; Fitzpatrick, A; Cushman, M; Knepper, L; Lima, J; Furberg, C D (Neurology, 2001)
BACKGROUND: Few population-based studies have examined in detail issues of stroke-related deaths in elderly people. METHODS: Participants in the Cardiovascular Health Study (CHS) are 65 years of age or older, have had extensive baseline evaluations, and have been followed-up for fatal and nonfatal cardiovascular and cerebrovascular disease outcomes. Investigators adjudicated these outcomes and classified strokes by types and subtypes. RESULTS: Over 7 years, 1,310 (22.2%) of 5,888 participants died, and 455 (7.7%) experienced incident stroke. For the 5,888, stroke mortality was 3.2 per 1,000 person-years. For the 455, it was 36.1 per 1,000 person-years, with the most lethal type being hemorrhagic and the ischemic subtype being cardioembolic. After controlling for age and stroke type, the only other independent predictor of death after any stroke was poor performance on a timed walk measured before the incident stroke. Considering only ischemic stroke, the independent predictors of death were African American race and poor performance on timed walk. CONCLUSION: In CHS, death attributable to stroke is common. As in other studies, the most lethal stroke type was hemorrhagic, and ischemic stroke subtype, cardioembolic. Slow walking, possibly a measure of frailty, was associated with an increased risk of death of stroke. Finally, African Americans faced a greater risk of death than others after an ischemic stroke.
Keywords: Aged; Aged, 80 and over; Clinical Trials as Topic; Female; Humans; Longitudinal Studies; Male; Predictive Value of Tests; Stroke; Survival Analysis; United States

Gait variability in community-dwelling older adults. - Brach, J S; Berthold, R; Craik, R; VanSwearingen, J M; Newman, A B (J Am Geriatr Soc, 2001)
OBJECTIVES: To describe gait variability at usual and fast walking speeds in community-dwelling older adults and to describe the effects of increasing gait speed on gait variability. DESIGN: Cross-sectional, descriptive study. SETTING: The Cardiovascular Health Study at the University of Pittsburgh. PARTICIPANTS: Ninety-five community-living older adults, 54 women and 41 men, age 65 and older (mean age +/- standard deviation 79.4 +/- 3.37). MEASUREMENTS: Gait measured at participant's usual and fast walking speed collected using an instrumented walkway. Step-length and step-width variability were determined using the coefficient of variation. RESULTS: Step-length variability was greatest in those who walked the slowest (r = -0.66, P < .001); step-width variability was smallest in those who walked the slowest (r -0.37, P < .001). Individuals who could not increase their walking speed (<0.10 m/second) on command had an increase in step-length variability and a decrease in step-width variability, whereas those who could increase their speed (>0.10 m/second) had an increase in step-width variability when walking at a faster speed. CONCLUSIONS: Step-length and step-width variability have opposite associations with gait speed in older adults. Improvement in step-length and step-width variability with attempted acceleration might be a key factor to examine in future studies of disability risk and therapeutic interventions.
Keywords: Aged; Aged, 80 and over; Aging; Body Height; Body Weight; Cross-Sectional Studies; Disability Evaluation; Female; Gait; Humans; Male; Residence Characteristics; Risk Factors; Time Factors; Walking

Hormone replacement therapy is associated with higher FEV1 in elderly women. - Carlson, C L; Cushman, M; Enright, P L; Cauley, J A; Newman, A B (Am J Respir Crit Care Med, 2001)
Estrogen and progesterone use have been associated with improved pulmonary function in premenopausal women. However, little research has examined the relationship between hormone replacement therapy (HRT) and pulmonary function in postmenopausal women. We examined the relationship of HRT with spirometry in 2,353 women aged 65 yr and older participating in the Cardiovascular Health Study in 1993/1994. Current use of HRT was hypothesized to be associated with higher FEV1, higher FVC, and less pulmonary obstruction (FEV1/FVC < 65%). FEV1 was higher among current HRT users compared to noncurrent users in the following groups: overall (1.82 L versus 1.66 L, p < 0.0001), among women without asthma (1.85 L versus 1.69 L, p < 0.0001), among former smokers (1.76 L versus 1.60 L, p = 0.013), and among never smokers (1.90 L versus 1.72 L, p < 0.0001). Overall, HRT use was associated with a lower prevalence of pulmonary obstruction (OR 0.75 [95% CI 0.55, 0.99]). After controlling for potential confounders, HRT use was significantly associated with higher FEV(1) (p = 0.031) and with a lower prevalence of obstruction (OR 0.67 [95% CI 0.48, 0.95]). We conclude that postmenopausal women who use HRT have higher levels of FEV1 and less obstruction, which could not be explained by their lower rates of smoking and other health factors associated with HRT use.
Keywords: Aged; Aged, 80 and over; Cohort Studies; Estrogen Replacement Therapy; Female; Forced Expiratory Volume; Humans; Longitudinal Studies; Spirometry; Vital Capacity

Importance of heart failure with preserved systolic function in patients > or = 65 years of age. CHS Research Group. Cardiovascular Health Study. - Kitzman, D W; Gardin, J M; Gottdiener, J S; Arnold, A; Boineau, R; Aurigemma, G; Marino, E K; Lyles, M; Cushman, M; Enright, P L (Am J Cardiol, 2001)
Although congestive heart failure (CHF) is a common syndrome among the elderly, there is a relative paucity of population-based data, particularly regarding CHF with normal systolic left ventricular function. A total of 4,842 independent living, community-dwelling subjects aged 66 to 103 years received questionnaires on medical history, family history, personal habits, physical activity, and socioeconomic status, confirmation of pre-existing cardiovascular and cerebrovascular disease, anthropometric measurements, casual seated random-zero blood pressure, forced vital capacity and expiratory volume in 1 second, 12-lead supine electrocardiogram, fasting glucose, creatinine, plasma lipids, carotid artery wall thickness by ultrasonography, and echocardiography-Doppler examinations. Participants with at least 1 confirmed episode of CHF by Cardiovascular Health Study criteria were considered prevalent for CHF. The prevalence of CHF was 8.8% and was associated with increased age, particularly for women, in whom it increased more than twofold from age 65 to 69 years (6.6%) to age > or = 85 years (14%). In multivariate analysis, subjects with CHF were more likely to be older (odds ratio [OR] 1.2 for 5-year difference, men OR 1.1), and more often had a history of myocardial infarction (OR 7.3), atrial fibrillation (OR 3.0), diabetes mellitus (OR 2.1), renal dysfunction (OR 2.0 for creatinine < or = 1.5 mg/ dl), and chronic pulmonary disease (OR 1.8; women only). The echocardiographic correlates of CHF were increased left atrial and ventricular dimensions. Importantly, 55% of subjects with CHF had normal left ventricular systolic function and 80% had either normal or only mildly reduced systolic function. Among subjects with CHF, women had normal systolic function more frequently than men (67% vs 42%; p < 0.001). Thus, CHF is common among community-dwelling elderly. It increases with age and is usually associated with normal systolic LV function, particularly among women. The finding that a large proportion of elderly with CHF have preserved LV systolic function is important because there is a paucity of data to guide management in this dominant subset.
Keywords: Aged; Aged, 80 and over; Analysis of Variance; Chi-Square Distribution; Echocardiography, Doppler; Female; Health Status; Heart Failure; Humans; Logistic Models; Longitudinal Studies; Male; Prevalence; Risk Factors; Surveys and Questionnaires; United States; Ventricular Function, Left

Incidence and predictors of coronary heart disease among older African Americans--the Cardiovascular Health Study. - Jackson, S A; Burke, G L; Thach, C; Cushman, M; Ives, D; Powe, N; Manolio, T A (J Natl Med Assoc, 2001)
Although coronary heart disease (CHD) is the leading cause of death and morbidity in older African Americans, relatively little is known about the incidence and predictors of CHD in this population. This study was undertaken to determine the incidence and predictors of CHD in African-American men and women aged 65 years and older. The participants in this study included a total of 924 African-American men and women aged 65 years of age and older who participated in the Cardiovascular Health Study (CHS). The overall CHD incidence was 26.6 per 1,000 person-years of risk. Rates were higher in men than women (35.3 vs. 21.6) and in those 75 years or older than in those less than 75 years (31.3 vs. 24.5). In multivariate analysis, factors associated with higher risk of incident disease were male gender [relative risk (RR) = 1.8, 95% confidence interval (CI) = 1.1, 2.7], diabetes mellitus (RR = 1.9, 95% CI = 1.2, 2.9), total cholesterol (RR for 40 mg/dL increment = 1.3, 95% CI = 1.0, 1.5), and low (i.e., <0.9) ankle-arm index (RR = 2.1, 95% CI = 1.3, 3.4) after adjusting for age. Within this cohort of older African Americans, male gender, diabetes mellitus, total cholesterol, and low ankle-arm index and were independently predictive of incident events. These results suggest that the ankle-arm index, a measure of advanced atherosclerosis, should be further evaluated for its efficacy in identifying older African Americans at risk for incident clinical events.
Keywords: Age Distribution; Aged; Black or African American; Coronary Disease; Female; Health Status; Humans; Incidence; Male; Predictive Value of Tests

Post-menopausal hormone therapy and concentrations of protein C and antithrombin in elderly women. - Cushman, M; Psaty, B M; Meilahn, E N; Dobs, A S; Kuller, L H (Br J Haematol, 2001)
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

Prevalence of clinical and isolated subclinical cardiovascular disease in older adults with glucose disorders: the Cardiovascular Health Study. - Barzilay, J I; Spiekerman, C F; Kuller, L H; Burke, G L; Bittner, V; Gottdiener, J S; Brancati, F L; Orchard, T J; O'Leary, D H; Savage, P J (Diabetes Care, 2001)
OBJECTIVE: Clinical cardiovascular disease (CVD) is highly prevalent among people with diabetes. However, there is little information regarding the prevalence of subclinical CVD and its relation to clinical CVD in diabetes and in the glucose disorders that precede diabetes. RESEARCH DESIGN AND METHODS: Participants in the Cardiovascular Health Study, aged > or = 65 years (n = 5,888), underwent vascular and metabolic testing. Individuals with known disease in the coronary, cerebral, or peripheral circulations were considered to have clinical disease. Those without any clinical disease in whom CVD was detected by ultrasonography, electrocardiography, or ankle arm index in any of the three vascular beds were considered to have isolated subclinical disease. RESULTS: Approximately 30% of the cohort had clinical disease, and approximately 60% of the remainder had isolated subclinical disease. In those with normal glucose status, isolated subclinical disease made up most of the total CVD. With increasing glucose severity, the proportion of total CVD that was clinical disease increased; 75% of men and 66% of women with normal fasting glucose status had either clinical or subclinical CVD. Among those with known diabetes, the prevalence was approximately 88% (odds ratio [OR] 2.46 for men and 4.22 for women, P < 0.0001). There were intermediate prevalences and ORs for those with impaired fasting glucose status and newly diagnosed diabetes. CONCLUSIONS: Isolated subclinical CVD is common among older adults. Glucose disorders are associated with an increased prevalence of total CVD and an increased proportion of clinical disease relative to subclinical disease.
Keywords: Aged; Angina Pectoris; Cardiovascular Diseases; Cerebrovascular Disorders; Cohort Studies; Diabetes Mellitus; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Electrocardiography; Female; Glucose Intolerance; Heart Diseases; Humans; Male; Peripheral Vascular Diseases; Prevalence; United States

Relation of hemodynamics and risk factors to ventricular-vascular interactions in the elderly: the Cardiovascular Health Study. - de Simone, G; McClelland, R; Gottdiener, J S; Celentano, A; Kronmal, R A; Gardin, J M (J Hypertens, 2001)
OBJECTIVE: To investigate the interaction between left ventricular (LV) geometry, carotid structure and arterial compliance in relation to hemodynamic stimuli and risk factors (plasma cholesterol, body mass index, insulin resistance, smoking habit, age, sex and race). DESIGN: Cross-sectional. METHODS: Echocardiography and carotid ultrasound were performed in 2375 elderly subjects without signs or history of prevalent cardiovascular disease, diabetes or renal disease (795 men; 298 non-whites; 1215 hypertensive), from the cohort of the Cardiovascular Health Study. Arterial compliance was estimated by the prognostically validated ratio of stroke volume to pulse pressure (SV/PP) as the percent deviation (Delta%) from the value predicted by individual age, heart rate and body weight. RESULTS: Intima-medial thickness (IMT) was higher in the presence of LV hypertrophy (LVH) in normotensive and hypertensive subjects and was greatest in the presence of concentric LVH. Maximum carotid lumen diameter (CLD) was also higher in the presence of LVH (and was greatest with eccentric LVH, in association with relatively high values for stroke volume). After adjusting for blood pressure, maximum carotid lumen diameter was directly correlated with stroke volume, and IMT to LV mass (all P < 0.001). Similarly, IMT was also related to maximum carotid lumen diameter, independently of prevalent risk factors (P < 0.001). SV/PP-Delta% was reduced in both groups with concentric LV remodeling (both P < 0.0001) or concentric LVH (both P < 0.05). Adjusting for risk factors did not affect these associations in normotensives, but made them insignificant in hypertensives. In normotensives, IMT was inversely related to SV/PP-Delta% (P < 0.001), independently of risk factors, whereas no significant relation was found in hypertensives. CONCLUSIONS: The magnitudes of carotid intima-medial thickness and lumen diameter parallel levels of LV mass and geometry, and are directly related to stroke volume and arterial stiffness; this interaction is most evident in the presence of normal blood pressure, whereas it is affected by other cardiovascular risk factors when arterial hypertension is present.
Keywords: Aged; Aged, 80 and over; Blood Pressure; Carotid Arteries; Compliance; Cross-Sectional Studies; Echocardiography; Female; Hemodynamics; Humans; Hypertension; Hypertrophy, Left Ventricular; Male; Reference Values; Risk Factors; Stroke Volume; Tunica Intima; Tunica Media; Ventricular Function, Left

The relation of markers of inflammation to the development of glucose disorders in the elderly: the Cardiovascular Health Study. - Barzilay, J I; Abraham, L; Heckbert, S R; Cushman, M; Kuller, L H; Resnick, H E; Tracy, R P (Diabetes, 2001)
Several studies suggest that inflammation plays a role in the pathogenesis of some glucose disorders in adults. We tested this hypothesis in a longitudinal cohort study of older individuals who had normal fasting glucose (FG) values at baseline. We compared the baseline levels of six inflammatory markers in participants who had developed glucose disorders at follow-up with those of participants whose FG remained normal at follow-up. Participants were members of the Cardiovascular Health Study, a prospective study of risk factors for cardiovascular disease in adults > or =65 years. All 5,888 participants had baseline testing, including FG and markers of inflammation: white blood cell and platelet counts and albumin, fibrinogen, C-reactive protein (CRP), and factor VIIIc levels. At 3-4 years of follow-up, 4,481 (84.5%) of those who were alive had FG levels retested. Participants who developed diabetes (n = 45) had higher median levels of CRP at baseline than those who remained normoglycemic. On multivariate analysis, those with elevated CRP levels (75th percentile [2.86 mg/l] vs. 25th percentile [0.82 mg/l]) were 2.03 times (95% confidence intervals, 1.44-2.86) more likely to have diabetes on follow-up. Adjustment for confounders and other inflammatory markers did not appreciably change this finding. There was no relationship between the development of diabetes and other markers of inflammation. Inflammation, as measured by CRP levels, is associated with the development of diabetes in the elderly. Understanding the role of inflammation in the pathogenesis of glucose disorders in this age-group may lead to better classification and treatment of glucose disorders among them.
Keywords: Aged; Biomarkers; Blood Glucose; C-Reactive Protein; Cardiovascular Diseases; Cohort Studies; Diabetes Mellitus; Female; Humans; Hypoglycemia; Inflammation; Longitudinal Studies; Male; Reference Values; Risk Factors

The role of comorbidity in the assessment of intermittent claudication in older adults. - Newman, A B; Naydeck, B L; Sutton-Tyrrell, K; Polak, J F; Kuller, L H (J Clin Epidemiol, 2001)
The prevalence of intermittent claudication (IC) in older adults by questionnaire is less than 5% while the prevalence of peripheral arterial disease (PAD) by non-invasive testing is 2-4-fold higher. Comorbid conditions may result in under-reporting intermittent claudication (IC) as assessed by the Rose Questionnaire. We examined characteristics of those who report leg pain in relationship to other comorbid conditions and disability in 5888 participants of the Cardiovascular Health Study (CHS). Older adults with exertional leg pain, not meeting criteria for IC, had a higher prevalence of PAD on non-invasive testing with the ankle-arm index than those without pain, as well as a higher prevalence of arthritis. The pattern of responses suggested that pain for both conditions was reported together. The Rose Questionnaire for IC is specific for PAD, but a negative questionnaire does not indicate a lack of symptoms, rather the presence of PAD along with other conditions that can cause pain.
Keywords: Aged; Angina Pectoris; Arterial Occlusive Diseases; Cerebrovascular Disorders; Cohort Studies; Comorbidity; Diabetes Mellitus; Female; Humans; Intermittent Claudication; Leg; Male; Prevalence; Sensitivity and Specificity; Surveys and Questionnaires

Silent MRI infarcts and the risk of future stroke: the cardiovascular health study. - Bernick, C; Kuller, L; Dulberg, C; Longstreth, W T; Manolio, T; Beauchamp, N; Price, T (Neurology, 2001)
BACKGROUND: Silent infarcts are commonly discovered on cranial MRI in the elderly. OBJECTIVE: To examine the association between risk of stroke and presence of silent infarcts, alone and in combination with other stroke risk factors. METHODS: Participants (3,324) in the Cardiovascular Health Study (CHS) without a history of stroke underwent cranial MRI scans between 1992 and 1994. Silent infarcts were defined as focal lesions greater than 3 mm that were hyperintense on T2 images and, if subcortical, hypointense on T1 images. Incident strokes were identified and classified over an average follow-up of 4 years. The authors evaluated the risk of subsequent symptomatic stroke and how it was modified by other potential stroke risk factors among those with silent infarcts. RESULTS: Approximately 28% of CHS participants had evidence of silent infarcts (n = 923). The incidence of stroke was 18.7 per 1,000 person-years in those with silent infarcts (n = 67) compared with 9.5 per 1,000 person-years in the absence of silent infarcts. The adjusted relative risk of incident stroke increased with multiple (more than one) silent infarcts (hazard ratio 1.9 [1.2 to 2.8]). Higher values of diastolic and systolic blood pressure, common and internal carotid wall thickness, and the presence of atrial fibrillation were associated with an increased risk of strokes in those with silent infarcts (n = 53 strokes). CONCLUSION: The presence of silent cerebral infarcts on MRI is an independent predictor of the risk of symptomatic stroke over a 4-year follow- up in older individuals without a clinical history of stroke.
Keywords: Aged; Cerebral Infarction; Cohort Studies; Female; Follow-Up Studies; Humans; Incidence; Magnetic Resonance Imaging; Male; Predictive Value of Tests; Risk Factors; Stroke

Weight change in old age and its association with mortality. - Newman, A B; Yanez, D; Harris, T; Duxbury, A; Enright, P L; Fried, L P (J Am Geriatr Soc, 2001)
OBJECTIVES: Previous studies of weight change and mortality in older adults have relied on self-reported weight loss, have not evaluated weight gain, or have had limited information on health status. Our objective was to determine whether 5% weight gain or loss in 3 years was predictive of mortality in a large sample of older adults. DESIGN: Longitudinal observational cohort study. SETTING: Four U.S. communities. PARTICIPANTS: Four thousand seven hundred fourteen community-dwelling older adults, age 65 and older. MEASUREMENTS: Weight gain or loss of 5% in a 3-year period was examined in relationship to baseline health status and interim health events. Risk for subsequent mortality was estimated in those with weight loss or weight gain compared with the group whose weight was stable. RESULTS: Weight changes occurred in 34.6% of women and 27.3% of men, with weight loss being more frequent than gain. Weight loss was associated with older age, black race, higher weight, lower waist circumference, current smoking, stroke, any hospitalization, death of a spouse, activities of daily living disability, lower grip strength, and slower gait speed. Weight loss but not weight gain of 5% or more was associated with an increased risk of mortality that persisted after multivariate adjustment (Hazard ratio (HR) = 1.67, 95% CI = 1.29-2.15) and was similar in those with no serious illness in the period of weight change. Those with weight loss and low baseline weight had the highest crude mortality rate, although the HR for weight loss was similar for all tertiles of baseline weight and for those with or without a special diet, compared with those whose weight was stable. CONCLUSIONS: This study confirms that even modest decline in body weight is an important and independent marker of risk of mortality in older adults.
Keywords: Aged; Analysis of Variance; Body Weight; Chi-Square Distribution; Female; Health Status; Humans; Longitudinal Studies; Male; Mortality; Proportional Hazards Models; Risk Factors; United States; Weight Gain; Weight Loss

Anticardiolipin antibodies as a risk factor for venous thromboembolism in a population-based prospective study. - Runchey, Shauna S; Folsom, Aaron R; Tsai, Michael Y; Cushman, Mary; McGovern, Paul D (Br J Haematol, 2002)
Anticardiolipin antibodies, one of the family of 'antiphospholipid' antibodies, increase the risk of venous thromboembolism in the presence of autoimmune disease. Our objective was to determine prospectively whether there is a positive association between anticardiolipin antibodies and venous thromboembolism in ostensibly healthy adults. We conducted a nested case-control study (n = 317 patients and n = 655 control subjects) in a longitudinal study of over 20 000 participants. Baseline (prediagnosis) anticardiolipin IgG and IgM antibodies were assessed by enzyme-linked immunoassays. Venous thromboembolism was validated using standardized criteria for venous thrombosis and pulmonary embolism. There was no association between anticardiolipin antibodies and subsequent venous thromboembolism occurrence, overall or in any subgroup. For example, the multivariate-adjusted relative risk was 0.88 (95% confidence interval, 0.43, 1.78) for greater than versus less than the 95th percentile of anticardiolipin IgG. In conclusion, in this general population sample, an elevated anticardiolipin antibody level was not a risk factor for venous thromboembolism.
Keywords: Aged; Aged, 80 and over; Antibodies, Anticardiolipin; Case-Control Studies; Female; Humans; Immunoglobulin G; Immunoglobulin M; Longitudinal Studies; Male; Middle Aged; Odds Ratio; Prospective Studies; Reference Values; Risk Factors; Thromboembolism; Venous Thrombosis

Calcium channel blocker use and gastrointestinal tract bleeding among older adults. - Kaplan, Robert C; Heckbert, Susan R; Koepsell, Thomas D; Rosendaal, Frits R; Furberg, Curt D; Cooper, Lawton S; Psaty, Bruce M (Age Ageing, 2002)
Keywords: Aged; Antihypertensive Agents; Calcium Channel Blockers; Gastrointestinal Hemorrhage; Geriatric Assessment; Health Services for the Aged; Humans; Hypertension; Prospective Studies; Risk Factors

Cardiovascular disease risk status in elderly persons with renal insufficiency. - Shlipak, Michael G; Fried, Linda F; Crump, Casey; Bleyer, Anthony J; Manolio, Teri A; Tracy, Russell P; Furberg, Curt D; Psaty, Bruce M (Kidney Int, 2002)
BACKGROUND: Renal insufficiency has been independently associated with incident cardiovascular disease events in some, but not all, prospective studies. We determined the prevalence of elevated cardiovascular disease risk status among elderly persons with renal insufficiency. METHODS: This study is a cross-sectional analysis using data collected at the baseline visit of the Cardiovascular Health Study, which enrolled 5888 community dwelling adults aged 65 years or older from four clinical centers in the United States. Renal insufficiency was defined as a serum creatinine level > or =1.3 mg/dL in women and > or =1.5 mg/dL in men. The outcomes of this study included prevalent cardiovascular disease [prior coronary heart disease (CHD) or stroke], subclinical cardiovascular disease (abnormal values of ankle-arm index, carotid ultrasound, and echocardiography) and elevated cardiovascular risk based upon a diagnosis of diabetes and the Framingham equations. The association between renal insufficiency and cardiovascular risk status was estimated with and without adjustment for other cardiovascular predictors. RESULTS: Among the 5808 participants with creatinine levels measured at entry, 15.9% of men (N = 394), and 7.6% of women (N = 254) had renal insufficiency. The prevalence of either clinical or subclinical cardiovascular disease was 64% in persons with renal insufficiency compared with 43% in those without it [odds ratio (OR) 2.34; 95% confidence interval (95% CI), 1.96, 2.80]. After adjustment for other cardiovascular risk factors, renal insufficiency remained significantly associated with clinical and subclinical cardiovascular disease (adjusted OR 1.43; 95% CI, 1.18, 1.75), but the magnitude of association was substantially reduced. After combining clinical and subclinical cardiovascular disease, diabetes, and an estimated risk>20% by the Framingham equations, 78% of men and 61% of women with renal insufficiency had elevated cardiovascular risk status. CONCLUSIONS: Renal insufficiency is a marker for elevated cardiovascular disease risk in community dwelling elderly adults.
Keywords: Age Distribution; Aged; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Creatinine; Cross-Sectional Studies; Female; Humans; Kidney Failure, Chronic; Male; Prevalence; Prospective Studies; Risk Factors

Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology. - Tsai, Albert W; Cushman, Mary; Rosamond, Wayne D; Heckbert, Susan R; Polak, Joseph F; Folsom, Aaron R (Arch Intern Med, 2002)
BACKGROUND: The association between traditional cardiovascular risk factors and risk of venous thromboembolism (VTE) has not been extensively examined in prospective studies. METHODS: To determine whether atherosclerotic risk factors are also associated with increased incidence of VTE, we conducted a prospective study of 19 293 men and women without previous VTE in 6 US communities between 1987 and 1998. RESULTS: There were 215 validated VTE events (1.45 per 1000 person-years) during a median of 8 years of follow-up. The age-adjusted hazard ratio was 1.4 (95% confidence interval [CI], 1.1-1.9) for men vs women, 1.6 (95% CI, 1.2-2.2) for blacks vs whites, and 1.7 (95% CI, 1.5-2.0) per decade of age. Cigarette smoking, hypertension, dyslipidemia, physical inactivity, and alcohol consumption were not associated with risk of VTE. Age-, race-, and sex-adjusted hazard ratios for body mass index categories (calculated as the weight in kilograms divided by the height in meters squared) of less than 25, 25 to less than 30, 30 to less than 35, 35 to less than 40, and 40 or more were 1.0, 1.5, 2.2, 1.5, and 2.7, respectively (P<.001 for the trend). Diabetes was also associated with an increased risk of VTE (adjusted hazard ratio, 1.5 [95% CI, 1.0-2.1]). CONCLUSIONS: Our data showing no relationship of some arterial risk factors with VTE corroborate the view that the etiology of VTE differs from atherosclerotic cardiovascular disease. In addition, the findings suggest a hypothesis that avoidance of obesity and diabetes or vigilance in prophylaxis in patients with those conditions may prevent some venous thromboses.
Keywords: Aged; Arteriosclerosis; Female; Humans; Incidence; Male; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Prospective Studies; Pulmonary Embolism; Risk Factors; United States; Venous Thrombosis

Cerebrovascular disease and evolution of depressive symptoms in the cardiovascular health study. - Steffens, David C; Krishnan, K Ranga Rama; Crump, Casey; Burke, Gregory L (Stroke, 2002)
BACKGROUND AND PURPOSE: Previous studies have reported an association between cerebrovascular disease and depressive symptoms. The Cardiovascular Health Study (CHS) provides an opportunity to examine the relationship between vascular brain pathology seen on neuroimaging and changes in depressive symptoms. METHODS: The sample included 3236 CHS participants who had an MRI brain scan. Demographic variables, medical history, functional status, and apolipoprotein E genotype were obtained at baseline. Annual scores on a modified version of the Centers for Epidemiologic Studies Depression (CES-D) scale were obtained initially and up to 7 years subsequently. RESULTS: After controlling for important covariates, occurrence of depressive symptoms (defined as modified CES-D score of >7) was associated with small lesions in the basal ganglia, large cortical white-matter lesions, and severe subcortical white-matter grade. Neuroimaging variables did not predict incident depression among those who were nondepressive at the time of MRI. Persistence of depressive symptoms across 2 consecutive time points was associated with small basal ganglia lesions and large cerebral cortical white-matter lesions. Worsening of depression (increase in CES-D score of > or =5) was associated with subcortical white-matter lesions. CONCLUSIONS: These findings suggest that cerebrovascular disease at baseline is related to depression symptoms over time. Further studies are needed to investigate the differential effects of subcortical white- versus gray-matter lesions on mood.
Keywords: Aged; Aged, 80 and over; Basal Ganglia Cerebrovascular Disease; Brain; Cerebrovascular Disorders; Cohort Studies; Comorbidity; Depression; Disease Progression; Female; Health Surveys; Humans; Incidence; Logistic Models; Magnetic Resonance Imaging; Male; Neuropsychological Tests; Odds Ratio; United States

Coagulation factors, inflammation markers, and venous thromboembolism: the longitudinal investigation of thromboembolism etiology (LITE). - Tsai, Albert W; Cushman, Mary; Rosamond, Wayne D; Heckbert, Susan R; Tracy, Russell P; Aleksic, Nena; Folsom, Aaron R (Am J Med, 2002)
PURPOSE: We sought to assess prospectively whether higher levels of blood coagulation factors and inflammation markers are risk factors for venous thromboembolism. SUBJECTS AND METHODS: In two pooled population-based cohort studies, we measured levels of factor VII, factor VIII, von Willebrand factor, fibrinogen, and C-reactive protein, and white blood cell count, in samples obtained from 19,237 adults with no baseline history of venous thromboembolism, cancer, or warfarin use. The endpoint was validated venous thromboembolism during follow-up (median, 7.8 years). RESULTS: A total of 159 venous thromboembolism events occurred. Factor VIII and von Willebrand factor were linearly associated with increased risk of venous thromboembolism (P for trend <0.0001). As compared with those in the lowest quartile, the multivariate-adjusted hazard ratio (HR) of venous thromboembolism was 2.6 (95% confidence interval [CI]: 1.6 to 4.3) for factor VIII levels in the highest quartile and 3.8 (95% CI: 2.0 to 7.2) for the highest fifth percentile. For von Willebrand factor, the hazard ratios in middle-aged subjects were 4.6 (95% CI: 2.2 to 9.2) for the highest quartile and 7.6 (95% CI: 3.1 to 18) for the highest fifth percentile. Factor VII levels above the 95th percentile, as compared with the lowest quartile, also conveyed a higher risk of venous thromboembolism (HR = 2.4; 95% CI: 1.2 to 4.8). In contrast, there was no association of venous thromboembolism with fibrinogen or C-reactive protein levels, or white cell count. CONCLUSIONS: In this prospective study, elevated factor VIII and von Willebrand factor levels were common, independent, and dose-dependent risk factors for venous thromboembolism, and an elevated factor VII level was a possible risk factor. Venous thromboembolism, unlike arterial disease, was not related to inflammatory markers.
Keywords: Aged; Biomarkers; Blood Coagulation Factors; C-Reactive Protein; Cohort Studies; Confidence Intervals; Factor VII; Female; Fibrinogen; Humans; Inflammation Mediators; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Prospective Studies; Risk Assessment; Risk Factors; Sensitivity and Specificity; Thromboembolism; Venous Thrombosis; von Willebrand Factor

Frailty and activation of the inflammation and coagulation systems with and without clinical comorbidities: results from the Cardiovascular Health Study. - Walston, Jeremy; McBurnie, Mary Ann; Newman, Anne; Tracy, Russell P; Kop, Willem J; Hirsch, Calvin H; Gottdiener, John; Fried, Linda P (Arch Intern Med, 2002)
BACKGROUND: The biological basis of frailty has been difficult to establish owing to the lack of a standard definition, its complexity, and its frequent coexistence with illness. OBJECTIVE: To establish the biological correlates of frailty in the presence and absence of concurrent cardiovascular disease and diabetes mellitus. METHODS: Participants were 4735 community-dwelling adults 65 years and older. Frail, intermediate, and nonfrail subjects were identified by a validated screening tool and exclusion criteria. Bivariate relationships between frailty level and physiological measures were evaluated by Pearson chi2 tests for categorical variables and analysis of variance F tests for continuous variables. Multinomial logistic regression was performed to evaluate multivariable relationships between frailty status and physiological measures. RESULTS: Of 4735 Cardiovascular Health Study participants, 299 (6.3%) were identified as frail, 2147 (45.3%) as intermediate, and 2289 (48.3%) as not frail. Frail vs nonfrail participants had increased mean +/- SD levels of C-reactive protein (5.5 +/- 9.8 vs 2.7 +/- 4.0 mg/L), factor VIII (13 790 +/- 4480 vs 11 860 +/- 3460 mg/dL), and, in a smaller subset, D dimer (647 +/- 1033 vs 224 +/- 258 ng/mL) (P< or =.001 for all, chi2 test for trend). These differences persisted when individuals with cardiovascular disease and diabetes were excluded and after adjustment for age, sex, and race. CONCLUSIONS: These findings support the hypothesis that there is a specific physiological basis to the geriatric syndrome of frailty that is characterized in part by increased inflammation and elevated markers of blood clotting and that these physiological differences persist when those with diabetes and cardiovascular disease are excluded.
Keywords: Aged; Aged, 80 and over; Blood Coagulation Disorders; Cardiovascular Diseases; Cohort Studies; Diabetes Complications; Diabetes Mellitus; Female; Frail Elderly; Geriatric Assessment; Humans; Inflammation; Longitudinal Studies; Male

Incidence, manifestations, and predictors of brain infarcts defined by serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. - Longstreth, W T; Dulberg, Corinne; Manolio, Teri A; Lewis, Michael R; Beauchamp, Norman J; O'Leary, Daniel; Carr, Jeff; Furberg, Curt D (Stroke, 2002)
BACKGROUND AND PURPOSE: MRI-defined infarcts are common in the elderly. We sought to explore incidence, manifestations, and predictors of such infarcts. METHODS: The Cardiovascular Health Study (CHS) is a population-based, longitudinal study of 5888 people aged > or =65 years. Participants have had extensive baseline and follow-up evaluations; 1433 participants underwent 2 MRI scans separated by 5 years and had no infarcts on initial MRI. RESULTS: On follow-up MRI, 254 participants (17.7%) had 1 or more infarcts. Most were single (75.6%), subcortical (79.9%), and small (3 to 20 mm in 87.0%). Only 11.4% of those with infarcts experienced a documented transient ischemic attack or stroke between the scans. Although participants were similar at initial MRI, those with MRI-defined infarcts on follow-up experienced greater decline than those without infarcts on the Modified Mini-Mental State Examination and Digit-Symbol Substitution test (both P<0.01). Severity of white matter changes on initial MRI was the strongest predictor of incident infarcts. When it was excluded from stepwise multivariable models, predictors were serum creatinine, age, and ankle-arm index. CONCLUSIONS: Incident MRI-defined infarcts commonly affect the elderly. Most are small, subcortical, and not associated with acute symptoms recognized as a transient ischemic attack or stroke. Nonetheless, they cannot be considered silent because of their association with subtle cognitive deficits. These covert infarcts are associated with white matter changes, which may share a common pathophysiology. Whether control of vascular risk factors, such as blood pressure, would reduce the risk of developing these infarcts and associated cognitive decline deserves further investigation.
Keywords: Aged; Brain Infarction; California; Cohort Studies; Creatinine; Follow-Up Studies; Humans; Incidence; Longitudinal Studies; Magnetic Resonance Imaging; Maryland; Multivariate Analysis; Neuropsychological Tests; North Carolina; Odds Ratio; Pennsylvania; Predictive Value of Tests; Risk Factors

Left atrial dimensions determined by M-mode echocardiography in black and white older (> or =65 years) adults (The Cardiovascular Health Study). - Manolio, Teri A; Gottdiener, John S; Tsang, Teresa S M; Gardin, Julius M (Am J Cardiol, 2002)
Stroke and atrial fibrillation are common and serious illnesses in the elderly, the risks of which are substantially increased by left atrial (LA) enlargement. Despite growing recognition of the importance of LA enlargement, the distribution and correlates of LA dimension in the elderly have not been well defined. A total of 3,882 women and men aged >65 years were studied. Increased LA dimension was independently associated with increased weight, mitral annular calcium, regional wall motion abnormalities, mitral early peak inflow velocity, and left ventricular (LV) fractional shortening. Increased LA dimension was negatively associated with aortic leaflet thickening. The relation with LV fractional shortening was curvilinear with a nadir at 35% to 40%. LA dimension in black men was approximately 1.9 mm less than in white men in multivariate analyses. Adjustment for spirometric lung volumes and chest dimensions appeared to diminish the race-LA dimension relation. Thus, LA dimension is strongly associated with weight and with several echocardiographic valvular abnormalities; its relation with LV fractional shortening is U-shaped with a nadir at the borderline of LV functional impairment.
Keywords: African Continental Ancestry Group; Age Factors; Aged; Blood Flow Velocity; Body Weight; Cardiovascular Diseases; Echocardiography; Electrocardiography; European Continental Ancestry Group; Evidence-Based Medicine; Female; Heart Atria; Heart Ventricles; Humans; Male; Multivariate Analysis; Prospective Studies; Risk Factors; Statistics as Topic; Ventricular Function, Left

No association of plasma prothrombin concentration or the G20210A mutation with incident cardiovascular disease: results from the Cardiovascular Health Study. - Smiles, Adam M; Jenny, Nancy S; Tang, Zhonghua; Arnold, Alice; Cushman, Mary; Tracy, Russell P (Thromb Haemost, 2002)
Prothrombin is a key factor in blood clotting, a process intimately involved in thrombotic disease. We assessed prothrombin levels and G20210A genotype in a case-control study within the Cardiovascular Health Study. Cases included angina, myocardial infarction, stroke, and the presence of MRI-detectable infarcts (n approximately 250 each). Population-based controls free of clinical cardiovascular disease (CVD) (n approximately 500) and a subset free of clinical and subclinical CVD (n approximately 250) were used for comparison. The 20210 A allele, frequency 2.9%, was associated with higher mean prothrombin levels: 166.3 vs. 139.5 microg/ml (P <0.001). Significant correlates of prothrombin included gender, plasma lipids, other vitamin K-dependent proteins, and inflammatory markers, but not race, smoking, hypertension, diabetes, measures of subclinical CVD, or markers of procoagulant activity. Compared to controls, neither genotype nor prothrombin level was associated with any CVD case group. We conclude that, in the elderly, neither prothrombin level nor 20210 genotype were associated with either CVD risk factors or events. This is consistent with the lack of association of prothrombin levels with measures of underlying CVD or procoagulant markers.
Keywords: 3' Untranslated Regions; Aged; Aged, 80 and over; Alleles; Angina Pectoris; Blood Proteins; Cardiovascular Diseases; Case-Control Studies; Comorbidity; Diabetes Mellitus; Female; Genetic Predisposition to Disease; Humans; Hyperlipidemias; Hypertension; Male; Mutation; Myocardial Infarction; Obesity; Promoter Regions, Genetic; Prothrombin; Risk Factors; Smoking; Stroke; Vermont

Outcome of congestive heart failure in elderly persons: influence of left ventricular systolic function. The Cardiovascular Health Study. - Gottdiener, John S; McClelland, Robyn L; Marshall, Robert; Shemanski, Lynn; Furberg, Curt D; Kitzman, Dalane W; Cushman, Mary; Polak, Joseph; Gardin, Julius M; Gersh, Bernard J; Aurigemma, Gerard P; Manolio, Teri A (Ann Intern Med, 2002)
BACKGROUND: Most persons with congestive heart failure are elderly, and many elderly persons with congestive heart failure have normal left ventricular systolic function. OBJECTIVE: To evaluate the relationship between left ventricular systolic function and outcome of congestive heart failure in elderly persons. DESIGN: Population-based longitudinal study of coronary heart disease and stroke. SETTING: Four U.S. sites: Forsyth County, North Carolina; Sacramento County, California; Allegheny County, Pennsylvania; and Washington County, Maryland. PARTICIPANTS: 5888 persons who were at least 65 years of age and were recruited from the community. MEASUREMENTS: Total mortality and cardiovascular morbidity and mortality. RESULTS: Of 5532 participants, 269 (4.9%) had congestive heart failure. Among these, left ventricular function was normal in 63%, borderline decreased in 15%, and overtly impaired in 22%. The mortality rate was 25 deaths per 1000 person-years in the reference group (no congestive heart failure and normal left ventricular function at baseline); 154 deaths per 1000 person-years in participants with congestive heart failure and impaired left ventricular systolic function; 87 and 115 deaths per 1000 person-years in participants with congestive heart failure and normal or borderline systolic function, respectively; and 89 deaths per 1000 person-years in persons with impaired left ventricular function but no congestive heart failure. Although the risk for death from congestive heart failure was lower in persons with normal systolic function than in those with impaired function, more deaths were associated with normal systolic function because more persons with heart failure fall into this category. CONCLUSIONS: Community-dwelling elderly persons, especially those with impaired left ventricular function, have a substantial risk for death from congestive heart failure. However, more deaths occur from heart failure in persons with normal systolic function because left ventricular function is more often normal than impaired in elderly persons with heart failure.
Keywords: Aged; Cause of Death; Echocardiography; Female; Heart Failure; Humans; Longitudinal Studies; Male; Myocardial Infarction; Prevalence; Prognosis; Risk Factors; Stroke; Ventricular Dysfunction, Right; Ventricular Function, Left

Prevalence of renovascular disease in the elderly: a population-based study. - Hansen, Kimberley J; Edwards, Matthew S; Craven, Timothy E; Cherr, Gregory S; Jackson, Sharon A; Appel, Richard G; Burke, Gregory L; Dean, Richard H (J Vasc Surg, 2002)
PURPOSE: The purpose of this investigation was to estimate the population-based prevalence of renovascular disease (RVD), defined as > or = 60% diameter-reducing renal artery stenosis or occlusion, and to define its associations with age, gender, race, and other potential risk factors among participants in the Cardiovascular Health Study (CHS). METHODS: The CHS is a multicenter, longitudinal cohort study of cardiovascular disease risk factors, morbidity, and mortality among free-living adults of more than 65 years of age. As part of an ancillary investigation, participants in the Forsyth County cohort of the CHS were invited to undergo renal duplex sonography (RDS) to define the presence or absence of RVD. RVD was defined as stenosis with a focal renal artery peak systolic velocity exceeding 1.8 m/s in the main renal artery and defined as occlusion when an imaged renal artery lacked a Doppler signal. Demographic and atherosclerotic risk factor data were gathered as part of the baseline CHS examination. Univariable tests of association were performed with chi(2) and Student t tests and logistic regression analysis. Multivariate associations were examined with logistic regression analysis. RESULTS: Eight hundred seventy CHS participants underwent RDS. Of these examinations, 834 (96%) were technically adequate to define the presence or absence of RVD. The RDS study cohort had a mean age of 77.2 +/- 4.9 years and consisted of 63% women and 37% men. Participant race was 76% white and 23% African American. The overall prevalence rate of RVD was 6.8%. Among the 57 patients with RVD, 50 (88%) had unilateral disease and seven (12%) had bilateral disease. Seven cases were seen of renal artery occlusion, including one case with contralateral renal artery stenosis. The mean ages of patients with and without RVD were 78.7 +/- 5.7 years and 77.1 +/- 4.9 years (P =.018). RVD was present in 5.5% of women and 9.1% of men (P =.053). RVD was present in 6.9% of white participants and 6.7% of African American participants (P =.933). Multivariate analysis revealed increasing participant age (P =.028; odds ratio, 1.34; 95% CI, 1.03, 1.73), high-density lipoprotein cholesterol levels of less than 40 mg/dL (P =.003; odds ratio, 2.63; 95% CI, 1.40, 4.93), and increasing systolic blood pressure (P =.007; odds ratio, 1.44; 95% CI, 1.10, 1.87) to be significantly and independently associated with the presence of RVD. CONCLUSION: This investigation provides the first population-based estimate of the prevalence of RVD among free-living, elderly black and white Americans. RVD was present in 6.8% of the study cohort. RVD showed no association with ethnicity. However, its presence was significantly and independently associated with increasing age, low high-density lipoprotein cholesterol levels, and increasing systolic blood pressure.
Keywords: Age Factors; Aged; Aged, 80 and over; Cohort Studies; Ethnic Groups; Female; Humans; Longitudinal Studies; Male; Prevalence; Prospective Studies; Renal Artery; Renal Artery Obstruction; Risk Factors; Sex Factors; Ultrasonography, Doppler, Duplex

Prospective study of the G20210A polymorphism in the prothrombin gene, plasma prothrombin concentration, and incidence of venous thromboembolism. - Folsom, Aaron R; Cushman, Mary; Tsai, Michael Y; Heckbert, Susan R; Aleksic, Nena (Am J Hematol, 2002)
Case-control studies have indicated increased risk of venous thrombosis associated with the prothrombin gene G20210A polymorphism and with elevated plasma prothrombin levels. We sought to confirm these results in a prospective population-based study of 21,690 persons. We measured G20210A and prothrombin antigen on pre-event blood samples of 302 participants who developed venous thromboembolism (VTE) and 626 participants who remained free of VTE. Approximately 4.0% of cases and 2.4% of controls carried the G20210A polymorphism, but only one of 137 African Americans did. The odds ratio in whites was 1.87 (95% CI = 0.85, 4.11)--higher for those who reported a prior history of VTE (OR = 5.44) than those reporting no VTE history (OR = 1.41) and in those with idiopathic VTE (OR = 2.51) than those with secondary VTE (OR = 1.38). There was no association between venous thromboembolism and plasma prothrombin antigen level. We estimated that the G20210A polymorphism may account for approximately 2.5% of venous thromboembolism events in United States whites.
Keywords: African Continental Ancestry Group; Age Factors; Aged; Case-Control Studies; European Continental Ancestry Group; Genotype; Humans; Incidence; Middle Aged; Odds Ratio; Polymorphism, Single Nucleotide; Prospective Studies; Prothrombin; Recurrence; Research Design; Risk Factors; Thromboembolism; United States

A prospective study of venous thromboembolism in relation to factor V Leiden and related factors. - Folsom, Aaron R; Cushman, Mary; Tsai, Michael Y; Aleksic, Nena; Heckbert, Susan R; Boland, Lori L; Tsai, Albert W; Yanez, N David; Rosamond, Wayne D (Blood, 2002)
The aim of this study was to examine the occurrence of venous thromboembolism (VTE) in relation to factor V-related risk factors. Using a nested case-control design combining 2 population-based prospective studies, we measured factor V Leiden, HR2 haplotype, activated protein C (APC) resistance, and plasma factor V antigen in 335 participants who developed VTE during 8 years of follow-up and 688 controls. The overall odds ratio (OR) of VTE was 3.67 (95% CI, 2.20-6.12) in participants carrying factor V Leiden compared with noncarriers. APC resistance measured after predilution with factor V-deficient plasma conferred an OR of 2.58 (95% CI, 1.62-4.10). All 3 participants homozygous for the HR2 haplotype had a VTE, and the OR of VTE for homozygosity was estimated to be 5.5 (95% CI, 2.45-12.5). Carriers of the HR2 haplotype otherwise were not at increased risk of VTE overall (OR = 1.05; 95% CI, 0.64-1.72), but double heterozygotes for HR2 and factor V Leiden carried an OR of idiopathic VTE of 16.3 (95% CI, 1.7-159) compared with noncarriers. Factor V antigen also was not associated with VTE overall, but for participants with the combination of high factor V antigen plus factor V Leiden the OR of idiopathic VTE was 11.5 (95% CI, 4.2-31.4). In the general population, APC resistance and factor V Leiden were important VTE risk factors; homozygosity for the HR2 haplotype may be a risk factor but was rare; otherwise, HR2 haplotype and factor V antigen were not risk factors except in carriers of factor V Leiden.
Keywords: Activated Protein C Resistance; Aged; Cohort Studies; Continental Population Groups; Factor V; Genotype; Haplotypes; Humans; Incidence; Longitudinal Studies; Middle Aged; Odds Ratio; Prospective Studies; Risk Factors; Thromboembolism; Venous Thrombosis

Protein C, antithrombin, and venous thromboembolism incidence: a prospective population-based study. - Folsom, Aaron R; Aleksic, Nena; Wang, Lu; Cushman, Mary; Wu, Kenneth K; White, Richard H (Arterioscler Thromb Vasc Biol, 2002)
Although deficiencies of protein C and antithrombin, 2 natural plasma anticoagulants, are known risk factors for venous thrombosis, population-based prospective incidence data on these associations are lacking. Venous thromboembolic events have been identified in adults in 2 longitudinal cohort studies, the Atherosclerosis Risk in Communities (ARIC) Study and the Cardiovascular Health Study (CHS). Incidence was examined in relation to prediagnostic plasma levels of protein C (ARIC Study only) and antithrombin. Over a mean of 8.1 years of follow-up, there were 130 incident venous thromboembolic events that were not due to cancer in the ARIC Study. The age-adjusted incidence was elevated 3.36-fold (95% CI 1.24 to 9.11) in the 1.1% of subjects with protein C values <2.0 mg/L compared with subjects with higher values. In contrast, in the ARIC Study and the CHS, there was no association between low plasma antithrombin and venous thromboembolism. In conclusion, in this population-based study, a low protein C, but not antithrombin, level has been determined to be associated with an increased incidence of venous thromboembolism. Attributable risk estimates suggest that low protein C levels account for approximately 2.5% of venous thromboembolic events in the ARIC population.
Keywords: Adult; Aged; Aged, 80 and over; Antithrombins; Arteriosclerosis; Cohort Studies; Humans; Incidence; Longitudinal Studies; Middle Aged; Odds Ratio; Population Surveillance; Prospective Studies; Protein C; Protein C Deficiency; Pulmonary Embolism; Thromboembolism; Venous Thrombosis

A regression model for longitudinal change in the presence of measurement error. - Yanez, N David; Kronmal, Richard A; Shemanski, Lynn R; Psaty, Bruce M (Ann Epidemiol, 2002)
PURPOSE: The analysis of change in measured variables has become quite popular in studies where data are collected repeatedly over time. The authors describe some of the potential pitfalls in the analysis of change when the variable for change is measured with error. They show that regression analysis is often biased, possibly leading to erroneous results. METHODS: A simple method to correct for measurement error bias in regression models that model change is presented. RESULTS AND CONCLUSIONS: The two examples illustrate how measurement error can adversely affect an analysis. The bias-corrected approach yields valid results.
Keywords: Aged; Bias; Coronary Disease; Humans; Lipoproteins; Models, Statistical; Regression Analysis; Risk Factors

Reproducibility of two approaches for assessing alcohol consumption among older adults. - Crum, RM; Puddey, I; Gilbert, CG; Fried, LP (Addiction Research and Theory, 2002)
Objectives: In this study, we hypothesized that there is greater disclosure in self reports of alcohol intake when details of quantity-frequency measures of alcohol consumption are ascertained in the context of a general health and life style questionnaire as compared to a directed interview on usual drinking habits. Methods: Data are from the 1993 to 1994 follow-up of the Washington County cohort of men and women 65 years and older, participating in the Cardiovascular Health Study. A total of 918 subjects completed a questionnaire evaluation of their usual alcohol consumption by two separate approaches: (1) alcohol intake was derived from responses to questions contained within a medical and personal history questionnaire; (2) the same questions were within a medical and personal history questionnaire. Results: The mean alcohol intake for the entire cohort, and for drinkers alone were almost identical when assessed by either questionnaire, with high correlation between the two estimates, irrespective of beverage type. There was 89% agreement classifying drinkers versus nondrinkers by both approaches, with the strength of the agreement good (k=0.76). This agreement became moderate if drinkers were further categorized into three levels of alcohol intake. Predictors of the differences in alcohol intake between the two questionnaires were explored by multiple regression. Differences were largest for those who stated that the reason they drank was because they were no longer working, and for those drinking on average more than 24g (greater than approximately 2 drinks) of alcohol daily. Discussion: Although agreement between the two approaches was generally comparable, some findings may indicate that older adults who are problem drinkers or drink heavily report lower consumption patterns when administered a more directed questionnaire specifically focusing on drinking behavior. These findings have implications in the design of studies measuring alcohol consumption among elderly persons with a relatively low background alcohol intake.
Keywords: alcohol; elderly; measurement; questionnaire

Serum potassium level and dietary potassium intake as risk factors for stroke. - Green, D M; Ropper, A H; Kronmal, R A; Psaty, B M; Burke, G L (Neurology, 2002)
BACKGROUND: Numerous studies have found that low potassium intake and low serum potassium are associated with increased stroke mortality, but data regarding stroke incidence have been limited. Serum potassium levels, dietary potassium intake, and diuretic use in relation to risk for stroke in a prospectively studied cohort were investigated. METHODS: The study comprised 5,600 men and women older than 65 years who were free of stroke at enrollment. Baseline data included serum potassium level, dietary potassium intake, and diuretic use. Participants were followed for 4 to 8 years, and the incidence and types of strokes were recorded. Low serum potassium was defined as less than 4.1 mEq/L, and low potassium intake as less than 2.4 g/d. RESULTS: Among diuretic users, there was an increased risk for stroke associated with lower serum potassium (relative risk [RR]: 2.5, p < 0.0001). Among individuals not taking diuretics, there was an increased risk for stroke associated with low dietary potassium intake (RR: 1.5, p < 0.005). The small number of diuretic users with lower serum potassium and atrial fibrillation had a 10-fold greater risk for stroke compared with those with higher serum potassium and normal sinus rhythm. CONCLUSIONS: A lower serum potassium level in diuretic users, and low potassium intake in those not taking diuretics were associated with increased stroke incidence among older individuals. Lower serum potassium was associated with a particularly high risk for stroke in the small number of diuretic users with atrial fibrillation. Further study is required to determine if modification of these factors would prevent strokes.
Keywords: Aged; Cohort Studies; Confidence Intervals; Diuretics; Humans; Linear Models; Male; Potassium; Potassium, Dietary; Proportional Hazards Models; Prospective Studies; Risk Factors; Stroke

A stroke prediction score in the elderly: validation and Web-based application. - Lumley, Thomas; Kronmal, Richard A; Cushman, Mary; Manolio, Teri A; Goldstein, Steven (J Clin Epidemiol, 2002)
The objective of this study was to construct a prediction model for predicting stroke in an elderly U.S. population, and to assess the accuracy in this population of other previously published prediction models. The subjects were participants in the Cardiovascular Health Study: 2,495 men and 3,393 women age 65 years and older at baseline, and followed for 6.3 years. Among 5,711 participants free of baseline stroke, 399 strokes occurred. Sex-specific prediction equations were constructed using study variables that were most importantly related to incident stroke: age, systolic blood pressure, diabetes, ECG diagnosis of atrial fibrillation or left ventricular hypertrophy, confirmed history of cardiovascular disease, diabetes, time to walk 15 ft, and serum creatinine. The prediction rule was implemented as a risk score and in a Web-based interactive Java applet. Overall, the model predicted 5-year stroke risks ranging from less than 1 to 59%. The 20% of subjects in the highest predicted risk group had a 5-year actual stroke incidence rate of 15%, while the 20% lowest risk group had a 1% incidence. Risk scores from two other studies performed well in these study participants. Effective discrimination between low and high stroke risk in the elderly was possible in this cohort with data that are easy to obtain. Evaluation of the generalizability and clinical usefulness of this prediction model requires further research.
Keywords: Aged; Aged, 80 and over; Blood Pressure; Female; Follow-Up Studies; Humans; Incidence; Male; Models, Cardiovascular; Predictive Value of Tests; Risk Factors; ROC Curve; Stroke; United States

Time trends in high blood pressure control and the use of antihypertensive medications in older adults: the Cardiovascular Health Study. - Psaty, Bruce M; Manolio, Teri A; Smith, Nicholas L; Heckbert, Susan R; Gottdiener, John S; Burke, Gregory L; Weissfeld, Joel; Enright, Paul; Lumley, Thomas; Powe, Neil; Furberg, Curt D (Arch Intern Med, 2002)
BACKGROUND: Control of high blood pressure (BP) in older adults is an important part of public health efforts at prevention. OBJECTIVE: To assess recent time trends in the awareness, treatment, and control of high BP and in the use of medications to treat high BP. METHODS: In the Cardiovascular Health Study, 5888 adults 65 years and older were recruited from 4 US centers. At baseline, participants underwent an extensive examination that included the measurement of BP, use of medications, and other risk factors. Participants were followed up with annual visits that assessed BP and medication use from baseline in 1989-1990 through the examination in 1998-1999. The primary outcome measures were control of BP to levels lower than than 140/90 mm Hg and the prevalence of use of various classes of antihypertensive medications. RESULTS: The awareness, treatment, and control of high BP improved during the 1990s. The proportions aware and treated were higher among blacks than whites, though control prevalences were similar. For both groups combined, the control of high BP to lower than 140/90 mm Hg increased from 37% at baseline to 49% in 1999. The 51% whose BP was not controlled generally had isolated mild to moderate elevations in systolic BP. Among treated persons, the improvement in control was achieved in part by a mean increase of 0.2 antihypertensive medications per person over the course of 9 years. Improved control was also achieved by increasing the proportion of the entire Cardiovascular Health Study population that was treated for hypertension, from 34.5% in 1990 to 51.1% in 1999. Time trends in antihypertensive drug use were pronounced. Among those without coronary disease, the use of low-dose diuretics and beta-blockers decreased, while the use of newer agents, such as calcium channel blockers, angiotensin-converting enzyme inhibitors, and alpha-blockers increased. CONCLUSIONS: While control of high BP improved in the 1990s, about half the participants with hypertension had uncontrolled BP, primarily mild to moderate elevations in systolic BP. Low-dose diuretics and beta-blockers--the preferred agents since 1993 according to the recommendations of the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure--remained underused. More widespread use of these agents will be an important intervention to prevent the devastating complications of hypertension, including stroke, myocardial infarction, and heart failure.
Keywords: Age Factors; Aged; Antihypertensive Agents; Awareness; Cohort Studies; Drug Therapy; Female; Health Knowledge, Attitudes, Practice; Humans; Hypertension; Male; Prospective Studies; Time Factors

The 6-min walk test: a quick measure of functional status in elderly adults. - Enright, Paul L; McBurnie, Mary Ann; Bittner, Vera; Tracy, Russell P; McNamara, Robert; Arnold, Alice; Newman, Anne B (Chest, 2003)
OBJECTIVES: To determine the correlates of the total 6-min walk distance (6MWD) in a population sample of adults > or = 68 years old. METHODS: The standardized 6-min walk test (6MWT) was administered to the Cardiovascular Health Study cohort during their seventh annual examination. RESULTS: Of the 3,333 participants with a clinic visit, 2,281 subjects (68%) performed the 6MWT. There were no untoward events. The mean 6MWD was 344 m (SD, 88 m). Independent general correlates of a shorter 6MWD in linear regression models in women and men included the following: older age, higher weight, larger waist, weaker grip strength, symptoms of depression, and decreased mental status. Independent disease or risk factor correlates of a shorter 6MWD included the following: a low ankle BP, use of angiotensin-converting enzyme inhibitors, and arthritis in men and women; higher C-reactive protein, diastolic hypertension, and lower FEV(1) in women; and the use of digitalis in men. Approximately 30% of the variance in 6MWD was explained by the linear regression models. Newly described bivariate associations of a shorter 6MWD included impaired activities of daily living; self-reported poor health; less education; nonwhite race; a history of coronary heart disease, transient ischemic attacks, stroke, or diabetes; and higher levels of C-reactive protein, fibrinogen, or WBC count. CONCLUSIONS: Most community-dwelling elderly persons can quickly and safely perform this functional status test in the outpatient clinic setting. The test may be used clinically to measure the impact of multiple comorbidities, including cardiovascular disease, lung disease, arthritis, diabetes, and cognitive dysfunction and depression, on exercise capacity and endurance in older adults. Expected values should be adjusted for the patient's age, gender, height, and weight.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Cardiovascular Diseases; Cohort Studies; Coronary Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Exercise Test; Female; Humans; Ischemic Attack, Transient; Linear Models; Male; Mass Screening; Sensitivity and Specificity; Stroke; United States; Walking

Alcohol consumption and carotid atherosclerosis in older adults: the Cardiovascular Health Study. - Mukamal, Kenneth J; Kronmal, Richard A; Mittleman, Murray A; O'Leary, Daniel H; Polak, Joseph F; Cushman, Mary; Siscovick, David S (Arterioscler Thromb Vasc Biol, 2003)
OBJECTIVE: The association of alcohol use with atherosclerosis is inconsistent in previous studies. METHODS AND RESULTS: For the Cardiovascular Health Study, 5888 adults aged 65 years and older underwent a standardized interview and examination. They reported beer, wine, and liquor use individually and underwent B-mode ultrasonography to determine internal and common carotid intima-media thickness (IMT). We compared composite carotid IMT values cross-sectionally using linear regression to adjust for demographic and clinical characteristics. Among 4247 participants free of cardiovascular disease, consumers of 1 to 6 drinks per week had 0.07+/-0.04-mm lower composite IMT and consumers of 14 or more drinks per week had 0.07+/-0.05-mm higher IMT than abstainers (P quadratic trend=0.02). We found similar relationships using internal and common carotid thickness measures and among men and women. The higher IMT associated with heavier alcohol use was particularly strong among 1592 participants with confirmed cardiovascular disease (0.24+/-0.09 mm greater than abstainers). Controlling for HDL cholesterol levels reduced the effect on composite IMT among consumers of 1 to 6 drinks per week by 22%. CONCLUSIONS: Relative to older adults who abstain from alcohol, consumption of 1 to 6 drinks per week had an inverse association with carotid atherosclerosis whereas consumption of 14 or more drinks had a positive association.
Keywords: Aged; Alcohol Drinking; Cardiovascular Diseases; Carotid Artery Diseases; Cross-Sectional Studies; Female; Health Surveys; Humans; Longitudinal Studies; Male; Prospective Studies

The association between time since last meal and blood pressure in older adults: the cardiovascular health study. - Smith, Nicholas L; Psaty, Bruce M; Rutan, Gale H; Lumley, Thomas; Yanez, David; Chaves, Paulo H M; Kronmal, Richard A (J Am Geriatr Soc, 2003)
OBJECTIVES: To demonstrate a postprandial hypotensive (PPH) phenomenon in older adults. DESIGN: Observational, prospective cohort study composed of baseline and nine follow-up visits. SETTING: Cardiovascular Health Study, an epidemiological study of risk factors for cardiovascular disease in older adults. PARTICIPANTS: Five thousand eight hundred eighty-eight community-dwelling adults aged 65 and older. MEASUREMENTS: Blood pressure and time since last meal were recorded synchronously at baseline and at follow-up clinic visits. Generalized estimating equations were used to estimate associations between time since last meal and blood pressure and to adjust variance estimates to account for repeated blood pressure measures within subjects across fasting times. RESULTS: Mean systolic and diastolic blood pressures were lower in the first hour after the last meal and were progressively higher through the fourth hour after the last meal than blood pressures measured immediately after the last meal (0 hour: 133.7/68.8 mmHg; 1st hour: 130.1/66.6 mmHg; 4th hour: 136.5/71.1 mmHg). Changes were significant for systolic and diastolic measures (P <.001 for both). Exploratory analyses suggested that the systolic PPH association was more pronounced in women. Little evidence was found that the degree of systolic or diastolic PPH varied by age, race, prevalent cardiovascular disease, heart rate, ejection fraction, treated hypertension or diabetes mellitus, or body mass index. CONCLUSION: These data support previous observations that there is a significant drop in blood pressure within 1 hour after a meal in older adults. Time since last meal may be an important factor to consider when measuring blood pressure in older adults, and perhaps national standards need to be set.
Keywords: Aged; Blood Pressure; Cardiovascular Diseases; Cohort Studies; Eating; Female; Humans; Hypotension; Male; Postprandial Period; Prospective Studies; Risk Factors; Time Factors

Cardiac benefits of fish consumption may depend on the type of fish meal consumed: the Cardiovascular Health Study. - Mozaffarian, Dariush; Lemaitre, Rozenn N; Kuller, Lewis H; Burke, Gregory L; Tracy, Russell P; Siscovick, David S (Circulation, 2003)
BACKGROUND: Few studies have examined associations of fish consumption with ischemic heart disease (IHD) risk among older adults or how different types of fish meals relate to IHD risk. METHODS AND RESULTS: In a population-based prospective cohort study, usual fish consumption was ascertained at baseline among 3910 adults aged > or =65 years and free of known cardiovascular disease in 1989 and 1990. Consumption of tuna and other broiled or baked fish correlated with plasma phospholipid long-chain n-3 fatty acids, whereas consumption of fried fish or fish sandwiches (fish burgers) did not. Over 9.3 years' mean follow-up, there were 247 IHD deaths (including 148 arrhythmic deaths) and 363 incident nonfatal myocardial infarctions (MIs). After adjustment for potential confounders, consumption of tuna or other broiled or baked fish was associated with lower risk of total IHD death (P for trend=0.001) and arrhythmic IHD death (P=0.001) but not nonfatal MI (P=0.44), with 49% lower risk of total IHD death and 58% lower risk of arrhythmic IHD death among persons consuming tuna/other fish 3 or more times per week compared with less than once per month. In similar analyses, fried fish/fish sandwich consumption was not associated with lower risk of total IHD death, arrhythmic IHD death, or nonfatal MI but rather with trends toward higher risk. CONCLUSIONS: Among adults aged > or =65 years, modest consumption of tuna or other broiled or baked fish, but not fried fish or fish sandwiches, is associated with lower risk of IHD death, especially arrhythmic IHD death. Cardiac benefits of fish consumption may vary depending on the type of fish meal consumed.
Keywords: Aged; Animals; Arrhythmias, Cardiac; Diet; Eating; Fatty Acids, Omega-3; Female; Fishes; Humans; Male; Myocardial Infarction; Myocardial Ischemia; Prospective Studies; Risk; Tuna

C-reactive protein, carotid intima-media thickness, and incidence of ischemic stroke in the elderly: the Cardiovascular Health Study. - Cao, Jie J; Thach, Chau; Manolio, Teri A; Psaty, Bruce M; Kuller, Lewis H; Chaves, Paulo H M; Polak, Joseph F; Sutton-Tyrrell, Kim; Herrington, David M; Price, Thomas R; Cushman, Mary (Circulation, 2003)
BACKGROUND: Increased carotid artery intima-media thickness (IMT) and elevated C-reactive protein (CRP) are both associated with the occurrence of stroke. We investigated whether elevated CRP is a risk factor for ischemic stroke independent of carotid IMT and studied the interaction between CRP and IMT. METHODS AND RESULTS: We studied 5417 participants aged 65 years or older without preexisting stroke or chronic atrial fibrillation who were participants in the Cardiovascular Health Study. The hazard ratio of incident ischemic stroke was estimated by Cox proportional hazards regression. During 10.2 years of follow-up, 469 incident ischemic strokes occurred. The adjusted hazard ratios for ischemic stroke in the 2nd to 4th quartiles of baseline CRP, relative to the 1st quartile, were 1.19 (95% CI 0.92 to 1.53), 1.05 (95% CI 0.81 to 1.37), and 1.60 (95% CI 1.23 to 2.08), respectively. With additional adjustment for carotid IMT, there was little confounding. The association of CRP with stroke was significantly different depending on IMT (P<0.02), with no association of CRP with stroke among those in the lowest IMT tertile and a significant association among those with higher levels of IMT. CONCLUSIONS: We conclude that elevated CRP is a risk factor for ischemic stroke, independent of atherosclerosis severity as measured by carotid IMT. The association of CRP with stroke is more apparent in the presence of a higher carotid IMT. CRP and carotid IMT may each be independent integrals in determining the risk of ischemic stroke.
Keywords: Aged; Brain Ischemia; C-Reactive Protein; California; Carotid Arteries; Cohort Studies; Comorbidity; Female; Follow-Up Studies; Humans; Incidence; Longitudinal Studies; Male; Maryland; North Carolina; Odds Ratio; Pennsylvania; Proportional Hazards Models; Risk Assessment; Risk Factors; Stroke; Tunica Intima; Tunica Media; Ultrasonography

Elevations of inflammatory and procoagulant biomarkers in elderly persons with renal insufficiency. - Shlipak, Michael G; Fried, Linda F; Crump, Casey; Bleyer, Anthony J; Manolio, Teri A; Tracy, Russell P; Furberg, Curt D; Psaty, Bruce M (Circulation, 2003)
BACKGROUND: Renal insufficiency has been associated with cardiovascular disease events and mortality in several prospective studies, but the mechanisms for the elevated risk are not clear. Little is known about the association of renal insufficiency with inflammatory and procoagulant markers, which are potential mediators for the cardiovascular risk of kidney disease. METHODS AND RESULTS: The cross-sectional association of renal insufficiency with 8 inflammatory and procoagulant factors was evaluated using baseline data from the Cardiovascular Health Study, a population-based cohort study of 5888 subjects aged > or =65 years. C-reactive protein, fibrinogen, factor VIIc, and factor VIIIc levels were measured in nearly all participants; interleukin-6, intercellular adhesion molecule-1, plasmin-antiplasmin complex, and D-dimer levels were measured in nearly half of participants. Renal insufficiency was defined as a serum creatinine level > or =1.3 mg/dL in women and > or =1.5 mg/dL in men. Multivariate linear regression was used to compare adjusted mean levels of each biomarker in persons with and without renal insufficiency after adjustment for other baseline characteristics. Renal insufficiency was present in 647 (11%) of Cardiovascular Health Study participants. After adjustment for baseline differences, levels of C-reactive protein, fibrinogen, interleukin-6, factor VIIc, factor VIIIc, plasmin-antiplasmin complex, and D-dimer were significantly greater among persons with renal insufficiency (P<0.001). In participants with clinical, subclinical, and no cardiovascular disease at baseline, the positive associations of renal insufficiency with these inflammatory and procoagulant markers were similar. CONCLUSION: Renal insufficiency was independently associated with elevations in inflammatory and procoagulant biomarkers. These pathways may be important mediators leading to the increased cardiovascular risk of persons with kidney disease.
Keywords: Aged; alpha-2-Antiplasmin; Biomarkers; Blood Coagulation Factors; C-Reactive Protein; Cardiovascular Diseases; Cohort Studies; Creatinine; Cross-Sectional Studies; Female; Fibrin Fibrinogen Degradation Products; Fibrinogen; Fibrinolysin; Humans; Inflammation; Interleukin-6; Male; Prospective Studies; Renal Insufficiency; Risk Factors

Fibrin fragment D-dimer and the risk of future venous thrombosis. - Cushman, Mary; Folsom, Aaron R; Wang, Lu; Aleksic, Nena; Rosamond, Wayne D; Tracy, Russell P; Heckbert, Susan R (Blood, 2003)
Plasma D-dimer concentration rises more than 100-fold during acute deep vein thrombosis, but there are no prospective data concerning D-dimer as a risk factor for incident venous thrombosis in a general population. Incident venous thrombosis was ascertained in 2 prospective observational studies, the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. Of 21 690 participants enrolled between 1987 and 1993, after 8 years of follow-up, D-dimer was measured using baseline stored plasma of 307 participants who developed venous thrombosis and 616 who did not. Relative to the first quintile of the distribution of D-dimer, the age-adjusted odds ratios for future venous thrombosis for the second to fifth quintiles of D-dimer were 1.6, 2.3, 2.3, and 4.2, respectively (P for trend <.0001). Following added adjustment for sex, race, body mass index, factor V Leiden, prothrombin 20210A, and elevated factor VIII coagulant activity (factor VIII:c), these odds ratios were 1.5, 2.1, 1.9, and 3.0, respectively (P for trend <.0001). Among those with idiopathic thrombosis or secondary thrombosis unrelated to cancer, the adjusted fifth quintile odds ratios were 3.5 and 4.8, respectively. By contrast, D-dimer in the fifth versus first quintile was not related to occurrence of cancer-associated thrombosis (odds ratio, 1.1). Odds ratios for elevated D-dimer were consistently elevated in subgroups defined by age, sex, race, duration of follow-up, and thrombosis type (deep vein thrombosis or pulmonary embolus). D-dimer is strongly and positively related to the occurrence of future venous thrombosis.
Keywords: Aged; Body Mass Index; Cohort Studies; Continental Population Groups; Factor V; Factor VIII; Female; Fibrin Fibrinogen Degradation Products; Humans; Longitudinal Studies; Male; Middle Aged; Odds Ratio; Prospective Studies; Prothrombin; Risk Factors; Venous Thrombosis

Hormone replacement therapy and the risk of incident congestive heart failure: the Cardiovascular Health Study. - Rea, Thomas D; Psaty, Bruce M; Heckbert, Susan R; Cushman, Mary; Meilahn, Elaine; Olson, Jean L; Lemaitre, Rozenn N; Smith, Nicholas L; Sotoodehnia, Nona; Chaves, Paulo H M (J Womens Health (Larchmt), 2003)
BACKGROUND: The development of congestive heart failure (CHF) in older persons is related to a variety of mechanisms. Hormone replacement therapy (HRT) affects several of the pathways that may be important in the development of CHF. We hypothesized that HRT would be associated with a decreased risk of incident CHF. METHODS: Using Cox proportional-hazards regression, we assessed the risk of incident CHF (n = 304) associated with time-dependent past and current use of HRT compared to never use. The Cardiovascular Health Study is a prospective cohort study of community-dwelling adults aged 65 years and older. This analysis included female participants without a history of CHF at baseline (n = 3223). RESULTS: At baseline, 62% were never users, 26% were past users, and 12% were current users of HRT. Compared with never users, the multivariable relative risk (RR) of CHF was 1.01 (95% confidence interval [95% CI] 0.76,1.34) for past users and 1.34 (0.93,1.94) for current users. Results were similar among most treatment and clinical subgroups, except that the association of current HRT with CHF appeared to depend on body mass index (BMI) or osteoporosis status. The RR was 0.82 (0.43,1.60) for normal weight women, 1.65 (0.95,2.88) for overweight women, and 2.22 (1.06,4.67) for obese women (p = 0.01 for interaction). Similarly, the RR was 0.15 (0.04,0.65) for women with osteoporosis and 1.82 (1.25,2.65) for women without osteoporosis (p = 0.001 for interaction). CONCLUSIONS: Overall, HRT was not associated with the risk of incident CHF, although BMI and osteoporosis appeared to modify the association of HRT with CHF. The risk of CHF was lower in patients with lower BMI or osteoporosis.
Keywords: Aged; Aged, 80 and over; Body Mass Index; Cohort Studies; Estrogen Replacement Therapy; Female; Heart Failure; Humans; Incidence; Life Style; Middle Aged; Multivariate Analysis; Obesity; Osteoporosis, Postmenopausal; Proportional Hazards Models; Prospective Studies; Risk; Risk Factors; United States; Women's Health

Inflammation as a risk factor for atrial fibrillation. - Aviles, Ronnier J; Martin, David O; Apperson-Hansen, Carolyn; Houghtaling, Penny L; Rautaharju, Pentti; Kronmal, Richard A; Tracy, Russell P; Van Wagoner, David R; Psaty, Bruce M; Lauer, Michael S; Chung, Mina K (Circulation, 2003)
BACKGROUND: The presence of systemic inflammation determined by elevations in C-reactive protein (CRP) has been associated with persistence of atrial fibrillation (AF). The relationship between CRP and prediction of AF has not been studied in a large population-based cohort. METHODS AND RESULTS: CRP measurement and cardiovascular assessment were performed at baseline in 5806 subjects enrolled in the Cardiovascular Health Study. Patients were followed up for a mean of 6.9+/-1.6 (median 7.8) years. AF was identified by self-reported history and ECGs at baseline and by ECGs and hospital discharge diagnoses at follow-up. Univariate and multivariate analyses were used to assess CRP as a predictor of baseline and future development of AF. At baseline, 315 subjects (5%) had AF. Compared with subjects in the first CRP quartile (<0.97 mg/L), subjects in the fourth quartile (>3.41 mg/L) had more AF (7.4% versus 3.7%, adjusted OR 1.8, 95% CI 1.2 to 2.5; P=0.002). Of 5491 subjects without AF at baseline, 897 (16%) developed AF during follow-up. Baseline CRP predicted higher risk for developing future AF (fourth versus first quartile adjusted hazard ratio 1.31, 95% CI 1.08 to 1.58; P=0.005). When treated as a continuous variable, elevated CRP predicted increased risk for developing future AF (adjusted hazard ratio for 1-SD increase, 1.24; 95% CI 1.11 to 1.40; P<0.001). CONCLUSIONS: CRP is not only associated with the presence of AF but may also predict patients at increased risk for future development of AF.
Keywords: Aged; Atrial Fibrillation; C-Reactive Protein; Cross-Sectional Studies; Female; Humans; Inflammation; Longitudinal Studies; Male; Risk Factors

Lack of association of the plasminogen activator inhibitor-1 4G/5G promoter polymorphism with cardiovascular disease in the elderly. - Crainich, P; Jenny, N S; Tang, Z; Arnold, A M; Kuller, L H; Manolio, T; Sharrett, A R; Tracy, R P (J Thromb Haemost, 2003)
Elevated circulating plasminogen activator inhibitor-1 (PAI-1) may increase risk of cardiovascular disease (CVD). The 4G allele of the 4G/5G PAI-1 promoter polymorphism is associated with higher levels of PAI-1. We examined the association of PAI-1 4G/5G genotype and CVD events in the elderly participants of the Cardiovascular Health Study (CHS). We measured 4G/5G genotype in a nested case-control study within the CHS. Cases included incident angina, myocardial infarction (MI), and stroke. 4G/5G genotype was not found to be associated with markers of fibrinolysis or CVD risk in the selected elderly cohort. There were no differences in genotype frequencies by case-control status (5G/5G frequency 16-22%; chi2P= 0.07). The 5G allele was not associated with incident CVD events when individuals with at least one 5G allele were compared to 4G/4G homozygotes. The presence of at least one 4G allele was likewise not associated with incident CVD when those with 4G/4G and 4G/5G genotypes were compared to 5G/5G homozygotes. Our results suggest that the PAI-1 4G/5G promoter polymorphism is not associated CVD risk factors or incident CVD events in the elderly.
Keywords: African Continental Ancestry Group; Aged; Alleles; Cardiovascular Diseases; Case-Control Studies; Cohort Studies; European Continental Ancestry Group; Female; Genotype; Homozygote; Humans; Male; Myocardial Infarction; Plasminogen Activator Inhibitor 1; Polymorphism, Genetic; Promoter Regions, Genetic; Risk

Lp(a) lipoprotein, vascular disease, and mortality in the elderly. - Ariyo, Abraham A; Thach, Chau; Tracy, Russell (N Engl J Med, 2003)
BACKGROUND: As compared with what is known about predictors of vascular events in middle-aged persons, less is known about these events in the elderly. Lp(a) lipoprotein, which plays an important part in atherothrombogenesis, has been associated with an increased risk of vascular disease. We investigated this relation among older U.S. adults. METHODS: In a prospective study of 5888 community-dwelling older adults (65 years of age or older) in the United States, 2375 women and 1597 men who were free of vascular disease provided base-line serum samples for analysis for levels of Lp(a) lipoprotein. These 3972 subjects were followed for a median of 7.4 years to evaluate the development of stroke and to track deaths from vascular causes and all causes. The men and women were divided into quintile groups according to the Lp(a) lipoprotein level at base line. RESULTS: Using Cox proportional-hazards models, we determined the risk associated with each quintile level of Lp(a) lipoprotein, with the lowest quintile serving as the reference group. As compared with those in the lowest quintile, men in the highest quintile had three times the unadjusted risk of stroke (relative risk, 3.00; 95 percent confidence interval, 1.59 to 5.65), almost three times the risk of death associated with vascular events (relative risk, 2.54; 95 percent confidence interval, 1.59 to 4.08), and nearly twice the risk of death from all causes (relative risk, 1.76; 95 percent confidence interval, 1.31 to 2.36). Adjustment for age; sex; the levels of total cholesterol, low-density lipoprotein cholesterol, and triglycerides; carotid-wall thickness; smoking status; the presence or absence of diabetes and systolic and diastolic hypertension; body-mass index; and other traditional risk factors had little effect on the final assessments. Similar analyses for women, which also included adjustment for estrogen use or nonuse, revealed no such relation. CONCLUSIONS: Among older adults in the United States, an elevated level of Lp(a) lipoprotein is an independent predictor of stroke, death from vascular disease, and death from any cause in men but not in women. These data support the use of Lp(a) lipoprotein levels in predicting the risk of these events in older men.
Keywords: Aged; Coronary Disease; Female; Humans; Incidence; Lipoprotein(a); Male; Mortality; Proportional Hazards Models; Prospective Studies; Risk Factors; Sex Factors; Stroke; Survival Analysis; United States; Vascular Diseases

Prevalence and classification of mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 1. - Lopez, Oscar L; Jagust, William J; DeKosky, Steven T; Becker, James T; Fitzpatrick, Annette; Dulberg, Corinne; Breitner, John; Lyketsos, Constantine; Jones, Beverly; Kawas, Claudia; Carlson, Michelle; Kuller, Lewis H (Arch Neurol, 2003)
OBJECTIVE: To examine the prevalence of mild cognitive impairment (MCI) and its diagnostic classification in the Cardiovascular Health Study (CHS) Cognition Study. DESIGN: The CHS Cognition Study is an ancillary study of the CHS that was conducted to determine the presence of MCI and dementia in the CHS cohort. SETTING: Multicenter population study. PATIENTS: We examined 3608 participants in the CHS who had undergone detailed neurological, neuropsychological, neuroradiological, and psychiatric testing to identify dementia and MCI. MAIN OUTCOME MEASURES: The prevalence of MCI was determined for the whole cohort, and specific subtypes of MCI were examined in detail only at the Pittsburgh, Pa, center (n = 927). Mild cognitive impairment was classified as either MCI amnestic-type or MCI multiple cognitive deficits-type. RESULTS: The overall prevalence of MCI was 19% (465 of 2470 participants); prevalence increased with age from 19% in participants younger than 75 years to 29% in those older than 85 years. The overall prevalence of MCI at the Pittsburgh center was 22% (130 of 599 participants); prevalence of the MCI amnesic-type was 6% and of the MCI multiple cognitive deficits-type was 16%. CONCLUSIONS: Twenty-two percent of the participants aged 75 years or older had MCI. Mild cognitive impairment is a heterogeneous syndrome, where the MCI amnestic-type is less frequent than the MCI multiple cognitive deficits-type. Most of the participants with MCI had comorbid conditions that may affect their cognitive functions.
Keywords: Aged; Aged, 80 and over; Cardiovascular Diseases; Cognition Disorders; Cohort Studies; Dementia; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Memory Disorders; Neuropsychological Tests; Pennsylvania; Population; Psychiatric Status Rating Scales

Prospective study of fibrinolytic markers and venous thromboembolism. - Folsom, Aaron R; Cushman, Mary; Heckbert, Susan R; Rosamond, Wayne D; Aleksic, Nena (J Clin Epidemiol, 2003)
Prior research has conflicted on whether increased levels of plasma fibrinolytic factors may identify patients at risk of venous thromboembolism (VTE). We therefore performed a nested case-control study of VTE within two prospective population-based studies. In 308 participants who developed VTE and 640 controls, we measured PAI-1 antigen, tPA/PAI-1 complex, plasmin-alpha 2-antiplasmin (PAP), and the PAI-1 -675 4G/5G promoter polymorphism on pre-event blood samples. There was no overall association between any of these fibrinolytic variables and VTE, after adjustment for age or for multiple VTE risk factors. There was weak evidence for an interaction of PAP with elevated factor VIIIc and elevated D-dimer in augmenting VTE risk. We conclude that, for the most part, these fibrinolytic markers do not identify healthy subjects at risk for VTE.
Keywords: Aged; alpha-2-Antiplasmin; Antifibrinolytic Agents; Biomarkers; Caenorhabditis elegans Proteins; Case-Control Studies; Female; Fibrinolysin; Fibrinolysis; Humans; Male; Middle Aged; Odds Ratio; Plasminogen Activator Inhibitor 1; Prognosis; Prospective Studies; Protein-Tyrosine Kinases; Risk Factors; Thromboembolism; Venous Thrombosis

Prospective study of the A455V polymorphism in the thrombomodulin gene, plasma thrombomodulin, and incidence of venous thromboembolism: the LITE Study. - Aleksic, N; Folsom, A R; Cushman, M; Heckbert, S R; Tsai, M Y; Wu, K K (J Thromb Haemost, 2003)
Plasma thrombomodulin (soluble TM; sTM) is considered to be a marker of endothelial injury, but a recent report indicated that the relationship of sTM with thrombosis is complex. Venous thromboembolic events were identified in adults in two longitudinal cohort studies, the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study, totaling 21 690 participants. After 8 years of follow-up, sTM was measured in baseline plasma of 305 participants who developed venous thrombosis and 607 who did not. Thrombomodulin A455V genotype was determined in 302 cases and 626 controls. There was no difference in the prevalence of the three TM genotypes between cases and controls and no difference in age-adjusted mean values of sTM by genotype. There were no associations of age-adjusted sTM or TMA455V genotype with overall venous thromboembolism or with thrombosis in any subtype of venous thromboembolism.
Keywords: Age Factors; Aged; Amino Acid Substitution; Case-Control Studies; Female; Genotype; Humans; Incidence; Male; Polymorphism, Genetic; Prevalence; Prospective Studies; Risk Factors; Thromboembolism; Thrombomodulin; Venous Thrombosis

Relationships between renovascular disease, blood pressure, and renal function in the elderly: a population-based study. - Edwards, Matthew S; Hansen, Kimberley J; Craven, Timothy E; Cherr, Gregory S; Bleyer, Anthony J; Burke, Gregory L; Dean, Richard H (Am J Kidney Dis, 2003)
BACKGROUND: The purpose of this study is to examine the associations between renovascular disease (RVD) and cross-sectional measures of blood pressure and renal function among participants in the Cardiovascular Health Study (CHS). METHODS: The CHS is a prospective cohort study of cardiovascular disease among elderly Americans. As part of an ancillary study, participants in the Forsyth County, NC, cohort of the CHS were invited to undergo renal duplex sonography (RDS) to define the presence or absence of RVD (defined as any focal peak systolic velocity > or = 1.8 milliseconds or the absence of a Doppler shifted signal from an imaged artery). Demographic, risk factor, blood pressure, and serum creatinine data were obtained at the time of RDS and from the annual CHS examination. RESULTS: Eight hundred thirty-four CHS participants (including 525 women [63%], 309 men [37%], 194 African Americans [23%], and 635 Caucasians [76%]) with a mean age of 77.2 +/- 4.9 years underwent successful RDS. RVD was present in 57 participants (6.8%). When examined according to the presence or absence of RVD, significant univariate differences were observed in the prevalence of clinical hypertension (72% versus 50%; P = 0.001), systolic blood pressure (145 versus 136 mm Hg; P = 0.001), and renal insufficiency (16% versus 8%; P = 0.041). Multivariate analyses showed significant and independent associations for the presence of RVD with increasing systolic blood pressure (P = 0.034), clinical hypertension (odds ratio, 2.68; 95% confidence interval, 1.44 to 4.99; P = 0.002), increasing serum creatinine level, and renal insufficiency (odds ratio, 2.21; 95% confidence interval, 1.02 to 4.79; P = 0.043). A significant interaction was observed between the presence of RVD and increasing systolic blood pressure in association with increasing serum creatinine levels (P = 0.041). CONCLUSION: These results suggest important population-based associations between RVD and cross-sectional measures of blood pressure and renal function. Furthermore, the observed relationship between RVD and increasing serum creatinine level was influenced strongly by increasing blood pressure.
Keywords: Aged; Blood Pressure; Female; Humans; Hypertension; Kidney; Kidney Diseases; Male; Prospective Studies; Ultrasonography, Doppler, Duplex; Vascular Diseases

Renal insufficiency as a predictor of cardiovascular outcomes and mortality in elderly individuals. - Fried, Linda F; Shlipak, Michael G; Crump, Casey; Bleyer, Anthony J; Gottdiener, John S; Kronmal, Richard A; Kuller, Lewis H; Newman, Anne B (J Am Coll Cardiol, 2003)
OBJECTIVES: This study was designed to evaluate the relationship between elevated creatinine levels and cardiovascular events. BACKGROUND: End-stage renal disease is associated with high cardiovascular morbidity and mortality. The association of mild to moderate renal insufficiency with cardiovascular outcomes remains unclear. METHODS: We analyzed data from the Cardiovascular Health Study, a prospective population-based study of subjects, aged >65 years, who had a serum creatinine measured at baseline (n = 5,808) and were followed for a median of 7.3 years. Proportional hazards models were used to examine the association of creatinine to all-cause mortality and incident cardiovascular mortality and morbidity. Renal insufficiency was defined as a creatinine level > or =1.5 mg/dl in men or > or =1.3 mg/dl in women. RESULTS: An elevated creatinine level was present in 648 (11.2%) participants. Subjects with elevated creatinine had higher overall (76.7 vs. 29.5/1,000 years, p < 0.001) and cardiovascular (35.8 vs. 13.0/1,000 years, p < 0.001) mortality than those with normal creatinine levels. They were more likely to develop cardiovascular disease (54.0 vs. 31.8/1,000 years, p < 0.001), stroke (21.1 vs. 11.9/1,000 years, p < 0.001), congestive heart failure (38.7 vs. 17/1,000 years, p < 0.001), and symptomatic peripheral vascular disease (10.6 vs. 3.5/1,000 years, p < 0.001). After adjusting for cardiovascular risk factors and subclinical disease measures, elevated creatinine remained a significant predictor of all-cause and cardiovascular mortality, total cardiovascular disease (CVD), claudication, and congestive heart failure (CHF). A linear increase in risk was observed with increasing creatinine. CONCLUSIONS: Elevated creatinine levels are common in older adults and are associated with increased risk of mortality, CVD, and CHF. The increased risk is apparent early in renal disease.
Keywords: Aged; Cardiovascular Diseases; Confidence Intervals; Creatinine; Female; Heart Failure; Humans; Intermittent Claudication; Kidney Failure, Chronic; Male; Odds Ratio; Predictive Value of Tests; Survival Analysis

Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. - Lopez, Oscar L; Jagust, William J; Dulberg, Corinne; Becker, James T; DeKosky, Steven T; Fitzpatrick, Annette; Breitner, John; Lyketsos, Constantine; Jones, Beverly; Kawas, Claudia; Carlson, Michelle; Kuller, Lewis H (Arch Neurol, 2003)
OBJECTIVE: To examine the risk factors for mild cognitive impairment (MCI) in a longitudinal population study-the Cardiovascular Health Study Cognition Study. DESIGN: We examined the factors that in the period 1991 through 1994 predicted the development of MCI in all participants of the Cardiovascular Health Study Cognition Study. Further examination was conducted in the Pittsburgh, Pa, cohort (n = 927), where participants with MCI were classified as having either the MCI amnestic-type or the MCI multiple cognitive deficits-type. SETTING: Multicenter population study. PATIENTS: This study includes all participants of the Cardiovascular Health Study Cognition Study (n = 3608) who had a magnetic resonance imaging (MRI) scan of the brain between 1991 and 1994, and detailed neuropsychological, neurological, and medical evaluations to identify the presence of MCI or dementia in the period 1998 to 1999. The mean time between the closest clinical examination to the MRI and the diagnostic evaluation for cognitive disorders was 5.8 years for the Cardiovascular Health Study Cognition Study cohort and 6.0 years for the Pittsburgh cohort. MAIN OUTCOME MEASURES: Risk factors for MCI at the time of the MRI were identified using logistic regression, controlling for age, race, educational level, baseline Modified Mini-Mental State Examination and Digit Symbol Test scores, measurements of depression, MRI findings (atrophy, ventricular volume, white matter lesions, and infarcts), the presence of the apolipoprotein E (APOE) epsilon4 allele, hypertension, diabetes mellitus, and heart disease. RESULTS: Mild cognitive impairment (n = 577) was associated with race (African American), low educational level, low Modified Mini-Mental State Examination and Digit Symbol Test scores, cortical atrophy, MRI-identified infarcts, and measurements of depression. The MCI amnestic-type was associated with MRI-identified infarcts, the presence of the APOE epsilon4 allele, and low Modified Mini-Mental State Examination scores. The MCI multiple cognitive deficits-type was associated with low Modified Mini-Mental State Examination and Digit Symbol Test scores. CONCLUSIONS: The development of MCI is associated with measurements of cognition and depression, racial and constitutional factors, and cerebrovascular disease. Early cognitive deficits seem to be a common denominator for the 2 forms of MCI; the presence of cerebrovascular disease and the APOE epsilon4 allele is associated with the amnestic type of MCI.
Keywords: Aged; Apolipoprotein E4; Apolipoproteins E; Brain; Cardiovascular Diseases; Cognition Disorders; Cohort Studies; Depressive Disorder; Female; Humans; Logistic Models; Longitudinal Studies; Magnetic Resonance Imaging; Male; Mood Disorders; Pennsylvania; Population; Risk Factors

Serum homocysteine, thermolabile variant of methylene tetrahydrofolate reductase (MTHFR), and venous thromboembolism: Longitudinal Investigation of Thromboembolism Etiology (LITE). - Tsai, Albert W; Cushman, Mary; Tsai, Michael Y; Heckbert, Susan R; Rosamond, Wayne D; Aleksic, Nena; Yanez, N David; Psaty, Bruce M; Folsom, Aaron R (Am J Hematol, 2003)
We sought to examine prospectively the association of serum homocysteine and the methylene tetrahydrofolate reductase (MTHFR) C677T gene polymorphism with risk of venous thromboembolism (VTE). We studied these relationships in a nested case-control study of 303 VTE cases and 635 matched controls from a population-based cohort of 21,680 adults from six U.S. communities. The highest quintile of serum homocysteine carried a non-statistically significant adjusted odds ratio of 1.55 (95% CI, 0.93-2.58) compared to the lowest quintile in the overall cohort but a significant association among adults aged 45-64 years (OR = 2.05, 95% CI, 1.10-3.83) and an inverse association in those > or = 65 years of age. Carriers of the MTHFR C677T polymorphism were not at higher risk for VTE than those with normal genotype (OR = 0.74, 95% CI = 0.56-0.98). Our prospective data showed, at most, a weak relationship between homocysteine and VTE risk, with associations larger among younger participants. MTHFR C677T was not a risk factor for VTE.
Keywords: Aged; Aging; Animals; Case-Control Studies; Cohort Studies; Factor V; Female; Genotype; Homocysteine; Humans; Longitudinal Studies; Male; Methylenetetrahydrofolate Reductase (NADPH2); Middle Aged; Odds Ratio; Oxidoreductases Acting on CH-NH Group Donors; Polymorphism, Genetic; Prospective Studies; Risk Factors; Venous Thrombosis

"Successful aging": effect of subclinical cardiovascular disease. - Newman, Anne B; Arnold, Alice M; Naydeck, Barbara L; Fried, Linda P; Burke, Gregory L; Enright, Paul; Gottdiener, John; Hirsch, Calvin; O'Leary, Daniel; Tracy, Russell (Arch Intern Med, 2003)
BACKGROUND: Cardiovascular diseases are the primary cause of death in older adults. Among those without clinical disease, high levels of subclinical disease are associated with poor survival. The effect of the extent of subclinical cardiovascular disease on the quality of the remaining years has not been defined. METHODS: In a longitudinal cohort study, 2932 men and women aged 65 years and older were followed up for 8 years to determine the likelihood of maintaining intact health and functioning. Successful aging was defined as remaining free of cardiovascular disease, cancer, and chronic obstructive pulmonary disease and with intact physical and cognitive functioning. RESULTS: Younger age at study entry and a lower extent of subclinical cardiovascular disease were independently associated with the likelihood of maintaining successful aging. In age-stratified summaries, those with subclinical disease had a trajectory of decline similar to subjects 5 years older without subclinical vascular disease. Regression analyses showed that the decline associated with subclinical disease was equivalent to 6.5 (95% confidence interval, 6.4-6.6) years of aging for women and 5.6 (95% confidence interval, 5.4-5.8) years of aging for men. Individual measures of the extent of cardiovascular disease, diabetes mellitus, smoking, and higher C-reactive protein level were also independently predictive of fewer years of successful aging, but none of these factors substantially attenuated the effect of age itself. CONCLUSIONS: There is a graded relationship between the extent of vascular disease measured noninvasively and the likelihood of maintaining intact health and function. Prevention of subclinical vascular disease may increase the quality and the quantity of years in late life.
Keywords: Aged; Aged, 80 and over; Aging; C-Reactive Protein; Cardiovascular Diseases; Female; Health Status; Humans; Longitudinal Studies; Male; Quality of Life; Regression Analysis; Risk Factors

Alcohol consumption and inflammatory markers in older adults: the Cardiovascular Health Study. - Mukamal, Kenneth J; Cushman, Mary; Mittleman, Murray A; Tracy, Russell P; Siscovick, David S (Atherosclerosis, 2004)
OBJECTIVE: We sought to determine the relation of alcohol intake and systemic inflammation in a population-based sample of older adults. METHODS AND RESULTS: As part of the Cardiovascular Health Study (CHS), 5865 adults aged 65 years and older reported their intake of beer, wine, and liquor. We determined white blood cell count (WBC), factor VIII coagulant activity (factor VIIIc), and levels of C-reactive protein (CRP), fibrinogen, and albumin as markers of systemic inflammation. Among participants without confirmed cardiovascular disease, alcohol consumption was inversely associated with WBC, factor VIIIc, and fibrinogen level, and positively associated with albumin concentration in multivariate analyses. We found no consistent modification of these results by sex, obesity, or beverage type. The relation of alcohol use and CRP levels was significantly modified by apoE genotype (P interaction 0.03), with a positive association among participants with an apoE4 allele (P = 0.05), but a trend toward an inverse association among those without an apoE4 allele (P = 0.15). CONCLUSIONS: Alcohol intake is associated with lower levels of inflammatory markers in older adults free of cardiovascular disease.
Keywords: Aged; Aged, 80 and over; Alcohol Drinking; Apolipoproteins E; C-Reactive Protein; Coronary Artery Disease; Female; Fibrinogen; Geriatric Assessment; Humans; Inflammation Mediators; Leukocyte Count; Logistic Models; Longitudinal Studies; Male; Probability; Prospective Studies; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index

Associates of bone mineral density in older African Americans. - Robbins, John; Hirsch, Calvin; Cauley, Jane (J Natl Med Assoc, 2004)
OBJECTIVES: To assess correlates of bone mineral density (BMD) in older African Americans. PARTICIPANTS: 189 women and 115 men over age 64. METHODS: Variables investigated: BMD by dual X-ray absorptiometry (DXA), medications, cardiovascular disease risk factors, demographic, lifestyle factors and functional status. Variables showing univariate correlation with BMD (p < or = 0.1) were entered into sex-stratified linear regression models. RESULTS: Age range 67-96 (mean 75). The mean BMD (gm/ cm2 +/- standard deviation) is reported for three sites. Total body: 1.03 (+/- 0.12) in women, 1.21 (+/- 0.11) in men. Spine: 1.05 (+/- 0.24) in women, 1.22 (+/- 0.26) in men. Total hip: 0.85 (+/- 0.15) in women, 1.04 (+/- 0.17) in men. Gender was significantly associated with BMD (t-test, p < 0.001). The R2 for tested variables were highly significant only for weight. Age was only significant for total hip in women (p < 0.05). Each kilogram of weight change was associated with a 5.3-6.8 mg/cm2 change in BMD. CONCLUSIONS: In a population-based cohort of older African Americans, average BMD was significantly greater in men than women. Weight accounted for most of the explained variability (R2) in BMD; age added little to the overall R2. Lower-weight, older African-American men and women are at significantly increased risk for low BMD and, thus, likely to be at greater risk for osteoporotic fracture.
Keywords: Aged; Body Weight; Bone Density; Cross-Sectional Studies; Female; Humans; Male; Osteoporosis; Risk Factors

The association of fasting glucose levels with congestive heart failure in diabetic adults > or =65 years: the Cardiovascular Health Study. - Barzilay, Joshua I; Kronmal, Richard A; Gottdiener, John S; Smith, Nicholas L; Burke, Gregory L; Tracy, Russell; Savage, Peter J; Carlson, Michelle (J Am Coll Cardiol, 2004)
OBJECTIVES: The purpose of this study was to determine if fasting glucose levels are an independent risk factor for congestive heart failure (CHF) in elderly individuals with diabetes mellitus (DM) with or without coronary heart disease (CHD). BACKGROUND: Diabetes mellitus and CHF frequently coexist in the elderly. It is not clear whether fasting glucose levels in the setting of DM are a risk factor for incident CHF in the elderly. METHODS: A cohort of 829 diabetic participants, age > or =65 years, without prevalent CHF, was followed for five to eight years. The Cox proportional hazards modeling was used to determine the risk of CHF by fasting glucose levels. The cohort was categorized by the presence or absence of prevalent CHD. RESULTS: For a 1 standard deviation (60.6 mg/dl) increase in fasting glucose, the adjusted hazard ratios for incident CHF among participants without CHD at baseline, with or without an incident myocardial infarction (MI) or CHD event on follow-up, was 1.41 (95% confidence interval 1.24 to 1.61; p < 0.0001). Among those with prevalent CHD at baseline, with or without another incident MI or CHD event on follow-up, the corresponding adjusted hazard ratio was 1.27 (95% confidence interval 1.02 to 1.58; p < 0.05). CONCLUSIONS: Among older adults with DM, elevated fasting glucose levels are a risk factor for incident CHF. The relationship of fasting glucose to CHF differs somewhat by the presence or absence of prevalent CHD.
Keywords: Aged; Biomarkers; Blood Glucose; Blood Pressure; Coronary Disease; Diabetes Mellitus; Diabetic Angiopathies; Fasting; Female; Follow-Up Studies; Heart Failure; Humans; Incidence; Male; Proportional Hazards Models; Risk Factors; Statistics as Topic; Stroke Volume; Ventricular Function, Left

The association of personal and neighborhood socioeconomic indicators with subclinical cardiovascular disease in an elderly cohort. The cardiovascular health study. - Nordstrom, Cheryl K; Diez Roux, Ana V; Jackson, Sharon A; Gardin, Julius M (Soc Sci Med, 2004)
There has been recent interest in determining whether neighborhood characteristics are related to the cardiovascular health of residents. However, there are no data regarding the relationship between neighborhood socioeconomic status (SES) and prevalence of subclinical cardiovascular disease (CVD) in the elderly. We related personal SES (education, income, and occupation type) and neighborhood socioeconomic characteristics (a block-group score summing six variables reflecting neighborhood income and wealth, education, and occupation) to the prevalence of subclinical CVD (asymptomatic peripheral vascular disease or carotid atherosclerosis, electrocardiogram or echocardiogram abnormalities, and/or positive responses to Rose Questionnaire claudication or angina pectoris) among 3545 persons aged 65 and over, without prevalent CVD, in the Cardiovascular Health Study. Sixty percent of participants had at least one indicator of subclinical disease. Compared to those without, those with subclinical disease had significantly lower education, income, and neighborhood scores and were more likely to have blue-collar jobs. After adjustment for age, gender, and race, those in the lowest SES groups had increased prevalence of subclinical disease compared with those in the highest SES groups (OR = 1.50; 95% CI 1.21, 1.86 for income; OR = 1.41; 95% CI 1.18, 1.69 for education; OR = 1.39; 95% CI 1.16, 1.67 for block-group score). Those reporting a blue-collar lifetime occupation had greater prevalence of subclinical disease relative to those reporting a white-collar occupation (OR = 1.29; 95% CI 1.02-1.59). After adjustment for behavioral and biomedical risk factors, all of these associations were reduced. Neighborhood score tended to remain inversely associated with subclinical disease after adjustment for personal socioeconomic indicators but associations were not statistically significant. Personal income and blue-collar occupation remained significantly associated with subclinical disease after simultaneous adjustment for neighborhood score and education. Personal and neighborhood socioeconomic indicators were associated with subclinical disease prevalence in this elderly cohort. These relationships were reduced after controlling for traditional CVD risk factors.
Keywords: Aged; California; Cardiovascular Diseases; Cohort Studies; Female; Geography; Humans; Male; Maryland; Medicare; North Carolina; Pennsylvania; Residence Characteristics; Risk Factors; Social Class; Socioeconomic Factors; Surveys and Questionnaires

Associations between renovascular disease and prevalent cardiovascular disease in the elderly: a population-based study. - Edwards, Matthew S; Hansen, Kimberley J; Craven, Timothy E; Bleyer, Anthony J; Burke, Gregory L; Levy, Pavel J; Dean, Richard H (Vasc Endovascular Surg, 2004)
Atherosclerotic renovascular disease (RVD) is a suspected contributor to the morbidity and mortality of cardiovascular disease (CVD) through its potential effects on blood pressure and excretory renal function as well as through its associations with other forms of CVD. However, population-based data regarding the associations between the presence of RVD and prevalent CVD are lacking. The Cardiovascular Health Study (CHS) is a prospective, multicenter cohort study of CVD among elderly Americans. As part of an ancillary study, participants in the Forsyth County, North Carolina, cohort of the CHS were invited to undergo renal duplex sonography (RDS) to establish the presence or absence of RVD (defined as any focal peak systolic velocity >/= 1.8 m/second or the absence of a Doppler-shifted signal from an imaged artery). Demographic, risk factor, and prevalent CVD data were obtained from the CHS coordinating center and matched with ancillary study participants. Eight hundred thirty-four CHS participants (including 525 women [63%], 309 men [37%], 194 African-Americans [23%], and 635 Caucasians [76%]) with a mean age of 77.2 +/-4.9 years underwent RDS examination. RVD was present in 57 participants (6.8%). Overall, clinical and/or subclinical manifestations of CVD were present in 603 participants (72.3%) at the time of RDS. Participants with RVD demonstrated a significantly greater prevalence of angina (p = 0.002), previous myocardial infarction (p < 0.001), >/= 25% diameter-reducing internal carotid artery stenosis (p = 0.010), increased carotid intimal medial thickness (p = 0.003), and major electrocardiographic abnormalities (p = 0.013). Following adjustment for demographics and cardiovascular risk factors, the presence of RVD demonstrated a significant and independent association with prevalent coronary artery disease but not with prevalent cerebrovascular or lower extremity vascular disease. These results suggest important population-based associations between RVD and both clinical and subclinical manifestations of CVD, especially coronary artery disease.
Keywords: Aged; Arteriosclerosis; Cardiovascular Diseases; Cohort Studies; Humans; Hypertension, Renovascular; Longitudinal Studies; Male; Multivariate Analysis; Prevalence; Prospective Studies; Renal Artery Obstruction; Ultrasonography; United States

Barriers to health care access among the elderly and who perceives them. - Fitzpatrick, Annette L; Powe, Neil R; Cooper, Lawton S; Ives, Diane G; Robbins, John A (Am J Public Health, 2004)
OBJECTIVES: We evaluated self-perceived access to health care in a cohort of Medicare beneficiaries. METHODS: We identified patterns of use and barriers to health care from self-administered questionnaires collected during the 1993-1994 annual examination of the Cardiovascular Health Study. RESULTS: The questionnaires were completed by 4889 (91.1%) participants, with a mean age of 76.0 years. The most common barriers to seeing a physician were the doctor's lack of responsiveness to patient concerns, medical bills, transportation, and street safety. Low income, no supplemental insurance, older age, and female gender were independently related to perceptions of barriers. Race was not significant after adjustment for other factors. CONCLUSIONS: Psychological and physical barriers affect access to care among the elderly; these may be influenced by poverty more than by race.
Keywords: Aged; Aged, 80 and over; Chi-Square Distribution; Female; Health Behavior; Health Services Accessibility; Humans; Logistic Models; Male; Medicare; Patients; Surveys and Questionnaires; United States

Cognitive impairment and decline are associated with carotid artery disease in patients without clinically evident cerebrovascular disease. - Johnston, S Claiborne; O'Meara, Ellen S; Manolio, Teri A; Lefkowitz, David; O'Leary, Daniel H; Goldstein, Steven; Carlson, Michelle C; Fried, Linda P; Longstreth, W T (Ann Intern Med, 2004)
BACKGROUND: Whether carotid artery disease is a cause of cognitive impairment in persons who have not had stroke is unknown. If this is the case, diminished performance on the Modified Mini-Mental State Examination should be more common in persons with left carotid artery disease than in those with right carotid artery disease. OBJECTIVE: To determine whether left carotid artery disease is associated with cognitive impairment. DESIGN: Cross-sectional and cohort study. SETTING: Four U.S. communities participating in the Cardiovascular Health Study. PATIENTS: 4006 right-handed men and women 65 years of age or older without history of stroke, transient ischemic attack, or carotid endarterectomy. MEASUREMENTS: Internal carotid artery stenosis and intima-media thickness of the common carotid artery were assessed by using duplex ultrasonography. Cognitive impairment was defined as a score less than 80 on the Modified Mini-Mental State Examination, and cognitive decline was defined as an average decrease of more than 1 point annually in Modified Mini-Mental State Examination score during up to 5 years of follow-up. Multivariate logistic regression models were used to estimate the risk for cognitive impairment and decline associated with left internal carotid artery stenosis and intima-media thickness, after adjustment for measures of right-sided disease and risk factors for vascular disease. RESULTS: After adjustment for right-sided stenosis, high-grade (> or =75% narrowing of diameter) stenosis of the left internal carotid artery (32 patients) was associated with cognitive impairment (odds ratio, 6.7 [95% CI, 2.4 to 18.1] compared with no stenosis) and cognitive decline (odds ratio, 2.6 [CI, 1.1 to 6.3]). Intima-media thickness of the left common carotid artery was associated with cognitive impairment and decline in univariate analysis, but this effect did not persist after adjustment. CONCLUSIONS: Cognitive impairment and decline are associated with asymptomatic high-grade stenosis of the left internal carotid artery. The persistence of the association after adjustment for right-sided stenosis indicates that the association is not due to underlying vascular risk factors or atherosclerosis in general.
Keywords: Aged; Carotid Stenosis; Cognition Disorders; Cohort Studies; Cross-Sectional Studies; Female; Humans; Male; Neuropsychological Tests; Odds Ratio; Risk Factors; Tunica Intima

Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. - Cushman, Mary; Tsai, Albert W; White, Richard H; Heckbert, Susan R; Rosamond, Wayne D; Enright, Paul; Folsom, Aaron R (Am J Med, 2004)
PURPOSE: To determine the incidence of deep vein thrombosis and pulmonary embolism in two cohorts representing regions of the United States. METHODS: The sample comprised 21,680 participants of the Atherosclerosis Risk in Communities study and the Cardiovascular Health Study. Subjects were aged >/=45 years, resided in six communities, and were followed for 7.6 years. All hospitalizations were identified and thromboses were validated by chart review. RESULTS: The age-standardized incidence of first-time venous thromboembolism was 1.92 per 1000 person-years. Rates were higher in men than women, and increased with age in both sexes. There was no antecedent trauma, surgery, immobilization, or diagnosis of cancer for 48% (175/366) of events. The 28-day case-fatality rate was 11% (29/265) after a first venous thromboembolism and 25% (17/67) for cancer-associated thrombosis. The recurrence rate 2 years after a first venous thromboembolism was 7.7% per year (95% confidence interval [CI]: 4.5% to 10.9% per year). Cancer was the only factor independently associated with 28-day fatality (relative risk [RR] = 5.2; 95% CI: 1.4 to 19.9) or recurrent thrombosis (RR = 9.2; 95% CI: 2.0 to 41.7). CONCLUSION: The incidence of venous thromboembolism in this cohort of middle- and older-aged subjects was similar to that observed in more geographically homogeneous samples. Half of cases were idiopathic. Short-term mortality and 2-year recurrence rates were appreciable, especially among subjects with cancer. Based on this study we estimate that 187,000 cases of first-time venous thromboembolism are diagnosed yearly in the United States among those aged 45 years or older.
Keywords: Aged; Case-Control Studies; Cohort Studies; Female; Follow-Up Studies; Humans; Incidence; Male; Middle Aged; Neoplasms; Population Surveillance; Pulmonary Embolism; Recurrence; Risk Factors; Survival Rate; Venous Thrombosis

Inflammatory and prothrombotic markers and the progression of renal disease in elderly individuals. - Fried, Linda; Solomon, Cam; Shlipak, Michael; Seliger, Stephen; Stehman-Breen, Catherine; Bleyer, Anthony J; Chaves, Paolo; Furberg, Curt; Kuller, Lewis; Newman, Anne (J Am Soc Nephrol, 2004)
Inflammatory and prothrombotic markers are elevated in individuals with mild to moderate renal disease. It was hypothesized that these markers may also be determinants of the progression of renal disease. The association of six markers-serum C-reactive protein (CRP), white blood cell (WBC) count, fibrinogen, factor VII, albumin, and hemoglobin-with subsequent elevations of creatinine and decline in estimated GFR in the Cardiovascular Health Study, a community-based cohort of elderly individuals, was analyzed. Linear regression was used to determine predictors of an annualized change in serum creatinine as the main outcome. Duration of follow-up was 7 yr for the original cohort and 4 yr for the more recently recruited black cohort. A total of 588 (12.7%) individuals had a decline in estimated GFR of at least 3 ml/min per yr per 1.73 m(2). Higher CRP (P < 0.001), WBC count (P < 0.001), fibrinogen (P < 0.001), and factor VII (P < 0.001) levels and lower albumin (P < 0.001) and hemoglobin levels (P < 0.001) were associated with a rise in creatinine, after adjusting for age. With additional adjustments for race, gender, baseline creatinine, systolic and diastolic BP, lipid levels, weight, and pack-years smoking, higher CRP, factor VII, fibrinogen, WBC count, and lower albumin and hemoglobin levels remained associated with a rise in creatinine. Similar results were found for decline in estimated GFR. The decline in GFR was greater with increasing number of inflammatory or prothrombotic markers that were above the median (below for hemoglobin and albumin). Inflammatory and prothrombotic markers are predictors for a change in kidney function in elderly individuals. Interventions that reduce inflammation might confer significant cardiovascular and renal benefits.
Keywords: Aged; Biomarkers; C-Reactive Protein; Creatinine; Factor VII; Female; Fibrinogen; Follow-Up Studies; Glomerular Filtration Rate; Hemoglobins; Humans; Leukocyte Count; Linear Models; Longitudinal Studies; Male; Predictive Value of Tests; Prospective Studies; Renal Insufficiency; Serum Albumin; Thrombosis

Mesenteric artery disease in the elderly. - Hansen, Kimberley J; Wilson, David B; Craven, Timothy E; Pearce, Jeffrey D; English, William P; Edwards, Matthew S; Ayerdi, Juan; Burke, Gregory L (J Vasc Surg, 2004)
PURPOSE: The purpose of this study was to estimate the population-based prevalence of mesenteric artery stenosis (MAS) and occlusion among independent elderly Americans. METHOD: As part of an ancillary investigation to the Cardiovascular Health Study (CHS), participants in the Forsyth County, NC cohort had visceral duplex sonography of the celiac arteries and superior mesenteric arteries (SMAs). Critical MAS was defined by celiac peak systolic velocity >or=2.0 m/s and/or SMA peak systolic velocity >or=2.7 m/s. Occlusion of either vessel was defined by lack of a Doppler-shifted signal within the imaged artery. Demographic data, blood pressures, and blood lipid levels were collected as part of the baseline CHS examination. Participants' weights were measured at baseline and before the duplex exam. Univariate tests of association were performed with two-way contingency tables, Student t tests, and Fisher exact tests. Multivariate associations were examined with logistic regression analysis. RESULTS: A total of 553 CHS participants had visceral duplex sonography technically adequate to define the presence or absence of MAS. The study group had a mean age of 77.2 +/- 4.9 years and comprised 63% women and 37% men. Participant race was 76% white and 23% African-American. Ninety-seven participants (17.5%) had MAS. There was no significant difference in age, race, gender, body mass index, blood pressure, cholesterol, or low-density lipoproteins for participants with or without MAS. Forward stepwise variable selection found renal artery stenosis (P =.008; odds ratio [OR], 2.85; 95% confidence interval [CI], 1.31, 6.21) and high-density lipoprotein >40 (P =.02; OR, 3.03; 95% CI, 1.17, 7.81) significantly associated with MAS in a multivariate logistic regression model. Eighty-three of the 97 participants with MAS (15.0% of the cohort) had isolated celiac stenosis. Seven participants (1.3% of the cohort) had combined celiac and SMA stenosis. Five participants (0.9% of the cohort) had isolated SMA stenosis. Two participants (0.4% of the cohort) had celiac occlusion. Considering all participants with MAS, there was no association with weight change. However, SMA stenosis and celiac occlusion demonstrated an independent association with annualized weight loss (P =.028; OR, 1.54; 95% CI, 1.05, 2.26) and with renal artery stenosis (P =.001; OR, 9.48; 95% CI, 2.62, 34.47). CONCLUSION: This investigation provides the first population-based estimate of the prevalence of MAS among independent elderly Americans. MAS existed in 17.5% of the study cohort. The majority had isolated celiac disease. SMA stenosis and celiac artery occlusion demonstrated a significant and independent association with weight loss and concurrent renal artery disease.
Keywords: Age Factors; Aged; Aged, 80 and over; Arteriosclerosis; Celiac Artery; Cohort Studies; Female; Humans; Male; Mesenteric Arteries; Mesenteric Artery, Superior; Mesenteric Vascular Occlusion; Prevalence; Ultrasonography, Doppler, Duplex; Weight Loss

Plasma total homocysteine levels and cranial magnetic resonance imaging findings in elderly persons: the Cardiovascular Health Study. - Longstreth, W T; Katz, Ronit; Olson, Jean; Bernick, Charles; Carr, J Jeffrey; Malinow, M René; Hess, David L; Cushman, Mary; Schwartz, Stephen M (Arch Neurol, 2004)
BACKGROUND: An elevated plasma total homocysteine (tHcy) level is associated with an increased risk of vascular disease. Some studies have shown associations between tHcy level and small-vessel disease of the brain on magnetic resonance imaging (MRI). DESIGN: In the Cardiovascular Health Study, 622 elderly participants without a history of transient ischemic attack or stroke had results for tHcy level and cranial MRI. We sought associations between tHcy level and MRI findings of ventricular grade, sulcal grade, white matter grade, and infarcts. We controlled for other factors, including levels of creatinine, folate, and vitamins B(6) and B(12) and methylenetetrahydrofolate reductase genotype. RESULTS: After controlling for age and sex, tHcy level was not associated with the individual MRI findings. Further adjustments for other factors and other blood tests had little effect on these findings. The only significant finding was a linear trend across quintiles of tHcy level and a pattern of MRI findings combining infarcts and high white matter grade. The linear trend remained significant after controlling for other risk factors and atherosclerotic markers (top quintile vs bottom quintile odds ratio, 3.3; 95% confidence interval, 0.96-11.20; P =.04 for linear trend) but was slightly diminished after further controlling for creatinine, folate, and vitamins B(6) and B(12) (odds ratio, 3.2; 95% confidence interval, 0.81-13.10; P =.07 for linear trend). CONCLUSION: We were unable to confirm the results of previous studies with respect to tHcy level and individual MRI findings, although an association was seen for an MRI pattern combining infarcts and high white matter grade.
Keywords: Aged; Aging; Brain; Brain Infarction; Female; Homocysteine; Humans; Magnetic Resonance Imaging; Male; Odds Ratio; Radiography; Risk Factors

Preclinical Alzheimer disease: neuropsychological test performance 1.5 to 8 years prior to onset. - Saxton, J; Lopez, O L; Ratcliff, G; Dulberg, C; Fried, L P; Carlson, M C; Newman, A B; Kuller, L (Neurology, 2004)
OBJECTIVE: To determine if individuals ultimately diagnosed with Alzheimer disease (AD) exhibited evidence of cognitive impairment on neuropsychological tests administered between 1.5 years and 8.1 years before dementia onset. METHODS: A total of 693 community-dwelling individuals, part of the Cardiovascular Health Study, completed a neuropsychological test battery in 1991/92. Subjects were followed annually over the next 8 years (median follow-up = 7.4 years). Seventy-two individuals were ultimately diagnosed with AD (median follow-up = 4.5 years): 24 with AD onset 1.5 to 3.4 years after baseline neuropsychological testing, 20 with AD onset 3.5 to 5.0 years after testing, and 28 with onset 5.1 to 8.1 years after testing. A total of 621 individuals remained nondemented throughout the 8 years of follow-up (median follow-up = 7.5 years). RESULTS: Subjects ultimately diagnosed with AD had poorer scores on baseline neuropsychological measures than subjects who remained nondemented. Although individuals closest to AD onset (i.e., 1.5 to 3.4 years) performed the most poorly, cognitive impairment was detected in individuals who did not develop AD until 5 to 8 years later. CONCLUSIONS: Cognitive changes can be detected well before onset of Alzheimer disease.
Keywords: Age of Onset; Alzheimer Disease; Cardiovascular Diseases; Cognition Disorders; Cohort Studies; Confounding Factors, Epidemiologic; Disease Progression; Early Diagnosis; Educational Status; Female; Follow-Up Studies; Humans; Male; Memory Disorders; Neuropsychological Tests; Predictive Value of Tests; Proportional Hazards Models; Risk; Sensitivity and Specificity; Time Factors

Predictors of falling cholesterol levels in older adults: the Cardiovascular Health Study. - Manolio, Teri A; Cushman, Mary; Gottdiener, John S; Dobs, Adrian; Kuller, Lewis H; Kronmal, Richard A (Ann Epidemiol, 2004)
PURPOSE: To estimate 4-year change in serum total cholesterol levels in a population-based sample of older adults and identify independent predictors of cholesterol decline. METHODS: Prospective study of 2837 adults aged 65 years and older with serum cholesterol measured in 1992-1993 and 1996-1997. RESULTS: Mean serum cholesterol levels declined 6.3 mg/dl between the two examinations. Declines were greater in white (-7.3 mg/dl) than black (-1.4 mg/dl) participants and in those in good/excellent health (-0.9 mg/dl) vs. fair/poor health (-3.1 mg/dl; both p < 0.01). Factors associated with greater decline on multivariate analysis included age, male gender, and higher white cell count, albumin, and baseline cholesterol. Cholesterol levels declined 2.0 mg/dl per 6 year increment in baseline age and 6.8 mg/dl more in men than women after adjustment for other factors. C-reactive protein levels were unrelated to cholesterol change. CONCLUSION: Declining cholesterol levels were associated with male gender, advanced age, weight loss, and white blood cell count but not with C-reactive protein levels. The role of declining cholesterol synthesis, due to as yet undefined age-related changes or to cytokine-mediated reductions related to illness, should be examined to help clarify the mechanisms of the sometimes marked declines in cholesterol levels observed at advanced ages.
Keywords: African Americans; Age Factors; Aged; Cardiovascular Diseases; Cholesterol; European Continental Ancestry Group; Female; Forecasting; Health Status; Humans; Male; Medicare; Prospective Studies; Risk Factors; Sex Distribution; Sex Factors; United States

Racial differences in endothelial function in postmenopausal women. - Loehr, Laura R; Espeland, Mark A; Sutton-Tyrrell, Kim; Burke, Gregory L; Crouse, John R; Herrington, David M (Am Heart J, 2004)
OBJECTIVE: Racial differences in cardiovascular mortality among women remain largely unexplained. Preliminary data suggest that African American and Caucasian differences in endothelial function may parallel differential cardiovascular disease (CVD) risk in women. To further study differences in endothelial function between African American and Caucasian women, we analyzed measures of brachial artery flow-mediated dilation (FMD) in women enrolled in the Cardiovascular Health Study (CHS). METHODS AND RESULTS: Brachial artery FMD was measured in the fasting state using established ultrasound techniques in 1330 Caucasian and 297 African American female participants in CHS (mean age 78.4 +/- 4.4 years). General linear models were used to compare FMD between African American and Caucasian women after adjusting for baseline brachial diameter, hypertension, diabetes, smoking, cholesterol, systolic blood pressure, body mass index, waist/hip ratio, age, education, income level; use of angiotensin-converting enzyme inhibitors, beta-blockers, nitroglycerin, estrogens and lipid-lowering drugs; and presence of clinical or subclinical disease. Adjusted absolute change and percent change in brachial artery diameter was significantly reduced in African American women compared with Caucasian women (P <.0001 and P =.0002, respectively). Similar results were found when the women were stratified by history of CVD (- CVD, P =.02; + CVD, P =.001) and CVD or subclinical vascular disease (- disease, P =.01, + disease, P =.03). CONCLUSIONS: In this cohort, brachial artery FMD was lower in African American women compared to Caucasian women, and this difference persisted after adjustment by multivariable analysis. The increased CVD risk in African American women may be related to impaired endothelial function. It remains to be determined whether African American women may uniquely benefit by interventions designed to improve endothelial health.
Keywords: African Continental Ancestry Group; Aged; Brachial Artery; Cohort Studies; Endothelium, Vascular; European Continental Ancestry Group; Female; Humans; Multivariate Analysis; Postmenopause; Risk Factors; Vasodilation

The relationship of cardiovascular risk factors to microalbuminuria in older adults with or without diabetes mellitus or hypertension: the cardiovascular health study. - Barzilay, Joshua I; Peterson, Do; Cushman, Mary; Heckbert, Susan R; Cao, Jie J; Blaum, Caroline; Tracy, Russell P; Klein, Ronald; Herrington, David M (Am J Kidney Dis, 2004)
BACKGROUND: Microalbuminuria is a risk factor for coronary heart disease (CHD). It occurs most commonly in the settings of diabetes and hypertension. The mechanisms by which it increases CHD risk are uncertain. METHODS: We examined the cross-sectional association of microalbuminuria with a broad range of CHD risk factors in 3 groups of adults aged 65 years or older with and without microalbuminuria: those with (1) no diabetes or hypertension (n = 1,098), (2) hypertension only (n = 1,450), and (3) diabetes with or without hypertension (n = 465). RESULTS: Three factors were related to microalbuminuria in all 3 groups: age, elevated systolic blood pressure, and markers of systemic inflammation. In patients with neither diabetes nor hypertension, increasing C-reactive protein levels were associated with microalbuminuria (odds ratio per 1-mg/L increase, 1.46; 95% confidence interval [CI], 1.15 to 1.84). Among those with diabetes, an increase in white blood cell (WBC) count was associated with microalbuminuria (odds ratio per 1,000-cell/mL increase, 2.57; 95% CI, 1.12 to 5.89). Among those with hypertension, an increase in WBC count (odds ratio per 1,000-cell/mL increase, 1.83; 95% CI, 1.04 to 3.23) and fibrinogen level (odds ratio per 10-mg/dL increase, 1.02; 95% CI, 1.00 to 1.05) were significantly associated with microalbuminuria. In all 3 groups, prevalent CHD was related to an elevated WBC count. In none of the 3 groups was brachial artery reactivity to ischemia, an in vivo marker of endothelial function, related to microalbuminuria. CONCLUSION: Microalbuminuria is associated with age, systolic blood pressure, and markers of inflammation. These associations reflect potential mechanisms by which microalbuminuria is related to CHD risk.
Keywords: Age Distribution; Aged; Aged, 80 and over; Albuminuria; Biomarkers; Brachial Artery; Comorbidity; Coronary Disease; Cross-Sectional Studies; Diabetes Mellitus; Female; Humans; Hypertension; Inflammation; Logistic Models; Male; Multivariate Analysis; Odds Ratio; Risk Factors; Smoking; Ultrasonography

Risk of congestive heart failure in an elderly population treated with peripheral alpha-1 antagonists. - Bryson, Chris L; Smith, Nicholas L; Kuller, Lewis H; Chaves, Paulo H M; Manolio, Teri A; Lewis, William; Boyko, Edward J; Furberg, Curt D; Psaty, Bruce M (J Am Geriatr Soc, 2004)
OBJECTIVES: To compare the risk of congestive heart failure (CHF) in elderly individuals treated with any peripheral alpha-1 antagonist for hypertension with any thiazide, test whether the risk persists in subjects without cardiovascular disease (CVD) at baseline, and examine CHF risk in normotensive men with prostatism treated with alpha antagonists. DESIGN: Prospective cohort study. SETTING: Four U.S. sites: Washington County, Maryland; Allegheny County, Pennsylvania; Sacramento County, California; and Forsyth County, North Carolina. PARTICIPANTS: A total of 5,888 community-dwelling subjects aged 65 and older. MEASUREMENTS: Adjudicated incident CHF. RESULTS: The 3,105 participants with treated hypertension were at risk for CHF; 22% of men and 8% of women took alpha antagonists during follow-up. The age-adjusted risk of CHF in those receiving monotherapy treated with alpha antagonists was 1.90 (95% confidence interval=1.03-3.50) compared with thiazides. In subjects without CVD at baseline receiving monotherapy, women taking an alpha antagonist had a 3.6 times greater age-adjusted risk of CHF, whereas men had no difference in risk. Adjustment for systolic blood pressure attenuated statistical differences in risk. There were 930 men without hypertension at risk for CHF; 5% used alpha antagonists during follow-up, with no observed increase in CHF risk. CONCLUSION: Subjects receiving alpha antagonist monotherapy for hypertension had a two to three times greater risk of incident CHF, also seen in lower-risk subjects, but differences in blood pressure control partly explained this.
Keywords: Adrenergic alpha-Antagonists; Aged; Antihypertensive Agents; Benzothiadiazines; Blood Pressure; Cohort Studies; Diuretics; Female; Heart Failure; Humans; Hypertension; Male; Risk Factors; Sodium Chloride Symporter Inhibitors; United States

Stroke risk factors and loss of high cognitive function. - Elkins, J S; O'Meara, E S; Longstreth, W T; Carlson, M C; Manolio, T A; Johnston, S C (Neurology, 2004)
BACKGROUND: Modifiable stroke risk factors may contribute to age-associated declines in cognitive function. Individuals with high levels of cognitive function after midlife may have less exposure to these stroke risk factors or may be less susceptible to their effects on cognition. METHODS: The Cardiovascular Health Study (CHS)* is a population-based, longitudinal cohort study of 5,888 people age 65 years and older. Participants (n = 4,129) who were free of dementia, stroke, or TIA at the time of baseline cranial MRI were selected for analysis. High cognitive function at baseline was defined by performance at or above midlife norms on the Modified Mini-Mental State Examination (3MS). RESULTS: The odds of having high cognitive function at baseline decreased by quartile of stroke risk (highest vs lowest risk quartile, adjusted odds ratio [OR] 0.68; 95% CI 0.52 to 0.88; p for trend = 0.005). Stroke risk was a predictor of decline on the 3MS in those with typical levels of cognitive function at baseline, even in the absence of incident stroke or TIA (highest vs lowest risk quartile for 3MS decline, adjusted OR 2.11; 95% CI 1.42 to 3.13; p for trend < 0.001). In contrast, stroke risk was not associated with decline on the 3MS in those with high cognitive function at baseline (p = 0.03 for interaction). CONCLUSIONS: In a cohort of older adults without stroke, TIA, or dementia, cognitive function and incident cognitive decline were associated with risk for stroke. Additional studies are needed to determine whether modification of stroke risk factors can reduce the cognitive decline that is often attributed to normal aging.
Keywords: Aged; Aged, 80 and over; Aging; Cognition Disorders; Cohort Studies; Comorbidity; Female; Follow-Up Studies; Higher Nervous Activity; Humans; Incidence; Male; Risk Assessment; Risk Factors; Sampling Studies; Sensitivity and Specificity; Severity of Illness Index; Stroke; United States

Subclinical cardiovascular disease in older adults: insights from the Cardiovascular Health Study. - Chaves, Paulo H M; Kuller, Lewis H; O'Leary, Daniel H; Manolio, Teri A; Newman, Anne B (Am J Geriatr Cardiol, 2004)
Knowledge about the epidemiology of subclinical cardiovascular disease (SCVD) in older adults may hold the key for improved opportunities for primary prevention of cardiovascular disease (CVD), a top clinical and public health priority. This review reports findings on the prevalence of SCVD and the ability of SCVD measures to predict incident and adverse outcomes from one of the largest (N=5888) and most comprehensive prospective observational studies on SCVD in older adults, the Cardiovascular Health Study. According to a composite index that combined SCVD measures from different vascular beds, the overall prevalence of SCVD was 37%, making it as common as clinically overt CVD in older adults. SCVD measures strongly predicted incident CVD, stroke, mortality, frailty, and physical and cognitive decline, even after adjustment for traditional CVD risk factors. Ongoing research will address the potential use of SCVD for clinical decision making in older adults.
Keywords: Aged; Cardiovascular Diseases; Coronary Artery Disease; Heart Failure; Humans; Longitudinal Studies; Prevalence; Risk Assessment; Risk Factors

Time trends in the use of beta-blockers and other pharmacotherapies in older adults with congestive heart failure. - Smith, Nicholas L; Chan, Jeannie D; Rea, Thomas D; Wiggins, Kerri L; Gottdiener, John S; Lumley, Thomas; Psaty, Bruce M (Am Heart J, 2004)
BACKGROUND: Evidence supporting pharmacotherapy of congestive heart failure (CHF) has grown substantially over the past decade and includes large, placebo-controlled trials with mortality end points. We describe beta-blocker and other medication temporal treatment trends of CHF in the Cardiovascular Health Study, a community-based cohort study of 5888 adults > or =65 years of age. METHODS: Prescription medication data were collected from hospital discharge summaries for incident CHF events and at in-study annual clinic visits for prevalent CHF cases from 1989 to 2000. Change in use of agents over time was estimated by using generalized estimating equations while adjusting for potential confounding factors of age, sex, race, and cardiovascular and pulmonary comorbidities. RESULTS: Among 1033 incident CHF events, beta-blocker use after diagnosis increased an average of 2.4 percentage points annually (95% CI, 1.5 to 3.4 points) from 1989 to 2000. The increasing trend was consistent throughout follow-up. Among participants with coronary disease and/or hypertension and among those with low ejection fractions (<45%), beta-blocker use remained flat from 1989 to 1994 and increased 4.7 points annually (2.5 to 6.9) and 10.0 points annually (6.1 to 13.8), respectively, from 1995 to 2000. Among participants without coronary disease or hypertension, there was no overall increase in use. Use of renin-angiotensin system inhibitors increased 2.3 points annually (1.0 to 3.5), digoxin use decreased 2.4 points annually (-3.6 to -1.1), and loop diuretic use remained flat between 1989 and 2000. In general, treatment trends were similar for prevalent CHF. CONCLUSIONS: Treatment of CHF has changed gradually in the 1990s and may in part reflect the influence of CHF clinical trial evidence.
Keywords: Adrenergic beta-Antagonists; Aged; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Cohort Studies; Drug Therapy; Drug Therapy, Combination; Female; Heart Failure; Humans; Male; Multivariate Analysis; Prevalence

Traditional and novel risk factors in older adults: cardiovascular risk assessment late in life. - Mukamal, Kenneth J; Kronmal, Richard A; Tracy, Russell P; Cushman, Mary; Siscovick, David S (Am J Geriatr Cardiol, 2004)
As a population-based, longitudinal study of nearly 6000 older American adults, the Cardiovascular Health Study provides an excellent opportunity to assess the roles of traditional and novel cardiovascular risk factors in the development of coronary heart disease. Cardiovascular Health Study investigators have analyzed both traditional risk factors, such as diabetes, hypertension, and smoking, and new risk factors, such as hemostatic factors, inflammatory markers, exposure to infectious agents, and genetic determinants. These analyses have led to several important conclusions. First, older adults without previous cardiovascular events have a tremendous burden of subclinical vascular disease, which may change how physicians view risk factor modification in this age group. Second, some traditional cardiovascular risk factors lose importance as predictors of cardiovascular disease among older adults. Third, even modest elevations in fasting blood glucose or systolic blood pressure-below the levels used to define diabetes or hypertension-may have prognostic implications. Fourth, novel cardiovascular risk factors may add further information about cardiovascular disease risk in older adults. Promising potential candidates identified in the Cardiovascular Health Study include markers of hemostatic activation, fibrinogen, factor VIII coagulant activity, C-reactive protein, and exposure to herpes simplex virus-1 and possibly chlamydia. Future Cardiovascular Health Study investigations will help to clarify which combination of traditional and newer risk factors provides the best estimate of cardiovascular risk for older adults.
Keywords: Aged; Blood Coagulation Factors; Cardiovascular Diseases; Cohort Studies; Diabetes Complications; Female; Genetic Predisposition to Disease; Humans; Hypertension; Infections; Inflammation; Lipids; Longitudinal Studies; Male; Obesity; Predictive Value of Tests; Risk Factors; Smoking; United States

White matter hyperintensity on cranial magnetic resonance imaging: a predictor of stroke. - Kuller, Lewis H; Longstreth, W T; Arnold, Alice M; Bernick, Charles; Bryan, R Nick; Beauchamp, Norman J (Stroke, 2004)
BACKGROUND AND PURPOSE: We have previously reported that several "silent" infarcts found on magnetic resonance imaging (MRI) were a risk factor for stroke. Several recent reports have shown that high white matter grade (WMG) and increasing WMG over time were risk factors for stroke. We tested the hypothesis that high WMG > or =2 was a predictor of risk for stroke, independent of other risk factors. METHODS: We examined the extent of white matter hyperintensity on cranial MRI of 3293 participants from the Cardiovascular Health Study (CHS). The degree of white matter hyperintensity was graded from least severe (grade=0) to most severe (grade=9). Participants were followed-up for an average of 7 years for the occurrence of a stroke. Clinical stroke diagnoses were based on hospital records reviewed by an adjudication committee expert in stroke diagnosis. During this period, 278 strokes occurred. Results The relative risk of stroke increased significantly as the WMG increased. The risk of stroke was 2.8% per year for participants with high WMG (grades > or =5), compared with only 0.6% for participants with grades 0 to 1.Conclusions The risk of stroke with high WMG is independent of traditional stroke risk factors and persists when controlling for MRI infarcts, another subclinical imaging marker of cerebrovascular disease. Assessment of white matter disease may be valuable in assessing future risk of stroke.
Keywords: Aged; Brain; Female; Humans; Leukoaraiosis; Magnetic Resonance Imaging; Male; Radiography; Risk Factors; Stroke

Alcohol use and risk of ischemic stroke among older adults: the cardiovascular health study. - Mukamal, Kenneth J; Chung, Hyoju; Jenny, Nancy S; Kuller, Lewis H; Longstreth, W T; Mittleman, Murray A; Burke, Gregory L; Cushman, Mary; Beauchamp, Norman J; Siscovick, David S (Stroke, 2005)
BACKGROUND AND PURPOSE: The association of light to moderate alcohol consumption with risk of ischemic stroke remains uncertain, as are the roles of potentially mediating factors and modification by apolipoprotein E (apoE) genotype. METHODS: We studied the prospective association of alcohol consumption and risk of ischemic stroke among 4410 participants free of cardiovascular disease at baseline in the Cardiovascular Health Study, a population-based cohort study of older adults from 4 US communities. Participants reported their consumption of alcoholic beverages yearly. RESULTS: During an average follow-up period of 9.2 years, 434 cases of incident ischemic stroke occurred. Compared with long-term abstainers, the multivariate relative risks of ischemic stroke were 0.85 (95% CI, 0.63 to 1.13), 0.75 (95% CI, 0.53 to 1.06), 0.82 (95% CI, 0.51 to 1.30), and 1.03 (95% CI, 0.68 to 1.57) among consumers of <1, 1 to 6, 7 to 13, and > or =14 drinks per week (P quadratic trend 0.06). ApoE genotype appeared to modify the alcohol-ischemic stroke relationship (P interaction 0.08), with generally lower risks among drinkers than abstainers in apoE4-negative participants but higher risks among drinkers than abstainers among apoE4-positive participants. We could not identify candidate mediators among lipid, inflammatory, and prothrombotic factors. CONCLUSIONS: In this study of older adults, the association of alcohol use and risk of ischemic stroke was U-shaped, with modestly lower risk among consumers of 1 to 6 drinks per week. However, apoE genotype may modify this association, and even moderate alcohol intake may be associated with an increased risk of ischemic stroke among apoE4-positive older adults.
Keywords: Aged; Alcohol Drinking; Apolipoproteins E; Brain Infarction; Brain Ischemia; Cohort Studies; Female; Follow-Up Studies; Genetic Predisposition to Disease; Genotype; Humans; Hypertension; Inflammation; Ischemia; Lipids; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Prospective Studies; Risk; Risk Factors; Stroke; Substance-Related Disorders; Thrombosis; Time Factors; Vascular Diseases

Association of beta-blocker use with mortality among patients with congestive heart failure in the Cardiovascular Health Study (CHS). - Chan, Jeannie D; Rea, Thomas D; Smith, Nicholas L; Siscovick, David; Heckbert, Susan R; Lumley, Thomas; Chaves, Paulo; Furberg, Curt D; Kuller, Lewis; Psaty, Bruce M (Am Heart J, 2005)
BACKGROUND: In clinical trials, beta-blocker therapy reduces all-cause mortality among people with congestive heart failure (CHF) characterized by depressed systolic function, but few trials included large numbers of elderly participants. This study assessed the association between beta-blocker therapy and mortality among community-dwelling older adults with CHF. METHODS: The Cardiovascular Health Study (CHS) is a longitudinal, population-based study of adults aged > or = 65 years. Recruitment began in 1989 with follow-up extending through June 2000 or death. Cox proportional hazard regression models were used to assess the association between beta-blocker therapy and all-cause mortality among 950 participants who developed new-onset CHF. RESULTS: beta-Blocker users (n = 157) were more likely than nonusers (n = 793) to have treated hypertension, clinical coronary artery disease, and valvular disease at the time of CHF diagnosis. Death occurred in 67 users and 446 nonusers during a median follow-up of 2.3 years. Compared with nonuse, use of beta-blockers was associated with a multivariable adjusted hazard ratio (HR) of 0.74 (95% CI 0.56-0.98) for all-cause mortality. Among the 520 participants who had left ventricular ejection fraction assessed within 90 days after CHF diagnosis, the risk for all cause mortality associated with beta-blocker use did not differ significantly between those with ejection fraction of < 40% and those with ejection fraction of > or = 40% (HR 0.56, 95% CI 0.27-1.13; HR 0.82, 95% CI 0.56-1.22, respectively; interaction P = .34). CONCLUSIONS: This observational study suggests that beta-blocker treatment is associated with a reduced risk of all-cause mortality among community-dwelling older adults with CHF.
Keywords: Adrenergic beta-Antagonists; Age Factors; Aged; Aged, 80 and over; Female; Follow-Up Studies; Heart Failure; Humans; Male

Associations between retinal microvascular abnormalities and declining renal function in the elderly population: the Cardiovascular Health Study. - Edwards, Matthew S; Wilson, David B; Craven, Timothy E; Stafford, Jeanette; Fried, Linda F; Wong, Tien Y; Klein, Ronald; Burke, Gregory L; Hansen, Kimberley J (Am J Kidney Dis, 2005)
BACKGROUND: Microvascular abnormalities in the kidney are common histopathologic findings in individuals with chronic kidney disease or renal failure. These abnormalities may represent one manifestation of ongoing systemic microvascular damage. We hypothesized that retinal microvascular abnormalities, when present, would be associated with progressive renal dysfunction in elderly individuals. METHODS: The Cardiovascular Health Study (CHS) is a prospective, multicenter, cohort study initiated in 1989 designed to examine cardiovascular risk factors, morbidity, and mortality in elderly Americans. As part of an ancillary study, CHS participants underwent retinal photography in 1997 and 1998. Retinal microvascular abnormalities were assessed and graded by using standardized measures. Retinal microvascular abnormalities were defined as retinopathy (hard and soft exudates, hemorrhages, or microaneurysms) and/or retinal arteriolar abnormalities (arteriovenous nicking, focal arteriolar narrowing, or lowest quartile arteriole-venule ratio). Associations between these abnormalities and observed 4-year changes in serum creatinine levels and estimated glomerular filtration rates (eGFRs) from study years 5 to 9 (encompassing years 1994 to 2001) were examined by using regression modeling. RESULTS: A total of 1,394 CHS participants had retinal and serum creatinine data. After adjustments for age, race, sex, weight, diabetes, hypertension, angiotensin-converting enzyme inhibitor use, and proteinuria, participants with retinopathy showed a significant increase in serum creatinine level and decline in eGFR compared with those without retinopathy during the 4-year study period (+0.24 mg/dL [+21 micromol/L] versus -0.21 mg/dL [-19 micromol/L] and -0.48 mL/min/1.73 m2 [-0.01 mL/s/1.73 m2] versus +1.74 mL/min/1.73 m2 [+0.03 mL/s/1.73 m2], respectively). Participants with retinopathy also were significantly more likely to have an observed significant deterioration in renal function, defined as a 0.3-mg/dL (27-micromol/L) increase in serum creatinine level or 20% or greater decline in eGFR (odds ratio, 3.20; 95% confidence interval, 1.58 to 6.50; and odds ratio, 2.84; 95% confidence interval, 1.56 to 5.16, respectively). These associations remained in separate stratified analyses of patients with and without diabetes. The presence of retinal arteriolar abnormalities was not associated with deteriorating renal function. CONCLUSION: Retinal microvascular abnormalities defined as retinopathy were significantly associated with renal function deterioration. The observed findings were independent of effects of any associated diabetes or hypertension. These findings suggest that systemic microvascular disease may be associated with progressive renal dysfunction in the elderly population.
Keywords: African Americans; Aged; Aged, 80 and over; Aging; Antihypertensive Agents; Capillaries; Cohort Studies; Comorbidity; Creatinine; Diabetes Mellitus; Disease Progression; European Continental Ancestry Group; Female; Glomerular Filtration Rate; Humans; Hypertension; Kidney; Male; Photography; Prospective Studies; Proteinuria; Retina; Retinal Diseases; Retinal Vessels

Benefits of fatty fish on dementia risk are stronger for those without APOE epsilon4. - Huang, T L; Zandi, P P; Tucker, K L; Fitzpatrick, A L; Kuller, L H; Fried, L P; Burke, G L; Carlson, M C (Neurology, 2005)
OBJECTIVE: To compare associations of lean fish vs fatty fish (tuna or other fish) intake with dementia, Alzheimer disease (AD), and vascular dementia (VaD) and in relation to APOE epsilon4 status in the Cardiovascular Health Cognition Study (CHCS). METHODS: Fish intake was assessed by food frequency questionnaires. Incident dementia, AD, and VaD were determined through a series of cognitive tests, physician's assessment, and committee consensus. We used Cox proportional hazards regression to calculate hazard ratios of dementia, AD, and VaD with lean fried fish, fatty fish, or total fish intake, which were then stratified by the presence of APOE epsilon4. RESULTS: Although consumption of lean fried fish had no protective effect, consumption of fatty fish more than twice per week was associated with a reduction in risk of dementia by 28% (95% CI: 0.51 to 1.02), and AD by 41% (95% CI: 0.36 to 0.95) in comparison to those who ate fish less than once per month. Stratification by APOE epsilon4 showed this effect to be selective to those without the epsilon4 allele. Adjustment by education and income attenuated the effect. CONCLUSION: In the Cardiovascular Health Cognition Study, consumption of fatty fish was associated with a reduced risk of dementia and Alzheimer disease for those without the APOE epsilon4 allele.
Keywords: Aged; Alzheimer Disease; Apolipoprotein E4; Apolipoproteins E; Cohort Studies; Dementia; Dietary Fats, Unsaturated; Fatty Acids, Omega-3; Feeding Behavior; Female; Fish Oils; Fish Products; Food, Formulated; Genetic Predisposition to Disease; Humans; Incidence; Male; Risk Factors; Socioeconomic Factors; Surveys and Questionnaires

Cardiovascular mortality risk in chronic kidney disease: comparison of traditional and novel risk factors. - Shlipak, Michael G; Fried, Linda F; Cushman, Mary; Manolio, Teri A; Peterson, Do; Stehman-Breen, Catherine; Bleyer, Anthony; Newman, Anne; Siscovick, David; Psaty, Bruce (JAMA, 2005)
CONTEXT: Elderly persons with chronic kidney disease have substantial risk for cardiovascular mortality, but the relative importance of traditional and novel risk factors is unknown. OBJECTIVE: To compare traditional and novel risk factors as predictors of cardiovascular mortality. DESIGN, SETTING, AND PATIENTS: A total of 5808 community-dwelling persons aged 65 years or older living in 4 communities in the United States participated in the Cardiovascular Health Study cohort. Participants were initially recruited from 1989 to June 1990; an additional 687 black participants were recruited in 1992-1993. The average length of follow-up in this longitudinal study was 8.6 years. MAIN OUTCOME MEASURES: Cardiovascular mortality among those with and without chronic kidney disease. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60 mL/min per 1.73 m2. RESULTS: Among the participants, 1249 (22%) had chronic kidney disease at baseline. The cardiovascular mortality risk rate was 32 deaths/1000 person-years among those with chronic kidney disease vs 16/1000 person-years among those without it. In multivariate analyses, diabetes, systolic hypertension, smoking, low physical activity, nonuse of alcohol, and left ventricular hypertrophy were predictors of cardiovascular mortality in persons with chronic kidney disease (all P values <.05). Among the novel risk factors, only log C-reactive protein (P = .05) and log interleukin 6 (P<.001) were associated with the outcome as linear predictors. Traditional risk factors were associated with the largest absolute increases in risks for cardiovascular deaths among persons with chronic kidney disease: for left ventricular hypertrophy, there were 25 deaths per 1000 person-years; current smoking, 20 per 1000 person-years; physical inactivity, 15 per 1000 person-years; systolic hypertension, 14 per 1000 person-years; diabetes, 14 per 1000 person-years; and nonuse of alcohol, 11 per 1000 person-years vs 5 deaths per 1000 person-years for those with increased C-reactive protein and 5 per 1000 person-years for those with increased interleukin 6 levels. A receiver operating characteristic analysis found that traditional risk factors had an area under the curve of 0.73 (95% confidence interval, 0.70-0.77) among those with chronic kidney disease. Adding novel risk factors only increased the area under the curve to 0.74 (95% confidence interval, 0.71-0.78; P for difference = .15). CONCLUSIONS: Traditional cardiovascular risk factors had larger associations with cardiovascular mortality than novel risk factors in elderly persons with chronic kidney disease. Future research should investigate whether aggressive lifestyle intervention in patients with chronic kidney disease can reduce their substantial cardiovascular risk.
Keywords: Aged; Cardiovascular Diseases; Chronic Disease; Humans; Kidney Diseases; Longitudinal Studies; Risk Factors

Cardiovascular risk factors for retinal vein occlusion and arteriolar emboli: the Atherosclerosis Risk in Communities & Cardiovascular Health studies. - Wong, Tien Yin; Larsen, Emily K Marino; Klein, Ronald; Mitchell, Paul; Couper, David J; Klein, Barbara E K; Hubbard, Larry D; Siscovick, David S; Sharrett, A Richey (Ophthalmology, 2005)
OBJECTIVE: To examine the associations of retinal vein occlusion and arteriolar emboli with cardiovascular disease. DESIGN: Population-based cross-sectional study. PARTICIPANTS: Pooled from the Atherosclerosis Risk in Communities Study (n = 12,642; mean age, 60 years) and the Cardiovascular Health Study (n = 2824; mean age, 79 years). METHODS: Retinal vein occlusion and arteriolar emboli were identified from a single nonmydriatic retinal photograph using a standardized protocol. Photographs were also graded for arteriovenous nicking and focal arteriolar narrowing. All participants had a comprehensive systemic evaluation, including standardized carotid ultrasonography. MAIN OUTCOME MEASURES: Retinal vein occlusion and arteriolar emboli. RESULTS: Prevalences of retinal vein occlusion and arteriolar emboli were 0.3% (n = 39 cases) and 0.2% (n = 34 cases), respectively. After adjusting for age, retinal vein occlusion was associated with hypertension (odds ratio [OR], 2.96; 95% confidence interval [CI], 1.43-6.14), systolic blood pressure (BP) (OR, 4.12; 95% CI, 1.40-12.16; highest quartile vs. lowest), diastolic BP (OR, 2.64; 95% CI, 1.07-6.46; highest quartile vs. lowest), carotid artery plaque (OR, 5.62; 95% CI, 2.60-12.16), body mass index (OR, 3.88; 95% CI, 1.23-12.18; highest quartile vs. lowest), plasma fibrinogen (OR, 3.29; 95% CI, 1.08-10.02; highest quartile vs. lowest), arteriovenous nicking (OR, 4.09; 95% CI, 2.00-8.36), and focal arteriolar narrowing (OR, 5.17; 95% CI, 2.59-10.29). After adjusting for age, retinal arteriolar emboli were associated with hypertension (OR, 3.14; 95% CI, 1.44-6.84), systolic BP (OR, 3.46; 95% CI, 1.13-10.65; highest quartile vs. lowest), prevalent coronary heart disease (OR, 2.33; 95% CI, 1.01-5.42), carotid artery plaque (OR, 4.62; 95% CI, 1.85-11.57), plasma lipoprotein (a) (OR, 3.69; 95% CI, 1.20-11.41; highest quartile vs. lowest), plasma fibrinogen (OR, 3.09; 95% CI, 0.98-9.76; highest quartile vs. lowest), and current cigarette smoking (OR, 3.08; 95% CI, 1.47-6.47). Approximately a quarter of participants with retinal vein occlusion and arteriolar emboli had evidence of carotid artery plaque as defined from ultrasound. CONCLUSIONS: Retinal vein occlusion and retinal arteriolar emboli are associated with carotid artery disease, hypertension, and other cardiovascular risk factors.
Keywords: Aged; Aged, 80 and over; Arterioles; Blood Pressure; Cardiovascular Diseases; Carotid Stenosis; Coronary Artery Disease; Cross-Sectional Studies; Embolism; Female; Fibrinogen; Humans; Hypertension; Lipoprotein(a); Male; Meta-Analysis as Topic; Middle Aged; Retinal Artery; Retinal Vein Occlusion; Risk Factors

Classification of vascular dementia in the Cardiovascular Health Study Cognition Study. - Lopez, O L; Kuller, L H; Becker, J T; Jagust, W J; DeKosky, S T; Fitzpatrick, A; Breitner, J; Lyketsos, C; Kawas, C; Carlson, M (Neurology, 2005)
OBJECTIVE: To describe the diagnostic classification of subjects with incident vascular dementia (VaD) participating in the Cardiovascular Health Study (CHS) Cognition Study. METHODS: The CHS classified 480 incident cases between 1994 and 1999 among 3,608 CHS participants who had brain MRI in 1992 through 1994 and in 1997 through 1998. The patients were diagnosed before and after reviewing the brain MRI. RESULTS: The pre-MRI classification showed that 52 participants had VaD and 76 had both Alzheimer disease (AD) and VaD. The post-MRI classification showed that the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) criteria classified 61 subjects as having VaD, the National Institute of Neurological Disorders and Stroke-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (NINDS-AIREN) criteria classified 43 subjects as having probable VaD and 10 as possible VaD, and the State of California Alzheimer's Disease Diagnostic and Treatment Center (ADDTC) criteria classified 117 as having probable VaD and 96 as possible. The combination of the ADDTC and National Institute of Neurological and Communication Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria was used to examine the spectrum of vascular disease in dementia. The dementia was attributable to only vascular factors in 56 cases (probable VaD); VaD coexisted with AD in 61 cases, although the VaD component was the leading cause of dementia (probable VaD with AD); AD was the leading cause of dementia in 61 cases (possible VaD and probable AD); and in 29 cases, it was not clear that either AD or VaD was the primary diagnosis (possible AD and possible VaD). CONCLUSIONS: None of the clinical criteria for VaD identified the same group of subjects. The diagnosis of vascular dementia is difficult in epidemiologic studies because poststroke dementia can be due to Alzheimer disease (AD) and evidence of vascular disease can be found in the MRI of dementia cases without clinical strokes. Whether the clinical progression is related to AD pathology or vascular disease is difficult to establish.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Brain; Cerebral Arteries; Cohort Studies; Dementia, Vascular; Diagnosis, Differential; Disease Progression; Female; Humans; Magnetic Resonance Imaging; Male; Predictive Value of Tests; Stroke; United States

Common promoter polymorphisms of inflammation and thrombosis genes and longevity in older adults: the cardiovascular health study. - Reiner, Alexander P; Diehr, Paula; Browner, Warren S; Humphries, Stephen E; Jenny, Nancy S; Cushman, Mary; Tracy, Russell P; Walston, Jeremy; Lumley, Thomas; Newman, Anne B; Kuller, Lewis H; Psaty, Bruce M (Atherosclerosis, 2005)
Inflammatory response genes may influence life span or quality at advanced ages. Using data from the population-based cardiovascular health study (CHS) cohort, we examined the associations between promoter polymorphisms of several inflammation and thrombosis genes with longevity. We ascertained genotypes for interleukin (IL)-6 -174 G/C, beta-fibrinogen -455 G/A, plasminogen activator inhibitor (PAI)-1 -675 4G/5G, and thrombin-activatable fibrinolysis inhibitor (TAFI) -438 G/A in 2224 men and women > or = 65 years old at baseline. During 10 years of follow-up, men with the TAFI -438 A/A genotype had decreased mortality due to all causes, and lived, on average, 0.9 more years of life, or 1.1 more years of healthy life, than men with the -438 G allele. The effects of TAFI -438 G/A in women were smaller and not statistically significant. PAI-1 4G/4G genotype appeared to be associated with lower non-cardiovascular mortality in men, but with greater cardiovascular mortality in women. In exploratory analyses, we observed a possible interaction among anti-inflammatory drugs, interleukin-6 -174 C/C genotype, and longevity. These findings suggest that modulators of fibrinolytic activity may have a generalized influence on aging, and merit further investigation in studies of genetic determinants of human longevity.
Keywords: Aged; Aging; Carboxypeptidase B2; Cause of Death; Cohort Studies; Female; Genotype; Health Status; Humans; Inflammation; Longevity; Male; Middle Aged; Plasminogen Activator Inhibitor 1; Polymorphism, Genetic; Promoter Regions, Genetic; Prospective Studies; Risk Factors; Thrombosis

C-reactive protein and the 10-year incidence of coronary heart disease in older men and women: the cardiovascular health study. - Cushman, Mary; Arnold, Alice M; Psaty, Bruce M; Manolio, Teri A; Kuller, Lewis H; Burke, Gregory L; Polak, Joseph F; Tracy, Russell P (Circulation, 2005)
BACKGROUND: High C-reactive protein (CRP) is associated with increased coronary heart disease risk. Few long-term data in the elderly are available. METHODS AND RESULTS: Baseline CRP was measured in 3971 men and women > or =65 years of age without prior vascular diseases; 26% had elevated concentrations (>3 mg/L). With 10 years of follow-up, 547 participants developed coronary heart disease (CHD; defined as myocardial infarction or coronary death). With elevated CRP, the 10-year cumulative CHD incidences were 33% in men and 17% in women. The age-, ethnicity-, and sex-adjusted relative risk of CHD for CRP >3 mg/L compared with <1 mg/L was 1.82 (95% CI, 1.46 to 2.28). Adjusting for conventional risk factors reduced the relative risk to 1.45 (95% CI, 1.14 to 1.86). The population-attributable risk of CHD for elevated CRP was 11%. Risk relationships did not differ in subgroups defined by baseline risk factors. We assessed whether CRP improved prediction by the Framingham Risk Score. Among men with a 10-year Framingham-predicted risk of 10% to 20%, the observed CHD incidence was 32% for elevated CRP. Among women, CRP discriminated best among those with a 10-year predicted risk >20%; the incidences were 31% and 10% for elevated and normal CRP levels, respectively. CONCLUSIONS: In older men and women, elevated CRP was associated with increased 10-year risk of CHD, regardless of the presence or absence of cardiac risk factors. A single CRP measurement provided information beyond conventional risk assessment, especially in intermediate-Framingham-risk men and high-Framingham-risk women.
Keywords: Age Factors; Aged; Aged, 80 and over; Biomarkers; C-Reactive Protein; Coronary Disease; Female; Humans; Incidence; Inflammation; Male; Myocardial Infarction; Predictive Value of Tests; Risk Factors

Cystatin C concentration as a risk factor for heart failure in older adults. - Sarnak, Mark J; Katz, Ronit; Stehman-Breen, Catherine O; Fried, Linda F; Jenny, Nancy Swords; Psaty, Bruce M; Newman, Anne B; Siscovick, David; Shlipak, Michael G (Ann Intern Med, 2005)
BACKGROUND: Previous studies that evaluated the association of kidney function with incident heart failure may be limited by the insensitivity of serum creatinine concentration for detecting abnormal kidney function. OBJECTIVE: To compare serum concentrations of cystatin C (a novel marker of kidney function) and creatinine as predictors of incident heart failure. DESIGN: Observational study based on measurement of serum cystatin C from frozen sera obtained at the 1992-1993 visit of the Cardiovascular Health Study. Follow-up occurred every 6 months. SETTING: Adults 65 years of age or older from 4 communities in the United States. PARTICIPANTS: 4384 persons without previous heart failure who had measurements of serum cystatin C and serum creatinine. MEASUREMENTS: Incident heart failure. RESULTS: The mean (+/-SD) serum concentrations of cystatin C and creatinine were 82 +/- 25 nmol/L (1.10 +/- 0.33 mg/L) and 89 +/- 34 micromol/L (1.01 +/- 0.39 mg/dL), respectively. During a median follow-up of 8.3 years (maximum, 9.1 years), 763 (17%) participants developed heart failure. After adjustment for demographic factors, traditional and novel cardiovascular risk factors, cardiovascular disease status, and medication use, sequential quintiles of cystatin C concentration were associated with a stepwise increased risk for heart failure in Cox proportional hazards models (hazard ratios, 1.0 [reference], 1.30 [95% CI, 0.96 to 1.75], 1.44 [CI, 1.07 to 1.94], 1.58 [CI, 1.18 to 2.12], and 2.16 [CI, 1.61 to 2.91]). In contrast, quintiles of serum creatinine concentration were not associated with risk for heart failure in adjusted analysis (hazard ratios, 1.0 [reference], 0.77 [CI, 0.59 to 1.01], 0.85 [CI, 0.64 to 1.13], 0.97 [CI, 0.72 to 1.29], and 1.14 [CI, 0.87 to 1.49]). LIMITATIONS: The mechanism by which cystatin C concentration predicts risk for heart failure remains unclear. CONCLUSIONS: The cystatin C concentration is an independent risk factor for heart failure in older adults and appears to provide a better measure of risk assessment than the serum creatinine concentration. *For a full list of participating Cardiovascular Health Study investigators and institutions, see http://www.chs-nhlbi.org.
Keywords: Aged; Biomarkers; Creatinine; Cystatin C; Cystatins; Female; Follow-Up Studies; Glomerular Filtration Rate; Heart Failure; Humans; Incidence; Kidney; Kidney Function Tests; Male; Risk Factors; United States

Cystatin-C and inflammatory markers in the ambulatory elderly. - Shlipak, Michael G; Katz, Ronit; Cushman, Mary; Sarnak, Mark J; Stehman-Breen, Catherine; Psaty, Bruce M; Siscovick, David; Tracy, Russell P; Newman, Anne; Fried, Linda (Am J Med, 2005)
PURPOSE: Inflammatory factors are elevated in persons with severe renal dysfunction, but their association across all levels of renal function is unclear. We compared cystatin-C, a novel marker of renal function, with creatinine and estimated glomerular filtration rate (eGFR) as predictors of C-reactive protein and fibrinogen levels. METHODS: This study is a cross-sectional analysis to evaluate cystatin-C, creatinine, and eGFR as predictors of the inflammatory markers C-reactive protein and fibrinogen. Participants included 4637 ambulatory elderly patients from the Cardiovascular Health Study. Multivariate linear regression was used to determine the independent associations of each renal function measurement with the inflammatory marker outcomes. RESULTS: After adjustment for confounding factors, cystatin-C was correlated with both C-reactive protein (coefficient = 0.13; 95% confidence interval: 0.10-1.16, P <.0001) and fibrinogen levels (0.15; 0.13-0.18, P <.0001). Associations were larger than those for creatinine and C-reactive protein (0.05; 0.02-0.07, P = .003) or fibrinogen (0.07; 0.04-0.10, P <.0001). Adjusted levels of C-reactive protein increased incrementally across quintiles of cystatin-C, from a median of 2.2 mg/L in quintile 1 to 3.7 mg/L in quintile 5. In contrast, both C-reactive protein and fibrinogen had U-shaped associations with quintiles of creatinine and eGFR, because the inflammatory markers were equivalently elevated in quintiles 1 and 5. CONCLUSIONS: The finding of a significant linear association of cystatin-C and inflammation markers suggests that even small reductions in renal function may be associated with adverse pathophysiologic consequences.
Keywords: Age Factors; Aged; Biomarkers; C-Reactive Protein; Cross-Sectional Studies; Cystatin C; Cystatins; Female; Fibrinogen; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Predictive Value of Tests; Sensitivity and Specificity

Kidney function as a predictor of noncardiovascular mortality. - Fried, Linda F; Katz, Ronit; Sarnak, Mark J; Shlipak, Michael G; Chaves, Paulo H M; Jenny, Nancy Swords; Stehman-Breen, Catherine; Gillen, Dan; Bleyer, Anthony J; Hirsch, Calvin; Siscovick, David; Newman, Anne B (J Am Soc Nephrol, 2005)
Chronic kidney disease is associated with a higher risk for cardiovascular mortality, as well as all-cause mortality. Whether chronic kidney disease is a predictor of noncardiovascular mortality is less clear. To further explore the latter, the association of kidney function with total noncardiovascular mortality and cause-specific mortality was assessed in the Cardiovascular Health Study, a community-based cohort of older individuals. Kidney disease was assessed using cystatin C and estimated GFR in 4637 participants in 1992 to 1993. Participants were followed until June 30, 2001. Deaths were adjudicated as cardiovascular or noncardiovascular disease by committee, and an underlying cause of death was assigned. The associations of kidney function with total noncardiovascular mortality and cause-specific mortality were analyzed by proportional hazards regression. Noncardiovascular mortality rates increased with higher cystatin C quartiles (16.8, 17.1, 21.6, and 50.0 per 1000 person-years). The association of cystatin C with noncardiovascular mortality persisted after adjustment for demographic factors; the presence of diabetes, C-reactive protein, hemoglobin, and prevalent cardiovascular disease; and measures of atherosclerosis (hazard ratio 1.69; 95% confidence interval 1.33 to 2.15, for the fourth quartile versus the first quartile). Results for estimated GFR were similar. The risk for noncardiac deaths attributed to pulmonary disease, infection, cancer, and other causes was similarly associated with cystatin C levels. Kidney function predicts noncardiovascular mortality from multiple causes in the elderly. Further research is needed to understand the mechanisms and evaluate interventions to reduce the high mortality rate in chronic kidney disease.
Keywords: Age Factors; Aged; Aged, 80 and over; Cardiovascular Diseases; Cause of Death; Cohort Studies; Confidence Intervals; Creatinine; Cystatin C; Cystatins; Female; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic; Kidney Function Tests; Longitudinal Studies; Male; Probability; Proportional Hazards Models; Risk Assessment; Severity of Illness Index; Survival Analysis; United States

Morphometric analysis of gray matter volume in demented older adults: exploratory analysis of the cardiovascular health study brain MRI database. - Rosano, C; Becker, J; Lopez, O; Lopez-Garcia, P; Carter, C S; Newman, A; Kuller, L; Aizenstein, H (Neuroepidemiology, 2005)
We tested the feasibility of a fully automated brain MRI voxel count technique--automated labeling pathway (ALP)--in a sample of 15 demented and 13 cognitively normal women (age 75-85 years) participating to the Cardiovascular Health Study (CHS). We hypothesized that ALP would replicate well-established findings of the anatomical correlates of dementia. In particular, we hypothesized that ALP volumetric measures would: (1) significantly differ between cognitively normal and demented women in those brain areas that are established markers for diagnosis of dementia (temporal and medial temporal lobes, hippocampus, amygdala and parahippocampus) but not in other brain areas (e.g., occipital lobe, visual cortex, motor cortex) and (2) correlate with visual ratings of brain disease which have been previously collected as part of the CHS. ALP required minimal operator intervention (input of brain images and verification of misalignments) and employed computer time of about 1 h per brain. ALP detected significant focal volumetric differences in the limbic system (p values between groups for hippocampus and parahippocampus: 0.002 and 0.005, respectively), temporal lobe (p < 0.0001) and caudate (p = 0.009), but not in other brain areas (e.g. occipital lobe, visual or motor cortex). Furthermore, ALP measures of medial temporal lobe atrophy strongly correlated with CHS visual ratings of ventricular enlargement (r(2) = 0.6, p = 0.002 for medial temporal lobe). In conclusion, ALP-detected focal brain atrophy was strongly associated with dementia. Because of its fully automated design, ALP technique is an ideal candidate to assess whether volumetric measures of specific areas can discriminate dementia better than currently available measures of global brain atrophy in large epidemiological studies.
Keywords: Aged; Aged, 80 and over; Brain; Dementia; Educational Status; Feasibility Studies; Female; Health Status; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Organ Size; Reproducibility of Results

Physical activity, APOE genotype, and dementia risk: findings from the Cardiovascular Health Cognition Study. - Podewils, Laura Jean; Guallar, Eliseo; Kuller, Lewis H; Fried, Linda P; Lopez, Oscar L; Carlson, Michelle; Lyketsos, Constantine G (Am J Epidemiol, 2005)
Physical activity may help preserve cognitive function and decrease dementia risk, but epidemiologic findings are inconsistent. The authors conducted a prospective study to determine the association between physical activity and risk of dementia, Alzheimer's disease, and vascular dementia. The US study population comprised 3,375 men and women aged 65 years or older, free of dementia at baseline, who participated in the Cardiovascular Health Cognition Study in 1992-2000. Leisure-time energy expenditure and an activity index reflecting number of different physical activities were calculated. Analyses were based on Cox proportional hazards models. There were 480 incident cases of dementia over an average of 5.4 years of follow-up. After multivariate adjustment, participants in the highest quartile of physical energy expenditure had a relative risk of dementia of 0.85 (95% confidence interval: 0.61, 1.19) compared with those in the lowest quartile, and participants engaging in >or=4 activities had a relative risk of dementia of 0.51 (95% confidence interval: 0.33, 0.79) compared with those engaging in 0-1 activity. These associations were more marked in apolipoprotein E genotype (APOE) epsilon4 allele noncarriers but were absent in carriers. A similar pattern was observed for Alzheimer's disease and vascular dementia. Mechanisms to explain the observed relations deserve further study.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Apolipoproteins E; Dementia; Dementia, Vascular; Female; Genotype; Humans; Male; Motor Activity; Proportional Hazards Models; Prospective Studies; Risk Factors; United States

Population structure, admixture, and aging-related phenotypes in African American adults: the Cardiovascular Health Study. - Reiner, Alexander P; Ziv, Elad; Lind, Denise L; Nievergelt, Caroline M; Schork, Nicholas J; Cummings, Steven R; Phong, Angie; Burchard, Esteban González; Harris, Tamara B; Psaty, Bruce M; Kwok, Pui-Yan (Am J Hum Genet, 2005)
U.S. populations are genetically admixed, but surprisingly little empirical data exists documenting the impact of such heterogeneity on type I and type II error in genetic-association studies of unrelated individuals. By applying several complementary analytical techniques, we characterize genetic background heterogeneity among 810 self-identified African American subjects sampled as part of a multisite cohort study of cardiovascular disease in older adults. On the basis of the typing of 24 ancestry-informative biallelic single-nucleotide-polymorphism markers, there was evidence of substantial population substructure and admixture. We used an allele-sharing-based clustering algorithm to infer evidence for four genetically distinct subpopulations. Using multivariable regression models, we demonstrate the complex interplay of genetic and socioeconomic factors on quantitative phenotypes related to cardiovascular disease and aging. Blood glucose level correlated with individual African ancestry, whereas body mass index was associated more strongly with genetic similarity. Blood pressure, HDL cholesterol level, C-reactive protein level, and carotid wall thickness were not associated with genetic background. Blood pressure and HDL cholesterol level varied by geographic site, whereas C-reactive protein level differed by occupation. Both ancestry and genetic similarity predicted the number and quality of years lived during follow-up, but socioeconomic factors largely accounted for these associations. When the 24 genetic markers were tested individually, there were an excess number of marker-trait associations, most of which were attenuated by adjustment for genetic ancestry. We conclude that the genetic demography underlying older individuals who self identify as African American is complex, and that controlling for both genetic admixture and socioeconomic characteristics will be required in assessing genetic associations with chronic-disease-related traits in African Americans. Complementary methods that identify discrete subgroups on the basis of genetic similarity may help to further characterize the complex biodemographic structure of human populations.
Keywords: African Americans; Aged; Aging; Algorithms; Cardiovascular Diseases; Cohort Studies; Female; Genetics, Population; Genotype; Humans; Male; Models, Genetic; Phenotype; Polymorphism, Single Nucleotide; Quantitative Trait Loci; Risk Factors; Socioeconomic Factors

A prospective study of anemia status, hemoglobin concentration, and mortality in an elderly cohort: the Cardiovascular Health Study. - Zakai, Neil A; Katz, Ronit; Hirsch, Calvin; Shlipak, Michael G; Chaves, Paulo H M; Newman, Anne B; Cushman, Mary (Arch Intern Med, 2005)
BACKGROUND: Anemia is viewed as a negative prognostic factor in the elderly population; its independent impact on survival is unclear. METHODS: Baseline hemoglobin quintiles and anemia, as defined by the World Health Organization criteria, were assessed in relation to mortality in the Cardiovascular Health Study, a prospective cohort study with 11.2 years of follow-up of 5888 community-dwelling men and women 65 years or older, enrolled in 1989-1990 or 1992-1993 in 4 US communities. RESULTS: A total of 1205 participants were in the lowest hemoglobin quintile (<13.7 g/dL for men; <12.6 g/dL for women), and 498 (8.5%) were anemic (<13 g/dL for men; <12 g/dL for women). A reverse J-shaped relationship with mortality was observed; age-, sex-, and race-adjusted hazard ratios (95% confidence interval [CI]) in the first and fifth quintiles, compared with the fourth quintile, were 1.42 (95% CI, 1.25-1.62) and 1.24 (95% CI, 1.09-1.42). After multivariate adjustment, these hazard ratios were 1.33 (95% CI, 1.15-1.54) and 1.17 (95% CI, 1.01-1.36). The demographic- and fully-adjusted hazard ratios of anemia for mortality were 1.57 (95% CI, 1.38-1.78) and 1.38 (95% CI, 1.19-1.54). Adjustment for causes and consequences of anemia (renal function, inflammation, or frailty) did not reduce associations. CONCLUSIONS: Lower and higher hemoglobin concentrations and anemia by World Health Organization criteria were independently associated with increased mortality. The World Health Organization criteria did not identify risk as well as a lower hemoglobin value. Additional study is needed on the clinically valid definition for and causes of anemia in the elderly and on the increased mortality at the extremes of hemoglobin concentrations.
Keywords: Age Factors; Aged; Anemia; California; Female; Follow-Up Studies; Health Status; Hemoglobins; Humans; Male; Maryland; Multivariate Analysis; North Carolina; Observation; Pennsylvania; Prospective Studies; Risk Factors; Severity of Illness Index; Survival Rate

Prostate carcinoma incidence in relation to prediagnostic circulating levels of insulin-like growth factor I, insulin-like growth factor binding protein 3, and insulin. - Chen, Chu; Lewis, S Kay; Voigt, Lynda; Fitzpatrick, Annette; Plymate, Stephen R; Weiss, Noel S (Cancer, 2005)
BACKGROUND: There have been several epidemiologic studies investigating the association between circulating levels of insulin-like growth factor I (IGF-I), insulin-like growth factor binding protein 3 (IGFBP-3), and insulin in relation to the risk of prostate carcinoma, with conflicting results. To examine this issue further, the authors conducted a nested case-control study within the Cardiovascular Health Study cohort. METHODS: In men who were diagnosed with prostate carcinoma (cases) between 1990 and 1999 (n=174), the levels of IGF-I, IGFBP-3, and insulin were measured on blood samples that were obtained 1-9 years prior to diagnosis (mean, 3.4 years). Similar measurements were made on 174 male participants without prostate carcinoma (controls) who were matched to cases based on the year blood was drawn, survival until the date of diagnosis, race, and age. RESULTS: Relative to the men with IGF-I levels in the first (lowest) quartile of the distribution, the risk of prostate carcinoma for men in the second, third, and fourth (upper) quartiles were 0.77 (95% confidence interval [95% CI], 0.43-1.38), 0.73 (95% CI, 0.41-1.30), and 0.67 (95% CI, 0.37-1.25), respectively. The results were influenced little by adjustment for levels of IGFBP-3 or, instead, by evaluating the molar IGF-I/IGFBP-3 ratio. An analysis that was restricted to men who had plasma prostate-specific antigen levels <4 ng/mL at the time of the blood draw yielded similar results. The corresponding relative risks for IGFBP-3 were 0.91 (95% CI, 0.49-1.68), 0.47 (95% CI, 0.25-0.94), and 0.65 (95% CI, 0.35-1.20), respectively. The distribution of serum insulin levels in cases and controls were nearly identical. CONCLUSIONS: The IGF-I level was not associated positively with the risk of prostate carcinoma; however, an increase in the IGFBP-3 level was associated with a modest decrease in risk.
Keywords: Aged; Aged, 80 and over; Carcinoma; Case-Control Studies; Humans; Hypoglycemic Agents; Incidence; Insulin; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Male; Prostatic Neoplasms; Risk Factors

Renal duplex parameters, blood pressure, and renal function in elderly people. - Pearce, Jeffrey D; Edwards, Matthew S; Craven, Timothy E; English, William P; Mondi, Matthew M; Reavis, Scott W; Hansen, Kimberley J (Am J Kidney Dis, 2005)
BACKGROUND: Changes in renal artery and renal parenchyma perfusion are believed to correlate with severity of hypertension and worsened renal function, but population-based studies of these associations are not available. This study examines relationships between parameters derived from renal duplex sonography (RDS), blood pressure (BP), and excretory renal function in a population-based cohort of elderly Americans. METHODS: Through an ancillary study to the Cardiovascular Health Study, 758 participants (37% men; mean age, 77 years) underwent RDS in which flow velocities and frequency shifts were determined from spectral analysis of Doppler-shifted signals obtained from the renal artery and parenchyma. Associations of these duplex parameters with BP and inverse serum creatinine were examined by using multivariate regression techniques. RESULTS: Main renal artery peak systolic flow velocity (PSV) showed independent associations with BP, with an SD increase in PSV (0.53 m/s) associated with a 3.3-mm Hg increase in systolic BP (SBP) and a 2.4-mm Hg decrease in diastolic BP (DBP). An SD decrease in end-diastolic frequency shift (EDF; 131 kHz) was associated with a 6.0-mm Hg increase in SBP, a 4.2-mm Hg decrease in DBP, and a significant 3.7% decrease in inverse serum creatinine. CONCLUSION: Increases in renal artery PSV and decreases in parenchymal EDF are associated with increased SBP and decreased DBP. Moreover, decreased parenchymal EDF showed significant associations with impaired excretory renal function. These results suggest that renal duplex parameters are associated with renal parenchymal changes caused by hypertension and progressive renal dysfunction in elderly people.
Keywords: African Americans; Aged; Aging; Arteriosclerosis; Blood Pressure; Cardiovascular Diseases; Cohort Studies; Creatinine; Cross-Sectional Studies; Diastole; Disease Progression; European Continental Ancestry Group; Female; Humans; Hypertension, Renovascular; Kidney; Kidney Diseases; Kidney Function Tests; Male; Renal Artery; Renal Artery Obstruction; Renal Circulation; Risk Factors; Sampling Studies; Systole; Ultrasonography, Doppler, Duplex; United States

Renovascular disease and the risk of adverse coronary events in the elderly: a prospective, population-based study. - Edwards, Matthew S; Craven, Timothy E; Burke, Gregory L; Dean, Richard H; Hansen, Kimberley J (Arch Intern Med, 2005)
BACKGROUND: Renovascular disease is a cause of secondary hypertension and renal insufficiency and is suspected to contribute to morbidity and mortality of coronary heart disease. This investigation prospectively examined associations between renovascular disease and adverse coronary events among a population-based sample of elderly Americans. METHODS: The Cardiovascular Health Study is a prospective, multicenter cohort study of cardiovascular disease risk factors, morbidity, and mortality among Americans older than 65 years. Renal duplex sonography was performed on 870 individuals between January 1995 and February 1997. Renovascular disease was defined as any focal peak systolic velocity of 1.8 m/s or greater (renal artery stenosis) or the absence of a Doppler-shifted signal from an imaged artery (renal artery occlusion). Adverse coronary events were defined as hospitalized angina, fatal or nonfatal myocardial infarction, and coronary revascularization. RESULTS: During a mean follow-up of 14 months, 68 participants experienced incident or recurrent adverse coronary events. The presence of renovascular disease demonstrated a significant relationship with adverse coronary events (hazard ratio, 1.96; 95% confidence interval, 1.00-3.83; P = .05) that remained after controlling for the effects of coexisting atherosclerotic risk factors and prevalent cardiovascular disease. The relationship between renovascular disease and adverse coronary events was not dependent on the effects of increased blood pressure. CONCLUSIONS: The presence of renovascular disease was associated with an increase in the risk of adverse coronary events in this sample. The increment in risk was not dependent on the effects of associated atherosclerotic risk factors, other prevalent cardiovascular disease, or increased blood pressure.
Keywords: Age Distribution; Aged; Aged, 80 and over; Analysis of Variance; Cohort Studies; Comorbidity; Coronary Disease; Female; Geriatric Assessment; Heart Function Tests; Humans; Hypertension, Renovascular; Incidence; Kidney Function Tests; Male; Multivariate Analysis; Probability; Prognosis; Prospective Studies; Risk Assessment; Severity of Illness Index; Sex Distribution; Survival Rate; Ultrasonography, Doppler; United States

Risk factors for declining ankle-brachial index in men and women 65 years or older: the Cardiovascular Health Study. - Kennedy, Margaret; Solomon, Cam; Manolio, Teri A; Criqui, Michael H; Newman, Anne B; Polak, Joseph F; Burke, Gregory L; Enright, Paul; Cushman, Mary (Arch Intern Med, 2005)
BACKGROUND: An ankle-brachial index (ABI) of less than 0.9 is a noninvasive measure of lower extremity arterial disease and a predictor of cardiovascular events. Little information is available on longitudinal change in ABI or on risk factors for declining ABI in a community-based population. METHODS: To assess risk factors for ABI decline, we studied 5888 participants in the Cardiovascular Health Study cohort (men and women 65 years or older). We measured ABI in 1992-1993 and again in 1998-1999. At baseline, we excluded individuals with an ABI less than 0.9, ABI greater than 1.4, or confirmed symptomatic lower extremity arterial disease (n = 823). The group with ABI decline included 218 participants with decline greater than 0.15 and to 0.9 or less. The comparison group comprised the remaining 2071 participants with follow-up ABI. RESULTS: The percentage of participants with ABI decline was 9.5% over 6 years of follow-up. The mean +/- SD decline was 0.33 +/- 0.12 in cases of ABI decline and 0.02 +/- 0.13 in non-cases. Independent predictors of ABI decline, reported as odds ratios, were age, 1.96 (95% confidence interval [CI], 1.42-2.71) for 75 to 84 years and 3.79 (95% CI, 1.36-10.5) for those older than 85 years compared with those younger than 75 years; current cigarette use, 1.74 (95% CI, 1.02-2.96); hypertension, 1.64 (95% CI, 1.18-2.28); diabetes, 1.77 (95% CI, 1.14-2.76); higher low-density lipoprotein cholesterol level, 1.60 (95% CI, 1.03-2.51), and lipid-lowering drug use 1.74 (95% CI, 1.05-2.89). CONCLUSION: Worsening lower extremity arterial disease, assessed as ABI decline, occurred in 9.5% of this elderly cohort over 6 years and was associated with modifiable vascular disease risk factors.
Keywords: Aged; Aged, 80 and over; Ankle; Brachial Artery; Cardiovascular Diseases; Female; Humans; Male; Peripheral Vascular Diseases; Risk Assessment; Risk Factors

Statins and cognitive function in the elderly: the Cardiovascular Health Study. - Bernick, C; Katz, R; Smith, N L; Rapp, S; Bhadelia, R; Carlson, M; Kuller, L (Neurology, 2005)
OBJECTIVE: To examine the association of statin drug use on cognitive and MRI change in older adults. METHODS: Participants in the Cardiovascular Health Study, a longitudinal study of people age 65 or older, were classified into three groups determined by whether they were taking statin drugs on a continuous basis, intermittently, or not at all. The untreated group was further divided into categories based on National Cholesterol Education Program recommendations for lipid-lowering treatment. Participants with prevalent or incident clinical TIA or stroke or with baseline Modified Mini-Mental State Examination (3MS) scores at or below 80 were excluded. Outcomes examined included rate of change on the 3MS over an average observational period of 7 years, along with changes in MRI white matter grade and measures of atrophy. RESULTS: Three thousand three hundred thirty-four participants had adequate data for analysis. At baseline, the untreated group in which lipid-lowering drug treatment was recommended were slightly older, less likely to be on estrogen replacement, and had higher serum cholesterol and lower 3MS scores than the statin-treated group. The rate of decline on the 3MS was 0.48 point/year less in those taking statins compared with the untreated group for which treatment was recommended (p = 0.069) and 0.49 point/year less in statin users compared with the group in which lipid-lowering treatment was not recommended (p = 0.009). This effect remained after controlling for serum cholesterol levels. One thousand seven hundred thirty participants with baseline 3MS scores of > 80 underwent cranial MRI scans on two occasions separated by 5 years. There was no significant difference in white matter grade change or atrophy measures between groups. CONCLUSION: Statin drug use was associated with a slight reduction in cognitive decline in an elderly population. This relationship could not be completely explained by the effect of statins on lowering of serum cholesterol.
Keywords: Aged; Aged, 80 and over; Aging; Anticholesteremic Agents; Atrophy; Brain; Cholesterol; Cognition Disorders; Cohort Studies; Dementia; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Longitudinal Studies; Male; Memory Disorders; Nootropic Agents; Treatment Outcome

Subclinical brain magnetic resonance imaging abnormalities predict physical functional decline in high-functioning older adults. - Rosano, Caterina; Kuller, Lewis H; Chung, Hyoju; Arnold, Alice M; Longstreth, William T; Newman, Anne B (J Am Geriatr Soc, 2005)
OBJECTIVES: To determine whether severity of subclinical brain magnetic resonance imaging (MRI) abnormalities predicts incident self-reported physical impairment or rate of decline in motor performance. DESIGN: Longitudinal analysis, average follow-up time: 4.0 years. SETTING: Cardiovascular Health Study (CHS). PARTICIPANTS: CHS participants with modified Mini-Mental State Examination (3MS) score of 80 or greater, no self-reported disability, no history of stroke, and at least one assessment of mobility (n=2,450, mean age=74.4). MEASUREMENTS: Brain MRI abnormalities (ventricular enlargement, white matter hyperintensities, subcortical and basal ganglia small brain infarcts), self-reported physical impairment (difficulty walking half a mile or with one or more activities of daily living), and motor performance (gait speed, timed chair stand). RESULTS: After adjusting for demographics, cardiovascular risk factors, and diseases, risk of incident self-reported physical impairment was 35% greater for those with severe ventricular enlargement than for those with minimal ventricular enlargement, 22% greater for those with moderate white matter hyperintensities than for those with minimal white matter hyperintensities, and 26% greater for participants with at least one brain infarct than for those with no infarcts. Those with moderate to severe brain abnormalities experienced faster gait speed decline (0.02 m/s per year) than those with no MRI abnormalities (0.01 m/s per year). Further adjustment for incident stroke, incident dementia, and 3MS score did not substantially attenuate hazard ratios for incident self-reported physical impairment or coefficients for decline in gait speed. CONCLUSION: Subclinical structural brain abnormalities in high-functioning older adults can increase the risk of developing physical disabilities and declining in motor performance.
Keywords: Activities of Daily Living; Aged; Aged, 80 and over; Brain; Female; Follow-Up Studies; Gait; Humans; Incidence; Magnetic Resonance Imaging; Male; Proportional Hazards Models; Psychomotor Disorders; Risk Factors; United States

10-year follow-up of subclinical cardiovascular disease and risk of coronary heart disease in the Cardiovascular Health Study. - Kuller, Lewis H; Arnold, Alice M; Psaty, Bruce M; Robbins, John A; O'Leary, Daniel H; Tracy, Russell P; Burke, Gregory L; Manolio, Teri A; Chaves, Paolo H M (Arch Intern Med, 2006)
BACKGROUND: The incidence of coronary heart disease (CHD) is very high among individuals 65 years or older. METHODS: We evaluated the relationships between measurements of subclinical disease at baseline (1989-1990) and at the third-year follow-up examination (1992-1993) and subsequent incidence of cardiovascular disease and total mortality as of June 2001. Approximately 61% of the participants without clinical cardiovascular disease at baseline had subclinical disease based on our previously described criteria from the Cardiovascular Health Study. RESULTS: The incidence of CHD was substantially increased for participants with subclinical disease compared with those who had no subclinical disease: 30.5 per 1000 person-years with and 16.3 per 1000 person-years without for white individuals, and 31.2 per 1000 person-years with and 12.5 per 1000 person-years without for black individuals. The risk persisted over the entire follow-up period. Incidence rates were higher for men than for women with or without subclinical disease, but there was little difference in rates for black individuals and white individuals. CONCLUSIONS: In multivariable models, subclinical disease at baseline remained a significant predictor of CHD in both men and women; the hazard ratios (95% confidence intervals) of their relative risks were 1.64 (1.30-2.06) and 1.49 (1.21-1.84), respectively. The presence of subclinical disease substantially increased the risk of subsequent CHD for participants with hypertension, diabetes mellitus, or elevated C-reactive protein. In summary, subclinical disease is very prevalent among older individuals, is independently associated with risk of CHD even over a 10-year follow-up period, and substantially increases the risk of CHD among participants with hypertension or diabetes mellitus.
Keywords: African Continental Ancestry Group; Aged; Blood Chemical Analysis; Cardiovascular Diseases; Comorbidity; Coronary Disease; Echocardiography; European Continental Ancestry Group; Female; Follow-Up Studies; Humans; Incidence; Male; Multivariate Analysis; Prevalence; Proportional Hazards Models; Regression Analysis; Risk Factors; Sex Distribution; United States

Adjusted mortality after hip fracture: From the cardiovascular health study. - Robbins, John A; Biggs, Mary L; Cauley, Jane (J Am Geriatr Soc, 2006)
OBJECTIVES: To estimate the risk of death associated with hip fracture (HFx), stratifying by sex and time since fracture. DESIGN: Prospective cohort study compared participants with and without hip fracture, matched on sex, age, race, recruitment period, and time since enrollment. SETTING: The Cardiovascular Health Study, a more-than-15-year longitudinal study of 5,888 older individuals from four U.S. sites. PARTICIPANTS: Three hundred seventy-nine individuals with HFx were compared with 1,134 without HFx. MEASUREMENTS: Extended Cox models were used to estimate mortality hazard ratios (HRs) for different periods after fracture, adjusting for prefracture health. RESULTS: Age- and race-adjusted excess mortality was 9% in women and 24% in men 1 year after fracture, and 24% in women and 26% men 5 years postfracture. Multivariable-adjusted HRs of mortality associated with HFx in women were 7.1 (95% confidence interval (CI) = 2.3-21.5), 2.1 (95% CI = 1.0-4.1), 1.4 (95% CI = 1.1-2.0), and 1.0 (95% CI = 0.6-1.5) for 0 to 1 months, 2 to 6 months, 7 months to 4 years, and 5 to 8 years, respectively, after index date. In men, respective HRs for the same time periods were 39.9 (95% CI = 5.2-308.7), 3.8 (95% CI = 1.4-10.3), 1.1 (95% CI = 0.7-1.8), and 1.0 (95% CI = 0.3-2.7). HRs adjusted for age and race were 20% to 40% higher. CONCLUSION: The risk of mortality was highest in the first 6 months after HFx. In men, the risk of death approximated that of men without HFx after 6 months; in women, a moderately greater risk persisted through the fourth year. Although the mortality pattern was different in women and men, excess mortality 5 years postfracture was similar for both sexes.
Keywords: Aged; Cohort Studies; Female; Health Status; Health Surveys; Hip Fractures; Humans; Male; Mortality; Multicenter Studies as Topic; Proportional Hazards Models; Sex Distribution; Time Factors; United States

Alcohol consumption and risk of coronary heart disease in older adults: the Cardiovascular Health Study. - Mukamal, Kenneth J; Chung, Hyoju; Jenny, Nancy S; Kuller, Lewis H; Longstreth, W T; Mittleman, Murray A; Burke, Gregory L; Cushman, Mary; Psaty, Bruce M; Siscovick, David S (J Am Geriatr Soc, 2006)
OBJECTIVES: To evaluate several aspects of the relationship between alcohol use and coronary heart disease in older adults, including beverage type, mediating factors, and type of outcome. DESIGN: Prospective cohort study. SETTING: Four U.S. communities. PARTICIPANTS: Four thousand four hundred ten adults aged 65 and older free of cardiovascular disease at baseline. MEASUREMENTS: Risk of incident myocardial infarction or coronary death according to self-reported consumption of beer, wine, and spirits ascertained yearly. RESULTS: During an average follow-up period of 9.2 years, 675 cases of incident myocardial infarction or coronary death occurred. Compared with long-term abstainers, multivariate relative risks of 0.90 (95% confidence interval (CI)=0.71-1.14), 0.93 (95% CI=0.73-1.20), 0.76 (95% CI=0.53-1.10), and 0.58 (95% CI=0.39-0.86) were found in consumers of less than one, one to six, seven to 13, and 14 or more drinks per week, respectively (P for trend=.007). Associations were similar for secondary coronary outcomes, including nonfatal and fatal events. No strong mediators of the association were identified, although fibrinogen appeared to account for 9% to 10% of the relationship. The associations were statistically similar for intake of wine, beer, and liquor and generally similar in subgroups, including those with and without an apolipoprotein E4 allele. CONCLUSION: In this population, consumption of 14 or more drinks per week was associated with the lowest risk of coronary heart disease, although clinicians should not recommend moderate drinking to prevent coronary heart disease based on this evidence alone, because current National Institute on Alcohol Abuse and Alcoholism guidelines suggest that older adults limit alcohol intake to one drink per day.
Keywords: Aged; Alcohol Drinking; Apolipoproteins E; Beer; Cohort Studies; Coronary Disease; Female; Genotype; Health Behavior; Humans; Incidence; Male; Residence Characteristics; Risk Assessment; Socioeconomic Factors; United States; Wine

Alcohol consumption in older adults and Medicare costs. - Mukamal, Kenneth J; Lumley, Thomas; Luepker, Russell V; Lapin, Pauline; Mittleman, Murray A; McBean, A Marshall; Crum, Rosa M; Siscovick, David S (Health Care Financ Rev, 2006)
We determined the relationship of alcohol consumption and Medicare costs among 4,392 participants in the Cardiovascular Health Study (CHS), a longitudinal, population-based cohort study of adults age 65 or over in four U.S. communities. We assessed 5-year Parts A and B costs and self-reported intake of beer, wine, and liquor at baseline. Among both sexes, total costs were approximately $2,000 lower among consumers of > 1-6 drinks per week than abstainers. The lower costs associated with moderate drinking were most apparent among participants with cardiovascular disease (CVD) and for hospitalization costs for CVD among healthy participants. Former drinkers had the highest costs.
Keywords: Aged; Alcohol Drinking; Cardiovascular Diseases; Female; Health Expenditures; Hospitalization; Humans; Longitudinal Studies; Male; Medicare; United States

The association of markers of inflammation with weight change in older adults: the Cardiovascular Health Study. - Barzilay, J I; Forsberg, C; Heckbert, S R; Cushman, M; Newman, A B (Int J Obes (Lond), 2006)
OBJECTIVE: Elevated levels of inflammation factors often precede weight loss and may be causally related to it. Newer studies suggest that elevated levels of inflammation factors also precede weight gain. In this study, we examined whether inflammation factors are elevated in individuals, age >or=65 years, who lost or gained >5% weight over a 3 year follow-up period compared to those with stable weight. SUBJECTS: In total, 3254 participants in the Cardiovascular Health Study whose weight was stable; 661 who gained >5% weight; and 842 who lost >5% weight. MEASUREMENTS: C-reactive protein (CRP), fibrinogen, factor VIIIc, white blood cell (WBC) and platelet counts, and interleukin-6 (IL-6) levels. RESULTS: As compared to participants whose weight was stable, those who lost >5% weight had higher baseline CRP concentration (1.05 (95% CI, 1.02, 1.08) per interquartile increase) and WBC count (1.10 (1.01, 1.19) per interquartile increase) on adjusted analyses. Those who gained >5% weight had higher baseline CRP (1.05 (1.01, 1.08)), fibrinogen (1.13 (1.01, 1.27)), and factor VIIIc (1.15 (1.03, 1.30)). CONCLUSIONS: Inflammation factors are associated with weight gain and weight loss in older individuals. These findings suggest that subclinical inflammation, or unknown factors associated with subclinical inflammation, contribute to weight change.
Keywords: Aged; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Factor VIII; Female; Fibrinogen; Humans; Inflammation; Interleukin-6; Leukocyte Count; Male; Platelet Count; Weight Gain; Weight Loss

The association of microalbuminuria with clinical cardiovascular disease and subclinical atherosclerosis in the elderly: the Cardiovascular Health Study. - Cao, Jie J; Barzilay, Joshua I; Peterson, Do; Manolio, Teri A; Psaty, Bruce M; Kuller, Lewis; Wexler, Jason; Bleyer, Anthony J; Cushman, Mary (Atherosclerosis, 2006)
PURPOSE: Microalbuminuria (MA) is a risk factor for cardiovascular disease (CVD). It is not known whether this association is due to the effect of MA on the development of subclinical atherosclerosis or whether MA destabilizes subclinical atherosclerosis, leading to clinical events. METHODS: In a cross-sectional analysis we evaluated 3312 Cardiovascular Health Study participants, age >or=65 years, who had MA testing. Participants were divided into three groups: those without diabetes or hypertension (33%), those with hypertension (52%) and those with diabetes, with or without hypertension (15%). Clinical CVD was defined as presence of coronary heart disease (angina, MI, CABG, PTCA), cerebrovascular disease (stroke, TIA) and peripheral arterial disease (requiring intervention). Among those without clinical disease, subclinical atherosclerosis was defined as increased carotid artery intima-media thickness, decreased ankle arm index or increased left ventricular mass. RESULTS: In each of the three groups of participants, the adjusted odds of prevalent clinical CVD in the presence of MA was 1.70-1.80-fold increased, independent of other risk factors. MA was not associated with risk of subclinical atherosclerosis in those without hypertension or diabetes (OR 1.14 [95% CI 0.59, 2.23]), whereas it was associated with subclinical atherosclerosis in those with hypertension (OR 1.58 [95% CI 1.08, 2.30]) or diabetes (OR 2.51 [95% CI 1.27, 4.94]). CONCLUSION: In the absence of hypertension or diabetes, MA was associated with clinical CVD but not with subclinical atherosclerosis. Thus, a hypothesis may be made that the mechanism of association of MA with clinical vascular disease involves destabilization of the vasculature, leading to clinical disease.
Keywords: Aged; Aged, 80 and over; Albuminuria; Atherosclerosis; Cardiovascular Diseases; Coronary Disease; Diabetes Mellitus; Female; Humans; Hypertension; Male; Peripheral Vascular Diseases; Prevalence; Risk Factors; Stroke; United States

Association of polymorphisms in the CRP gene with circulating C-reactive protein levels and cardiovascular events. - Lange, Leslie A; Carlson, Christopher S; Hindorff, Lucia A; Lange, Ethan M; Walston, Jeremy; Durda, J Peter; Cushman, Mary; Bis, Joshua C; Zeng, Donglin; Lin, Danyu; Kuller, Lewis H; Nickerson, Deborah A; et al. (JAMA, 2006)
CONTEXT: C-reactive protein (CRP) is an inflammation protein that may play a role in the pathogenesis of cardiovascular disease (CVD). OBJECTIVE: To assess whether polymorphisms in the CRP gene are associated with plasma CRP, carotid intima-media thickness (CIMT), and CVD events. DESIGN, SETTING, AND PARTICIPANTS: In the prospective, population-based Cardiovascular Health Study, 4 tag single-nucleotide polymorphisms (SNPs) (1919A/T, 2667G/C, 3872G/A, 5237A/G) were genotyped in 3941 white (European American) participants and 5 tag SNPs (addition of 790A/T) were genotyped in 700 black (African American) participants, aged 65 years or older, all of whom were without myocardial infarction (MI) or stroke before study entry. Median follow-up was 13 years (1989-2003). MAIN OUTCOME MEASURES: Baseline CIMT; occurrence of MI, stroke, and CVD mortality during follow-up. RESULTS: In white participants, 461 incident MIs, 491 incident strokes, and 490 CVD-related deaths occurred; in black participants, 67 incident MIs, 78 incident strokes, and 75 CVD-related deaths occurred. The 1919T and 790T alleles were associated with higher CRP levels in white and black participants, respectively. The 3872A allele was associated with lower CRP levels in both populations, and the 2667C allele was associated with lower CRP levels in white participants only. There was no association between CIMT and any CRP gene polymorphism in either population. In white participants, the 1919T allele was associated with increased risk of stroke for TT vs AA (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.06-1.87) and for CVD mortality (HR, 1.40; 95% CI, 1.10-1.90). In black participants, homozygosity for the 790T allele was associated with a 4-fold increased risk of MI compared with homozygosity for the 790A allele (95% CI, 1.58-10.53). The minor alleles of the 2 SNPs associated with lower plasma CRP concentration in white participants (2667C and 3872A) were associated with decreased risk of CVD mortality. CONCLUSIONS: Genetic variation in the CRP gene is associated with plasma CRP levels and CVD risk in older adults.
Keywords: African Continental Ancestry Group; Aged; C-Reactive Protein; Cardiovascular Diseases; Carotid Arteries; European Continental Ancestry Group; Female; Genotype; Humans; Male; Myocardial Infarction; Polymorphism, Single Nucleotide; Proportional Hazards Models; Risk; Stroke; Tunica Intima

The association of race with frailty: the cardiovascular health study. - Hirsch, Calvin; Anderson, Melissa L; Newman, Anne; Kop, Willem; Jackson, Sharon; Gottdiener, John; Tracy, Russell; Fried, Linda P (Ann Epidemiol, 2006)
PURPOSE: Frailty, which has been conceptualized as a state of decreased physiologic reserve contributing to functional decline, has a prevalence among older African Americans that is twice that in older whites. This study assesses the independent contribution of race to frailty. METHODS: We evaluated 786 African-American and 4491 white participants of the Cardiovascular Health Study (CHS). Frailty is defined as meeting three or more of five criteria derived from CHS measures: lowest quintile for grip strength, self-reported exhaustion, unintentional weight loss of 10 lbs or greater in 1 year, slowest quintile for gait speed, and lowest quintile for physical activity. Controlling for age, sex, comorbidity, socioeconomic factors, and race, multinomial logistic regression estimated the odds ratio (OR) of prefrail (one or two criteria) to not frail and frail to not frail. RESULTS: Among African Americans, 8.7% of men and 15.0% of women were frail compared with 4.6% and 6.8% of white men and women, respectively. In adjusted models, nonobese African Americans had a fourfold greater odds of frailty compared with whites. The increased OR of frailty associated with African-American race was less pronounced among those who were obese or disabled. CONCLUSION: African-American race is associated independently with frailty.
Keywords: African Americans; Aged; Asthenia; Cardiovascular Diseases; Cohort Studies; Cross-Sectional Studies; European Continental Ancestry Group; Female; Frail Elderly; Health Status; Humans; Male; Middle Aged; Motor Activity; Odds Ratio; United States; Weight Loss

Beta2-adrenergic receptor genetic variants and risk of sudden cardiac death. - Sotoodehnia, Nona; Siscovick, David S; Vatta, Matteo; Psaty, Bruce M; Tracy, Russell P; Towbin, Jeffrey A; Lemaitre, Rozenn N; Rea, Thomas D; Durda, J Peter; Chang, Joel M; Lumley, Thomas S; Kuller, Lewis H; et al. (Circulation, 2006)
BACKGROUND: Sympathetic activation influences the risk of ventricular arrhythmias and sudden cardiac death (SCD), mediated in part by the beta2-adrenergic receptor (B2AR). We investigated whether variation in the B2AR gene is associated with SCD risk. METHODS AND RESULTS: In this study, 4441 white and 808 black Cardiovascular Health Study (CHS) participants were followed up prospectively for SCD and genotyped for B2AR Gly16Arg and Gln27Glu polymorphisms. The study was replicated in 155 case and 144 control white subjects in a population-based case-control study of SCD, the Cardiac Arrest Blood Study (CABS). In CHS, Gly16 and Gln27 allele frequencies were 62.4% and 57.1% among white and 50.1% and 81.4% among black participants. Over a median follow-up of 11.1 years, 156 and 39 SCD events occurred in white and black participants, respectively. The Gln27Glu variant was associated with SCD risk (P=0.008 for general model). SCD risk was higher in Gln27 homozygous participants than in Glu27 carriers (ethnicity-adjusted hazard ratio [HR], 1.56; 95% confidence interval [CI], 1.17 to 2.09; P=0.003). The increased risk did not differ significantly between white (HR, 1.62; 95% CI, 1.18 to 2.23) and black (HR, 1.23; 95% CI, 0.61 to 2.48) participants, although the confidence interval was wide in blacks. In the CABS replication study, Gln27 homozygous participants similarly had higher SCD risk than Glu27 carriers (odds ratio, 1.64; 95% CI, 1.02 to 2.63; P=0.040). Gly16Arg was not associated with SCD risk in either study. CONCLUSIONS: Gln27 homozygous individuals have an increased risk of SCD in 2 study populations. Our findings suggest that B2AR plays a role in SCD in humans. Study of genetic variation within the B2AR gene may help identify those at increased SCD risk.
Keywords: African Continental Ancestry Group; Aged; Case-Control Studies; Death, Sudden, Cardiac; European Continental Ancestry Group; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Glutamine; Haplotypes; Homozygote; Humans; Male; Polymorphism, Single Nucleotide; Receptors, Adrenergic, beta-2; Reproducibility of Results

Cardiovascular morbidity and mortality in community-dwelling elderly individuals with calcification of the fibrous skeleton of the base of the heart and aortosclerosis (The Cardiovascular Health Study). - Barasch, Eddy; Gottdiener, John S; Marino Larsen, Emily K; Chaves, Paulo H M; Newman, Anne B (Am J Cardiol, 2006)
In the elderly, mitral annular calcification (MAC) and aortic valve sclerosis (AVS) are associated with increased cardiovascular morbidity and mortality. Aortic annular calcification (AAC) commonly occurs with MAC. However, the prognostic value of AAC, singly or in combination with MAC and AVS, for incident cardiovascular disease and mortality is unknown. From the Cardiovascular Health Study, we analyzed 3,782 participants (76 +/- 5 years of age, 60% women) who had an echocardiogram at the 1994 to 1995 examination and who were prospectively followed for an average of 6.6 years (range 0.01 to 8.5). All 3 calcification categories were associated with incident congestive heart failure (MAC: hazard ratio [HR] 1.71, 95% confidence interval [CI] 1.35 to 2.18, AAC: HR 1.62, 95% CI 1.28 to 2.06, and AVS: HR 1.50, 95% CI 1.19 to 1.89) and death. A stronger association with incident cardiovascular disease and mortality was observed with a larger number of calcification categories and with increased MAC severity. Moreover, in the participants with prevalent cardiovascular disease at echocardiographic examination (n = 1,054), MAC and AAC were still associated with cardiovascular mortality (MAC: HR 1.91, 95% CI 1.04 to 3.50; AAC: HR 2.11, 95% CI 1.16 to 3.85) even in fully adjusted models. In conclusion, MAC, AAC, and AVS are associated with a significant risk of incident congestive heart failure, cardiovascular and all-cause mortalities, and worse outcome in older patients with preexisting cardiovascular disease. Elderly patients with these findings represent a high-risk group and may require close medical attention.
Keywords: Aged; Aortic Valve; Calcinosis; Echocardiography; Female; Follow-Up Studies; Heart Failure; Heart Valve Diseases; Humans; Male; Mitral Valve; Prospective Studies; Risk Factors; Sclerosis; Severity of Illness Index; United States

CFH, ELOVL4, PLEKHA1 and LOC387715 genes and susceptibility to age-related maculopathy: AREDS and CHS cohorts and meta-analyses. - Conley, Yvette P; Jakobsdottir, Johanna; Mah, Tammy; Weeks, Daniel E; Klein, Ronald; Kuller, Lewis; Ferrell, Robert E; Gorin, Michael B (Hum Mol Genet, 2006)
Age-related maculopathy (ARM) is an important cause of visual impairment in the elderly population. It is of crucial importance to identify genetic factors and their interactions with environmental exposures for this disorder. This study was aimed at investigating the CFH, ELOVL4, PLEKHA1 and LOC387715 genes in independent cohorts collected using different ascertainment schemes. The study used a case-control design with subjects originally recruited through the Cardiovascular Health Study (CHS) and the Age-Related Eye Disease Study (AREDS). CFH was significantly associated with ARM in both cohorts (P</=0.00001). A meta-analysis confirmed that the risk allele in the heterozygous or homozygous state (OR, 2.4 and 6.2; 95% CI, 2.2-2.7 and 5.4-7.2, respectively) confers susceptibility. LOC387715 was also significantly associated with ARM in both cohorts (P</=0.00001) and a meta-analysis confirmed that the risk allele in the heterozygous and homozygous state (OR, 2.5 and 7.3; 95% CI, 2.2-2.9 and 5.7-9.4, respectively) confers susceptibility. Both CFH and LOC387715 showed an allele-dose effect on the ARM risk, individuals homozygous at either locus were at more than two-fold risk compared to those heterozygous. PLEKHA1, which is closely linked to LOC387715, was significantly associated with ARM status in the AREDS cohort, but not the CHS cohort and ELOVL4 was not significantly associated with ARM in either cohort. Joint action of CFH and LOC387715 was best described by independent multiplicative effect without significant interaction in both cohorts. Interaction of both genes with cigarette smoking was insignificant in both cohorts. This study provides additional support for the CFH and LOC387715 genes in ARM susceptibility via the evaluation of cohorts that had different ascertainment schemes regarding ARM status and through the meta-analyses.
Keywords: Aged; Aged, 80 and over; Case-Control Studies; Cohort Studies; Complement Factor H; Eye Proteins; Female; Genetic Predisposition to Disease; Humans; Intracellular Signaling Peptides and Proteins; Macular Degeneration; Male; Membrane Proteins; Proteins

Cigarette smoking and nocturnal sleep architecture. - Zhang, Lin; Samet, Jonathan; Caffo, Brian; Punjabi, Naresh M (Am J Epidemiol, 2006)
Cigarette smoking has been associated with a high prevalence of sleep-related complaints. However, its effects on sleep architecture have not been fully examined. The primary objective of this investigation was to assess the impact of cigarette smoking on sleep architecture. Polysomnography was used to characterize sleep architecture among 6,400 participants of the Sleep Heart Health Study (United States, 1994-1999). Sleep parameters included total sleep time, latency to sleep onset, sleep efficiency, and percentage of time in each sleep stage. The study sample consisted of 2,916 never smokers, 2,705 former smokers, and 779 current smokers. Compared with never smokers, current smokers had a longer initial sleep latency (5.4 minutes, 95% confidence interval (CI): 2.9, 7.9) and less total sleep time (14.0 minutes, 95% CI: 6.4, 21.7). Furthermore, relative to never smokers, current smokers also had more stage 1 sleep (relative proportion = 1.24, 95% CI: 1.14, 1.33) and less slow wave sleep (relative proportion = 0.86, 95% CI: 0.78, 0.95). Finally, no differences in sleep architecture were noted between former and never smokers. The results of this study show that cigarette smoking is independently associated with disturbances in sleep architecture, including a longer latency to sleep onset and a shift toward lighter stages of sleep. Nicotine in cigarette smoke and acute withdrawal from it may contribute to disturbances in sleep architecture.
Keywords: Aged; Arousal; Chi-Square Distribution; Female; Humans; Male; Middle Aged; Polysomnography; Prevalence; Regression Analysis; Risk Factors; Sleep Stages; Sleep Wake Disorders; Smoking; United States

Clinical course of mesenteric artery stenosis in elderly americans. - Wilson, David B; Mostafavi, Kian; Craven, Timothy E; Ayerdi, Juan; Edwards, Matthew S; Hansen, Kimberley J (Arch Intern Med, 2006)
BACKGROUND: To examine prospectively the relationship between stenosis or occlusion of the celiac and superior mesenteric arteries and symptoms of chronic intestinal ischemia in free-living elderly patients in the United States. METHODS: As part of an ancillary study to the Cardiovascular Health Study, participants in the Forsyth County (North Carolina) cohort underwent visceral duplex ultrasonography of the celiac and superior mesenteric arteries. Critical mesenteric artery stenosis (MAS) or occlusion was defined by Doppler flow ultrasound-derived criteria. Clinical outcomes were assessed at annual follow-up examinations and review of death certificates. Multivariate associations between the presence of MAS and all-cause mortality and adverse cardiovascular events were analyzed. Participants with MAS were contacted to determine the presence of symptoms consistent with chronic intestinal ischemia. RESULTS: Of 553 participants who underwent visceral duplex ultrasonography, 97 (17.5%) had disease of the celiac or superior mesenteric artery. At a mean follow-up of 6(1/2) years, 20 participants with MAS (20.6%) and 93 without MAS (20.4%) had died (relative risk, 1.01; 95% confidence interval, 0.66-1.55). No deaths were attributed to intestinal infarction. No association existed between the presence of MAS and prevalent cardiovascular disease, all-cause mortality, or adverse cardiovascular events. A questionnaire was completed by 71% of the surviving participants with MAS. No participant reported symptoms or weight loss consistent with chronic intestinal ischemia. CONCLUSIONS: Mesenteric artery stenosis was a common finding in free-living elderly patients. At long-term follow-up, the presence of asymptomatic MAS was not associated with death or adverse cardiovascular events. Participants with asymptomatic MAS by duplex ultrasonographic criteria did not experience intestinal infarction or develop chronic intestinal ischemia.
Keywords: Aged; Aged, 80 and over; Cohort Studies; Comorbidity; Female; Humans; Male; Mesenteric Arteries; Mesenteric Vascular Occlusion; Proportional Hazards Models; Prospective Studies; Radiography; Risk Factors; Surveys and Questionnaires; Ultrasonography

Clinical significance of calcification of the fibrous skeleton of the heart and aortosclerosis in community dwelling elderly. The Cardiovascular Health Study (CHS). - Barasch, Eddy; Gottdiener, John S; Larsen, Emily K Marino; Chaves, Paulo H M; Newman, Anne B; Manolio, Teri A (Am Heart J, 2006)
BACKGROUND: Mitral annular calcification (MAC), aortic annular calcification (AAC), and aortic valve sclerosis (AVS) are associated with aging, and MAC and AVS are markers of advanced atherosclerosis. No studies have examined the prevalence and the clinical relevance of all 3 forms of calcification in a single free-living elderly population. METHODS: We used 2-dimensional echocardiography to evaluate MAC, AAC, AVS and all 3 combined in 3929 participants, mean age 76 +/- 5 years, 60% women, in the Cardiovascular Health Study, a prospective community-based observational study designed to assess cardiovascular disease (CVD) risk factors and outcomes in elderly persons. RESULTS: Mitral annular calcification was found in 1640 (42 %) subjects, AAC in 1710 (44 %), AVS in 2114 (54 %), and all 3 combined in 662 (17 %). The participants with these findings were older than those without them, and those with MAC had worse cardiovascular, renal, metabolic, and functional profile than those with AAC and AVS. Age-, sex-, and race-adjusted logistic regression analysis found a significant association between the 3 calcification categories and CVD, the strongest being between the combined group with congestive heart failure (odds ratio 2.04, 95% CI 1.34-3.09). In highly adjusted models, only MAC was associated with CVD, and the strength of association was related to the severity of MAC. CONCLUSIONS: In free-living elderly, MAC, AAC, and AVS are highly prevalent and are associated with CVD. Mitral annular calcification in particular has strong association with CVD, and with an adverse biomedical profile.
Keywords: Aged; Aortic Valve; Calcinosis; Female; Heart Valve Diseases; Humans; Male; Mitral Valve; Prevalence; Prospective Studies; Risk Factors; Sclerosis; Ultrasonography

Comparison of mortality risk for electrocardiographic abnormalities in men and women with and without coronary heart disease (from the Cardiovascular Health Study). - Rautaharju, Pentti M; Ge, Sijian; Nelson, Jennifer C; Marino Larsen, Emily K; Psaty, Bruce M; Furberg, Curt D; Zhang, Zhu-Ming; Robbins, John; Gottdiener, John S; Chaves, Paulo H M (Am J Cardiol, 2006)
Mortality risk associated with electrocardiographic (ECG) abnormalities has been commonly reported to be lower in women than in men. We compared coronary heart disease (CHD) and all-cause mortality risk for ECG variables during a mean 9.1-year follow-up in 4,912 participants in the Cardiovascular Health Study who were > or = 65 years of age. The hypothesis was that mortality risk for ECG abnormalities is not lower in women than in men. Five ECG variables were significant mortality predictors in Cox regression models that were adjusted for demographic, clinical, and medication variables. Gender differences were significant and mortality risk was higher in women for ECG estimates of left ventricular mass for both end points and for nondipolar QRS voltage for all-cause mortality. When evaluated simultaneously in multiple ECG variable risk models in subgroups that were stratified by baseline CHD status, no gender difference was significant. In the latter models, ST depression was a strong predictor of CHD mortality in groups with and without previous CHD. Other significant ECG predictors were previous myocardial infarction in the previous CHD group and nondipolar QRS voltage in the CHD-free group. Four ECG abnormalities were significant predictors of all-cause mortality in the CHD-free group, with risk increases of 18% to 50%. The risk of all-cause mortality in the previous CHD group was significantly increased for ST depression (by 64%), the ECG estimate of left ventricular mass (by 48%), and previous myocardial infarction (by 34%). In conclusion, we found no evidence that the relative risk of mortality for ECG abnormalities is lower in women than in men.
Keywords: Aged; Coronary Disease; Electrocardiography; Female; Humans; Male; Risk

A cross-sectional study of vitamin C and cognitive function in older adults: the differential effects of gender. - Sato, R; Helzlsouer, K J; Comstock, G W; Hoffman, S C; Norkus, E P; Fried, L P (J Nutr Health Aging, 2006)
Previous studies have suggested that vitamin C status may be associated with cognitive function in community-dwelling populations. However, this has not been consistent across all studies due to methodological differences. This cross-sectional study assessed the association between vitamin C and cognitive function in 544 community-dwelling older adults aged 65 or older who participated in both the Cardiovascular Health Study (CHS) and the CLUE II study in 1989. Three percent of the subjects had low plasma vitamin C concentrations (< 40 mg/dL) and 15% had low total vitamin C intake (< 60 mg/day). Most participants (96.7 percent) had normal cognitive function. In the unadjusted analyses, the highest fifth of plasma vitamin C concentration was associated with better Digit Symbol Substitution Test (DSST) scores and marginally associated with Mini-Mental State Examination (MMSE) compared to the lowest fifth. Total vitamin C intake, measured by Block's food frequency questionnaire, was generally associated with higher MMSE scores, though it was not significant. Adjusting for numerous factors did not substantially change results. In a stratified analysis by gender, higher plasma concentrations or intake were associated with higher MMSE scores for men but not for women. These mixed results do not provide strong evidence of an association between vitamin C concentrations or intake and cognitive function.
Keywords: Aged; Aging; Ascorbic Acid; Cognition; Cross-Sectional Studies; Diet; Female; Health Surveys; Humans; Male; Mental Status Schedule; Nutrition Surveys; Nutritional Requirements; Sex Factors; Surveys and Questionnaires

Factors associated with geographic variations in stroke incidence among older populations in four US communities. - El-Saed, Aiman; Kuller, Lewis H; Newman, Anne B; Lopez, Oscar; Costantino, Joseph; McTigue, Kathleen; Cushman, Mary; Kronmal, Richard (Stroke, 2006)
BACKGROUND AND PURPOSE: In the Cardiovascular Health Study (CHS), we previously observed lower stroke incidence in Allegheny County, PA compared with the other 3 study sites. The purpose of this study was to study possible reasons for the lower stroke incidence in Allegheny County. METHODS: CHS participants 65 years or older who were stroke-free at baseline (n=5639) were followed between 1989 to 1990 and 2000 for the development of stroke. Risk factors at baseline and their subsequent control were compared among both groups. Site-specific hazard ratios for stroke incidence were calculated using Cox regression models. RESULTS: The unadjusted hazard ratio for total stroke incidence in Forsyth County, NC; Sacramento County, CA; and Washington County, MD combined compared with Allegheny County, PA was 1.74 (95% CI: 1.42, 2.14). After adjustment for age and other traditional risk factors, there was modest reduction of the excess hazard in non-Allegheny sites compared with Allegheny County (hazard ratio=1.52, 95% CI: 1.17, 1.98). Between baseline and the seventh-year visits, control of hypertension, diabetes, lipids, smoking, atrial fibrillation and transient ischemic attack were similar across sites. White matter grade > or = 3 on the baseline brain MRI was less common in Allegheny County (25.8% versus 36.3%, respectively; P<0.001) and accounted for 25% of the excess hazard in non-Allegheny sites compared with Allegheny County. CONCLUSIONS: Site differences in stroke risk factors at baseline and subsequent control only partially explain site differences in stroke incidence. White matter grade as a possible integrated measure of exposure and control of risk factors may help in explaining geographic variations in stroke incidence.
Keywords: Aged; Brain; California; Female; Humans; Incidence; Magnetic Resonance Imaging; Male; Maryland; North Carolina; Pennsylvania; Proportional Hazards Models; Risk Assessment; Risk Factors; Stroke

Geographic variations in stroke incidence and mortality among older populations in four US communities. - El-Saed, Aiman; Kuller, Lewis H; Newman, Anne B; Lopez, Oscar; Costantino, Joseph; McTigue, Kathleen; Cushman, Mary; Kronmal, Richard (Stroke, 2006)
BACKGROUND AND PURPOSE: Stroke is a leading cause of death and disability in the US. There is limited data on geographic variations in stroke incidence among older US populations who experience the majority of stroke burden. The purpose of this study was to compare stroke incidence and mortality rates in 4 US communities. METHODS: Participants in the Cardiovascular Health Study (CHS) who had no history of stroke at baseline (n=5639) were followed for 10 or 7 years in predominantly white (n=5002) and black (n=637) participants, respectively. Incident stroke was validated by a stroke adjudication committee after ascertainment at annual visits, interim telephone contacts, and review of Medicare hospitalization data. RESULTS: The 2000 US population age and sex standardized total stroke incidence rate for all CHS participants was 17.7 per 1000 person-years (95% CI: 15.9, 19.5). The rate was significantly lower in Allegheny County, Pennsylvania 9.6/1000 person-years (95% CI: 7.7, 11.5) than Forsyth County, North Carolina 19.2/1000 person-years (95% CI: 15.6, 22.8), Sacramento County, California 20.7/1000 person-years (95% CI: 16.9, 24.5), and Washington County, Maryland 19.8/1000 person-years (95% CI: 16.1, 23.5). The lower stroke incidence rate in Allegheny County was consistent in gender, race, and age groups. Though not statistically significant, stroke mortality was also lower in Allegheny County than other 3 sites. The 1-month case fatality rate was similar in the 4 sites for all strokes, and by stroke types. CONCLUSIONS: Understanding geographic variations in stroke incidence may be an important step in improving preventive practices of stroke.
Keywords: Aged; Aged, 80 and over; California; Female; Humans; Incidence; Male; Maryland; North Carolina; Pennsylvania; Stroke

Kidney function predicts the rate of bone loss in older individuals: the Cardiovascular Health Study. - Fried, Linda F; Shlipak, Michael G; Stehman-Breen, Catherine; Mittalhenkle, Anuja; Seliger, Stephen; Sarnak, Mark; Robbins, John; Siscovick, David; Harris, Tamara B; Newman, Anne B; Cauley, Jane A (J Gerontol A Biol Sci Med Sci, 2006)
BACKGROUND: Results of cross-sectional analyses of the association of kidney function with bone mineral density (BMD) have been conflicting. We examined the association of cystatin-C, a new marker of kidney function that is unrelated to lean mass, with initial and follow-up BMD, in an ancillary study of the Cardiovascular Health Study, a population-based cohort of individuals > or = 65 years old. METHODS: Two years after measurement of cystatin-C and other covariates, the first BMD was measured in Pittsburgh, Pennsylvania and Davis, California, by using dual energy x-ray absorptiometry. Follow-up BMD was measured in Pittsburgh 4 years later. Associations of cystatin-C with initial BMD and the change in BMD (%/y) at the hip were examined with linear regression. Analyses were conducted separately for men and women. RESULTS: In 1519 participants who had cystatin-C and initial BMD assessed, 614 had follow-up BMD. The percent annual change in BMD at the total hip by cystatin-C quartiles was -0.24, -0.13, -0.40, and -0.66%/y (first to fourth quartile) in women and -0.02, -0.30, -0.18, and -0.94%/y in men. After adjusting for potential confounders, cystatin-C was marginally associated with initial BMD in men but not women. Cystatin-C was associated with bone loss in men; after adjustment for weight loss, cystatin-C was not associated with bone loss in women. CONCLUSION: Kidney dysfunction, as assessed by cystatin-C, is associated with a more rapid loss of BMD at the hip, especially in men. Further studies are needed to confirm these findings and to determine whether this loss leads to an elevated risk of fracture.
Keywords: Absorptiometry, Photon; Aged; Bone Density; Creatinine; Cystatin C; Cystatins; Female; Hip; Humans; Kidney Diseases; Kidney Function Tests; Linear Models; Longitudinal Studies; Male; Osteoporosis; Predictive Value of Tests

Mortality and cardiovascular risk across the ankle-arm index spectrum: results from the Cardiovascular Health Study. - O'Hare, Ann M; Katz, Ronit; Shlipak, Michael G; Cushman, Mary; Newman, Anne B (Circulation, 2006)
BACKGROUND: A low ankle-arm index (AAI) is a strong predictor of mortality and cardiovascular events. A high AAI also appears to be associated with higher mortality risk in select populations. However, mortality and cardiovascular risk across the AAI spectrum have not been described in a more broadly defined population. METHODS AND RESULTS: We examined total and cardiovascular mortality and cardiovascular events across the AAI spectrum among 5748 participants in the Cardiovascular Health Study (CHS). The mean age of the sample population was 73+/-6 years, and the sample included 3289 women (57%) and 883 blacks (15%). The median duration of follow-up was 11.1 (0.1 to 12) years for mortality and 9.6 (0.1 to 12.1) years for cardiovascular events. There were 2311 deaths (953 of which were cardiovascular) and 1491 cardiovascular events during follow-up. After adjustment for potential confounders, AAI measurements < or =0.60 (hazard ratio [HR] 1.82, 95% CI 1.42 to 2.32), 0.61 to 0.7 (HR 2.08, 95% CI 1.61 to 2.69), 0.71 to 0.8 (HR 1.80, 95% CI 1.44 to 2.26), 0.81 to 0.9 (HR 1.73 95% CI 1.43 to 2.11), 0.91 to 1.0 (HR 1.40, 95% CI 1.20 to 1.63), and >1.40 (HR 1.57, 95% CI 1.07 to 2.31) were associated with higher mortality risk from all causes compared with the referent group (AAI 1.11 to 1.20). The pattern was similar for cardiovascular mortality. For cardiovascular events, risk was higher at all AAI levels <1 but not for AAI levels >1.4 (HR 1.00, 95% CI 0.57 to 1.74). The association of a high AAI with mortality was stronger in men than in women and in younger than in older cohort members. CONCLUSIONS: In a cohort of community-dwelling elders, mortality risk was higher than the referent category of 1.11 to 1.2 among participants with AAI values above the traditional cutpoint of 0.9 (ie, 0.91 to 1.0 and >1.4), and the specific association of AAI with mortality varied by age and gender.
Keywords: Aged; Ankle; Arm; Blood Pressure; Body Mass Index; Cholesterol, LDL; Female; Follow-Up Studies; Humans; Longitudinal Studies; Male; Peripheral Vascular Diseases; Risk Factors; Smoking

Neuropsychological characteristics of mild cognitive impairment subgroups. - Lopez, O L; Becker, J T; Jagust, W J; Fitzpatrick, A; Carlson, M C; DeKosky, S T; Breitner, J; Lyketsos, C G; Jones, B; Kawas, C; Kuller, L H (J Neurol Neurosurg Psychiatry, 2006)
OBJECTIVE: To describe the neuropsychological characteristics of mild cognitive impairment (MCI) subgroups identified in the Cardiovascular Health Study (CHS) cognition study. METHODS: MCI was classified as MCI-amnestic type (MCI-AT): patients with documented memory deficits but otherwise normal cognitive function; and MCI-multiple cognitive deficits type (MCI-MCDT): impairment of at least one cognitive domain (not including memory), or one abnormal test in at least two other domains, but who had not crossed the dementia threshold. The MCI subjects did not have systemic, neurological, or psychiatric disorders likely to affect cognition. RESULTS: MCI-AT (n = 10) had worse verbal and non-verbal memory performance than MCI-MCDT (n = 28) or normal controls (n = 374). By contrast, MCI-MCDT had worse language, psychomotor speed, fine motor control, and visuoconstructional function than MCI-AT or normal controls. MCI-MCDT subjects had memory deficits, though they were less pronounced than in MCI-AT. Of the MCI-MCDT cases, 22 (78.5%) had memory deficits, and 6 (21.5%) did not. MCI-MCDT with memory disorders had more language deficits than MCI-MCDT without memory disorders. By contrast, MCI-MCDT without memory deficits had more fine motor control deficits than MCI-MCDT with memory deficits. CONCLUSIONS: The most frequent form of MCI was the MCI-MCDT with memory deficits. However, the identification of memory impaired MCI groups did not reflect the true prevalence of MCI in a population, as 16% of all MCI cases and 21.5% of the MCI-MCDT cases did not have memory impairment. Study of idiopathic amnestic and non-amnestic forms of MCI is essential for an understanding of the aetiology of MCI.
Keywords: Aged; Aged, 80 and over; Alzheimer Disease; Amnesia; Cognition Disorders; Female; Humans; Male; Neuropsychological Tests; Psychometrics; Reference Values

Obstructive sleep apnea-hypopnea and neurocognitive functioning in the Sleep Heart Health Study. - Quan, Stuart F; Wright, Ron; Baldwin, Carol M; Kaemingk, Kristine L; Goodwin, James L; Kuo, Tracy F; Kaszniak, Alfred; Boland, Lori L; Caccappolo, Elise; Bootzin, Richard R (Sleep Med, 2006)
BACKGROUND AND PURPOSE: Obstructive sleep apnea-hypopnea (OSAH) is associated with sleep fragmentation and nocturnal hypoxemia. In clinical samples, patients with OSAH frequently are found to have deficits in neuropsychological function. However, the nature and severity of these abnormalities in non-clinical populations is less well defined. PATIENTS AND METHODS: One hundred and forty-one participants from the Tucson, AZ and New York, NY field centers of the Sleep Heart Health Study completed a battery of neuropsychological tests for 9-40 months (mean=24 months, SD=7 months) after an unattended home polysomnogram. Sixty-seven participants had OSAH (AHI>10) and 74 did not have OSAH (control (CTL), apnea-hypopnea index (AHI)<5). In addition to the individual tests, composite variables representing attention, executive function, MotorSpeed and processing speed were constructed from the neuropsychological test battery. RESULTS: There were no significant differences in any individual neuropsychological test or composite variable between the OSAH and CTL groups. However, when time spent with O(2) saturations less than 85% was dichotomized into those participants in the top quartile of the distribution and those in the lower three quartiles, motor speed was significantly impaired in those who were more hypoxemic. In addition, poorer motor speed (model adjusted R(2)=0.242, P<0.001) and processing speed performance (model adjusted R(2)=0.122, P<0.001) were associated with more severe oxygen desaturation even after controlling for degree of daytime sleepiness, age, gender and educational level. CONCLUSIONS: Mild to moderate OSAH has little impact on the selected measures of attention, executive function, motor speed and processing speed. However, hypoxemia adversely affects both motor and processing speed. These results suggest that in middle-aged to elderly adults the neuropsychological effects of clinically unrecognized mild to moderate OSAH are neither global nor large.
Keywords: Brain; Cognition Disorders; Continuous Positive Airway Pressure; Demography; Disorders of Excessive Somnolence; Electromyography; Electrooculography; Female; Health Status; Humans; Hypoxia; Male; Middle Aged; Neuropsychological Tests; Oxygen; Polysomnography; Severity of Illness Index; Sleep Apnea, Obstructive; Surveys and Questionnaires

Progression of atherosclerotic renovascular disease: A prospective population-based study. - Pearce, Jeffrey D; Craven, Brandon L; Craven, Timothy E; Piercy, K Todd; Stafford, Jeanette M; Edwards, Matthew S; Hansen, Kimberley J (J Vasc Surg, 2006)
OBJECTIVE: Previous reports from select hypertensive patients suggest that atherosclerotic renovascular disease (RVD) is rapidly progressive and associated with a decline in kidney size and kidney function. This prospective, population-based study estimates the incidence of new RVD and progression of established RVD among elderly, free-living participants in the Cardiovascular Health Study (CHS). METHOD: The CHS is a multicenter, longitudinal cohort study of cardiovascular risk factors, morbidity, and mortality among men and women aged >65 years old. From 1995 through 1996, 834 participants underwent renal duplex sonography (RDS) to define the presence or absence of significant RVD. Between 2002 and 2005, a second RDS study was performed in 119 participants (mean study interval, 8.0 +/- 0.8 years). Significant RVD was defined as hemodynamically significant stenosis (renal artery peak systolic velocity [RA-PSV] exceeding 1.8 m/s) or renal artery occlusion. Prevalent RVD was significant RVD at the first RDS, and incident disease was defined as new significant RVD at the second RDS. Significant change of RVD was defined as a change in RA-PSV of greater than two times the standard deviation of expected change over time, regardless of hemodynamic significance or progression to renal artery occlusion. RESULTS: The second RDS study cohort included 119 CHS participants with 235 kidneys (35% men; mean age, 82.8 +/- 3.4). On follow-up, no prevalent RVD (n = 13 kidneys; 6.0%) progressed to occlusion. Twenty-nine kidneys without RVD at the first RDS demonstrated significant change in PSV at the second RDS; including nine kidneys with new significant RVD (8 new stenoses; 1 new occlusion). Controlling for within-subject correlation, the overall estimated change in RVD among all 235 kidneys was 14.0% (95% confidence interval [CI], 9.2% to 21.4%), with progression to significant RVD in 4.0% (95% CI, 1.9% to 8.2%). Longitudinal increase in diastolic blood pressure and decrease in renal length were significantly associated with progression to new (ie, incident) significant RVD but not prevalent RVD. CONCLUSIONS: This is the first prospective, population-based estimate of incident RVD and progression of prevalent RVD among free-living elderly Americans. In contrast to previous reports among select hypertensive patients, CHS participants with a low rate of clinical hypertension demonstrated a significant change of RVD in only 14.0% of kidneys on follow-up of 8 years (annualized rate, 1.3% per year). Progression to significant RVD was observed in only 4.0% (annualized rate, 0.5% per year), and no prevalent RVD progressed to occlusion.
Keywords: Aged; Aged, 80 and over; Atherosclerosis; Blood Flow Velocity; Blood Pressure; Disease Progression; Female; Follow-Up Studies; Humans; Incidence; Male; North Carolina; Population Surveillance; Prognosis; Prospective Studies; Renal Artery Obstruction; Severity of Illness Index; Time Factors; Ultrasonography, Doppler, Duplex

Quantitative retinal venular caliber and risk of cardiovascular disease in older persons: the cardiovascular health study. - Wong, Tien Yin; Kamineni, Aruna; Klein, Ronald; Sharrett, A Richey; Klein, Barbara E; Siscovick, David S; Cushman, Mary; Duncan, Bruce B (Arch Intern Med, 2006)
BACKGROUND: Small vessel disease may contribute to the risk of cardiovascular disease in older persons. We describe the relation of retinal vascular caliber to incident coronary heart disease (CHD) and stroke in elderly persons. METHODS: Prospective population-based cohort study composed of 1992 men and women aged 69 to 97 years living in 4 US communities. Retinal arteriolar and venular calibers were measured from retinal photographs using a computer-assisted method. Incident CHD and stroke events were ascertained using standardized methods. RESULTS: After 5 years of follow-up, there were 115 incident CHD events and 113 incident stroke events. Participants with larger retinal venular caliber had a higher incidence of CHD (11.7%; 95% confidence interval [CI], 8.7%-15.8%, vs 8.1%; 95% CI, 5.7%-11.6%), comparing largest with smallest venular caliber quartiles, and stroke (8.4%; 95% CI, 6.0-11.7, vs 5.8%; 95% CI, 3.9-8.4). At multivariable analysis, controlling for age, sex, race, arteriolar caliber, systolic and diastolic blood pressure, diabetes, glucose concentration, cigarette smoking, pack-years of smoking, and high-density-lipoprotein and low-density lipoprotein cholesterol levels, larger retinal venular caliber was associated with incident CHD (rate ratio, 3.0; 95% CI, 1.6-5.7, comparing largest with smallest venular caliber quartiles; P(trend) = .001) and incident stroke (rate ratio, 2.2; 95% CI, 1.1-4.3; P(trend) = .02). Additional adjustment for C-reactive protein and common and internal carotid artery intimal-media thickness had minimal effect on these associations. At multivariable analysis, smaller retinal arteriolar caliber was associated with incident CHD (rate ratio, 2.0; 95% CI, 1.1-3.7, comparing largest with smallest arteriolar caliber quartiles; P = .03) but not stroke (rate ratio,1.1; 95% CI, 0.5-2.2; P = .73). CONCLUSION: Larger retinal venular caliber is independently associated with risk of cardiovascular disease in elderly persons.
Keywords: Aged; Aged, 80 and over; Algorithms; Cardiovascular Diseases; Cohort Studies; Female; Humans; Image Processing, Computer-Assisted; Incidence; Male; Photography; Prospective Studies; Retinal Diseases; Retinal Vein; Retinal Vessels; Risk Factors; Stroke; United States

The sensitivity and specificity of markers for event times. - Cai, Tianxi; Pepe, Margaret Sullivan; Zheng, Yingye; Lumley, Thomas; Jenny, Nancy Swords (Biostatistics, 2006)
The statistical literature on assessing the accuracy of risk factors or disease markers as diagnostic tests deals almost exclusively with settings where the test, Y, is measured concurrently with disease status D. In practice, however, disease status may vary over time and there is often a time lag between when the marker is measured and the occurrence of disease. One example concerns the Framingham risk score (FR-score) as a marker for the future risk of cardiovascular events, events that occur after the score is ascertained. To evaluate such a marker, one needs to take the time lag into account since the predictive accuracy may be higher when the marker is measured closer to the time of disease occurrence. We therefore consider inference for sensitivity and specificity functions that are defined as functions of time. Semiparametric regression models are proposed. Data from a cohort study are used to estimate model parameters. One issue that arises in practice is that event times may be censored. In this research, we extend in several respects the work by Leisenring et al. (1997) that dealt only with parametric models for binary tests and uncensored data. We propose semiparametric models that accommodate continuous tests and censoring. Asymptotic distribution theory for parameter estimates is developed and procedures for making statistical inference are evaluated with simulation studies. We illustrate our methods with data from the Cardiovascular Health Study, relating the FR-score measured at enrollment to subsequent risk of cardiovascular events.
Keywords: Aged; Aged, 80 and over; Biomarkers; Biometry; Cardiovascular Diseases; Female; Humans; Male; Models, Statistical; Risk Factors; ROC Curve; Sensitivity and Specificity; Time Factors

Subclinical atherosclerosis and the risk of future venous thrombosis in the Cardiovascular Health Study. - van der Hagen, P B; Folsom, A R; Jenny, N S; Heckbert, S R; O'Meara, E S; Reich, L M; Rosendaal, F R; Cushman, M (J Thromb Haemost, 2006)
BACKGROUND: Recent reports have suggested an association of atherosclerosis with risk of venous thrombosis. OBJECTIVE: To confirm whether subclinical atherosclerosis is a risk factor for venous thrombosis (VT) among men and women age 65 and older. METHODS: Participants of the Cardiovascular Health Study (n = 4,108) without baseline clinical cardiovascular disease, anticoagulant use or previous VT were followed for a median of 11.7 years after non-invasive assessment of subclinical atherosclerosis using carotid ultrasound (intima-media thickness and presence of plaques), ankle-brachial blood pressure index and electrocardiogram. Each event was classified as idiopathic or secondary. We used Cox proportional hazards regression to estimate the relative risk of overall and idiopathic VT for individuals with and without baseline subclinical atherosclerosis. RESULTS: There were 133 first time VT events. No subclinical atherosclerosis measures were associated with increased risk of overall or idiopathic VT. The adjusted relative risks of overall and idiopathic VT for presence of any type of subclinical disease were 0.60 (95% confidence interval 0.39-0.91) and 0.32 (0.18-0.59), respectively. Most of this association was explained by an inverse association of high-risk carotid plaques (prevalent in 54% of those at risk) with VT. CONCLUSION: Non-invasively measured subclinical atherosclerosis was not associated with increased risk of overall or idiopathic VT in this observational study. Carotid plaques and arterial events during follow up were inversely associated, a finding that requires further study.
Keywords: Aged; Aged, 80 and over; Atherosclerosis; Carotid Artery Thrombosis; Cohort Studies; Female; Humans; Male; Proportional Hazards Models; Risk Factors; Ultrasonography; Venous Thrombosis

Thyroid status, cardiovascular risk, and mortality in older adults. - Cappola, Anne R; Fried, Linda P; Arnold, Alice M; Danese, Mark D; Kuller, Lewis H; Burke, Gregory L; Tracy, Russell P; Ladenson, Paul W (JAMA, 2006)
CONTEXT: Previous studies have suggested that subclinical abnormalities in thyroid-stimulating hormone levels are associated with detrimental effects on the cardiovascular system. OBJECTIVE: To determine the relationship between baseline thyroid status and incident atrial fibrillation, incident cardiovascular disease, and mortality in older men and women not taking thyroid medication. DESIGN, SETTING, AND PARTICIPANTS: A total of 3233 US community-dwelling individuals aged 65 years or older with baseline serum thyroid-stimulating hormone levels were enrolled in 1989-1990 in the Cardiovascular Health Study, a large, prospective cohort study. MAIN OUTCOME MEASURES: Incident atrial fibrillation, coronary heart disease, cerebrovascular disease, cardiovascular death, and all-cause death assessed through June 2002. Analyses are reported for 4 groups defined according to thyroid function test results: subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism. RESULTS: Individuals with overt thyrotoxicosis (n = 4) were excluded because of small numbers. Eighty-two percent of participants (n = 2639) had normal thyroid function, 15% (n = 496) had subclinical hypothyroidism, 1.6% (n = 51) had overt hypothyroidism, and 1.5% (n = 47) had subclinical hyperthyroidism. After exclusion of those with prevalent atrial fibrillation, individuals with subclinical hyperthyroidism had a greater incidence of atrial fibrillation compared with those with normal thyroid function (67 events vs 31 events per 1000 person-years; adjusted hazard ratio, 1.98; 95% confidence interval, 1.29-3.03). No differences were seen between the subclinical hyperthyroidism group and euthyroidism group for incident coronary heart disease, cerebrovascular disease, cardiovascular death, or all-cause death. Likewise, there were no differences between the subclinical hypothyroidism or overt hypothyroidism groups and the euthyroidism group for cardiovascular outcomes or mortality. Specifically, individuals with subclinical hypothyroidism had an adjusted hazard ratio of 1.07 (95% confidence interval, 0.90-1.28) for incident coronary heart disease. CONCLUSION: Our data show an association between subclinical hyperthyroidism and development of atrial fibrillation but do not support the hypothesis that unrecognized subclinical hyperthyroidism or subclinical hypothyroidism is associated with other cardiovascular disorders or mortality.
Keywords: Aged; Atrial Fibrillation; Cardiovascular Diseases; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Proportional Hazards Models; Risk Factors; Thyroid Gland; Thyrotropin

ABO blood group, other risk factors and incidence of venous thromboembolism: the Longitudinal Investigation of Thromboembolism Etiology (LITE). - Ohira, T; Cushman, M; Tsai, M Y; Zhang, Y; Heckbert, S R; Zakai, N A; Rosamond, W D; Folsom, A R (J Thromb Haemost, 2007)
BACKGROUND: Numerous case-control studies have reported higher prevalence of non-O blood type among venous thromboembolism (VTE) patients than controls, but potential mechanisms or effect modifiers for the association are not fully established. PATIENTS/METHODS: Using a nested case-control design combining the Atherosclerosis Risk in Communities and the Cardiovascular Health Study cohort, ABO blood type and other VTE risk factors were measured on pre-event blood samples of 492 participants who subsequently developed VTE and 1008 participants who remained free of VTE. RESULTS: A total of 64.4% of cases and 52.5% of controls had non-O blood type. Among controls, mean values of factor VIIIc (FVIIIc) and von Willebrand factor among the non-O blood type group were higher than among the O group. Compared with O blood type, the age-adjusted odds ratio (OR) of VTE for non-O blood type was 1.64 (95% CI, 1.32-2.05) and was similar for the two parent studies and race groups. Further adjustment for sex, race, body mass index, diabetes mellitus and FVIIIc reduced the OR: 1.31 (95% CI, 1.02-1.68). Factor V Leiden (FV Leiden) appeared to modify the non-O blood type association with VTE in a supra-additive fashion, with an age-, sex- and race-adjusted OR of 6.77 (95% CI, 3.65-12.6) for having both risk factors. CONCLUSIONS: Non-O blood type was independently associated with risk of VTE, and added to the risk associated with FV Leiden.
Keywords: ABO Blood-Group System; Aged; Case-Control Studies; Diabetes Complications; Factor V; Factor VIII; Female; Humans; Longitudinal Studies; Male; Middle Aged; Risk Factors; Thromboembolism; Venous Thrombosis; von Willebrand Factor

Acceleration of cerebral ventricular expansion in the Cardiovascular Health Study. - Carmichael, Owen T; Kuller, L H; Lopez, O L; Thompson, P M; Dutton, R A; Lu, A; Lee, S E; Lee, J Y; Aizenstein, H J; Meltzer, C C; Liu, Y; Toga, A W; et al. (Neurobiol Aging, 2007)
Interactions between prevalent late-life medical conditions and expansion of the cerebral ventricles are not well understood. Thirty elderly subjects received three magnetic resonance (MR) scans each, in 1997-1999, 2002-2004, and 2003-2005. A linear expansion model of MR-measured lateral ventricle volume was estimated for each subject by fitting a line to a plot of their 1997-1999 and 2002-2004 volumes as a function of time. Acceleration in ventricular expansion was defined as the deviation between the 2003-2005 volumes measured from MR and the 2003-2005 volumes predicted by the linear expansion model. Ventricular acceleration was analyzed in a multivariate model with age, race, history of heart disease, diabetes, and hypertension as fixed effects. Ventricular acceleration was significantly higher in non-whites, diabetics, and those without heart disease (p<0.05). Ventricular acceleration was higher in subjects with a history of hypertension, but the difference was not statistically significant (p=0.08). Acceleration of ventricular expansion in the elderly may be related to demographic and cardiovascular factors.
Keywords: Aged; Analysis of Variance; Cardiovascular Diseases; Cerebral Ventricles; Female; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Male; Reference Values; Retrospective Studies; Sex Factors; Time Factors

Alcohol consumption, bone density, and hip fracture among older adults: the cardiovascular health study. - Mukamal, K J; Robbins, J A; Cauley, J A; Kern, L M; Siscovick, D S (Osteoporos Int, 2007)
INTRODUCTION: Previous studies have found inconsistent relationships of alcohol consumption with risk of hip fracture, and the importance of bone mineral density and risk of falls in mediating such a relationship has not been determined. METHODS: As part of the Cardiovascular Health Study, a population-based cohort study of adults aged 65 years and older from four U.S. communities, 5,865 participants reported their use of beer, wine, and liquor yearly. We identified cases of hip fracture unrelated to malignancy or motor vehicle accidents using hospitalization discharge diagnoses. A subgroup of 1,567 participants in two communities underwent dual-energy x-ray absorptiometry scans to assess bone mineral density. RESULTS: A total of 412 cases of hip fracture occurred during an average of 12 years of follow-up. There was a significant U-shaped relationship between alcohol intake and risk of hip fracture (p quadratic 0.02). Compared with long-term abstainers, the adjusted hazard ratios for hip fracture were 0.78 (95% confidence interval [CI], 0.61-1.00) among consumers of up to 14 drinks per week and 1.18 (95% CI, 0.77-1.81) among consumers of 14 or more drinks per week. Alcohol intake was associated with bone mineral density of the total hip and femoral neck in a stepwise manner, with approximately 5% (95% CI, 1%-9%) higher bone density among consumers of 14 or more drinks per week than among abstainers. These relationships were all similar among men and women. CONCLUSIONS: Among older adults, moderate alcohol consumption has a U-shaped relationship with risk of hip fracture, but a graded positive relationship with bone mineral density at the hip.
Keywords: Absorptiometry, Photon; Aged; Alcohol Drinking; Alcoholic Beverages; Apolipoproteins E; Bone Density; Female; Femur Neck; Genotype; Hip; Hip Fractures; Humans; Longitudinal Studies; Male; Risk Assessment; Risk Factors; Sex Distribution; United States

The association of alpha-fibrinogen Thr312Ala polymorphism and venous thromboembolism in the LITE study. - Rasmussen-Torvik, Laura J; Cushman, Mary; Tsai, Michael Y; Zhang, Yan; Heckbert, Susan R; Rosamond, Wayne D; Folsom, Aaron R (Thromb Res, 2007)
INTRODUCTION: The alpha-fibrinogen Thr312Ala variant has been shown to influence clot structure through increased factor XIII cross-linking and formation of thicker fibrin fibers. However, the effect of this common variant on risk of venous thromboembolism (VTE) is unclear. This paper reports the association between the Thr312Ala variant and VTE in the LITE study. MATERIALS AND METHODS: 506 cases and 1014 controls frequency matched on age, sex, race, and study were drawn from two prospective studies and included in the analysis. Logistic regression was used to examine the association between Thr312Ala and VTE. RESULTS: In a logistic regression model minimally adjusted for the matching variables, the Thr312Ala TA and AA genotypes were associated with a significantly higher risk of VTE than the TT genotype (TA OR and 95% confidence interval 1.27 [1.01-1.60], AA OR 1.49 [1.00-2.22]). Associations were similar in analyses of PE and DVT considered separately and across racial and study subgroups. The association between alpha-fibrinogen Thr312Ala and VTE was modified by both BMI and the FXIII Val34Leu variant; the combination of elevated BMI or FXIII Val34Leu with alpha-fibrinogen Thr312Ala conveyed lower odds of VTE than would be expected by an additive or multiplicative model of individual risk factors. CONCLUSIONS: These results suggest that alpha-fibrinogen Thr312Ala is involved in the pathogenesis of VTE and that its action may be modified by other VTE risk factors.
Keywords: African Continental Ancestry Group; Aged; Case-Control Studies; European Continental Ancestry Group; Female; Fibrinogen; Genotype; Humans; Logistic Models; Male; Middle Aged; Mutation, Missense; Polymorphism, Genetic; Venous Thromboembolism

Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: the Cardiovascular Health Study. - Cao, Jie J; Arnold, Alice M; Manolio, Teri A; Polak, Joseph F; Psaty, Bruce M; Hirsch, Calvin H; Kuller, Lewis H; Cushman, Mary (Circulation, 2007)
BACKGROUND: Carotid atherosclerosis, measured as carotid intima-media thickness or as characteristics of plaques, has been linked to cardiovascular disease (CVD) and to C-reactive protein (CRP) levels. We investigated the relationship between carotid atherosclerosis and CRP and their joint roles in CVD prediction. METHODS AND RESULTS: Of 5888 participants in the Cardiovascular Health Study, an observational study of adults aged > or = 65 years, 5020 without baseline CVD were included in the analysis. They were followed up for as long as 12 years for CVD incidence and all-cause mortality after baseline ultrasound and CRP measurement. When CRP was elevated (> 3 mg/L) among those with detectable atherosclerosis on ultrasound, there was a 72% (95% CI, 1.46 to 2.01) increased risk for CVD death and a 52% (95% CI, 1.37 to 1.68) increased risk for all-cause mortality. Elevated CRP in the absence of atherosclerosis did not increase CVD or all-cause mortality risk. The proportion of excess risk attributable to the interaction of high CRP and atherosclerosis was 54% for CVD death and 79% for all-cause mortality. Addition of CRP or carotid atherosclerosis to conventional risk factors modestly increased in the ability to predict CVD, as measured by the c statistic. CONCLUSIONS: In older adults, elevated CRP was associated with increased risk for CVD and all-cause mortality only in those with detectable atherosclerosis based on carotid ultrasound. Despite the significant associations of CRP and carotid atherosclerosis with CVD, these measures modestly improve the prediction of CVD outcomes after one accounts for the conventional risk factors.
Keywords: African Americans; Aged; Biomarkers; C-Reactive Protein; Cardiovascular Diseases; Carotid Artery Diseases; Cohort Studies; Comorbidity; Diabetes Mellitus; European Continental Ancestry Group; Female; Follow-Up Studies; Humans; Hyperlipidemias; Hypertension; Incidence; Inflammation; Kaplan-Meier Estimate; Male; Mass Screening; Mortality; Myocardial Infarction; Obesity; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; ROC Curve; Smoking; Stroke; Survival Analysis; Tunica Intima; Tunica Media; Ultrasonography; United States

Association of kidney function with incident hip fracture in older adults. - Fried, Linda F; Biggs, Mary Louise; Shlipak, Michael G; Seliger, Stephen; Kestenbaum, Bryan; Stehman-Breen, Catherine; Sarnak, Mark; Siscovick, David; Harris, Tamara; Cauley, Jane; Newman, Anne B; Robbins, John (J Am Soc Nephrol, 2007)
Kidney dysfunction is associated with bone loss, and patients with ESRD have an increased risk for hip fracture. However, the association of mild to moderate kidney disease with hip fracture has not been studied previously. The association of kidney function with incident hip fracture was examined among participants in the Cardiovascular Health Study, a community-based cohort of older individuals. The primary measure of kidney function was serum cystatin C, a measure that does not depend on lean mass. Hip fractures were identified using International Classification of Diseases, Ninth Revision codes for hospitalizations. A total of 4699 individuals had cystatin C measured in 1992 to 1993 and did not have a hip fracture before cystatin C measurement. The association of kidney function with hip fracture was analyzed with Cox proportional hazards models. Analyses were conducted separately for men and women. After a mean follow-up of 7.1 yr, 195 incident hip fractures occurred in women and 79 occurred in men. Higher cystatin C levels were associated with a higher risk for fracture in women (hazard ratio [HR] 1.26; 95% confidence interval [CI] 1.14 to 1.38 per SD) and in men (HR 1.27; 95% CI 1.11 to 1.46). After multivariable adjustment, higher cystatin C levels were significantly associated with hip fracture in women (HR 1.16; 95% CI 1.01, 1.33) but not in men (HR 1.14; 95% CI 0.86 to 1.52), although the magnitude of the association was similar. Kidney dysfunction, as assessed by cystatin C, is associated with an increased risk for hip fracture. Further studies are needed to evaluate potential mediators of this relationship and to assess whether interventions can decrease this risk.
Keywords: Aged; Aged, 80 and over; Cystatin C; Cystatins; Female; Hip Fractures; Humans; Kidney; Kidney Failure, Chronic; Longitudinal Studies; Male; Osteoporosis; Prospective Studies; Risk Factors; Sex Factors

Association of total insulin-like growth factor-I, insulin-like growth factor binding protein-1 (IGFBP-1), and IGFBP-3 levels with incident coronary events and ischemic stroke. - Kaplan, Robert C; McGinn, Aileen P; Pollak, Michael N; Kuller, Lewis H; Strickler, Howard D; Rohan, Tom E; Cappola, Anne R; Xue, XiaoNan; Psaty, Bruce M (J Clin Endocrinol Metab, 2007)
CONTEXT: Prior observational studies have demonstrated that the GH/IGF axis is associated with cardiovascular disease. However, this association has not been extensively studied among older adults. OBJECTIVE: The objective of this study was to assess the association between levels of total IGF-I and IGF binding proteins (IGFBP-1, IGFBP-3) and risk of incident coronary events and ischemic stroke. DESIGN AND PARTICIPANTS: A case-cohort analysis was conducted among adults 65 yr and older in the Cardiovascular Health Study. MAIN OUTCOME MEASURES: A total of 534 coronary events [316 nonfatal myocardial infarctions (MIs), 48 fatal MIs, and 170 fatal coronary heart disease events] and 370 ischemic strokes were identified on follow-up. Comparison subjects were 1122 randomly selected participants from the Cardiovascular Health Study. RESULTS: Mean follow-up time was 6.7 yr for coronary events, 5.6 yr for strokes, and 9.3 yr for comparison subjects. Hazard ratios (95% confidence intervals) associated with baseline levels of total IGF-I and IGFBPs were estimated using multivariate adjusted Cox proportional hazards models. Neither IGF-I nor IGFBP-1 levels predicted risk of incident coronary events or stroke. IGFBP-3 had an inverse association with risk of coronary events [adjusted hazard ratio per sd=0.88 (0.78-1.00), P=0.05] but was not associated with stroke. Exploratory analyses suggested that low IGF-I and low IGFBP-3 levels were significantly associated with higher risk of nonfatal MI (P<0.05) but not with risk of fatal MI or fatal coronary heart disease. CONCLUSION: Circulating levels of total IGF-I or IGFBP-1 were not associated with risk of total coronary events or ischemic stroke among older adults, whereas low IGFBP-3 level was associated with increased risk of incident coronary events.
Keywords: Aged; Cardiovascular Diseases; Case-Control Studies; Cohort Studies; Coronary Disease; Female; Humans; Insulin-Like Growth Factor Binding Protein 1; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Male; Multivariate Analysis; Risk Factors; Stroke

Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study. - Yeboah, Joseph; Crouse, John R; Hsu, Fang-Chi; Burke, Gregory L; Herrington, David M (Circulation, 2007)
BACKGROUND: The relationship between impaired brachial flow-mediated dilation (FMD) and subsequent clinical cardiovascular events is not well established, especially in older adults whose FMD is often diminished. We assessed the hypothesis that FMD predicts incident cardiovascular events in a population-based cohort of older adults. METHODS AND RESULTS: FMD was measured at the 1997 to 1998 Cardiovascular Health Study clinic visit in 2792 adults aged 72 to 98 years (82.7% white, 58.6% women) recruited at 4 clinic sites in the United States. Log-rank test and Cox proportional hazard models were used to examine the association between FMD and adjudicated cardiovascular events. A total of 674 subjects (24.1%) had an adjudicated event over the 5-year follow-up period. Event-free survival rates for cardiovascular events were significantly higher in subjects with FMD greater than the sex-specific medians than in subjects with FMD less than or equal to the sex-specific medians (78.3% versus 73.6%, log-rank P=0.006). FMD remained a significant predictor of cardiovascular events after adjustment for age, gender, diabetes mellitus, cigarette smoking, systolic and diastolic blood pressure, baseline cardiovascular disease status, and total cholesterol (hazard ratio, 0.91 [95% CI, 0.83 to 0.99], P=0.02 per unit SD of FMD) but added only approximately 1% to the prognostic accuracy of the best Cox model. Brachial artery diameter was also predictive of CV events in the adjusted Cox proportional hazard model (hazard ratio, 1.12 [95% CI, 1.02 to 1.28], P=0.025) and also added approximately 1% to the accuracy of our best Cox model. CONCLUSIONS: FMD is a predictor of future cardiovascular events but adds very little to the prognostic accuracy of traditional cardiovascular risk scores/factors in older adults. FMD and brachial artery diameter may have similar predictive values for cardiovascular events in older adults.
Keywords: Aged; Aged, 80 and over; Atherosclerosis; Biomarkers; Brachial Artery; Cardiovascular Diseases; Cohort Studies; Disease-Free Survival; Endothelium, Vascular; Female; Hemorheology; Humans; Hyperemia; Male; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prospective Studies; Reproducibility of Results; Risk Factors; Stress, Mechanical; Tourniquets; Ultrasonography; United States; Vasodilation

Cerebral ventricular changes associated with transitions between normal cognitive function, mild cognitive impairment, and dementia. - Carmichael, Owen T; Kuller, Lewis H; Lopez, Oscar L; Thompson, Paul M; Dutton, Rebecca A; Lu, Allen; Lee, Sharon E; Lee, Jessica Y; Aizenstein, Howard J; Meltzer, Carolyn C; Liu, Yanxi; Toga, Arthur W; et al. (Alzheimer Dis Assoc Disord, 2007)
Expansion of the cerebral ventricles may occur at an accelerated rate in subjects with dementia, but the time course of expansion during transitions between normal cognitive function, mild cognitive impairment (MCI), and dementia is not well understood. Furthermore, the effects of cardiovascular risk factors on rate of ventricular expansion are unclear. We used a fully automated segmentation technique to measure change rate in lateral ventricle-to-brain ratio (VBR) on 145 longitudinal pairs of magnetic resonance images of subjects in the Cardiovascular Health Study Cognition Study from the Pittsburgh Center. A multivariate model analyzed VBR change rate, accounting for dementia statuses at both imaging times (normal, MCI, or dementia), age, sex, education, race, magnetic resonance-defined infarcts, Center for Epidemiology Studies Depression Scale, baseline ventricular volume, and cardiovascular risk factors. VBR change was faster in subjects who were demented or transitioned from MCI to dementia, compared with subjects normal at both images and subjects who transitioned from normal to MCI or dementia. Patients with diabetes had faster VBR change. Ventricular expansion may accelerate late in the progression from normal cognitive function to dementia, and may be modulated by diabetes.
Keywords: Aged; Aged, 80 and over; Case-Control Studies; Cerebral Ventricles; Cognition Disorders; Dementia; Disease Progression; Female; Humans; Image Processing, Computer-Assisted; Longitudinal Studies; Magnetic Resonance Imaging; Male; Risk Factors; Severity of Illness Index; Time Factors

Clinical factors, but not C-reactive protein, predict progression of calcific aortic-valve disease: the Cardiovascular Health Study. - Novaro, Gian M; Katz, Ronit; Aviles, Ronnier J; Gottdiener, John S; Cushman, Mary; Psaty, Bruce M; Otto, Catherine M; Griffin, Brian P (J Am Coll Cardiol, 2007)
OBJECTIVES: The purpose of this study was to examine the relationship between C-reactive protein (CRP) and calcific aortic valve disease in a large, randomly selected, population-based cohort. BACKGROUND: The pathobiology of calcific aortic stenosis involves an active inflammatory, atheromatous, osteogenic process. Elevations in CRP, a measure of systemic inflammation, have been associated with aortic stenosis. METHODS: Two-dimensional and Doppler echocardiography and CRP measurement were performed at baseline in 5,621 participants in the Cardiovascular Health Study. Multivariable analysis was used to identify CRP as a predictor of baseline and incident aortic stenosis. RESULTS: At a mean echocardiographic follow-up of 5 years, 9% of subjects with aortic sclerosis progressed to some degree of aortic stenosis. Increasing age (odds ratio [OR] 1.13, 95% confidence interval [CI] 1.09 to 1.16; p < 0.001) and male gender (OR 3.05, 95% CI 1.76 to 5.27; p < 0.001) were related to risk of incident aortic stenosis, whereas increasing height (OR 0.96, 95% CI 0.94 to 0.99; p = 0.013) and African-American ethnicity conveyed a lower risk (OR 0.49, 95% CI 0.25 to 0.95; p = 0.035). C-reactive protein, treated as a continuous variable, was not associated with baseline aortic stenosis, progression to aortic sclerosis (adjusted OR 0.93, 95% CI 0.85 to 1.02; p = 0.107), or progression to aortic stenosis (adjusted OR 0.85, 95% CI 0.70 to 1.03; p = 0.092). CONCLUSIONS: In this large population-based cohort, approximately 9% of subjects with aortic sclerosis progressed to aortic stenosis over a 5-year follow-up period. There was no association between CRP levels and the presence of calcific aortic-valve disease or incident aortic stenosis. C-reactive protein appears to be a poor predictor of subclinical calcific aortic-valve disease.
Keywords: Aged; Aged, 80 and over; Aortic Valve; Aortic Valve Stenosis; C-Reactive Protein; Calcinosis; Cardiovascular Diseases; Cohort Studies; Disease Progression; Female; Follow-Up Studies; Heart Valve Diseases; Humans; Male; Risk Factors

Collaborative meta-analysis of individual participant data from observational studies of Lp-PLA2 and cardiovascular diseases. - Ballantyne, C; Cushman, M; Psaty, B; Furberg, C; Khaw, K T; Sandhu, M; Oldgren, J; Rossi, G P; Maiolino, G; Cesari, M; Lenzini, L; James, S K; et al. (Eur J Cardiovasc Prev Rehabil, 2007)
BACKGROUND: A large number of observational epidemiological studies have reported generally positive associations between circulating mass and activity levels of lipoprotein-associated phospholipase A2 (Lp-PLA2) and the risk of cardiovascular diseases. Few studies have been large enough to provide reliable estimates in different circumstances, such as in different subgroups (e.g., by age group, sex, or smoking status) or at different Lp-PLA2 levels. Moreover, most published studies have related disease risk only to baseline values of Lp-PLA2 markers (which can lead to substantial underestimation of any risk relationships because of within-person variability over time) and have used different approaches to adjustment for possible confounding factors. OBJECTIVES: By combination of data from individual participants from all relevant observational studies in a systematic 'meta-analysis', with correction for regression dilution (using available data on serial measurements of Lp-PLA2), the Lp-PLA2 Studies Collaboration will aim to characterize more precisely than has previously been possible the strength and shape of the age and sex-specific associations of plasma Lp-PLA2 with coronary heart disease (and, where data are sufficient, with other vascular diseases, such as ischaemic stroke). It will also help to determine to what extent such associations are independent of possible confounding factors and to explore potential sources of heterogeneity among studies, such as those related to assay methods and study design. It is anticipated that the present collaboration will serve as a framework to investigate related questions on Lp-PLA2 and cardiovascular outcomes. METHODS: A central database is being established containing data on circulating Lp-PLA2 values, sex and other potential confounding factors, age at baseline Lp-PLA2 measurement, age at event or at last follow-up, major vascular morbidity and cause-specific mortality. Information about any repeat measurements of Lp-PLA2 and potential confounding factors has been sought to allow adjustment for possible confounding and correction for regression dilution. The analyses will involve age-specific regression models. Synthesis of the available observational studies of Lp-PLA2 will yield information on a total of about 15 000 cardiovascular disease endpoints.
Keywords: 1-Alkyl-2-acetylglycerophosphocholine Esterase; Cardiovascular Diseases; Humans; Phospholipases A2

Costs of the metabolic syndrome in elderly individuals: findings from the Cardiovascular Health Study. - Curtis, Lesley H; Hammill, Bradley G; Bethel, M Angelyn; Anstrom, Kevin J; Gottdiener, John S; Schulman, Kevin A (Diabetes Care, 2007)
OBJECTIVE: The cardiovascular consequences of the metabolic syndrome and its component risk factors have been documented in elderly individuals. Little is known about how the metabolic syndrome and its individual components translate into long-term medical costs. RESEARCH DESIGN AND METHODS: We used log-linear regression models to assess the independent contributions of the metabolic syndrome and its individual components to 10-year medical costs among 3,789 individuals aged > or = 65 years in the Cardiovascular Health Study. RESULTS: As defined by the National Cholesterol Education Program Third Adult Treatment Panel report, the metabolic syndrome was present in 47% of the sample. Total costs to Medicare were 20% higher among participants with the metabolic syndrome ($40,873 vs. $33,010; P < 0.001). Controlling for age, sex, race/ethnicity, and other covariates, we found that abdominal obesity, low HDL cholesterol, and elevated blood pressure were associated with 15% (95% CI 4.3-26.7), 16% (1.7-31.8), and 20% (10.1-31.7) higher costs, respectively. When added to the model, the metabolic syndrome composite variable did not contribute significantly (P = 0.32). CONCLUSIONS: Abdominal obesity, low HDL cholesterol, and hypertension but not the metabolic syndrome per se are important predictors of long-term costs in the Medicare population.
Keywords: Aged; Aged, 80 and over; Cholesterol, HDL; Continental Population Groups; Cost of Illness; Diabetic Angiopathies; Female; Humans; Hypertension; Interviews as Topic; Male; Medicare; Metabolic Syndrome; Multivariate Analysis; Obesity; Patient Education as Topic; Prospective Studies; Regression Analysis; United States

Depressive symptoms, inflammation, and ischemic stroke in older adults: a prospective analysis in the cardiovascular health study. - Arbelaez, Jose J; Ariyo, Abraham A; Crum, Rosa M; Fried, Linda P; Ford, Daniel E (J Am Geriatr Soc, 2007)
OBJECTIVES: To investigate the mediator role of inflammation in any relationship between depressive symptoms and ischemic stroke. DESIGN: Longitudinal prospective study. SETTING: Review of medical records, death certificates, and the Medicare healthcare utilization database for hospitalizations. PARTICIPANTS: Total of 5,525 elderly men and women aged 65 and older who were prospectively followed from 1989 to 2000 as participants in the Cardiovascular Health Study. MEASUREMENTS: Depression symptom scores, inflammatory markers. RESULTS: Greater depressive symptoms were associated with risk of ischemic stroke (unadjusted hazard ratio (HR)=1.32, 95% confidence interval (CI)=1.09-1.59; HR=1.26, 95% CI=1.03-1.54, adjusted for traditional risk factors). When a term for inflammation (C-reactive protein (CRP)) was introduced in the model, the HRs were not appreciably altered (unadjusted HR=1.31, 95% CI=1.08-1.58; adjusted HR=1.25, 95% CI=1.02-1.53), indicating that CRP at baseline was not a mediator in this relationship. In analyses stratified according to CRP levels, a J-shaped relationship between depressive symptoms and stroke was evident in the unadjusted analyses; in the fully adjusted model, only CRP in the highest tertile was associated with a higher risk for stroke in the presence of higher depressive symptoms scores. CONCLUSION: The analyses from this prospective study provide evidence of a positive association between depressive symptoms and risk of incident stroke. Inflammation, as measured according to CRP at baseline, did not appear to mediate the relationship between depressive symptoms and stroke.
Keywords: Aged; C-Reactive Protein; Cardiovascular Diseases; Cerebral Infarction; Cohort Studies; Depression; Female; Geriatric Assessment; Humans; Inflammation; Kaplan-Meier Estimate; Longitudinal Studies; Male; Multivariate Analysis; Personality Assessment; Proportional Hazards Models; Prospective Studies; Psychoneuroimmunology; Risk Factors; Socioeconomic Factors; Statistics as Topic; United States

Determinants of serum total and free testosterone levels in women over the age of 65 years. - Cappola, Anne R; Ratcliffe, Sarah J; Bhasin, Shalender; Blackman, Marc R; Cauley, Jane; Robbins, John; Zmuda, Joseph M; Harris, Tamara; Fried, Linda P (J Clin Endocrinol Metab, 2007)
CONTEXT: Little is known about testosterone (T) levels and their determinants in women of late postmenopausal age. OBJECTIVE: We describe levels of total and free T and selected factors that influence these levels in a random sample of older women. DESIGN: Levels of serum total T and free T by microdialysis were measured using ultrasensitive assays in 347 community-dwelling women aged 65-98 yr enrolled in the Cardiovascular Health Study. Cross-sectional analyses were performed to define factors associated with total and free T levels. RESULTS: In adjusted models: 1) total T levels declined with age until 80, whereas free T levels did not vary by age; 2) women with bilateral oophorectomy had 23% lower total T and 16% lower free T levels than those with at least one intact ovary; 3) oral estrogen users had total and free T levels that were 47% lower than never users; 4) obese women had 47% higher total T and 20% higher free T levels, and overweight women had 24% higher total T and 14% higher free T levels, than normal weight women; and 5) free T levels were 51% higher in black women. Corticosteroid users had 75% lower total T and 43% lower free T levels than nonusers. CONCLUSIONS: Bilateral oophorectomy, estrogen use, corticosteroid use, and low body mass index are independent risk factors for lower T levels in women aged 65 yr and over. Although highly prevalent in women of this age, the physiological significance of low T levels in late postmenopausal women requires further investigation.
Keywords: Age Distribution; Aged; Aged, 80 and over; Aging; Body Mass Index; Cross-Sectional Studies; Estrogen Replacement Therapy; Female; Humans; Hypogonadism; Multivariate Analysis; Nonlinear Dynamics; Obesity; Ovariectomy; Ovary; Postmenopause; Predictive Value of Tests; Prevalence; Risk Factors; Testosterone

The effect of different public health interventions on longevity, morbidity, and years of healthy life. - Diehr, Paula; Derleth, Ann; Cai, Liming; Newman, Anne B (BMC Public Health, 2007)
BACKGROUND: Choosing cost-effective strategies for improving the health of the public is difficult because the relative effects of different types of interventions are not well understood. The benefits of one-shot interventions may be different from the benefits of interventions that permanently change the probability of getting sick, recovering, or dying. Here, we compare the benefits of such types of public health interventions. METHODS: We used multi-state life table methods to estimate the impact of five types of interventions on mortality, morbidity (years of life in fair or poor health), and years of healthy life (years in excellent, very good, or good health). RESULTS: A one-shot intervention that makes all the sick persons healthy at baseline would increase life expectancy by 3 months and increase years of healthy life by 6 months, in a cohort beginning at age 65. An equivalent amount of improvement can be obtained from an intervention that either decreases the probability of getting sick each year by 12%, increases the probability of a sick person recovering by 16%, decreases the probability that a sick person dies by 15%, or decreases the probability that a healthy person dies by 14%. Interventions aimed at keeping persons healthy increased longevity and years of healthy life, while decreasing morbidity and medical expenditures. Interventions focused on preventing mortality had a greater effect on longevity, but had higher future morbidity and medical expenditures. Results differed for older and younger cohorts and depended on the value to society of an additional year of sick life. CONCLUSION: Interventions that promote health and prevent disease performed well, but other types of intervention were sometimes better. The value to society of interventions that increase longevity but also increase morbidity needs further research. More comprehensive screening and treatment of new Medicare enrollees might improve their health and longevity without increasing future medical expenditures.
Keywords: Actuarial Analysis; Cost-Benefit Analysis; Disease Management; Health Priorities; Health Promotion; Health Services; Health Status; Humans; Life Expectancy; Medicare; Models, Biological; Morbidity; United States; United States Public Health Service

The Emerging Risk Factors Collaboration: analysis of individual data on lipid, inflammatory and other markers in over 1.1 million participants in 104 prospective studies of cardiovascular diseases. - Danesh, J; Erqou, S; Walker, M; Thompson, S G; Tipping, R; Ford, C; Pressel, S; Walldius, G; Jungner, I; Folsom, A R; Chambless, L E; Knuiman, M; et al. (Eur J Epidemiol, 2007)
Many long-term prospective studies have reported on associations of cardiovascular diseases with circulating lipid markers and/or inflammatory markers. Studies have not, however, generally been designed to provide reliable estimates under different circumstances and to correct for within-person variability. The Emerging Risk Factors Collaboration has established a central database on over 1.1 million participants from 104 prospective population-based studies, in which subsets have information on lipid and inflammatory markers, other characteristics, as well as major cardiovascular morbidity and cause-specific mortality. Information on repeat measurements on relevant characteristics has been collected in approximately 340,000 participants to enable estimation of and correction for within-person variability. Re-analysis of individual data will yield up to approximately 69,000 incident fatal or nonfatal first ever major cardiovascular outcomes recorded during about 11.7 million person years at risk. The primary analyses will involve age-specific regression models in people without known baseline cardiovascular disease in relation to fatal or nonfatal first ever coronary heart disease outcomes. This initiative will characterize more precisely and in greater detail than has previously been possible the shape and strength of the age- and sex-specific associations of several lipid and inflammatory markers with incident coronary heart disease outcomes (and, secondarily, with other incident cardiovascular outcomes) under a wide range of circumstances. It will, therefore, help to determine to what extent such associations are independent from possible confounding factors and to what extent such markers (separately and in combination) provide incremental predictive value.
Keywords: Albumins; Biomarkers; Cardiovascular Diseases; Databases, Factual; Far East; Humans; Inflammation; Leukocyte Count; Lipids; Lipoproteins, HDL; Prospective Studies; Risk Factors; Triglycerides

Ethnic-specific prevalence of peripheral arterial disease in the United States. - Allison, Matthew A; Ho, Elena; Denenberg, Julie O; Langer, Robert D; Newman, Anne B; Fabsitz, Richard R; Criqui, Michael H (Am J Prev Med, 2007)
BACKGROUND: Individuals diagnosed with peripheral arterial disease (PAD) are at increased risk for future functional limitations as well as cardiovascular morbidity and mortality. The aim of this study was to estimate the age-, gender-, and ethnic-specific burden of PAD in the United States for the year 2000. METHODS: Data were collected from seven community-based studies that assessed subjects for the presence of PAD using the ankle-brachial index (ABI). Using standardized weighting criteria, age-, gender-, and ethnic-specific prevalence rates were computed and then multiplied by the corresponding 2000 Census population totals to estimate the burden of PAD in the United States for that year. Evidence-based adjustments for studies which did not consider possible subclavian stenosis, prior revascularization for PAD, or both were employed. RESULTS: In 2000, it is conservatively estimated that at least 6.8 million (5.8%) individuals aged 40 years or older had PAD based on an ABI of less than 0.9 or previous revascularization for PAD, and that that there are an additional 1.7 million Americans with PAD but "normal" ABIs. Including this group gives a total of 8.5 million (7.2%) individuals with PAD. CONCLUSIONS: Roughly one in 16 individuals residing in the United States in 2000 who were aged 40 years and older had PAD. Clinicians are encouraged to screen for the presence of PAD using the ABI.
Keywords: Adult; Aged; Aged, 80 and over; Databases as Topic; Female; Humans; Male; Middle Aged; Peripheral Vascular Diseases; United States

Factor VII coagulant activity, factor VII -670A/C and -402G/A polymorphisms, and risk of venous thromboembolism. - Folsom, A R; Cushman, M; Heckbert, S R; Ohira, T; Rasmussen-Torvik, L; Tsai, M Y (J Thromb Haemost, 2007)
BACKGROUND: Most epidemiological studies have found no association between levels of factor (F) VII:C and venous thromboembolism (VTE). Our Longitudinal Investigation of Thromboembolism Etiology (LITE) had, in contrast, reported an independent, increased risk of VTE after 7.8 years of follow-up for those with high baseline levels of FVII:C. OBJECTIVE: To confirm whether FVII:C is associated with VTE after 12.6 years of follow-up and to examine whether two FVII gene polymorphisms (-670A/C and -402G/A) are related to VTE occurrence. METHODS: In 19 091 LITE participants with no prior history of VTE or cancer, we measured FVII:C at baseline and identified 404 new VTEs. We also performed a nested case-control study to relate the polymorphisms to VTE (n = 490 without exclusion for cancer or prior VTE). RESULTS: FVII:C was not independently associated with VTE occurrence after extended follow-up. Multivariable-adjusted rate ratios for VTE were 1.00, 1.00, 0.94, 1.00, and 1.38 (P-trend = 0.48) for the <25th, 25th-49th, 50th-74th, 75th-94th, and >or=95th percentiles of FVII:C, respectively. The -670C and -402A alleles were in high linkage disequilibrium, and both were associated with greater FVII:C levels. However, neither polymorphism was associated with VTE occurrence. CONCLUSION: After extended follow-up, LITE offers little evidence that a greater FVII level is a risk factor for VTE.
Keywords: Alleles; Antigens; Coagulants; Factor VII; Female; Genotype; Humans; Male; Polymorphism, Genetic; Prospective Studies; Risk Factors; Thromboembolism; Venous Thrombosis

Frailty and risk of venous thromboembolism in older adults. - Folsom, Aaron R; Boland, Lori L; Cushman, Mary; Heckbert, Susan R; Rosamond, Wayne D; Walston, Jeremy D (J Gerontol A Biol Sci Med Sci, 2007)
BACKGROUND: Frailty is a common risk factor for morbidity and mortality in elderly persons. Recent evidence links frailty to activation of coagulation and inflammatory pathways. We aimed to determine whether frailty in community-dwelling older adults is a risk factor for venous thromboembolism (VTE). METHODS: We conducted a prospective cohort study in four U.S. communities involving 4859 participants 65 years old and older. At baseline, in 1989-1993, we assessed frailty based on weight loss, grip strength, feelings of exhaustion, walk time, and physical activity. Incident VTE (deep vein thrombosis or pulmonary embolus) through 2002 was identified by review of hospital records. RESULTS: Fifty-two percent of the sample was classified as having intermediate or definite frailty. After adjustment for age, race, sex, body mass index, and diabetes, the relative risk of total VTE (n = 150) for people who were frail compared with no frailty was 1.31 (95% confidence interval [CI], 0.93-1.84). The comparably adjusted relative risk for idiopathic VTE (n = 58) was 1.79 (95% CI, 1.02-3.13). CONCLUSIONS: The incidence rates of idiopathic VTE was higher in community-dwelling older adults with baseline frailty compared with no frailty. Further studies of the clotting process in frailty may allow the development of an improved strategy to determine VTE risk in this vulnerable subset of older adults.
Keywords: Age Factors; Aged; Aged, 80 and over; Female; Follow-Up Studies; Frail Elderly; Humans; Male; Morbidity; Motor Activity; Prospective Studies; Risk Factors; Thromboembolism; United States; Venous Thrombosis

IL-6 gene variation is associated with IL-6 and C-reactive protein levels but not cardiovascular outcomes in the Cardiovascular Health Study. - Walston, Jeremy D; Fallin, M Daniele; Cushman, Mary; Lange, Leslie; Psaty, Bruce; Jenny, Nancy; Browner, Warren; Tracy, Russell; Durda, Peter; Reiner, Alex (Hum Genet, 2007)
Interleukin-6 (IL-6) and C-reactive protein (CRP) levels increase with age and likely play a role in adverse health outcomes in older adults. The relationship between IL-6 gene tag single nucleotide polymorphisms (SNPs) and circulating IL-6 and CRP levels, cardiovascular disease (CVD) outcomes, and mortality in Caucasian (CA) and African American (AA) participants of the Cardiovascular Health Study (CHS) was evaluated using ANCOVA and Cox proportional hazards models. The minor allele of the promoter SNP 1510 and intronic SNP 3572 associates with significantly higher serum IL-6 and CRP levels in CA but not AA. The CRP association persisted after CA and AA populations were combined and after accounting for multiple comparisons. These associations did not carry through to cardiovascular disease outcomes. Decreased risk of stroke was identified in CA, with the minor allele of SNP 1111 (HRR 0.71, 95% CI 0.52, 0.95), P = 0.02, and increased risk of CVD and all-cause mortality (HRR 1.31, 95% CI 1.05-1.64) in AAs heterozygote for SNP 2989. While genetic variation in the IL-6 gene was associated with circulating IL-6 and especially with CRP concentrations in this study, there is little evidence for association between common IL-6 gene variation and adverse health outcomes in this population of older adults.
Keywords: African Americans; Aged; Alleles; C-Reactive Protein; Cardiovascular Diseases; Cohort Studies; European Continental Ancestry Group; Female; Gene Frequency; Genetic Predisposition to Disease; Genetic Variation; Humans; Interleukin-6; Introns; Longitudinal Studies; Male; Polymorphism, Single Nucleotide; Promoter Regions, Genetic

Individual and neighborhood socioeconomic status and progressive chronic kidney disease in an elderly population: The Cardiovascular Health Study. - Merkin, Sharon Stein; Diez Roux, Ana V; Coresh, Josef; Fried, Linda F; Jackson, Sharon A; Powe, Neil R (Soc Sci Med, 2007)
Few studies have focused on the association between socioeconomic status (SES) and progressive chronic kidney disease (pCKD) in an elderly population. We conducted a cohort study of 4735 Cardiovascular Health Study participants, ages 65 and older and living in 4 US communities, to examine the independent risk of pCKD associated with income, education and living in a low SES area. pCKD was defined as creatinine elevation 0.4 mg/dL (35 micromol/L) over a 4-7 year follow-up or CKD hospitalization. Area SES was characterized using measures of income, wealth, education and occupation for 1990 (corresponding to time of enrollment) US Census block groups of residence. Age and study site-adjusted incidence rates (per 1000 person years) of pCKD by quartiles of area-level SES score, income and education showed decreasing rates with increasing SES. Cox proportional hazards models showed that living in the lowest SES area quartile, as opposed to the highest, was associated with 50% greater risk of pCKD, after adjusting for age, gender, study site, baseline creatinine, and individual-level SES. This increased risk and trend persisted after adjusting for lifestyle risk factors, diabetes and hypertension. We found no significant independent associations between pCKD and individual-level income or education (after adjusting for all other SES factors). As such, living in a low SES area is associated with greater risk of pCKD in an elderly US population.
Keywords: Age Factors; Aged; Cohort Studies; Female; Humans; Incidence; Kidney Failure, Chronic; Male; Proportional Hazards Models; Residence Characteristics; Risk Factors; Sex Factors; Social Class; United States

Inflammation and hemostasis biomarkers and cardiovascular risk in the elderly: the Cardiovascular Health Study. - Zakai, N A; Katz, R; Jenny, N S; Psaty, B M; Reiner, A P; Schwartz, S M; Cushman, M (J Thromb Haemost, 2007)
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

Longitudinal association between depressive symptoms and incident type 2 diabetes mellitus in older adults: the cardiovascular health study. - Carnethon, Mercedes R; Biggs, Mary L; Barzilay, Joshua I; Smith, Nicholas L; Vaccarino, Viola; Bertoni, Alain G; Arnold, Alice; Siscovick, David (Arch Intern Med, 2007)
BACKGROUND: Prospective studies indicate that a single self-report of high depressive symptoms is associated with an increased risk of developing type 2 diabetes mellitus. METHODS: We tested whether a single report of high depressive symptoms, an increase in depressive symptoms, or persistently high depressive symptoms over time were associated with the development of diabetes in adults 65 years and older. Participants from the Cardiovascular Health Study completed the 10-item Center for Epidemiological Studies-Depression Scale (CES-D) annually from 1989 to 1999. A single report of high depressive symptoms (CES-D score, >/=8), an increase in symptoms during follow-up (>/=5 from baseline), and persistently high symptoms (2 consecutive scores >/=8) were each studied in relation to incident diabetes, defined by initiation of diabetes control medications among participants who were free from diabetes at baseline (n = 4681). RESULTS: The mean CES-D score at baseline was 4.5 (SD, 4.5). The incidence rate of diabetes was 4.4 per 1000 person-years. Following adjustment for baseline demographic characteristics and measures of physical activity, smoking, alcohol intake, body mass index, and C-reactive protein during follow-up, each measure of depressive symptoms was significantly associated with incident diabetes (high baseline CES-D score: hazard ratio, 1.6 [95% confidence interval, 1.1-2.3]; CES-D score increase: hazard ratio, 1.5 [95% confidence interval, 1.1-2.2]; and persistently high symptoms: hazard ratio, 1.5 [95% confidence interval, 1.1-2.3]). CONCLUSION: Older adults who reported higher depressive symptoms were more likely to develop diabetes than their counterparts; this association was not fully explained by risk factors for diabetes.
Keywords: Aged; Body Mass Index; C-Reactive Protein; Depression; Diabetes Mellitus, Type 2; Drinking; Female; Humans; Longitudinal Studies; Male; Smoking

The number of sick persons in a cohort. - Diehr, P; Derleth, A; Newman, AB; Cai, L (Research on Aging, 2007)
In the Cardiovascular Health Study, a cohort study of older adults followed up to 14 years, the number of sick persons was approximately constant over time. This was true whether we defined “sick” based on self-rated health, ADL or IADL difficulties, the timed walk, bed days, depression, cognitive problems, or cardiovascular disease. To better understand this phenomenon, we estimated the probabilities of transition among the healthy, sick, and dead states, and projected the number who would be in each health state over time for a birth cohort. The estimated number of sick persons in the birth cohort increased slowly over time and was approximately constant from ages 55-75, after which it decreased. The relative excess of older persons who are sick in later life is caused by a decline in the number of healthy persons rather than an increase in the number who are sick. Estimated total medical expenditures for a birth cohort may decline after about age 73. These findings may suggest a different way of thinking about trends in the health and medical expenditures of the population over time.
Keywords: Aging; equilibrium; transition probabilities; years of healthy life

The relationship of heart rate and heart rate variability to non-diabetic fasting glucose levels and the metabolic syndrome: the Cardiovascular Health Study. - Stein, P K; Barzilay, J I; Domitrovich, P P; Chaves, P M; Gottdiener, J S; Heckbert, S R; Kronmal, R A (Diabet Med, 2007)
BACKGROUND: Increased heart rate (HR) and diminished heart rate variability (HRV) are signs of early cardiovascular autonomic neuropathy. We tested the hypotheses that increased HR and diminished HRV are present in people: (i) with increased fasting glucose (FG) levels not in the range of diabetes mellitus (DM), and (ii) in people with the metabolic syndrome (MetS) independent of elevated FG levels. METHODS: HR and HRV were determined in 1267 adults (mean age 72 years) who had Holter monitoring and FG measures: 536 had normal FG levels (NORM, FG 4.5-5.5 mmol/l), 363 had mildly impaired FG (IFG-1, FG 5.6-6.0 mmol/l), 182 had significantly impaired FG (IFG-2, FG 6.1-6.9 mmol/l) and 178 had DM (FG > 6.9 mmol/l or use of glucose-lowering agents/insulin). HR and HRV in NORM/IFG-1 was further compared by the number of components of the MetS and compared by the presence or absence of MetS in IFG-2/DM. RESULTS: HRV indices were more impaired in IFG-2 and DM than in NORM or IFG-1. There were few differences in HRV indices between NORM and IFG-1 or between IFG-2 and DM. In NORM/IFG-1 participants, having > or = 2 components of the MetS was associated with a greater decrease in HRV compared with having no or one components. In IFG-2/DM participants, MetS was associated with decreased HRV compared with no MetS. CONCLUSIONS: Increased HR and diminished HRV occur in the non-diabetic FG range. Diminished HRV is associated with the MetS, independent of FG levels. Both these results suggest that factors associated with increasing non-diabetic FG levels and the MetS play a role in the onset of cardiac autonomic impairment.
Keywords: Aged; Aged, 80 and over; Arrhythmias, Cardiac; Blood Glucose; Fasting; Female; Glucose Intolerance; Heart Rate; Humans; Male; Metabolic Syndrome; Risk Factors

Relationship of uric acid with progression of kidney disease. - Chonchol, Michel; Shlipak, Michael G; Katz, Ronit; Sarnak, Mark J; Newman, Anne B; Siscovick, David S; Kestenbaum, Bryan; Carney, Jan Kirk; Fried, Linda F (Am J Kidney Dis, 2007)
BACKGROUND: Uric acid levels are increased in patients with kidney dysfunction. We tested the hypothesis that uric acid may be associated with kidney disease progression. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 5,808 participants of the Cardiovascular Health Study. PREDICTOR: Uric acid levels. OUTCOMES & MEASUREMENTS: Kidney disease progression was defined as a decrease in estimated glomerular filtration rate (GFR) of 3 mL/min/1.73 m(2) per year or greater (>or=0.05 mL/s) and as incident chronic kidney disease (CKD). Measures of kidney function were estimated GFR using the Modification of Diet in Renal Disease Study equation. RESULTS: Higher quintiles of uric acid levels were associated with greater prevalences of estimated GFR less than 60 mL/min/1.73 m(2) (<1.00 mL/s) of 7%, 14%, 12%, 25%, and 42% for quintiles 1 (<or=4.41 mg/dL [<or=262 micromol/L]), 2 (4.41 to 5.20 mg/dL [262 to 309 micromol/L]), 3 (5.21 to 5.90 mg/dL [310 to 351 micromol/L]), 4 (5.91 to 6.90 mg/dL [352 to 410 micromol/L]), and 5 (>6.90 mg/dL [>410 micromol/L]), respectively. In comparison, there was only a modest, but significant, association between quintiles of uric acid levels and progression of kidney function decrease, with adjusted odds ratios of 1.0, 0.88 (95% confidence interval [CI], 0.64 to 1.21), 1.23 (95% CI, 0.87 to 1.75), 1.47 (95% CI, 1.04 to 2.07), and 1.49 (95% CI, 1.00 to 2.22) for quintiles 1 through 5, respectively. No significant association was found between uric acid level and incident CKD (adjusted odds ratio, 1.00; 95% CI, 0.89 to 1.14). LIMITATIONS: Measurements of albuminuria were not available. CONCLUSIONS: Uric acid levels are associated strongly with prevalent CKD. In comparison, greater uric acid levels had a significant, but much weaker, association with progression of kidney disease.
Keywords: Aged; Aged, 80 and over; Cohort Studies; Cross-Sectional Studies; Disease Progression; Female; Glomerular Filtration Rate; Humans; Kidney Diseases; Male; Prospective Studies; Uric Acid

Risk factors for intracerebral hemorrhage in a pooled prospective study. - Sturgeon, Jared D; Folsom, Aaron R; Longstreth, W T; Shahar, Eyal; Rosamond, Wayne D; Cushman, Mary (Stroke, 2007)
BACKGROUND AND PURPOSE: Few prospective studies have reported risk factors for intracerebral hemorrhage (ICH), and results are inconsistent. We studied risk factors for ICH in a pooled cohort of the Atherosclerosis Risk in Communities Study (ARIC) and the Cardiovascular Health Study (CHS). METHODS: The ARIC cohort was recruited in 1987 to 1989 and involves 15 792 men and women, aged 45 to 64 years at baseline, sampled from 4 US communities. The CHS cohort was recruited in 1989 to 1993 and involves 5888 men and women, aged 65 or over at baseline, sampled from 4 US communities. Baseline measurements included many potential vascular risk factors. The cohorts were followed for incident stroke events. RESULTS: Over 263 489 person-years of follow-up, 135 incident ICH events occurred. In a multivariable model, age, African-American ethnicity (versus Whites), and hypertension were positively associated with incident ICH, whereas low-density lipoprotein cholesterol and triglycerides were inversely related to incident ICH. Participants with systolic blood pressure >or=160 mm Hg or diastolic blood pressure >/=110 mm Hg had 5.55 (95% CI 3.07 to 10.0) times the rate of ICH as nonhypertensives. Sex, smoking, alcohol intake, body mass index, waist-to-hip ratio, waist circumference, and diabetes were not related to ICH. CONCLUSIONS: In this pooled cohort the risk factors for ICH were older age, African-American ethnicity, hypertension, lower LDL-C, and lower triglycerides.
Keywords: African Americans; Age Distribution; Cerebral Hemorrhage; Cholesterol, LDL; Female; Follow-Up Studies; Humans; Hypertension; Incidence; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Prevalence; Prospective Studies; Risk Factors; Stroke; Triglycerides

USF1 gene variants, cardiovascular risk, and mortality in European Americans: analysis of two US cohort studies. - Reiner, Alexander P; Carlson, Christopher S; Jenny, Nancy S; Durda, J Peter; Siscovick, David S; Nickerson, Deborah A; Tracy, Russell P (Arterioscler Thromb Vasc Biol, 2007)
OBJECTIVE: A common haplotype of the upstream transcription factor 1 gene (USF1) has been associated with decreased susceptibility to familial combined hyperlipidemia (FCHL) and, paradoxically, with increased risk of cardiovascular disease (CVD) and all-cause mortality. METHODS AND RESULTS: We assessed associations between USF1 tagSNPs, CVD risk factors, and aging-related phenotypes using data from 2 large population-based cohorts, Coronary Artery Risk Development in Young Adults (CARDIA) and the Cardiovascular Health Study (CHS), comprising younger and older adults, respectively. In CARDIA, each additional copy of the FCHL low-risk allele was associated with 2.4 mg/dL lower levels of LDL cholesterol (P=0.01) and decreased risk of subclinical atherosclerosis as assessed by coronary artery calcium (odds ratio 0.79; 95%CI 0.63 to 0.98). Whereas there was little association between USF1 genotype and metabolic or CVD traits in older adults from CHS, the USF1 low-risk dyslipidemia allele was associated with higher plasma C-reactive protein and interleukin (IL)-6 levels and with increased risk of mortality, particularly attributable to noncardiovascular causes. CONCLUSIONS: There appears to be a complex and possibly age-dependent relationship between USF1 genotype, atherosclerosis phenotypes, and CVD risk. USF1 may influence mortality through pathways distinct from atherosclerosis. Alternatively, linkage disequilibrium with neighboring polymorphisms in other genes such as F11R may be responsible for the observed USF1 genotype-phenotype associations in older adults.
Keywords: Adult; Age Factors; Aged; Aged, 80 and over; Aging; Blood Glucose; C-Reactive Protein; Calcium; Cardiovascular Diseases; Carotid Artery, Common; Cohort Studies; Coronary Artery Disease; Coronary Vessels; European Continental Ancestry Group; Female; Follow-Up Studies; Genetic Predisposition to Disease; Humans; Hyperlipidemia, Familial Combined; Insulin; Interleukin-6; Linkage Disequilibrium; Lipids; Male; Odds Ratio; Phenotype; Polymorphism, Single Nucleotide; Prospective Studies; Risk Assessment; Risk Factors; Time Factors; United States; Upstream Stimulatory Factors

Ventricular volume and dementia progression in the Cardiovascular Health Study. - Carmichael, Owen T; Kuller, Lewis H; Lopez, Oscar L; Thompson, Paul M; Dutton, Rebecca A; Lu, Allen; Lee, Sharon E; Lee, Jessica Y; Aizenstein, Howard J; Meltzer, Carolyn Cidis; Liu, Yanxi; Toga, Arthur W; et al. (Neurobiol Aging, 2007)
Elevated cerebral ventricular volume may be associated with dementia risk and progression. A fully-automated technique that agreed highly with radiological readings was used to estimate lateral ventricle volume on MR scans done at baseline in 1997-99 of 377 subjects in the Cardiovascular Health Study (CHS) from the Pittsburgh Center. 327 subjects were normal or diagnosed with mild cognitive impairment (MCI) at baseline and were evaluated 4 years later. Baseline ventricular volume was analyzed in multivariate models with age, gender, education level, presence and incidence of cerebral infarcts, and dementia category (normal, MCI, or dementia) at baseline and follow-up as fixed effects. Ventricular volume at baseline was significantly higher among subjects normal at baseline and demented 4 years later. Age, gender, education level, and dementia progression were significant factors affecting ventricular volume. Ventricular volume was higher in dementia compared to MCI, higher in MCI compared to controls, and higher in Possible-Alzheimer's-disease (AD) dementia compared to Probable-AD. Larger ventricles in healthy subjects may indicate susceptibility to, or progression of, dementia-related pathology.
Keywords: Aged; Aged, 80 and over; Aging; Cognition Disorders; Cross-Sectional Studies; Dementia; Disease Progression; Female; Follow-Up Studies; Humans; Lateral Ventricles; Linear Models; Magnetic Resonance Imaging; Male; Predictive Value of Tests; Prospective Studies; Retrospective Studies; Time Factors

Abnormal regional cerebral blood flow in cognitively normal elderly subjects with hypertension. - Dai, Weiying; Lopez, Oscar L; Carmichael, Owen T; Becker, James T; Kuller, Lewis H; Gach, H Michael (Stroke, 2008)
BACKGROUND AND PURPOSE: The purpose of this study was to examine regional cerebral blood flow (rCBF) in normal cognitive-performing subjects with hypertension (HTN) using continuous arterial spin-labeled MRI. The most common explanation for the effect of blood pressure on cognition is that HTN increases the risk of cerebrovascular disease, and it may increase the risk for Alzheimer disease possibly through small vessel disease, ischemia, oxidative stress, and inflammation. However, few studies to date have examined the rCBF of cognitively normal subjects with HTN in population-based cohorts, and none have used continuous arterial spin-labeled MRI. This is a noninvasive technique that does not require either injections or ionizing radiation and can measure absolute rCBF rates over the entire brain. METHODS: rCBF was measured at 1.5 T using continuous arterial spin-labeled MRI in 41 cognitively normal subjects who were participating in the Cardiovascular Health Study Cognition Study. A deformable atrophy-corrected registration method was used to warp the rCBF maps to the standard colin27 brain space. Image and cluster-based statistical analyses were performed between subject groups. RESULTS: Cognitively normal subjects with HTN (n=19) had decreased rCBF in the putamen, globus pallidus, bilaterally, and in the left hippocampus compared with normotensives (n=22). In addition, decreased rCBF was observed in the right and left anterior cingulate gyrus with extension to the subcallosal region, left posterior cingulate gyrus and medial precuneus, left lateral inferior and superior frontal, and inferior parietal, left orbitofrontal, and left superior temporal cortices. CONCLUSIONS: rCBF is affected in normal subjects with HTN, not only in the subcortical regions, but also in limbic and paralimbic structures. We hypothesize that the HTN creates a vulnerability state for the development of neurodegenerative disorders, especially Alzheimer disease.
Keywords: Aged; Aged, 80 and over; Cerebral Cortex; Cerebrovascular Circulation; Cognition; Cognition Disorders; Female; Globus Pallidus; Gyrus Cinguli; Humans; Hypertension; Magnetic Resonance Imaging; Male; Putamen; Spin Labels

Alcohol consumption and lower extremity arterial disease among older adults: the cardiovascular health study. - Mukamal, Kenneth J; Kennedy, Margaret; Cushman, Mary; Kuller, Lewis H; Newman, Anne B; Polak, Joseph; Criqui, Michael H; Siscovick, David S (Am J Epidemiol, 2008)
Few studies of the relation of alcohol intake to lower-extremity arterial disease (LEAD) have included clinical events and objective measurements repeated longitudinally. As part of the Cardiovascular Health Study, a study of older adults from four US communities, 5,635 participants reported their use of beer, wine, and spirits yearly. Incident LEAD was identified by hospitalization surveillance. Technicians measured ankle-brachial index 6 years apart in 2,298 participants. A total of 172 cases of LEAD were documented during a mean of 7.5 years of follow-up between 1989 and 1999. Compared with abstention, the multivariable-adjusted hazard ratios were 1.10 (95% confidence interval (CI): 0.71, 1.71) for <1 alcoholic drink per week, 0.56 (95% CI: 0.33, 0.95) for 1-13 drinks per week, and 1.02 (95% CI: 0.53, 1.97) for > or =14 drinks per week (p for quadratic trend = 0.04). These relations were consistent within strata of sex, age, and apolipoprotein E genotype, and neither lipids nor inflammatory markers appeared to be important intermediates. Change in ankle-brachial index showed a similar relation (p for quadratic trend = 0.01). Alcohol consumption of 1-13 drinks per week in older adults may be associated with lower risk of LEAD, but heavier drinking is not associated with lower risk.
Keywords: Aged; Alcohol Drinking; Female; Follow-Up Studies; Health Surveys; Humans; Intermittent Claudication; Male; Prevalence; Prospective Studies; Risk Factors; Surveys and Questionnaires; Time Factors; United States

Anemia is associated with the progression of white matter disease in older adults with high blood pressure: the cardiovascular health study. - Inzitari, Marco; Studenski, Stephanie; Rosano, Caterina; Zakai, Neil A; Longstreth, William T; Cushman, Mary; Newman, Anne B (J Am Geriatr Soc, 2008)
OBJECTIVES: To investigate whether anemia predicts worsening white matter hyperintensities (WMHs) in older community-dwellers. DESIGN: Prospective cohort study. SETTING: Older community-dwellers. PARTICIPANTS: One thousand eight hundred forty-six Cardiovascular Health Study (CHS) participants (mean age 73.7 +/- 4.4, 41% male, 15.6% African American). MEASUREMENTS: Participants had hemoglobin measured and brain magnetic resonance imaging (MRI) in 1992/93 and a second brain MRI in 1997/98. Anemia was defined according to World Health Organization criteria (hemoglobin <12 g/dL in women and <13 g/dL in men). Worsening WMHs were determined according to standardized side-by-side readings. RESULTS: After 5 years, WMHs worsened in 517 participants (28%). Progression was not associated with anemia in the whole sample, in sex or race strata, or in other prespecified subgroups (participants with renal dysfunction or diabetes mellitus), except in participants with high blood pressure (>or=140/90 mmHg). Of the 678 participants with high blood pressure, those with anemia (10.5%) had a 1.79 times greater risk of WMHs worsening (95% confidence interval=1.06-2.98; P for interaction between anemia and high blood pressure=.01) independent of demographics, baseline WMHs, cardiovascular risk factors and comorbidities, medications, renal function, inflammation, and incident stroke (logistic regression models). There was no greater risk in participants with anemia with normal blood pressure. CONCLUSION: Anemia may contribute to worsening of WMHs in older adults with high blood pressure.
Keywords: Aged; Anemia; Brain; Cardiovascular Diseases; Disease Progression; Female; Humans; Hypertension; Leukoaraiosis; Magnetic Resonance Imaging; Male

Ankle brachial index combined with Framingham Risk Score to predict cardiovascular events and mortality: a meta-analysis. - Fowkes, F G R; Murray, G D; Butcher, I; Heald, C L; Lee, R J; Chambless, L E; Folsom, A R; Hirsch, A T; Dramaix, M; deBacker, G; Wautrecht, J-C; Kornitzer, M; et al. (JAMA, 2008)
CONTEXT: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction. OBJECTIVE: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction. DATA SOURCES: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies. STUDY SELECTION: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality. DATA EXTRACTION: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease. RESULTS: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women. CONCLUSION: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.
Keywords: Adult; Age Factors; Aged; Aged, 80 and over; Ankle; Atherosclerosis; Blood Pressure; Brachial Artery; Cardiovascular Diseases; Cohort Studies; Confidence Intervals; Female; Global Health; Humans; Male; Middle Aged; Odds Ratio; Predictive Value of Tests; Risk Assessment; Risk Factors; Severity of Illness Index

Antidepressant treatment and worsening white matter on serial cranial magnetic resonance imaging in the elderly: the Cardiovascular Health Study. - Steffens, David C; Chung, Hyoju; Krishnan, K Ranga R; Longstreth, W T; Carlson, Michelle; Burke, Gregory L (Stroke, 2008)
BACKGROUND AND PURPOSE: In some studies, late life depression is associated with white matter lesions on MRI. The effect of different classes of antidepressants on progression of white matter lesions is unknown. Selective serotonergic reuptake inhibitors (SSRIs) may decrease platelet aggregation. We hypothesized that Cardiovascular Health Study participants taking SSRIs would less often have worsening white matter on serial MRI than participants not on antidepressants. METHODS: Among 1826 participants who were not using an antidepressant at initial MRI scan, we examined the association of worsening in white matter grade from initial to follow-up MRI scans, 5 years apart on average, and antidepressant use between the scans. Logistic regression models were used, controlling for a variety of potential confounding variables. RESULTS: Use of any antidepressant during the period of study was associated with worsening white matter. In a multivariable model, risk was slightly increased, not reduced, with use of serotonergic agents (OR 1.36, 95% CI 0.87 to 2.12) and was significantly increased with the use of tricyclic antidepressants (OR 1.77, 95% CI 1.07 to 2.94). CONCLUSIONS: The association between worsening white matter and use of tricyclic antidepressants was an unexpected finding that may relate to indications for use other than depression or to side effects such as hypotension. Protection against worsening was not seen with use of serotonergic agents.
Keywords: Aged; Antidepressive Agents; Antidepressive Agents, Tricyclic; Cohort Studies; Disease Progression; Female; Follow-Up Studies; Humans; Leukoaraiosis; Magnetic Resonance Imaging; Male; Multivariate Analysis; Risk Assessment; Serotonin Uptake Inhibitors

Association between brachial artery reactivity and cardiovascular disease status in an elderly cohort: the cardiovascular health study. - Yeboah, Joseph; Sutton-Tyrrell, Kim; McBurnie, Mary Ann; Burke, Gregory L; Herrington, David M; Crouse, John R (Atherosclerosis, 2008)
BACKGROUND AND OBJECTIVES: The association of brachial flow-mediated dilation (FMD) and cardiovascular disease (CVD) status is unclear especially in older adults whose FMD is greatly diminished. We assessed the association of FMD and the presence or absence of subclinical and clinical CVD in a population based cohort of older adults. METHODS AND RESULTS: FMD was measured in 2971 adults aged 72-98 years (mean age 78.6 years) who participated in the Cardiovascular Health Study. Multiple linear regression analysis was used to examine the association between FMD and CVD status (clinical, subclinical and free of CVD). Out of 2791 with complete data, 82.7% were Caucasians and 59% females. Seven hundred and forty-three were classified as having clinical CVD, 607 as subclinical CVD and 1441 as neither clinical CVD nor subclinical CVD (CVD free). FMD was higher in the CVD free group compared with either the clinical (3.13+/-0.05% vs 2.93+/-0.07%, p=0.025) or the subclinical CVD group (3.13+/-0.05% vs 2.95+/-0.08%, p=0.05) after adjusting for covariates. There was no significant difference between the FMD of subjects with clinical and subclinical CVD (2.93+/-0.07% vs 2.95+/-0.08%, p=0.84). Similar but inverted associations were observed between height adjusted brachial artery diameter (BAD) and CVD status. However, FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD. CONCLUSION: Among older adults, those with either clinical or subclinical CVD have lower FMD than CVD free subjects. BAD showed similar but inverted associations with CVD status in this cohort. FMD and BAD had poor diagnostic accuracies for identifying older adults with subclinical CVD.
Keywords: Aged; Aged, 80 and over; Biomarkers; Brachial Artery; Cardiovascular Diseases; Cohort Studies; Female; Hemorheology; Humans; Male; Peripheral Vascular Diseases; ROC Curve; Ultrasonography; Vasodilation

Associations between common fibrinogen gene polymorphisms and cardiovascular disease in older adults. The Cardiovascular Health Study. - Carty, Cara L; Cushman, Mary; Jones, Daniel; Lange, Leslie A; Hindorff, Lucia A; Rice, Kenneth; Jenny, Nancy S; Durda, J Peter; Walston, Jeremy; Carlson, Christopher S; Nickerson, Debbie; Tracy, Russell P; et al. (Thromb Haemost, 2008)
Elevated plasma fibrinogen is a risk factor for cardiovascular disease (CVD), but associations between fibrinogen single nucleotide polymorphisms (SNPs) and disease risk are inconsistent. We investigated whether common (> or = 5% minor allele frequency) variation in the fibrinogen genes (FGA, FGB, FGG) is associated with fibrinogen concentration, carotid artery intima-medial thickness (IMT) and risk of incident myocardial infarction (MI), ischemic stroke and CVD mortality in European- (EA) and African-descent (AA) adults (> or = 65 years) from the Cardiovascular Health Study. TagSNPs were genotyped in 3,969 EA and 719 AA free of MI or stroke at baseline. Race-specific models included multiple testing correction and adjustment for sex, age and site. Among EA, minor alleles of FGA3807, FGB1437 and FGG902 were associated with higher fibrinogen levels; whereas FGA251, FGA2224, FGA6534 and FGG10034 were associated with lower levels, p<0.004 for each. Strongest associations were seen for FGB1437; each additional copy of the minor allele was associated with 13 mg/dl (95%CI: 9-16) higher fibrinogen level. Similar trends in AA were not significant. Fibrinogen haplotypes were not significantly associated with internal or common carotid IMT. No associations with MI or CVD mortality were seen in EA, though FGB1038 and FGG902 were significantly associated with increased and decreased risk of stroke in men, respectively, as were related haplotypes. FGB1038 was also associated with CVD mortality in AA, HR = 1.9 (95%CI: 1.3-2.7). In conclusion, while fibrinogen genetic variation was strongly associated with fibrinogen levels, there was less evidence of association with the more complex outcomes of IMT and CVD events.
Keywords: African Americans; Age Factors; Aged; Brain Ischemia; Cardiovascular Diseases; Carotid Artery Diseases; European Continental Ancestry Group; Female; Fibrinogen; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Male; Myocardial Infarction; Polymorphism, Single Nucleotide; Population Surveillance; Proportional Hazards Models; Prospective Studies; Reproducibility of Results; Risk Assessment; Risk Factors; Sex Factors; Stroke; United States