A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

Guidelines for investigating causality of sequence variants in human disease.

The discovery of rare genetic variants is accelerating, and clear guidelines for distinguishing disease-causing sequence variants from the many potentially functional variants present in any human genome are urgently needed. Without rigorous standards we risk an acceleration of false-positive reports of causality, which would impede the translation of genomic research findings into the clinical diagnostic setting and hinder biological understanding of disease. Here we discuss the key challenges of assessing sequence variants in human disease, integrating both gene-level and variant-level support for causality. We propose guidelines for summarizing confidence in variant pathogenicity and highlight several areas that require further resource development.

Education and the cognitive decline associated with MRI-defined brain infarct.

OBJECTIVE: To assess whether educational attainment, a correlate of cognitive reserve, predicts the amount of cognitive decline associated with a new brain infarct. METHODS: The Cardiovascular Health Study is a population-based, longitudinal study of people aged 65 years and older. Cognitive function was measured annually using the Modified Mini-Mental State Examination (3MS) and the Digit-Symbol Substitution Test (DSST). The authors tested whether education level modified 1) the cross-sectional association between cognitive performance and MRI-defined infarct and 2) the change in cognitive function associated with an incident infarct at a follow-up MRI. RESULTS: In cross-sectional analysis (n = 3,660), MRI-defined infarct was associated with a greater impact on 3MS performance in the lowest education quartile when compared with others (p for heterogeneity = 0.012). Among those with a follow-up MRI who had no infarct on initial MRI (n = 1,433), education level was not associated with the incidence, size, or location of new brain infarct. However, a new MRI-defined infarct predicted substantially greater decline in 3MS scores in the lowest education group compared with the others (6.3, 95% CI 4.4- to 8.2-point decline vs 1.7, 95% CI 0.7- to 2.7-point decline; p for heterogeneity < 0.001). Higher education was not associated with smaller declines in DSST performance in the setting of MRI-defined infarct. CONCLUSIONS: Education seems to modify an individual's decline on a test of general cognitive function when there is incident brain infarct. These findings are consistent with the hypothesis that cognitive reserve influences the impact of vascular injury in the brain.

Vascular events, mortality, and preventive therapy following ischemic stroke in the elderly.

BACKGROUND: The authors studied mortality, vascular events, and preventive therapies following ischemic stroke among adults aged > or =65 years. METHODS: The authors identified 546 subjects with first ischemic stroke during 1989 to 2001 among Cardiovascular Health Study participants. Deaths, recurrent strokes, and coronary heart disease (CHD) events were identified over 3.2 years (median) follow-up. RESULTS: During the first year of follow-up, rates were 105.4/1,000 for recurrent stroke and 59.3/1,000 for CHD. After the first year, the stroke rate was 52.0/1,000 and the CHD rate was 46.5/1,000. Cardioembolic strokes had the highest mortality (185.4/1,000) and recurrence rates (86.6/1,000). Lacunar strokes had the lowest mortality (119.3/1,000) and recurrence rates (43.0/1,000). Age and male sex predicted death and CHD, but not recurrence. Outcomes did not differ by race. Following stroke, 47.8% used aspirin and 13.5% used other antiplatelet agents; 52.6% of patients with atrial fibrillation used warfarin; 31.3% of hyperlipidemic subjects, 57.0% of diabetic patients, and 81.5% of hypertensive patients were drug-treated; and 40.0% of hypertensive patients had blood pressure (BP) <140/90 mm Hg. Older subjects were less likely to use lipid-lowering therapy, women were less likely to have BP <140/90 mm Hg, and low-income subjects were less likely to use diabetes medications. CONCLUSIONS: Recurrent strokes were nearly twice as frequent as coronary heart disease (CHD) events during the first year after initial stroke, but stroke and CHD rates were similar after the first year. Preventive drug therapies were underused, which may reflect clinical uncertainty due to the lack of clinical trials among the elderly. Utilization was lower among the oldest patients, women, and low-income individuals.

Respiratory muscle strength and the risk of incident cardiovascular events.

BACKGROUND: Maximal inspiratory pressure (MIP) is a measure of inspiratory muscle strength. The prognostic importance of MIP for cardiovascular events among elderly community dwelling individuals is unknown. Diminished forced vital capacity (FVC) is a risk factor for cardiovascular events which remains largely unexplained. METHODS: MIP was measured at the baseline examination of the Cardiovascular Health Study. Participants had to be free of prevalent congestive heart failure (CHF), myocardial infarction (MI), and stroke. RESULTS: Subjects in the lowest quintile of MIP had a 1.5-fold increased risk of MI (HR 1.48, 95% CI 1.07 to 2.06) and cardiovascular disease (CVD) death (HR 1.54, 95% CI 1.09 to 2.15) after adjustment for non-pulmonary function covariates. There was a potential inverse relationship with stroke (HR 1.36, 95% CI 0.97 to 1.90), but there was little evidence of an association between MIP and CHF (HR 1.22, 95% CI 0.93 to 1.60). The addition of FVC to models attenuated the HR associated with MIP only modestly; similarly, addition of MIP attenuated the HR associated with FVC only modestly. CONCLUSIONS: A reduced MIP is an independent risk factor for MI and CVD death, and a suggestion of an increased risk for stroke. This association with MIP appeared to be mediated through mechanisms other than inflammation.

Stroke risk factors and loss of high cognitive function.

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.

Incidence and predictors of coronary heart disease among older African Americans--the Cardiovascular Health Study.

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.

Characterization of idiopathic scoliosis in a clinically well-defined population.

Idiopathic scoliosis is a highly prevalent disorder, familial in nature, with marked clinical variability. The purpose of this study was to characterize idiopathic scoliosis in a large series of families to be used for a genome-wide search. One hundred thirty-one multigenerational families (892 individuals) with at least two affected individuals were studied. Data obtained included curve pattern, treatment, and back pain. Maximum curvature as a continuous variable was evaluated using t tests for dichotomous characteristics and linear correlation for continuous variables. An analysis of familial loading was done. Four hundred forty-four individuals were classified as affected (82% female; 18% male). The right thoracic and left lumbar curves had the highest mean curvature (49 degrees). Mean curve size was greater in individuals with back pain. Back pain was most prevalent in the right thoracic and left lumbar curve pattern. The Pearson correlation coefficient between the number of affected family members and the maximum degree of curvature was 0.16, suggesting that the greater the lateral curvature, the higher the proportion of family members affected with scoliosis. The sample population is consistent with those of previous studies in relation to gender and curve size. Statistically, the familial nature of this disorder is supported.

Unrecognized myocardial infarction.

This review addresses myocardial infarctions that escape clinical recognition. It focuses on the prevalence, predisposing factors, and prognosis of these unrecognized infarctions, and incorporates data from relevant epidemiologic studies, basic science investigations, and review articles. These data indicate that at least one fourth of all myocardial infarctions are clinically unrecognized. The demographic characteristics and coronary risk factor profiles of persons with previously unrecognized myocardial infarctions appear to be similar to those of persons whose infarctions are clinically detected. Impaired symptom perception may contribute to lack of recognition, but both patients' and physicians' perceptions about the risk for myocardial infarction may also play an important role. Finally, mortality rates after unrecognized and recognized myocardial infarction are similar. Given the public health implications of unrecognized myocardial infarction, future studies should address screening strategies, risk stratification after detection of previously unrecognized myocardial infarction, and the role of standard postinfarction therapies in affected patients.

Cluster analysis and patterns of findings on cranial magnetic resonance imaging of the elderly: the Cardiovascular Health Study.

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.

Cardiovascular disease and mortality in older adults with small abdominal aortic aneurysms detected by ultrasonography: the cardiovascular health study.

BACKGROUND: Persons with abdominal aortic aneurysm are more likely to have a higher prevalence of risk factors for and clinical manifestations of cardiovascular disease. It is unknown whether these factors explain the high mortality rate associated with abdominal aortic aneurysm. OBJECTIVE: To describe the risk for mortality, cardiovascular mortality, and cardiovascular morbidity in persons screened for abdominal aortic aneurysm. DESIGN: Longitudinal cohort study. SETTING: Four communities in the United States. PARTICIPANTS: 4734 men and women older than 65 years of age recruited from Medicare eligibility lists. MEASUREMENTS: Abdominal ultrasonography was used to measure the aortic diameter and the ratio of infrarenal to suprarenal measurement of aortic diameter in 1992-1993. Abdominal aortic aneurysm was defined as aortic diameter of 3 cm or greater or infrarenal-to-suprarenal ratio of 1.2 or greater. Mortality, cardiovascular disease mortality, incident cardiovascular disease, and repair or rupture were assessed after 4.5 years. RESULTS: The prevalence of aneurysm was 8.8%, and 87.7% of aneurysms were 3.5 cm or less in diameter. Rates of total mortality (65.1 vs. 32.8 per 1000 person-years), cardiovascular mortality (34.3 vs. 13.8 per 1000 person-years), and incident cardiovascular disease (47.3 vs. 31.0 per 1000 person-years) were higher in participants with aneurysm than in those without aneurysm; after adjustment for age, risk factors, and presence of other cardiovascular disease, the respective relative risks were 1.32, 1.36, and 1.57. Rates of repair and rupture were low. CONCLUSIONS: Rates of total mortality, cardiovascular disease mortality, and incident cardiovascular disease were higher in participants with abdominal aortic aneurysm than in those without aneurysm, independent of age, sex, other clinical cardiovascular disease, and extent of atherosclerosis detected by noninvasive testing. Persons with smaller aneurysms detected by ultrasonography should be advised to modify risk factors for cardiovascular disease while under surveillance for increase in the size of the aneurysm.

Predictors of loss of lung function in the elderly: the Cardiovascular Health Study.

Pulmonary function, as measured by spirometry (FEV1 or FVC), is an important independent predictor of morbidity and mortality in elderly persons. In this study we examined the predictors of longitudinal decline in lung function for participants of the Cardiovascular Health Study (CHS). The CHS was started in 1990 as a population-based observational study of cardiovascular disease in elderly persons. Spirometry testing was conducted at baseline, 4 and 7 yr later. The data were analyzed using a random effects model (REM) including an AR(1) error structure. There were 5,242 subjects (57.6% female, mean age 73 yr, 87.5% white and 12.5% African-American) with eligible FEV1 measures representing 89% of the baseline cohort. The REM results showed that African-Americans had significantly lower spirometry levels than whites but that their rate of decline with age was significantly less. Subjects reporting congestive heart failure (CHF), high systolic blood pressure (> 160 mm Hg), or taking beta-blockers had significantly lower spirometry levels; however, the effects of high blood pressure and taking beta-blockers diminished with increasing age. Chronic bronchitis, pneumonia, emphysema, and asthma were associated with reduced spirometry levels. The most notable finding of these analyses was that current smoking (especially for men) was associated with more rapid rates of decline in FVC and FEV1. African-Americans (especially women) had slower rates of decline in FEV1 than did whites. Although participants with current asthma had a mean 0.5 L lower FEV1 at their baseline examination, they did not subsequently experience more rapid declines in FEV1.

Incidence and correlates of hypertension in the Atherosclerosis Risk in Communities (ARIC) study and the Monitoring Trends and Determinants of Cardiovascular Disease (POL-MONICA) project.

OBJECTIVE: The purpose of this research is to assess short-term blood pressure change and hypertension incidence, and identify correlates of incident hypertension in the USA and Poland. DESIGN AND METHODS: Population-based samples aged 45-64 years at enrollment from the Atherosclerosis Risk in Communities (ARIC) and the Pol-MONICA studies: including 3777 whites from Minneapolis, Minnesota, USA suburbs (urban), 3635 whites from Washington County, Maryland, USA (semi-rural) and 3109 blacks from Jackson, Mississippi, USA surveyed in 1987-1989 and 1990-1992; and 389 persons from Warsaw, Poland (urban) and 322 from Tarnobrzeg Province, Poland (semi-rural) surveyed in 1987-1988 and 1992-1993. RESULTS: Age-standardized systolic and diastolic blood pressures at both screens were 9-20 and 5-9 mmHg higher in the Polish samples than in US blacks, who had higher levels than US whites. Age-adjusted annual hypertension incidence in both Polish male cohorts (6-8%) was higher than that in US white men (4%) and approaching that of US black men (7%); rates were also higher in Polish female cohorts (8-9%) than in US black women (8%), but nearly twice those in US white women (4%). Factors independently related to hypertension incidence included age, family history, smoking, baseline blood pressures and body mass index, and increase in body mass index and alcohol consumption between screenings. After adjustment for these factors, annualized hypertension incidence was similar in US white and Polish men (2.3 and 2.7%) compared with US black men (3.4%), and in US white and Polish women (1.5 and 1.3%) compared with US black women (3.9%). CONCLUSIONS: Despite substantial differences in blood pressure levels and age-standardized hypertension incidence rates, the differences in incidence between Polish and US white men appear to be explained largely by differences in risk factors for hypertension.

Clinical correlates of ventricular and sulcal size on cranial magnetic resonance imaging of 3,301 elderly people. The Cardiovascular Health Study. Collaborative Research Group.

To identify potential risk factors for and clinical manifestations of ventricular and sulcal enlargement on cranial magnetic resonance imaging (MRI), 3,301 community-dwelling people 65 years or older without a history of stroke or transient ischemic attack underwent extensive standardized evaluations and MRI. In the multivariate model, increased age and white matter grade on MRI were the dominant risk factors for ventricular and sulcal grade. For ventricular grade, other than race, for which non-Blacks had higher grades, models for men and women shared no other factors. For sulcal grades, models for men and women shared variables reflecting cigarette smoking and diabetes. Clinical features were correlated more strongly with ventricular than sulcal grade and more strongly for women than men. Significant age-adjusted correlations between ventricular grade and the Digit-Symbol Substitution Test were found for men and women. Prospective studies will be needed to extend findings of this cross-sectional analysis.

Prevalence, predisposing factors, and prognosis of clinically unrecognized myocardial infarction in the elderly.

OBJECTIVES: This study was designed to determine the prevalence of unrecognized myocardial infarction (UMI), as well as risk factors, and to compare prognosis after detection of previously UMI to that after recognized myocardial infarction (RMI). BACKGROUND: Past studies revealed that a significant proportion of MIs escape recognition, and that prognosis after such events is poor, but the epidemiology of UMI has not been reassessed in the contemporary era. METHODS: The Cardiovascular Health Study (CHS) database, composed of individuals > or =65, was queried for participants who, at entry, demonstrated electrocardiographic evidence of a prior Q-wave MI, but who lacked a history of this diagnosis. The features and outcomes of this group were compared to those of individuals with prevalent RMI. RESULTS: Of 5,888 participants, 901 evidenced a past MI, and 201 (22.3%) were previously unrecognized. The independent predictors of UMI were the absence of angina and the absence of congestive heart failure (CHF). Six-year mortality did not significantly differ between the two groups. CONCLUSIONS: 1) In the elderly, UMI continues to represent a significant proportion of all MIs; 2) associations with angina and CHF may reflect complex neurological issues, but they also may represent diagnosis bias; 3) these individuals can otherwise not be distinguished from those with recognized infarctions; and 4) mortality rates after UMI and RMI are similar. Future studies should address screening for UMI, risk stratification after detection of previously UMI, and the role of standard post-MI therapies.

Association of lipids and lipoprotein level with total mortality and mortality caused by cardiovascular and cancer diseases (Poland and United States collaborative study on cardiovascular epidemiology).

This study evaluates the relation between total serum cholesterol, triglycerides, and high-density lipoprotein (HDL) cholesterol, and subsequent total, cardiovascular, and cancer mortality. These data are from 4,946 US and 5,198 Polish men and women aged 35 to 64 years at baseline with mortality follow-up over 13 years. Total cholesterol showed a U-shaped or J-shaped relation to age-adjusted total and cancer mortality across all samples, with significance only in Polish women. The multivariable adjusted relative risk for total and cancer mortality was higher in the lowest cholesterol category only in Poland and significant only for cancer. Cardiovascular mortality was positively related to cholesterol, but only in Polish men and US women was mortality significantly higher in the highest versus the lowest cholesterol category. The multivariable adjusted relative risk of cardiovascular death was greater in the highest versus the lowest cholesterol category, but this trend was significant only in the US. HDL cholesterol was inversely related to total (significant only in US men) and cardiovascular mortality (significant only in US and Polish men). A similar, but not significant, association of HDL cholesterol was found with cancer mortality. The multivariable adjusted relative risk of total mortality was inversely related to HDL cholesterol significant in both the US and Poland. The relative risk of cardiovascular mortality was significantly lower at higher HDL cholesterol levels in all samples. The relative risk of cancer mortality was highest and significant at the lowest HDL cholesterol level in the US and Poland. Elevated triglycerides were associated with increased risk of total and cardiovascular mortality, but this trend was significant only in the US. Cancer mortality was not significantly related to triglycerides. The present study indicates that in geographically and culturally diverse populations, the relation of lipids with cardiovascular mortality is similar. The relation with total and cancer mortality varies by country, gender, and lipids. This suggests that relations of total and cancer mortality with lipids or lipoproteins are weaker than associations with cardiovascular mortality.

Anthropometric and physiologic correlates of mitral valve prolapse in a biethnic cohort of young adults: the CARDIA study.

OBJECTIVE: To describe the epidemiology of echocardiographic mitral valve prolapse (MVP) and its anthropometric, physiologic, and psychobehavioral correlates with a cross-sectional analysis at 4 urban clinical centers. PATIENTS: A biethnic, community-based sample of 4136 young (aged 23 to 35 years) adult participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study who had echocardiograms during their third examination between 1990 and 1991. MEASUREMENTS: Echocardiographic mitral valve prolapse, Doppler mitral regurgitation, blood pressure, anthropometry, and 4 psychobehavioral scales. RESULTS: Definite echocardiographic MVP prevalence was 0.6% overall and was similar across the 4 ethnicity/sex groups. Most participants (21 of 26, 80%) with definite echocardiographic MVP were unaware of their condition. Relative to persons with normal echocardiograms, those with echocardiographic MVP were taller (174.6 cm vs 171.0 cm, P <.01), leaner (26.7 mm vs 37.4 mm sum of triceps and subscapular skinfolds, P <.01), had lower body mass index (22.0 kg/m(2) vs 26.2 kg/m(2), P <.01), and more often has Doppler mitral regurgitation (34.8% vs 11. 8%, P <.01). Women with echocardiographic MVP had higher ethnicity-adjusted hostility scores (19.9 vs 16.1, P <.05) than women with no MVP. Among 111 (2.7%) of 4136 participants reporting prior physician diagnosis of MVP, only 5 (0.45%) of 111 had definite echocardiographic MVP. CONCLUSIONS: These data document a low prevalence of definite echocardiographic MVP and suggest a constellation of anthropometric, physiologic, and psychobehavioral characteristics in young adults with echocardiographic MVP. Most definite echocardiographic MVP diagnoses were discordant with self-reported MVP status, and false-positive diagnoses of echocardiographic MVP were made more often in women and whites.

Temporal trends in the use of anticoagulants among older adults with atrial fibrillation.

BACKGROUND: Several recent randomized clinical trials have demonstrated that warfarin sodium treatment, and to a lesser extent aspirin, reduces risk of stroke and death compared with placebo in persons with atrial fibrillation. Insufficient documentation exists on the extent to which the use of these therapies following trial publications has continued to increase in the elderly with atrial fibrillation. METHODS: We used data from the Cardiovascular Health Study, a study of 5888 community-dwelling adults aged 65 years or older, to determine the prevalence of warfarin and aspirin use in persons with electrocardiogram-identified atrial fibrillation. Electrocardiogram examinations were conducted at baseline from 1989 through 1990, and at 6 subsequent annual examinations through 1995-1996. Medication data were collected by inventory methods at each examination. Temporal change in use of anticoagulants was analyzed by comparing percentage use in 1990 to use in each year through 1996. RESULTS: The use of warfarin increased 4-fold from 13% in 1990 to 50% in 1996 among participants with prevalent atrial fibrillation (P<.001). Daily use of aspirin did not increase over time. Participants younger than 80 years were 4 times more likely to use warfarin in 1996 (P<.001) than those 80 years and older. Use of aspirin did not vary significantly with age. CONCLUSIONS: Warfarin use in community-dwelling elderly persons with electrocardiogram-documented atrial fibrillation increased steadily following the first publication of its treatment benefit, reaching 50% by 1996. In contrast, use of aspirin was unchanged during this same period. Continued efforts to promote appropriate anticoagulation therapy to physicians and their patients may still be needed.

The role of APOE epsilon4 in modulating effects of other risk factors for cognitive decline in elderly persons.

CONTEXT: Cognitive decline in elderly persons is often an early predictor of dementia. Subclinical cardiovascular disease (CVD) and diabetes mellitus may contribute to substantial decline in cognitive function in the elderly. These risks may be modified by gene-environment interactions between apolipoprotein E (APOE) genotype and CVD risk factors or subclinical CVD. OBJECTIVES: To examine the association between subclinical CVD and decline in cognitive functioning in the elderly and to examine effect modification by the APOE genotype of the association between subclinical disease and cognitive decline. DESIGN: The Cardiovascular Health Study, a population-based, prospective cohort study. SETTING AND POPULATION: A total of 5888 randomly selected Medicare-eligible participants from Sacramento County, California; Forsyth County, North Carolina; Washington County, Maryland; and Pittsburgh, Pa, aged 65 years or older, who were recruited in 1989-1990 (n = 5201) and in 1992-1993 (n = 687) and who were followed up for 7 and 5 years, respectively. MAIN OUTCOME MEASURES: Change over time in scores on the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test as a function of APOE genotype, subclinical CVD, and diabetes mellitus. RESULTS: Seventy percent of participants had no significant decline on the Modified Mini-Mental State Examination. Systolic blood pressure, the ankle-arm brachial index, atherosclerosis of the internal carotid artery, diabetes mellitus, and several diagnoses of prevalent CVD were significantly associated with declines in scores on the Modified Mini-Mental State Examination and the Digit Symbol Substitution Test. The rate of cognitive decline associated with peripheral vascular disease, atherosclerosis of the common and internal carotid arteries, or diabetes mellitus was increased by the presence of any APOE epsilon4 allele. CONCLUSIONS: Most healthy elderly people did not experience cognitive decline. Measures of subclinical CVD were modest predictors of cognitive decline. Those with any APOE epsilon4 allele in combination with atherosclerosis, peripheral vascular disease, or diabetes mellitus were at substantially higher risk of cognitive decline than those without the APOE epsilon4 allele or subclinical CVD. High levels of atherosclerosis increased cognitive decline independently of APOE genotype.