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.

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.

Genetic variation among 82 pharmacogenes: The PGRNseq data from the eMERGE network.

Genetic variation can affect drug response in multiple ways, although it remains unclear how rare genetic variants affect drug response. The electronic Medical Records and Genomics (eMERGE) Network, collaborating with the Pharmacogenomics Research Network, began eMERGE-PGx, a targeted sequencing study to assess genetic variation in 82 pharmacogenes critical for implementation of "precision medicine." The February 2015 eMERGE-PGx data release includes sequence-derived data from ∼5,000 clinical subjects. We present the variant frequency spectrum categorized by variant type, ancestry, and predicted function. We found 95.12% of genes have variants with a scaled Combined Annotation-Dependent Depletion score above 20, and 96.19% of all samples had one or more Clinical Pharmacogenetics Implementation Consortium Level A actionable variants. These data highlight the distribution and scope of genetic variation in relevant pharmacogenes, identifying challenges associated with implementing clinical sequencing for drug treatment at a broader level, underscoring the importance for multifaceted research in the execution of precision medicine.

Blood pressure response during treadmill testing as a risk factor for new-onset hypertension. The Framingham heart study.

BACKGROUND: Although systolic blood pressure (SBP) response to exercise has been shown to predict subsequent hypertension in small samples of men, this association has not been studied in a large population-based sample of middle-aged men and women. The purpose of this study was to examine, in normotensive subjects, the relations of SBP and diastolic blood pressure (DBP) during the exercise and recovery periods of a graded treadmill test to the risk of developing new-onset hypertension. METHODS AND RESULTS: BP data from exercise testing in 1026 men and 1284 women (mean age, 42+/-10 years; range, 20 to 69 years) from the Framingham Offspring Study who were normotensive at baseline were related to the incidence of hypertension 8 years later. New-onset hypertension, defined as an SBP >/=140 mm Hg or DBP >/=90 mm Hg or the initiation of antihypertensive drug treatment, occurred in 228 men (22%) and 207 women (16%). Exaggerated SBP (Ex-SBP 2) and DBP (Ex-DBP 2) response and delayed recovery of SBP (R-SBP 3) and DBP (R-DBP 3) were defined as an age-adjusted BP greater than the 95th percentile during the second stage of exercise and third minute of recovery, respectively. After multivariable adjustment, Ex-DBP 2 was highly predictive of incident hypertension in both men (OR, 4.16; 95% CI, 2.15, 8.05) and women (OR, 2.17; CI, 1.19, 3.96). R-SBP 3 was predictive of hypertension in men in a multivariable model that included exercise duration and peak exercise BP (OR, 1.92; CI, 1.00, 3.69). Baseline resting SBP (chi2, 23.4 in men and 34.7 in women) and DBP (chi2, 11.3 in men and 13.1 in women) had stronger associations with new-onset hypertension than exercise DBP (chi2, 16.4 in men and 6.1 in women) and recovery SBP (chi2, 6.5 in men and 2.1 in women) responses. CONCLUSIONS: An exaggerated DBP response to exercise was predictive of risk for new-onset hypertension in normotensive men and women. An elevated recovery SBP was predictive of hypertension in men. These findings may reflect subtle pathophysiological features in the preclinical stage of hypertension.

Cardiac function in smokers and nonsmokers: the CARDIA study. The Coronary Artery Risk Development in Young Adults Study.

OBJECTIVES: This study assessed clinical and echocardiographic measures of cardiac function at rest in smokers and nonsmokers to determine the associations of cigarette smoking with various measures of left and right ventricular performance. BACKGROUND: Whereas the immediate cardiovascular effects of cigarette smoking have been well described, the long-term effects in an otherwise healthy cohort have not. Of particular interest were associations with heart rate, left ventricular end-systolic stress and left ventricular mass because higher levels of these measures would suggest increased myocardial oxygen consumption. METHODS: In year 5 of the Coronary Artery Risk Development in Young Adults (CARDIA) study, 3,366 smokers and nonsmokers (ex-smokers were excluded) underwent echocardiography as well as assessment of heart rate, anthropometric measurements and blood pressure. Participants ranged in age from 23 to 35 years and were equally distributed by race and gender. Echocardiographic measures included pulsed Doppler pulmonary artery acceleration time (a decrease suggests increased pulmonary artery pressure), left ventricular mass, left ventricular end-systolic stress and left ventricular fractional shortening. RESULTS: All comparisons were between smokers and nonsmokers. Heart rate at rest was significantly higher in smokers by 1.5 to 5 beats/min in all race/gender groups except black men. In men who smoked, pulmonary artery acceleration time was significantly lower by 4 to 8 ms. Except for black male smokers, there was a trend toward increased left ventricular mass (3 to 8 g) in all race/gender groups, significant in black women. Left ventricular end-systolic stress was significantly higher in women who smoked (4 to 6 dynes/cm2). There were no differences for systolic blood pressure or left ventricular fractional shortening. CONCLUSION: In an assessment of cardiovascular function at rest in young adults, quantifiable differences between smokers and nonsmokers that predict increased rest myocardial oxygen consumption in smokers were found. Some of these differences were gender specific.

Lung function and pulmonary regurgitation limit exercise capacity in postoperative tetralogy of Fallot.

Fifty-five patients with repair of tetralogy of Fallot were evaluated with treadmill exercise, pulmonary function testing and rest two-dimensional and Doppler echocardiography to determine the relation among cardiopulmonary function, exercise capacity and ventricular arrhythmias. The mean age at repair was 8.1 +/- 2.1 years; age at the time of study ranged from 15 to 37 years (mean follow-up time after repair 18 +/- 5 years). Exercise duration was 92 +/- 17% of predicted. Maximal heart rate was 94 +/- 7% of predicted. No exercise test was stopped because of an arrhythmia. Thirty patients had oxygen consumption and ventilation measured during their final minute of exercise. Peak oxygen consumption was 31 +/- 8 ml/kg per min (86 +/- 18% of predicted). Twenty-five patients (45%) had low vital capacity at rest (less than 80% of predicted). Pulmonary regurgitation was identified in 42 (75%) of the patients and judged to be moderate in 10 (18%). Mild tricuspid valve regurgitation was identified in 64%. Doppler estimated right ventricular outflow gradient was greater than 15 mm Hg in 15% of the patients (mean gradient 24 mm Hg [range 16 to 56]). Age at repair, duration of follow-up and type of repair did not correlate with echocardiographic variables, ventilatory data, exercise performance or arrhythmias. Moderate pulmonary regurgitation was associated with increased right ventricular diastolic area and both were inversely related to exercise duration and vital capacity. Decreased breathing reserve during maximal exercise was associated with moderate pulmonary regurgitation and decreased vital capacity. The results indicate that exercise capacity in these patients is in general good; however, right ventricular volume loading and ventilatory dysfunction may produce exercise limitation.

Relation of alcohol intake to left ventricular mass: The Framingham Study.

Alcohol has direct toxic effects on the myocardium and is associated with elevated blood pressure, but its relation to left ventricular mass independent of blood pressure level has not been assessed. Reported alcohol intake and left ventricular mass measured by echocardiography were evaluated in 1,980 men and 2,511 women 17 to 90 years of age and free of cardiovascular disease in the Framingham offspring and cohort study. The relation of reported alcohol intake to left ventricular mass was assessed by gender-specific multivariate regression analysis adjusting for age, height, body mass index, systolic blood pressure, history of hypertension and cigarette smoking. Alcohol intake was positively associated with left ventricular mass in men (p less than 0.01) but not in women (p = 0.64). When stratified by beverage type, beer and wine in both men and women and liquor in men were positively related to left ventricular mass. The lack of association of total alcohol intake to left ventricular mass in women appeared to be due to a negative association (p less than 0.01) with liquor. The strongest positive associations were with wine in men (p less than 0.001) and beer in women (p less than 0.05). Alcohol use is independently associated with left ventricular mass; this association may vary by beverage type. In persons with unexplained left ventricular hypertrophy, excessive alcohol intake should be considered.

Cardiac arrhythmias on 24-h ambulatory electrocardiography in older women and men: the Cardiovascular Health Study.

OBJECTIVES: This study describes the prevalence and correlates of cardiac arrhythmias in older persons. BACKGROUND: Cardiac arrhythmias are frequent in selected samples of elderly persons, but their prevalence and association with cardiovascular disease and its risk factors have not been examined in a large population-based sample. METHODS: In 1,372 participants in the Cardiovascular Health Study, a population-based study of cardiovascular disease risk factors, 24-h ambulatory electrocardiography was performed. RESULTS: Serious arrhythmias, such as sustained ventricular tachycardia and complete atrioventricular block, were uncommon, but brief episodes of ventricular tachycardia (> or = 3 consecutive ventricular depolarizations) were detected in 4.3% of women and 10.3% of men. Ventricular arrhythmias as a group (excluding ectopic beats < 15/h) were more common in men than in women but were not significantly associated with age. The same patterns were true for bradycardia/conduction blocks. Supraventricular arrhythmias as a group (excluding ectopic beats < 15/h), in contrast, did not differ by gender but were strongly associated with increased age. Multivariate analyses showed associations with arrhythmias to differ by gender, with only one association (increased age and supraventricular arrhythmias) present in both women and men. Ventricular arrhythmias, particularly in men, were associated with a higher prevalence of cardiovascular disease and its risk factors and with subclinical disease, as measured by increased left ventricular mass and impaired left ventricular function. CONCLUSIONS: Arrhythmias are common in the elderly, and their association with cardiovascular disease differs by gender. Although risk related to arrhythmias can only be determined by prospective study, such studies should have adequate power to examine potential gender differences in associations.

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.

Trends in pharmacologic management of hypertension in the United States.

BACKGROUND: Two new classes of antihypertensive agents were introduced in the 1980s, but their effectiveness in preventing heart disease and stroke has not been demonstrated. Lack of evidence of their efficacy might reasonably be expected to discourage their widespread use in management of hypertension. METHODS: Use of various classes of antihypertensive agents was estimated from published drug use information in an effort to estimate trends in antihypertensive drug use and evaluate the impact of these trends on costs of antihypertensive therapy in the United States. RESULTS: Proportionate use of the five major antihypertensive drug classes shifted markedly between 1982 and 1993. Diuretics accounted for 56% of all hypertensive drug mentions in 1982 but only 27% in 1993, a relative decline of 52%. Use of beta-blockers and central agents also declined during this period. Proportionate use of calcium antagonists showed the greatest gains, increasing from 0.3% to 27%, while the use of angiotensin-converting enzyme inhibitors increased from 0.8% to 24%. Given the higher costs of the newer agents, and assuming an estimated total cost of antihypertensive medications in 1992 of $7 billion, approximately $3.1 billion would have been saved had 1982 prescribing practices remained in effect in 1992. CONCLUSIONS: Use of calcium antagonists and angiotensin-converting enzyme inhibitors in hypertension has increased dramatically in the past 10 years. Without convincing evidence of the advantages of these agents, it is difficult to explain the continued decline in the use of less expensive agents, such as diuretics and beta-blockers, which are the only antihypertensive agents proved to reduce stroke and coronary disease in hypertensive patients.

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.

Properties of the random zero sphygmomanometer.

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

Utility of new electrocardiographic models for left ventricular mass in older adults. The Cardiovascular Health Study Collaborative Research Group.

Several multivariate statistical models have recently been introduced for estimation of left ventricular mass from standard 12-lead electrocardiographic measurements. The validity of these algorithms has not been adequately evaluated. The objective of this investigation was to compare the associations between echocardiographic and electrocardiographic left ventricular mass values with clinical and subclinical indexes of coronary heart disease. The evaluation was performed with participants of the Cardiovascular Health Study, a population-based sample of 5201 men and women aged 65 years and older. Echocardiographic M-mode measurements of left ventricular mass were performed from videotape recordings with the use of a strictly standardized protocol. Electrocardiographic algorithms of the Novacode program and new algorithms derived from the Cardiovascular Health Study population were used for left ventricular mass prediction. Echocardiographic and electrocardiographic determinations of left ventricular mass were technically successful in 3410 (65.6%) and 5013 (96.4%) participants, respectively. The Novacode model overestimated echocardiographic left ventricular mass. Compared with the Novacode model, the new Cardiovascular Health Study electrocardiographic model, which includes adjustment for body weight, eliminated left ventricular mass prediction bias and improved the correlation between echocardiographic and electrocardiographic left ventricular mass from .33 to .54 in women and from .46 to .51 in men. Echocardiographic and electrocardiographic models both demonstrated similar and about equally strong associations with overt and subclinical disease and with risk factors for left ventricular hypertrophy. These observations demonstrate the potential utility of electrocardiographic models for left ventricular mass estimation.

Meat consumption and its associations with other diet and health factors in young adults: the CARDIA study.

Using cross-sectional data from the longitudinal Coronary Artery Risk Development in Young Adults (CARDIA) study, we assessed associations between meat consumption and other dietary- and health-status indicators. Less than one percent of this sample (n = 32) ate no red meat or poultry, and another 1% (n = 47) ate red meat or poultry less than once per week. Individuals who ate red meat and poultry less than once per week were less likely to drink alcohol (P = 0.003); reported more physical activity (P less than or equal to 0.001); had lower [corrected] Keys scores (P less than or equal to 0.001); consumed diets higher in carbohydrates, starch, fiber, vitamins A and C, and calcium and lower in energy, fat, and protein (P less than or equal to 0.001); had smaller body sizes as indicated by the body mass index [calculated as wt(kg)/ht(m2)] (P = 0.01); and had lower concentrations of total serum cholesterol (P = 0.001), low-density-lipoprotein cholesterol (P = 0.001), and triglycerides (P = 0.015) compared with individuals who consumed meat more frequently.

Lacunar infarcts defined by magnetic resonance imaging of 3660 elderly people: the Cardiovascular Health Study.

OBJECTIVE: To identify risk factors for and functional consequences of lacunar infarct in elderly people. METHODS: The Cardiovascular Health Study (CHS) is a longitudinal study of people 65 years or older, in which 3660 participants underwent cranial magnetic resonance imaging (MRI). Neuroradiologists read scans in a standard fashion without any clinical information. Lacunes were defined as subcortical areas consistent with infarcts measuring 3 to 20 mm. In cross-sectional analyses, clinical correlates were contrasted among groups defined by MRI findings. RESULTS: Of the 3660 subjects who underwent MRI, 2529 (69%) were free of infarcts of any kind and 841 (23%) had 1 or more lacunes without other types present, totaling 1270 lacunes. For most of these 841 subjects, their lacunes were single (66%) and silent (89%), namely without a history of transient ischemic attack or stroke. In multivariate analyses, factors independently associated with lacunes were increased age, diastolic blood pressure, creatinine, and pack-years of smoking (listed in descending order of strength of association; for all, P < .005), as well as maximum internal carotid artery stenosis of more than 50% (odds ratio [OR], 1.81; P < .005), male sex (OR, 0.74; P < .005), and history of diabetes at entrance into the study (OR, 1.33; P < .05). Models for subgroups of single, multiple, silent, and symptomatic lacunes differed only minimally. Those with silent lacunes had more cognitive, upper extremity, and lower extremity dysfunction not recognized as stroke than those whose MRIs were free of infarcts. CONCLUSIONS: In this group of older adults, lacunes defined by MRI are common and associated with factors that likely promote or reflect small-vessel disease. Silent lacunes are also associated with neurologic dysfunction.

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.

Silent MRI infarcts and the risk of future stroke: the cardiovascular health study.

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.

Lack of association of the plasminogen activator inhibitor-1 4G/5G promoter polymorphism with cardiovascular disease in the elderly.

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.

Oral anticoagulation in patients with atrial fibrillation: adherence with guidelines in an elderly cohort.

PURPOSE: To determine adherence with practice guidelines in a population-based cohort of elderly persons aged 70 years or older with atrial fibrillation. SUBJECTS AND METHODS: This was a cross-sectional analysis of a subgroup of participants in the Cardiovascular Health Study, a prospective observational study involving four communities in the United States. Subjects were participants with atrial fibrillation on electrocardiogram at one or more yearly examinations from 1993 to 1995. The outcome measure was self-reported use of warfarin in 1995. RESULTS: In 1995, 172 (4.1%) participants had atrial fibrillation together with information regarding warfarin use and no preexisting indication for its use. Warfarin was used by 63 (37%) of these participants. Of the 109 participants not reporting warfarin use, 92 (84%) had at least one of the clinical risk factors (aside from age) associated with stroke in patients with atrial fibrillation. Among participants not taking warfarin, 47% were taking aspirin. Several characteristics were independently associated with warfarin use, including age [odds ratio (OR) = 0.6 per 5-year increment, 95% CI 0.5-0.9], a modified mini-mental examination score <85 points [OR = 0.3, 95% confidence interval (CI) 0.1-0.9], and among patients without prior stroke, female sex (OR = 0.5, 95% CI 0.2-1.0). CONCLUSIONS: Despite widely publicized practice guidelines to treat patients who have atrial fibrillation with warfarin, most participants who had atrial fibrillation were at high risk for stroke but were not treated with warfarin. More studies are needed to determine why elderly patients with atrial fibrillation are not being treated with warfarin.

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.