Eyal Shahar

HYPERTENSION AND ANTIHYPERTENSIVE THERAPY AS RISK FACTORS FOR TYPE 2 DIABETES MELLITUS

BACKGROUND Previous research has suggested that thiazide diuretics and beta-blockers may promote the development of type 2 diabetes mellitus. However, the results of previous studies have been inconsistent, and many studies have been limited by inadequate data on outcomes and by potential confounding. METHODS We conducted a prospective study of 12,550 adults 45 to 64 years old who did not have diabetes. An extensive health evaluation conducted at base line included assessment of medication use and measurement of blood pressure with a random-zero sphygmomanometer. The incidence of new cases of diabetes was assessed after three years and after six years by measurement of serum glucose concentrations while the subjects were fasting. RESULTS After simultaneous adjustment for age, sex, race, education, adiposity, family history with respect to diabetes, physical-activity level, other health-related behavior, and coexisting illnesses, subjects with hypertension who were taking thiazide diuretics were not at greater risk for the subsequent development of diabetes than were subjects with hypertension who were not receiving any antihypertensive therapy (relative hazard, 0.91; 95 percent confidence interval, 0.73 to 1.13). Likewise, subjects who were taking angiotensin-converting-enzyme inhibitors and calcium-channel antagonists were not at greater risk than those not taking any medication. In contrast, subjects with hypertension who were taking beta-blockers had a 28 percent higher risk of subsequent diabetes (relative hazard, 1.28; 95 percent confidence interval, 1.04 to 1.57). CONCLUSIONS Concern about the risk of diabetes should not discourage physicians from prescribing thiazide diuretics to nondiabetic adults who have hypertension. The use of beta-blockers appears to increase the risk of diabetes, but this adverse effect must be weighed against the proven benefits of beta-blockers in reducing the risk of cardiovascular events.

Prospective Study of Obstructive Sleep Apnea and Incident Coronary Heart Disease and Heart Failure The Sleep Heart Health Study

Background— Clinic-based observational studies in men have reported that obstructive sleep apnea is associated with an increased incidence of coronary heart disease. The objective of this study was to assess the relation of obstructive sleep apnea to incident coronary heart disease and heart failure in a general community sample of adult men and women. Methods and Results— A total of 1927 men and 2495 women ≥40 years of age and free of coronary heart disease and heart failure at the time of baseline polysomnography were followed up for a median of 8.7 years in this prospective longitudinal epidemiological study. After adjustment for multiple risk factors, obstructive sleep apnea was a significant predictor of incident coronary heart disease (myocardial infarction, revascularization procedure, or coronary heart disease death) only in men ≤70 years of age (adjusted hazard ratio 1.10 [95% confidence interval 1.00 to 1.21] per 10-unit increase in apnea-hypopnea index [AHI]) but not in older men or in women of any age. Among men 40 to 70 years old, those with AHI ≥30 were 68% more likely to develop coronary heart disease than those with AHI <5. Obstructive sleep apnea predicted incident heart failure in men but not in women (adjusted hazard ratio 1.13 [95% confidence interval 1.02 to 1.26] per 10-unit increase in AHI). Men with AHI ≥30 were 58% more likely to develop heart failure than those with AHI <5. Conclusions— Obstructive sleep apnea is associated with an increased risk of incident heart failure in community-dwelling middle-aged and older men; its association with incident coronary heart disease in this sample is equivocal.

Sleep-disordered breathing and mortality: A prospective cohort study

In a cohort of 6,441 volunteers followed over an average of 8.2 years, Naresh Punjabi and colleagues find sleep-disordered breathing to be independently associated with mortality and identify predictive characteristics.

Obstructive sleep apnea-hypopnea and incident stroke: the sleep heart health study.

RATIONALE Although obstructive sleep apnea is associated with physiological perturbations that increase risk of hypertension and are proatherogenic, it is uncertain whether sleep apnea is associated with increased stroke risk in the general population. OBJECTIVES To quantify the incidence of ischemic stroke with sleep apnea in a community-based sample of men and women across a wide range of sleep apnea. METHODS Baseline polysomnography was performed between 1995 and 1998 in a longitudinal cohort study. The primary exposure was the obstructive apnea-hypopnea index (OAHI) and outcome was incident ischemic stroke. MEASUREMENTS AND MAIN RESULTS A total of 5,422 participants without a history of stroke at the baseline examination and untreated for sleep apnea were followed for a median of 8.7 years. One hundred ninety-three ischemic strokes were observed. In covariate-adjusted Cox proportional hazard models, a significant positive association between ischemic stroke and OAHI was observed in men (P value for linear trend: P = 0.016). Men in the highest OAHI quartile (>19) had an adjusted hazard ratio of 2.86 (95% confidence interval, 1.1-7.4). In the mild to moderate range (OAHI, 5-25), each one-unit increase in OAHI in men was estimated to increase stroke risk by 6% (95% confidence interval, 2-10%). In women, stroke was not significantly associated with OAHI quartiles, but increased risk was observed at an OAHI greater than 25. CONCLUSIONS The strong adjusted association between ischemic stroke and OAHI in community-dwelling men with mild to moderate sleep apnea suggests that this is an appropriate target for future stroke prevention trials.

Recent trends in acute coronary heart disease : Mortality, morbidity, medical care, and risk factors

BACKGROUND Mortality from coronary heart disease (CHD) has declined in the United States since the late 1960s. To understand the reasons for the decline during the period form 1985 to 1990, we examined trends in mortality and morbidity due to CHD, medical care, and risk factors for CHD in a large metropolitan population. METHODS We identified all deaths from CHD in residents of the Minneapolis-St. Paul, Minnesota, metropolitan area who were 30 to 74 years old and classified the deaths according to whether they occurred in or out of the hospital. For 1985 and 1990, we obtained lists of patients in this age range who were discharged with a diagnosis of acute CHD from all area hospitals, and we selected the medical records of 50 percent of these patients for abstraction. Definite myocardial infarctions were identified with standardized diagnostic algorithm. The 1985 and 1990 cohorts of patients hospitalized for myocardial infarction were followed for at least three years to identify those who died from any cause. Trends in risk factors for CHD were investigated through surveys of 25-to-74-year-olds that were conducted in 1985 through 1987 and 1990 through 1992. RESULTS Between 1985 and 1990, mortality from CHD fell by 25 percent for both men and women, and the decline in in-hospital mortality (41 percent) exceeded the decline in out-of-hospital mortality (17 percent) among men. The rates of hospitalization for acute myocardial infarction declined slightly, by 5 to 10 percent, between 1985 and 1990. Survival among patients hospitalized for acute myocardial infarction increased substantially during that period. After adjustment for age and previous myocardial infarction, the relative risk of dying within three years of hospitalization for a myocardial infarction (for the 1990 cohort as compared with the 1985 cohort) was 0.76 for men (95 percent confidence interval, 0.65 to 0.89) and 0.84 for women (95 percent confidence interval, 0.71 to 1.00). Substantial increases in the use of thrombolytic therapy, heparin, aspirin, and coronary angioplasty paralleled the survival trends. In general, the risk-factor profile of the area population with respect to CHD also improved considerably during that time. CONCLUSIONS The recent decline in mortality due to CHD in the Minneapolis-St. Paul metropolitan area can be explained by both the declining incidence of myocardial infarction in the population and the improved survival of patients with myocardial infarction.

Stroke Incidence and Survival Among Middle-Aged Adults 9-Year Follow-Up of the Atherosclerosis Risk in Communities (ARIC) Cohort

BACKGROUND AND PURPOSE Although stroke mortality rates in the United States are well documented, assessment of incidence rates and case fatality are less well studied. METHODS A cohort of 15 792 men and women aged 45 to 64 years from a population sample of households in 4 US communities was followed from 1987 to 1995, an average of 7. 2 years. Incident strokes were identified through annual phone contacts and hospital record searching and were then validated. RESULTS Of the 267 incident definite or probable strokes, 83% (n=221) were categorized as ischemic strokes, 10% (n=27) were intracerebral hemorrhages, and 7% (n=19) were subarachnoid hemorrhages. The age-adjusted incidence rate (per 1000 person-years) of total strokes was highest among black men (4.44), followed by black women (3.10), white men (1.78), and white women (1.24). The black versus white age-adjusted rate ratio (RR) for ischemic stroke was 2.41 (95% CI, 1.85 to 3.15), which was attenuated to 1.38 (95% CI, 1.01 to 1.89) after adjustment for baseline hypertension, diabetes, education level, smoking status, and prevalent coronary heart disease. There was a tendency for the adjusted case fatality rates to be higher among blacks and men, although none of the case fatality comparisons across sex or race was statistically significant. CONCLUSIONS After accounting for established baseline risk factors, blacks still had a 38% greater risk of incident ischemic stroke compared with whites. Identification of new individual and community-level risk factors accounting for the elevated incidence of stroke requires further investigation and incorporation into intervention planning.

Retinal microvascular abnormalities and incident stroke: the Atherosclerosis Risk in Communities Study

BACKGROUND Retinal microvascular abnormalities reflect damage from hypertension and other vascular processes. We examined the relation of such abnormalities to incident stroke. METHODS A cohort of 10358 men and women (aged 51 to 72 years) living in four US communities underwent retinal photography and standard grading for retinal microvascular abnormalities. The calibres of all retinal arterioles and venules were measured after digital conversion of the photographs, and a summary arteriole-to-venule ratio (AVR) was calculated as an index of arteriolar narrowing (smaller AVR indicates greater narrowing). Cases of incident stroke admitted to hospital were identified and validated by case record reviews. FINDINGS Over an average of 3.5 years, 110 participants had incident strokes. After adjustment for age, sex, race, 6-year mean arterial blood pressure, diabetes, and other stroke risk factors, most retinal microvascular characteristics were predictive of incident stroke, with adjusted relative risks of 2.58 (1.59-4.20) for any retinopathy, 3.11 (1.71-5.65) for microaneurysms, 3.08 (1.42-6.68) for soft exudates, 2.55 (1.27-5.14) for blot haemorrhages, 2.26 (1.00-5.12) for flame-shaped haemorrhages, and 1.60 (1.03-2.47) for arteriovenous nicking. The relative risk of stroke increased with decreasing AVR (p=0.03). The associations were similar for ischaemic strokes specifically, and for strokes in individuals with hypertension, either with or without diabetes. INTERPRETATION Retinal microvascular abnormalities are related to incident stroke. The findings support a microvascular role in the pathogenesis of stroke. They suggest that retinal photography may be useful for cerebrovascular-risk stratification in appropriate populations.

Ethnic Differences in Coronary Calcification The Multi-Ethnic Study of Atherosclerosis (MESA)

Background—There is substantial evidence that coronary calcification, a marker for the presence and quantity of coronary atherosclerosis, is higher in US whites than blacks; however, there have been no large population-based studies comparing coronary calcification among US ethnic groups. Methods and Results—Using computed tomography, we measured coronary calcification in 6814 white, black, Hispanic, and Chinese men and women aged 45 to 84 years with no clinical cardiovascular disease who participated in the Multi-Ethnic Study of Atherosclerosis (MESA). The prevalence of coronary calcification (Agatston score >0) in these 4 ethnic groups was 70.4%, 52.1%, 56.5%, and 59.2%, respectively, in men (P<0.001) and 44.6%, 36.5%, 34.9%, and 41.9%, respectively, (P<0.001) in women. After adjustment for age, education, lipids, body mass index, smoking, diabetes, hypertension, treatment for hypercholesterolemia, gender, and scanning center, compared with whites, the relative risks for having coronary calcification were 0.78 (95% CI 0.74 to 0.82) in blacks, 0.85 (95% CI 0.79 to 0.91) in Hispanics, and 0.92 (95% CI 0.85 to 0.99) in Chinese. After similar adjustments, the amount of coronary calcification among those with an Agatston score >0 was greatest among whites, followed by Chinese (77% that of whites; 95% CI 62% to 96%), Hispanics (74%; 95% CI 61% to 90%), and blacks (69%; 95% CI 59% to 80%). Conclusions—We observed ethnic differences in the presence and quantity of coronary calcification that were not explained by coronary risk factors. Identification of the mechanism underlying these differences would further our understanding of the pathophysiology of coronary calcification and its clinical significance. Data on the predictive value of coronary calcium in different ethnic groups are needed.

Recent trends in acute coronary heart disease

BACKGROUND Mortality from coronary heart disease (CHD) has declined in the United States since the late 1960s. To understand the reasons for the decline during the period form 1985 to 1990, we examined trends in mortality and morbidity due to CHD, medical care, and risk factors for CHD in a large metropolitan population. METHODS We identified all deaths from CHD in residents of the Minneapolis-St. Paul, Minnesota, metropolitan area who were 30 to 74 years old and classified the deaths according to whether they occurred in or out of the hospital. For 1985 and 1990, we obtained lists of patients in this age range who were discharged with a diagnosis of acute CHD from all area hospitals, and we selected the medical records of 50 percent of these patients for abstraction. Definite myocardial infarctions were identified with standardized diagnostic algorithm. The 1985 and 1990 cohorts of patients hospitalized for myocardial infarction were followed for at least three years to identify those who died from any cause. Trends in risk factors for CHD were investigated through surveys of 25-to-74-year-olds that were conducted in 1985 through 1987 and 1990 through 1992. RESULTS Between 1985 and 1990, mortality from CHD fell by 25 percent for both men and women, and the decline in in-hospital mortality (41 percent) exceeded the decline in out-of-hospital mortality (17 percent) among men. The rates of hospitalization for acute myocardial infarction declined slightly, by 5 to 10 percent, between 1985 and 1990. Survival among patients hospitalized for acute myocardial infarction increased substantially during that period. After adjustment for age and previous myocardial infarction, the relative risk of dying within three years of hospitalization for a myocardial infarction (for the 1990 cohort as compared with the 1985 cohort) was 0.76 for men (95 percent confidence interval, 0.65 to 0.89) and 0.84 for women (95 percent confidence interval, 0.71 to 1.00). Substantial increases in the use of thrombolytic therapy, heparin, aspirin, and coronary angioplasty paralleled the survival trends. In general, the risk-factor profile of the area population with respect to CHD also improved considerably during that time. CONCLUSIONS The recent decline in mortality due to CHD in the Minneapolis-St. Paul metropolitan area can be explained by both the declining incidence of myocardial infarction in the population and the improved survival of patients with myocardial infarction.

Genomewide Association Studies of Stroke

BACKGROUND The genes underlying the risk of stroke in the general population remain undetermined. METHODS We carried out an analysis of genomewide association data generated from four large cohorts composing the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, including 19,602 white persons (mean [+/-SD] age, 63+/-8 years) in whom 1544 incident strokes (1164 ischemic strokes) developed over an average follow-up of 11 years. We tested the markers most strongly associated with stroke in a replication cohort of 2430 black persons with 215 incident strokes (191 ischemic strokes), another cohort of 574 black persons with 85 incident strokes (68 ischemic strokes), and 652 Dutch persons with ischemic stroke and 3613 unaffected persons. RESULTS Two intergenic single-nucleotide polymorphisms on chromosome 12p13 and within 11 kb of the gene NINJ2 were associated with stroke (P<5x10(-8)). NINJ2 encodes an adhesion molecule expressed in glia and shows increased expression after nerve injury. Direct genotyping showed that rs12425791 was associated with an increased risk of total (i.e., all types) and ischemic stroke, with hazard ratios of 1.30 (95% confidence interval [CI], 1.19 to 1.42) and 1.33 (95% CI, 1.21 to 1.47), respectively, yielding population attributable risks of 11% and 12% in the discovery cohorts. Corresponding hazard ratios were 1.35 (95% CI, 1.01 to 1.79; P=0.04) and 1.42 (95% CI, 1.06 to 1.91; P=0.02) in the large cohort of black persons and 1.17 (95% CI, 1.01 to 1.37; P=0.03) and 1.19 (95% CI, 1.01 to 1.41; P=0.04) in the Dutch sample; the results of an underpowered analysis of the smaller black cohort were nonsignificant. CONCLUSIONS A genetic locus on chromosome 12p13 is associated with an increased risk of stroke.