F. Javier Nieto

Neighborhood of Residence and Incidence of Coronary Heart Disease

BACKGROUND Where a person lives is not usually thought of as an independent predictor of his or her health, although physical and social features of places of residence may affect health and health-related behavior. METHODS Using data from the Atherosclerosis Risk in Communities Study, we examined the relation between characteristics of neighborhoods and the incidence of coronary heart disease. Participants were 45 to 64 years of age at base line and were sampled from four study sites in the United States: Forsyth County, North Carolina; Jackson, Mississippi; the northwestern suburbs of Minneapolis; and Washington County, Maryland. As proxies for neighborhoods, we used block groups containing an average of 1000 people, as defined by the U.S. Census. We constructed a summary score for the socioeconomic environment of each neighborhood that included information about wealth and income, education, and occupation. RESULTS During a median of 9.1 years of follow-up, 615 coronary events occurred in 13,009 participants. Residents of disadvantaged neighborhoods (those with lower summary scores) had a higher risk of disease than residents of advantaged neighborhoods, even after we controlled for personal income, education, and occupation. Hazard ratios for coronary events in the most disadvantaged group of neighborhoods as compared with the most advantaged group--adjusted for age, study site, and personal socioeconomic indicators--were 1.7 among whites (95 percent confidence interval, 1.3 to 2.3) and 1.4 among blacks (95 percent confidence interval, 0.9 to 2.0). Neighborhood and personal socioeconomic indicators contributed independently to the risk of disease. Hazard ratios for coronary heart disease among low-income persons living in the most disadvantaged neighborhoods, as compared with high-income persons in the most advantaged neighborhoods were 3.1 among whites (95 percent confidence interval, 2.1 to 4.8) and 2.5 among blacks (95 percent confidence interval, 1.4 to 4.5). These associations remained unchanged after adjustment for established risk factors for coronary heart disease. CONCLUSIONS Even after controlling for personal income, education, and occupation, we found that living in a disadvantaged neighborhood is associated with an increased incidence of coronary heart disease.

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.

Associations of ankle-brachial index with clinical coronary heart disease, stroke and preclinical carotid and popliteal atherosclerosis:: the Atherosclerosis Risk in Communities (ARIC) Study

The resting ankle-brachial index (ABI) is a non-invasive method to assess the patency of the lower extremity arterial system and to screen for the presence of peripheral occlusive arterial disease. To determine how the ABI is associated with clinical coronary heart disease (CHD), stroke, preclinical carotid plaque and far wall intimal-medial thickness (IMT) of the carotid and popliteal arteries, we conducted analyses in 15 106 middle-aged adults from the baseline examination (1987-1989) of the Atherosclerosis Risk in Communities (ARIC) Study. The prevalence of clinical CHD, stroke/transient ischemic attack (TIA) and preclinical carotid plaque increased with decreasing ABI levels, particularly at those of < 0.90. Individuals with ABI < 0.90 were twice as likely to have prevalent CHD as those with ABI > 0.90 (age-adjusted odds ratio (OR) ranging from 2.2 (95% CI: 1.0-5.1) in African-American men to 3.3 (95% CI: 2.1-5.0) in white men). Men with ABI < 0.90 were more than four times as likely to have stroke/TIA as those with ABI > 0.90 (age-adjusted OR: 4.2 (95% CI: 1.8-9.5) in African-American men and 4.9 (95% CI: 2.6-9.0) in white men). In women the association was weaker and not statistically significant. Among those free of clinical cardiovascular disease, individuals with ABI < or = 0.90 had statistically significantly higher prevalence of preclinical carotid plaque compared to those with ABI > 0.90 (age-adjusted ORs ranging from 1.5 (95% CI: 1.0-1.9) in white women to 2.6 (95% CI: 1.0-6.6) in african-american men). The ABI was also inversely associated with far wall IMT of the carotid arteries (in both men and women) and the popliteal arteries (in men only). The associations of ABI with clinical CHD, stroke, preclinical carotid plaque and IMT of the carotid and popliteal arteries were attenuated and often not statistically significant after further adjustment for LDL cholesterol, cigarette smoking, hypertension and diabetes. These data demonstrate that low ABI levels, particularly those of < 0.90, are indicative of generalized atherosclerosis.

Retinal Microvascular Abnormalities and their Relationship with Hypertension, Cardiovascular Disease, and Mortality

Retinal microvascular abnormalities, such as generalized and focal arteriolar narrowing, arteriovenous nicking and retinopathy, reflect cumulative vascular damage from hypertension, aging, and other processes. Epidemiological studies indicate that these abnormalities can be observed in 2-15% of the nondiabetic general population and are strongly and consistently associated with elevated blood pressure. Generalized arteriolar narrowing and arteriovenous nicking also appear to be irreversible long-term markers of hypertension, related not only to current but past blood pressure levels as well. There are data supporting an association between retinal microvascular abnormalities and stroke, but there is no convincing evidence of an independent or direct association with atherosclerosis, ischemic heart disease, or cardiovascular mortality. New computer-related imaging methods are currently being developed to detect the presence and severity of retinal arteriolar narrowing and other microvascular characteristics. When reliably quantified, retinal microvascular abnormalities may be useful as risk indicators for cerebrovascular diseases.

Prospective study of markers of hemostatic function with risk of ischemic stroke

BACKGROUND Several markers of hemostatic function and inflammation have been associated with increased risk of coronary heart disease, but prospective evidence for their role in ischemic stroke is scant. METHODS AND RESULTS The Atherosclerosis Risk in Communities (ARIC) Study measured several of these markers in more than 14 700 participants 45 to 64 years old who were free of cardiovascular disease and were followed up for 6 to 9 years for occurrence of ischemic stroke (n=191). There was no apparent association between ischemic stroke incidence and factor VIIc, antithrombin III, platelet count, or activated partial thromboplastin time. After adjustment for multiple cardiovascular risk factors, von Willebrand factor, factor VIIIc, fibrinogen, and white blood cell count were positively associated and protein C was negatively but nonsignificantly associated with ischemic stroke incidence in regression analyses based on either continuous variables or fourths of the variable distributions. The adjusted relative risk (and 95% CI) for ischemic stroke in those in the highest versus lowest fourth were: von Willebrand factor, 1.71 (1.1 to 2.7); factor VIIIc, 1.93 (1.2 to 3.1); white blood cell count, 1.50 (0.9 to 2.4); fibrinogen, 1.26 (0.8 to 2.0); and protein C, 0.65 (0.4 to 1.0). CONCLUSIONS This study offers modest support for the hypothesis that some markers of hemostatic function and inflammation can identify groups of middle-aged adults at increased risk of stroke. These factors may play a role in the pathogenesis of ischemic stroke.

Uric acid and serum antioxidant capacity: a reaction to atherosclerosis?

BACKGROUND the evidence of a potential beneficial role of antioxidants in preventing atherosclerotic disease is not entirely consistent. OBJECTIVE to assess the longitudinal association of serum total antioxidant capacity and serum antioxidants with the presence of subclinical carotid atherosclerosis. METHODS Prospective case-control study nested within an historical cohort. Cases were 150 individuals with elevated carotid intimal-medial thickness measured by B-mode ultrasound at the first two examinations of the Atherosclerosis Risk in Communities Study (1987-92). Controls were 150 age-gender-matched individuals with low carotid intimal-medial thickness. Serum antioxidant vitamins, uric acid, and serum total antioxidant capacity were measured in frozen serum samples collected from the same individuals in 1974 (13-15 years prior to the determination of case-control status). RESULTS Compared to controls, atherosclerosis cases had significantly higher levels of serum total antioxidant capacity in 1974 than controls. This difference was almost entirely explained by increased serum concentration of uric acid in cases. In contrast with cross-sectional results, uric acid serum concentration in 1974, was significantly higher in cases than in controls, even after adjusting for the main cardiovascular risk factors. Cases had significantly lower levels of alpha-carotene in the 1974 sera than controls, but no other differences in serum antioxidant vitamin concentrations were observed. CONCLUSIONS The higher serum uric acid concentration seemed associated with elevated total serum antioxidant capacity among individuals with atherosclerosis. This finding is consistent with experimental evidence suggesting that hyperuricemia may be a compensatory mechanism to counteract oxidative damage related to atherosclerosis and aging in humans.

Alcohol Consumption and the Incidence of Hypertension: The Atherosclerosis Risk in Communities Study

Abstract—A close relationship between alcohol consumption and hypertension has been established, but it is unclear whether there is a threshold level for this association. In addition, it has infrequently been studied in longitudinal studies and in black people. In a cohort study, 8334 of the Atherosclerosis Risk in Communities (ARIC) Study participants, aged 45 to 64 years at baseline, who were free of hypertension and coronary heart disease had their blood pressures ascertained after 6 years of follow-up. Alcohol consumption was assessed by dietary interview. The type of alcoholic beverage predominantly consumed was defined by the source of the largest amount of ethanol consumed. Incident hypertension was defined as a systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg or use of antihypertensive medication. There was an increased risk of hypertension in those who consumed large amounts of ethanol (≥210 g per week) compared with those who did not consume alcohol over the 6 years of follow-up. The adjusted odds ratios (95% confidence interval) were 1.2 (0.85 to 1.67) for white men, 2.02 (1.08 to 3.79) for white women, and 2.31 (1.11 to 4.86) for black men. Only 4 black women reported drinking >210 g ethanol per week. At low to moderate levels of alcohol consumption (1 to 209 g per week), the adjusted odds ratios (95% confidence interval) were 0.88 (0.71 to 1.08) in white men, 0.89 (0.73 to 1.09) in white women, 1.71 (1.11 to 2.64) in black men, and 0.88 (0.59 to 1.33) in black women. Systolic and diastolic blood pressures were higher in black men who consumed low to moderate amounts of alcohol compared with the nonconsumers but not in the 3 other race-gender strata. Models with polynomial terms of alcohol exposure suggested a nonlinear association in white and black men. Higher levels of consumption of all types of alcoholic beverages were associated with a higher risk of hypertension for all race-gender strata. The consumption of alcohol in amounts ≥210 g per week is an independent risk factor for hypertension in free-living North American populations. The consumption of low to moderate amounts of alcohol also appears to be associated with a higher risk of hypertension in black men.

Coronary heart disease risk prediction in the Atherosclerosis Risk in Communities (ARIC) study

Risk prediction functions for incident coronary heart disease (CHD) were estimated using data from the Atherosclerosis Risk in Communities (ARIC) Study, a prospective study of CHD in 15,792 persons recruited in 1987-1989 from four U.S. communities, with follow-up through 1998. Predictivity of which individuals had incident CHD was assessed by increase in area under ROC curves resulting from adding nontraditional risk factors and markers of subclinical disease to a basic model containing only traditional risk factors. We also assessed the increase in population attributable risk. The additional factors were body mass index; waist-hip ratio; sport activity index; forced expiratory volume; plasma fibrinogen, factor VIII, von Willebrand factor, and Lp(a); heart rate; Keys score; pack-years smoking; and subclinical disease marker carotid intima-media thickness. These factors substantially improved prediction of future CHD for men, less for women, and also increased attributable risks.

Prospective Study of Pathogen Burden and Risk of Myocardial Infarction or Death

Background—We previously demonstrated that the risk of coronary artery disease (CAD) increased in relation to the number of pathogens (the “pathogen burden”) in a cross-sectional study. In the present prospective study with a different patient cohort, we evaluated the effect of pathogen burden on the risk of myocardial infarction (MI) or death among CAD patients. Methods and Results—IgG antibodies to cytomegalovirus (CMV), hepatitis A virus (HAV), herpes simplex virus type 1 (HSV1), HSV type 2 (HSV2), Chlamydia pneumoniae and Helicobacter pylori, and C-reactive protein (CRP) levels were tested in baseline blood samples from 890 patients who had significant CAD on angiography. The mean follow-up period was 3 years. The baseline prevalence of antibodies directed against CMV, HAV, HSV1, or HSV2, but not C pneumoniae and H pylori, was significantly higher among patients who subsequently developed MI or death than among control subjects. After adjustment for traditional risk factors, number of diseased vessels, and clinical presentation, relative hazards (95% confidence limits) for MI or death were 2.0 (1.4 to 3.2) for CMV, 1.6 (1.1 to 2.3) for HAV, and 1.5 (1.0 to 2.2) for HSV2. Increasing pathogen burden was significantly associated with increasing risk of MI or death in a dose-response fashion. Adjusted relative hazards of MI or death associated with pathogen burden were significant among individuals with low or high CRP levels. Conclusions—The results suggest that infection plays an important role in incident MI or death and that the risk posed by infection is independently related to the pathogen burden.

Cohort Study of Cytomegalovirus Infection as a Risk Factor for Carotid Intimal-Medial Thickening, a Measure of Subclinical Atherosclerosis

BACKGROUND Animal studies as well as clinical and cross-sectional epidemiological studies in humans have suggested a possible role of cytomegalovirus (CMV) and other herpesvirus infections in the development of cardiovascular disease. METHODS AND RESULTS The present report is based on a case-control study nested within a historical cohort. The case group comprised 150 individuals with elevated carotid intimal-medial thickness (IMT) measured by B-mode ultrasound at the first two examinations of the Atherosclerosis Risk in Communities (ARIC) Study (1987 through 1992). The control group comprised 150 age- and sex-matched individuals with low IMT. Antibody titers for CMV and herpesvirus 1 and 2 were determined in sera obtained in 1974 as part of a community-wide survey conducted in Washington County, Maryland. Case subjects had higher mean CMV antibody titers in 1974 sera than control subjects, although the difference was not statistically significant when adjusted for other cardiovascular risk factors. There was evidence of a graded relation between the odds of intimal-medial thickening and the levels of CMV antibodies that remained significant after adjustment for the main cardiovascular risk factors (P = .013). The adjusted odds ratio for a high CMV antibody titer (a positive/negative value > or = 20) compared with a positive/negative value < 4 was 5.3 (95% confidence interval, 1.5 to 18.0). CONCLUSIONS The results from this first population-based cohort study of CMV infection and carotid IMT are compatible with the hypothesis of a causal role of CMV in atherosclerosis.