Ronald J. Prineas

DIETARY ANTIOXIDANT VITAMINS AND DEATH FROM CORONARY HEART DISEASE IN POSTMENOPAUSAL WOMEN

Background. The role of dietary antioxidant vitamins in preventing coronary heart disease has aroused considerable interest because of the knowledge that ox- idative modification of low-density lipoprotein may pro- mote atherosclerosis. Methods. We studied 34,486 postmenopausal wom- en with no cardiovascular disease who in early 1986 com- pleted a questionnaire that assessed, among other fac- tors, their intake of vitamins A, E, and C from food sources and supplements. During approximately seven years of follow-up (ending December 31, 1992), 242 of the women died of coronary heart disease. Results. In analyses adjusted for age and dietary en- ergy intake, vitamin E consumption appeared to be in- versely associated with the risk of death from coronary heart disease. This association was particularly striking in the subgroup of 21,809 women who did not consume vitamin supplements (relative risks from lowest to highest quintile of vitamin E intake, 1.0, 0.68, 0.71, 0.42, and 0.42; P for trend � 0.008). After adjustment for possible con- founding variables, this inverse association remained (rel- ative risks from lowest to highest quintile, 1.0, 0.70, 0.76, 0.32, and 0.38; P for trend � 0.004). There was little evi- dence that the intake of vitamin E from supplements was associated with a decreased risk of death from coronary heart disease, but the effects of high-dose supplementa- tion and the duration of supplement use could not be de- finitively addressed. Intake of vitamins A and C did not appear to be associated with the risk of death from cor- onary heart disease. Conclusions. These results suggest that in postmeno- pausal women the intake of vitamin E from food is inverse- ly associated with the risk of death from coronary heart disease and that such women can lower their risk without using vitamin supplements. By contrast, the intake of vita- mins A and C was not associated with lower risks of dying from coronary disease. (N Engl J Med 1996;334:1156-62.)

Common variants at ten loci modulate the QT interval duration in the QTSCD Study

The QT interval, a measure of cardiac repolarization, predisposes to ventricular arrhythmias and sudden cardiac death (SCD) when prolonged or shortened. A common variant in NOS1AP is known to influence repolarization. We analyze genome-wide data from five population-based cohorts (ARIC, KORA, SardiNIA, GenNOVA and HNR) with a total of 15,842 individuals of European ancestry, to confirm the NOS1AP association and identify nine additional loci at P < 5 × 10−8. Four loci map near the monogenic long-QT syndrome genes KCNQ1, KCNH2, SCN5A and KCNJ2. Two other loci include ATP1B1 and PLN, genes with established electrophysiological function, whereas three map to RNF207, near LITAF and within NDRG4-GINS3-SETD6-CNOT1, respectively, all of which have not previously been implicated in cardiac electrophysiology. These results, together with an accompanying paper from the QTGEN consortium, identify new candidate genes for ventricular arrhythmias and SCD.

Echocardiographic correlates of left ventricular structure among 844 mildly hypertensive men and women in the Treatment of Mild Hypertension Study (TOMHS).

BackgroundEchocardiography provides a noninvasive means of assessing left ventricular (LV) structure and evidence of LV wall remodeling in hypertensive persons. The relation of demographic, biological, and other factors with LV structure can be assessed. Methods and ResultsLV structure was assessed by M-mode echocardiograms for 511 men and 333 women with mild hypertension (average blood pressure, 140/91 mm Hg). Measurements ofLV wall thicknesses and internal dimensions were made, and estimates of LV mass indexes and other derivations of structure were calculated. LV hypertrophy criteria were based on previously reported echocardiographic population studies of normal subjects. These measures were compared by age, sex, race, body mass index, systolic blood pressure, antihypertensive drug use, physical activity, alcohol intake, cigarette smoking, and urinary sodium excretion. Despite virtual absence of ECG-determined LV hypertrophy, 13% of men and 20%o ofwomen had echocardiographically determined LV hypertrophy indexed by body surface area (g/m2), and 24% of men and 45% of women had LV hypertrophy indexed by height (g/m). Black participants had slightly higher mean levels of wall thickness than nonblack participants but similar LV mass. Systolic blood pressure and urinary sodium excretion were significantly and independently associated with LV mass index and LV hypertrophy using both g/m2 and g/m. Body mass index was significantly related to LV mass index and LV hypertrophy using g/m. Smoking was significantly associated with LV mass index, i.e., using continuous measurement but not using the dichotomy for LV hypertrophy. ConclusionThis study of a large population of men and women with mild primary hypertension, largely without ECG evidence of LV hypertrophy, showed a substantial percentage of participants with echocardiographically determined LV hypertrophy. LV mass indexes correlated positively with systolic blood pressure, body mass index, urinary sodium excretion, and smoking.

Increased incidence of diabetes mellitus in relation to abdominal adiposity in older women.

The relationship between body fat distribution, measured by the ratio of waist-to-hip circumferences (WHR), and the 2 year incidence of diabetes mellitus was examined in a cohort of 41,837 women aged 55-69 years. The 399 women who reported the new onset of diabetes had a significantly greater mean body mass index (kg/m2) and WHR than non-cases. After adjustment for body mass index (BMI), age and education level using multivariate logistic regression, WHR was a significant independent predictor of diabetes in a dose-response fashion. Cases were 4.6 times (95% CI = 3.8, 5.6) more likely than non-cases to be in the upper tertile of WHR and 2.2 times (95% CI = 1.8, 2.7) more likely to be in the middle tertile. Women in the highest tertiles of both WHR and BMI had a 14.4-fold (95% CI = 9.5, 21.9) higher risk of diabetes than women in the lowest tertiles. These results demonstrate that increased abdominal adiposity is a significant independent risk factor for the development of diabetes mellitus in older women.

Central adiposity and increased risk of coronary artery disease mortality in older women

The relation between central adiposity, measured by the waist/hip circumference ratio (WHR), and 4-year risk of fatal coronary artery disease was examined in a large cohort (n = 32,898) of women aged 55 to 69 years. The age-adjusted relative risk of death from coronary artery disease (115 deaths) was 3.3 for women in the highest tertile of WHR compared to the lowest tertile (95% confidence interval: 2.0, 5.6). After adjustment for age, body mass, smoking, physical activity, estrogen use, marital status, and alcohol intake, the relative risk of coronary death for women in the middle and highest tertiles versus those in the lowest tertile of WHR were 1.3 and 2.8, respectively (P for linear trend < 0.001). Further adjustment for hypertension and diabetes mellitus reduced the estimates slightly to 1.2 and 2.0, but the trend in relative risk remained statistically significant (P = 0.03). In contrast, body mass index showed no independent association with coronary death. Hypertension, diabetes mellitus, cigarette smoking, estrogen nonuse, and being unmarried were significant predictors of greater risk of coronary death in the multivariate model. These results indicate that central adiposity, reflected by an increased WHR, is an important risk factor for death from coronary artery disease in women, most of whom were postmenopausal. The association of central adiposity with risk of coronary death is independent, for the most part, of its association with hypertension and diabetes.

Sudden death and acute myocardial infarction in a metropolitan area, 1970-1980. The Minnesota Heart Survey

To determine the causes of the nationwide decline in deaths due to coronary heart disease, the Minnesota Heart Survey enumerated coronary deaths among persons 30 to 74 years old in Minneapolis-St. Paul. The survey also ascertained rates of hospitalization and case fatality during hospitalization for acute myocardial infarction. For deaths occurring between 1970 and 1978 that were due to coronary heart disease, the rates outside the hospital declined by 43 per cent in men and 40 per cent in women, and the rates in hospital emergency rooms increased by 311 per cent in men and 200 per cent in women. In both these years about two thirds of all such deaths occurred outside hospital wards. Between 1970 and 1980, hospitalization rates for acute infarction in persons 30 to 74 years old declined 8 per cent among men and 26 per cent among women, and case fatality in the hospital in persons 45 to 74 years old declined 29 per cent in men and 27 per cent in women. These changes are probably due to the combined influence of changes in risk factors in the population and improved care of patients with acute myocardial infarction before and during hospitalization.

Associations of abdominal adiposity, fasting insulin, sex hormone binding globulin, and estrone with lipids and lipoproteins in post-menopausal women

The associations of abdominal adiposity, fasting serum levels of insulin, and sex hormones with blood lipids, lipoproteins, and apolipoproteins A-I and B were studied cross-sectionally in 75 healthy, postmenopausal white women. In univariate analyses, abdominal adiposity (increased waist-to-hip girth ratio) and fasting insulin concentrations were negatively and significantly associated (P less than 0.05) with plasma high density lipoprotein cholesterol (r = -0.47 and -0.38, respectively) and apolipoprotein A-I (r = -0.37 and -0.36), and positively associated with log triglycerides (r = 0.54 and 0.33) and apolipoprotein B (r = 0.43 and 0.22). Sex hormone binding globulin was positively and significantly associated with high density lipoprotein cholesterol (r = 0.32) and negatively associated with log triglyceride (r = -0.45) and apolipoprotein B (r = -0.36). Estrone was positively and significantly associated with high density lipoprotein cholesterol (r = 0.27), apolipoprotein A-I (r = 0.23) and negatively associated with low density lipoprotein cholesterol (r = -0.24) and apolipoprotein B (r = -0.25). Total estradiol, free estradiol, free testosterone, and total testosterone were more weakly associated with the lipid measures. In multivariate analyses, abdominal adiposity remained significantly associated with high density lipoprotein cholesterol, log triglycerides, apolipoproteins A-I and B after adjustment for sex hormone binding globulin, estrone, and insulin concentrations. Insulin remained associated only with apolipoprotein A-I after adjustment for abdominal adiposity, estrone, and sex hormone binding globulin. Sex hormone binding globulin remained marginally associated with log triglyceride (P = 0.07) after adjustment for the remaining three factors. Estrone remained significantly associated with high density lipoprotein cholesterol.(ABSTRACT TRUNCATED AT 250 WORDS)

Genome-wide association analysis identifies multiple loci related to resting heart rate

Higher resting heart rate is associated with increased cardiovascular disease and mortality risk. Though heritable factors play a substantial role in population variation, little is known about specific genetic determinants. This knowledge can impact clinical care by identifying novel factors that influence pathologic heart rate states, modulate heart rate through cardiac structure and function or by improving our understanding of the physiology of heart rate regulation. To identify common genetic variants associated with heart rate, we performed a meta-analysis of 15 genome-wide association studies (GWAS), including 38,991 subjects of European ancestry, estimating the association between age-, sex- and body mass-adjusted RR interval (inverse heart rate) and approximately 2.5 million markers. Results with P < 5 × 10(-8) were considered genome-wide significant. We constructed regression models with multiple markers to assess whether results at less stringent thresholds were likely to be truly associated with RR interval. We identified six novel associations with resting heart rate at six loci: 6q22 near GJA1; 14q12 near MYH7; 12p12 near SOX5, c12orf67, BCAT1, LRMP and CASC1; 6q22 near SLC35F1, PLN and c6orf204; 7q22 near SLC12A9 and UfSp1; and 11q12 near FADS1. Associations at 6q22 400 kb away from GJA1, at 14q12 MYH6 and at 1q32 near CD34 identified in previously published GWAS were confirmed. In aggregate, these variants explain approximately 0.7% of RR interval variance. A multivariant regression model including 20 variants with P < 10(-5) increased the explained variance to 1.6%, suggesting that some loci falling short of genome-wide significance are likely truly associated. Future research is warranted to elucidate underlying mechanisms that may impact clinical care.

Cigarette Smoking, Alcohol Use, and Physical Activity in Relation to Serum Leptin Levels in a Multiethnic Population: The Miami Community Health Study

PURPOSE To examine the correlates of plasma leptin, including fasting insulin, adiposity, and several health habits and behaviors among a nondiabetic multiethnic population. METHODS A cross-sectional study was conducted among 25-44 year old African-Americans (n = 126), Cuban-Americans (n = 107), and non-Hispanic whites (n = 189) randomly selected from Dade County Florida. Fasting leptin levels were correlated with fasting insulin, percent body fat, smoking, alcohol use, and physical activity within each sex. Multiple linear regression and analysis of covariance were used to estimate the independent determinants of plasma leptin concentration separately among men and women. RESULTS Stepwise linear regression analyses revealed statistically significant associations of leptin with percent body fat, fasting insulin, cigarette smoking, and physical activity (both inversely) among men (p < 0.05 for each). Among women, percent body fat, fasting insulin (both positively), cigarette smoking, and alcohol use (inversely) were independent predictors of leptin levels explaining over 70% of the variance. Analyses of covariance revealed that women had higher adjusted mean leptin levels than men (13.1 ng/ml vs. 5.9 ng/ml; p < 0.001), whereas no separate effect of ethnicity was noted. CONCLUSIONS Although adiposity was the strongest correlate of leptin levels, fasting insulin and several health habits and behaviors were independently associated with leptin. After adjustment for these factors, women had significantly higher mean leptin levels than men. The independent association among leptin and insulin levels is intriguing and suggests additional avenues for epidemiologic research.

The Influence of Oral Potassium Chloride on Blood Pressure in Hypertensive Men on a Low-Sodium Diet

Clinical and epidemiologic studies suggest that the intake of potassium chloride lowers blood pressure. To investigate whether supplemental potassium chloride (96 mmol of microcrystalline potassium chloride a day) reduced the need for antihypertensive medication in hypertensive men on a restricted-sodium diet, we conducted a randomized, placebo-controlled, double-blind clinical trial. A total of 287 men 45 to 68 years of age, 142 given potassium chloride and 145 given placebo, were followed for an average of 2.2 years after the withdrawal of their antihypertensive medication. Men in both groups received instructions on following a low-sodium diet. Overnight urinary sodium excretion fell from 63 mmol per eight hours at base line to an average of 45 mmol per eight hours during follow-up. Participants given supplemental potassium chloride had significantly higher (P less than 0.001) serum potassium levels and urinary potassium excretion (averaging 4.5 mmol per liter and 42.5 mmol per eight hours, respectively) during follow-up than participants given placebo (4.2 mmol per liter and 20.0 mmol per eight hours). Seventy-nine participants in each group required reinstitution of antihypertensive medication according to strict indications defined by the protocol. No significant differences in systolic or diastolic blood pressure were observed between the two groups. During follow-up, systolic and diastolic blood pressure averaged 130.6 and 82.5 mm Hg, respectively, for participants given supplemental potassium, and 132.5 and 83.1 mm Hg for participants given placebo. We conclude that supplemental potassium chloride does not reduce the need for antihypertensive medication in hypertensive men on a restricted-sodium diet.