Lewis H. Kuller

Relation of Apolipoprotein E Phenotype to Myocardial Infarction and Mortality from Coronary Artery Disease

The apolipoprotein E polymorphism is a genetic determinant of low-density lipoprotein (LDL) cholesterol. Its status as a risk factor for coronary artery disease (CAD), either through a causal relation with LDL cholesterol level or independently, is less clearly established. Data from the Multiple Risk Factor Intervention Trial were used to examine the influence of apolipoprotein E phenotype on risk of coronary events. Of the 12,866 randomized participants, 619 were studied in a nested case-control design. CAD deaths (93) and nonfatal myocardial infarctions (113) were matched to 412 controls. The allele frequencies of apolipoprotein E in the white subset (epsilon 2 = 0.06, epsilon 3 = 0.79, and epsilon 4 = 0.15) were very similar to other nonselected white American populations, and the relation of apolipoprotein E on total and LDL cholesterol was generally similar to that seen in other studies, with the epsilon 2 allele being associated with lower and the epsilon 4 allele with higher total and LDL cholesterol. Allele frequencies were not the same for patients and control subjects. The presence of epsilon 4 was associated with an increased risk of CAD that was most evident for fatal cases. There was no relation between changes in LDL cholesterol over time during the trial and apolipoprotein E phenotypes.

Total and cardiovascular mortality in relation to cigarette smoking serum cholesterol concentration and diastolic blood pressure among black and white males followed up for five years

The Multiple Risk Factor Intervention Trial screening program provided an opportunity (1) to study the association of diastolic blood pressure level, serum cholesterol concentration, and cigarettes per day with all-cause and cause-specific mortality after 5 years among 23,490 black males and (2) to compare these associations with those observed among 325,384 white males. The relationship of serum cholesterol concentration and reported cigarettes per day to all-cause, coronary heart disease (CHD), and cerebrovascular disease mortality was similar for black and white males. Diastolic blood pressure was more positively associated with cerebrovascular disease death among black males than white males (p = 0.047) according to logistic regression analysis. The lower CHD mortality among black males compared to white males was most apparent among hypertensive males (diastolic blood pressure greater than or equal to 90 mm Hg). The relative risk (black vs white) of CHD death adjusted for age, serum cholesterol concentration, and cigarettes per day was 0.69 for hypertensive males compared to 1.15 for nonhypertensive males (p = 0.012 for difference in relative risk estimates). These findings suggest that the causes of CHD and cerebrovascular disease may be different for black and white males, particularly in regard to how these disease processes relate to blood pressure.

Impact of weight loss on plasminogen activator inhibitor (PAI-1), factor VII, and other hemostatic factors in moderately overweight adults.

Based on previous cross-sectional findings, we hypothesized that weight loss could improve several hemostatic factors associated with cardiovascular disease. In a randomized controlled trial, moderately overweight men and women were assigned to one of four weight loss treatment groups or to a control group. Measurements of plasminogen activator inhibitor-1 (PAI-1) antigen, tissue-type plasminogen activator (t-PA) antigen, D-dimer antigen, factor VII activity, fibrinogen, and protein C antigens were made at baseline and after 6 months in 90 men and 88 women. Net treatment weight loss was 9.4 kg in men and 7.4 kg in women. There was no net change (p > 0.05) in D-dimer, fibrinogen, or protein C with weight loss. Significant (p < 0.05) decreases were observed in the combined treatment groups compared with the control group for mean PAI-1 (31% decline), t-PA antigen (24% decline), and factor VII (11% decline). Decreases in these hemostatic variables were correlated with the amount of weight lost and the degree that plasma triglycerides declined; these correlations were stronger in men than women. These findings suggest that weight loss can improve abnormalities in hemostatic factors associated with obesity.

Alcohol Consumption and Risk of Coronary Heart Disease in Older Adults: The Cardiovascular Health Study

OBJECTIVES: To evaluate several aspects of the relationship between alcohol use and coronary heart disease in older adults, including beverage type, mediating factors, and type of outcome.

Racial differences in high-density lipoprotein cholesterol and coronary heart disease incidence in the usual-care group of the multiple risk factor intervention trial

To test the hypothesis that higher levels of high-density lipoprotein cholesterol (HDL-C) in black men than in white men may offer the former greater protection against coronary heart disease (CAD), the relation between HDL-C and 7-year incidence of CAD was examined in the 5,792 white men and in the 465 black men assigned to the usual-care group of the Multiple Risk Factor Intervention Trial. CAD events included nonfatal myocardial infarction diagnosed on the basis of serial electrocardiographic change or medical record review, and fatal CAD events including sudden CAD deaths, deaths attributed to myocardial infarction or congestive heart failure caused by CAD, and deaths associated with coronary artery bypass surgery. At baseline, mean diastolic blood pressure and prevalence of cigarette smoking were significantly higher in black men, but the reverse was true for serum cholesterol (246 vs 254 mg/dl, p less than 0.01). Mean HDL-C was higher in black men than in white men (49.3 vs 41.6 mg/dl, p less than 0.01), but low-density lipoprotein cholesterol (LDL-C) levels were similar (159 vs 160 mg/dl). An inverse association between HDL-C and socioeconomic status was observed in black men, whereas a direct association was observed in white men. During follow-up, small reductions occurred in HDL-C and LDL-C in both groups. No black men died of stroke; 16 black and 404 white men sustained CAD events (5.1 vs 10.4/1,000 person-years of risk). The black-white relative risk was 0.49 (p = 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Risk Factors for the Development of Type II Diabetes Among Men Enrolled in the Usual Care Group of the Multiple Risk Factor Intervention Trial

OBJECTIVE To study the association between selected risk factors and the subsequent incidence of type II diabetes over a 5-yr period. RESEACH DESIGN AND METHODS Between 1973 and 1976, a cohort of men from 22 clinical centers throughout the U.S. enrolled in the Usual Care group of the Multiple Risk Factor Intervention Trial. The men (5420 white, 428 black, 56 Asian, 70 Hispanic, and 26 other) were nondiabetic at baseline, were in the upper 15% of risk for coronary heart disease, and had at least two annual follow-up visits for fasting glucose measurements. The average age was 46 yr and average body mass index was 27.6 kg/m . Incidence of diabetes was defined as use of insulin or hypoglycemic agents, fasting glucose ≥140 mg/dl on two consecutive annual visits, or fasting glucose ≥ 140 mg/dl followed the next year by insulin or hypoglycemic use. Observations were taken annually over a 5-yr period. RESULTS Cumulative incidence of diabetes over 5 yr was 4.1%, with 247 incident cases. Development of diabetes was directly associated with race (blacks higher than non-blacks), reported parental history of diabetes, and with baseline levels of body mass index, fasting glucose, and glucose 1 h after a 75-g oral glucose load. These associations were statistically significant in both univariate and multivariate models. A significant interaction was observed between race and reported parental history of diabetes in development of diabetes, particularly within black men who reported a parental history. These individuals had higher than expected rates of diabetes development. CONCLUSIONS The data from men in the Usual Care group enrolled in the Multiple Risk Factor Intervention Trial confirm previous findings regarding the associations between the development of diabetes and baseline glucose levels, obesity, race, and parental history of diabetes. The identification of these risk factors provides very powerful tools to identify individuals at high risk of diabetes mellitus who may be amenable to intervention, thereby reducing their risk of developing the disease and its complications.

Measures of adiposity and future risk of ischemic stroke and coronary heart disease in older men and women

The relation between measures of general and central adiposity and individual cardiovascular endpoints remains understudied in older adults. This study investigated the association of measures of body size and composition with incident ischemic stroke or coronary heart disease (1989-2007) in 3,754 community-dwelling US adults aged 65-100 years. Standardized anthropometry and bioelectric impedance measurements were obtained at baseline. Body mass index at age 50 years (BMI50) was calculated on the basis of recalled weight. Although only waist/hip ratio was significantly associated with ischemic stroke in quintile analysis in women, dichotomized body mass index (BMI) (≥ 30 kg/m²) was the only significant predictor in men. For coronary heart disease, there were significant positive adjusted associations for all adiposity measures, without interaction by sex. This was true for both quintiles and conventional cutpoints for obesity, although BMI-defined overweight (25-29.9 kg/m² was significant at midlife but not at baseline. Strengths of association for extreme quintiles (quintile 5 vs. quintile 1) were broadly comparable, but the highest effect estimates were for waist/hip ratio (hazard ratio = 1.56, 95% confidence interval: 1.25, 1.94) and BMI50 (hazard ratio = 1.71, 95% confidence interval: 1.37, 2.14), both of which remained significant after adjustment for mediators, BMI, or each other. Whether these differences translate to better risk prediction will require meta-analytical approaches, as will determination of prognostic cutpoints.

Greater adipose tissue infiltration in skeletal muscle among older men of African ancestry

CONTEXTnThere is substantial variability across ethnic groups in the predisposition to obesity and associated metabolic abnormalities. Skeletal muscle fat has been identified as an important depot that increases with aging and may contribute to the development of diabetes.nnnOBJECTIVEnWe tested whether men of African ancestry have greater calf intermuscular adipose tissue (IMAT), compared to Caucasian men, and whether IMAT is associated with type 2 diabetes (T2D).nnnDESIGNnWe measured fasting serum glucose, body mass index, total body fat by dual-energy x-ray absorptiometry, and calf skeletal muscle composition by quantitative computed tomography in 1105 Caucasian and 518 Afro-Caribbean men aged 65+.nnnRESULTSnCompared to Caucasian men, we found greater IMAT and lower sc adipose tissue in Afro-Caribbean men at all levels of total adiposity (P < 0.0001), including the subset of men matched on age and dual-energy x-ray absorptiometry total body fat percentage (P < 0.001). In addition, IMAT was 29 and 23% greater, whereas sc adipose tissue was 6 and 8% lower among Caucasian and Afro-Caribbean men with T2D, respectively, compared to men without T2D (P < 0.01). Observed differences in intermuscular and sc fat, both ethnic and between men with and without T2D, were independent of age, height, calf skeletal muscle and total adipose tissue, and lifestyle factors.nnnCONCLUSIONSnOur analyses suggest that despite lower total adiposity, skeletal muscle fat infiltration is greater among African than among Caucasian ancestry men and is associated with T2D in both ethnic groups. Additional studies are needed to determine the mechanisms contributing to ethnic differences in skeletal muscle adiposity and to define the metabolic and health implications of this fat depot.