Although each of the major lipoprotein fractions is composed of various subclasses that may differ in atherogenicity, the importance of this heterogeneity has been difficult to ascertain owing to the labor-intensive nature of subclass measurement methods. We have recently developed a procedure, using proton nuclear magnetic resonance (NMR) spectroscopy, to simultaneously quantify levels of subclasses of very low density (VLDL), low density (LDL), and high density (HDL) lipoproteins; subclass distributions determined with this method agree well with those derived by gradient gel electrophoresis. The objective of the current study of 158 men was to examine whether NMR-derived lipoprotein subclass levels improve the prediction of arteriographically documented coronary artery disease (CAD) when levels of lipids and lipoproteins are known. We found that a global measure of CAD severity was positively associated with levels of large VLDL and small HDL particles and inversely associated with intermediate size HDL particles; these associations were independent of age and standard lipid measurements. At comparable lipid and lipoprotein levels, for example, men with relatively high (higher than the median) levels of either small HDL or large VLDL particles were three to four times more likely to have extensive CAD than were the other men; the 27 men with high levels of both large VLDL and small HDL were 15 times more likely to have extensive CAD than were men with low levels. In contrast, adjustment for levels of triglycerides or HDL cholesterol greatly reduced the relation of small LDL particles to CAD. These findings suggest that large VLDL and small HDL particles may play important roles in the development of occlusive disease and that their measurement, which is not possible with routine lipid testing, may lead to more accurate risk assessment.

BACKGROUNDAlthough counts of leukocytes differ substantially between blacks and whites, and are predictive of ischaemic heart disease (IHD), racial differences in counts of leukocyte subpopulations have received less attention.METHODSWe examined black/white differences in leukocyte subpopulations among 3467 white and 493 black 31-45 year-old-men who had previously served in the US Army. Laboratory determinations were performed at a central location during 1985-1986.RESULTSBlack men had an 840 cell/microliter (or 15%) lower mean total leukocyte count than did white men, largely due to a 960 cell/microliter (or 25%) lower mean neutrophil count. Although black men also had a 20% lower mean monocyte count (= 70 cells/microliter) than did white men, their mean lymphocyte count was 10% higher (approximately = 200 cells/microliter). Counts of various leukocyte subpopulations were associated with cigarette smoking, haemoglobin levels, platelet counts, and several other characteristics, but black/white differences in counts of neutrophils, lymphocytes, monocytes and other subpopulations could not be attributed to any of the examined covariates.CONCLUSIONSDespite the relatively low counts of leukocytes and neutrophils among black men, their lymphocyte counts are generally higher than those among white men. It is possible that black/white differences in counts of various cell types may influence race-specific rates of IHD, and future studies should attempt to assess the importance of leukocyte subpopulations in the development of clinical disease.

Because of previously reported associations among the total leukocyte count, cigarette smoking, and risk of cardiovascular disease, we examined the relation of cigarette smoking to various leukocyte subpopulations among 3467 men aged 31 to 45 years. The median total leukocyte count was 36% higher (7840 vs. 5760 cells/mL) among current cigarette smokers than among men who had never smoked, and both stratification and regression analyses were used to examine independent associations with leukocyte subpopulations. At equivalent counts of other subpopulations, CD4+ lymphocytes and neutrophils were the cell types most strongly associated with cigarette smoking; each standard deviation change in counts of these subpopulations increased the odds of current (vs. never) smoking by approximately threefold. Furthermore, whereas 15% of the 238 men with relatively low (< 25 percentile) counts of both neutrophils and CD4+ lymphocytes were cigarette smokers, 96% of the 249 men with relatively high counts of both subpopulations were current smokers. Counts of T lymphocytes also tended to be higher among the 32 men with self-reported ischemic heart disease than among other men. These results, along with previous reports of immunologically active T lymphocytes in atherosclerotic plaques, suggest that this subpopulation may be of particular interest in studies examining the relation of leukocytes to cardiovascular disease.

Because of previously reported associations between a high leukocyte count and risk of ischemic heart disease (IHD), we examined the relation of leukocyte counts to various characteristics among 3591 white and 506 black 31- to 45-year-old men. The mean leukocyte count was approximately 1000 cells/μL higher among whites than among blacks, and approximately 1900 cells/μL higher among current smokers than among nonsmokers. The leukocyte count was also higher among men who had recently stopped smoking and among men who reported their general health as poor or fair. Independent of these relations, the leukocyte count was associated positively with the platelet count (r = 0.29), triglyceride level (r = 0.21), heart rate (r = 0.15), and use of corticosteroids and beta-blockers; and inversely with alcohol consumption and prothrombin time (r = −0.10). The examined characteristics could together account for 37% of the variability in leukocyte counts. These relatively strong associations indicate that it may be difficult to disentangle the relation of the leukocyte count to IHD from that of other risk factors.

Although levels of coagulation factor VII and fibrinogen are predictive of cardiovascular disease, relatively little data describe hemostatic characteristics in healthy populations. The cross-sectional associations between the prothrombin time, a measure of the activity of the extrinsic and common pathways of coagulation, and traits associated with the risk of cardiovascular disease were therefore examined among 3,604 white and 514 black, male, US Army veterans aged 31-45 years. The prothrombin time measurements, performed in 1985 and 1986, were precise, with an intraclass correlation of 0.98 (202 pairs). Overall, the mean prothrombin time was 12.4 seconds (standard deviation, 0.4 seconds), and 11 percent of the men had a value of less than 12 seconds. Many of the observed associations with the prothrombin time paralleled those that have been reported with clotting factor VII and fibrinogen. The mean prothrombin time was 0.15 seconds shorter among whites than among blacks and was 0.2 seconds shorter among current cigarette smokers than among men who had never smoked. Inverse associations were also seen with relative weight and with levels of total cholesterol and triglycerides (r = -0.09 to -0.16). All associations were statistically significant at the 0.01 level, and the examined characteristics could jointly account for about 12 percent of the variability in prothrombin times. Additional data on characteristics related to coagulation may help elucidate the natural history of cardiovascular disease and aid in the design of clinical trials.

An elevation of serum cholesterol has been one of the more frequently cited risk factors for coronary heart disease, found in both case-control and cohort studies. As a result, this country has undertaken massive screening of adults older than 20 years of age in an attempt to identify those persons with cholesterol levels greater than 200 mg/dl, and follow up with an active approach for intervention. The suggested cutpoints for borderline (200–240 mg/dl), and definite (⩾ 240 mg/dl) hypercholesterolemia have been applied to all age groups despite suggestions of a diminution of risk conferred by cholesterol in the elderly. This study of 2544 white men undergoing coronary angiography shows that for all men, aged 25–84 years, plasma cholesterol levels were associated with an increase in coronary artery occlusion (rs = 0.15, p < 0.01). However, when stratified by age, this association held only for the younger men, the association diminishing to near zero in the oldest age group. The negative interaction between cholesterol levels and age in predicting coronary artery disease proved highly significant (p < 0.001) in multivariable linear regression analysis, suggesting that cholesterol levels are much less predictive of coronary artery disease in the elderly as compared to the young. These results point to the need for a more finely tuned set of criteria for the evaluation of hypercholesterolemia, one that takes into account the age of the screenee.

The present study was designed to investigate the effect of ethanol (EtOH) dose on low density lipoprotein (LDL) and platelet composition. Male squirrel monkeys were divided into three groups designated Control, Low, and High EtOH, and fed isocaloric liquid diets containing 0%, 12%, and 24% of calories as EtOH, respectively. After four months of treatment, monkeys fed the 12% alcohol dose had LDL and platelet cholesterol concentrations similar to Controls. By contrast, platelet membranes from High EtOH animals contained significantly more cholesterol which was associated with higher levels of plasma LDL cholesterol and apolipoprotein B. Blood platelet count, size, and mass were similar for all groups and circulating platelet aggregates were absent in the two alcohol cohorts. Despite elevations in platelet cholesterol mass and thromboxane A2 (TXA2) precursor, phospholipid arachidonate, platelet responsiveness, measured as thromboxane formed in response to a collagen challengein vitro, and the cholesterol/phospholipid molar ration, were not significantly altered by high dose alcohol. Normal platelet activity in High EtOH monkeys may have resulted from a significant increase in the platelet phospholipid polyunsaturated/saturated fatty acid ratio and a non-significant increase in platelet phospholipid mass, both of which would have a fluidizing effect on platelet membranes. Our data indicate that low EtOH intake has no effect on platelet composition and function while unfavorable platelet cholesterol enrichment following consumption of high dose ethanol may arise from elevations in plasma LDL. Potentially thrombogenic (TXA2 formation, platelet aggregate formation) consequences of increased platelet cholesterol in squirrel monkeys fed high levels of alcohol may be averted by compensatory physicochemical changes in platelet membrane lipid composition although persistent elevations in circulating LDL may contribute to increased risk of cardiovascular disease.

Although levels of high density lipoprotein (HDL) cholesterol in males decrease during adolescence and after treatment with testosterone derivatives, several studies have reported that levels of HDL cholesterol are positively associated with endogenous levels of testosterone in men. This association was further examined using data collected during 1985 and 1986 from 3,562 white and 500 black men who ranged in age from 31 to 45 years. Black men had higher mean levels of both HDL cholesterol (8 mg/dl) and total testosterone (33 ng/dl) than white men, and positive associations were observed between testosterone and HDL cholesterol levels (r = 0.22, whites; r = 0.26, blacks). In addition, levels of testosterone were related positively to alcohol consumption and cigarette smoking and negatively to age, Quetelet index, and use of beta-blockers. We used stratification and regression analyses to determine if any of these characteristics could account for the positive association between levels of HDL cholesterol and total testosterone. Although controlling for most factors had little influence, adjusting for Quetelet index reduced the strength of the association between levels of testosterone and HDL cholesterol by approximately 30%. These findings suggest that the positive association between levels of testosterone and HDL cholesterol may not be causal. Multivariable analyses that control for obesity and other potentially confounding characteristics should be used in studies that assess the relation of testosterone levels to coronary heart disease.

The role of body fat distribution, as assessed by the ratio of waist-to-hip circumferences (WHR), in statistically explaining differences in levels of lipoproteins between men and women was studied using data collected in 1985-1986 from employed adults (mean age, 40 years). As compared with the 415 women, the 709 men had higher mean levels of triglycerides (+38 mg/dl) and apolipoprotein B (+11 mg/dl) as well as lower mean levels of high density lipoprotein (HDL) cholesterol (-15 mg/dl) and apolipoprotein A-I (-19 mg/dl). Additionally, men were more overweight, consumed more alcohol, and exercised more frequently than women but were less likely to smoke cigarettes. Controlling for these characteristics, however, did not alter the differences in lipoprotein levels between men and women. In contrast, adjustment for WHR (which was greater among men) reduced the sex differences in levels of apolipoprotein B (by 98%), triglycerides (by 94%), HDL cholesterol (by 33%), and apolipoprotein A-I (by 21%). Similar results were obtained using analysis of covariance, stratification, or matching; at comparable levels of WHR, differences in lipid and lipoprotein levels between men and women were greatly reduced. Although these results are based on cross-sectional analyses of employed adults and need to be replicated in other populations, the findings emphasize the relative importance of body fat distribution. Whereas generalized obesity and body fat distribution are associated with lipid levels, fat distribution (or a characteristic influencing fat patterning) can be an important determinant of sex differences in levels of triglycerides, HDL cholesterol, and apolipoproteins B and A-I.

Lipids and clinical changes including diabetes and hypertension were monitored in morbidly obese patients after Roux-Y gastric bypass. Total cholesterol (Chol), high-density-lipoprotein (HDL) cholesterol, and triglycerides at 1 and at 5-7 y postoperatively in 33 patients and at 1 y in 23 patients (including apolipoproteins A-I and B) were compared with preoperative concentrations. Mean concentrations of Chol and both apolipoproteins were unchanged. Elevated serum triglycerides became normal, and reduced concentrations persisted at 5-7 y in men (p < 0.025). HDL-cholesterol concentrations increased at 1 y (p < 0.01) and remained higher at 5-7 y in women. Ratios of Chol to HDL cholesterol were lower at 1 y (pless than 0.01) in both men and women. Diabetes (9 patients) and hypertension (22 patients) also were reduced at 1 y (p < 0.01) and remained lower at 5-7 y. A mean 61% of excess weight was lost in 1 y whereas a 12% weight gain occurred by 5-7 y. The beneficial changes in most coronary risk factors lasted 5-7 y after surgery.

Differences in the importance of risk factors according to the anatomic location of coronary artery disease (CAD) were assessed in 4722 men and 1069 women who underwent arteriography. Examined characteristics included total and high-density lipoprotein (HDL)-cholesterol, triglycerides, obesity, smoking, alcohol consumption, diabetes, and hypertension. Of these risk factors, the ratio of total to HDL-cholesterol showed the highest correlation with the overall severity of CAD (r = 0.24, men; r = 0.38, women); in contrast, its relation to left main (LM) disease was much lower (r = 0.10, men; r = 0.08 women) than were correlations with stenotic disease in the left anterior descending, circumflex, and right coronary arteries. Other risk factors also showed weaker associations with LM disease than with stenoses in other vessels, and none was related to increased LM disease after controlling for disease in other vessels. For example, as compared with men who had no significant CAD, those with 1-, 2-, and 3-vessel disease had mean increases in total cholesterol of 12, 18, and 19 mg/dl, respectively. In contrast, after adjusting for disease in other vessels, LM disease (present in 293 men) was associated with only a 4 mg/dl increase in mean cholesterol levels (P = 0.20). These results indicate that the relation of risk factors to CAD differs according to the location of the stenotic disease, and that LM disease is poorly predicted by the standard risk factors.

Although levels of triglycerides have consistently shown a strong association with cardiovascular disease in both case-control and cohort studies, it remains controversial whether this relation exists independently of levels of cholesterol and other risk factors. The association of arteriographically documented coronary artery disease with plasma levels of triglycerides, total cholesterol, and high density lipoprotein (HDL) cholesterol was therefore examined in 5,216 white adults (81% were male) referred to two Milwaukee hospitals between 1972 and 1986. Elevated levels of triglycerides were related to the extent of coronary artery disease (estimated using the total number and severity of stenoses) in both sexes; this association existed independently of total cholesterol, age, obesity, hypertension, smoking, and alcohol consumption. In addition, the association between triglycerides and coronary artery occlusion was strongest at total cholesterol levels less than or equal to 250 mg/dl. However, both stratified and regression analyses indicated there was no residual association between triglyceride levels and occlusion after controlling for HDL cholesterol. (Levels of HDL cholesterol and triglycerides showed a moderate inverse association: r = -0.39 to -0.51.) These results indicate that the association between coronary artery occlusion and levels of triglycerides is indirect, and that the disparate findings of earlier studies may have resulted from not controlling for HDL cholesterol.

Although the leading cause of death among black men in the United States is coronary artery disease (CAD), risk factors have not been well documented in black populations. Therefore, possible racial differences in the relation of several characteristics to the extent of CAD were assessed in 4,722 white and 169 black men who underwent arteriography. Associations between an occlusion score (ranging from 0 to 300), reflecting the severity of CAD, and levels of total and high-density lipoprotein (HDL) cholesterol, triglycerides, cigarette smoking, alcohol intake, relative weight, systemic hypertension and diabetes mellitus were examined. Most risk factors were significantly related to the extent of CAD in both races, but lipid levels showed stronger associations with CAD among blacks: correlations between CAD and total cholesterol were 0.16 (whites) vs 0.29 (blacks) and associations with HDL cholesterol were −0.22 (whites) vs −0.49 (blacks). In addition, at adverse levels of certain risk factors, blacks had more extensive CAD than did whites: mean occlusion scores were 148 (whites) and 238 (blacks) at HDL cholesterol levels <30 mg/dl. As assessed by multiple linear regression, however, only triglyceride levels were differentially related to CAD between whites (β = 0) and blacks (β = 0.47), p < 0.01 for racial contrast. These results document the importance of risk factors in black men and indicate black/white differences in the relation of triglycerides to CAD.

High rates of tranquilizer use in coronary disease have been previously reported. In patients being evaluated for coronary disease, tranquilizer use has been related to myocardial infarction, angina pectoris, neurotic traits, employment and the use of cardioactive and other medications. In this study, responses of 1046 male patients to a questionnaire assessing biological, psychological and social variables before and after coronary bypass surgery were related to tranquilizer use. The effect of CABG was to decrease tranquilizer use. Tranquilizer use prior to coronary bypass operations was related to neuroticism, myocardial infarction and taking cardiac and analgesic medication. Similar findings were noted after coronary bypass operations except that angina pectoris was added as a contributor to tranquilizer use. The multivariate analysis tended to confirm the univariate findings, except that neurotic traits did not make an independent contribution. These results indicate that in patients undergoing coronary evaluations, cardiac disease variables other than coronary atherosclerosis determine tranquilizer use. Neurotic traits play a secondary role. Relief of angina pectoris appears to be particularly important in reducing tranquilizer use. The finding of angina pectoris after coronary bypass operation may have special significance for the continuation of tranquilizer use.