Excess Coronary Heart Disease Research Articles

Role of known risk factors in explaining the difference in the risk of coronary heart disease between eastern and southwestern Finland

We analysed to what extent cardiovascular risk factors may explain the observed difference in the risk of coronary heart disease (CHD) between two areas with markedly different CHD incidence. The study included 7049 men aged 25-64 years who had participated in a baseline survey in 1982 or in 1987 in the Kuopio and North Karelia provinces of eastern Finland and in the Turku-Loimaa region of southwestern Finland. During the baseline surveys the following factors were determined: smoking, blood pressure, cholesterol, high-density lipoprotein cholesterol, diabetes, height, body mass index, family history of CHD and socioeconomic status. The cohorts were followed for coronary events until the end of 1994. CHD risk was about 40% higher in eastern than in southwestern Finland. The levels of most of the measured risk factors were also higher in eastern Finland. Differences in risk factor levels explained about 40% of the excess CHD risk in eastern Finland. The impact of the classical risk factors, such as smoking, cholesterol and blood pressure, on the regional difference was smaller than expected. Single risk factor measurements in our population surveys, however, may not have correctly reflected the long-term exposure of individuals to these risk factors, particularly because the surveys were carried out within a period during which these risk factors were undergoing favourable changes in the Finnish population. In addition to the classical risk factors, regional differences in body height and socioeconomic status were associated with the regional differences in CHD risk.

Cholesteryl ester transfer protein activity enhances plasma cholesteryl ester formation. Studies in CETP transgenic mice and human genetic CETP deficiency.

The plasma cholesteryl ester transfer protein (CETP) promotes the removal of HDL cholesteryl esters and is thought to stimulate reverse cholesterol transport (RCT). However, mechanisms by which CETP may stimulate RCT are poorly understood. Thus, we examined the relationship between plasma CETP expression and plasma cholesteryl ester formation in CETP transgenic (Tg) mice, hamsters, and human subjects with genetic CETP deficiency. Incubation of CETP Tg mouse plasma showed a 20% to 40% increase in plasma cholesterol esterification rate (CER, P < .05) compared with control mice. Injection of a neutralizing CETP monoclonal antibody (MAb) (TP2) into natural flanking region CETP Tg mice resulted in an increase in plasma free cholesterol (FC) concentration, FC/CE ratio, FC/phosphatidylcholine ratio, and hepatic CETP mRNA. In hamsters, CETP inhibition also resulted in an increase in plasma FC/phosphatidylcholine ratio and increased CETP mRNA in adipose tissue. In humans with two common CETP gene mutations (an intron 14 splicing defect and a D442G missense mutation), mean plasma CERs were 39 and 60, respectively, compared with 89 nmol x mL-1 x h-1 in normal subjects. By contrast, lecithin:cholesterol acyltransferase (LCAT) mass was normal in CETP-deficient subjects. MAb neutralization of CETP activity in incubated human plasma did not alter the LCAT reaction, even after supplementation with discoidal HDL and VLDL. Thus, genetic alterations in CETP levels lead to secondary changes in the plasma LCAT reaction, possibly because of remodeling of HDL by CETP acting in concert with other factors in vivo. In human genetic CETP deficiency, a moderate impairment in the plasma LCAT reaction may contribute to a defect in RCT, providing a potential mechanism to explain the recently observed excess of coronary heart disease in these subjects.

Isolated low HDL cholesterol as a risk factor for coronary heart disease mortality. A 21-year follow-up of 8000 men.

For the purpose of screening individuals at high risk for coronary heart disease (CHD), serum total cholesterol (TC) of 5.2 mmol/L, has been set as a value dividing "desirable" from intermediate high or elevated levels, and HDL cholesterol (HDL-C) < 0.9 mmol/L has been labeled as abnormally low, implying high CHD risk. It has been conjectured that low HDL-C poses no risk in the absence of elevated LDL cholesterol or TC. To assess the risk of CHD-free men with "isolated low HDL-C," ie, abnormally low HDL-C with desirable TC, we examined the CHD and all-cause mortality of some 8000 Israeli men aged 42 years and older during 1965 through 1986. Men with isolated low HDL-C represented one sixth of the cohort. CHD mortality among these men was 36% higher (age adjusted) than in counterparts with desirable TC, of which > 0.9 mmol/L was contained in the high-density fraction. In men with TC > 5.2 mmol/L, abnormally low HDL-C was associated with a virtually identical CHD mortality risk ratio, 38%. These findings persisted after adjustment for multiple CHD risk factors. The excess CHD risk associated with isolated low HDL-C appeared particularly increased in men with diabetes mellitus, whose death rate was 65% higher than in diabetics with HDL-C > 0.9 mmol/L. A second subgroup result was consistent with equal CHD mortality risk among men in the "desirable" TC range, with or without low HDL-C, if systolic blood pressure was > 160 mm Hg. These are post hoc findings, and hypotheses arising from these observations would require independent examination. Total mortality was not increased in men with isolated low HDL-C compared with men who had HDL-C < 0.9 mmol/L and TC > 5.2 mmol/L at baseline. These results indicate that an increased risk of CHD death is associated with abnormally low HDL-C for cholesterol ranges both below and above 5.2 mmol/L. For the individual, therefore, the risk is multiplied by the same amount regardless of TC. Quitting smoking, increasing physical activity, and decreasing body weight would all contribute to raise HDL-C in individuals of most or all age groups. When examined from a community perspective, the results are consistent with a relatively low population-attributable fraction among CHD-free men. This would tend to support the recommended practice of considering a TC level of 5.2 mmol/L (200 mg/dL) as a threshold for further evaluation in screened individuals without manifest CHD.

Hormone replacement therapy and cardiovascular risk in post-menopausal women with NIDDM.

Female patients with NIDDM have a high prevalence of, and mortality from, coronary heart disease (CHD). Hormone replacement therapy (HRT) may favourably influence several CHD risk factors in post-menopausal NIDDM patients, including dyslipidaemia, hypertension, prothrombotic changes, and endothelial dysfunction. Insulin resistance appears to have a central role in the pathogenesis of these abnormalities and can also be modified by HRT. However, the potentially beneficial effects of HRT in women with NIDDM have been extrapolated from the results of studies in non-diabetic females, as to date there have been few studies in NIDDM patients. In view of their excessive CHD mortality, further research is needed to investigate the effects of different HRT preparations on lipid and non-lipid risk factors in this high-risk population.

The 25-Year Health Care Costs of Women Who Remain Overweight After 40 Years of Age

Previously published reports strongly suggest that being overweight is a risk factor for coronary heart disease, hypertension, diabetes, gallstones, and osteoarthritis in women. Substantial health care and medication costs are associated with these chronic health conditions. We used an incidence-based analysis to estimate the excess costs associated with women maintaining an overweight status during the 25-year period from age 40 to 65 years. The health care costs of three hypothetical cohorts of 10,000 40-year-old women were extrapolated to age 65. The non-overweight cohort maintained a body mass index (BMI; weight [kg]/height [m2]) of 21 to 24.9; the moderately overweight cohort maintained a BMI of 25 to 28.9; the severely overweight cohort maintained a BMI of > or = 29. The number of fatal and nonfatal health outcomes in each cohort for heart disease, hypertension, diabetes mellitus, gallstones, and osteoarthritis was calculated with their associated costs. We estimated that when compared with the non-overweight cohort of 10,000 women, the cohort of 10,000 women who had a BMI of > or = 29 incurred excess costs of $53 million over a 25 year period (discounted at 3% per year) and 497 excess deaths. The cohort of 10,000 women who had a BMI of 25-28.9 incurred excess costs of $22 million (discounted at 3% per year) and 212 excess deaths, compared with the non-overweight cohort. The results of this study indicate that an estimated $16 billion will be spent during the next 25 years treating health outcomes associated with overweight in middle-aged women in the United States. Thus, a substantial health burden is associated with the increasing prevalence of overweight women in the United States. Preventing excess coronary heart disease, gall-stones, osteoarthritis, hypertension, and diabetes through prevention of weight gain, particularly among reproductive-aged women, may be a cost-effective strategy.

Criteria for Metabolic Control and Intervention in Diabetes

Guidelines for optimal management of diabetes advocate comprehensive strategies to treat all established risk factors for coronary heart disease (CHD). The targets for treatment should be optimization of glycemic control, weight reduction, lowering of elevated blood pressure, correction of lipid abnormalities, and stopping smoking. Recently, strong evidence has emerged to demonstrate that poor glycemic control is a powerful predictor for excess CHD risk. The fact that dyslipidemia and hypertension are frequent in NIDDM patients at the time of diagnosis indicates that these risk factors may cause damage for years before the actual diagnosis of NIDDM. This article highlights the current background knowledge for the guidelines of therapeutic strategies for dyslipidemias in NIDDM.

Diabetes, mortality and coronary heart disease in the prospective Dubbo study of Australian elderly.

A prospective study of Australian elderly living in Dubbo has shown that diabetes is a significant predictor of all-causes mortality and coronary heart disease (CHD). To examine and contrast clinical and socio-demographic predictors of these outcomes in those with and without diabetes. The data are derived from a community-based sample of subjects 60 years and older followed over 62 months since 1988. Of 1155 men and 1472 women, 9.2% and 6.9% respectively manifested diabetes at baseline, based on history or fasting hyperglycaemia. In the presence of diabetes, all-causes mortality was increased twofold in both sexes, CHD incidence was increased twofold in men and threefold in women, stroke incidence was increased twofold in women but little changed in men. Proportional hazards models were derived separately for persons with and without diabetes and risk factors differentially predictive in diabetes were sought. Significant predictors of death in diabetes were old age and current smoking. Those factors differentially predictive were 'being married' (Relative Risk [RR] 1.60 with diabetes and 0.69 without diabetes) and higher body mass index (BMI) (RR 1.03 with diabetes and 0.79 without diabetes). Significant predictors of CHD in diabetes were old age, prior CHD, severe hypertension, low HDL cholesterol and self-rated health. Those factors differentially predictive were higher body mass index (RR 1.14 vs 0.83) and physical disability (RR 0.69 vs 1.55). Differential predictions with regard to BMI may relate in part to excess CHD and mortality at low BMI in non-diabetic subjects. The vascular disease burden of diabetes in the elderly has been confirmed, especially in women. A number of conventional risk factors are contributing to this burden and may be amenable to treatment.

Rapid decline in FEV1. A new risk factor for coronary heart disease mortality.

Coronary heart disease (CHD) is the leading cause of mortality in the United States. The present cohort study was conducted to determine whether rate of FEV1 loss independently predicts CHD mortality in apparently healthy men. White male Baltimore Longitudinal Study of Aging (BLSA) participants without CHD underwent clinical evaluation at 2-yr intervals; 883 had satisfactory pulmonary and lipid studies and returned for a least one visit. Cases were BLSA subjects without CHD on entry who died a "coronary death" (death from acute myocardial infarction, sudden death, or congestive heart failure in the presence of coronary artery disease). Forced expiratory maneuvers followed American Thoracic Society guidelines. Serum cholesterol, blood pressure, cigarette smoking, and body mass index were obtained from the BLSA database. There were 79 CHD deaths and 804 survivors during an average follow-up of 17.4 yr. After adjustment for age, initial FEV1% predicted, smoking status, hypertension, and cholesterol, a time-dependent proportional hazards model showed that cardiac mortality, but not all causes of mortality, generally increased with increasing quintile of FEV1 decline for the entire cohort (relative risk [RR] 2.92-5.13) and separately for the subset of never-smokers. Thus, excess CHD mortality follows a large decline in FEV1, independent of the initial FEV1% predicted, cigarette smoking, and other common CHD risk factors.

Fatty acid composition of erythrocytes and plasma triglyceride and cardiovascular risk in Asian diabetic patients

The excess of coronary heart disease in Indian Asians compared with Europeans is unexplained by conventional risk factors, although the high prevalence of diabetes may play a part. To explore the contribution of diet we compared the fatty acid composition of erythrocyte membrane phospholipid and plasma triglyceride in 36 Gujarati Asians and 24 Europeans with non-insulin-dependent diabetes. Erythrocytes from Asian subjects contained higher proportions of linoleic, dihomogammalinolenic, and arachidonic acids, and lower proportions of oleic and n-3 series fatty acids; triglycerides contained higher linoleic and lower oleic acid levels. For example, mean percentage (SE) of oleic acid (18:1n-9) in erythrocytes was 16·7 (0·2) in Asians and 20·5 (0·6) in Europeans (p=0 0001), and total n-6:n-3 ratio was, respectively, 12·8 (0·7) and 6·7 (0·7) (p=0·0001). A high dietary intake of linoleic acid may not be cardioprotective unless balanced by significant intakes of oleic and n-3 series fatty acids, at least in diabetic Indian Asians. By itself, the conventional recommendation to substitute polyunsaturated for saturated fat in the diet may be inadequate to reduce thrombogenesis, and the overall balance of fatty acids, including monounsaturates, should be considered.

Lipoprotein(a) as a risk factor for preclinical atherosclerotic disease in a biracial cohort: the Atherosclerosis Risk in Communities (ARIC) Study

Lipoprotein(a) (Lp(a)) is a risk factor for clinically manifest coronary heart disease (CHD) and cerebrovascular disease in Caucasian and in Asian populations. The role of Lp(a) as a risk factor in blacks has not been described, despite the markedly higher levels of Lp(a) and excess CHD and stroke prevalence observed in middle-aged blacks compared with whites. Further, little information exists on the association of Lp(a) and asymptomatic atherosclerosis in any race or gender group. In this report, 15 700 middle-aged black and white participants in the Atherosclerosis Risk in Communities (ARIC) Study had complete B-mode ultrasound scans of their extracranial carotid arteries. Of the 13 384 individuals with complete B-mode data at the carotid bifurcation, those with mean carotid bifurcation intima-media wall thicknesses at or above the 90th percentile of the population distribution (≌ 1.2 mm) were considered to have carotid atherosclerosis. Lp(a) was measured as its total protein content by double-antibody ELISA for apo(a) detection. Blacks in this study had mean Lp(a) protein values that were twice as high as those of whites (168.9, 147.1, 86.6, and 75.1 μg/ml for black females, black males, white females, and white males, respectively). For all race and gender groups, Lp(a) protein concentrations were higher among individuals with carotid atherosclerosis than for those without. From these cross-sectional data, we conclude that Lp(a) protein is a risk factor for preclinical atherosclerosis as well as for clinically manifest cardiovascular disease. The high Lp(a) levels in blacks, without correspondingly thickened intima-media walls at the carotid bifurcation, suggest that race and gender differences in apo(a) phenotypes, hemostatic activity, or other unrelated risk factors may contribute to this paradox.

Association Between an Excessive Body Mass Index and Coronary Heart Disease Risk Factors in Military Personnel

The purpose of this study was to document the extent of coronary heart disease (CHD) risk factors in military personnel (412 men, 50 women) classified as seriously overweight (body mass index [BMI] 27.0-29.9 kg/m2) or obese (BMI > or = 30 kg/m2) and to evaluate the utility of the BMI to discriminate among individuals with an adverse CHD risk profile. Mean body weight and BMI greatly exceeded Canadian norms, whereas mean heights were average. There were low but significant correlations between BMI and resting and submaximal exercise (stage A of the Canadian Aerobic Fitness Test) heart rates and blood pressures, while the correlation with predicted VO2max was negative. Except for blood glucose level (GLU) in men, there were no significant correlations between BMI and various biochemical indices. Compared to "overweight" men, the percentage of "obese" men with abnormal values for risk factors were higher, particularly for an adverse exercise blood pressure response and low predicted VO2max. In summary, the correlations between BMI and the various CHD risk factors, except for GLU and the exercise parameters, were minimal or moderate at best. It was concluded that in overweight and obese individuals, BMI does not appear to be a particularly sensitive indicator of body fat and risk factors.

Hypertension and coronary artery disease in non-insulin dependent diabetes--cause and effect?

There is a log-linear increase in the risk of coronary heart disease with elevation of levels of blood pressure. Allowing for the phenomenon of regression dilution bias, this corresponds to around a 20 to 25% increase in risk for each 5 to 6 mm Hg elevation in usual diastolic blood pressure. In diabetic subjects, a similar relationship occurs, but of somewhat lesser degree. Recent overviews of therapy suggest that in nondiabetics, reducing blood pressure reverses around 50% of the excess coronary heart disease risk, but this has not yet been conclusively shown in patients with diabetes. The reduction in risk with therapy is a prerequisite to defining the antecedent as a causal influence on outcome, but it is as likely that the incomplete reversibility of excess risk represents other pathways of connection between hypertension and coronary heart disease as a consequent of iatrogenic effects of current treatments. Several alternative mechanisms are outlined, and the suggestion is made that only in the context of randomized controlled studies could the possible benefits on coronary heart disease of agents influencing such mechanisms be assessed.

Adverse effects of diuretics.

Analysis of the available evidence indicates that diuretics do not increase coronary heart disease morbidity and mortality. The multiclinic trials supporting the cardiotoxicity hypothesis are few in number and flawed in design. The majority of the trials, including the well designed trials, indicate no excess of coronary heart disease (CHD) events in diuretic-treated patients compared with those given other drugs or placebo. Recent studies indicate no increase in cardiac arrhythmias after diuretic treatment. Also, although depletion of intracellular potassium and magnesium occurs in patients with congestive heart failure even without diuretics, intracellular concentration of these ions is not significantly reduced by diuretics in patients with uncomplicated hypertension. Modest elevations of serum cholesterol may occur during the first 6 to 12 months of treatment with thiazide diuretics. However, after this time these elevations fall to or below the pretreatment level. The fall may be greater in patients receiving other drugs but the differences are small and their clinical significance is questionable. The incidences of hyperglycaemia and diabetes were only minimally increased in long term clinical trials while the importance of hyperinsulinism and insulin resistance in causing CHD remains unproven in patients. Thiazides remain, therefore, a safe and effective treatment for patients with hypertension.

Epidemiology of some peripheral arterial findings in diabetic men and women: Experiences from the Framingham study

purpose and patients and methods: The purpose of this study was to determine the relationship between diabetes and the development of some peripheral arterial findings—carotid and femoral bruits and nonpalpable pedal pulse—and acute cardiovascular events in 1,196 men and 1,582 women based on 20-year-follow-up data in the Framingham Study. results: For both men and women without diabetes, the incidence of carotid bruits and nonpalpable pedal pulses increased significantly with age (p <0.05) without any apparent male predominance. In contrast, diabetic men and women were at an elevated risk of each peripheral arterial condition that was not appreciably different across age groups. Compared with women without diabetes, those with diabetes experienced nearly a twofold excess of femoral bruits (p <0.05) and a 50% excess of nonpalpable pedal pulses (p <0.01). Among men, diabetes nearly doubled the risk of carotid bruits (p <0.05). Those who had both diabetes and symptoms of peripheral arterial disease were at especially high risk of incident cardiovascular events. In particular, nonpalpable pedal pulses were associated with more than a twofold excess of coronary heart disease (p <0.05) and stroke (p <0.01) in diabetic women and more than a twofold excess of coronary heart disease and cardiac failure in diabetic men (p <0.01). Femoral bruits doubled the risk of coronary heart disease in diabetic men (p <0.05). conclusion: We conclude that while diabetes predisposes to various forms and locations of peripheral arterial disease, the enhanced risk of acute cardiovascular events experienced by diabetic patients is increased further when diabetes is accompanied by indications of a peripheral arterial condition. Since signs of peripheral arterial disease may suggest an impending or coexistent atherosclerotic process, careful examination of arterial circulation by evaluating peripheral pulses and assessing whether bruits are present is important.

Gout and coronary heart disease: The framingham study

The relationship between gout, not associated with the use of diuretics, and the development of coronary heart disease was examined in 5209 subjects originally enrolled in the Framingham Study. Based on 32 years of follow-up, the two year incidence of gout was six times greater in men (3.2/1000) as compared to women (0.5/1000). For both sexes, the incidence of gout showed no clear relationship with age. Among men who never received diuretics, those afflicted by gout, as compared to those without gout, experienced a 60% excess of coronary heart disease (95% confidence limits, 1.1–2.2), primarily attributed to a two fold excess of angina pectoris (95% confidence limits, 1.2–3.1). Although gout was usually associated with other atherogenic risk factors, control of systolic blood pressure, total cholesterol, alcohol intake, body mass index, and diabetes failed to alter the effect of gout on the preceding coronary events in men. For women, there were no significant associations between gout and coronary heart disease. We conclude that gout, unrelated to the intake of diuretics, imparts an additional risk of coronary heart disease in men, unexplained by clinically measured risk factors.

Enhanced risk of coronary heart disease mortality in lean hypertensive men.

A recently presented hypothesis contends that the excess coronary heart disease mortality associated with hypertension is more prominent in lean men than in overweight men. This hypothesis was addressed using data collected in the Israeli Ischemic Heart Disease Study (n = 10,059). The ratios of age-adjusted 15-year death rates in hypertensive and normotensive men were 4.7, 2.8, 2.0, and 1.9 in the Quetelet index groups of less than 2.29, 2.29 to 2.56, 2.56 to 2.83 and greater than 2.83 g/cm2, respectively. The corresponding ratios for all-cause mortality were 2.2, 2.1, 2.0, and 1.7, respectively. The group with the highest all-cause age-adjusted mortality, at 33.6%, was that of the leanest (less than 2.29 g/cm2, bottom 20% of the Quetelet index distribution) hypertensive subjects. The same group also displayed the highest coronary heart disease mortality (age-adjusted rate, 18.2%). The findings persisted for both smokers and nonsmokers and after exclusion of men with coronary heart disease or diabetics at intake, men on antihypertensive medication, or those who died in the first 2 years of follow-up (1963-1965). A multivariate risk score for developing myocardial infarction was calculated, based on levels of age, systolic blood pressure, total cholesterol, high density lipoprotein cholesterol, cigarette smoking, diabetes mellitus, and Quetelet index. This score varied little across the four Quetelet index groups in hypertensive men: 5-year mean estimated risks of myocardial infarction were between 70 and 74/1000. In normotensive men the scores increased from 19/1000 in the leanest subjects to 29/1000 in the overweight ones.(ABSTRACT TRUNCATED AT 250 WORDS)

Alcoholic intemperance, coronary heart disease and mortality in middle-aged Swedish men.

High alcohol consumption is one of the major risk indicators for premature death in middle-aged men. An indicator of alcohol abuse--registration with the social authorities for alcoholic problems--was used to evaluate the role of alcohol in relation to general and cause-specific mortality in a general population sample. Altogether 1,116 men (11%) out of a total population of 10,004 men were registered for alcoholic problems. Total mortality during 11.8 years' follow-up was 10.4% among the non-registered men, compared to 20.5% among men with occasional convictions for drunkenness and 29.6% among heavy abusers. Fatal cancer as a whole was not independently associated with alcohol abuse, but oropharyngeal and oesophageal cancers together were seven times more common in the alcohol-registered groups. Total coronary heart disease (CHD) was significantly and independently associated with alcohol abuse, but nearly all the excess CHD mortality among the alcohol-registered men could be attributed to sudden coronary death. Cases with definite recent myocardial infarction were not more common in the alcoholic population. A combined effect of coronary arteriosclerosis and heart muscle damage secondary to alcohol abuse is suggested. Other causes of death strongly associated with registration for alcohol abuse include pulmonary embolism, pneumonia and peptic ulcer, as well as death from liver cirrhosis and alcoholism. Of the excess mortality among alcohol-registered subjects, 20.1% could be attributed to CHD, 18.1% to violent death, 13.6% to alcoholism without another diagnosis and 11.1% to liver cirrhosis.

Linkage and segregation analyses of apolipoproteins A1 and B, and lipoprotein cholesterol levels in a large pedigree with excess coronary heart disease: the Bogalusa Heart Study.

Robust methods were employed, using data from a single large pedigree, to screen serum apolipoprotein A1 and B levels, serum lipoprotein cholesterol levels, and ratios of serum lipoprotein cholesterol fractions to apolipoprotein A1 and B levels for genetic linkage to 31 polymorphic markers. Segregation analyses were performed for each of the apolipoprotein and lipoprotein cholesterol fractions to obtain estimates for use in applying likelihood methods of linkage analysis. Trait-marker combinations for which linkages were suggested from the robust methods were then reexamined for linkage using the likelihood (lod score) method. Results from the segregation analyses were consistent with major gene determination of apo B and HDL-C levels, the HDL-C to apo A1 ratio, the LDL-C to apo B ratio, and a measure of relative content of cholesterol in HDL-C and LDL-C. Linkage between haptoglobin and the HDL-C/apo A1 ratio was suggested, with a lod score of 1.72 at theta = 0.05.

Unexpected effects of treating hypertension in men with electrocardiographic abnormalities: a critical analysis.

The relationship between diuretic therapy and possible increased risk of coronary heart disease (CHD), especially sudden death, is controversial. The initial report from the Multiple Risk Factor Intervention Trial (MRFIT) raised the possibility that the increased CHD mortality observed in a subset of special intervention men with hypertension and certain electrocardiographic abnormalities on their baseline examination might be an unexpected adverse effect of diuretic therapy. Subsequent reports from the MRFIT have revealed a stronger association of CHD mortality to hydrochlorothiazide than to chlorthalidone. There was no consistent relationship of CHD mortality to the dose of either drug, to the most recent serum potassium level, or to the presence of ventricular premature beats. Unfavorable trends of the same magnitude were also seen among similar white men in the Hypertension Detection and Follow-up Program and in the Oslo hypertension trial, although the sample sizes in these two studies were too small to yield clearcut conclusions. Clinical studies have shown an increased risk of CHD death among hypertensive men with left ventricular hypertrophy. Such men are also noted to have a higher frequency of ventricular premature beats, even in the absence of diuretic therapy. Other studies have shown that diuretic-induced hypokalemia is accentuated in the presence of epinephrine and that low potassium levels decrease the threshold for ventricular fibrillation. Thus, although the evidence is still incomplete, it is possible that the excess CHD mortality among MRFIT special intervention men with electrocardiographic abnormalities may have been caused by a combination of increased left ventricular mass in the presence of coronary atherosclerosis, and hypokalemia caused by good compliance with diuretic therapy and accentuated by stress-induced increases in circulating catecholamines. Given the very large population of patients receiving diuretic therapy, further evaluation of this possibility is important.

Diabetes and Coronary Heart Disease

Clinically manifest coronary heart disease (CHD) is not uncommon in diabetics with insulin-dependent type of the disease below the age of 40, particularly when the duration of diabetes is long. Clinically manifest CHD is very common in diabetics with maturity-onset, non-insulin-dependent type of the disease, and in this type of diabetes the frequency of CHD shows little or no relation to the duration of diabetes. Premenopausal female diabetics have a clinically manifest CHD almost as often as male diabetics of the same age--a situation in sharp contrast to that in non-diabetics with large excess of CHD in males. The incidence of all manifestations of CHD (sudden and nonsudden CHD death, non-fatal myocardial infarction, "silent" myocardial infarction, and angina pectoris) is increased in diabetics as compared to non-diabetics, but the excess of CHD mortality in diabetics is especially marked, being 3 to 4 times higher than in non-diabetics. The incidence of congestive heart failure is markedly increased in diabetics and this is in part independent of increased occurrence of CHD and hypertension among diabetics. Subclinical abnormalities of left ventricular function are common in diabetics and these abnormalities appear to show some relationship to the metabolic control of diabetes and in insulin-dependent diabetics also to the presence of microangiopathy. Diabetes is associated with changes in general CHD risk factors to atherogenic direction. These changes include abnormalities in the levels and composition of plasma lipids and lipoproteins and increased frequency of hypertension. The impact of general risk factors on CHD risk appears to be similar in diabetics and non-diabetics.(ABSTRACT TRUNCATED AT 250 WORDS)