Michael F. Oliver

The Influence of the Sex Hormones on the Circulating Lipids and Lipoproteins in Coronary Sclerosis

The administration of ethinyl estradiol to 100 survivors of myocardial infarction resulted in uniform correction of the abnormal circulating lipid and lipoprotein concentrations. Gynecomastia and depression of libido were well tolerated by the patients but were not ameliorated by an androgen preparation nor by a progesterone analogue. Methyl testosterone, which partly inhibited the estrogen effect, increased the concentration of cholesterol on the beta lipoprotein fraction. Progesterone had no significant effect on the circulating lipids and lipoproteins. Assessment of the effect of ethinyl estradiol on human atherogenesis must depend on long-term evaluation of its influence on morbidity and mortality rates.

Sudden Death and Myocardial Infarction

SUDDEN DEATH during an acute heart attack is perhaps the greatest therapeutic challenge of the moment. The success of coronary care units in preventing and treating cardiac arrest in the hospital has served to emphasize our inability to manage this condition outside the hospital. Before considering how approaches might be made to resolve this, it is necessary to define what the problem is. Unfortunately, not enough is known about the circumstances and pattern of sudden deaths, and analysis of data already reported is made difficult by differences in the definition of the term sudden death. By this term, some have meant unexpected death either instantaneously or within an hour1-3 of the onset of symptoms, whereas others have meant death within 24 hours4 5 or even in as long a period as six days.6 From the point of view of management, such differences are of great importance. Those who die within an hour seldom have the opportunity to obtain medical attention, and their deaths could only be prevented by some prophylactic measure. On the other hand, those deaths that occur later on might be preventable by the more rapid avail+ ability of medical care. For the purpose of this paper, we define sudden death as death occurring within one hour of the onset of symptoms, and early death as death occurring within the first 24 hours. An appraisal of the importance of sudden and early death in acute myocardial infarction and of the ways in which it might be predicted or prevented is needed. In order to do this, evidence will be presented in this paper concerning the proportion of early deaths in acute myocardial infarction, the time relationship between death and the onset of symptoms, the relationship between death and preceding health, and the probable contribution of myocardial ischemia to sudden death.

Metabolic causes and prevention of ventricular fibrillation during acute coronary syndromes.

The mechanisms leading to ventricular fibrillation that occur during acute myocardial ischemia are ill understood. Whether primary ventricular fibrillation is due to a transient imbalance of electrolytes, an alteration of membrane permeability, electrical re-entry phenomena, or other factors, one overriding influence is the development of regional myocardial energy crises. Acute alteration in the balance of substrate supply may lead, during greatly reduced blood flow, to instability of myocardial electrical conduction with the development of re-entry circuits. An immediate response to the angor animi and initial symptoms of an acute coronary syndrome is a rapid and marked increase in catecholamine release, which leads to adipose tissue lipolysis with an acute increase in plasma free fatty acid concentrations, suppression of insulin activity, and a reduction in glucose uptake by the myocardium. The utilization of free fatty acids instead of glucose by the ischemic myocardium could precipitate regional oxygen or energy crises. Prevention therefore should focus on minimizing the catecholamine response and providing the myocardium with an optimum supply of energy substrates. Since catecholamines are inotropic, the aim should be to redress the imbalance of substrate availability by controlling adipose lipolysis with reduction of plasma free fatty acid concentrations, increasing the availability of glucose, or both. Other approaches include inhibition of acylcarnitine transport and manipulation of fatty acid intermediaries. To combat primary ventricular fibrillation, preventive treatment must be established within 6 to 10 hours of the onset of ischemia. There is already experimental and clinical evidence that antilipolytic drugs decrease the incidence of ventricular fibrillation, but their potential has not been explored extensively.

Glucose tolerance, plasma insulin, HDL cholesterol and obesity: 12-year follow-up and development of coronary heart disease in Edinburgh men

The insulin response to a standard oral glucose tolerance test (OGTT) and other anthropometric and biochemical risk factors for coronary heart disease (CHD) were measured in a random sample of 107 Edinburgh men, who were initially studied in 1976 when they were 40 and who were reexamined in 1988-89. Fasting glucose and glucose response to OGTT were higher in 1988-89 than in 1976. In contrast, insulin levels did not differ between the initial and follow-up study either before or after the glucose load. Body mass indices increased, except triceps skinfold. Changing patterns in both fasting and OGTT insulin or glucose levels in individuals were related to changes in bodyweight or in subscapular skinfolds. Modifications in serum total and HDL cholesterol were related to changes in fasting insulin and insulin area, respectively, but not to glucose data. Eleven men developed clinical CHD. Neither glucose nor insulin measures obtained in 1976 differed between those with and without CHD. Weight-height index and abdominal skin-folds were higher in those with CHD. HDL cholesterol was significantly lower (P less than 0.05). Abdominal skin-fold but not body mass index remained significant when adjusted for HDL cholesterol. This small study confirms the importance of central obesity and low HDL cholesterol but failed to identify insulin as a risk factor for CHD in this Scottish population.

Low plasma vitamins E and C. Increased risk of angina in Scottish men.

Cross-cultural studies suggest that low plasma antioxidant levels contribute to the high incidence of coronary heart disease (CHD) in Scotland. One hundred twenty-five cases of angina without reported history were identified by a postal WHO chest pain questionnaire from a systemic population sample of 6000 Edinburgh men (35-54 years). Classical CHD risk factors (lipids, blood pressure, smoking, and relative weight), plasma vitamins, and a new independent CHD risk factor, adipose tissue linoleate, were measured in angina (n = 125) and healthy controls (n = 430). Cigarette smoking was common in angina (46% vs. 29%, p less than 0.01), and adipose tissue linoleate was lower (8.77 +/- 0.18% vs. 9.81 +/- 0.14% (p less than 0.01). Classical CHD risk factors were not different. Vitamin E/cholesterol molar ratio (micron/mM) was lower in angina than in controls: 1.58 +/- 0.03 vs. 1.66 +/- 0.02 (p less than 0.01). Plasma vitamin C was also lower in angina than in controls: 23.6 +/- 1.7 vs. 30.5 +/- 1.1 microM (p less than 0.001). The relative risk of angina for those in the lowest versus those in the highest quintile of the vitamin E/cholesterol ratio distribution was 2.2:1, irrespective of other risk factors (p less than 0.009). Adipose tissue linoleate removed the association between vitamin E and angina. The relative risk of angina for those in the lowest versus those in the highest quintile of plasma vitamin C was 2.6:1 (p less than 0.01), and the increased risk was also independent of classical risk factors, but closely related to a smoking habit. Low plasma vitamin E or adipose linoleate predisposes to angina, and smoking may increase the risk of angina by lowering plasma vitamin C levels in Scottish men.

The effect of estrogens on the plasma lipids in coronary artery disease.

Abstract 1. 1. Small doses of ethinyl estradiol depressed the plasma ester cholesterol in twenty hypercholesterolemic men with coronary artery disease. As the plasma phospholipids were uninfluenced, the plasma total-cholesterol: phospholipid ratio was also depressed. 2. 2. Some aspects of the role of the estrogenic hormones in lipid metabolism and atherosclerosis are discussed.

Effect of myocardial ischaemia and antilipolytic agents on lipolysis and fatty acid metabolism in the in situ dog heart.

Myocardial metabolism was studied in open-chest dogs before and during induction of myocardial ischaemia by coronary artery occlusion. Blood was sampled from a local coronary vein draining ischaemic tissue and from coronary sinus draining predominantly nonischaemic tissue. In the basal state, induction of myocardial ischaemia stimulated myocardial lipolysis as shown by release of glycerol from the ischaemic zone. During isoprenaline infusion, free fatty acids (FFA) extraction across the ischaemic myocardium was substantially increased, but no glycerol release occurred. Pretreatment with nicotinic acid or sodium salicylate markedly depressed FFA extraction across ischaemic myocardium, both during basal and isoprenaline stimulated lipolysis and nicotinic acid most likely inhibited lipolysis in the ischaemic zone. Thus, reduced severity of acute ischaemic injury by antilipolytic treatment might be due to a combination of inhibited myocardial lipolysis and reduced FFA extraction.

Adipose fatty acid composition and the risk of serious ventricular arrhythmias in acute myocardial infarction

The relation between subcutaneous adipose tissue fatty acid composition and serious ventricular arrhythmias during acute myocardial infarction was studied in 2 groups of patients. In group 1 (n = 42), studied retrospectively, patients with ventricular fibrillation or tachycardia had a higher concentration of long-chain saturated fatty acids than those without (32.5 +/- 0.8% vs 29.7 +/- 0.4% [mean +/- standard error of the mean], p less than 0.01). In a prospective study, patients with arrhythmias (n = 106) had higher levels of long-chain saturated fatty acids (32.1 +/- 0.5% vs 30.7 +/- 0.4%, p less than 0.05) and of stearic acid (4.9 +/- 0.2% vs 4.4 +/- 0.1%, p less than 0.02) and a lower concentration of palmitoleic acid (7.3 +/- 0.3% vs 8.1 +/- 0.2%, p less than 0.005). When peak plasma creatine kinase concentrations were included with the individual fatty acid levels in a multiple logistic regression, only creatine kinase correlated significantly with ventricular arrhythmias (p less than 0.01). Thus, saturated fatty acids in cardiac membranes may lead to greater vulnerability to ventricular arrhythmias, although infarct size is the only statistically significant predictor after multiple regression analysis.

Effects of Maxepa on serum lipids in hypercholesterolaemic subjects

The effect of dietary supplementation with 20 capsules/day Maxepa or olive oil on serum lipids has been studied in 21 hypercholesterolaemic patients using a double-blind crossover design. Platelet membrane eicosapentaenoic acid percentage rose by more than 10-fold after 2 months dietary supplementation with Maxepa. Total serum cholesterol was unchanged and there was a rise in LDL-cholesterol and HDL-cholesterol concentration in men, but no change in LDL-cholesterol, and a fall in HDL-cholesterol in women. In men and women there was a marked fall in total serum triglyceride, VLDL-triglyceride and VLDL-cholesterol levels. Thus, Maxepa is not an effective treatment for isolated hypercholesterolaemia.

Effects of p-chlorophenoxyisobutyrate on myocardial free fatty acid extraction, ventricular blood flow, and epicardial ST-segment elevation during coronary occlusion in dogs.

The effect of p-chlorophenoxyisobutyrate (CPIB) on ST-segment elevation in epicardial electrocardiographic recordings was studied during coronary artery occlusion in dogs. Occlusion alone raised the sum of ST-segment elevations (2ST) to 26 ± 6 mV (mean ±SEM). Intravenous (i.v.) administration of CPIB 30 min before re-occlusion reduced 2ST to 14 ± 3 mV (P < 0.03). A continuous i.v. infusion of isoproterenol increased ZST to 74 ± 11 mV. Pretreatment with CPIB reduced 2ST during isoproterenol infusion to 40 ± 7 mV (P < 0.005). CPIB had no effect on mean aortic blood pressure, heart rate, or regional myocardial blood flow, as measured by radioactive microspheres. Arterial free fatty acid (FFA) concentrations were reduced by CPIB from 466 ± 41 to 221 ± 44, aEq/L (P < 0.001) in the basal state, and from 1966 ± 183 to 1429 ± 209 μEq/L (P < 0.001) during isoproterenol infusion. The reduction in arterial FFA concentration was associated with a proportionate decrease in the myocardial extraction of FFA. Similar changes were observed when CPIB was administered during an occlusion which had been established 10 min earlier. These observations support other evidence that the severity of acute myocardial ischemic injury in dogs is positively correlated with the myocardial extraction of FFA, and that the severity of the ischemic injury can be reduced by effective antilipolytic therapy.