Sudden cardiac death: the lost fatty acid hypothesis.

Evidence that an excess of plasma free fatty acids (FFA) might lead to primary ventricular fibrillation and sudden cardiac death has hardened over the 36 years since the hypothesis was proposed. When the sympathetic nervous system is stimulated during the onset of an acute coronary syndrome, catecholamine-induced tissue lipolysis occurs, with a surge of plasma FFA. This may overload the acutely ischaemic myocardium and impair glucose utilization. Myocardial oxygen consumption can increase in regional areas of ischaemia, and could lead to abnormal electrophysiological conduction and refractoriness, with irreversible ventricular arrhythmias. Efforts to combat the adverse effects of excess FFA include beta-blockade, increasing glucose availability and extraction, or inhibition of lipolysis. This last approach appears promising, but no method has yet been clearly shown to prevent primary ventricular fibrillation or sudden cardiac death. The hypothesis remains viable. More research is needed to derive treatment that can be applied as soon as the onset of acute myocardial ischaemia is suspected.

Inverse relationship between serum Lp(a) levels and first-phase insulin secretion.

Relationships between serum Lp(a) levels and insulin metabolism were investigated in 147 healthy nonobese men attending an executive health-screening program. Each subject received an IVGTT with measurement of plasma levels of glucose, insulin, and C-peptide. An inverse relationship was seen with the first-phase plasma insulin response when subjects were stratified into quartile ranges of the serum Lp(a) distribution. This relationship was supported by mathematical modeling analyses of these data, which revealed an inverse relationship between serum Lp(a) levels and first-phase pancreatic insulin secretion and plasma insulin responsiveness to glucose.

Lack of impact of prevention on sudden cardiac death.

There are many different and relatively discrete mechanisms leading to ventricular fibrillation. Therefore, any single approach to prevention is likely to be unsuccessful, particularly because the circumstances that finally cause sudden cardiac death may not be present for more than a short time before the onset of ventricular fibrillation. It should not be surprising, therefore, that neither primary nor secondary prevention trials directed at correcting risk factors for coronary heart disease have been associated with a reduction in the incidence of sudden cardiac death. More trials are needed in patients with unstable angina, in whom there is a relatively high incidence of sudden cardiac death within a short period. Methods of modulating catecholamine response, myocardial vulnerability and thrombotic mechanisms require more formal testing. However, because the sensitivity and specificity of prediction of those likely to die suddenly are so poor, it may become necessary to accept that the majority of sudden cardiac deaths is not yet preventable and focus on continuing to improve cardiopulmonary resuscitation services.

Ventricular refractoriness during acute myocardial ischaemia and its relationship to ventricular fibrillation.

Studies were made in anaesthetised dog of the effects of repeated acute occlusions of a branch of the anterior descending coronary artery on ventricular refractory periods in adjacent ischaemic and non-ischaemic myocardium. Differences occurred in refractoriness between normal and ischaemic areas in the ventricle. This was greatest 2.5 min after occlusion, and on release of occlusion, ventricular refractory periods reverted to normal within 5 min. Spontaneous ventricular fibrillation was directly and significantly related to the degree of dispersion of refractoriness in a given dog immediately preceding release and following release of occlusion. Infusion of isoprenaline caused significant shortening of refactory period and increased dispersion of refractoriness during ischaemia. Studies of dispersion of refractoriness should prove valuable in assessing the efficiency of metabolic or antiarrhythmic protection against ventricular fibrillation.

Patterns of flow and conduction during early ventricular arrhythmias following coronary arterial occlusion in the dog.

The early ventricular arrhythmias of acute myocardial ischaemia arise against a background of rapid alterations in regional myocardial blood flow and electrophysiological properties. The relation between patterns of flow and epicardial activation has been examined in eight open chest anaesthetised dogs at time of onset of these arrhythmias following a proximal occlusion of the left anterior descending coronary artery. Data were derived from 80 epicardial and endocardial sites within a 4 X 5 cm area of left ventricular free wall and processed utilising a three-dimensional computer plotting program. Mean flow within the ischaemic zone was reduced to 0.27 and 0.24 cm3 x g-1 x min-1 in epicardium and endocardium respectively. Marked epicardial activation delays and fragmentation of conduction were observed confined to areas of flow less than 0.3 cm3 x g-1 x min-1. 74% of endocardial and 71% of epicardial tissue samples within the ischaemic zone derived from this area and analysis of flow distribution between adjacent samples demonstrated spatial heterogeneity of flow. It is suggested that local spatial variability in flow within the central ischaemic region may be a prerequisite for abnormal fractionation of conduction leading to re-entrant excitation at the time of onset of early ventricular arrhythmias.

Effects of dichloroacetate on myocardial substrate extraction, epicardial ST-segment elevation, and ventricular blood flow following coronary occlusion in dogs.

Glucose metabolism in the healthy heart is stimulated by dichloroacetate (DCA). The possibility has been examined in dogs that DCA, by increasing glucose utilization, might limit the severity of acute myocardial ischaemic injury. Intravenous administration of DCA reduced the degree of epicardial ST-segment elevation induced by subsequent coronary occlusion, both under basal conditions and during isoprenaline infusion. A similar result was obtained when DCA was given during an established coronary occlusion. This effect could not be explained by changes in mean aortic blood pressure, heart rate, or regional myocardial blood flow as measured by radioactive microspheres. Measurements in arterial and coronary sinus blood demonstrated an increase in the extraction of glucose and a decrease in that of FFA by the heart. Glucose extraction also tended to be increased in the ischaemic zone, as shown by the differences in the concentrations of these substrates between arterial blood and blood obtained from the local vein draining that zone. Lactate release by the ischaemic zone was markedly reduced.

Relationship of neurosympathetic responsiveness to early ventricular arrhythmias in ischaemic myocardium.

Myocardial catecholamine overflow has been measured in open-chest anaesthetised dogs after graded stimulation of the left ansa subclavia before and during left anterior descending coronary artery occlusion and on reperfusion. Sequential 1 min periods of ansa stimulation over 3 h resulted in reproducible, frequency dependent regional myocardial noradrenaline (NA) overflow without tachyphylaxis. In seven dogs, two successive 10 min periods of LAD occlusion did not modify peak myocardial NA overflow from the predominantly ischaemic (I) or non-ischaemic (NI) areas at either low (1 Hz) or high (10 Hz) frequency ansa stimulation. In a second group of nine dogs, myocardial catecholamine overflow was related to changes in ischaemic area epicardial activation delay during repeated ansa stimulation on four occasions during 75 min of ischaemia. Stimulation at the period of peak spontaneous arrhythmias 5 and 17 min after coronary occlusion resulted in NA overflow from I of 2.8 +/- 1.3 and 3.0 +/- 1.6 pmol X ml-1 respectively and a significant increase in mean activation delay in I of 12 +/- 4 ms at 5 min and 9 +/- 4 ms at 17 min (p less than 0.05). In contrast, stimulation 30 and 60 min after coronary occlusion, when spontaneous arrhythmias are rare, was not associated with NA overflow from ischaemic areas (0.3 +/- 0.3 and 0.9 +/- 0.5 pmol X ml-1 respectively) and resulted in a minor reduction in mean activation delay in ischaemic areas of 2 +/- 3 ms at 30 min and 3 +/- 4 ms at 60 min. NA overflow from non-ischaemic areas and increases in blood pressure and myocardial lactate release were similar during each period of ansa stimulation. Coronary reperfusion induced massive overflow of NA (11.4 +/- 2.8 pmol X ml-1) and reduced extraction of adrenaline (A) from ischaemic areas with a time course similar to early reperfusion arrhythmias. Stimulation-evoked release of NA in ischaemic myocardium is thus maintained during the early period of enhanced vulnerability to arrhythmias and during reperfusion but is inhibited after 30 min. This temporal variability may be a factor in the time course of spontaneous arrhythmias in this model.

It is more important to increase the intake of unsaturated fats than to decrease the intake of saturated fats: evidence from clinical trials relating to ischemic heart disease.

The evidence from formal, controlled, long-term clinical trials that changes in dietary fats reduce the incidence of ischemic (coronary) heart disease (IHD) is unimpressive. Mostly these trials were underpowered and in several the rigor of dietary control in the intervention and control groups was inadequate. Six controlled clinical trials in healthy people of diets low in saturated fat and cholesterol, also accompanied by changes in other risk factors, were unsuccessful in reducing the incidence of IHD. An exception was the Oslo trial in which concurrent cigarette smoking was almost halved. Similarly, in the only two clinical trials of the secondary prevention of IHD through use of diets low in saturated fats and cholesterol there was no significant effect on IHD recurrence rate. This may relate to poor compliance outside strict clinic conditions. In contrast, five of six secondary prevention trials in which diets low in saturated fats were supplemented with polyunsaturated fats reduced IHD deaths and, to a lesser extent, all-cause mortality. No formal trial has been reported of the effects on IHD of diets high in monounsaturated fats. The greatest benefit for patients with IHD has come from diets supplemented with n-3 fatty acids (two trials), and this benefit was independent of changes in plasma lipoproteins. The evidence from these clinical trials indicates that more emphasis should be given in national and international dietary recommendations to supplementation with polyunsaturated fats, particularly foods rich in n-3 fatty acids, than to diets low in total and saturated fats.

Alcohol consumption and nutrient intake in middle-aged Scottish men.

The relation between alcohol consumption and dietary intake was examined in 164 middle-aged Scottish men taking part in a study of risk factors for coronary heart disease (CHD). A 7-d weighed dietary record was used to assess alcohol and nutrient intake. The mean daily intake of alcohol was 26 g (SD 31 g). Energy derived from alcohol tended to replace energy derived from other nutrients and increasing intake of alcohol was associated with a decrease in the amounts of carbohydrate, total fat, and saturated and monounsaturated fatty acids in the diet. Those with a low alcohol intake (0.1-9 g alcohol/d) had a higher intake of total fiber, cereal fiber, polyunsaturated fatty acids, and linoleic acid and a smaller proportion smoked cigarettes. The differences are small but may contribute to the lower mortality from CHD reported by other studies in those with a low alcohol intake.

Effect of pindolol versus atenolol on lipid profile in hypertensive patients.

The effect of pindolol (a beta-blocker with intrinsic sympathomimetic activity, ISA) on fasting plasma lipid profile in 30 hypertensive patients was compared with atenolol (without ISA) in a crossover single blind study. Both drugs lowered blood pressure. HDL-cholesterol increased significantly with pindolol (from 1.15 +/- 0.05 to 1.34 +/- 0.05 mmol/l at 12 weeks, P less than 0.001), but not with atenolol. VLDL-cholesterol increased with atenolol (from 0.57 +/- 0.09 to 0.86 +/- 0.14 mmol/l at 12 weeks, P less than 0.002), while there was no change with pindolol. These changes in lipoprotein profile suggest a more favourable effect of pindolol than of atenolol on lipid profile.

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 safflower oil and evening primrose oil in men with a low dihomo-gamma-linolenic level.

Low levels of essential polyunsaturated fatty acids of the n-6 series are associated with coronary heart disease. Linoleic acid, but not gamma-linolenic acid requires the activity of delta 6-desaturase for its conversion to dihomo-gamma-linolenic and arachidonic acid. Evening primrose oil (EPO) and safflower oil (SO) are rich in linoleic acid, but EPO contains also 9% gamma-linolenic acid. The effect of EPO (10, 20 and 30 ml/day) and SO (20 ml/day) for 4 months on the deposition of linoleic acid metabolites in adipose tissue of 4 groups of 6-9 men with low adipose dihomo-gamma-linolenic acid was examined. EPO but not SO increased adipose dihomo-gamma-linolenic acid level from 0.080 +/- 0.005% to 0.101 +/- 0.005% (P less than 0.01; 20 ml/day for 4 months). Adipose dihomo-gamma-linolenic/linoleic acid ratio increased with EPO from 0.99 +/- 0.16 X 10(2) to 1.13 +/- 0.14 X 10(2) and fell on SO from 1.04 +/- 0.10 X 10(2) to 0.90 +/- 0.07 X 10(2) (P less than 0.01). Similar qualitative changes in the relative amount of dihomo-gamma-linolenic acid in serum triglyceride and cholesteryl ester fractions were observed. At the dose of 20 ml/day, SO and EPO did not differ in their effect on serum cholesterol (7.13 +/- 0.43 vs. 7.33 +/- 0.42 mmol/l (NS)), LDL-cholesterol (5.10 +/- 0.32 vs. 4.88 +/- 0.46 mmol/l (NS)) nor did the 2 oils differ in their effect on HDL-cholesterol. These results suggest that linoleic acid is not readily converted to dihomo-gamma-linolenic acid due to a low activity of delta 6-desaturase in these highly selected men. EPO was not an effective hypocholesterolaemic agent in this study.

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.

Relationships of plasma viscosity, coagulation and fibrinolysis to coronary risk factors and angina.

Plasma viscosity, molecular markers of activated coagulation and fibrinolysis (fibrinopeptides A and B beta 15-42), coagulation factors (fibrinogen and factor VII) and antiplasmins were measured in 529 men aged 35-54 years and related to new angina pectoris (n = 117) and to coronary risk factors in controls without angina (n = 412). Five major risk factors (cigarette-smoking, blood pressure, cholesterol, triglyceride and body mass index) were each associated with increases in plasma viscosity, coagulation factors, and imbalance of coagulation over fibrinolysis (increased ratio of fibrinopeptide A/fibrinopeptide B beta 15-42). Increased viscosity and fibrinogen in smokers were partly reversed in ex-smokers, but the imbalance of coagulation and fibrinolysis persisted. Cholesterol and triglyceride were also associated with increased antiplasmin activity. In men with angina, only fibrinogen was elevated compared to controls. We suggest that increased plasma viscosity and an imbalance of coagulation over fibrinolysis may be mechanisms by which known risk factors promote arterial thrombosis, but are not present in stable angina.

Mechanisms of phase 1a and 1b early ventricular arrhythmias during acute myocardial ischemia in the dog.

Two phases of ventricular arrhythmia occur within the first 30 minutes of experimental myocardial ischemia. Possible differences in their mechanisms of pathogenesis were investigated in anesthetized dogs by detailed mapping of patterns of epicardial activation and regional myocardial blood flow during phase 1a and phase 1b early ventricular arrhythmias induced by high ligation of the left anterior descending coronary artery. Data were derived from 80 sites in a 4 by 5 cm area of left ventricular anterior free wall and displayed using computer graphics. Regional myocardial blood flow and the relation of regional flow to epicardial delay did not differ significantly during the 2 phases of arrhythmia in central ischemic or nonischemic areas, although epicardial flow in border region segments was increased during phase 1b. Significantly greater mean epicardial delays and spatial heterogeneity of epicardial delay (assessed by intersite variance within the ischemic area) occurred during phase 1a arrhythmias. Serial studies show striking increases in spatial heterogeneity of delays during phase 1a, but not during phase 1b, relating to temporal dispersion of a phenomenon of transient prolongation of activation delay at individual electrode sites. These data are consistent with the concept that phase 1a and 1b arrhythmias arise through different electrophysiologic mechanisms independent of flow-dependent effects.

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.

Rationale and design of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study that evaluates atorvastatin in unstable angina pectoris and in non-Q-wave acute myocardial infarction.

The goal of the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) study is to determine whether early, rapid, and profound cholesterol lowering therapy with atorvastatin can reduce early recurrent ischemic events in patients with unstable angina or non-Q-wave acute myocardial infarction. Within 1 to 4 days of hospitalization for one of these conditions, 2,100 patients will be randomly assigned to receive atorvastatin, 80 mg/day, or placebo in a double-blind design. Both groups receive dietary counseling. Over a 16-week follow-up period, the primary outcome measure is the time to occurrence of an ischemic event, defined as death, nonfatal acute myocardial infarction, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization. Secondary outcome measures are the time to occurrence and incidence of each of the primary outcome components, as well as nonfatal stroke, worsening angina, congestive heart failure requiring hospitalization, and need for coronary revascularization not anticipated before randomization. The sample size of 1,050 patients in each group is expected to provide 95% power to detect a 30% reduction in the primary outcome measure with a 5% level of significance. The results of the MIRACL study will determine the utility of profound cholesterol lowering as an early intervention in acute coronary syndromes.

Blood pressure, cigarette smoking and heart attack in the WHO co-operative trial of clofibrate.

In the WHO sponsored trial of clofibrate and its follow-up, about 15,000 men were observed for a mean period of 13.2 years. As expected, incidence of heart attacks (HA) was directly related to serum cholesterol, blood pressure (BP) and cigarette smoking. The previously reported lower incidence of HA in men receiving clofibrate compared with controls was most noticeable in hypertensive heavy smokers (P less than 0.01). BP was slightly lower in smokers than non-smokers (P less than 0.01). The difference in BP was greater in the trial visit before HA. Smokers also had higher plasma fibrinogen levels (P less than 0.05). The combination of reduced diastolic BP, and therefore myocardial perfusion pressure, with an increased thrombogenic tendency, might explain the high incidence of HA in smokers. Clofibrate apparently reduced fibrinogen levels, which might account for its specially good effect in preventing HA in smokers. However, the ill effects of smoking are still evident at a lower level in the men taking clofibrate and the drug is no substitute for giving up the habit. Clofibrate is not recommended for widespread use, except in subjects with marked lipid and/or blood fibrinogen abnormalities after dietary measures have been tried.

Adipose tissue fatty acids and blood pressure in middle-aged men from southern Italy.

Adipose tissue (AT) biopsies were performed in a random population sample of 74 clinically healthy middle-aged men (40-49 years) from southern Italy. The percentage of saturated fatty acids (FA) in AT was directly correlated with systolic (SBP) and diastolic (DBP) blood pressure (p less than 0.01). This relationship was independent of smoking habit and body weight. AT of men in the upper DBP quintile (range 90-102 mmHg) was significantly richer in palmitic acid (p less than 0.01) compared to that of men in the lowest DBP quintile. Dietary history demonstrated that the overall intake of saturated fat (% energy) was similar in the two extreme DBP quintiles. There was a relatively higher consumption of fish by those in the lowest DBP quintile (p less than 0.05). The amount of monounsaturated fat consumed (% energy) was also higher (p less than 0.05) in men with low blood pressure. Men in the upper quintile of DBP consumed more eggs (p less than 0.05).

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.