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The cumulative occlusion rates of aorto-coronary artery venous bypass grafts average from 16 to 26% per distal anastomosis within 12 months and about 2% per following year. The potential benefit of oral anticoagulants and platelet inhibitor drugs has been tested to prevent graft occlusion and to retard the atherosclerotic process. Oral anticoagulants started on the third postoperative day do not significantly reduce graft occlusion after 6 months. Among the platelet inhibitor drugs, dipyridamole started before surgery, followed by dipyridamole and aspirin soon after surgery, was the drug regimen with the best results. More randomised double-blind clinical trials are highly desirable to confirm these findings and to resolve the question of relative efficacy and safety for the various drugs reported to have shown benefit when used in combination.

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.

The scoring of premature ventricular contractions (PVC) after myocardial infarction provides little accurate information about infarct size or about other ventricular arrhythmias, although it might be of some immediate prognostic value. Continuous recording with computer analysis and differentiation of serious ventricular arrhythmias has shown in untreated patients that the incidence of PVC does not reflect that of other ventricular arrhythmias. Ventricular tachycardia and R-on-apex T PVC continue without significant decrease in incidence up to 12 hours after the onset of symptoms. Primary ventricular fibrillation is rare after about 5 hours and stands on its own in significance.

[Profound alterations in metabolism occur within the first few minutes of myocardial ischaemia which may induce or modulate myocardial electrophysiological abnormalities and arrhythmogenesis, Fatty acid oxidation is inhibited with accumulation of long-chain acyl CoA esters and glycolysis is stimulated but later inhibited. This may be worsened by a peripheral sympathetic response. In particular regional variations in glycolytic ATP productions which can modulate "slow channel" ion flux and hence slow conducting "slow response" potential activity, could influence patterns of slow conduction in ischaemic myocardium of importance in generating early re-entrant arrhythmias. This possibility has been examined in open chest anaesthetised dogs following experimental coronary occlusion by detailed computer aided analysis and construction of three dimensional maps of regional metabolism, blood flow and epicardial activation patterns at the time of early ventricular arrhythmias. Activation patterns were obtained using an electronic multiplexing system, flow using tracer microspheres and metabolic changes by analysis of multiple tissue samples for lactate and indices of glycolytic activity after rapid excision and freezing of the heart. Marked spacial inhomogeneities in flow, lactate and glycolytic activity were associated with delayed and fragmented activation in the central ischaemic region. Within the border region of flow, however, glycolytic activity was enhanced and conduction generally little impaired. It is suggested that transient changes in the homogeneity of myocardial metabolism and flow are critical in determining patterns of conduction and hence arrhythmogenesis. This may provide a basis for understanding anti-arrhythmic effects of metabolic interventions.

Free fatty acid concentrations in plasma measured after in vivo heparinisation are often overestimated because of ex vivo lipolysis of variable degrees. A new method has been developed using immediate extraction of blood which obviates this and shows that the true rise in plasma free fatty acid concentration after heparin in ambulant ward patients and in patients with acute myocardial infarction is less than previously reported. The small rise in plasma free fatty acid concentration after heparin is unlikely to have adverse metabolic effects in most patients during acute myocardial infarction.

An autopsy protocol, devised specifically for the pathologic study of sudden cardiac death, is presented. In addition to providing guidelines for the precise clinical documentation of the patients studied, it emphasizes a number of areas of potential importance needing further and detailed exploration, including the cardiac conducting system, and the intramyocardial microvascular circulatory bed. Some of the problems and procedural approaches recommended are briefly discussed.

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).

The relation between coronary heart disease (CHD) and fatty acid composition of adipose tissue and platelets was examined in a random sample of 448 middle-aged Scottish men. The linoleic acid (18:2n6) content in adipose tissue of 28 men with previously unidentified CHD was significantly lower than that in the rest of the group. Platelet linoleic and other fatty acids were not significantly different in men with new CHD. Fatty acid content of adipose tissue reflects long-term dietary intake, and a 7-day weighed dietary record in a random sub-sample of 164 men confirmed that intake of linoleic acid in 10 of the 28 new CHD cases was significantly lower than in the healthy men. In a multiple logistic analysis adipose tissue linoleic acid, age, high density lipoprotein cholesterol, and weight/height index each made an independent contribution to the explanation of new CHD. When all fatty acids were included in a second regression analysis, low concentrations of dihomo-gamma-linolenic (20:3n6) acid in adipose tissue showed a more significant relation with new CHD than did linoleic acid.

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.

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 (sigmaST) to 26 +/- 6 mV (mean +/- SEM). Intravenous (i.v.) administration of CPIB 30 min before re-occlusion reduced sigmaST to 14 +/- 3 mV (P less than 0.03). A continuous i.v. infusion of isoproterenol increased sigmaST to 74 +/- 11 mV. Pretreatment with CPIB reduced sigmaST during isoproterenol infusion to 40 +/- 7 mV (P less than 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 muEq/L (P less than 0.001) in the basal state, and from 1966 +/- 183 to 1429 +/- 209 muEq/L (P less than 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.

The effects of sulphinpyrazone on heart-rate and blood-pressure responses to exercise were assessed in 15 normal volunteers by a randomised double-blind crossover technique. Submaximal exercise tests were performed 1 and 2 hours after either sulphinpyrazone (SPZ) 200 mg orally or placebo. Heart-rate and blood-pressure responses were unchanged at rest and during exercise 1 hour after SPZ but after 2 hours there was a significant fall in the product of heart-rate and blood-pressure during exercise (peak 35.8 +/- 1.5 x 10(-3) mmHg beats/min, placebo: 33.0 +/- 1.3 x 10(-3) sulphinpyrazone, p < 0.005) and for the first 2 minutes of recovery. This was mainly due to a decreased exercise-induced rise in systolic blood-pressure with lesser effects on heart-rate. This haemodynamic effect of SPZ has a potentially protective oxygen-sparing effect on the normal myocardium during exercise and may explain its apparent benefit in reducing sudden cardiac death after myocardial infarction.

1. The turnover of plasma glucose and free fatty acids was measured in ten patients within 24 h of the onset of symptoms of acute myocardial infarction and in two with symptoms of acute myocardial ischaemia. The measurements were repeated in seven of the patients 12-40 weeks after the acute episode. 2. Both for the patients with acute myocardial infarction alone and for all the individuals studied the turnover of glucose increased with plasma glucose concentration but was not related to the turnover of free fatty acids or the plasma concentrations of free fatty acids, insulin or total catecholamines. There was no obvious difference in the nature of the glucose turnover-concentration relationship between the patients with acute myocardial infarction, with acute myocardial ischaemia and on re-examination. 3. For all the individuals studied the turnover of free fatty acids increased with the concentration of these but was not related to the turnover of glucose or the plasma concentrations of glucose, insulin or total catecholamines. There was no obvious difference in the nature of the free fatty acids turnover-concentration relaionship between the patients with acute myocardial infarction, with acute myocardial ischaemia and on re-examination.

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.

In middle-aged men and women, mortality from ischaemic heart disease and cerebrovascular disease is highest in the north and west of Britain. The worst region is West Central Scotland. Statistical analysis using a linear logistic model shows that the differences between the regions are significant and the yearly fluctuation in numbers of deaths contributes little to the overall variation.

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.

The effect of lowering raised plasma-free-fatty acids (F.F.A.) on the incidence of serious ventricular arrhythmias after myocardial infarction was assessed by a double-blind trial in eighty-one patients. A nicotinic-acid analogue (N.A.A.) with very slight haemodynamic effects was given within 12 hours of the onset of myocardial infarction to lower plasma-F.F.A. When treatment with N.A.A. was started within 5 hours of the onset of symptoms, the numbers of patients with ventricular symptoms, the numbers of patients with ventricular tachycardia were significantly reduced, provided elevated plasma-F.F.A. levels were rapidly lowered and maintained in the normal range throughout the treatment period. The incidence of R-on-apex T ventricular premature beats and beats in which the ectopic R wave interrupted the apex of the T wave of a previous ventricular premature beat was also reduced in patients receiving N.A.A within 5 hours of the onset of symptoms. Plasma-total-catecholamines and serum-creatine-kinase levels were similar in the N.A.A.-treated and placebo groups. N.A.A. rarely caused skin flushing, but vomiting occurred in some patients after many hours of treatment. These findings suggest that treatment directed towards stabilsing the matabolism of the ischaemic myocardium can be of therapeutic value and lead to fewer serious ventricular arrhythmias.

The effects of carbocromen on myocardial substrate uptake, myocardial oxygen consumption (MVO2), and the mechanical activity of the heart was studied in eight intact, anaesthetized dogs. Carbocromen was given i.v. as an injection of 2 mg/kg body weight, and measurements performed in the basal condition and during isoprenaline infusion. Carbocromen increased myocardial blood flow and reduced coronary vascular resistance 15 and 30 min after administration, whereas these values returned to normal after 60 min. The myocardial performance, net myocardial uptake of free fatty acids (FFA), glucose and lactate and MVO2 were not changed by carbocromen. A second isoprenaline infusion 90 min following carbocromen administration induced changes in myocardial performance, net substrate uptake and oxygen consumption not significantly different from isoprenaline infusion prior to carbocromen administration. The antianginal effects by carbocromen observed in clinical studies are more likely to be mediated through its known coronary vasodilator effect than any influence on myocardial metabolism.

In order to determine whether the development of myocardial infarction in different countries is associated with different risk factors, 240 male survivors, aged 40 or less, were studied in nine countries. In the seven centres in developed countries (Auckland, Melbourne, Los Angles/Atlanta, Cape Town, Tel Avic, Heidelberg, and Edinburgh) there was a high procedure of risk factors, particularly of hyperlipidaemia and cigarette smoking. The prevalence of hypertension, obesity, hyperglycaemia, and hyperuricaemia varied from centre to centre. Risk factors were less prevalent in Bombay and Singapore: the most common risks operating in Bombay seemed to be cigarette smoking and hyperglycaemia, while in Singpore cigarette smoking was the commonest. The mean age of the whole group was 35.4 years. Serum cholesterol levels of 7.25 mmol/l (280 mg/dl) or more were present in 25 per cent of all patients, serum triglyceride levels of 2.26 mmol/l )l200 mg/dl) or more in 35 per cent. 80 per cent of the patients were smokers, and 15 per cent were either for hypertension before myocardial infarction or had a raised blood pressure after myocardial infarction. Obesity was found in 19 per cent of all patients and serum uric acid levels over 0.5 mmol/l (8.5 mg/dl) in 17 per cent. 10 per cent of all patients were either treated for diabetes mellitus before myocardial infarction or showed an abnormal glucose tolerance after myocardial infarction. This collaborative study may help, by showing differences in the prevalence of risk factors, to indicate to each centre and to national and to international organizations, the direction for their future studies into the causation and prevention of myocardial infarction in young men.

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.

Plasma concentrations of adenosine 3':5' cyclic monophosphate (cyclic AMP) and free fatty acids have been measured in 15 patients with acute myocardial infarction and in 6 dogs given infusions of isoprenaline. Plasma total catecholamines were also estimated in the patients. Inhibition of adipose tissue lipolysis with a nicotinic acid analogue did not decrease plasma cyclic AMP concentrations, either in the patients or when elevated in the dogs, thus suggesting that this tissue is not a major source of the nucleotide in plasma.