L.H. Opie

Effects of glucose and fatty acids on myocardial ischaemia and arrhythmias

Evidence for the utilisation of substrates by the ischaemic myocardium and its dependence for viability on a critical supply of glucose was established many years ago. It was recognised that an excess of free fatty acids (FFA) could increase the severity of ischaemic damage and possibly be arrhythmogenic. But metabolic intervention to improve survival during acute myocardial infarction was not regarded as a priority, perhaps because of uncertainty about its value and the advent of trials of beta-blocker and antiarrhythmic drugs. There has never been an adequate trial of the benefit to the ischaemic or infarcting myocardium of increasing local glucose concentrations or reducing the availability of FFA. We have taken into account new knowledge of the effects of fatty acids on cation channels and brought up to date the arguments for metabolic intervention with glucose-insulin solutions or antilipolytic drugs sustained ischaemia.

SUDDEN DEATH AND SPORT

Of 21 sudden deaths in sportsmen, 18 were thought to be caused by heart attacks either during or after sport. There was firm evidence of ischaemic heart-disease in 9, strongly suggestive evidence in 7, but in 2 there was only suggestive clinical evidence. As a group, these subjects were characterised by (1) a mean age above thirty (above twenty-five for rugby players); (2) a family history of early heart-attacks; and (3) antecedent symptoms of chest pain or pressure in 9, fatigue or blackout in 4, and minor complaints in 2. Most were known to their medical practitioners. Psychological factors were thought to be important in 8. Doctors, players and referees should be aware that severe sporting exertion as in rugby football involves a risk which for most players is relatively minor, but in the minority predisposed to heart-attacks by family history, smoking, or age (as in referees) the risk is more serious. To reduce hazard of sudden death in exercise, players and referees should be warned against smoking and informed of the serious implications of the development of chest pain, pressure, or undue tiredness before, during, or after sport.

PROPOSED METABOLIC VICIOUS CIRCLE IN PATIENTS WITH LARGE MYOCARDIAL INFARCTS AND HIGH PLASMA-FREE-FATTY-ACID CONCENTRATIONS

The relation between peak plasma-free-fatty-acid (F.F.A) concentration and size of infarct--as estimated by the plasma-creatine-kinase technique--was investigated in twenty patients with acute myocardial infarction. In eight patients with large infarcts (more than 65 g equivalents) mean infarct size was 136+/-21 g equivalents and mean peak F.F.A. value in the first 12 h was 1-99+/-0-14 mmol/l (mean +/-S.E.M.). In twelve patients with small infarcts, mean infarct size was 36+/-5 g equivalents and mean peak F.F.A. was 1-22+/-0-13 mmol/l (P less than 0-001). Experimental evidence suggests that high circulating F.F.A. concentrations could further extend ischaemic damage. The association between high plasma-F.F.A. and infarct size may give rise to a vicious circle which increases the severity of the ischaemic process in patients with high plasma-F.F.A.

Cyclic adenosine monophosphate, ventricular fibrillation, and antiarrhythmic drugs.

It is proposed that the development of ventricular fibrillation in the context of ischaemic heart-disease and myocardial infarction can be related to accumulation of cyclic adenosine 3,5 monophosphate (A.M.P.) in the ischaemic zone. The known electrophysiological and metabolic actions of cyclic A.M.P. are consonant with the hypothesis, which also provides a framework for the better understanding of the action of antiarrhythmic drugs.

Protective action of amiodarone against ventricular fibrillation in the isolated perfused rat heart

The pretreatment of rats with amiodarone for 2 minutes to 3 weeks before the excision of their hearts caused a dose-related decrease in heart rate and an increase in the ventricular fibrillation threshold both before and after coronary arterial ligation. Similarly, amiodarone decreased the incidence of ventricular premature extrasystoles, ventricular tachycardia and fibrillation during the period of regional ischemia after coronary arterial ligation and also after reperfusion of the ischemic myocardium. There was no evidence of a metabolic protective effect on ischemic myocardium because tissue high energy phosphate content decreased to a similar extent in ischemic myocardium from control and amiodarone-treated rats. Instead, the protective effect of amiodarone against fibrillation was accompanied by attenuation of the increase in tissue cyclic adenosine monophosphate in ischemic myocardium after coronary arterial ligation. It is proposed that amiodarone exerts a potent antifibrillatory effect by decreasing tissue cyclic adenosine monophosphate in ischemic myocardium.

LIPID METABOLISM OF THE HEART AND ARTERIES IN RELATION TO ISCHÆMIC HEART-DISEASE

Abstract A knowledge of the lipid metabolism of the arterial wall and the myocardium makes it possible to identify metabolic factors, other than increased cholesterol and triglyceride levels, which might be important in the development of ischaemic heart-disease. Special attention is paid to the possible roles of catecholamines and free fatty acids both in accelerating the atheromatous process and in increasing the oxygen demand of the heart.

CYCLIC A.M.P. AND ARRHYTHMIAS REVISITED

Further evidence is presented for a hypothesis linking cyclic adenosine 3, 5 monophosphate (cyclic A.M.P.) and arrhythmias: in the isolated rat heart, changes in tissue cyclic A.M.P. are accompanied by changes in the ventricular-fibrillation threshold; and in the pig, large infarcts are associated with raised tissue cyclic A.M.P. and ventricular fibrillation, whereas small infarcts are not. Data showing that changes in the metabolism of potassium, glucose, fatty acids, and lactate can influence the action-potential duration are incorporated into a revised hypothesis which allows for multifactorial arrhythmogenic mechanisms in the early stages of acute myocardial infarction.

The effects of oral sucrose and of estimated infarct size on plasma free fatty acids, plasma glucose and serum insulin in the early stages of acute myocardial infarction

Abstract. Twenty‐two patients with early myocardial infarction were studied to test the effect of oral sucrose as an antilypolytic agent. Without sucrose, plasma free fatty acids rose to a peak (mean 1.48 mM/l 8 h after onset of symptoms) and then fell spontaneously by 32% of the peak level in 2 h. Sucrose had no effect on the peak fatty acid level and did not accelerate the initial rate of fall in the first 2 h. Where the peak free fatty acid was less than 1.5 mM/l, however, it fell to a lower level in patients given sucrose (P < 0.05). A subsequent rebound of free fatty acid values, as seen in starved patients, was delayed for about 6 h in sucrose‐fed patients. The responses of free fatty acid, glucose and insulin varied according to the size of the infarct as estimated by the plasma creatine kinase method. Patients with larger infarcts (>65 creatine kinase gram equivalents) had higher insulin and blood sugar levels on and after admission, and had higher plasma free fatty acid peaks than patients with smaller infarcts (≤65 creatine kinase gram equivalents). When patients with larger infarcts were given oral sucrose, the rise in blood glucose was higher and more sustained than in patients with small infarcts and there was no insulin response. The insulin response to sucrose was normal in those with smaller infarcts. Thus oral sucrose was an effective antilipolytic agent only in patients with smaller infarcts.

Anti-ischemic properties of calcium-channel blockers: Lessons from cardiac surgery

Calcium-channel blocking agents (CCBs) (or calcium antagonists) were originally introduced to counteract myocardial ischemia and, in particular, angina pectoris. It was only later that their antihypertensive qualities came to be understood and commercially exploited. About 25 years ago, when the