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Plasma free fatty acids (non-esterified fatty acids) increase in the first hour of the onset of acute myocardial ischaemia. This results from catecholamine stimulation of adipose tissue lipolysis. It can lead to a metabolic crisis in the injured myocardium with the development of ventricular arrhythmias and increased early mortality. Preconditioning, β-adrenergic blockade and glucose-insulin-potassium are possible therapeutic approaches, but anti-lipolytic agents, such as some nicotinic acid derivatives, can reduce plasma free fatty acid concentrations within minutes and have untried potential. A clinical trial of their effectiveness is needed from the first moment when a patient with an acute coronary syndrome is seen by paramedics.

During the onset of an acute coronary syndrome, an immediate increase in plasma free fatty acid (FFA) concentrations presents the ischaemic underperfused myocardium with a metabolic challenge to its survival. For the maintenance of contraction and to counter ventricular arrhythmias, parenteral treatment to reduce FFA availability should be available for paramedics when the patient is first seen. The best treatment options are insulin which partly inhibits FFA release from adipose tissue, immediate reduction of adipose tissue lipolysis, perhaps by new analogues of nicotinic acid, or measures to decrease the FFA/molar binding ratio with albumin. None has yet been tested in appropriate clinical trials.

Fatal ventricular fibrillation is a common complication of acute coronary syndromes. Effective preventive measures are not available. Immediate restriction of free fatty acid availability should optimize ischemic myocardial metabolism, reduce ventricular vulnerability, and increase glucose utilization. Rapid inhibition of lipoprotein lipase activity will achieve this. The clinical effects of antilipolytic treatment require further study.

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.

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.

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.

1. The mechanism whereby p-chlorophenoxyisobutyrate (CPIB) lowers plasma non-esterified fatty acid concentrations has been studied in dogs by measuring the associated changes in adipose tissue metabolism. 2. CPIB lowered arterial concentrations of non-esterified fatty acids during isoprenaline infusion by a mean value of 41%. 3. This was accompanied by a proportionate decrease (45%) in the release of non-esterified fatty acids from subcutaneous adipose tissue in situ, and by a lesser reduction (22%) in than of glycerol. 4. Adipose tissue blood flow was unchanged by CPIB. 5. These findings indicate that the lowering effect of CPIB on non-esterified fatty acid concentrations derives principally from decreased mobilization rather than from increased tissue uptake of the fatty acids, and that this reflects both inhibited lipolysis and enhanced re-esterification of the fatty acids in adipose tissue.

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.

1. Intravenous infusions of lipid-free albumin were used to lower the arterial non-esterified fatty acids (NEFA)/albumin ratio during coronary occlusion in dogs. 2. Reduction of the NEFA/albumin ratio was accompanied by proportionate reductions in myocardical uptake of NEFA and the degree of ST segment elevation in epicardial electrocardiographic recordings from the ischaemic zone. Aortic pressure and heart rate were unchanged. 3. Infusions of control albumin preparations had no effect on the NEFA/albumin ratio or ST segment elevation. 4. These observations support the proposition that the disturbance of cellular function during myocardial ischaemia is influenced by the degree of saturation of albumin-binding sites with NEFA and by their availability.

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.

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.

Free fatty acids (FFA) are elevated in plasma soon after the onset of symptoms associated with developing myocardial infarction. Levels above 1200 mu Eq./L. are associated with a significantly increased incidence of serious ventricular arrhythmias, heart block and sudden death. Evidence is presented from experimental myocardial infarction in dogs to show that high levels of FFA can themselves cause arrhythmia, although catecholamines are mainly responsible for the mobilization of FFA during clinical episodes of acute myocardial ischemia. It is postulated that high concentrations of FFA irrespective of the mode of elevation have a deleterious effect on the function of the heart during hypoxia. These observations offer a new therapeutic approach to the management of arrhythmias and of acute myocardial infarction. Attention should be directed to blocking FFA release from adipose tissue and to providing the hypoxic myocardial cells with a concentration of glucose which will provide adequate substrate for all energy requirements of the heart.