The investigation was undertaken to study the effect of free fatty acids (FFA) on the performance of the ischaemic myocardium and the role of myocardial lipolysis in contributing to tissue FFA concentration. An initial investigation using heart muscle extracts demonstrated cyclic-AMP stimulation of lipase hydrolysis of triglycerides but not monoglyceride. Subsequently, an investigation of the role of myocardial lipolysis in the ischaemically-perfused rat heart was begun. The results demonstrated the deleterious effects on heart performance of FFA generated from myocardial triglyceride. Exogenous FFA had much less effect, arguing for a more potent effect or greater availability of endogenously-generated FFA. With hearts from normally-fed rats, adrenaline induced inotropic and chronotropic (first phase) responses. These were followed by marked (second phase) deteriorations in performance - decline in beatrate and developed tension, increases in resting tension and incidence of arrhythmias - which were proportional to the rates of lactate and FFA release. The deteriorations were greatly reduced by the abolition of the lipolytic component of the adrenaline challenge with nicotinic acid, at concentrations which did not inhibit the first phase responses. Reduction of FFA release also encouraged glucose oxidation. With hearts from fat-fed rats (depending exclusively upon endogenous lipid as an energy source) performance was depressed whilst lipolysis was stimulated relative to the normally-fed series. In addition, the performance of these hearts declined more markedly after adrenaline - the high incidence of ventricular fibrillation (V.F.) being particularly marked. Nicotinic acid again offered protection - in particular, abolishing V.F. In both series, adrenaline challenge increased the tissue FFA concentration and this was offset with nicotinic acid. In addition, adrenaline greatly stimulated the accumulation of FFA within the myocardium. The deteriorative effects on performance could not be ascribed solely to FFA since lactate was usually increased. However, several observations suggest that FFA are of primary significance and these factors are discussed.
|Date of Award||1975|