FREE FATTY-ACID METABOLISM DURING MYOCARDIAL-ISCHEMIA AND REPERFUSION

Long chain free fatty acids (FFA) are the preferred metabolic substrat es of myocardium under aerobic conditions. However, under ischemic con ditions long chain FFA have been shown to be harmful both clinically a nd experimentally. Serum levels of free fatty acids frequently are ele vated in patients with myocardial ischemia. The proposed mechanisms of the detrimental effects of free fatty acids include: (1) accumulation of toxic intermediates of fatty acid metabolism, such as long chain a cyl-CoA thioesters and long chain acylcarnitines, (2) inhibition of gl ucose utilization, particularly glycolysis, during ischemia and/or rep erfusion, and (3) uncoupling of oxidative metabolism from electron tra nsfer. The relative importance of these mechanisms remains controversi al. The primary site of FFA-induced injury appears to be the sarcolemm al and intracellular membranes and their associated enzymes. Inhibitor s of free fatty acid metabolism have been shown experimentally to decr ease the size of myocardial infarction and lessen postischemic cardiac dysfunction in animal models of regional and global ischemia. The mec hanism by which FFA inhibitors improve cardiac function in the postisc hemic heart is controversial. Whether the effects are dependent on dec reased levels of long chain intermediates and/or enhancement of glucos e utilization is under investigation. Manipulation of myocardial fatty acid metabolism may prove beneficial in the treatment of myocardial i schemia, particularly during situations of controlled ischemia and rep erfusion, such as percutaneous transluminal coronary angioplasty and c oronary artery bypass grafting.