Myocardial energy metabolism during ischemia and the mechanisms of metabolic therapies.
The primary effect of ischemia is reduced aerobic adenosine triphosphate (ATP) formation in mitochondria. This triggers accelerated glycolysis and reduced cell pH, Ca(2+) accumulation, K(+) efflux, adenosine formation, and the clinical signs of ischemia: chest pain and a shift in the ST segment. Traditional therapies for angina are aimed at either decreasing the need for ATP by suppressing heart rate, blood pressure, and cardiac contractility, or at increasing oxygen delivery to the mitochondria, or both. An additional approach to treating angina is to suppress myocardial fatty acid oxidation, increase pyruvate oxidation, and reduce anaerobic glycolysis. High fatty acid levels result in oxygen wasting and inhibit the oxidation of pyruvate in the mitochondria. In experimental models, the partial inhibition of myocardial fatty acid oxidation with agents such as oxfenicine, ranolazine, and trimetazidine stimulates glucose oxidation and reduces lactate production during ischemia. Clinical studies demonstrate that this approach is as effective as traditional hemodynamic therapies at improving exercise tolerance and reducing the frequency of angina. Moreover, because these agents do not suppress heart rate, blood pressure, or contractility, they are effective as add-on therapy to Ca(2+)-channel and beta-adrenergic receptor antagonists.
Stanley
William C
WC
Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA. wcs4@case.edu
D000818:Animals; D050260:Carbohydrate Metabolism; D004311:Double-Blind Method; D004734:Energy Metabolism / Q000187:drug effects / Q000502:physiology; D005227:Fatty Acids / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000627:therapeutic use; D006019:Glycolysis / Q000187:drug effects; D006801:Humans; D017202:Myocardial Ischemia / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism*; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D019289:Pyruvic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000627:therapeutic use; D013312:Stress, Physiological / Q000150:complications / Q000378:metabolism
D005227:Fatty Acids; D019289:Pyruvic Acid