Regulation of myocardial carbohydrate metabolism under normal and ischaemic conditions Potential for pharmacological interventions

Abstract

Time for primary review 28 days. The regulation of mammalian myocardial carbohydrate metabolism is complex in that it is linked to arterial substrate and hormone levels, coronary flow, inotropic state and the nutritional status of the tissue. Optimal cardiac function under normal and pathological conditions is dependent upon glycolysis and pyruvate oxidation. The purpose of this review is to examine the regulation of myocardial carbohydrate metabolism under physiological conditions, and during myocardial ischaemia and reperfusion. The therapeutic potential of a variety of pharmacological interventions affecting myocardial carbohydrate metabolism will then be discussed. The tricarboxylic acid cycle (TCA cycle) provides reducing equivalents for mitochondrial oxidative phosphorylation, resulting in the condensation of ADP and inorganic phosphate to regenerate ATP, and is fueled by acetyl-CoA formed primarily from oxidation of pyruvate and fatty acids (Fig. 1). Cardiomyocytes oxidise fatty acids derived from both the plasma and the breakdown of intracellular triacylglycerol stores, while pyruvate is derived from either lactate dehydrogenase or glycolysis. The rates of these metabolic pathways are tightly coupled to the rate of contractile work, and conversely, contractile work is coupled to the supply of oxygen and the rate of oxidative phosphorylation (Fig. 1). Early studies in animals [1] and human [2, 3] showed that after an overnight fast the heart extracts free fatty acids (FFA), lactate and glucose from the blood, and that if one assumes complete oxidation of extracted substrates, fatty acids are the major oxidative fuel for the heart (60–100% of the oxygen consumption), with a lesser contribution from lactate and glucose (0–20% from each) [2, 3]. Subsequent studies by others using a variety of experimental approaches have confirmed these early results (see [4–7] for reviews).