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).



Fig. 1 
Schematic depiction of myocardial substrate metabolism. Abbreviations: G 6-P, glucose 6-phosphate; TCA, tricarboxylic acid; GT, GLUT 1 and GLUT 4 glucose …

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

Regulation of fatty acid oxidation in the mammalian heart in health and disease.

https://era.library.ualberta.ca/items/9a2153b4-e031-4b45-97a8-6f1b11f4a614/view/d7c73d88-d526-4081-ba8d-aa52851f1105/NN10589.pdf

Acetyl-CoA carboxylase regulation of fatty acid oxidation in the heart.

Control of mitochondrial beta-oxidation flux.

The chronically failing heart has been shown to be metabolically abnormal, in both animal models and in patients. Little data are available on the rate of myocardial glucose, lactate and fatty acid metabolism and oxidation in heart failure patients, thus at present, it is not possible to draw definitive conclusions about cardiac substrate preference in the various stages and manifestations of the disease. Normal cardiac function is dependent on a constant resynthesis of ATP by oxidative phosphorylation in the mitochondria. The healthy heart gets 60-90% of its energy for oxidative phosphorylation from fatty acid oxidation, with the balance from lactate and glucose. There is some indication that compensated NYHA Class III heart failure patients have a significantly greater rate of lipid oxidation, and decreased glucose uptake and carbohydrate oxidation compared to healthy age-matched individuals, and that therapies that acutely switch the substrate of the heart away from fatty acids result in improvement in left ventricular function. Clinical studies using long-term therapy with beta-adrenergic receptor antagonists show improved left ventricular function that corresponds with a switch away from fatty acid oxidation towards more carbohydrate oxidation by the heart. These findings suggest that chronic manipulation of myocardial substrate oxidation toward greater carbohydrate oxidation and less fatty acid oxidation may improve ventricular performance and slow the progression of left ventricular dysfunction in heart failure patients. At present, this intriguing hypothesis requires further evaluation.

F DiLisa

Papers

Quantitation of the effect of L-carnitine on the levels of acid-soluble short-chain acyl-CoA and CoASH in rat heart and liver mitochondria.