Role of Metabolic Modulation in the Management of Chronic Ischemic Heart Disease

Coronary artery disease (CAD) is a major cause of morbidity and mortality in the world. Therapy for stable CAD is currently based on conventional medical therapy, including nitrates, β-blockers and calcium-channels antagonists and, more recently, metabolic therapy, of which a pivotal therapeutic role is increasingly recognized. Under normoxic condition, the healthy heart derives 2/3 of its energy from the free fatty acid (FFA) pathway, the other source of energy being derived from glucose oxidation. However, glycolysis requires less O2 per mole of ATP generated compared with FFA oxidation. On this basis, shifting energy substrate utilization from fatty acid metabolism to glucose metabolism can be more efficient in terms of ATP production per mole of oxygen utilized. A number of different approaches have been used to manipulate energy metabolism in the heart. These approaches include direct agents, such as dichloroacetate, L-carnitine, ribose or lipoic acid which directly increase glucose oxidation, or indirect methods, through the inhibition of free fatty acids oxidation. Among these, the most important are carnitil-palmitoyl-transpherase I (CPT-I) inhibitors, which inhibit FFA mitochondrial uptake (e.g. etomoxir, perhexiline, oxphenicine), or 3-ketoacyl-coenzyme-A thiolase (3-KAT) inhibitors, such as trimetazidine, which inhibits the last enzyme involved in β-oxidation. In most patients with ischemic heart disease metabolic abnormali- ties, if not adequately treated, will heavily contribute to the occurrence of complications, of whom severe left ventricular dysfunction is at present one of the most frequent and insidious. In this paper, all possible metabolic approaches to ischemic heart disease are reviewed and discussed.