Metabolic Modulation in Heart Disease

Abstract

Ischemic heart disease and pulmonary arterial hypertension are often accompanied by a drastic change in myocardial energy metabolism that favors fatty acid oxidation and glycolysis, respectively, over glucose oxidation. This form of energy production is both inefficient and detrimental to the myocardium. However, both the glucose and fatty acid oxidative pathways can be targeted to improve cardiac function. Specifically, decreasing fatty acid oxidation and/or increasing glucose metabolism can improve cardiac efficiency in these disease states. This thesis examines the metabolic changes in pulmonary hypertension and demonstrates the therapeutic advantages of metabolic modulation with dichloroacetate through restoring oxidative metabolism. We also investigate the effect of altered fatty acid metabolism on cardiac recovery following an ischemic episode using the acetyl CoA carboxylase-2 knockout mouse. Increased rates of fatty acid oxidation impair cardiac efficiency, but following ischemia these hearts sustain little injury owing to an adaptation in the 5’-AMPK–ACC–malonyl CoA pathway.