Is it time to reassess the role of myocardial metabolic modulation for the treatment of heart failure?

Abstract

Under normal conditions, the heart utilizes a variety of substrates (primarily fatty acids, glucose, and lactate) to support overall oxidative metabolism which is the primary engine for energy production. The biochemical reactions that control the metabolism of these various substrates provide dynamic and uniquely reciprocal control of substrate flux through myocardial fatty acid (FA) b-oxidation and glycolytic pathways as dictated by ever-changing physiologic conditions such as the plasma substrate environment, neurohumoral milieu, and level of cardiac work. These acute adaptations in substrate selection and metabolism are central to cardiac myocyte health.However, in the progression of cardiac hypertrophy to left ventricular (LV) dysfunction this flexibility in substrate use is lost. Nearly 50 years ago, Wittels and Spann made the seminal observation in pig heart that systolic dysfunction, in response to aortic constriction, was associated with a decrease in the oxidation of palmitate, a long-chain fatty acid.1 This observation was confirmed by numerous subsequent studies that led to the general paradigm that the expression of genes encoding for enzymes regulating b-oxidation are coordinately decreased, resulting in a shift in myocardial substrate metabolism to primarily glucose use, similar to that seen in the fetal heart.2 These metabolic changes are paralleled by re-expression of fetal isoforms of a variety of contractile and calcium regulatory proteins. It should be noted that this metabolic adaptation becomes more complex when there is concomitant insulin resistance.