Modulation of Myocardial Energetics

Abstract

The traditional paradigm for heart failure management centered on mitigating the hemodynamic changes that occur in response to the failing heart. Subsequently, pharmacological modulation of neurohormonal activation and more recently cardiac resynchronization have been shown to reverse ventricular remodeling and to slow disease progression. Despite these advances in therapy, successful treatment of heart failure remains challenging, with rates of hospitalization in the United States exceeding 1 million per year and the annual number of heart failure–related deaths increasing steadily.1 Unfortunately, the history of drug development for heart failure has been marked by many disappointments, most notably the excess mortality associated with oral positive inotropes that were targeted at improving hemodynamics. In addition, more recent interventions aimed at interrupting endothelin and cytokine signaling or reducing oxidative stress have yet to fulfill hopes for novel biological therapies. Thus, new therapeutic strategies are needed to alter the natural history of the disease and to slow or reverse current epidemiological trends. The report by Lee and colleagues2 in this issue of Circulation points toward the promise of an alternative approach based on favorably influencing the efficiency of myocardial energetics, thereby increasing cardiac performance without depending on changes in oxygen consumption or improvement in hemodynamics. Article p 3280 The study of agents aimed at enhancing myocardial energy efficiency has focused principally on shifting myocardial substrate use toward more oxygen-efficient pathways.3 Although the complete oxidation of fatty acids to CO2 yields more adenosine triphosphate (ATP) per molecule of CO2 produced than does complete oxidation of glucose, a greater amount of oxygen is required to completely oxidize a fatty acid of equivalent carbon-chain length. Therefore, for a given amount of oxygen consumed, metabolism of glucose is more “oxygen efficient,” producing ≈15% more ATP (Figure).3,4 Production of ATP and consumption of …