Effective Metabolic Approaches for the Energy Starved Failing Heart: Bioenergetic Resiliency via Redundancy or Something Else?

Abstract

One of the major unresolved questions in cardiovascular physiology is which steps in the cascade of carbon substrate preference, mitochondrial ATP production, conduction, and utilization ultimately limit maximal performance of a normal heart or contribute to the dysfunction of a failing heart.1–4 For the past 3 decades or more, scientists have been trying to modulate carbon substrate utilization by increasing or decreasing glucose or free fatty acid utilization and more recently by modulating ketone body metabolism, as a metabolic therapeutic approach to treat heart failure.5 Approaches have included modulating carbon substrate utilization and flux by altering the expression of substrate transporters, key metabolic enzymes, allosteric regulators of these pathways, or mitochondrial oxidative capacity as metabolic approaches to examine the old hypothesis that a failing heart is energy starved. Some of these studies have supported the hypothesis although others have not. There is no question that myocardial energy flux and mitochondrial capacity is reduced in the failing heart.3,4,6 The question is whether these changes are causal or a secondary adaptation of the failing heart. For example, increasing substrate flux capacity before the insult has in some instances decreased the susceptibility to heart failure,7,8 however, the modulation of metabolism at the time of the hemodynamic insult might not prevent contractile dysfunction.9 Moreover, increasing mitochondrial biogenesis might not prevent left ventricular (LV) dysfunction despite maintaining mitochondrial capacity.10 Examination of myocardial substrate intermediates before and after LV assist device implantation suggest the existence of mitochondrial plasticity, and examination of mitochondrial respirometry in isolated mitochondria from failing hearts in vitro have not revealed overt defects in oxidative capacity.11 Two concepts that warrant further …