Ketone Bodies as a Therapeutic Strategy for Heart Failure

Abstract

The heart undergoes fuel metabolic re-programming during the pathologic remodeling process that leads to the syndrome of heart failure resulting in reduced capacity to burn fatty acids, the chief fuel for the normal heart. This fuel utilization impairment sets the stage for a vicious cycle of energy starvation and contractile dysfunction. Using integrated proteomic and metabolomic profiling, we identified signatures of increased ketone body oxidation in the failing mouse heart. Others found similar signatures in failing human heart. We have embarked on a series of studies aimed at determining whether a shift to ketone body oxidation is adaptive for the failing heart. Mice lacking â-hydroxybutyrate dehydrogenase 1 (BDH1), the enzyme that catalyzes the first step in 3-hydroxybutyrate (3HB) oxidation, developed a more severe heart failure phenotype than wild-type animals when subjected to a pressure overload/ischemic insult protocol. Administration of a ketogenic diet to wild-type mice reduced abnormal ventricular remodeling in the mouse heart failure model. To further determine whether increased ketone body delivery could ameliorate the development of heart failure, 3HB was infused in a well-defined canine tachypacing heart failure model. 3HB infusion resulted in dramatic improvement of ventricular dysfunction and remodeling. Studies conducted in human failing cardiac myocytes demonstrated a benefit of administering 3HB, along with fatty acids and glucose as fuels. Lastly, a series of studies in isolated mitochondria, in the context of limiting fatty acids, demonstrated that 3HB enhances oxidative phosphorylation efficiency and respiratory thermodynamics due, in part, to maintaining a more reduced redox (NADH/NAD) state. Taken together, we conclude that the shift to ketone body oxidation in heart failure is adaptive and that strategies to increase myocardial ketone body delivery show promise for the treatment of heart failure.