Comprehensive Fuel Metabolism Of The Human Heart And The Role For Enhancing Branched Chain Amino Acid Catabolism In Protection Against Heart Failure

Danielle Murashige, University of Pennsylvania

Abstract

Heart failure is a leading cause of morbidity and mortality worldwide. Despite a wide recognition that heart failure is characterized by an inability of the heart to produce sufficient ATP from available fuel sources, a comprehensive map of fuel metabolism in the human heart is lacking. Such an understanding would be of great clinical value, as there is growing interest in the potential for metabolically-directed agents as a novel class of therapeutics for heart failure treatment. Using metabolomics on paired arterial, coronary sinus, and femoral venous blood samples from patients with or without heart failure, we measured uptake and release of over 275 metabolites by the heart and leg. Our results confirmed that the human heart voraciously consumes fatty acids and that cardiac reliance upon fatty acids as fuel source is attenuated in heart failure. We further found that both non-failing and failing human heart consume ketones in direct proportion to circulating availability. Failing heart significantly increased reliance on ketones as fuel, which was predominantly due to increased ketone availability with a relatively minor increase in fractional uptake. Unexpectedly, the heart secretes, rather than consumes, abundant amino acids such as alanine and glutamine, indicating active protein breakdown that is significantly increased in heart failure. We next focused on branched chain amino acid (BCAA) metabolism, as diminished cardiac BCAA catabolism has been suggested as a causative element in HF progression. Using in vivo isotope infusions, we found that cardiac BCAA oxidation increases, rather than decreases, across multiple models of murine heart failure. Using various genetic models we then showed that cardiac-specific activation of BCAA oxidation does not protect against HF, even though systemic activation of BCAA oxidation does. Surprisingly, activation of BCAA catabolism lowers blood pressure, a well-established cardioprotective mechanism. Mendelian randomization studies revealed that elevations in plasma BCAAs predict higher blood pressure in large human cohorts, lending support to a role for BCAA metabolism in blood pressure regulation. Collectively, these studies provide a quantitative framework for understanding human cardiac metabolism and suggest a novel means by which enhanced systemic BCAA catabolism may protect against HF progression.