Branched chain amino acids in heart failure

SUMMARY Heart failure (HF) is a leading cause of death worldwide, and the leading cause of hospital admissions in patients over 65 in the US. Novel therapies, addressing novel pathways, are direly needed. The role of metabolism in cardiac pathology has long been of interest. We have focused for several years on the role of branched chain amino acids (BCAAs: leucine, valine, isoleucine), which have been noted for decades to be elevated in heart failure, and often to predict adverse outcomes. Preclinical studies from numerous labs including ours has provided compelling evidence that systemic activation of BCAA catabolism is beneficial in heart failure, and multiple pharmaceutical companies are actively developing novel agents to do so in humans. Despite these efforts, mechanistically how activation of BCAA catabolism protects from heart failure remains surprisingly unknown. During the current funding period we have made substantial headway in addressing this question, and we have come to surprising conclusions, most notably: (1) that the cardiac benefits of promoting BCAA catabolism are not direct, but rather occur secondary to BCAA oxidation in other tissue(s), and (2) that BCAA catabolism promotes vasodilation. These data and additional preliminary data thus lead us to hypothesize that: Systemic activation of BCAA catabolism activates BCAA catabolism in smooth muscle cells (SMCs), leading to SMC relaxation, cardiac vasodilation, improved myocardial blood flow (MBF), and cardioprotection. We will test this hypothesis by: Aim 1: Identify how BCAA catabolism in SMCs inhibits vasoconstriction. Aim 2: Test if BCAA catabolism in smooth muscle cells promotes cardiac vasodilation and MBF. Aim 3: Test the role of smooth muscle BCAA catabolism in cardioprotection. Aim 4: Test if systemic activation of BCAA catabolism promotes cardiac MBF in humans. These highly focused studies will elucidate the role of BCAA catabolism in cardio-protection. Deep understanding of BCAA catabolism in the context of heart failure may lead to novel therapeutics.