Abstract 15504: Impaired Branched-Chain Amino Acid Catabolism is Associated With Chemotherapy-Induced Heart Failure and Rescued by Metformin

Abstract

Introduction: Heart failure resulting from cancer therapies represents a major cause of morbidity in cancer survivors. Interventional strategies to prevent and treat heart dysfunction in cardio-oncology patients continue to remain a challenge. Hypothesis: We posit that Branched-Chain Amino Acid Catabolism (BCAA) catabolism dysfunction is a likely causal mechanistic pathway in the pathogenesis of CTHF. Methods: In this study, we leveraged electronic health records , human-induced pluripotent stem cell ( iPSC )-derived cardiomyocyte model-based mechanistic studies, murine models, and network medicine-basedtranscriptomics analytic methodologies, to suggest that rescuing BCAA catabolic dysfunction is a promising approach for managing chemotherapy-induced heart failure, using doxorubicin as a prototypical example. Results: In our large-scale cardio-oncology cohort, we observed a significant incidence of heart dysfunction and abnormal NT-proBNP levels among patients treated with doxorubicin. Using murine heart failure models, we identified significant correlations between the abundance of branched-chain amino acids (isoleucine, leucine, and valine) and cardiac dysfunction after doxorubicin exposure. Mechanistic observations in human-induced pluripotent stem cell (iPSC)-derived cardiomyocyte models further support impaired branched-chain amino acid (BCAA) catabolism by doxorubicin. Through metabolite-enzyme network analysis, we identified metformin as a repurposable drug capable of restoring branched-chain amino acid catabolism, thereby improving mitochondrial function. Human iPSC-based mechanistic studies revealed that metformin combined with doxorubicin resulted in improved insulin signaling, endothelial cell reprogramming, increased RARA gene expression (a key doxorubicin-induced heart failure GWAS gene) and reduced pro-fibrotic signaling. Furthermore, we demonstrate that metformin improved murine cardiac function following doxorubicin exposure. Conclusions: Our findings utilized electronic health records, iPSC-based mechanistic studies, and murine models to suggest that BCAA catabolic dysfunction may be a promising approach for managing chemotherapy-induced heart failure.