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

分解代谢 医学 心力衰竭 支链氨基酸 阿霉素 二甲双胍 癌症 药理学 内科学 癌症研究 内分泌学 氨基酸 化疗 生物 生物化学 新陈代谢 亮氨酸 胰岛素
作者
Feixiong Cheng,Jessica C. Lal,Yuan Hou,Jonathan Smith,David R. Van Wagoner,Patrick Collier,Mina K. Chung
出处
期刊:Circulation [Lippincott Williams & Wilkins]
卷期号:148 (Suppl_1)
标识
DOI:10.1161/circ.148.suppl_1.15504
摘要

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.

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