2547-P: BCKDK Protects against Obesity-Related Heart Failure with Preserved Ejection Fraction by Modulating Mitochondrial ROS-Driven JNK/p38 MAPK Signaling

Introduction and Objective: Obesity is highly prevalent in heart failure with preserved ejection fraction (HFpEF). Impaired branched-chain amino acid (BCAA) catabolism has been implicated in HFpEF, and systemic inhibition of branched-chain ketoacid dehydrogenase kinase (BCKDK), a key negative regulator of BCAA oxidation, improves cardiac function. However, whether cardiomyocyte-specific manipulation of BCAA catabolism is sufficient to confer cardioprotection remains unknown. Methods: Cardiomyocyte-specific BCKDK knockout and overexpression mouse models were generated and subjected to echocardiography, transcriptomic, metabolomic, and molecular analyses in vivo and in vitro. Results: Despite reduced myocardial BCAA levels, cardiomyocyte-specific BCKDK deletion unexpectedly exacerbated cardiac dysfunction and ventricular remodelling in obese HFpEF. Notably, cardiac BCKDK expression is reduced in obese HFpEF. In contrast, cardiomyocyte-specific BCKDK overexpression markedly improved cardiac function and remodelling, accompanied by enhanced mitochondrial respiratory capacity and suppression of MAPK-driven inflammatory signalling, despite further reductions in myocardial BCAA levels. Mechanistically, mitochondrial ROS scavenging with mitoTEMPO rescued mitochondrial dysfunction and inflammatory activation induced by BCKDK deficiency. Conclusion: These findings reveal an unexpected BCAA-independent role of BCKDK in preserving cardiomyocyte mitochondrial function and restraining inflammatory signalling in obese HFpEF. Our study identifies cardiac BCKDK as a potential therapeutic target, while cautioning that systemic BCKDK inhibition may exert unanticipated adverse cardiac effects and overestimate cardioprotection driven primarily by extracardiac mechanisms. Disclosure Y. Liu: None. Y. Guo: None. H. Wang: None. Y. Fan: None. Z. Sun: None. Funding National Natural Science Foundation of China (82000334; 82270848), China Postdoctoral Science Foundation (2023M730571), Medical Research Project of Jiangsu Provincial Health Commission (MQ2024041), Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX22_0298)