Abstract Body: Background: Heart failure with preserved ejection fraction (HFpEF) is among the leading causes of cardiovascular mortality and morbidity. Recent multi-omics data sets underscore severely impaired branched-chain amino acid (BCAA) catabolism in the failing hearts of HFpEF patients. 3-mercaptopyruvate sulfurtransferase (3-MST) is a mitochondrial hydrogen sulfide (H₂S) synthase that regulates mitochondrial biogenesis, function, and substrate metabolism.
Research Questions and Goals: In the current study, we aimed to elucidate the role of 3-MST in myocardial BCAA catabolism in cardiometabolic HFpEF.
Methods: 3-MST knockout or wild-type (WT) mice were subjected to control or L-NAME and high fat diet - induced HFpEF. Echocardiographic measurements, invasive hemodynamic assessment, and exercise capacity testing were conducted to determine HFpEF severity. Metabolomic analysis was performed to study BCAA catabolism. Additionally, a H₂S donor, SG1002 was administered to increase H₂S bioavailability in the setting of 3-MST deficiency and HFpEF.
Results: We observed progressive deterioration in left ventricular (LV) diastolic function and exercise performance from mice subjected to HFpEF. Genetic ablation of 3-MST further-exacerbated HFpEF severity as evidenced by significantly increased E/e’ ratio, elevated LV end-diastolic pressure, and reduced exercise performance. Metabolomic analysis revealed pathological accumulation of intermediate metabolites of BCAA in the HFpEF hearts, suggesting a major derangement in myocardial BCAA catabolism. 3-MST KO hearts exhibited further BCAA catabolic defects as compared to those from WT. Importantly, H₂S donor treatment significantly attenuated BCAA catabolic defect and alleviated HFpEF severity in both WT and 3-MST KO HFpEF mice.
Conclusion: Our results demonstrate that deficiency of 3-MST impairs myocardial BCAA catabolism, which results in exacerbated HFpEF severity in a “two-Hit” mouse model of HFpEF. These data suggest 3-MST is critically involved in physiological substrate metabolism within the mitochondria and exerts beneficial effects in HFpEF. Future experiments are underway to delineate the mechanisms by which 3-MST regulates BCAA catabolism.