BACKGROUND AND AIMS: Hypertrophic cardiomyopathy (HCM) is a genetic cardiac disorder characterized by left ventricular hypertrophy (LVH), diastolic dysfunction, and impaired metabolic efficiency. This study investigates the therapeutic potential of the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin (EMPA) in ameliorating these pathological features in a mouse model carrying the myosin R403Q mutation. METHODS: Male mice harbouring the R403Q mutation were treated with EMPA for 16 weeks. Multi-nuclear magnetic resonance spectroscopy (31P, 13C, and 23Na MRS), echocardiography, transcriptomic, proteomic, and phosphoproteomic profiling were utilized to assess metabolic, structural, and functional changes. RESULTS: Empagliflozin facilitated the coupling of glycolysis with glucose oxidation and normalized elevated intracellular sodium levels. Treatment resulted in a significant reduction in LVH and myocardial fibrosis as evidenced by echocardiography and histopathology. These structural improvements correlated with enhancements in mitochondrial adenosine triphosphate (ATP) synthesis, fatty acid oxidation, and branched-chain amino acid catabolism. Furthermore, EMPA improved left ventricular diastolic function and contractile reserve, underscored by improved ATP production and reduced energy cost of contraction. Notably, these benefits were linked to down-regulation of the mammalian target of rapamycin signalling pathway and normalization of myocardial substrate metabolic fluxes. CONCLUSIONS: Empagliflozin significantly mitigates structural and metabolic dysfunctions in a mouse model of HCM, underscoring its potential as a therapeutic agent for managing this condition. These findings suggest broader applicability of SGLT2i in cardiovascular diseases, including those due to myocardial-specific mutations, warranting further clinical investigation.

Center for Network Systems Biology Department of Biochemistry Boston University School of Medicine Boston MA USA

Department of Anesthesia Critical Care and Pain Medicine Massachusetts General Hospital Boston MA USA

Department of Biomedical Engineering Boston University Boston MA USA

Department of Biomedical Engineering University of Arizona Tucson AZ USA

Department of Genetics Harvard Medical School Boston MA USA

Department of Medicine University of Arizona Tucson AZ USA

Division of Cardiovascular Medicine Brigham and Women's Hospital Boston MA USA

Harvard MIT Program in Health Sciences and Technology Institute for Medical Engineering and Science Massachusetts Institute of Technology Cambridge MA USA

Howard Hughes Medical Institute Chevy Chase MD USA

Laboratory of Metabolism of Bioactive Lipids Institute of Physiology of the Czech Academy of Sciences Prague Czech Republic

Myocardial Biology Unit Boston University School of Medicine 650 Albany Street Evans Biomed Research Ctr Boston MA 02118 USA

Physiological NMR Core Laboratory Brigham and Women's Hospital Harvard Medical School Boston MA USA

Wyss Institute for Biologically Inspired Engineering Harvard University Boston MA USA

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doi: 10.1093/eurheartj/ehaf395 PubMed

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