Empagliflozin enhances metabolic efficiency and improves left ventricular hypertrophy in a hypertrophic cardiomyopathy mouse model

Tomas Baka; Jarrod Moore; Fuzhong Qin; Salva R Yurista; Aifeng Zhang; Huamei He; Jordan M Chambers; Dominique Croteau; Raghuveera K Goel; Hunter Smith; Miranda C Wang; Christopher S Chen; Ion A Hobai; Martina Rombaldova; Ondrej Kuda; Jil C Tardiff; James A Balschi; David R Pimentel; Christine E Seidman; Jonathan G Seidman; Andrew Emili; Wilson S Colucci; Ivan Luptak

doi:10.1093/eurheartj/ehaf324

Empagliflozin enhances metabolic efficiency and improves left ventricular hypertrophy in a hypertrophic cardiomyopathy mouse model

Eur Heart J. 2025 May 21:ehaf324. doi: 10.1093/eurheartj/ehaf324. Online ahead of print.

Authors

Tomas Baka¹, Jarrod Moore², Fuzhong Qin¹, Salva R Yurista¹, Aifeng Zhang¹, Huamei He³, Jordan M Chambers¹, Dominique Croteau¹, Raghuveera K Goel², Hunter Smith¹, Miranda C Wang^{4

5

6}, Christopher S Chen^{4

5}, Ion A Hobai⁷, Martina Rombaldova⁸, Ondrej Kuda⁸, Jil C Tardiff^{9

10}, James A Balschi³, David R Pimentel¹, Christine E Seidman^{11

12

13}, Jonathan G Seidman¹¹, Andrew Emili², Wilson S Colucci¹, Ivan Luptak¹

Affiliations

¹ Myocardial Biology Unit, Boston University School of Medicine, 650 Albany Street, Evans Biomed Research Ctr (room 704B), Boston, MA 02118, USA.
² Center for Network Systems Biology, Department of Biochemistry, Boston University School of Medicine, Boston, MA, USA.
³ Physiological NMR Core Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
⁴ Department of Biomedical Engineering, Boston University, Boston, MA, USA.
⁵ Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA, USA.
⁶ Harvard-MIT Program in Health Sciences and Technology, Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁷ Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Boston, MA, USA.
⁸ Laboratory of Metabolism of Bioactive Lipids, Institute of Physiology of the Czech Academy of Sciences, Prague, Czech Republic.
⁹ Department of Biomedical Engineering, University of Arizona, Tucson, AZ, USA.
¹⁰ Department of Medicine, University of Arizona, Tucson, AZ, USA.
¹¹ Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹² Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹³ Howard Hughes Medical Institute, Chevy Chase, MD, USA.

PMID: 40396194
DOI: 10.1093/eurheartj/ehaf324

Abstract

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.

Keywords: Branched-chain amino acids; Cardiac energetics; Cardiac metabolism; Hypertrophic cardiomyopathy; Metabolic reprogramming; SGLT2 inhibition; Uncoupled glycolysis; mTOR.

Abstract

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