The SGLT2 Inhibitor Empagliflozin Enhances Metabolic Efficiency and Ameliorates Left Ventricular Hypertrophy in Myosin R403Q Mutant Hypertrophic Cardiomyopathy Mice

Background: 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 empagliflozin (EMPA) in ameliorating these pathological features in a mouse model carrying the myosin R403Q mutation. Methods: Male mice harboring the R403Q mutation were treated with EMPA for 16 weeks. We utilized multinuclear magnetic resonance spectroscopy (31P, 13C, 23Na MRS), alongside echocardiography, transcriptomic, proteomic, and phosphoproteomic profiling to assess metabolic, structural, and functional changes. Results: EMPA 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 ATP synthesis, fatty acid oxidation (FAO), and branched-chain amino acid (BCAA) catabolism. Furthermore, empagliflozin 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 downregulation of the mTOR signaling pathway and normalization of myocardial substrate metabolic fluxes. Conclusion: EMPA 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 SGLT2 inhibitors in cardiovascular diseases, including those due to myocardial-specific mutations, warranting further clinical investigation. Overall design: We hypothesized that treatment with EMPA would improve cardiac energetics, contractile function and structure in HCM. To test this hypothesis, we studied mice carrying the myosin R403Q mutation treated with EMPA for 16 weeks. Through the application of multinuclear MR spectroscopy (31P, 13C, and 23Na MRS), alongside transcriptomic, proteomic, and phosphoproteomic profiling, we determined that EMPA treatment facilitates the coupling of glycolysis with glucose oxidation and normalizes the elevated intracellular sodium levels observed in HCM myocardium. Nine-to-ten-week-old male mice harboring R403Q mutation in cardiac myosin heavy chain or wild-type littermates were fed ad libitum a control diet or the same diet enriched with EMPA for 16 weeks. Transcriptomic analysis was conducted in 12-week-old R403Q hearts prior to the onset of left ventricular hypertrophy.