Abstract 15515: SGLT2 Inhibitor Empagliflozin Increases Fatty Acid Oxidation, Coupling Between Glycolysis and Glucose Oxidation, and Decreases Left Ventricular Hypertrophy in Mice With Hypertrophic Cardiomyopathy Due to Myosin R403Q Mutation

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Background: A metabolic switch from fatty acid oxidation (FAO) to glycolysis associates with LV hypertrophy (LVH). Glucagon signaling increases FAO in the heart and sodium-glucose co-transporter 2 inhibitors (SGLT2i) raise glucagon/insulin ratio (GIR) in patients. We have shown that SGLT2i reprogram cardiac metabolic genes favoring FAO, yet the mechanism is unknown. Hypothesis: SGLT2i increases GIR, thereby increasing FAO and glycolysis/glucose oxidation coupling (GGC), which in turn attenuates LVH and fibrosis in a murine model of HCM (R403Q myosin mutation). Methods: Mice 9 weeks of age were treated ± SGLT2i empagliflozin (EMPA, 0.15 mg/g chow). After 2 weeks, prior to LVH onset, myocardial transcriptomic analysis was performed. After 16 weeks, echocardiography, proteomics, fasted GIR, and histology were obtained. Glucose fluxes, energetics and 13 C substrate oxidation were measured in isolated beating hearts by 31 P and 13 C NMR spectroscopy. Results: R403Q mice had ↓GIR which was normalized by EMPA. Transcriptomics (2 weeks) and proteomics (16 weeks) confirmed downregulation of electron transport and FAO pathways, and upregulation of LVH and fibrosis pathways. At 16 weeks, R403Q hearts exhibited LVH, fibrosis, ↓diastolic function and ↓contractile reserve (rate pressure product increase between low and high workload). Metabolically, R403Q had ↑glucose uptake and ↓GGC with ↑lactate production; ↓FAO and impaired energetics (↓free energy of ATP hydrolysis, ΔG ~ATP , at both workloads). The HCM phenotype and all measures of metabolic dysfunction were partially or completely prevented by EMPA. Conclusion: R403Q hearts display marked metabolic reprogramming that appears early in the disease process and leads to energetic dysfunction. SGLT2i corrects GIR, attenuates metabolic reprogramming and the energetic, structural and functional features of HCM. SGLT2i and possibly other measures to modulate glucagon signaling hold therapeutic potential in HCM.