Empagliflozin reduced left ventricular mass from 119 ± 18 mg to 94 ± 15 mg and improved LV ejection fraction from 56 ± 3% to 65 ± 2% in a mouse model of LVH (both p<0.0001).
Does empagliflozin improve cardiac structure and function in a mouse model of established left ventricular hypertrophy?
Empagliflozin reverses established pressure-overload-induced left ventricular hypertrophy and improves systolic function in mice via metabolic reprogramming and restoration of mitochondrial oxidative metabolism.
Abstract Background Left ventricular hypertrophy (LVH) represents a maladaptive response to chronic pressure overload and a key precursor of heart failure. Metabolic inflexibility and mitochondrial dysfunction are central contributors to this process. Sodium–glucose cotransporter-2 inhibitors (SGLT2i) exert robust cardioprotective effects, yet their myocardial mechanisms in LVH remain incompletely understood. Objective To test whether empagliflozin (EMPA) reverses established LVH in association with cardiometabolic reprogramming. Methods Adult male (n=59) and female (n=53) A/J mice underwent transverse aortic constriction (TAC). Four weeks post-surgery, animals received EMPA (30 mg/kg/day, p.o.) or vehicle for four weeks. Cardiac structure and function were assessed by serial echocardiography. Left-ventricular bulk RNA sequencing, metabolic enzyme assays, and high-resolution respirometry (glutamate/malate, octanoyl-carnitine, ADP) were performed to delineate cardiometabolic remodeling. Results TAC induced pronounced LVH (p0.0001), systolic dysfunction (LV-EF: baseline TAC 72 ± 2 %, TAC+EMPA 71 ± 4 %; week 4 TAC 57 ± 6 %, TAC+EMPA 56 ± 3 %, p0.0001), and metabolic derangement (p0.05) in both sexes. EMPA treatment significantly reduced LV mass (119 ± 18 mg vs 94 ± 15 mg, p0.0001) and improved LV-EF (week 8 TAC 56 ± 3 % vs TAC+EMPA 65 ± 2 %, p0.0001). Transcriptomic profiling revealed restoration of oxidative phosphorylation, fatty-acid β-oxidation, and TCA-cycle programs (FDR0.05), with suppression of PI3K–AKT signaling, extracellular-matrix remodeling, and inflammatory cascades (FDR0.05). Despite comparable structural and functional recovery in both sexes, enhanced mitochondrial respiration was restricted to females, suggesting sex-dependent modulation of EMPA’s mitochondrial effects. Enzymatic profiling confirmed a metabolic shift toward oxidative pathways, evidenced by increased pyruvate and succinate dehydrogenase activities, elevated pyruvate:lactate ratio, and reduced glycolytic enzyme activity (p0.05). Conclusion Empagliflozin promotes structural and functional recovery in established pressure-overload-induced LVH through coordinated transcriptional and metabolic reprogramming that restores mitochondrial oxidative metabolism. These findings identify SGLT2i as a promising disease-modifying approach capable of inducing reverse remodeling in hypertrophic heart disease.
Ernst et al. (2026) studied this question. Empagliflozin reduced left ventricular mass from 119 ± 18 mg to 94 ± 15 mg and improved LV ejection fraction from 56 ± 3% to 65 ± 2% in a mouse model of LVH (both p<0.0001).