Empagliflozin promotes structural and functional recovery through cardiometabolic reprogramming in a mouse model of left ventricular hypertrophy
Abstract
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.
To test whether empagliflozin (EMPA) reverses established LVH in association with cardiometabolic reprogramming.
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.
TAC induced pronounced LVH (p<0.0001), systolic dysfunction (LV-EF: baseline TAC 72 ± 2 %, TAC+EMPA 71 ± 4 %; week 4 TAC 57 ± 6 %, TAC+EMPA 56 ± 3 %, p<0.0001), and metabolic derangement (p<0.05) in both sexes. EMPA treatment significantly reduced LV mass (119 ± 18 mg vs 94 ± 15 mg, p<0.0001) and improved LV-EF (week 8 TAC 56 ± 3 % vs TAC+EMPA 65 ± 2 %, p<0.0001). Transcriptomic profiling revealed restoration of oxidative phosphorylation, fatty-acid β-oxidation, and TCA-cycle programs (FDR<0.05), with suppression of PI3K–AKT…
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