Empagliflozin promotes reverse remodeling via cardiometabolic reprogramming in established pressure-overload left ventricular hypertrophy

Abstract

Left ventricular hypertrophy (LVH) due to chronic pressure overload is a major precursor of heart failure (HF) and is characterized by metabolic inflexibility and mitochondrial dysfunction. Sodium–glucose cotransporter-2 inhibitors (SGLT2i) improve HF outcomes; however, their myocardial mechanisms in LVH remain incompletely defined. To determine whether empagliflozin (EMPA) reverses established LVH and systolic dysfunction and to delineate the underlying cardiometabolic mechanisms using integrated multi-omics and functional mitochondrial analyses. Adult male (n=59) and female (n=53) A/J mice underwent transverse aortic constriction (TAC). Four weeks after surgery—once hypertrophy and systolic dysfunction were established—mice received EMPA (30 mg/kg/day, oral) or vehicle for four weeks. Serial echocardiography and cardiac PET-MRI assessed cardiac structure, function and metabolism. LV-tissue underwent bulk RNA sequencing, untargeted metabolomics, metabolic enzyme activity assays, and high-resolution mitochondrial respirometry. Multi-omics pathway integration identified coordinately regulated metabolic programs. TAC induced marked LVH, increasing LV mass from baseline by 34.8±17.4 mg in males and 31.8±15.9 mg in females (both p<0.001), with corresponding reductions in LVEF by 14±5% and 15±2% (both p<0.001). This remodeling phenotype was associated with impaired mitochondrial oxidative metabolism and increased glycolytic activity (p<0.05). EMPA attenuated hypertrophy versus TAC, reducing heart weight/tibia length in males (0.61±0.06 vs. 0.78±0.10 mg/mm, p<0.0001) and females (0.56±0.05 vs. 0.67±0.10 mg/mm, p<0.001), and improved LVEF by 9±3% and 10±2%, respectively (both p<0.0001). RNA sequencing revealed upregulation of oxidative phosphorylation and mitochondrial fatty acid oxidation pathways (both FDR<0.05). Integrated metabolomics and enzyme assays identified fatty acid oxidation as the predominant regulated pathway (FDR<0.05, p<0.05), accompanied by increased tricarboxylic acid cycle activity, elevated pyruvate:lactate ratio and reduced glycolytic signatures (all p<0.05). High-resolution mitochondrial respirometry confirmed increased complex I– and II–supported respiratory capacity (p<0.05), with a more pronounced effect in females despite comparable recovery of systolic function. Empagliflozin promotes reverse remodeling in established pressure-overload LVH by restoring mitochondrial oxidative metabolism through coordinated transcriptional and metabolic reprogramming. These findings provide mechanistic evidence that SGLT2 inhibition modulates myocardial energetic remodeling and support its role as a disease-modifying strategy in hypertrophic heart disease.LV Structure and FunctionMetabolism and Mitochondrial Respiration