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Background We determined if the sodium glucose co‐transporter 2 inhibitor empagliflozin attenuates pressure overload‐induced heart failure in non‐diabetic mellitus mice by direct cardiac effects and the mechanisms involved. Methods and Results Male C57BL/6J mice (4–6 months of age) were subjected to sham surgeries or transverse aortic constriction to produce cardiac pressure overload. Two weeks after transverse aortic constriction, empagliflozin (10 mg/kg per day) or vehicle was administered daily for 4 weeks. Empagliflozin increased survival rate and significantly attenuated adverse left ventricle remodeling and cardiac fibrosis after transverse aortic constriction. Empagliflozin also attenuated left ventricular systolic and diastolic dysfunction, evaluated by echocardiography, and increased exercise endurance by 36% in mice with transverse aortic constriction‐induced heart failure. Empagliflozin significantly increased glucose and fatty acid oxidation in failing hearts, while reducing glycolysis. These beneficial cardiac effects of empagliflozin occurred despite no significant changes in fasting blood glucose, body weight, or daily urine volume. In vitro experiments in isolated cardiomyocytes indicated that empagliflozin had direct effects to improve cardiomyocyte contractility and calcium transients. Importantly, molecular docking analysis and isolated perfused heart experiments indicated that empagliflozin can bind cardiac glucose transporters to reduce glycolysis, restore activation of adenosine monophosphate‐activated protein kinase and inhibit activation of the mammalian target of rapamycin complex 1 pathway. Conclusions Our study demonstrates that empagliflozin may directly bind glucose transporters to reduce glycolysis, rebalance coupling between glycolysis and oxidative phosphorylation, and regulate the adenosine monophosphate‐activated protein kinase mammalian target of rapamycin complex 1 pathway to attenuate adverse cardiac remodeling and progression of heart failure induced by pressure‐overload in non‐diabetic mellitus mice.

journal of the american heart association. cardiovascular and cerebrovascular disease

Direct Cardiac Actions of the Sodium Glucose Co‐Transporter 2 Inhibitor Empagliflozin Improve Myocardial Oxidative Phosphorylation and Attenuate Pressure‐Overload Heart Failure