Empagliflozin ameliorated adverse cardiac remodeling and improved LV systolic function in nondiabetic pigs with induced heart failure by switching myocardial fuel utilization toward ketone bodies.
RCT (n=14)
randomized
Does empagliflozin improve adverse left ventricular remodeling and myocardial energetics in a nondiabetic porcine model of heart failure?
Empagliflozin ameliorates adverse cardiac remodeling and improves LV systolic function in a nondiabetic porcine model of heart failure by shifting myocardial metabolism from glucose to ketone bodies, free fatty acids, and branched-chain amino acids.
BACKGROUND Empagliflozin cardiac benefits in the EMPA-REG OUTCOME (Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial cannot be explained exclusively by its antihyperglycemic activity. OBJECTIVES The hypothesis was that empagliflozin's cardiac benefits are mediated by switching myocardial fuel metabolism away from glucose toward ketone bodies (KB), which improves myocardial energy production. METHODS Heart failure was induced in nondiabetic pigs (n = 14) by 2-h balloon occlusion of the proximal left anterior descending artery. Animals were randomized to empagliflozin or placebo for 2 months. Animals were evaluated with cardiac magnetic resonance imaging and 3-dimensional echocardiography. Myocardial metabolite consumption was analyzed by simultaneous blood sampling from coronary artery and coronary sinus. Myocardial samples were obtained for molecular evaluation. Nonmyocardial infarction animals served as comparison. RESULTS Despite similar initial ischemic myocardial injury in both groups, the empagliflozin group showed amelioration of adverse remodeling at 2 months (lower left ventricular LV mass, reduced LV dilatation, less LV sphericity) versus the control group. LV systolic function (LV ejection fraction and echocardiography-derived strains) was improved, as was neurohormonal activation. Compared with nonmyocardial infarction, control animals increased myocardial glucose consumption mainly through anaerobic glycolysis while reducing utilization of free fatty acid (FFA) and branched-chain amino acid (BCAA). Empagliflozin-treated pigs did not consume glucose (reduction in myocardial glucose uptake, and glucose-related enzymes) but instead switched toward utilization of KB, FFA, and BCAA (increased myocardial uptake of these 3 metabolites, and enhanced expression/activity of the enzymes implicated in the metabolism of KB/FFA/BCAA). Empagliflozin increased myocardial ATP content and enhanced myocardial work efficiency. CONCLUSIONS Empagliflozin ameliorates adverse cardiac remodeling and heart failure in a nondiabetic porcine model. Empagliflozin switches myocardial fuel utilization away from glucose toward KB, FFA, and BCAA, thereby improving myocardial energetics, enhancing LV systolic function, and ameliorating adverse LV remodeling.
“Our study identifies why this drug [empagliflozin] is effective – because it improves heart function, something that has not been understood until now. Many doctors are afraid of prescribing a drug they do not understand, and our findings will help clinicians feel more comfortable giving this to patients once approved.”
Santos‐Gallego et al. (Mon,) conducted a rct in Heart failure (n=14). Empagliflozin vs. Placebo was evaluated on Adverse left ventricular remodeling and myocardial fuel metabolism. Empagliflozin ameliorated adverse cardiac remodeling and improved LV systolic function in nondiabetic pigs with induced heart failure by switching myocardial fuel utilization toward ketone bodies.
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