Abstract 17367: Infusion of the Ketone Body β-Hydroxybutyrate Improves Left Ventricular Systolic Function in an Animal Model of Heart Failure With Reduced Ejection Fraction

Introduction: In vitro, ketone bodies (KB) are the most energetically efficient fuel for myocardium. Ex vivo, KB infusion in the perfusion medium of working rat hearts increases the heat of combustion (produced energy) by 31%. However, there is no report about the in vivo effects of KB on LV function. We hypothesized that KB infusion in HFREF would improve energy production and thus LV systolic function. Methods: HFREF was induced in 15 pigs by 2-hour balloon occlusion of LAD: proximal LAD (n=8, severe HREF) and mid LAD (n=7, moderate HFREF). At 2 months, LV systolic function was evaluated during saline infusion and during infusion of the KB β-hydroxybutyrate. Severe HFREF animals underwent cardiac MRI for baseline LVEF, feature tracking strains, and contractile reserve (ΔLVEF under dobutamine 5μg/kg/min). Moderate HFREF pigs underwent invasive hemodynamic assessment (dP/dt) and 3D-echocadiography (3D-LVEF and 3D-strains). Simultaneous sampling from coronary artery and coronary sinus was performed to measure myocardial fuel consumption. Results: Proximal and mid LAD occlusion resulted in severe and moderate LV systolic dysfunction, respectively. In the severe HFREF, ketone infusion improved baseline LVEF, feature-tracking strains (both longitudinal and circumferencial strain), and contractile reserve. In the moderate HFREF, ketone infusion improved 3D-LVEF, 3D-strains and dP/dt (Table). Ketone infusion switched myocardial metabolism from glucose to ketone consumption. Conclusions: Continuous infusion of the KB hydroxybutyrate improves LV systolic function independent of LV systolic dysfunction severity via a shift in myocardial fuel metabolism away from glucose oxidation (energy inefficient) toward a more energy-efficient fuel like KB. This effect can explain the mechanism of action of the benefits of SGLT2 inhibitors in heart failure, as empagliflozin-induced mild kyperketonemia may increase LV systolic function and thus improve patient outcomes.