PROJECT SUMMARY/ABSTRACT Heart failure (HF) affects 6.5 million individuals in the US (87). Diabetes and HF frequently occur together and each disorder increases the risk for the other. Recent trials (9-16) have demonstrated that SGLT2 inhibitors (SGLT2i) reduce hospitalization for heart failure and cardiovascular (CV) mortality. However, the mechanism(s) via which the SGLT2i benefit heart failure remain to be determined. Following SGLT2i therapy the plasma ketone concentration rises. Ketones are avidly taken up by the myocardium and, when oxidized, generate more ATP per molecule of oxygen compared to glucose and fatty acids. Therefore, the SGLT2i-induced rise in plasma ketones has been suggested to explain the drug’s beneficial effect on the heart. In Protocol I of the present grant we will examine in type 2 diabetic subjects with HF and reduced ejection fraction the effect of three infusion rates of beta-hydroxybutyrate (designed to span the physiologic and pharmacologic range of plasma ketone concentrations) on: (1) LV systolic and diastolic function using cardiac MRI; (2) myocardial blood flow with PET/15O-H2O; (3) myocardial glucose uptake with PET/18F-2-DOG ; (4) skeletal muscle glucose and ketone uptake. In Protocol II we will examine the effect of 3 months of dapagliflozin, an SGLT2i, versus placebo on: (1) LV systolic and diastolic function using cardiac MRI; (2) myocardial blood flow; (3) myocardial ketone uptake with PET/11C--OH-B, (4) skeletal muscle glucose and ketone uptake in type 2 diabetic subjects with HF and reduced ejection fraction. In Protocol III we examine whether inhibition of the dapagliflozin-induced rise in plasma ketone concentration with acipimox can block the beneficial effects of dapagliflozin on myocardial function and blood flow. Acipimox, an inhibitor of lipolysis, reduces the plasma ketone concentration to <0.02 mM and has no other known metabolic effects.