Effect of Hyperketonemia on Myocardial Function in Patients with Heart Failure and Type 2 Diabetes

ABSTRACT We examined the effect of increased plasma ketones on left ventricular (LV) function, myocardial glucose uptake (MGU), and myocardial blood flow (MBF) in type 2 diabetes (T2DM) patients with heart failure (HF). Three groups (I,II,III) of T2DM (12 per group) with LV ejection fraction £50% received incremental infusions of β-OH-B for 3-6 hours to raise plasma b-OH-B concentration throughout the physiologic (Groups I and II) and pharmacologic (Group III) range. Cardiac MRI was performed at baseline and after each b-OH-B infusion to provide measures of cardiac function. On a separate day, Group II also received NaHCO3 infusion, thus serving as their own control for time, volume, and pH. Additionally, Group II underwent positron emission tomography study with 18F-fluoro-2-deoxyglucose to examine effect of hyperketonemia on MGU. Groups I, II, III achieved plasma b-OH-B levels of 0.7±0.3, 1.6±0.2, 3.2±0.2 mmol/L, respectively. Cardiac output, LVEF, and stroke volume increased significantly during b-OH-B infusion in Groups II (CO, 4.54 to 5.30; EF, 39.9 to 43.8; SV, 70.3 to 80.0) and III (CO, 5.93 to 7.16; EF, 41.1 to 47.5; SV, 89.0 to 108.4) and did not change with NaHCO3 infusion in Group II. The increase in LVEF was greatest in Group III (p<0.001 vs Group II). MGU and MBF were not altered by β-OH-B. In T2DM patients with LVEF£50%, increased plasma b-OH-B significantly increased LV function dose-dependently. Since MGU did not change, the myocardial benefit of b-OH-B resulted from providing an additional fuel for the heart without inhibiting MGU. HIGHLIGHTS · SGLT2 inhibitor therapy is associated with an increase in plasma ketone concentration · We examined in type 2 diabetes patients with HFrEF the effect of b-OH-B infusion, spanning the physiologic and pharmacologic range of plasma b-OH-B concentrations (0.7, 1.6, and 3.2 mmol/L), on myocardial function (MRI), myocardial blood flow (PET/H215O), and myocardial glucose uptake (PET/18F—DOG) · b-OH-B caused a dose-response increase in left ventricular ejection fraction and myocardial blood flow without altering myocardial glucose uptake These results suggest that the SLGT2i-induced increase in plasma ketone concentration may contribute to its beneficial effects on myocardial function