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

Abstract

We examined the effect of increased levels of plasma ketones on left ventricular (LV) function, myocardial glucose uptake (MGU), and myocardial blood flow (MBF) in patients with type 2 diabetes (T2DM) with heart failure. Three groups of patients with T2DM (n = 12 per group) with an LV ejection fraction (EF) ≤50% received incremental infusions of β-hydroxybutyrate (β-OH-B) for 3-6 h to increase the plasma β-OH-B concentration throughout the physiologic (groups I and II) and pharmacologic (group III) range. Cardiac MRI was performed at baseline and after each β-OH-B infusion to provide measures of cardiac function. On a separate day, group II also received a sodium bicarbonate (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, and III achieved plasma β-OH-B levels (mean ± SEM) of 0.7 ± 0.3, 1.6 ± 0.2, 3.2 ± 0.2 mmol/L, respectively. Cardiac output (CO), LVEF, and stroke volume (SV) increased significantly during β-OH-B infusion in groups II (CO, from 4.54 to 5.30; EF, 39.9 to 43.8; SV, 70.3 to 80.0) and III (CO, from 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 patients with T2DM and LVEF ≤50%, increased plasma β-OH-B level significantly increased LV function dose dependently. Because MGU did not change, the myocardial benefit of β-OH-B resulted from providing an additional fuel for the heart without inhibiting MGU.

Graphical abstract

Figure 1

Study design. NYHA, New York Heart Association.

Figure 2

Plasma β-OH-B concentration within each group before and after β-OH-B infusion. The mean plasma ketone level for group I was 0.7 ± 0.3 (A); for group II, 1.6 ± 0.2 (B); and for group III, 3.2 ± 0.2 mmol/L. Results shown are mean ± SEM. ****P ≤ 0.0001, paired t test; n = 12/group.

Figure 3

Effect of β-OH-B infusion on LV function in group I (A–C), group II (D–F), and group III (G–I). CO, LV EF, and SV were measured with cardiac MRI. Results shown are mean ± SEM. *P ≤ 0.05, **P ≤ 0.01, paired t test; n = 12/group.

Figure 4

Effect of NaHCO₃ infusion on LV function in group II (A–C). CO, LV EF, and SV were measured with cardiac MRI. Results shown are mean ± SEM; paired t test; n = 12. *P ≤ 0.05; **P ≤ 0.01; ****P ≤ 0.001.