Ketone Body Infusion With 3-Hydroxybutyrate Reduces Myocardial Glucose Uptake and Increases Blood Flow in Humans: A Positron Emission Tomography Study

Abstract

Background: High levels of ketone bodies are associated with improved survival as observed with regular exercise, caloric restriction, and-most recently-treatment with sodium-glucose linked transporter 2 inhibitor antidiabetic drugs. In heart failure, indices of ketone body metabolism are upregulated, which may improve energy efficiency and increase blood flow in skeletal muscle and the kidneys. Nevertheless, it is uncertain how ketone bodies affect myocardial glucose uptake and blood flow in humans. Our study was therefore designed to test whether ketone body administration in humans reduces myocardial glucose uptake (MGU) and increases myocardial blood flow.

Methods and results: Eight healthy subjects, median aged 60 were randomly studied twice: (1) During 390 minutes infusion of Na-3-hydroxybutyrate (KETONE) or (2) during 390 minutes infusion of saline (SALINE), together with a concomitant low-dose hyperinsulinemic-euglycemic clamp to inhibit endogenous ketogenesis. Myocardial blood flow was measured by ¹⁵O-H₂O positron emission tomography/computed tomography, myocardial fatty acid metabolism by ¹¹C-palmitate positron emission tomography/computed tomography and MGU by ¹⁸F-fluorodeoxyglucose positron emission tomography/computed tomography. Similar euglycemia, hyperinsulinemia, and suppressed free fatty acids levels were recorded on both study days; Na-3-hydroxybutyrate infusion increased circulating Na-3-hydroxybutyrate levels from zero to 3.8±0.5 mmol/L. MGU was halved by hyperketonemia (MGU [nmol/g per minute]: 304±97 [SALINE] versus 156±62 [KETONE], P<0.01), whereas no effects were observed on palmitate uptake oxidation or esterification. Hyperketonemia increased heart rate by ≈25% and myocardial blood flow by 75%.

Conclusions: Ketone bodies displace MGU and increase myocardial blood flow in healthy humans; these novel observations suggest that ketone bodies are important cardiac fuels and vasodilators, which may have therapeutic potentials.

Keywords: 11C‐palmitate; 18F‐fluorodeoxyglucose; cardiac metabolism; hyperketonemia; myocardial glucose uptake; myocardial perfusion; nuclear medicine; positron emission tomography/computed tomography.

Figure 1

Study protocol. Study days (SALINE and KETONES) were identical except for the intervention, which was either infusion of Na‐betahydroxybutyrate (OHB) or NaCl (0.9%). PET/CT scans were initiated at t=180 minutes at which point quasi‐stable concentrations of metabolites were expected. CT indicates computed tomography; FDG, fluorodeoxyglucose; FFA, free fatty acids.

Figure 2

Hemodynamics. Systolic (treatment×time, P=0.54) blood pressure was comparable on the 2 study days (A), whereas heart diastolic blood pressure (treatment×time, P<0.001) decreased and heart rate (treatment×time, P<0.001) increased significantly during the KETONES study day (B). BPM indicates beats per minute.

Figure 3

Hormones and metabolites. A, Circulating 3‐OHB concentrations were below detection threshold (50 μmol/L) during the SALINE study day and increased to between 3 and 4 mmol/L between t=120 and 390 during the KETONE study day. By design, FFA concentrations (B) were suppressed to ≈50 μmol/L during both study days by the HE‐clamp, which increased insulin levels (C) to between 160 and 180 pmol/L. Glucose levels (D) were clamped ≈5 mmol/L through the study days, although a tendency to increasing glucose concentrations was observed from t=300 minutes and onwards. P‐values refer to the mixed model treatment vs time interaction. N=8, error bars are ±SE. FFA indicates free fatty acids; HE, hyperinsulinemic–euglycemic; 3‐OHB, 3‐hydroxybutyrate.

Figure 4

Glucose infusion rates reached plateau levels at t=180 minutes and started decreasing from t=300 onwards. No difference in insulin sensitivity was observed. N=8, error bars are ±SE for the GIR curves. Open boxes = KETONES, closed circles = SALINE. GIR indicates glucose infusion rates.

Figure 5

Myocardial ¹⁸F‐FDG uptake. Summed images (t=10–50 minutes) from a representative subject are presented in the left panel. Infusion of OHB significantly decreased ¹⁸F‐FDG uptake in all subjects, resulting in significantly lower relative uptake rates (Ki) when compared with the SALINE study day (A). Since blood glucose levels were clamped at ≈5 mmol/L, the resulting absolute MGU was roughly halved (B). N=8, error bars are SD. FDG indicates fluorodeoxyglucose; MGU, myocardial glucose uptake; OHB, hydroxybutyrate; SUV, standardized uptake value.

Figure 6

Myocardial fatty acid metabolism. A, Summed images (t=10–50 minutes) from a representative subject are presented in the left panel. There was no visible difference in accumulated ¹¹C‐palmitate in most subjects. B, Myocardial ¹¹C‐palmitate metabolism. The 3‐tissue compartment model has 3 free parameters (black arrows) and 3 fixed parameters (dotted arrows). C, No differences were observed in myocardial fatty acid uptake, esterification, or oxidation (black bar: Saline, white bar: Ketone). N=7, error bars are SD. MFAE indicates myocardial fatty acid esterification; MFAO, myocardial fatty acid oxidation; MFAU, myocardial fatty acid uptake; SUV, standardized uptake value.