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

Abstract

BackgroundHigh 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 ResultsEight 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%.ConclusionsKetone 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.

The failing heart utilizes 3-hydroxybutyrate as a metabolic stress defense

“…This likely reflects the high rates of β-oxidation and derivative acetyl-CoA production in the normal heart. The substrate competition results in the normal canine heart shown here differ from those of a recent report that described a reduction on cardiac glucose uptake with acute infusion of 3OHB in humans without HF (45). The basis for this discrepancy is unclear but could relate to species differences or the impact of acute versus chronic infusion of 3OHB.…”

Sodium–glucose co‐transporter 2 inhibition with empagliflozin improves cardiac function in non‐diabetic rats with left ventricular dysfunction after myocardial infarction

“…Ketones are considered to be more energy efficient under conditions of metabolic stress as they require less oxygen per molecule of ATP generated . In addition, ketone oxidation does not inhibit the oxidation of other substrates through the Randel cycle, and ketones appear to improve myocardial blood flow . A single dose of EMPA was recently shown to increase myocardial ATP, which was strongly correlated with the changes in circulating ketone levels .…”

Sodium-glucose cotransporter 2 inhibitors and death and heart failure in type 2 diabetes

“…In healthy humans, ketone body (3-hydroxybutyrate) has been shown to decrease myocardial glucose uptake and to elevate myocardial blood flow, suggesting that ketone bodies are crucial fuels for heart and ketone bodies work as vasodilators. This proposes potentials of ketone bodies for the treatment of heart failure (18), supporting the usefulness of SGLT2i for treatment of heart failure. In summary, the CVD-REAL study (6) showed a significant contribution of SGLT2i to a risk reduction in hospitalization for heart failure and all-cause death, and also proved that the benefits seen with empagliflozin in the EMPA-REG OUTCOME trial may be a class effect.…”