Cardiovascular and Metabolic Effects of Modulating Circulating Ketone Bodies With 1,3-Butanediol in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND

Oral treatment with the exogenous ketone body 3-hydroxybutyrate improves cardiac function in patients with heart failure with reduced ejection fraction, but ketosis is limited to 3 to 4 hours. Treatment with (R)-1,3-butanediol (BD) provides prolonged ketosis in healthy controls, but the hemodynamic and metabolic profile is unexplored in patients with heart failure with reduced ejection fraction.

METHODS AND

RESULTS

This was a randomized, single-blind, placebo-controlled, crossover study. Transthoracic echocardiography and venous blood samples were performed at baseline and hourly for 6 hours after an oral dose of BD (0.5 g/kg) or taste-matched placebo. The primary end point was the average between-treatment difference in cardiac output during the 6-hour period after intake. Secondary end points were stroke volume, heart rate, left ventricular ejection fraction, circulating 3-hydroxybutyrate, and free fatty acids. Twelve patients with heart failure with reduced ejection fraction were included. BD treatment provided significant increase in circulating 3-hydroxybutyrate by 1400 μmol/L (95% CI, 1262-1538 μmol/L, P<0.001) and increased cardiac output by 0.9 L/min (95% CI, 0.7-1.1 L/min, P<0.001) compared with placebo. Stroke volume increased by 15 mL (95% CI, 11-19 mL, P<0.001), and heart rate remained similar between treatments (P=0.150). Left ventricular ejection fraction increased by 3 percentage points (95% CI, 1-4 percentage points, P<0.001). Global longitudinal strain improved (P<0.001). Left ventricular contractility estimates increased after BD intake, and parameters of afterload were reduced. Finally, free fatty acids and glucose levels decreased.

CONCLUSIONS

Oral dosing of BD led to prolonged ketosis and cardiovascular and metabolic benefits in patients with heart failure with reduced ejection fraction. Treatment with BD is an attractive option to achieve beneficial effects from sustained therapeutic ketosis.

REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05768100.