Crossover Trial of Exogenous Ketones on Cardiometabolic Endpoints in Heart Failure With Preserved Ejection Fraction

The etiology of exercise intolerance in heart failure with preserved ejection fraction (HFpEF) is multifactorial. Several contributing pathways may be improved by ketone ester (KE).

This study aims to determine whether KE improves exercise tolerance in HFpEF.

KETO-HFpEF (Ketogenic Exogenous Therapies in HFpEF) is a randomized, crossover, placebo-controlled trial of acute KE dosing in 20 symptomatic HFpEF participants. Coprimary endpoints include peak oxygen consumption (VO₂) during incremental cardiopulmonary exercise testing and time to exhaustion during an additional constant-intensity exercise (75% peak workload) bout.

The average age was 71 ± 8 years, 60% were women, and 65% were White. KE did not improve peak VO₂ (KE: 10.4 ± 3.6 vs placebo: 10.5 ± 4.0 mL/kg/min; P = 0.75). At rest, heart rate, biventricular systolic function, and cardiac output (0.6 L/min [95% CI: 0.3-1.0 L/min]) were greater with KE vs placebo, whereas total peripheral resistance (-3.2 WU [95% CI: -5.2 to -1.2 WU]) and the arteriovenous oxygen content difference (-0.7 mL of O₂/dL blood [95% CI: -1.2 to -0.2 mL]) were lower. These differences mostly disappeared during incremental exercise. KE did not improve exercise endurance during the constant-intensity protocol (9.7 ± 7.3 minutes vs 8.7 ± 4.4 minutes; P = 0.51). In 6 participants receiving 6,6-²H₂-glucose infusions during constant-intensity exercise, plasma glucose appearance rate before and during exercise was lower with KE (-0.24 mg/kg/min; P < 0.001). During both exercise protocols, KE lowered: 1) respiratory exchange ratios, demonstrating decreased systemic carbohydrate use; 2) nonesterified fatty acids and glucose; and 3) estimated left ventricular filling pressures (E/e').

Despite robust ketosis, shifting substrate use away from carbohydrates, and decreasing estimated left ventricular filling pressures, acute KE supplementation did not improve peak VO₂ or constant-intensity exercise in HFpEF. (Ketogenic Exogenous Therapies in HFpEF [KETO-HFpEF]; NCT04633460).