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

BACKGROUND: 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). OBJECTIVES: This study aims to determine whether KE improves exercise tolerance in HFpEF. METHODS: 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. RESULTS: 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'). CONCLUSIONS: 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).