Selvaraj S; Division of Cardiology, Hospital of the University of
Pennsylvania, Philadelphia, Pennsylvania, USA
Karaj A; Chirinos JA; Denney N; Grosso G; Fernando M; Chambers
K; Demastus C; Reddy R; Langham M; Kumar D; Maynard H; Pourmussa B;
Prenner SB; Cohen JB; Ischiropoulos H; Rickels MR; Poole DC; Church DD;
Wolfe RR; Kelly DP; Putt M; Margulies KB; Zamani P

JACC Heart Failure. 13(12):102435, 2025 Dec.

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.