Introduction: The Persistent Challenge of HFpEF
Heart failure with preserved ejection fraction (HFpEF) remains one of the most significant challenges in modern cardiology. Representing approximately half of all heart failure cases, HFpEF is characterized by a complex interplay of diastolic dysfunction, systemic inflammation, microvascular rarefaction, and metabolic abnormalities. Perhaps the most debilitating symptom for these patients is profound exercise intolerance, which significantly reduces quality of life and is a strong predictor of adverse clinical outcomes.
While recent advances, such as SGLT2 inhibitors and GLP-1 receptor agonists, have provided new therapeutic avenues for HFpEF, the underlying mechanisms of exercise intolerance—specifically the inability to increase oxygen consumption (VO2) during physical exertion—remain only partially addressed. This has led researchers to explore novel metabolic interventions, including the use of exogenous ketones to bypass impaired myocardial and skeletal muscle energy production.
The Rationale for Ketogenic Therapies in Heart Failure
Ketone bodies, particularly beta-hydroxybutyrate (BHB), have emerged as a potential “super fuel” for the failing heart. In states of heart failure, the myocardium often undergoes a metabolic shift, becoming less efficient at oxidizing fatty acids and increasingly reliant on glucose and ketones. Mechanistically, ketones are more oxygen-efficient than fatty acids, requiring less oxygen per molecule of ATP produced.
Furthermore, ketones possess pleiotropic effects, including anti-inflammatory properties and the ability to act as signaling molecules that may improve endothelial function and systemic hemodynamics. Preclinical models and early-phase studies in heart failure with reduced ejection fraction (HFrEF) suggested that ketone esters (KE) could increase cardiac output and improve myocardial efficiency. The KETO-HFpEF trial was designed to rigorously test whether these benefits would translate into improved functional capacity in the HFpEF population.
Study Design: The KETO-HFpEF Trial
The KETO-HFpEF (Ketogenic Exogenous Therapies in HFpEF) trial was a randomized, double-blind, placebo-controlled, crossover study. The trial enrolled 20 symptomatic patients with HFpEF, defined by standard clinical criteria including an ejection fraction of 50% or greater and objective evidence of heart failure.
Participants underwent two separate study visits. In a randomized order, they received either an acute dose of a ketone ester drink or a taste-matched placebo. The primary objectives were to evaluate the impact of acute ketosis on two rigorous exercise metrics:
1. Peak oxygen consumption (VO2) during an incremental cardiopulmonary exercise test (CPET).
2. Time to exhaustion during a constant-intensity exercise protocol set at 75% of the participant’s peak workload.
To gain deeper mechanistic insights, the investigators also utilized 6,6-2H2-glucose infusions in a subset of participants to track glucose kinetics and performed comprehensive hemodynamic monitoring, including echocardiographic assessments of biventricular function and left ventricular filling pressures (E/e’).
Key Findings: Hemodynamic Shifts at Rest
The administration of the ketone ester successfully induced robust ketosis. At rest, the KE group exhibited several favorable hemodynamic changes compared to the placebo group. Heart rate and biventricular systolic function were significantly higher, and cardiac output increased by an average of 0.6 L/min (95% CI: 0.3-1.0 L/min).
Concurrently, total peripheral resistance (TPR) decreased by 3.2 Wood Units (95% CI: -5.2 to -1.2 WU), suggesting a vasodilatory effect of the ketones. Perhaps most importantly from a clinical perspective, KE led to a reduction in the estimated left ventricular filling pressure (E/e’), a hallmark of HFpEF pathophysiology. However, it was also noted that the arteriovenous oxygen content difference (A-vO2 diff) was lower at rest with KE (-0.7 mL O2/dL blood), indicating potentially reduced peripheral oxygen extraction or a compensatory response to increased cardiac output.
The Exercise Paradox: Primary Endpoints and Metabolic Results
Despite the promising resting hemodynamic improvements, the primary endpoints of the study were not met. There was no statistically significant difference in peak VO2 between the ketone ester and placebo groups (KE: 10.4 ± 3.6 vs. Placebo: 10.5 ± 4.0 mL/kg/min; P = 0.75). Similarly, the time to exhaustion during the constant-intensity exercise protocol did not improve (9.7 ± 7.3 minutes for KE vs. 8.7 ± 4.4 minutes for placebo; P = 0.51).
During the transition from rest to incremental exercise, the hemodynamic advantages observed with KE largely dissipated. The increase in cardiac output seen at rest did not persist at peak exercise, and the reduction in peripheral resistance became non-significant as systemic vasodilation occurred naturally during exertion.
On the metabolic front, KE significantly altered substrate utilization. During both exercise protocols, the respiratory exchange ratio (RER) was lower in the KE group, indicating a shift away from carbohydrate oxidation and toward ketone and fatty acid utilization. Isotope tracer data confirmed this, showing a lower plasma glucose appearance rate both before and during exercise. Despite this “glucose-sparing” effect and the shift in fuel source, the mechanical efficiency of the exercise was not enhanced.
Expert Analysis: Why Did Ketones Fail to Improve Performance?
The findings of KETO-HFpEF provide a nuanced view of ketone metabolism in heart failure. While ketones did improve cardiac output and lower filling pressures at rest, the failure to translate these into better exercise performance likely stems from the multifactorial nature of HFpEF.
One critical observation was the reduction in the arteriovenous oxygen difference. In HFpEF, exercise intolerance is often driven not just by the heart (central factors) but also by the skeletal muscle’s inability to extract and utilize oxygen (peripheral factors). If KE increases cardiac output but simultaneously lowers the A-vO2 difference, the net effect on peak VO2—which is the product of these two variables—remains neutral. This suggests that in acute settings, ketones may not address the microvascular rarefaction or mitochondrial dysfunction inherent in the skeletal muscle of HFpEF patients.
Furthermore, the shift away from carbohydrate utilization (lower RER and glucose appearance) might actually be counterproductive during high-intensity exercise. Carbohydrates are the most efficient fuel source at near-maximal workloads; by suppressing glucose utilization, KE might have inadvertently limited the participants’ ability to reach higher workloads, essentially “locking” the metabolic engine into a lower-intensity fuel mode.
Conclusion and Future Directions
In summary, the KETO-HFpEF trial demonstrates that acute ketone ester supplementation, while metabolically active and hemodynamically beneficial at rest, does not serve as a performance enhancer in the short term for patients with HFpEF. The study highlights the dissociation between resting hemodynamic parameters and peak exercise capacity in this population.
Future research may need to explore whether chronic, rather than acute, ketone supplementation can induce structural or mitochondrial adaptations in skeletal muscle that might eventually improve VO2. Additionally, investigating the role of ketones in specific HFpEF phenotypes—such as those with more pronounced metabolic syndrome or obesity—may yield different results. For now, while ketones remain a fascinating area of cardiometabolic research, they are not yet ready for clinical use as a tool to improve functional capacity in HFpEF.
Funding and Clinical Trial Information
This study was supported by various grants, including those from the National Institutes of Health. The trial is registered at ClinicalTrials.gov under the identifier NCT04633460 (Ketogenic Exogenous Therapies in HFpEF [KETO-HFpEF]).
References
1. Selvaraj S, Karaj A, Chirinos JA, et al. Crossover Trial of Exogenous Ketones on Cardiometabolic Endpoints in Heart Failure With Preserved Ejection Fraction. JACC Heart Fail. 2025 Dec;13(12):102435.
2. Borlaug BA. Evaluation and management of heart failure with preserved ejection fraction. Nat Rev Cardiol. 2020;17(9):559-573.
3. Gormsen LC, Svart M, Thomsen HH, et al. Ketone Body Infusion With 3-Hydroxybutyrate Reduces Myocardial Glucose Uptake and Increases Intermediate Metabolites in Humans. JACC Basic Transl Sci. 2017;2(3):255-266.