Ketone metabolism in HFpEF: a phenotype‑focused synthesis of fuel, signaling and therapeutic considerations
The review by Yao et al. examines how ketone handling is altered in heart failure with preserved ejection fraction, proposes a framework that integrates systemic ketone availability, myocardial transport, and oxidative capacity, and argues that future interventions should be tested in phenotype‑stratified cohorts with direct metabolic endpoints.
Study and findings
Yao and colleagues provide a narrative synthesis of experimental and human data on ketone metabolism in HFpEF. They note that myocardial metabolomic and proteomic analyses reveal extensive oxidative remodeling, yet no consistent defect in ketone oxidation is demonstrated across patients. Evidence for reduced expression of key transporters and enzymes (MCT1, BDH1, SCOT/OXCT1) comes mainly from selected animal or mechanistic models, while direct measurements of myocardial ketone flux in humans are limited. The authors distinguish circulating β‑hydroxybutyrate levels, trans‑cardiac extraction, myocardial uptake, and complete mitochondrial oxidation as separate variables that may diverge. They also discuss non‑fuel signaling actions of β‑OHB, such as redox modulation, inhibition of histone deacetylases, and lysine β‑hydroxybutyrylation, but acknowledge that causal links in HFpEF patients are not established. Acute ketone infusion studies have shown transient hemodynamic effects without reproducible gains in exercise capacity, and trials of SGLT2 inhibitors have not clarified whether ketone metabolism mediates their benefit.
Clinical interpretation
The review suggests that ketone metabolism in HFpEF cannot be treated as uniformly up‑ or down‑regulated. Instead, a phenotype‑dependent approach is warranted: patients with abundant systemic ketones but limited myocardial transport may benefit from strategies that enhance uptake, whereas those with preserved transport but impaired mitochondrial oxidation might require interventions that boost oxidative capacity. Because the existing human data are sparse and largely observational, any therapeutic claim remains provisional. The authors therefore recommend that future trials incorporate direct flux measurements (e.g., tracer studies) and select functional endpoints that reflect the specific metabolic step targeted, rather than relying on surrogate outcomes such as circulating β‑OHB alone.
Limitations and open questions
The primary limitation highlighted is the paucity of human myocardial ketone flux data; most mechanistic insights derive from animal models that may not translate to the heterogeneous HFpEF population. Additionally, the review does not provide quantitative effect sizes for the hemodynamic changes observed with acute ketone administration, limiting assessment of clinical relevance. Open questions include which HFpEF phenotypes (e.g., based on comorbidities, mitochondrial reserve, or transporter expression) are most likely to respond to ketone‑targeted therapies, and what duration and dosage of ketone supplementation are required to achieve meaningful metabolic remodeling. Addressing these gaps will require phenotype‑stratified, mechanistic trials with robust metabolic endpoints.
Source
Yao Y, Gu Z, Hu J, Zhu W, Lin Q. Ketone metabolism in heart failure with preserved ejection fraction: Fuel, signaling, and therapeutic opportunities. Pharmacological Research. 2026 Sep 21.