Ketone metabolism in heart failure with preserved ejection fraction: Fuel, signaling, and therapeutic opportunities

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous multisystem syndrome characterized by diastolic dysfunction, metabolic inflexibility, and impaired mitochondrial reserve. Human myocardial metabolomic and proteomic studies support broad oxidative and mitochondrial remodeling, but they do not establish a uniform primary defect in ketone oxidation across HFpEF. Evidence for reduced MCT1, BDH1, or SCOT/OXCT1 and for a ketolytic bottleneck is strongest in selected experimental cardiometabolic or multifactorial models; direct human myocardial ketone flux data remain sparse. Circulating β-hydroxybutyrate (β-OHB), transcardiac extraction, myocardial uptake, and complete mitochondrial oxidation are distinct measurements and may change in different directions. We therefore propose a phenotype-dependent framework that interprets systemic ketone supply together with myocardial transport and ketolysis, mitochondrial oxidative reserve, and extra-cardiac comorbidity, rather than treating ketone metabolism as a single uniformly activated or impaired pathway. β-OHB may also influence redox, inflammatory, histone deacetylase (HDAC), and lysine β-hydroxybutyrylation (Kbhb) pathways, although these effects are metabolically coupled and direct causal evidence in human HFpEF is lacking. Acute and short-term ketone interventions have produced selected hemodynamic changes without consistent improvement in exercise capacity, and clinical trials have not established ketone metabolism as a mediator of sodium-glucose cotransporter 2 inhibitor benefit. Ketone-targeted strategies should therefore be tested in phenotype-stratified studies using direct flux and mechanism-specific functional endpoints.