Circulating ketone bodies are inversely associated with myocardial ketone body oxidative capacity in human failing hearts

Introduction/Purpose Heart failure with reduced ejection fraction (HF) is characterized by distorted energy metabolism. Ketone bodies (KBs) have emerged as potentially relevant reserve energy substrates and a potential therapeutic target. Previous data suggest that failing hearts display increased KB utilization. However, a ketone paradox remains: While ketone body supplementation may be beneficial in HF, elevated circulating KBs in HF are associated with disease severity and adverse outcomes. Therefore, whether systemic KB availability reflects myocardial mitochondrial KB oxidative capacity remains unclear. Using ketone-specific HRR we aimed to evaluate the association between KB-dependent mitochondrial respiration and circulating KBs in human HF. Methods As part of the prospective single-center METAB-HTX study, 22 participants suffering from HF with reduced ejection fraction undergoing diagnostic endomyocardial biopsy, left ventricular assist device (LVAD) implantation or orthotopic heart transplantation (HTX) between February 2023 and December 2025 were enrolled. During those procedures, myocardial samples were collected. Two HRR protocols were then applied in parallel: one assessing maximal mitochondrial oxidative phosphorylation (OXPHOS) capacity using conventional substrates, and the second, recently developed protocol quantifying KB-dependent mitochondrial respiration using beta-hydroxybutyrate (HBA) and acetoacetate (ACA). HBA levels were measured in serum samples collected peri-procedurally using a point of care ketone meter (StatStrip; Nova Biomedical Corporation, USA). Results Participants presented with a mean left ventricular ejection fraction of 25.22% (±8.18%), a mean age of 55.17 (±9.49) years and were 57% male. Serum HBA levels were inversely associated with absolute KB-dependent OXPHOS capacity (r=-0.560, p=0.007). A similar trend was observed for the relative contribution of KBs to maximum OXPHOS (r=-0.379, p=0.082). No significant association was observed between circulating HBA levels and respiration restricted to the initial step of ketolysis catalyzed by HBA-dehydrogenase 1 (BDH1) (r=-0.075, p=0.740), suggesting that the observed impairment may primarily involve downstream ketolytic or mitochondrial oxidative processes. Conclusion Our results indicate that higher endogenous KB levels are not associated with enhanced but rather reduced cardiac KB oxidation capacity in HF. Thus, there appears to be a metabolically maladaptive state in HF characterized by elevated circulating KBs accompanied by impaired cardiac KB oxidation capacity. This dissociation may contribute to an explanation of the ketone paradox in HF and suggests that ketone based therapeutic strategies in HF could be less efficient in those metabolically maladaptive stages of the disease.