A DUEL OF FATES: THE ROLE OF KETONE BODIES IN HEART FAILURE WITH PRESERVED EJECTION FRACTION

RATIONALE: More than half of patients with heart failure have preserved ejection fraction (HFpEF), a deadly syndrome where pathophysiology is unclear and therapeutic options are limited. Cardiac metabolism derangements and the role of ketone bodies in HFpEF are still under investigation. OBJECTIVE: To explore, in a mouse model of cardiometabolic HFpEF, the dual fate of β-hydroxybutyrate (BOH) as both an energy substrate and a signaling molecule. METHODS AND RESULTS: In the “2-hit” HFpEF model, we observed a reduction in both glucose and BOH oxidative pathways. In HFpEF, BOH drove a significant increase in a novel post translational modification (PTM) called lysine (K) β-hydroxybutyrylation (Kbhb). Among the Kbhb targets, we identified 2 components of the malate-aspartate shuttle (MAS), namely the mitochondrial enzymes MDH2 and GOT2. Both MAS and GOT2 activity were increased in HFpEF. Modeling Kbhb in vitro, we described a role for this post translational modification in restoring GOT2 activity under hypoxia, arguably contributing to the modulation of MAS activity in HFpEF. CONCLUSIONS: In a mouse model of cardiometabolic HFpEF, glucose and ketone bodies oxidation are defective. BOH promotes Kbhb, a new PTM, arguably involved in the increase in MAS activity.