Improving cardiac resilience to ischemia/reperfusion: The role of butyrate in mitochondrial and metabolic recovery.

BACKGROUND OR PURPOSE: Cardiac transplantation is a critical treatment for advanced heart failure. Donation after circulatory death (DCD) hearts offer a solution to the organ shortage but face high rates of primary graft dysfunction (PGD), primarily due to severe metabolic disturbances. Butyrate (BT), a short-chain fatty acid, demonstrates potential as a metabolic therapy to restore mitochondrial function and ATP production, as shown in a novel cardiomyocyte-based ischemia/reperfusion (I/R) model.

METHOD: Human cardiac myocytes isolated from adult ventricles were used to perform in vitro cell perfusion (IVCP). Metabolic therapy was introduced during cold ischemia time (CIT) in UW solutions after warm ischemia time (WIT). Perfusates and cells were collected for spectrometric metabolite analysis and molecular studies using standard techniques.

RESULTS

BT significantly improves metabolic function in cardiomyocyte under I/R stress by enhancing glycolysis-mitochondrial respiration coupling and ATP synthesis. It restores redox homeostasis by increasing the NAD+/NADPH pool and lowering the ADP/ATP ratio, while inhibiting histone deacetylation and promoting mitochondrial biogenesis via Parkin/PINK1-mediated mitophagy. By facilitating the replacement of damaged mitochondria with functional ones, BT reduces mitochondrial ROS, boosts electron transport chain activity, and restores oxidative phosphorylation, effectively preventing apoptosis and promoting metabolic recovery in cardiomyocytes.

CONCLUSION

BT efficiently repairs mitochondrial dysfunction and restores ATP production, extending its benefits beyond metabolic recovery in cardiomyocytes affected by I/R associated injury. Broadly, BT treatment could play a role in mitigating I/R-induced metabolic dysfunction in other ischemic insults to the heart, particularly following myocardial infarction, and holds significant promise for enhancing transplant organ viability.