Targeting long-chain acylcarnitine accumulation to protect cardiac mitochondrial homeostasis after complete revascularization.

Abstract

Approximately 20% of acute myocardial infarction (AMI) patients with multivessel disease experience adverse outcomes after complete revascularization. We aim to investigate the underlying metabolic mechanism of ischemia-reperfusion injury responsible for abnormal hemodynamic stresses in high-risk patients undergoing complete revascularization. Elevated preoperative serum levels of long-chain acylcarnitine (LCAC) 16:1 are associated with an increased risk of poor prognosis following complete revascularization. Multi-omics analyses reveal that reperfusion injury activates fatty acid degradation, and carnitine palmitoyltransferase 1A (CPT1A) is identified as a key regulator of LCACs in the interaction network in porcine models. In the early stages of reperfusion injury in non-culprit lesions, the release and prolonged elevation of circulating LCACs primarily depend on the activation of endothelial CPT1A through hemodynamic injury, which can be reduced using an inhibitor (etomoxir). Excess LCACs enter cardiomyocytes via the organic cation transporter 2, leading to imbalanced mitochondrial quality control and causing cardiomyocyte death.