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

## TL;DR

This study identifies how long-chain acylcarnitines (LCACs) contribute to heart damage after revascularization and suggests targeting LCAC accumulation to prevent injury.

## Contribution

The study reveals LCAC C16:1 as a prognostic biomarker and identifies CPT1A and OCTN2 as key players in reperfusion injury after heart procedures.

## Key findings

- LCAC C16:1 is a prognostic biomarker for poor outcomes after complete revascularization.
- Endothelial CPT1A activation leads to LCAC accumulation during reperfusion injury.
- Etomoxir reduces LCAC levels and mitigates cardiac damage.

## 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.

•LCAC C16:1 as a prognostic biomarker after complete revascularization•Hemodynamic injury activates endothelial CPT1A-LCAC metabolic pathway•Excess LCACs uptake through OCTN2 disrupts cardiac mitochondrial quality control•Etomoxir reduces LCAC accumulation to ameliorate post-reperfusion cardiac remodeling

LCAC C16:1 as a prognostic biomarker after complete revascularization

Hemodynamic injury activates endothelial CPT1A-LCAC metabolic pathway

Excess LCACs uptake through OCTN2 disrupts cardiac mitochondrial quality control

Etomoxir reduces LCAC accumulation to ameliorate post-reperfusion cardiac remodeling

Lin et al. reveal that metabolic dysregulation of long-chain acylcarnitines (LCACs) is a key factor underlying adverse outcomes after complete revascularization in acute myocardial infarction (AMI) patients with multivessel disease. Targeting LCAC accumulation may help prevent reperfusion-induced injury in high-risk AMI patients.