Abstract
Polyunsaturated fatty acid-derived oxylipins regulate systemic inflammation and exert cardiovascular effects, yet their role in ST-segment elevation myocardial infarction (STEMI) remains unclear. Herein, we used targeted metabolomics and machine learning algorithms to develop an oxylipin-based risk model to accurately predict recurrent major adverse cardiovascular events (MACE) after STEMI in two independent prospective cohorts with 2 years of follow-up. The in vivo effects of significant oxylipin predictors were explored via a murine myocardial ischemia‒reperfusion model and functional metabolomics. Among the 130 plasma oxylipins detected in discovery cohort (n = 645), patients with and without recurrent MACE exhibited significant differences in a variety of oxylipin subclasses. We constructed an oxylipin-based prediction model that showed powerful performance in predicting recurrent MACE in the discovery cohort (predictive accuracy: 91.5%). The predictive value of the oxylipin marker panel was confirmed in an independent external validation cohort (predictive accuracy: 89.9%; n = 401). Furthermore, we found that the anti-inflammatory/pro-resolving oxylipin (ARO) predictor panel showed better prognostic performance than the pro-inflammatory oxylipin predictor panel in both cohorts. Compared with the treatment of pro-inflammatory oxylipin predictor panel, combined treatment of six ARO predictors, including 14,15 epoxy-eicosatrienoic acid, 14(15)-epoxy-eicosatetraenoic acid, 12,13-epoxy-octadecenoic acid, lipoxin A4, resolving D1, and 6 keto-prostaglandin F1 showed significant cardiac activities and synergistic metabolic actions in myocardial infarction‒reperfusion model mice. We also mechanistically identified an important role of ARO predictors in restraining ceramide/lysophosphatidylcholine synthesis and inhibiting inflammatory responses. Overall, the present study depicted the landscape of oxylipin profiles in the largest panel of STEMI patients worldwide. Our results also highlight the great potential of bioactive oxylipins in prognostic prediction and therapeutics after STEMI.