The prognostic and therapeutic significance of polyunsaturated fatty acid‐derived oxylipins in ST‐segment elevation myocardial infarction
Zhiyong Du,
Yingyuan Lu,
Ying Ma,
Yunxiao Yang,
Wei Luo,
Sheng Liu,
Ming Zhang,
Yong Wang,
Lei Li,
Chun Li,
Wei Wang,
Hai Gao
Affiliations
Zhiyong Du
Key Laboratory of Remodeling‐Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital Capital Medical University Beijing China
Yingyuan Lu
School of Pharmaceutical Sciences, State Key Laboratory of Natural and Biomimetic Drugs, Peking University Peking University Beijing China
Ying Ma
The State Key Laboratory for Quality Ensurance and Sustainable Use of Dao‐di Herbs, National Resource Center for Chinese Materia Medica, China, Academy of Chinese Medical Sciences Beijing China
Yunxiao Yang
Key Laboratory of Remodeling‐Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital Capital Medical University Beijing China
Wei Luo
Key Laboratory of Remodeling‐Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital Capital Medical University Beijing China
Sheng Liu
Key Laboratory of Remodeling‐Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital Capital Medical University Beijing China
Ming Zhang
Key Laboratory of Remodeling‐Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital Capital Medical University Beijing China
Yong Wang
Dongzhimen Hospital of Beijing University of Chinese Medicine Beijing China
Lei Li
Department of Cardiology Peking University Third Hospital Beijing China
Chun Li
Institute of Traditional Chinese Medicine Beijing University of Chinese Medicine Beijing China
Wei Wang
Institute of Traditional Chinese Medicine Beijing University of Chinese Medicine Beijing China
Hai Gao
Key Laboratory of Remodeling‐Related Cardiovascular Diseases, Ministry of Education, National Clinical Research Center for Cardiovascular Diseases, Beijing Institute of Heart Lung and Blood Vessel Disease, Beijing Anzhen Hospital Capital Medical University Beijing China
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.
