The prognostic and therapeutic significance of polyunsaturated fatty acid-derived oxylipins in ST-segment elevation myocardial infarction

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.

Keywords

functional metabolomics / inflammation / oxylipins / prognostic markers / ST-segment elevation myocardial infarction

References

[1] Vogel, Birgit, Bimmer E. Claessen, Suzanne V. Arnold, Danny Chan, David J. Cohen, Evangelos Giannitsis, C. Michael Gibson, et al. 2019. “ST-Segment Elevation Myocardial Infarction.” Nature Reviews Disease Primers 5: 39. https://doi.org/10.1038/s41572-019-0090-3

[2] Szummer, Karolina, Tomas Jernberg, and Lars Wallentin. 2019. “From Early Pharmacology to Recent Pharmacology Interventions in Acute Coronary Syndromes.” Journal of the American College of Cardiology 74: 1618-1636. https://doi.org/10.1016/j.jacc.2019.03.531

[3] Lechner, Ivan, Martin Reindl, Christina Tiller, Magdalena Holzknecht, Priscilla Fink, Felix Troger, Georg Angerer, et al. 2023. “Temporal Trends in Infarct Severity Outcomes in ST-Segment-Elevation Myocardial Infarction: A Cardiac Magnetic Resonance Imaging Study.” Journal of the American Heart Association 12: e028932. https://doi.org/10.1161/JAHA.122.028932

[4] Jernberg, Tomas, Pål Hasvold, Martin Henriksson, Hans Hjelm, Marcus Thuresson, and Magnus Janzon. 2015. “Cardiovascular Risk in Post-Myocardial Infarction Patients: Nationwide Real World Data Demonstrate the Importance of a Long-Term Perspective.” European Heart Journal 36: 1163-1170. https://doi.org/10.1093/eurheartj/ehu505

[5] Li, Jing, Xi Li, Qing Wang, Shuang Hu, Yongfei Wang, Frederick A. Masoudi, John A. Spertus, Harlan M. Krumholz, and Lixin Jiang, China PEACE Collaborative Group. 2015. “ST-Segment Elevation Myocardial Infarction in China From 2001 to 2011 (The China Peace-Retrospective Acute Myocardial Infarction Study): A Retrospective Analysis of Hospital Data.” The Lancet 385: 441-451. https://doi.org/10.1016/S0140-6736(14)60921-1

[6] Niccoli, Giampaolo, Rocco A. Montone, Borja Ibanez, Holger Thiele, Filippo Crea, Gerd Heusch, Heerajnarain Bulluck, et al. 2019. “Optimized Treatment of ST-Elevation Myocardial Infarction.” Circulation Research 125: 245-258. https://doi.org/10.1161/CIRCRESAHA.119.315344

[7] Tona, Francesco, Giovanni Civieri, Marta Vadori, Giulia Masiero, Laura Iop, Martina Perazzolo Marra, Valentina Perin, et al. 2024. “Association of Angiotensin II Receptor Type 1 and Endothelin-1 Receptor Type A Agonistic Autoantibodies With Adverse Remodeling and Cardiovascular Events After Acute Myocardial Infarction.” Journal of the American Heart Association 13: e032672. https://doi.org/10.1161/JAHA.123.032672

[8] Seropian, Ignacio M., Chiara Sonnino, Benjamin W. Van Tassell, Luigi M. Biasucci, and Antonio Abbate. 2016. “Inflammatory Markers in ST-Elevation Acute Myocardial Infarction.” European Heart Journal: Acute Cardiovascular Care 5: 382-395. https://doi.org/10.1177/2048872615568965

[9] Mewton, Nathan, François Roubille, Didier Bresson, Cyril Prieur, Claire Bouleti, Thomas Bochaton, Fabrice Ivanes, et al. 2021. “Effect of Colchicine on Myocardial Injury in Acute Myocardial Infarction.” Circulation 144: 859-869. https://doi.org/10.1161/CIRCULATIONAHA.121.056177

[10] Matter, Michael A., Francesco Paneni, Peter Libby, Stefan Frantz, Barbara E. Stähli, Christian Templin, Alessandro Mengozzi, et al. 2024. “Inflammation in Acute Myocardial Infarction: The Good, the Bad and the Ugly.” European Heart Journal 45: 89-103. https://doi.org/10.1093/eurheartj/ehad486

[11] Lawler, Patrick R., Deepak L. Bhatt, Lucas C. Godoy, Thomas F. Lüscher, Robert O. Bonow, Subodh Verma, and Paul M. Ridker. 2021. “Targeting Cardiovascular Inflammation: Next Steps in Clinical Translation.” European Heart Journal 42: 113-131. https://doi.org/10.1093/eurheartj/ehaa099

[12] Stanger, Livia, and Michael Holinstat. 2023. “Bioactive Lipid Regulation of Platelet Function, Hemostasis, and Thrombosis.” Pharmacology & Therapeutics 246: 108420. https://doi.org/10.1016/j.pharmthera.2023.108420

[13] Stanger, Livia, Adriana Yamaguchi, Pooja Yalavarthi, Sylviane Lambert, Devin Gilmore, Andrew Rickenberg, Catherine Luke, et al. 2023. “The Oxylipin Analog CS585 Prevents Platelet Activation and Thrombosis Through Activation of the Prostacyclin Receptor.” Blood 142: 1556-1569. https://doi.org/10.1182/blood.2023020622

[14] Welch, Barrett M., Erin E. McNell, Matthew L. Edin, and Kelly K. Ferguso. 2022. “Inflammation and Oxidative Stress as Mediators of the Impacts of Environmental Exposures on Human Pregnancy: Evidence From Oxylipins.” Pharmacology & Therapeutics 239: 108181. https://doi.org/10.1016/j.pharmthera.2022.108181

[15] Wang, Bei, Lujin Wu, Jing Chen, Lingli Dong, Chen Chen, Zheng Wen, Jiong Hu, Ingrid Fleming, and Daowen Wang. 2021. “Metabolism Pathways of Arachidonic Acids: Mechanisms and Potential Therapeutic Targets.” Signal Transduction and Targeted Therapy 6: 94. https://doi.org/10.1038/s41392-020-00443-w

[16] Schunck, Wolf-Hagen, Anne Konkel, Robert Fischer, and Karsten-Henrich Weylandt. 2018. “Therapeutic Potential of Omega-3 Fatty Acid-Derived Epoxyeicosanoids in Cardiovascular and Inflammatory Diseases.” Pharmacology & Therapeutics 183: 177-204. https://doi.org/10.1016/j.pharmthera.2017.10.016

[17] Cai, Wenbin, Le Liu, Xuelian Shi, Yanan Liu, Jin Wang, Xuan Fang, Zhipeng Chen, et al. 2023. “Alox15/15-HpETE Aggravates Myocardial Ischemia-Reperfusion Injury by Promoting Cardiomyocyte Ferroptosis.” Circulation 147: 1444-1460. https://doi.org/10.1161/CIRCULATIONAHA.122.060257

[18] Ma, Ke, Jie Yang, Yihui Shao, Ping Li, Hongchang Guo, Jianing Wu, Yi Zhu, et al. 2022. “Therapeutic and Prognostic Significance of Arachidonic Acid in Heart Failure.” Circulation Research 130: 1056-1071. https://doi.org/10.1161/CIRCRESAHA.121.320548

[19] Thiele, Holger, Ibrahim Akin, Marcus Sandri, Georg Fuernau, Suzanne de Waha, Roza Meyer-Saraei, Peter Nordbeck, et al. 2017. “PCI Strategies in Patients With Acute Myocardial Infarction and Cardiogenic Shock.” New England Journal of Medicine 377: 2419-2432. https://doi.org/10.1056/NEJMoa1710261

[20] Thrane, Pernille Gro, Kevin Kris Warnakula Olesen, Troels Thim, Christine Gyldenkerne, Martin Bødtker Mortensen, Steen Dalby Kristensen, and Michael Maeng. 2023. “Mortality Trends After Primary Percutaneous Coronary Intervention for ST-Segment Elevation Myocardial Infarction.” Journal of the American College of Cardiology 82: 999-1010. https://doi.org/10.1016/j.jacc.2023.06.025

[21] Ong, Sang-Bing, Sauri Hernández-Reséndiz, Gustavo E. Crespo-Avilan, Regina T. Mukhametshina, Xiu-Yi Kwek, Hector A. Cabrera-Fuentes, and Derek J. Hausenloy. 2018. “Inflammation Following Acute Myocardial Infarction: Multiple Players, Dynamic Roles, and Novel Therapeutic Opportunities.” Pharmacology & Therapeutics 186: 73-87. https://doi.org/10.1016/j.pharmthera.2018.01.001

[22] Zordoky, Beshay N. M., and Ayman O. S. El-Kadi. 2010. “Effect of Cytochrome P450 Polymorphism on Arachidonic Acid Metabolism and Their Impact on Cardiovascular Diseases.” Pharmacology & Therapeutics 125: 446-463. https://doi.org/10.1016/j.pharmthera.2009.12.002

[23] Nayeem, Mohammed A. 2018. “Role of Oxylipins in Cardiovascular Diseases.” Acta Pharmacologica Sinica 39: 1142-1154. https://doi.org/10.1038/aps.2018.24

[24] Pinckard, Kelsey M., Vikram K. Shettigar, Katherine R. Wright, Eaman Abay, Lisa A. Baer, Pablo Vidal, Revati S. Dewal, et al. 2021. “A Novel Endocrine Role for the Bat-Released Lipokine 12,13-Dihome to Mediate Cardiac Function.” Circulation 143: 145-159. https://doi.org/10.1161/CIRCULATIONAHA.120.049813

[25] Wang, Menglong, Menglin Liu, Jishou Zhang, Jianfang Liu, Jing Ye, Yao Xu, Zhen Wang, et al. 2020. “Resolvin D1 Protects Against Sepsis-Induced Cardiac Injury in Mice.” Biofactors 46: 766-776. https://doi.org/10.1002/biof.1668

[26] Hiram, Roddy, Feng Xiong, Patrice Naud, Jiening Xiao, Martin Sirois, Jean-François Tanguay, Jean-Claude Tardif, and Stanley Nattel. 2021. “The Inflammation-Resolution Promoting Molecule Resolvin-D1 Prevents Atrial Proarrhythmic Remodelling in Experimental Right Heart Disease.” Cardiovascular Research 117: 1776-1789. https://doi.org/10.1093/cvr/cvaa186

[27] Wang, Menglong, Wei Pan, Cheng Wei, Jianfang Liu, Jishou Zhang, Junping Yu, Mengmeng Zhao, et al. 2023. “The Anti-inflammatory Mediator 17(r)-Resolvin D1 Attenuates Pressure Overload-Induced Cardiac Hypertrophy and Fibrosis.” Drug Design, Development and Therapy 17: 3073-3083. https://doi.org/10.2147/DDDT.S421894

[28] Olivares-Silva, Francisco, Nicole De Gregorio, Jenaro Espitia-Corredor, Claudio Espinoza, Raúl Vivar, David Silva, José Miguel Osorio, et al. 2021. “Resolvin-D1 Attenuation of Angiotensin II-Induced Cardiac Inflammation in Mice is Associated With Prevention of Cardiac Remodeling and Hypertension.” Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 1867: 166241. https://doi.org/10.1016/j.bbadis.2021.166241

[29] Node, Koichi, Yuqing Huo, Xiulu Ruan, Baichun Yang, Martin Spiecker, Klaus Ley, Darryl C. Zeldin, and James K. Liao. 1999. “Anti-Inflammatory Properties of Cytochrome P450 Epoxygenase-Derived Eicosanoids.” Science 285: 1276-1279. https://doi.org/10.1126/science.285.5431.1276

[30] Dai, Meiyan, Lujin Wu, Zuowen He, Shasha Zhang, Chen Chen, Xizhen Xu, Peihua Wang, et al. 2015. “Epoxyeicosatrienoic Acids Regulate Macrophage Polarization and Prevent LPS-Induced Cardiac Dysfunction.” Journal of Cellular Physiology 230: 2108-2119. https://doi.org/10.1002/jcp.24939

[31] Zhou, Zhou, Min Zhang, Chengcheng Zhao, Xu Gao, Zheng Wen, Junfang Wu, Chen, Chen, et al. 2023. “Epoxyeicosatrienoic Acids Prevent Cardiac Dysfunction in Viral Myocarditis via Interferon Type I Signaling.” Circulation Research 133: 772-788. https://doi.org/10.1161/CIRCRESAHA.123.322619

[32] Yang, Lei, Li Ni, Quanlu Duan, Xingxu Wang, Chen Chen, Song Chen, Sandip Chaugai, et al. 2015. “CYP epoxygenase 2J2 Prevents Cardiac Fibrosis by Suppression of Transmission of Pro-Inflammation From Cardiomyocytes to Macrophages.” Prostaglandins & Other Lipid Mediators 116-117: 64-75. https://doi.org/10.1016/j.prostaglandins.2015.01.004

[33] Butler, David K., Lauren E. Yasuda, and Meng-Chao Yao. 1996. “Induction of Large DNA Palindrome Formation in Yeast: Implications for Gene Amplification and Genome Stability in Eukaryotes.” Cell 87: 1115-1122. https://doi.org/10.1016/s0092-8674(00)81805-x

[34] Schilling, Tom, and Claudia Eder. 2010. “Importance of Lipid Rafts for Lysophosphatidylcholine-Induced Caspase-1 Activation and Reactive Oxygen Species Generation.” Cellular Immunology 265: 87-90. https://doi.org/10.1016/j.cellimm.2010.08.003

[35] Maayah, Zaid H., and Ayman O. S. El-Kadi. 2016. “The Role of Mid-Chain Hydroxyeicosatetraenoic Acids in the Pathogenesis of Hypertension and Cardiac Hypertrophy.” Archives of Toxicology 90: 119-136. https://doi.org/10.1007/s00204-015-1620-8

[36] Maayah, Zaid H., Hassan N. Althurwi, Ghada Abdelhamid, Gabriela Lesyk, Paul Jurasz, and Ayman O. S. El-Kadi. 2016. “CYP1B1 Inhibition Attenuates Doxorubicin-Induced Cardiotoxicity Through a Mid-chain HETEs-Dependent Mechanism.” Pharmacological Research 105: 28-43. https://doi.org/10.1016/j.phrs.2015.12.016

[37] Rocic, Petra, and Michal Laniado Schwartzman. 2018. “20-HETE in the Regulation of Vascular and Cardiac Function.” Pharmacology & Therapeutics 192: 74-87. https://doi.org/10.1016/j.pharmthera.2018.07.004

[38] Folcik, V. A., and M. K. Cathcart. 1994. “Predominance of Esterified Hydroperoxy-Linoleic Acid in Human Monocyte-Oxidized LDL.” Journal of Lipid Research 35: 1570-1582. https://doi.org/10.1016/S0022-2275(20)41155-1

[39] Krämer, H. J., J. Stevens, F. Grimminger, and W. Seeger. 1996. “Fish Oil Fatty Acids and Human Platelets: Dose-dependent Decrease in Dienoic and Increase in Trienoic Thromboxane Generation.” Biochemical Pharmacology 52: 1211-1217. https://doi.org/10.1016/0006-2952(96)00473-x

[40] Li, Lei, Yingyuan Lu, Zhiyong Du, Meng Fang, Ying Wei, Wenxin Zhang, Yisheng Xu, et al. 2024. “Integrated Untargeted/Targeted Metabolomics Identifies a Putative Oxylipin Signature in Patients With Atrial Fibrillation and Coronary Heart Disease.” Journal of Translational Medicine 12: 495-509. https://doi.org/10.1515/jtim-2023-0141

[41] Fan, Qin, Rong Tao, Hang Zhang, Hongyang Xie, Lin Lu, Ting Wang, Min Su, et al. 2019. “Dectin-1 Contributes to Myocardial Ischemia/reperfusion Injury by Regulating Macrophage Polarization and Neutrophil Infiltration.” Circulation 139: 663-678. https://doi.org/10.1161/CIRCULATIONAHA.118.036044

[42] Gao, Zhao, Zhiyong Du, Yu Hou, Kun Hua, Pengfei Tu, Xiaoni Ai, and Yong Jiang. 2024. “A Microfluidic Coculture Model for Mapping Signaling Perturbations and Precise Drug Screening Against Macrophage-Mediated Dynamic Myocardial Injury.” Acta Pharmaceutica Sinica B 14: 5393-5406. https://doi.org/10.1016/j.apsb.2024.11.004

[43] Du, Zhiyong, Fan Li, Linyi Li, Yu Wang, Jianping Li, Ya Yang, Long Jiang, Luya Wang, and Yanwen Qin. 2022. “Low-Density Lipoprotein Receptor Genotypes Modify the Sera Metabolome of Patients With Homozygous Familial Hypercholesterolemia.” iScience 25: 105334. https://doi.org/10.1016/j.isci.2022.105334

[44] Chen, Xu, Zhiyong Du, Dongqing Guo, Jincheng Guo, Qianbin Sun, Tiantian Liu, Kun Hua, et al. 2024. “Activation of the Macrophage-Associated Inflammasome Exacerbates Myocardial Fibrosis Through the 15-Hete-Mediated Pathway in Acute Myocardial Infarction.” Engineering 42: 143-156. https://doi.org/10.1016/j.eng.2024.05.015

[45] Du, Zhiyong, Fan Li, Long Jiang, Linyi Li, Yunhui Du, Huahui Yu, Yan Luo, et al. 2023. “Metabolic Systems Approaches Update Molecular Insights of Clinical Phenotypes and Cardiovascular Risk in Patients With Homozygous Familial Hypercholesterolemia.” BMC Medicine 21: 275. https://doi.org/10.1186/s12916-023-02967-8

RIGHTS & PERMISSIONS

2025 The Author(s). iMeta published by John Wiley & Sons Australia, Ltd on behalf of iMeta Science.