Serum cytokines levels in patients with myocardial infarction with non-obstructive and obstructive coronary arteries

Aim. To compare the concentrations of proinflammatory and anti-inflammatory cytokines in patients with myocardial infarction with non-obstructive (MINOCA) and obstructive coronary arteries (MIOCA) in the early postinfarction period and after 1-year follow-up.

Material and methods. The study included 40 patients with myocardial infarction (experimental group, 19 patients; control group, 21 patients). Three (15,7%) patients with diagnosed acute myocarditis were excluded from the final analysis. Blood samples were taken upon admission, on the 2^nd, 4^th and 7^th days from hospitalization, and also after 1-year follow-up. Twenty-three parameters were analyzed using multiplex analysis and the Multiplex Instrument FLEXMAP 3D system (Luminex Corporation), as well as the MILLIPLEX map Human Cytokine/ Chemokine Panel II.

Results. According to multiplex analysis of blood serum of the studied groups, a comparable increase in proinflammatory cytokines CCL-15, CCL-26, CCL-27 in the early postinfarction period and after 1-year follow-up, as well as antiinflammatory and regenerative cytokines CXCL-12, TPO in the early postinfarction period and after 1-year follow-up. In patients with MINOCA, higher concentrations of the following proinflammatory cytokines were determined: IL-16 upon admission (p=0,03), IL-20 on days 2 and 4 of the early postinfarction period (p=0,005 and p = 0.03), as well as CCL-15 on days 4 and 7 (p=0,05 and p=0,02). After 1-year follow-up, among the proinflammatory cytokines, a greater increase in CCL-21 (p=0,02) was noted in the patients of experimental group. Also, in patients with MINOCA, a greater increase in TPO was determined upon admission and on the 2nd day (p=0,02 and p=0,02), SCF — on the 7th day and after 1-year follow-up (p=0,04 and p=0,04), and LIF on the 4th day of early postinfarction period (p=0,007). In contrast, MIOCA patients showed a greater increase in CXCL-12 levels upon admission (p=0,04). At the same time, patients with MINOCA showed a higher level of C-reactive protein on the 1st day, as well as a higher relative monocyte count after 1-year follow-up.

Conclusion. Despite a comparable increase in the cytokines CCL-8, CCL-13, CCL26, CCL-27 in patients of both groups, in patients with MINOCA there was a greater increase in proinflammatory cytokines IL-16, IL-20, CCL-15, CCL-21, and also CXCL-12, LIF, TPO, SCF, which have anti-inflammatory and regenerative activity. After 1 year follow-up, MINOCA patients showed a significant increase in CCL-21 and SCF, with a comparable increase in other proinflammatory cytokines in patients of both groups. A greater increase in proinflammatory cytokines in patients with MINOCA may indicate a more aggressive atherosclerosis course and lead to plaque destabilization followed by ischemic event.

1. Pasupathy S, Air TM, Dreyer RP, et al. Systematic Review of Patients Presenting With Suspected Myocardial Infarction and Nonobstructive Coronary Arteries. Circulation. 2015;131(10):861-70. doi:10.1161/CIRCULATIONAHA.114.011201.

2. Scalone G, Niccoli G, Crea F. Editor’s Choice- Pathophysiology, diagnosis and management of MINOCA: an update. European Heart Journal. Acute Cardiovascular Care. 2019;8(1):54-62. doi:10.1177/2048872618782414.

3. Thygesen K, Alpert JS, Jaffe AS, et al. Fourth Universal Definition of Myocardial Infarction. J Am Coll Cardiol. 2018;72(18):2231-64. doi:10.1016/j.jacc.2018.08.1038.

4. Hjort M, Eggers KM, Lindhagen L, et al. Increased inflammatory activity in patients 3 months after myocardial infarction with nonobstructive coronary arteries. Clin Chem. 2019;65:1023-30. doi:10.1373/clinchem.2018.301085.

5. Lopez-Pais J, Coronel BI, Gil DG. Clinical characteristics and prognosis of myocardial infarction with non-obstructive coronary arteries (MINOCA): A prospective single-center study. Cardiol J. 2020. doi:10.5603/CJ.a2020.0146.

6. Simsek EC, Sar C, Kucukokur M, et al. Endothelial dysfunction in patients with myocardial ischemia or infarction and nonobstructive coronary arteries. J Clin Ultrasound. 2021;49(4):334-40. doi:10.1002/jcu.22902.

7. Reynolds HR, Srichai MB, Iqbal SN, et al. Mechanisms of myocardial infarction in women without angiographically obstructive coronary artery disease. Circulation. 2011;124(13):1414-25. doi:10.1161/CIRCULATIONAHA.111.026542.

8. Poredos P, Spirkoska A, Lezaic L, et al. Patients with an Inflamed Atherosclerotic Plaque have Increased Levels of Circulating Inflammatory Markers. J Atheroscler Thromb. 2017;24(1):39-46. doi:10.5551/jat.34884.

9. Fatkhullina AR, Peshkova IO, Koltsova EK. The Role of Cytokines in the Development of Atherosclerosis. Biochemistry (Mosc). 2016;81(11):1358-70. doi:10.1134/S0006297916110134.

10. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Eur Heart J. 2012;33(22):2551-67. doi:10.1093/eurheartj/ehs184.

11. Gotshal D, Azrad M, Hamo Z, et al. IL-16 and BCA-1 Serum Levels Are Associated with Disease Severity of C. difficile Infection. Pathogens. 2021;10(5):631. doi:10.3390/pathogens10050631.

12. Schernthaner C, Paar V, Wernly B, et al. Elevated plasma levels of interleukin-16 in patients with acute myocardial infarction. Medicine (Baltimore). 2017;96(44):e8396. doi:10.1097/MD.0000000000008396.

13. Richmond J, Tuzova M, Cruikshank W, Center D. Regulation of cellular processes by interleukin-16 in homeostasis and cancer. J Cell Physiol. 2014;229(2):139-47. doi:10.1002/jcp.24441.

14. Angeles-Martínez J, Posadas-Sánchez R, Bravo-Flores E, et al. Common Variants in IL-20 Gene are Associated with Subclinical Atherosclerosis, Cardiovascular Risk Factors and IL-20 Levels in the Cohort of the Genetics of Atherosclerotic Disease (GEA) Mexican Study. Biomolecules. 2020;10(1):75. doi:10.3390/biom10010075.

15. Tsai KL, Hsieh PL, Chou WC, et al. IL-20 promotes hypoxia/reoxygenation-induced mitochondrial dysfunction and apoptosis in cardiomyocytes by upregulating oxidative stress by activating the PKC/NADPH oxidase pathway. Biochim Biophys Acta Mol Basis Dis. 2020;1866(5):165684. doi:10.1016/j.bbadis.2020.165684.

16. Neri M, Fineschi V, Di Paolo M. Cardiac oxidative stress and inflammatory cytokines response after myocardial infarction. Curr Vasc Pharmacol. 2015;13(1):26-36. doi:10.2174/15701611113119990003.

17. Akhavanpoor M, Gleissner CA, Gorbatsch S, et al. CCL19 and CCL21 modulate the inflammatory milieu in atherosclerotic lesions. Drug Des Devel Ther. 2014;8:2359-71. doi:10.2147/DDDT.S72394.

18. Ueland T, Aukrust P, Caidahl K. CCL21 and prognosis in acute coronary syndrome Aging (Albany NY). 2019;11(21):9225-6. doi:10.18632/aging.102443.

19. Dieden A, Malan L, Mels CMC, et al. Exploring biomarkers associated with deteriorating vascular health using a targeted proteomics chip: The SABPA study. Medicine (Baltimore). 2021;100(20):e25936. doi:10.1097/MD.0000000000025936.

20. Hyung Park K, Hoon Lee T, Woo Kim C, Kim J. Enhancement of CCL15 Expression and Monocyte Adhesion to Endothelial Cells (ECs) after Hypoxia/Reoxygenation and Induction of ICAM-1 Expression by CCL15 via the JAK2/STAT3 Pathway in ECs. J Immunol. 2013;190(12):6550-8. doi:10.4049/jimmunol.1202284.

21. Vorobieva DA, Lugacheva YuG, Kapilevich NA, Ryabov VV. Comparative analysis of prothrombotic activity in patients with myocardial infarction with and without obstructive coronary artery disease. Russian Journal of Cardiology. 2021;26(2):3939. (In Russ.) doi:10.15829/1560-4071-2021-3939.

22. Zouein FA, Kurdi M, Booz GW. LIF and the heart: just another brick in the wall? Eur Cytokine Netw. 2013;24(1):11-9. doi:10.1684/ecn.2013.0335.

23. Kanda M, Nagai T, Takahashi T, et al. Leukemia Inhibitory Factor Enhances Endogenous Cardiomyocyte Regeneration after Myocardial Infarction. PLoS One. 2016;11(5):e0156562. doi:10.1371/journal.pone.0156562.

24. de Graaf CA, Metcalf D. Thrombopoietin and hematopoietic stem cells. Cell Cycle. 2011;10(10):1582-9. doi:10.4161/cc.10.10.15619.

25. Liu L, Xu WH, Zhou LX, Yang M. Changes of Thrombopoietin Levels in Patients with Acute Inflammatory Disease and Its Significance. Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2017;25(3):860-5. doi:10.7534/j.issn.1009-2137.2017.03.041.

26. Wu W, Zhong W, Lang B, et al. Tang Thrombopoietin could protect cerebral tissue against ischemia-reperfusion injury by suppressing NF-κB and MMP-9 expression in rats. Int J Med Sci. 2018;15(12):1341-8. doi:10.7150/ijms.27543.

27. Geng X, Ye J, Yeghiazarians Y, et al. Myocardial Production and Release of Stem Cell Factor Following Myocardial Infarction. Journal of Biomaterials and Tissue Engineering. 2017;7(1):77-82. doi:10.1166/jbt.2017.1543.

28. Wang X, Chen Y, Kuang D, et al. The cardioprotective effects of erythropoietin in myocardial ischemic injury via upregulation of SDF-1 by JAK2/STAT3. Int J Cardiol. 2012;156(3):320-2. doi:10.1016/j.ijcard.2012.01.102.

29. Recio-Mayoral A, Rimoldi OE, Camici PG, Kaski JC. Inflammation and microvascular dysfunction in cardiac syndrome X patients without conventional risk factors for coronary artery disease. JACC Cardiovasc Imaging. 2013;6(6):660-7. doi:10.1016/j.jcmg.2012.12.011.

30. Padro T, Manfrini O, Bugiardini R, et al. ESC Working Group on Coronary Pathophysiology and Microcirculation position paper on ‘coronary microvascular dysfunction in cardiovascular disease’. Cardiovasc Res. 2020;116(4):741-55. doi:10.1093/cvr/cvaa003.