Genetic markers of endothelial dysfunction as predictors of coronary microvascular obstruction in endovascular treatment of myocardial infarction

• Alexey A. Frolov
• Ilya G. Pochinka
• Kirill V. Kuzmichev
• Natalia A. Shchelchkova
• Vladimir I. Pershin
• Natalya S. Maksimova
• Maria L. Budkina
• Irina V. Predeina
• Aleksey S. Mukhin

Abstract

Objective – ​to investigate the association between genetic markers of endothelial dysfunction and the development of coronary microvascular obstruction (CMVO) during percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI).

Material and methods. A single-center matched case-control study was conducted. We included patients with STEMI who underwent PCI. CMVO was defined as TIMI flow grade <3 or Myocardial Blush Grade <2. Genetic markers of endothelial dysfunction were analyzed, including allelic variants of the following single nucleotide polymorphisms (SNPs): rs4961 (ADD 1 gene), rs5443 (GNB 3), rs2070744 and rs1799983 (eNOS), and rs5370 (EDN1). We also considered predictors of CMVO from the large prognostic model NORPACS score: total ischemic time, cardiogenic shock before PCI, unstable left main coronary artery lesion, TIMI flow grade before PCI, and the length and diameter of the infarct-related lesion.

Results. A total of 80 patients were included: 40 (50%) with CMVO and 40 (50%) without CMVO (matched 1:1 by sex and age). Statistically significant differences between the groups were found for the SNP rs4961: “mutant” allelic variants (GT or TT) were observed in 14 (35%) patients in the CMVO group and in 25 (63%) patients in the non-CMVO group (p=0.04, McNemar’s test). The allele frequency distribution of rs4961 followed the Hardy–Weinberg equilibrium. According to multivariate analysis, considering other CMVO predictors, the odds ratio for the development of CMVO for the rs4961 allelic variants was 4.18 (95% confidence interval 1.10–15.92; p=0.04, conditional logistic regression). The area under the ROC curve for the identified CMVO marker was 0.64 (95% confidence interval 0.52–0.76).

Conclusion. SNP rs4961 is associated with the development of CMVO during PCI in patients with STEMI.

Keywords: genetics; myocardial infarction; no-reflow phenomenon; percutaneous coronary intervention; polymorphism; single nucleotide

References

1. Gilyarov M. Yu., Ivanov I.I., Konstantinova E.V., et al. No-reflow phenomenon and reperfusion injury. Mechanisms and treatment. Klinitsist [Clinician]. 2021; 15 (1-4): 10–9. DOI: https://doi.org/10.17650/1818-8338-2021-15-1-4-K645 (in Russian)

2. Khalirahmanov A.F., Gaziev E.A., Sharafeev A.Z., Sharafutdinov B.M. Development of the “no-reflow” phenomenon after percutaneous coronary interventions: modern aspects. Diagnosticheskaya i interventsionnaya radiologiya [Diagnostic and interventional radiology]. 2019; 13 (4): 57–6. DOI: https://doi.org/10.25512/DIR.2019.13.4.06 (in Russian)

3. Tasar O., Karabay A.K., Oduncu V., Kirma C. Predictors and outcomes of no-reflow phenomenon in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention. Coron Artery Dis. 2019; 30 (4): 270–6. DOI: https://doi.org/10.1097/mca.0000000000000726

4. Kaur G., Baghdasaryan P., Natarajan B., et al. Pathophysiology, diagnosis, and management of coronary no-reflow phenomenon. Int J Angiol. 2021; 30 (1): 15–1. DOI: https://doi.org/10.1055/s-0041-1725979

5. Frolov A.A., Frolov I.A., Ulanova N.D., et al. Phenotypes of coronary microvascular obstruction phenomenon (no-reflow) during percutaneous coronary interventions in myocardial infarction. Byulleten` sibirskoy meditsiny [Bulletin of Siberian medicine]. 2023; 22 (4): 137–46. DOI: https://doi.org/10.20538/1682-0363-2023-4-137-146 (in Russian)

6. Frolov A.A., Kashtanov M.G., Korotkikh A.V., et al. Prognostic value of no-reflow phenomenon in myocardial infarction: the role of the severity of ischemic damage. Rossiyskiy kardiologicheskiy zhurnal [Russian journal of cardiology]. 2024; 29 (12): 6075. DOI: https://doi.org/10.15829/1560-4071-2024-6075 (in Russian)

7. Zhuravlev A.S, Azarov A.V, Semitko S.P, Ioseliani D.G. The no-reflow phenomenon during primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction due to massive coronary thrombosis. Pathogenesis and predictors of no-reflow. Kardiologiya [Cardiology]. 2021; 61 (2): 99–105. DOI: https://doi.org/10.18087/cardio.2021.2.n1175 (in Russian)

8. Elbendary M.A.W., Saleh M.A., Sabet S.S., Bastawy I. Correlation between endothelial dysfunction and occurrence of no-reflow in patients undergoing post-thrombolysis early invasive percutaneous intervention for ST-elevation myocardial infarction. Egypt Heart J. 2022; 74 (1): 70. DOI: https://doi.org/10.1186/s43044-022-00309-2

9. Popyhova E.B., Stepanova T.V., Lagutina D.D., et al. The role of diabetes in the onset and development of endothelial dysfunction. Problemy endokrinologii [Problems of Endocrinology]. 2020; 66 (1): 47–55. DOI: https://doi.org/10.14341/probl12212 (in Russian)

10. Eitel I., Nowak M., Stehl C., et al. Endothelin-1 release in acute myocardial infarction as a predictor of long-term prognosis and no-reflow assessed by contrast-enhanced magnetic resonance imaging. Am Heart J. 2010; 159 (5): 882–90. DOI: https://doi.org/10.1016/j.ahj.2010.02.019

11. Sgueglia G.A., Niccoli G., Spaziani C., et al. Baseline von Willebrand factor plasma levels and no-reflow phenomenon after primary percutaneous coronary intervention for ST segment elevation myocardial infarction. Int J Cardiol. 2010; 145 (2): 230–2. DOI: https://doi.org/10.1016/j.ijcard.2009.07.046

12. Rodi Tosu A., Cinar T., Kalyoncuoglu M., et al. Predictive value of C-reactive protein/albumin ratio for no-reflow in patients with non-ST-elevation myocardial infarction. J Cardiovasc Thorac Res. 2022; 14 (4): 214–9. DOI: https://doi.org/10.34172/jcvtr.2022.30549

13. Jin H., Huang Y., Yang G. Association between α-adducin rs4961 polymorphism and hypertension: A meta-analysis based on 40 432 subjects. J Cell Biochem. 2019; 120 (3): 4613–19. DOI: https://doi.org/10.1002/jcb.27749

14. Ford T.J., Corcoran D., Padmanabhan S., et al. Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction. Eur Heart J. 2020; 41 (34): 3239–52. DOI: https://doi.org/10.1093/eurheartj/ehz915

15. Glueck C.J., Haque M., Winarska M., et al. Stromelysin-1 5A/6A and eNOS T-786C polymorphisms, MTHFR C 677T and A1298C mutations, and cigarette-cannabis smoking: a pilot, hypothesis-generating study of gene-environment pathophysiological associations with Buerger’s disease. Clin Appl Thromb Hemost. 2006; 12 (4): 427–39. DOI: https://doi.org/10.1177/1076029606293429

16. Acute myocardial infarction with ST segment elevation of the electrocardiogram. Clinical guidelines 2020. Russian Society of Cardiology, Association of Cardiovascular Surgeons of Russia. Rossiyskiy kardiologicheskiy zhurnal [Russian journal of cardiology]. 2020; 25 (11): 4103. DOI: https://doi.org/10.15829/1560-4071-2020-4103 (in Russian)

17. Mueller H.S., Dyer A., Greenberg M.A., The TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. N Engl J Med. 1985; 312 (14): 932–6. DOI: https://doi.org/10.1056/nejm198504043121437

18. van‘t Hof A.W., Liem A., Suryapranata H., et al; Myocardial Infarction Study Group. Angiographic assessment of myocardial reperfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade. Circulation. 1998; 97 (23): 2302–6. DOI: https://doi.org/10.1161/01.cir.97.23.2302

19. Dawson L.P., Rashid M., Dinh D.T., et al. No-Reflow Prediction in Acute Coronary Syndrome During Percutaneous Coronary Intervention: The NORPACS Risk Score. Circ Cardiovasc Interv. 2024; 17 (4): e013738. DOI: https://doi.org/10.1161/circinterventions.123.013738

20. Sianos G., Papafaklis M.I., Serruys P.W. Angiographic thrombus burden classification in patients with ST-segment elevation myocardial infarction treated with percutaneous coronary intervention. J Invasive Cardiol. 2010; 22 (10, Suppl B): 6B–14B.

21. Moztarzadeh S., Radeva M.Y., Sepic S., et al. Lack of adducin impairs the stability of endothelial adherens and tight junctions and may be required for cAMP-Rac1-mediated endothelial barrier stabilization. Sci Rep. 2022; 12 (1): 14940. DOI: https://doi.org/10.1038/s41598-022-18964-5

22. Jin H., Huang Y., Yang G. Association between α-adducin rs4961 polymorphism and hypertension: A meta-analysis based on 40 432 subjects. J Cell Biochem. 2019; 120 (3): 4613–9. DOI: https://doi.org/10.1002/jcb.27749

23. Poredos P., Poredos A.V., Gregoric I. Endothelial dysfunction and its clinical implications. Angiology. 2021; 72 (7): 604–15. DOI: https://doi.org/10.1177/0003319720987752

24. Kalinin R.E., Suchkov I.A., Korotkova N.V., Mzhavanadze N.D. Study of molecular mechanisms of endothelial dysfunction in vitro. Geny i kletki [Genes and cells]. 2019; 14 (1): 22–32. DOI: https://doi.org/10.23868/201903003 (in Russian)

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