Т.П. Пронько, В.А. Снежицкий, С.А. Ляликов
УО «Гродненский государственный медицинский университет», Гродно, Республика Беларусь
Цель. Определить детерминанты повторных ишемических событий в течение 30 дней у пациентов с острым инфарктом миокарда (ИМ).
Методы. В проспективное обсервационное исследование включены 405 пациентов, разделенные на основании конечных точек на 2 группы, группа 1 – 369 человек без событий, группа 2 – 36 пациентов с повторными ишемическими событиями (тромбоз стента, рецидив инфаркта миокарда, периинфарктная стенокардия). Выполнены исследования в 1–2 сутки ИМ: мультиэлектродная агрегометрия, общий анализ крови с тромбоцитарными индексами, иммуноферментное определение растворимого лиганда CD40, sP-селектина, фактора Виллебранда и эндотелина-1, генотипирование CYP2C19, P2RY12, ITGB3, ITGA2, eNOS3 генов.
Результаты. При помощи пошагового дискриминантного анализа построено уравнение: Y = –15,9829 + 0,0211 × Х1 + 0,0777 × Х2 + + 1,1012 × Х3 + 0,0183 × Х4++0,1002 × Х5 + 0,0455 × Х6 + 0,1653 × Х7 + + 0,5568 × Х8 + 0,1546 × Х9 + 0,3175 × Х10, где: Х1 – возраст, годы; Х2 – окружность талии, см; Х3 – ФК NYHA; Х4 – скорость оседания эритроцитов, мм/ч; Х5 – количество лейкоцитов в общем анализе крови; Х6 – значение ADP-test (U) агрегатограммы; Х7 – содержание фибриногена (г/л) в плазме крови; Х8 – результаты генотипирования полиморфного маркера G681A (*2) гена CYP2C19, где носительство генотипа GG = 0, носительство генотипа GA = 1, носительство генотипа AA = 2; Х9 – результаты генотипирования полиморфного маркера C807T гена ITGA2, где носительство генотипа СС = 0, носительство генотипа СТ = 1, носительство генотипа ТТ = 2; Х10 – результаты генотипирования полиморфного маркера T786C гена eNOS3, где носительство генотипа ТТ = 0, носительство генотипа ТС = 1, носительство генотипа СС = 2. Если Y > 0 – вероятность развития повторных коронарных событий в течение 30 суток от начала развития ИМ высокая. Если Y ≤ 0 – вероятность развития повторных коронарных событий в течение 30 суток от начала развития ИМ невысокая. Диагностическая чувствительность модели составляет 77,7%, диагностическая специфичность – 80,0%, точность – 77,9%, прогностическая значимость отрицательного результата (благоприятный прогноз) – 97,6%, прогностическая значимость положительного результата (неблагоприятный прогноз) – 25,3%.
Заключение. На краткосрочный прогноз оказывают влияние возраст, абдоминальное ожирение, воспаление и недостаточная эффективность клопидогрела, носительство мутантных аллелей генов CYP2C19, ITGA2 и eNOS3, продукты которых влияют на метаболизм клопидогрела и активность тромбоцитов.
ключевые слова: инфаркт миокарда, прогноз, высокая остаточная реактивность тромбоцитов, полиморфизм генов CYP2C19, P2RY12, ITGB3, ITGA2, eNOS3
для цитирования: Т.П. Пронько, В.А. Снежицкий, С.А. Ляликов. Детерминанты повторных ишемических событий в течение 30 дней у пациентов с острым инфарктом миокарда. Неотложная кардиология и кардиоваскулярные риски, 2024, Т. 8, № 2, С. 2300–2308
Determinants of recurrent ischemic events within 30 days in patients with acute myocardial infarction
T.P. Pronko, V.A. Snezhitskiy, S.A. Lialikau
Aim. To identify the determinants of recurrent ischemic events within 30 days in patients with acute myocardial infarction (MI).
Methods. The prospective observational study included 405 patients, divided into 2 groups based on endpoints. Group 1 included 369 people without events; group 2 included 36 patients with recurrent ischemic events (stent thrombosis, recurrent myocardial infarction, peri-infarction angina). The following studies were performed: multielectrode aggregometry, blood test with platelet indices, enzyme-linked immunosorbent determination of soluble CD40 ligand, sP-selectin, von Willebrand factor and endothelin-1 on days 1–2 of MI, genotyping of CYP2C19, P2RY12, ITGB3, ITGA2, eNOS3 genes.
Results. Using step-by-step discriminant analysis, the following equation was constructed: Y = –15,9829 + 0,0211 × X1 + 0,0777 × X2 + 1,1012 × X3 + + 0,0183 × X4++0,1002 × X5 + 0,0455 × Х6 + 0,1653 × Х7 + 0,5568 × Х8 + + 0,1546 × Х9 + 0,3175 × Х10, where: Х1 – age, years; X2 – waist circumference, cm; X3 – NYHA FC; X4 – erythrocyte sedimentation rate in a blood test, mm/h; X5 – the number of leukocytes in a blood test; X6 – ADP-test (U) value of the aggregogram; X7 – fibrinogen level (g/l) in blood plasma; X8 – results of genotyping of the polymorphic marker G681A (*2) of the CYP2C19 gene, where carriage of genotype GG = 0, carriage of genotype GA = 1, carriage of genotype AA = 2; X9 – results of genotyping of the C807T polymorphic marker of the ITGA2 gene, where carriage of genotype CC = 0, carriage of genotype ST = 1, carriage of genotype TT = 2; X10 – results of genotyping of the T786C polymorphic marker of the eNOS3 gene, where carriage of the TT genotype = 0, carriage of the TC genotype = 1, carriage of the CC genotype = 2. If Y > 0, the probability of developing recurrent ischemic events within 30 days from the onset of MI is high. If Y ≤ 0, the probability of developing recurrent ischemic events within 30 days from the onset of MI is low. The diagnostic sensitivity of the model is 77.7%, diagnostic specificity is 80.0%, accuracy is 77.9%, the predictive value of a negative result (favorable prognosis) is 97.6%, the predictive value of a positive result (unfavorable prognosis) is 25.3 %.
Conclusions. Short-term prognosis is influenced by age, abdominal obesity, inflammation and insufficient efficacy of clopidogrel, carriage of mutant alleles of the CYP2C19, ITGA2 and eNOS3 genes, the products of which affect the metabolism of clopidogrel and platelet activity.
keywords: myocardial infarction, prognosis, high residual platelet reactivity, polymorphism of the CYP2C19, P2RY12, ITGB3, ITGA2, eNOS3 genes
for references: T.P. Pronko, V.A. Snezhitskiy, S.A. Lialikau. Determinants of recurrent ischemic events within 30 days in patients with acute myocardial infarction. Neotlozhnaya kardiologiya i kardiovaskulyarnye riski [Emergency cardiology and cardiovascular risks], 2024, vol. 8, no. 2, pp. 2300–2308.
1. Shishkina E.A., Khlynova O.V., Tuev A.V. et al. Prediction of recurrent myocardial infarction in working-age patients. Russian Journal Cardiology, 2020, no. 25(8), pp. 3909. doi:10.15829/1560-4071-2020-3909. (in Russian).
2. Martsevich S.Yu. Recurrent myocardial infarction as an unsolved problem of evidence-based medicine. Cardiovascular Therapy and Prevention, 2024, no 23(6), pp. 4019. doi: 10. 15829/1728-8800-2024-4019. (in Russian).
3. Kukula K., Klopotowski M., Kunicki P. et al. Platelet aggregation and the risk of stent thrombosis or bleeding in elective percutaneous coronary intervention patients. Blood Coagul Fibrinolysis, 2017, vol. 28(5), pp. 383-388. doi: 10.1097/MBC.0000000000000614.
4. Stoyko O.A., Shalaev S.V. Clinical and prognostic value of the residual activity of platelets in patients with acute coronary syndrome without ST segment elevation. Kardiologiia, 2019, no. 59(7S), pp. 40-46 (in Russian).
5. Chan M.V., Knowles R.B., Lundberg M.H. et al. P2Y12 receptor blockade synergizes strongly with nitric oxide and prostacyclin to inhibit platelet activation. Br J Clin Pharmacol, 2016, vol. 81(4), pp. 621-633. doi: 10.1111/bcp.12826.
6. Parker W.A.E., Storey R.F. The role of platelet P2Y12 receptors in inflammation. Br J Pharmacol, 2024, vol. 181(4), pp. 515-531. doi: 10.1111/bph.16256.
7. Tang X.F., Zhang J.H., Wang J. et al. Effects of coexisting polymorphisms of CYP2C19 and P2Y12 on clopidogrel responsiveness and clinical outcome in patients with acute coronary syndromes undergoing stent-based coronary intervention. Chinese Medical Journal, 2013, vol. 126(6), pp. 1069-1075.
8. Muslimova E.F., Rebrova T.Yu., Afanasiev S.A. et al. Genotype -786CC of the endothelial nitric oxide synthase gene NOS3 as a factor of adverse coronary heart disease course and increased on-treatment platelet aggregation. Russ J Cardiol, 2017, no. 10(150), pp. 29-32 doi:10.15829/1560-4071-2017-10-29-32. (in Russian).
9. Izmozherova N.V., Popov A.A., Antropova I.P. et al. The role of the T1565C gene polymorphism encoding integrin beta 3 in the development of thrombotic events and its influence on the efficiency of anti-platelet therapy. Pathological Physiology and Experimental Therapy, Russian Journal, 2023, no. 67(2), pp. 94-105. doi: 10.25557/0031-2991.2023.02.94-105. (in Russian).
10. Kropacheva E.S. Pharmacogenetics of antithrombotic drugs: status update on the problem. Atherothrombosis, 2018, no. 2, pp. 115-129. doi:10.21518/2307-1109-2018-2-115-129. (in Russian).
11. Pronko T.P., Snezhitskiy V.A., Stepuro T.L. et al. Association of polymorphic variants of CYP2C19, P2RY12, ITGB3, ITGA2 and eNOS3 genes with high residual platelet reactivity while taking clopidogrel and acetylsalicylic acid at different terms of myocardial infarction. Rational Pharmacotherapy Cardiology, 2023, no. 19(3), pp. 222-229. doi:10.20996/1819-6446-2023-2904. (in Russian).
12. Fatini C., Sticchi E., Bolli P. et al. eNOS gene influences platelet phenotype in acute coronary syndrome patients on dual antiplatelet treatment. Platelets, 2009, vol. 20(8), pp. 548-554. doi:10.3109/09537100903337401.
13. Mayer K., Schulz S., Bernlochner I. et al. A comparative cohort study on personalised antiplatelet therapy in PCI-treated patients with high on-clopidogrel platelet reactivity. Results of the ISAR-HPR registry. Thromb Haemost, 2014, vol. 112(2), pp. 342-351. doi: 10.1160/TH13-10-0874.
14. Jakimov T., Mrdović I., Filipović B. et al. Comparison of RISK-PCI, GRACE, TIMI risk scores for prediction of major adverse cardiac events in patients with acute coronary syndrome. Croat Med J, 2017, vol. 58(6), pp. 406-415. doi: 10.3325/cmj.2017.58.406.
15. Lomakin N.V., Buryachkovskaya L.I., Sumarokov A.B. et al. Relation of Functional Activity of Platelets to Prognosis of Unfavorable Cardiovascular Events in Patients with Acute Coronary Syndrome. Results of a Registry Study. Kardiologiia, 2019, no. 59(10), pp. 5-13. doi: 10.18087/cardio.2019.10.n678. (in Russian).
16. Barbarash O.L., Sedykh D.Yu., Gorbunova E.V. Key factors determining the risk of recurrent myocardial infarction. Russian Heart Journal, 2017, no. 16(1), pp. 10-50. doi: 10.18087 / rhj.2017.1.2280. (in Russian).
17. Khalill R., Lei H., Chang J. The TIMI, GRACE or PURSUIT risk models. The use of risk scores for stratification of acute coronary syndrome patients. Br. J. Cardiol, 2009, vol. 16, pp. 265-267.
18. Zykov M.V., Dyachenko N.V., Velieva R.M. et al. Combined use of the GRACE ACS risk score and comorbidity indices to increase the effectiveness of hospital mortality risk assessment in patients with acute coronary syndrome. Ter Arkh, 2022, no. 94(7), pp. 816-821. doi: 10.26442/00403660.2022.07.201742. (in Russian).
19. Alnaser M., Sychev I.V., Pushkina Ya.A. et al. Comparative assessment of short-term prognosis in patients with ST-segment elevation acute coronary syndrome without percutaneous coronary intervention based on the GRACE, TIMI, RECORD, PREDICT scales. Cardiovascular Therapy and Prevention, 2022, no. 21(1), pp. 2850. doi: 10.15829/1728-8800-2022-2850. (in Russian).
20. Jia Y., Li D., Cao Y. et al. Inflammation-based Glasgow Prognostic Score in patients with acute ST-segment elevation myocardial infarction: A prospective cohort study. Medicine (Baltimore). 2018, vol. 97(50), pp. e13615. doi: 10.1097/MD.0000000000013615.
21. Yu J., Mehran R., Baber U. et al. Sex Differences in the Clinical Impact of High Platelet Reactivity After Percutaneous Coronary Intervention With Drug-Eluting Stents: Results From the ADAPT-DES Study (Assessment of Dual Antiplatelet Therapy With Drug-Eluting Stents). Circ Cardiovasc Interv, 2017, vol. 10(2), pp. e003577. doi: 10.1161/CIRCINTERVENTIONS.116.003577.
22. Lim S., Hong S.J., Kim J.H. et al. High platelet reactivity strongly predicts early stent thrombosis in patients with drug-eluting stent implantation. Sci Rep, 2024, vol. 14(1), pp. 520. doi: 10.1038/s41598-023-50920-9.
23. Alfredsson J., Lindahl T.L., Gustafsson K.M. et al. Large early variation of residual platelet reactivity in Acute Coronary Syndrome patients treated with clopidogrel: results from Assessing Platelet Activity in Coronary Heart Disease (APACHE). Thromb Res, 2015, vol. 136(2), pp. 335-40. doi: 10.1016/j.thromres.2015.05.021.
24. Kounis N.G., Soufras G.D., Tsigkas G. et al. White blood cell counts, leukocyte ratios, and eosinophils as inflammatory markers in patients with coronary artery disease. Clin. Appl. Thromb. Hemost, 2015, vol. 21(2), pp. 139-143. doi: 10.1177/1076029614531449.
25. Chaudhary P.K., Kim S., Kim S. An Insight into Recent Advances on Platelet Function in Health and Disease. Int. J. Mol. Sci, 2022, vol. 23, pp. 6022. doi: 10.3390/ijms23116022.
26. Mitkovskaya N.P., Galitskaya S.S., Gubar E.N. et al. Inflammation and necrosis biomarkers, hemostasis system disturbances in unfavourable course of myocardial infarction in patients treated with percutaneous coronary interventions. Medical news, 2016, no. 8, pp. 61-64. (in Russian).
27. Babes E.E., Zaha D.C., Tit D.M. et al. Value of hematological and coagulation parameters as prognostic factors in acute coronary syndromes. Diagnostics, 2021, vol. 11(5), pp. 850. doi: 10.3390/diagnostics11050850.
28. Surma S., Banach M. Fibrinogen and Atherosclerotic Cardiovascular Diseases-Review of the Literature and Clinical Studies. Int J Mol Sci, 2021, vol. 23(1), pp. 193. doi: 10.3390/ijms23010193.
29. Kryczka K.E., Kruk M., Demkow M. et al. Fibrinogen and a triad of thrombosis, inflammation, and the reninangiotensin system in premature coronary artery disease in women: A new insight into sex-related differences in the pathogenesis of the disease. Biomolecules, 2021, vol. 11, pp. 1036.
30. Zhou Z.F., Hu C.F., Gao M.F. et al. The predictive value of serum fibrinogen and platelet distribution width for long-term cardiac death in acute myocardial infarction patients. J Thorac Dis, 2024, vol. 16(8), pp. 5073-5085. doi: 10.21037/jtd-24-204.
31. Singh M., Shah T., Adigopula S. et al. CYP2C19*2/ABCB1-C3435T polymorphism and risk of cardiovascular events in coronary artery disease patients on clopidogrel: is clinical testing helpful? Indian Heart J, 2012, vol. 64(4), pp. 341-352. doi: 10.1016/ j.ihj.2012.06.003.
32. Kurupanova A.S., Lareva N.V. Association of ITGB3 and ITGA2 polymorphisms with clinical course and outcomes in acute coronary syndrome with ST segment elevation. Transbaikal Medical Bulletin, 2019, no. (2), pp. 27-39. (in Russian).
33. Rath D., Schaeffeler E., Winter S. et al. GPla Polymorphisms Are Associated with Outcomes in Patients at High Cardiovascular Risk. Front Cardiovasc Med, 2017, vol. 4, pp. 52. doi: 10.3389/fcvm.2017.00052.
34. Kong X.Z., Zhang Z.Y., Wei L.H. et al. The Endothelial Nitric Oxide Synthase Gene T-786C Polymorphism Increases Myocardial Infarction Risk: A Meta-Analysis. Med Sci Monit, 2017, vol. 23, pp. 759-766. doi: 10.12659/msm.899905.
