Predicting the development of adverse events in patients with acute coronary syndrome including genetics in the long-term follow-up

Aim To study a relationship of several factors (clinical and genetical markers) with unfavorable outcomes in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) in long-term follow-up.
Material and methods This full-design, prospective study included 415 patients with NSTE-ACS. 266 patients were evaluated for the presence of multifocal atherosclerosis (MFA). Typing of polymorphic variants rs1041981 LTA, rs1800629 TNF, rs4986790, and rs498679 TLR4, and also rs3024491 and rs1800872 IL10 was performed. Follow-up period lasted for 67±4 months. By the end of this period, information about clinical outcomes for 396 patients became available.
Results During the entire follow-up period, unfavorable outcomes were observed in 239 (57.5 %) patients with NSTE-ACS. The following clinical signs were associated with unfavorable outcomes: history of myocardial infarction, age >56 years, left ventricular ejection fraction (LV EF) ≤50 % and GRACE score ≥100, significant stenosis of brachiocephalic arteries, MFA, carriage of genotype А / А rs1041981 LTA (OR, 6.1; р=0.02) and allele А (OR, 1.9; р=0.01). According to results of a multifactorial analysis, the most significant predictors included LV EF <50 %, MFA, and carriage of genotype А / А rs1041981 LTA.
Conclusion Stratification of patients with NSTE-ACS into groups of high or low risk for having an unfavorable outcome within the next 6 years is possible using the prognostic model developed and presented in this study. The model includes the following signs: LV EF <50 %, MFA, and carriage of genotype А / А rs1041981 LTA.

1. Federal State Statistics Service. Death statistics according to Rosstat. Available at: https://rosinfostat.ru/smertnost/#i-4. 2018. [Russian: Федеральная служба государственной статистики. Статистика смертности по данным Росстат. Доступно на: https://rosinfostat.ru/smertnost/#i-4] [Internet] 2018.

2. Roffi M, Patrono C, Collet J-P, Mueller C, Valgimigli M, Andreotti F et al. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). European Heart Journal. 2016;37(3):267–315. DOI: 10.1093/eurheartj/ehv320

3. Feldman L, Steg PG, Amsallem M, Puymirat E, Sorbets E, Elbaz M et al. Editor’s Choice-Medically managed patients with non–ST-elevation acute myocardial infarction have heterogeneous outcomes, based on performance of angiography and extent of coronary artery disease. European Heart Journal: Acute Cardiovascular Care. 2017;6(3):262–71. DOI: 10.1177/2048872615626354

4. Maddox TM, Reid KJ, Rumsfeld JS, Spertus JA. One-year health status outcomes of unstable angina versus myocardial infarction: a prospective, observational cohort study of ACS survivors. BMC Cardiovascular Disorders. 2007;7(1):28. DOI: 10.1186/1471-2261-7-28

5. Kaul P, Savu A, Hamza S, Knudtson ML, Bainey K, Brass N et al. Outcomes of medically managed patients with myocardial infarction. European Heart Journal: Acute Cardiovascular Care. 2019;8(6):571–81. DOI: 10.1177/2048872618812135

6. Sanchis-Gomar F, Perez-Quilis C, Leischik R, Lucia A. Epidemiology of coronary heart disease and acute coronary syndrome. Annals of Translational Medicine. 2016;4(13):256–256. DOI: 10.21037/atm.2016.06.33

7. Vagnarelli F, Taglieri N, Ortolani P, Norscini G, Cinti L, Bacchi Reggiani ML et al. Long-Term Outcomes and Causes of Death After Acute Coronary Syndrome in Patients in the Bologna, Italy, Area. The American Journal of Cardiology. 2015;115(2):171–7. DOI: 10.1016/j.amjcard.2014.10.019

8. Erdem G, Bakhai A, Taneja AK, Collinson J, Banya W, Flather MD. Rates and causes of death from non-ST elevation acute coronary syndromes: Ten year follow-up of the PRAIS-UK registry. International Journal of Cardiology. 2013;168(1):490–4. DOI: 10.1016/j.ijcard.2012.09.160

9. Berns S.A., Shmidt E.A., Nagirnyak O.A., Klimenkova A.V., Litvinova M.N., Sergeeva T.Yu. et al. Assessment of Outcomes and Treatment Tactics in Patients with Non-ST-Elevation Acute Coronary Syndrome: Data of Five-Year Follow-up. Kardiologiia. 2018;17(7):32–40. [Russian: Бернс С.А., Шмидт Е.А., Нагирняк О.А., Клименкова А.В., Литвинова М.Н., Сергеева Т.Ю. и др. Оценка исходов и тактики лечения пациентов с острым коронарным синдромом без подъема сегмента ST по данным 5-летнего наблюдения. Кардиология. 2018;58(7):32-40]. DOI: 10.18087/cardio.2018.7.10141

10. Vershinina E.O., Repin A.N., Ryabova T.R. The impact of multifocal atherosclerosis on the early and late outcomes of planned endovascular treatment of ischemic heart disease. Siberian Medical Journal (Tomsk). 2014;29 (3):87–93. [Russian: Вершинина Е. О., Репин А. Н., Рябова Т. Р. Влияние мультифокального атеро­склероза на ближайшие и отдаленные результаты планового эндоваскулярного лечения ишемической болезни сердца. Сибирский медицинский журнал (г. Томск). 2014;29(3):87–93]

11. Güneri S. Interventional therapy indications in the elderly – are they different? Turk Kardiyoloji Dernegi Arsivi-Archives of the Turkish Society of Cardiology. 2017;45(Suppl 5):39–41. DOI: 10.5543/tkda.2017.99165

12. Mamutov R.S., Mamaradjapova D.A. The prognostic importance ofrisk factors and medical history data on the mortality of patients of stable angina at 5 years prospective study (fragment of the register ACS/AMI. Eurasian Cardiology Journal. 2017; 1:44–8. [Russian: Мамутов Р.Ш., Мамараджапова Д.А. Прогностическая значимость факторов риска и анамнестических данных на смертность больных стабильной стенокардии при 5 летнем проспективном наблюдении (фрагмент регистра окс/ОИМ). Евразийский кардиологический журнал. 2017;1:44–8]

13. Yuan M-J, Pan Y-S, Hu W-G, Lu Z-G, Zhang Q-Y, Huang D et al. A pilot study of prognostic value of non-invasive cardiac parameters for major adverse cardiac events in patients with acute coronary syndrome treated with percutaneous coronary intervention. International Journal of Clinical and Experimental Medicine. 2015;8(12):22440–9. PMID: 26885226

14. Shakhov E.B., Shakhov B.E., Petrova E.B. Determination of the stages of endovascular revascularization of the myocardium in patients with acute coronary syndrome and multivessel lesions of the venous bed. International Journal of Interventional Cardioangiology. 2017;48–49:97. [Russian: Шахов Е.Б., Шахов Б.Е., Петрова Е.Б. Определение этапности эндоваскулярной реваскуляризации миокарда у больных с острым коронарным синдромом и многососудистым поражением венечного русла. Международный журнал интервенционной кардиоангиологии. 2017;48-49:97]

15. Berns S. A., Zykova D. S., Zykov M. V., Shmidt E. A., Yukhno E. S., Nagirnyak O.A. et al. The Role of Multifocal Atherosclerosis in Realization of New Cardiovascular Complications During One Year After Non ST-Elevation Acute Coronary Syndrome. Kardiologiia. 2013;53 (8):15–23. [Russian: Бернс С. А., Зыкова Д. С., Зыков М. В., Шмидт Е. А., Юхно Е. С., Нагирняк О. А. и др. Роль мультифокального атеросклероза в реализации новых сердечнососудистых осложнений у пациентов в течение года после перенесенного острого коронарного синдрома без подъема сегмента ST. Кардиология. 2013;53(8):15-23]

16. Zykov M.V., Zykova D.S., Kashtalap V.V., Pecherina T.B., Barbarash O.L. The prognostic value of peripheral arteries diseases in patients with st-segment elevation myocardial infarction. Atherosclerosis. 2012;8 (1):14–20. [Russian: Зыков М. В., Зыкова Д. С., Кашталап В. В., Печерина Т. Б., Барбараш О. Л. Значимость мультифокального атеросклероза для модификации шкалы отдаленного риска смертности GRACE у больных острым коронарным синдромом с подъемом сегмента ST. Атеросклероз. 2012;8(1):14-20]

17. Selvasandran K, Makhoul G, Jaiswal PK, Jurakhan R, Li L, Ridwan K et al. A Tumor Necrosis Factor-α and Hypoxia-Induced Secretome Therapy for Myocardial Repair. The Annals of Thoracic Surgery. 2018;105(3):715–23. DOI: 10.1016/j.athoracsur.2017.09.005

18. The International Genome Sample Resource. 1000 Genomes. A Deep Catalog of Human Genetic Variation. [Internet] Available at: https://www.internationalgenome.org/home

19. Ikeda S, Tanaka N, Arai T, Chida K, Muramatsu M, Sawabe M. Polymorphisms of LTA, LGALS2, and PSMA6 genes and coronary atherosclerosis: A pathological study of 1503 consecutive autopsy cases. Atherosclerosis. 2012;221(2):458–60. DOI: 10.1016/j.atherosclerosis.2012.01.003

20. Shmidt E.A., Berns S.A., Zhidkova I.I., Makeeva O.A., Goncharova I.A., Nagirnyak O.A. et al. Association of a lymphotoxin-α variable site rs1041981 with development of long-term unfavorable outcomes in patients with acute coronary syndrome without ST-segment elevation. Medical Immunology. 2018;20(1):73–84. [Russian: Шмидт Е. А., Бернс С. А., Жидкова И. И., Макеева О. А., Гончарова И. А., Нагирняк О. А. и др. Связь вариабельного сайта rs1041981 гена лимфотоксина-α с развитием неблагоприятных исходов у пациентов с острым коронарным синдромом без подъема сегмента ST в отдаленном периоде. Медицинская иммунология. 2018;20(1):73-84]. DOI: 10.15789/1563-0625-2018-1-73-84

21. Kutikhin A.G., Sinitsky M.Yu., Ponasenko A.V. The role of mutagenesis in atherosclerosis. Complex Issues of Cardiovascular Diseases. 2017; 1:92–101. [Russian: Кутихин А.Г., Синицкий М.Ю., Понасенко А.В. Роль мутагенеза в развитии атеросклероза. Комплексные проблемы сердечно-сосудистых заболеваний. 2017; 1:92-101]. DOI: 10.17802/2306-1278-2017-1-92-101

22. Lozhkina N.G., Khasanova M.H., Kuimov A.D., Tsygankova O.V., Ragino Yu.I., Maksimov V.N. et al. Multifactorial Prognostication of Remote Outcomes in Patients with Non-ST Elevation Acute Coronary Syndrome. Kardiologiia. 2017;17 (8):28–33. [Russian: Ложкина Н. Г., Хасанова М. Х., Куимов А. Д., Цыганкова О. В., Рагино Ю. И., Максимов В. Н. и др. Многофакторное прогно­зирование отдаленных исходов у пациентов, перенесших острый коронарный синдром без стойкого подъема сегмента ST. Кардиология. 2017;57(8):28–33]. DOI: 10.18087/cardio.2017.8.10014

23. Konenkov V.I., Poveshchenko O.V., Prokofiev V.F., Shevchenko A.V., Kim I.N., Bondarenko N.A. et al. The analysis of clinical, functional, laboratory and genetic parameters values on the condition of patients after myocardial infarction, and prognosis of intramyocardial autologic cell therapy effectiveness for chronic heart failure. Cardiovascular Therapy and Prevention. 2015;14 (1):23–9. [Russian: Коненков В. И., Повещенко О. В., Прокофьев В. Ф., Шевченко А. В., Ким И. Н., Бондаренко Н. А. и др. Анализ информативности клинических, функциональных, лабораторных и генетических показателей оценки состояния пациентов, перенесших инфаркт миокарда, в прогнозе эффективности интрамиокардиальной аутологичной клеточной терапии хронической сердечной недостаточности Кардиоваскулярная терапия и профилактика. 2015;14(1):23–9]. DOI: 10.15829/1728-8800-2015-1-23-29

24. Guo P, Harris R. The effectiveness and experience of self-management following acute coronary syndrome: A review of the literature. International Journal of Nursing Studies. 2016; 61:29–51. DOI: 10.1016/j.ijnurstu.2016.05.008

25. Eshah NF. Predischarge education improves adherence to a healthy lifestyle among Jordanian patients with acute coronary syndrome: Predischarge education improves lifestyle. Nursing & Health Sciences. 2013;15(3):273–9. DOI: 10.1111/nhs.12018