Evaluation of the effectiveness of combined treatment of coronary heart disease – coronary artery bypass grafting, transplantation of autologous bone marrow mononuclear cells: a randomized, double-blind, placebo-controlled study

Introduction. Despite resounding success in treatment of patients with coronary heart disease (CHD), researchers are yet unable to significantly reduce mortality in this disease. With this in mind, there are ongoing studies everywhere, which are aimed at investigating new techniques in order to boost the efficiency of existing standards. One of such promising techniques is cell/regenerative therapy with autologous bone marrow mononuclear cells (ABMMCs). However, even though ABMMCs have been studied for more than 10 years, there are no unambiguous data yet on several issues. Objective: to evaluate the outcome of ABMMC transplantation during coronary artery bypass grafting (CABG) surgery in combined treatment of CHD. Materials and methods. The data of 408 patients admitted to the clinic from 2013 to 2016 for planned surgical treatment of CHD were analyzed. The work included 117 people based on the design of the study. Patients were randomized in 3 groups: Group 0 (control group) – CABG surgery and intramyocardial injection of 0.9% NaCl solution, Group 1 – CABG surgery and intramyocardial injection of ABMMCs, Group 2 – CABG surgery, intramyocardial and intra-graft injection of ABMMCs. The dynamics was assessed 12 months later – functional class of angina pectoris and heart failure, echocardiography, speckle tracking (assessment of the degree of myocardial deformation), treadmill test, 6-minute walk test, daily ECG monitoring, quality of life questionnaires, coronary angiography. Qualitative indicators were calculated using the Pearson’s chi-squared test and Fisher criteria. Quantitative indicators were calculated using the Kruskal–Wallis and Wilcoxon tests. Factor analysis was used to identify certain severity factors and to study data homogeneity. Discriminant analysis was performed to investigate the leading characteristics that determine differentiation between the groups. For analysis of variance, taking into account various factors, the model of variance analysis for dependent samples – Repeated Measures ANOVA – was used. Results. In the observation groups, an improvement in both systolic and diastolic myocardial function was universally noted. A six-minute walk test showed statistically significant increase in Groups 1 and 2 compared with the control Group 0 – 315.06 ± 17.6 (433.54 ± 20.6), Group 1 – 319.8 ± 24.5 (524.4 ± 28.7), Group 2 – 329.9 ± 25.3 (452.7 ± 29.7) meters. A significant decrease in the functional class of exertional angina pectoris in Groups 1 and 2 was noted unlike in the control group. The percentage of functioning coronary shunts after a 12-month follow-up period was 87.6% in Group 0. In Groups 1 and 2, this ratio was 96.2% and 97.3%, respectively. Predictors of overall effectiveness were identified: smoking, initial diastolic myocardial dysfunction, left ventricular ejection fraction. Conclusion. In addition to surgical treatment of coronary heart disease, ABMMC transplantation can improve myocardial contractility, boost exercise tolerance, and increase the duration of the functioning of coronary shunts at the follow-up period of 12 months. The study showed the need for stage-by-stage analytical calculations with the aim of possible correction of further work.

clinical trial, coronary artery bypass grafting, revascularization, reperfusion injury, coronary heart disease, speckle tracking, diastolic dysfunction, diastolic heart failure, autologous bone marrow mononuclear cells, intramyocardial injection

1. Kontsevaya AV, Drapkina OM, Balanova YA et al. Economic burden of cardiovascular diseases in the Russian Federation in 2016. Ration Pharmacother Cardiol. 2018; 14 (2): 156–166.

2. Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. Plos Med. 2006; 3 (11): 442.

3. Mozaffarian D, Benjamin EJ, Go AS. Heart disease and stroke statistics – 2015 update: a report from the American Heart Association. Circulation. 2015 Jan 27; 131 (4): 329–322.

4. Баранов АА, Денисов ИН, Чучалин АГ. Руководство по первичной медико-санитарной помощи. М.: ГЭОТАР-Медиа, 2006: 549–550.

5. Alvares-Dolado M, Pardal R, Garcia-Verdugo JM et al. Fusion of bone marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature. 2003; 425: 968–973.

6. Anversa P, Leri A, Kajstura J. Cardiac regeneration. J Am Coll Cardiol. 2006; 47: 1769–1777.

7. Balsam LB, Wagers AJ, Christensen JL et al. Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature. 2004; 428 (6983): 668–673.

8. Behbahan IS, Keating А, Gale RP. Bone Marrow Therapies for Chronic Heart Disease. Stem Cells. 2015 Nov; 33 (11): 3212–3227.

9. Oh H, Bradfute SB, Gallardo TD et al. Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci USA. 2003; 100: 12313–12318.

10. Orlic D, Kajstura J, Chimenti S et al. Bone marrow cells regenerate infarcted myocardium. Nature. 2001; 410: 701–705.

11. Kaminski A, Steinhoff G. Current status of intramyocardial bone marrow stem cell transplantation. Semin Thorac Cardiovasc Surg. 2008; 20: 119–125.

12. Patel AN, Geffner L, Vina RF et al. Surgical treatment for congestive heart failure with autologous stem cell transplantation: a prospective randomized study. J Thorac Cardiovasc Surg. 2005. 130: 1631–1639.

13. Stamm C, Westphal B, Kleine HD et al. Autologous bone-marrow stem-cell transplantation for myocardial regeneration. Lancet. 2003; 361: 45–46.

14. Zhao Q, Sun Y, Xia L et al. Randomized study of mononuclear bone marrow cell transplantation in patients with coronary surgery. Ann Thorac Surg. 2008; 86: 18331840.

15. Laguna G, Stefano S, Maroto L et al. Effect of direct intramyocardial autologous stem cell grafting in the subacute phase after myocardial infarction. J Cardiovasc Surg (Torino). 2018 Apr; 59 (2): 259–267. doi: 10.23736/S0021-9509.17.10126-6.

16. Kurazumi H, Fujita A, Nakamura T. Short- and longterm outcomes of intramyocardial implantation of autologous bone marrow-derived cells for the treatment of ischaemic heart disease. Interact Cardiovasc Thorac Surg. 2017 Mar 1; 24 (3): 329–334. doi: 10.1093/icvts/ivw412.

17. Lang RM, Badano LP, Mor-Avi V et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Car-diovascular Imaging. Eur Heart J Cardiovasc Imaging. 2015 Mar; 16 (3): 233–270. doi: 10.1093/ehjci/jev014.

18. Комок ВВ, Буненков НС, Белый СА и др. Оценка безопасности трансплантации аутологичных мононуклеаров костного мозга в комбинированном лечении ишемической болезни сердца. Результаты рандомизированного, слепого, плацебо контролируемого исследования (TAMIS). Вестник трансплантологии и искусственных органов. 2019; 21 (2): 112–120. https://doi.org/10.15825/1995-11912019-2-112-120.

19. Бурнос СН, Немков АС, Белый СА и др. Фракция выброса и размеры левого желудочка сердца после интракоронарного введения аутологичных мононуклеарных клеток костного мозга у больных ишемической болезнью сердца со сниженной фракцией выброса. Вестник хирургии имени И.И. Грекова. 2011; 170 (4): 16–19.

20. Немков АС, Белый СА, Нестерук ЮА и др. Качество жизни у больных ишемической болезнью сердца после применения клеточной терапии. Вестник хирургии имени И.И. Грекова. 2012; 171 (1): 16–20.

21. Нестерук ЮА, Немков АС, Белый СА. Оценка динамики кровоснабжения и метаболизма миокарда после интракоронарного введения аутологичных мононуклеаров костного мозга. Регионарное кровообращение и микроциркуляция. 2014; 13 № 3 (51): 23–30.

22. Немков АС, Белый СА, Комок ВВ и др. Имплантация аутологичных мононуклеров костного мозга как первый этап комплексного хирургического лечения ишемической болезни сердца в сочетании с аортокоронарным шунтированием (клиническое многолетнее наблюдение). Вестник хирургии имени И.И. Грекова. 2015; 174 (6): 85–88.

23. Nemkov A, Belyy S, Komok V et al. Correction of coronary endothelial dysfunction is a possible accessory mechanism for cellular therapy of the heart. Cellular Therapy and Transplantation. 2016. June; 5 (2). P. 33–39.

24. Белый СА, Лукашенко ВИ, Комок ВВ, Хубулава ГГ. Клеточная терапия в комплексном лечении пациента с дилатационной кардиомиопатией. Клиническое наблюдение. Кардиология. 2019; 59 (4S). doi: 10.18087/cardio.2555.

25. Sample Size Calculation in Clinical Research. Eds. Shein Chung Chow. 2008 by Taylor and Francis Group, LLC.

26. Hendrikx M, Hensen K, Clijsters C et al. Recovery of regional but not global contractile function by the direct intramyocardial autologous bone marrow transplantation: results from a randomized controlled clinical trial. Circulation. 2006; 114: I101e7.

27. Perin EC, Silva GV, Henry TD et al. A randomized study of transendocardial injection of autologous bone marrow mononuclear cells and cell function analysis in ische-mic heart failure (FOCUS-HF). Am Heart J. 2011; 161: 1078e87.e3.

28. Perin EC, Willerson JT, Pepine CJ et al. Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial. JAMA. 2012; 307: 1717e26.

29. Perin EC, Silva GV, Zheng Y et al. Randomized, double-blind pilot study of transendocardial injection of autologous aldehyde dehydrogenase-bright stem cells in patients with ischemic heart failure. Am Heart J. 2012; 163: 415e21. 21 e1.

30. Schaefer A, Meyer GP, Fuchs M et al. Impact of intracoronary bone marrow cell transfer on diastolic function in patients after acute myocardial infarction: results from the BOOST trial. European Heart Journal. 2006; 27: 929–935. doi: 10.1093/eurheartj/ehi817.

31. Yao K, Huang R, Qian J et al. Administration of intracoronary bone marrow mononuclear cells on chronic myocardial infarction improves diastolic function. Heart. 2008 Sep; 94 (9): 1147–1153. doi: 10.1136/hrt.2007.137919.