vestarВестник аритмологииJournal of Arrhythmology1561-86412658-7327НАО «Инкарт»10.35336/VA-1588MJMZYCvestar-1666Research ArticleОБЗОРЫREVIEWSБиоинженерная генерация сердечного ритма: роль биопейсмейкерных клетокBioengineering generation of heart rhythm: the role of biopacemaker cellshttps://orcid.org/0000-0001-9066-3227ШабановВ. В.ShabanovV. V.

Новосибирск, ул. Речкуновская, д.15 

Novosibirsk, 15 Rechkunovskaya str. 

https://orcid.org/0009-0004-4327-4420КосенкоЭ. В.KosenkoE. V.

Косенко Эдуард Валериевич 

Новосибирск, ул. Речкуновская, д.15 

Eduard V. Kosenko

Novosibirsk, 15 Rechkunovskaya str. 

kosenko_e@meshalkin.ruhttps://orcid.org/0000-0002-0315-6145ЗейналовД. Ф.ZeinalovD. F.

Новосибирск, ул. Речкуновская, д.15 

Novosibirsk, 15 Rechkunovskaya str. 

https://orcid.org/0009-0002-3272-9560ХалхожаевТ. У.KhalkhozhaevT. U.

Новосибирск, ул. Речкуновская, д.15 

Novosibirsk, 15 Rechkunovskaya str. 

https://orcid.org/0000-0002-5027-6561СергеевичевД. С.SergeyevichevD. S.

Новосибирск, ул. Речкуновская, д.15 

Novosibirsk, 15 Rechkunovskaya str. 

https://orcid.org/0000-0001-8068-7276ФилиппенкоА. Г.FilippenkoA. G.

Новосибирск, ул. Речкуновская, д.15 

Novosibirsk, 15 Rechkunovskaya str. 

https://orcid.org/0000-0002-6958-6690РомановА. Б.RomanovA. B.

Новосибирск, ул. Речкуновская, д.15 

Novosibirsk, 15 Rechkunovskaya str. 

Novosibirsk, 52 Krasny Prospekt str 

ФГБУ «НМИЦ им. академика Е.Н.Мешалкина» МЗ РФРоссияFSBI “Academician E.N.Meshalkin National Medical Research Center” of the MH RFRussian FederationФГБУ «НМИЦ им. академика Е.Н.Мешалкина» МЗ РФРоссияFSBI “Academician E.N.Meshalkin National Medical Research Center” of the MH RF; Novosibirsk State Medical University of the MH RFRussian Federation202613062026332e1-e11Copyright © Шабанов В.В., Косенко Э.В., Зейналов Д.Ф., Халхожаев Т.У., Сергеевичев Д.С., Филиппенко А.Г., Романов А.Б., 20262026Шабанов В.В., Косенко Э.В., Зейналов Д.Ф., Халхожаев Т.У., Сергеевичев Д.С., Филиппенко А.Г., Романов А.Б.Shabanov V.V., Kosenko E.V., Zeinalov D.F., Khalkhozhaev T.U., Sergeyevichev D.S., Filippenko A.G., Romanov A.B.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vestar.elpub.ru/jour/article/view/1666

Представлены анатомо-физиологические особенности синусового узла как модели для биопейсмейкеров, проанализированы современные подходы к их созданию: трансплантация клеток синусового узла, использование плюрипотентных стволовых клеток, генная терапия (экспрессия HCN, подавление IK1, трансдукция TBX18 и др.), комбинированные и перепрограммирующие стратегии. Отдельное внимание уделено собственному опыту - достижениям в тканевой инженерии. Обозначены ключевые препятствия на пути клинического внедрения: проблемы безопасности, стабильности эффекта, адекватности моделей и контроля активности. Несмотря на существующие ограничения, развитие технологий генной инженерии, стволовых клеток и биоматериалов открывает перспективы для создания полноценных физиологических альтернатив электрокардиостимуляторов.

This review summarizes the anatomical and physiological characteristics of the sinoatrial node as a model for bio­ pacemakers and analyzes current approaches to their development, including sinoatrial node cell transplantation, the use of pluripotent stem cells, gene therapy (HCN overexpression, IK1 suppression, TBX18 transduction, and others), as well as combined and reprogramming strategies Special attention is given to the authors’ own experience and achievements in tissue engineering. Key obstacles to clinical translation are outlined, including safety concerns, stability of therapeutic effects, adequacy of experimental models, and control of biological pacemaker activity. Despite existing limitations, pro­ gress in gene engineering, stem cell technologies, and biomaterials offers promising opportunities for the development of fully physiological alternatives to electronic pacemakers.

брадиаритмииэлектрокардиостимуляторбиологические пейсмейкерыгенная инженериястволовые клеткиbradyarrhythmiapacemakerartificialbiological pacemakersgenetic engineeringstem cellsИсследование выполнено при финансовой поддержке Российского научного фонда (Соглашение № 25-65-00037 от 22.05.2025).The study was carried out with the financial support of the Russian Science Foundation (Agreement No. 25- 65-00037 dated May 22, 2025).ReferencesРевишвили АШ, Глезер МГ, Артюхина ЕА, и др. Брадиаритмии и нарушения проводимости. Клинические рекомендации 2025. Российский кардиологический журнал. 2025;30(11): 6669. https://doi.org/10.15829/1560-4071-2025-6669.Revishvili AS, Glezer MG, Artyukhina EA, et al. Bradyarrhythmias and conduction disorders. Clinical guidelines 2025. Russian Journal of Cardiology. 2025;30(11): 6669. (In Russ.) https://doi.org/10.15829/1560-4071-2025-6669.Панфилов СВ, Резепин СА, Короткова РП, и др. Современные подходы к диагностике и лечению бради-и тахиаритмий. Патология кровообращения и кардиохирургия. 1999;(1): 67-68.Panfilov SV, Rezepin SA, Korotkova RP, et al. Modern approaches to diagnosis and treatment of brady- and tachyarrhythmias. Circulation Pathology and Cardiac Surgery. 1999;(1): 67-68. (In Russ.)Голухова ЕЗ, Милиевская ЕБ, Филатов АГ, и др. Аритмология - 2023. Нарушения ритма сердца и проводимости. М.: ФГБУ «НМИЦ ССХ им. А.Н. Бакулева» Минздрава России; 2024. 212 с. ISBN 978-5-7982-0465-6.Golukhova EZ, Milievskaya EB, Filatov AG, et al. Arrhythmology - 2023. Cardiac rhythm and conduction disorders. Moscow: National Medical Research Center for Cardiovascular Surgery named after A.N.Bakulev; 2024. 212 p. (In Russ.) ISBN 978-5-7982-0465-6.Sugiharto F, Asmara AD, Sari WP, et al. Types of Complications and Associated Factors in Patients Undergoing Permanent Cardiac Pacemaker Implantation: A Systematic Review. J Multidiscip Healthc. 2025 Jan 11;18: 83-100. https://doi.org/10.2147/JMDH.S489600.Sugiharto F, Asmara AD, Sari WP, et al. Types of Complications and Associated Factors in Patients Undergoing Permanent Cardiac Pacemaker Implantation: A Systematic Review. J Multidiscip Healthc. 2025 Jan 11;18: 83-100. https://doi.org/10.2147/JMDH.S489600.Гордеев ОЛ, Егоров ДФ, Воронцов ИМ, и др. Опыт реимплантации электрокардиостимуляторов у детей. Вестник аритмологии. 2001;22: 13-19.Gordeev OL, Egorov DF, Vorontsov IM, et al. Experience with pacemaker reimplantation in children. Journal of Arrhythmology. 2001;22: 13-19. (In Russ.)Komosa ER, Wolfson DW, Bressan M, et al. Implementing Biological Pacemakers: Design Criteria for Successful Transition From Concept to Clinic. Circulation: Arrhythmia and Electrophysiology. 2021;14(10): e009957. https://doi.org/10.1161/CIRCEP.121.009957.Komosa ER, Wolfson DW, Bressan M, et al. Implementing Biological Pacemakers: Design Criteria for Successful Transition From Concept to Clinic. Circulation: Arrhythmia and Electrophysiology. 2021;14(10): e009957. https://doi.org/10.1161/CIRCEP.121.009957.Kiviniemi MS, Pirnes MA, Kettunen RV, et al. Complications related to permanent pacemaker therapy. Pacing Clin Electrophysiol. 1999 May;22(5): 711-20. https://doi.org/10.1111/j.1540-8159.1999.tb00534.x.Kiviniemi MS, Pirnes MA, Kettunen RV, et al. Complications related to permanent pacemaker therapy. Pacing Clin Electrophysiol. 1999 May;22(5): 711-20. https://doi.org/10.1111/j.1540-8159.1999.tb00534.x.Harcombe AA, Newell SA, Ludman PF, et al. Late complications following permanent pacemaker implantation or elective unit replacement. Heart. 1998 Sep;80(3): 240-4. https://doi.org/10.1136/hrt.80.3.240.Harcombe AA, Newell SA, Ludman PF, et al. Late complications following permanent pacemaker implantation or elective unit replacement. Heart. 1998 Sep;80(3): 240-4. https://doi.org/10.1136/hrt.80.3.240.Link MS, Estes 3rd NA, Griffin JJ, et al. Complications of dual chamber pacemaker implantation in the elderly. Pacemaker Selection in the Elderly (PASE) Investigators. J Interv Card Electrophysiol. 1998 Jun;2(2): 175-9. https://doi.org/10.1023/a:1009707700412.Link MS, Estes 3rd NA, Griffin JJ, et al. Complications of dual chamber pacemaker implantation in the elderly. Pacemaker Selection in the Elderly (PASE) Investigators. J Interv Card Electrophysiol. 1998 Jun;2(2): 175-9. https://doi.org/10.1023/a:1009707700412.Sohail MR, Uslan DZ, Khan AH, et al. Risk factor analysis of permanent pacemaker infection. Clin Infect Dis. 2007 Jul 15;45(2): 166-73. https://doi.org/10.1086/518889.Sohail MR, Uslan DZ, Khan AH, et al. Risk factor analysis of permanent pacemaker infection. Clin Infect Dis. 2007 Jul 15;45(2): 166-73. https://doi.org/10.1086/518889.Aggarwal RK, Connelly DT, Ray SG, et al. Early complications of permanent pacemaker implantation: no difference between dual and single chamber systems. Br Heart J. 1995 Jun;73(6): 571-5. https://doi.org/10.1136/hrt.73.6.571.Aggarwal RK, Connelly DT, Ray SG, et al. Early complications of permanent pacemaker implantation: no difference between dual and single chamber systems. Br Heart J. 1995 Jun;73(6): 571-5. https://doi.org/10.1136/hrt.73.6.571.Harcombe AA, Newell SA, Ludman PF, et al. Late complications following permanent pacemaker implantation or elective unit replacement. Heart. 1998 Sep;80(3): 240-4. https://doi.org/10.1136/hrt.80.3.240.Harcombe AA, Newell SA, Ludman PF, et al. Late complications following permanent pacemaker implantation or elective unit replacement. Heart. 1998 Sep;80(3): 240-4. https://doi.org/10.1136/hrt.80.3.240.Mazza A, Bendini MG, Leggio M, et al. Incidence and predictors of heart failure hospitalization and death in permanent pacemaker patients: a single-centre experience over medium-term follow-up. Europace. 2013 Sep;15(9): 1267-72. https://doi.org/10.1093/europace/eut041.Mazza A, Bendini MG, Leggio M, et al. Incidence and predictors of heart failure hospitalization and death in permanent pacemaker patients: a single-centre experience over medium-term follow-up. Europace. 2013 Sep;15(9): 1267-72. https://doi.org/10.1093/europace/eut041.Картофелева ЕО, Плотникова ИВ, Свинцова ЛИ, и др. Осложнения постоянной электрокардиостимуляции у детей в зависимости от способа имплантации. Сибирский журнал клинической и экспериментальной медицины. 2023;38(2): 174-179. https://doi.org/10.29001/2073-8552-2023-38-2-174-179.Kartofeleva EO, Plotnikova IV, Svintsova LI, et al. Complications of permanent pacemaker implantation in children depending on the implantation technique. Siberian Journal of Clinical and Experimental Medicine. 2023;38(2): 174-179. (In Russ.) https://doi.org/10.29001/2073-8552-2023-38-2-174-179.Милюков ВЕ, Брюханов ВА, Нгуен КК. Клиническая реализация анатомо-физиологических свойств синоатриального узла. Клиническая медицина. 2022;100(9-10). https://doi.org/10.30629/0023-2149-2022-100-9-10-425-431.Milyukov V.E., Bryukhanov V.A., Nguyen С.С. Clinical realization of anatomical and physiological properties of the sinoatrial node. Clinical Medicine. 2022;100(9-10): 425-431. (In Russ.) https://doi.org/10.30629/0023-2149-2022-100-9-10-425-431.Irisawa H, Brown HF, Giles W. Cardiac pacemaking in the sinoatrial node. Physiol Rev. 1993 Jan;73(1): 197-227. https://doi.org/10.1152/physrev.1993.73.1.197.Irisawa H, Brown HF, Giles W. Cardiac pacemaking in the sinoatrial node. Physiol Rev. 1993 Jan;73(1): 197-227. https://doi.org/10.1152/physrev.1993.73.1.197.DiFrancesco D. The role of the funny current in pacemaker activity. Circ Res. 2010 Feb 19;106(3): 434-46. https://doi.org/10.1161/CIRCRESAHA.109.208041.DiFrancesco D. The role of the funny current in pacemaker activity. Circ Res. 2010 Feb 19;106(3): 434-46. https://doi.org/10.1161/CIRCRESAHA.109.208041.Baruscotti M, Bucchi A, DiFrancesco D. Physiology and pharmacology of the cardiac pacemaker (“funny”) current. Pharmacol Ther. 2005 Jul;107(1): 59-79. https://doi.org/10.1016/j.pharmthera.2005.01.005.Baruscotti M, Bucchi A, DiFrancesco D. Physiology and pharmacology of the cardiac pacemaker (“funny”) current. Pharmacol Ther. 2005 Jul;107(1): 59-79. https://doi.org/10.1016/j.pharmthera.2005.01.005.Morad M, Zhang XH. Mechanisms of spontaneous pacing: sinoatrial nodal cells, neonatal cardiomyocytes, and human stem cell derived cardiomyocytes. Can J Psysiol Pharmacol. 2017 Oct;95(10): 1100-1107. https://doi.org/10.1139/cjpp-2016-0743.Morad M, Zhang XH. Mechanisms of spontaneous pacing: sinoatrial nodal cells, neonatal cardiomyocytes, and human stem cell derived cardiomyocytes. Can J Psysiol Pharmacol. 2017 Oct;95(10): 1100-1107. https://doi.org/10.1139/cjpp-2016-0743.Lakatta EG, Maltsev VA, Vinogradova TM. A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart’s pacemaker. Circ Res. 2010 Mar 5;106(4): 659- 73. https://doi.org/10.1161/CIRCRESAHA.109.206078.Lakatta EG, Maltsev VA, Vinogradova TM. A coupled SYSTEM of intracellular Ca2+ clocks and surface membrane voltage clocks controls the timekeeping mechanism of the heart’s pacemaker. Circ Res. 2010 Mar 5;106(4): 659- 73. https://doi.org/10.1161/CIRCRESAHA.109.206078.Joung B, Chen P.S. Function and dysfunction of human sinoatrial node. Korean Circ J. 2015 May;45(3): 184- 91. https://doi.org/10.4070/kcj.2015.45.3.184.Joung B, Chen P.S. Function and dysfunction of human sinoatrial node. Korean Circ J. 2015 May;45(3): 184- 91. https://doi.org/10.4070/kcj.2015.45.3.184.Turner D, Kang C, Mesirca P, et al. Electrophysiological and Molecular Mechanisms of Sinoatrial Node Mechanosensitivity. Front Cardiovasc Med. 2021 Aug 9;8: 662410. https://doi.org/10.3389/fcvm.2021.662410.Turner D, Kang C, Mesirca P, et al. Electrophysiological and Molecular Mechanisms of Sinoatrial Node Mechanosensitivity. Front Cardiovasc Med. 2021 Aug 9;8: 662410. https://doi.org/10.3389/fcvm.2021.662410.Unudurthi SD, Wolf RM, Hund TJ. Role of sinoatrial node architecture in maintaining a balanced sourcesink relationship and synchronous cardiac pacemaking. Front Physiol. 2014;5: 446. https://doi.org/10.3389/fphys.2014.00446.Unudurthi SD, Wolf RM, Hund TJ. Role of sinoatrial node architecture in maintaining a balanced sourcesink relationship and synchronous cardiac pacemaking. Front Physiol. 2014;5: 446. https://doi.org/10.3389/fphys.2014.00446.Rylant P. Contribution à l’ètude de l’automatisme et de la conduction dans le Coeur. Bulletin de l’Académie royale de médecine de Belgique. 1927: 161-200.Rylant P. Contribution à l’ètude de l’automatisme et de la conduction dans le Coeur. Bulletin de l’Académie royale de médecine de Belgique. 1927: 161-200.Ernst RW, Paulson DL. Pedicle grafting of the sino-auricular node to the right ventricle for the treatment of complete atrioventricular block. J. Thorac. Cardiovasc. Surg. 1962;44: 681-686. https://doi.org/10.1016/S0022-5223(19)32933-2.Ernst RW, Paulson DL. Pedicle grafting of the sino-auricular node to the right ventricle for the treatment of complete atrioventricular block. J. Thorac. Cardiovasc. Surg. 1962;44: 681-686. https://doi.org/10.1016/S0022-5223(19)32933-2.Morishita Y, Poirier RA, Rohner RF. Sino-Atrial Node Transplantation in the Dog. Vasc. Endovascular Surg. 1981;15: 388-393. https://doi.org/10.1177/153857448101500603.Morishita Y, Poirier RA, Rohner RF. Sino-Atrial Node Transplantation in the Dog. Vasc. Endovascular Surg. 1981;15: 388-393. https://doi.org/10.1177/153857448101500603.Ruhparwar A, Tebbenjohanns J, Niehaus M, et al. (2002). Transplanted fetal cardiomyocytes as cardiac pacemaker. Eur. J. Cardiothorac. Surg. 2002;21: 853-857. https://doi.org/10.1016/s1010-7940(02) 00066-0.Ruhparwar A, Tebbenjohanns J, Niehaus M, et al. (2002). Transplanted fetal cardiomyocytes as cardiac pacemaker. Eur. J. Cardiothorac. Surg. 2002;21: 853-857. https://doi.org/10.1016/s1010-7940(02) 00066-0.Lin G, Cai J, Jiang H, et al. Biological pacemaker created by fetal cardiomyocyte transplantation. J. Biomed. Sci. 2005;12: 513-519. https://doi.org/10.1007/s11373-005-6794-2.Lin G, Cai J, Jiang H, et al. Biological pacemaker created by fetal cardiomyocyte transplantation. J. Biomed. Sci. 2005;12: 513-519. https://doi.org/10.1007/s11373-005-6794-2.Zhang H, Lau DH, Shlapakova IN, et al. Implantation of sinoatrial node cells into canine right ventricle: biological pacing appears limited by the substrate. Cell Transpl. 2011;20: 1907-1914. https://doi.org/10.3727/096368911X565038.Zhang H, Lau DH, Shlapakova IN, et al. Implantation of sinoatrial node cells into canine right ventricle: biological pacing appears limited by the substrate. Cell Transpl. 2011;20: 1907-1914. https://doi.org/10.3727/096368911X565038.Kehat I, Khimovich L, Caspi O, et al. Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat. Biotechnol. 2004;22: 1282-1289. https://doi.org/10.1038/nbt1014.Kehat I, Khimovich L, Caspi O, et al. Electromechanical integration of cardiomyocytes derived from human embryonic stem cells. Nat. Biotechnol. 2004;22: 1282-1289. https://doi.org/10.1038/nbt1014.Xue T, Cho HC, Akar FG, et al. (2005). Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes: insights into the development of cell based pacemakers. Circulation. 2005;111: 11-20. https://doi.org/10.1161/01. CIR.0000151313.18 547.A2.Xue T, Cho HC, Akar FG, et al. (2005). Functional integration of electrically active cardiac derivatives from genetically engineered human embryonic stem cells with quiescent recipient ventricular cardiomyocytes: insights into the development of cell based pacemakers. Circulation. 2005;111: 11-20. https://doi.org/10.1161/01. CIR.0000151313.18 547.A2.Protze SI, Liu J, Nussinovitch U, et al. Sinoatrial node cardiomyocytes derived from human pluripotent cells function as a biological pacemaker. Nat. Biotechnol. 2016;35: 56-68. https://doi.org/10.1038/nbt.3745.Protze SI, Liu J, Nussinovitch U, et al. Sinoatrial node cardiomyocytes derived from human pluripotent cells function as a biological pacemaker. Nat. Biotechnol. 2016;35: 56-68. https://doi.org/10.1038/nbt.3745.Menasché P, Vanneaux V, Hagège A, et al. Transplantation of human embryonic stem cell-derived cardiovascular progenitors for severe ischemic left ventricular dysfunction. J. Am. Coll. Cardiol. 2018;71: 429-438. https://doi.org/10.1016/j.jacc.2017.11.047.Menasché P, Vanneaux V, Hagège A, et al. Transplantation of human embryonic stem cell-derived cardiovascular progenitors for severe ischemic left ventricular dysfunction. J. Am. Coll. Cardiol. 2018;71: 429-438. https://doi.org/10.1016/j.jacc.2017.11.047.Miyagawa S, Kainuma S, Kawamura T, et al. Case report: Transplantation of human induced pluripotent stem cell-derived cardiomyocyte patches for ischemic cardiomyopathy. Front Cardiovasc Med. 2022 Aug 16;9: 950829. https://doi.org/10.3389/fcvm.2022.950829.Miyagawa S, Kainuma S, Kawamura T, et al. Case report: Transplantation of human induced pluripotent stem cell-derived cardiomyocyte patches for ischemic cardiomyopathy. Front Cardiovasc Med. 2022 Aug 16;9: 950829. https://doi.org/10.3389/fcvm.2022.950829.Edelberg JM. Molecular enhancement of porcine cardiac chronotropy. Heart. 2001;86: 559-562. https://doi.org/10.1136/heart.86.5.559. 36. Miake J, Marbán E, Nuss HB. Biological pacemakercreatedbygene transfer. Nature. 2002;419: 132-133. https:// doi.org/10.1038/419132b.Edelberg JM. Molecular enhancement of porcine cardiac chronotropy. Heart. 2001;86: 559-562. https://doi.org/10.1136/heart.86.5.559. 36. Miake J, Marbán E, Nuss HB. Biological pacemakercreatedbygene transfer. Nature. 2002;419: 132-133. https:// doi.org/10.1038/419132b.Edelberg JM, Aird WC, Rosenberg RD. Enhancement of murine cardiac chronotropy by the molecular transfer of the human beta2 adrenergic receptor cDNA. J. Clin. Invest. 1998;101: 337-343. https://doi.org/10.1172/JCI1330.Edelberg JM, Aird WC, Rosenberg RD. Enhancement of murine cardiac chronotropy by the molecular transfer of the human beta2 adrenergic receptor cDNA. J. Clin. Invest. 1998;101: 337-343. https://doi.org/10.1172/JCI1330.Cho HC, Kashiwakura Y, Marbán E. Creation of a biological pacemaker by cell fusion. Circ. Res. 2007;100: 1112-1115. https://doi.org/10.1161/01. RES.0000265845.04439.78.Cho HC, Kashiwakura Y, Marbán E. Creation of a biological pacemaker by cell fusion. Circ. Res. 2007;100: 1112-1115. https://doi.org/10.1161/01. RES.0000265845.04439.78.Qu J, Plotnikov AN, Danilo P, et al. Expression and function of a biological pacemaker in canine heart. Circulation. 2003;107: 1106-1109. https://doi.org/10.1161/01. CIR.0000059939.97249.2C.Qu J, Plotnikov AN, Danilo P, et al. Expression and function of a biological pacemaker in canine heart. Circulation. 2003;107: 1106-1109. https://doi.org/10.1161/01. CIR.0000059939.97249.2C.Tse HF, Xue T, Lau CP, et al. Bioartificial sinus node constructed via in vivo gene transfer of an engineered pacemaker HCN channel reduces the dependence on electronic pacemaker in a sick-sinus syndrome model. Circulation. 2006;114: 1000-1011. https://doi.org/10.1161/CIRCULATIONAHA.106.615385.Tse HF, Xue T, Lau CP, et al. Bioartificial sinus node constructed via in vivo gene transfer of an engineered pacemaker HCN channel reduces the dependence on electronic pacemaker in a sick-sinus syndrome model. Circulation. 2006;114: 1000-1011. https://doi.org/10.1161/CIRCULATIONAHA.106.615385.Boink GJ, Duan L, Nearing BD, et al. HCN2/SkM1 gene transfer into canine left bundle branch induces stable, autonomically responsive biological pacing at physiological heart rates. J. Am. Coll. Cardiol. 2013;61: 1192-1201. https://doi.org/10.1016/j.jacc.2012.12.031.Boink GJ, Duan L, Nearing BD, et al. HCN2/SkM1 gene transfer into canine left bundle branch induces stable, autonomically responsive biological pacing at physiological heart rates. J. Am. Coll. Cardiol. 2013;61: 1192-1201. https://doi.org/10.1016/j.jacc.2012.12.031.Ruhparwar A, Kallenbach K, Klein G, et al. Adenylate-cyclase vi transforms ventricular cardiomyocytes into biological pacemaker cells. Tissue Eng. 2010;Part A 16: 1867-1872. https://doi.org/10.1089/ten.tea.2009.0537.Ruhparwar A, Kallenbach K, Klein G, et al. Adenylate-cyclase vi transforms ventricular cardiomyocytes into biological pacemaker cells. Tissue Eng. 2010;Part A 16: 1867-1872. https://doi.org/10.1089/ten.tea.2009.0537.D’Souza A, Pearman CM, Wang Y, et al. Targeting miR-423-5p reverses exercise training-induced HCN4 channel remodeling and sinus bradycardia. Circ. Res. 2017;121: 1058-1068. https://doi.org/10.1161/CIRCRESAHA.117.311607.D’Souza A, Pearman CM, Wang Y, et al. Targeting miR-423-5p reverses exercise training-induced HCN4 channel remodeling and sinus bradycardia. Circ. Res. 2017;121: 1058-1068. https://doi.org/10.1161/CIRCRESAHA.117.311607.Kapoor N, Liang W, Marbán E, et al. Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nat. Biotechnol. 2013;31: 54-62. https://doi.org/10.1038/nbt.2465.Kapoor N, Liang W, Marbán E, et al. Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of Tbx18. Nat. Biotechnol. 2013;31: 54-62. https://doi.org/10.1038/nbt.2465.Hu YF, Dawkins JF, Cho HC, et al. Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block. Sci. Transl. Med. 2014;6: 245ra94-245ra94. https://doi.org/10.1126/scitranslmed.3008681.Hu YF, Dawkins JF, Cho HC, et al. Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block. Sci. Transl. Med. 2014;6: 245ra94-245ra94. https://doi.org/10.1126/scitranslmed.3008681.Potapova I, Plotnikov A, Lu Z, et al. Human mesenchymal stem cells as a gene delivery system to create cardiac pacemakers. Circ. Res. 2004;94: 952-959. https://doi. org/10.1161/01.RES.0000123827.60210.72. 47. Plotnikov AN, Shlapakova I, Szabolcs MJ, et al. Xenografted adult human mesenchymal stem cells provide a platform for sustained biological pacemaker function in canine heart. Circulation. 2007;116: 706-713. https://doi.org/10.1161/CIRCULATIONAHA.107.703231.Potapova I, Plotnikov A, Lu Z, et al. Human mesenchymal stem cells as a gene delivery system to create cardiac pacemakers. Circ. Res. 2004;94: 952-959. https://doi. org/10.1161/01.RES.0000123827.60210.72. 47. Plotnikov AN, Shlapakova I, Szabolcs MJ, et al. Xenografted adult human mesenchymal stem cells provide a platform for sustained biological pacemaker function in canine heart. Circulation. 2007;116: 706-713. https://doi.org/10.1161/CIRCULATIONAHA.107.703231.Zhou YF, Yang XJ, Li HX, et al. Genetically-engineered mesenchymal stem cells transfected with human HCN1 gene to create cardiac pacemaker cells. J. Int. Med. Res. 2013;41: 1570-1576. https://doi.org/10.1177/0300060513501123.Zhou YF, Yang XJ, Li HX, et al. Genetically-engineered mesenchymal stem cells transfected with human HCN1 gene to create cardiac pacemaker cells. J. Int. Med. Res. 2013;41: 1570-1576. https://doi.org/10.1177/0300060513501123.Zhang Z, Song Z, Cheng J, et al. The integration and functional evaluation of rabbit pacing cells transplanted into the left ventricular free wall. Int. J. Med. Sci. 2012;9: 513-520. https://doi.org/10.7150/ijms.4971.Zhang Z, Song Z, Cheng J, et al. The integration and functional evaluation of rabbit pacing cells transplanted into the left ventricular free wall. Int. J. Med. Sci. 2012;9: 513-520. https://doi.org/10.7150/ijms.4971.Nong Y, Zhang C, Wei L, et al. In situ investigation of allografted mouse HCN4 gene-transfected rat bone marrow mesenchymalstromalcells with the useofpatch-clamp recordingofventricular slices. Cytotherapy. 2013;15: 905- 919. https://doi.org/10.1016/j.jcyt.2013.03.010.Nong Y, Zhang C, Wei L, et al. In situ investigation of allografted mouse HCN4 gene-transfected rat bone marrow mesenchymalstromalcells with the useofpatch-clamp recordingofventricular slices. Cytotherapy. 2013;15: 905- 919. https://doi.org/10.1016/j.jcyt.2013.03.010.Boink GJ, Lu J, Driessen HE, et al. Effect of skeletal muscle Na + channel delivered via a cell platform on cardiac conduction and arrhythmia induction. Circ. Arrhythmia Electrophysiol. 2012;5: 831-840. https://doi.org/10.1161/CIRCEP.111.969907.Boink GJ, Lu J, Driessen HE, et al. Effect of skeletal muscle Na + channel delivered via a cell platform on cardiac conduction and arrhythmia induction. Circ. Arrhythmia Electrophysiol. 2012;5: 831-840. https://doi.org/10.1161/CIRCEP.111.969907.Végh AM, Verkerk AO, Cócera Ortega L, et al. Toward biological pacing by cellular delivery of Hcn2/SkM1. Front. Physiol. 2021;11: 588679. https://doi.org/10.3389/fphys.2020.588679.Végh AM, Verkerk AO, Cócera Ortega L, et al. Toward biological pacing by cellular delivery of Hcn2/SkM1. Front. Physiol. 2021;11: 588679. https://doi.org/10.3389/fphys.2020.588679.Zhang J, Huang C. A new combination of transcription factors increases the harvesting efficiency of pacemaker-like cells. Mol. Med. Rep. 2019;19: 3584-3592. https://doi.org/10.3892/mmr.2019.10012.Zhang J, Huang C. A new combination of transcription factors increases the harvesting efficiency of pacemaker-like cells. Mol. Med. Rep. 2019;19: 3584-3592. https://doi.org/10.3892/mmr.2019.10012.Цвелая ВА, Чепелева ЕВ, Павлова СВ, и др. Применение полилактидных нановолоконных матриксов в качестве носителя для культивирования кардиомиоцитов Тезисы докладов международной конференции «Перспективные материалы с иерархической структурой для новых технологий и надежных конструкций», 1 - 5 октября 2018 года, Томск, Россия. Издательский Дом ТГУ, 2018. С. 313-314. https://doi.org/10.17223/9785946217408/195.Tsvelaya VA, Chepeleva EV, Pavlova SV, et al. Application of polylactide nanofiber matrices as a carrier for cardiomyocyte cultivation. In: Abstracts of the International Conference «Hierarchically Structured Materials for New Technologies and Reliable Structures»; October 1-5, 2018; Tomsk, Russia. Tomsk: TSU Publishing House; 2018. p. 313-314. (In Russ.) С. 313-314. https://doi.org/10.17223/9785946217408/195.Чепелева ЕВ, Балашов ВА, Докучаева АА. (2017). Исследование биологической совместимости полилактидных нановолоконных матриксов, заселенных фибробластами сердца, в эксперименте на мини-свиньях. Гены и клетки. 2017;12(4): 62-68. https://doi.org/10.23868/201707031.Chepeleva EV, Balashov VA, Dokuchaeva AA. Study of biocompatibility of polylactide nanofiber matrices seeded with cardiac fibroblasts in a mini-pig experiment. Genes and Cells. 2017;12(4): 62- 68. (In Russ.)https://doi.org/10.23868/201707031.Пономаренко АВ, Чепелева ЕВ, Павлова СВ. Оценка безопасности и эффективности инъекционного метода трансплантации кардиомиоцитов человека, обладающих пейсмейкерной активностью, полученных из индуцированных плюрипотентных стволовых клеток. Гены и клетки. 2018;13(4): 31-36. https://doi.org/10.23868/201812044.Ponomarenko AV, Chepeleva EV, Pavlova SV. Safety and efficacy evaluation of the injection method of transplantation of human cardiomyocytes with pacemaker activity derived from induced pluripotent stem cells. Genes and Cells. 2018;13(4): 31-36. (In Russ.)] https://doi.org/10.23868/201812044.Павлова СВ, Леонова ЕА, Чепелева ЕВ. Мониторинг трансплантации клеток кардиосфер в фибриновом геле в зону ишемического повреждения миокарда с использованием люциферазной репортерной системы. Гены и клетки. 2017;12(4): 69-75. https://doi.org/10.23868/201707032.Pavlova SV, Leonova EA, Chepeleva EV. Monitoring of cardiosphere cell transplantation in fibrin gel into the area of ischemic myocardial injury using a luciferase reporter system. Genes and Cells. 2017;12(4): 69-75. (In Russ.) https://doi.org/10.23868/201707032.

The authors declare that there are no conflicts of interest present.