russjcardiolРоссийский кардиологический журналRussian Journal of Cardiology1560-40712618-7620«SILICEA-POLIGRAF» LLC10.15829/1560-4071-2025-6397DSTJODrussjcardiol-6397Research ArticleОБЗОРЫ ЛИТЕРАТУРЫREVIEWНовый взгляд на процессы фиброза миокарда: «холодный» и «горячий» фенотипы. Особенности патогенеза и потенциальные терапевтические стратегииA fresh angle on myocardial fibrosis processes: cold and hot phenotypes. Pathogenesis features and potential therapeutic strategieshttps://orcid.org/0000-0002-6531-6255ДрагомирецкаяН. А.DragomiretskayaN. A.

Наталья Александровна Драгомирецкая — д.м.н., доцент кафедры факультетской терапии № 2ИКМ им. Н. В. Склифосовского

Москва

Moscow

dragomiretsksya_n_a@staff.sechenov.ruhttps://orcid.org/0009-0008-9395-903XВолчковИ. И.VolchkovI. I.

Иван Игоревич Волчков —студент ИКМ им. Н. В. Склифосовского

Москва

Moscow

ivanvolchkovvlss@gmail.comhttps://orcid.org/0009-0003-5066-6695БеловА. К.BelovA. K.

Андрей Константинович Белов — студент ИКМ им. Н. В. Склифосовского

Москва

Moscow

andreybelo.ov@gmail.comhttps://orcid.org/0009-0004-1194-9462ГонцоваЛ. А.GontsovaL. A.

Лилия Александровна Гонцова — врач отделения терапии УКБ № 4 Клинического центра

Москва

Moscow

gontsova_l_a_1@staff.sechenov.ruhttps://orcid.org/0000-0001-9733-4813ВетлужскаяМ. В.VetluzhskayaM. V.

Лилия Александровна Гонцова — врач отделения терапии УКБ № 4 Клинического центра

Москва

Moscow

vetluzhskaya_m_v@staff.sechenov.ruhttps://orcid.org/0000-0002-0758-5609ПодзолковВ. И.PodzolkovV. I.

Валерий Иванович Подзолков — д.м.н., профессор, зав. кафедрой факультетской терапии № 2 ИКМ им. Н. В. Склифосовского

Москва

Moscow

podzolkov_v_i@staff.sechenov.ruФГАОУ ВО Первый МГМУ им. И. М. Сеченова Минздрава России (Сеченовский Университет)РоссияSechenov First Moscow State Medical UniversityRussian Federation202514102025309SОбзоры литературы, мнения по проблеме63976397Copyright © Драгомирецкая Н.А., Волчков И.И., Белов А.К., Гонцова Л.А., Ветлужская М.В., Подзолков В.И., 20252025Драгомирецкая Н.А., Волчков И.И., Белов А.К., Гонцова Л.А., Ветлужская М.В., Подзолков В.И.Dragomiretskaya N.A., Volchkov I.I., Belov A.K., Gontsova L.A., Vetluzhskaya M.V., Podzolkov V.I.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://russjcardiol.elpub.ru/jour/article/view/6397

Фиброз — это процесс, характеризующийся чрезмерным накоплением компонентов внеклеточного матрикса в ответ травму, ишемию, хроническое метаболическое и иммунное воспаление. В норме гомеостаз внеклеточного матрикса регулируется за счет поддержания баланса между интенсивностью фиброгенеза и фибролиза. В данном обзоре впервые в отечественной литературе освещается новая концепция «холодного» и «горячего» фиброза, основанная на особенностях взаимодействия внеклеточного матрикса и иммунной системы. Наряду с этим обсуждается роль целого ряда биологически активных веществ, выступающих в роли биомаркеров-кандидатов фиброза и антифибротического ответа. Разработка подобной биомаркерной концепции может рассматриваться как основа для создания стратегий антифибротической терапии, актуальной для лечения различных кардиологических заболеваний

Fibrosis is a process characterized by excessive accumulation of extracellular matrix components in response to injury, ischemia, and chronic metabolic and immune inflammation. Normally, extracellular matrix homeostasis is regulated by maintaining a balance between the intensity of fibrogenesis and fibrolysis. In this review, for the first time in the Russian literature, a new concept of "cold" and "hot" fibrosis is highlighted, based on the peculiarities of the interaction of the extracellular matrix and the immune system. The role of biologically active substances acting as candidate biomarkers for fibrosis and antifibrotic response is discussed. The development of such a biomarker concept can be considered as a basis for the creation of antifibrotic therapy strategies relevant for the treatment of various cardiac diseases.

холодный фиброзгорячий фиброзмиофибробластымакрофагихроническая сердечная недостаточностьcold fibrosishot fibrosismyofibroblastsmacrophageschronic heart failureReferencesZawadzki A, Leeming DJ, Sanyal AJ, et al. Hot and Cold Fibrosis: The Role of Serum Biomarkers to assess the Immune Mechanisms and ECM-Cell Interactions in Human Fibrosis. J Hepatol. 2025: S0168-8278(25)00148-5. doi:10.1016/j.jhep.2025.02.039.Zawadzki A, Leeming DJ, Sanyal AJ, et al. Hot and Cold Fibrosis: The Role of Serum Biomarkers to assess the Immune Mechanisms and ECM-Cell Interactions in Human Fibrosis. J Hepatol. 2025: S0168-8278(25)00148-5. doi:10.1016/j.jhep.2025.02.039.Miyara S, Adler M, Umansky KB, et al. Cold and hot fibrosis define clinically distinct cardiac pathologies. Cell Syst. 2025;16(3):101198. doi:10.1016/j.cels.2025.101198.Miyara S, Adler M, Umansky KB, et al. Cold and hot fibrosis define clinically distinct cardiac pathologies. Cell Syst. 2025;16(3):101198. doi:10.1016/j.cels.2025.101198.Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature. 2020;587(7835):555-66. doi:10.1038/s41586-020-2938-9.Henderson NC, Rieder F, Wynn TA. Fibrosis: from mechanisms to medicines. Nature. 2020;587(7835):555-66. doi:10.1038/s41586-020-2938-9.Alon U. Systems Medicine, Physiological Circuits and the Dynamics of Disease (1st ed.) Chapman and Hall/CRC. 2023;270. doi:10.1201/9781003356929.Alon U. Systems Medicine, Physiological Circuits and the Dynamics of Disease (1st ed.) Chapman and Hall/CRC. 2023;270. doi:10.1201/9781003356929.Jiang W, Xiong Y, Li X, Yang Y. Cardiac Fibrosis: Cellular Effectors, Molecular Pathways, and Exosomal Roles. Front Cardiovasc Med. 2021;8:715258. doi:10.3389/fcvm.2021.715258.Jiang W, Xiong Y, Li X, Yang Y. Cardiac Fibrosis: Cellular Effectors, Molecular Pathways, and Exosomal Roles. Front Cardiovasc Med. 2021;8:715258. doi:10.3389/fcvm.2021.715258.Соломахина Н. И., Беленков Ю. Н., Варшавский В. А. Фиброз миокарда при систолической и диастолической хронической сердечной недостаточности: монография. М.: ИД "Медпрактика-М", 2014, 64 с. ISBN: 978-5-98803-315-8.Solomakhina NI, Belenkov YuN, Varshavsky VA. Myocardial fibrosis in systolic and diastolic chronic heart failure: monograph. Moscow: Publishing house "Medpraktika-M", 2014, 64 p. (In Russ.) ISBN: 978-5-98803-315-8.Ye L, D’Agostino G, Loo SJ, et al. Early regenerative capacity in the porcine heart. Circulation 2018;138:2798-808. doi:10.1161/circulationaha.117.031542.Ye L, D’Agostino G, Loo SJ, et al. Early regenerative capacity in the porcine heart. Circulation 2018;138:2798-808. doi:10.1161/circulationaha.117.031542.Haubner BJ, Schneider J, Schweigmann U, et al. Functional recovery of a human neonatal heart after severe myocardial infarction. Circ. Res. 2016;118:216-21. doi:10.1161/circresaha.115.307017.Haubner BJ, Schneider J, Schweigmann U, et al. Functional recovery of a human neonatal heart after severe myocardial infarction. Circ. Res. 2016;118:216-21. doi:10.1161/circresaha.115.307017.Tzahor E, Poss KD. Cardiac regeneration strategies: Staying young at heart. Science. 2017;356:1035-9. doi:10.1126/science.aam5894.Tzahor E, Poss KD. Cardiac regeneration strategies: Staying young at heart. Science. 2017;356:1035-9. doi:10.1126/science.aam5894.O’Reilly S, Tsou PS, Varga J. Senescence and tissue fibrosis: opportunities for therapeutic targeting. Trends Mol Med. 2024;30(12):1113-25. doi:10.1016/j.molmed.2024.05.012.O’Reilly S, Tsou PS, Varga J. Senescence and tissue fibrosis: opportunities for therapeutic targeting. Trends Mol Med. 2024;30(12):1113-25. doi:10.1016/j.molmed.2024.05.012.Maruyama K, Imanaka-Yoshida K. The pathogenesis of cardiac fibrosis: a review of recent progress. Int J Mol Sci. 2022;23(5):2617. doi:10.3390/ijms23052617.Maruyama K, Imanaka-Yoshida K. The pathogenesis of cardiac fibrosis: a review of recent progress. Int J Mol Sci. 2022;23(5):2617. doi:10.3390/ijms23052617.de Castro Brás LE, Frangogiannis NG. Extracellular matrix-derived peptides in tissue remodeling and fibrosis. Matrix Biol. 2020;91-2:176-87. doi:10.1016/j.matbio.2020.04.006.de Castro Brás LE, Frangogiannis NG. Extracellular matrix-derived peptides in tissue remodeling and fibrosis. Matrix Biol. 2020;91-2:176-87. doi:10.1016/j.matbio.2020.04.006.Espeland T, Lunde IG, H Amundsen B, et al. Myocardial fibrosis. Tiedsskr Nor Laegeforen. 2018;138(16). English, Norwegian. doi:10.4045/tidsskr.17.1027.Espeland T, Lunde IG, H Amundsen B, et al. Myocardial fibrosis. Tiedsskr Nor Laegeforen. 2018;138(16). English, Norwegian. doi:10.4045/tidsskr.17.1027.Hilgendorf I, Frantz S, Frangogiannis NG. Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities. Circ Res. 2024;134(12):1718-51. doi:10.1161/CIRCRESAHA.124.323658.Hilgendorf I, Frantz S, Frangogiannis NG. Repair of the Infarcted Heart: Cellular Effectors, Molecular Mechanisms and Therapeutic Opportunities. Circ Res. 2024;134(12):1718-51. doi:10.1161/CIRCRESAHA.124.323658.Pakshir P, Hinz B. The big five in fibrosis: Macrophages, myofibroblasts, matrix, mechanics, and miscommunication. Matrix Biol. 2018;68:81-93. doi:10.1016/j.matbio.2018.01.019.Pakshir P, Hinz B. The big five in fibrosis: Macrophages, myofibroblasts, matrix, mechanics, and miscommunication. Matrix Biol. 2018;68:81-93. doi:10.1016/j.matbio.2018.01.019.Buechler MB, FuW, Turley SJ. Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer. Immunity. 2021;54:903-15. doi:10.1016/j.immuni.2021.04.021.Buechler MB, FuW, Turley SJ. Fibroblast-macrophage reciprocal interactions in health, fibrosis, and cancer. Immunity. 2021;54:903-15. doi:10.1016/j.immuni.2021.04.021.Rao W, Li D, Zhang Q, et al. Complex regulation of cardiac fibrosis: insights from immune cells and signaling pathways. J Transl Med. 2025;23(1):242. doi:10.1186/s12967-025-06260-5.Rao W, Li D, Zhang Q, et al. Complex regulation of cardiac fibrosis: insights from immune cells and signaling pathways. J Transl Med. 2025;23(1):242. doi:10.1186/s12967-025-06260-5.Adler M, Mayo A, Zhou X, et al. Principles of cell circuits for tissue repair and fibrosis. iScience. 2020;23(2):100841. doi:10.10.16/j.isci.2020.100841.Adler M, Mayo A, Zhou X, et al. Principles of cell circuits for tissue repair and fibrosis. iScience. 2020;23(2):100841. doi:10.10.16/j.isci.2020.100841.Adhyatmika A, Putri KS, Beljaars L, Melgert BN. The elusive antifibrotic macrophage. Front Med (Lausanne). 2015;2:81. doi:10.3389/fmed.2015.00081.Adhyatmika A, Putri KS, Beljaars L, Melgert BN. The elusive antifibrotic macrophage. Front Med (Lausanne). 2015;2:81. doi:10.3389/fmed.2015.00081.Kokubo K, Onodera A, Kiuchi M, et al. Conventional and pathogenic Th2 cells in inflammation, tissue repair, and fibrosis. Front Immunol. 2022;13:945063. doi:10.3389/fimmu.2022.945063.Kokubo K, Onodera A, Kiuchi M, et al. Conventional and pathogenic Th2 cells in inflammation, tissue repair, and fibrosis. Front Immunol. 2022;13:945063. doi:10.3389/fimmu.2022.945063.Hesketh M, Sahin KB, West ZE, Murray RZ. Macrophage phenotypes regulate scar formation and chronic wound healing. Int J Mol Sci. 2017;18(7):1545. doi:10.3390/ijms18071545.Hesketh M, Sahin KB, West ZE, Murray RZ. Macrophage phenotypes regulate scar formation and chronic wound healing. Int J Mol Sci. 2017;18(7):1545. doi:10.3390/ijms18071545.Yan L, Wang J, Cai X, et al. Macrophage plasticity: signaling pathways, tissue repair, and regeneration. MedComm 2024;5(8):e658. doi:10.1002/mco2.658.Yan L, Wang J, Cai X, et al. Macrophage plasticity: signaling pathways, tissue repair, and regeneration. MedComm 2024;5(8):e658. doi:10.1002/mco2.658.Calcagno DM, Taghdiri N, Ninh VK, et al. Single-cell and spatial transcriptomics of the infarcted heart define the dynamic onset of the border zone in response to mechanical destabilization. Nat CardioVasc Res. 2022;1:1039-55. doi:10.1038/s44161-022-00160-3.Calcagno DM, Taghdiri N, Ninh VK, et al. Single-cell and spatial transcriptomics of the infarcted heart define the dynamic onset of the border zone in response to mechanical destabilization. Nat CardioVasc Res. 2022;1:1039-55. doi:10.1038/s44161-022-00160-3.Walraven M, Hinz B. Therapeutic approaches to control tissue repair and fibrosis: Extracellular matrix as a game changer. Matrix Biol. 2018;71-72:205-24. doi:10.1016/j.matbio.2018.02.020.Walraven M, Hinz B. Therapeutic approaches to control tissue repair and fibrosis: Extracellular matrix as a game changer. Matrix Biol. 2018;71-72:205-24. doi:10.1016/j.matbio.2018.02.020.Sharma N, Kumar P, Shukla KS, et al. AGE RAGE Pathways: cardiovascular disease and oxidative stress. Drug Res (Stuttg). 2023;73(7):408-11. doi:10.1055/a-2047-3896.Sharma N, Kumar P, Shukla KS, et al. AGE RAGE Pathways: cardiovascular disease and oxidative stress. Drug Res (Stuttg). 2023;73(7):408-11. doi:10.1055/a-2047-3896.Ke D, Cao M, Ni J, et al. Macrophage and fibroblast trajectory inference and crosstalk analysis during myocardial infarction using integrated single-cell transcriptomic datasets. J Transl Med. 2024;22(1):560. doi:10.1186/s12967-024-05353-x.Ke D, Cao M, Ni J, et al. Macrophage and fibroblast trajectory inference and crosstalk analysis during myocardial infarction using integrated single-cell transcriptomic datasets. J Transl Med. 2024;22(1):560. doi:10.1186/s12967-024-05353-x.Fu X, Khalil H, Kanisicak O, et al. Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart. J Clin Invest. 2018;128(5):2127-43. doi:10.1172/JCI98215.Fu X, Khalil H, Kanisicak O, et al. Specialized fibroblast differentiated states underlie scar formation in the infarcted mouse heart. J Clin Invest. 2018;128(5):2127-43. doi:10.1172/JCI98215.Patrick R, Janbandhu V, Tallapragada V, et al. Integration mapping of cardiac fibroblast single-cell transcriptomes elucidates cellular principles of fibrosis in diverse pathologies. Sci Adv. 2024;10(25):eadk8501. doi:10.1126/sciadv.adk8501.Patrick R, Janbandhu V, Tallapragada V, et al. Integration mapping of cardiac fibroblast single-cell transcriptomes elucidates cellular principles of fibrosis in diverse pathologies. Sci Adv. 2024;10(25):eadk8501. doi:10.1126/sciadv.adk8501.Bastos JM, Scala N, Perpétuo L, et al. Integrative bioinformatic analysis of prognostic biomarkers in heart failure: Insights from clinical trials. Eur J Clin Invest. 2025;55(4):e70010. doi:10.1111/eci.70010.Bastos JM, Scala N, Perpétuo L, et al. Integrative bioinformatic analysis of prognostic biomarkers in heart failure: Insights from clinical trials. Eur J Clin Invest. 2025;55(4):e70010. doi:10.1111/eci.70010.Wang S, Li K, Pickholz E, et al. An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Sci Transl Med. 2023;15:eadd3949. doi:10.1126/scitranslmed.add3949.Wang S, Li K, Pickholz E, et al. An autocrine signaling circuit in hepatic stellate cells underlies advanced fibrosis in nonalcoholic steatohepatitis. Sci Transl Med. 2023;15:eadd3949. doi:10.1126/scitranslmed.add3949.Higashikuni Y, Liu W, Numata G, et al. NLRP3 inflammasome activation through heart-brain interaction initiates cardiac inflammation and hypertrophy during pressure overload. Circulation. 2023;147(4):338-55. doi:10.1161/CIRCULATIONAHA.122.060860.Higashikuni Y, Liu W, Numata G, et al. NLRP3 inflammasome activation through heart-brain interaction initiates cardiac inflammation and hypertrophy during pressure overload. Circulation. 2023;147(4):338-55. doi:10.1161/CIRCULATIONAHA.122.060860.Bomb R, Heckle MR, Sun Y, et al. Myofibroblast secretome and its auto-/paracrine signaling. Expert Rev Cardiovasc Ther. 2016;14(5):591-8. doi:10.1586/14779072.2016.1147348.Bomb R, Heckle MR, Sun Y, et al. Myofibroblast secretome and its auto-/paracrine signaling. Expert Rev Cardiovasc Ther. 2016;14(5):591-8. doi:10.1586/14779072.2016.1147348.Setten E, Castagna A, Nava-Sedeño JM, et al. Understanding fibrosis pathogenesis via modeling macrophage-fibroblast interplay in immune-metabolic context. Nat. Commun. 2022;13:6499. doi.10.1038/s41467-022-34241-5.Setten E, Castagna A, Nava-Sedeño JM, et al. Understanding fibrosis pathogenesis via modeling macrophage-fibroblast interplay in immune-metabolic context. Nat. Commun. 2022;13:6499. doi.10.1038/s41467-022-34241-5.Подзолков В. И., Драгомирецкая Н. А., Казадаева А. В. и др. Взаимосвязи активности нейрогормональных систем и параметров внутрисердечной гемодинамики у больных хронической сердечной недостаточностью: фокус на галектин-3. Российский кардиологический журнал. 2022;27(4):4957. doi:10.15829/1560-4071-2022-4957.Podzolkov VI, Dragomiretskaya NA, Kazadaeva AV, et al. Relationships between the activity of neurohormonal systems and intracardiac hemodynamics in patients with heart failure: focus on galectin-3. Russian Journal of Cardiology. 2022;27(4):4957. (In Russ.) doi:10.15829/1560-4071-2022-4957.Aghajanian H, Kimura T, Rurik JG, et al. Targeting cardiac fibrosis with engineered T cells. Nature. 2019;573:430-3. doi:10.1038/s41586-019-1546-z.Aghajanian H, Kimura T, Rurik JG, et al. Targeting cardiac fibrosis with engineered T cells. Nature. 2019;573:430-3. doi:10.1038/s41586-019-1546-z.Vagnozzi RJ, Maillet M, Sargent MA, et al. An acute immune response underlies the benefit of cardiac stem cell therapy. Nature. 2020;577:405-9. doi:10.1038/s41586-019-1802-2.Vagnozzi RJ, Maillet M, Sargent MA, et al. An acute immune response underlies the benefit of cardiac stem cell therapy. Nature. 2020;577:405-9. doi:10.1038/s41586-019-1802-2.Alexanian M, Przytycki PF, Micheletti R, et al. A transcriptional switch governs fibroblast activation in heart disease. Nature. 2021;595:438-43. doi:10.1038/s41586-021-03674-1.Alexanian M, Przytycki PF, Micheletti R, et al. A transcriptional switch governs fibroblast activation in heart disease. Nature. 2021;595:438-43. doi:10.1038/s41586-021-03674-1.Драгомирецкая Н. А., Толмачева А. В., Иванников А. А. и др. Фенотипические кластеры и профиль биомаркеров у больных с хронической сердечной недостаточностью с сохраненной и умеренно сниженной фракцией выброса левого желудочка. Терапевтический архив. 2024;96(12):1137-43. doi:10.26442/00403660.2024.12.203003.Dragomiretskaya NA, Tolmacheva AV, Ivannikov AA, et al. Phenotypic clusters and biomarkers profile in patients with chronic heart failure with preserved and mildly reduced left ventricular ejection fraction. Terapevticheskii Arkhiv (Ter. Arkh.). 2024;96(12):1137-43. (In Russ.) doi:10.26442/00403660.2024.12.203003.Sethi R, Vishwakarma P, Pradhan A. Evidence for aldosterone antagonism in heart failure. Card Fail Rev. 2024;10:e15. doi:10.15420/cfr.2024.10.Sethi R, Vishwakarma P, Pradhan A. Evidence for aldosterone antagonism in heart failure. Card Fail Rev. 2024;10:e15. doi:10.15420/cfr.2024.10

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