cardiotomskСибирский журнал клинической и экспериментальной медициныSiberian Journal of Clinical and Experimental Medicine2713-29272713-265XTSU publishing10.29001/2073-8552-2022-37-3-19-28cardiotomsk-1499Research ArticleОБЗОРЫ И ЛЕКЦИИREVIEWS AND LECTURESОбзор потенциальных предикторов антрациклин-индуцированной кардиотоксичности с позиции патогенеза заболеванияReview of potential predictors of anthracycline-induced cardiotoxicity from the position of disease pathogenesishttps://orcid.org/0000-0002-8070-2234КужелеваЕ. А.KuzhelevaE. A.

Кужелева Елена Андреевна, канд. мед. наук, старший научный сотрудник, отделение патологии миокарда

634012, Томск, ул. Киевская, 111а

Elena A. Kuzheleva, Cand. Sci. (Med.), Senior Research Scientist, Department of Myocardial Pathology

111a, Kievskaya str., Tomsk, 634012

kea@cardio-tomsk.ruhttps://orcid.org/0000-0002-9488-6900ГарганееваА. А.GarganeevaA. A.

Алла Анатольевна, – д-р мед. наук, заведующий отделением патологии миокарда, Научно-исследовательский институт кардиологии

634012, Томск, ул. Киевская, 111а

Alla A. Garganeeva, Dr. Sci. (Med.), Professor, Head of the Department of Myocardial Pathology, Cardiology Research Institute

111a, Kievskaya str., Tomsk, 634012

aag@cardio-tomsk.ruhttps://orcid.org/0000-0002-7661-5808ТукишО. В.TukishO. V.

Тукиш Ольга Викторовна, – канд. мед. наук, научный сотрудник, отделение патологии миокарда

634012, Томск, ул. Киевская, 111а

Olga V. Tukish, Cand. Sci. (Med.), Research Scientist, Department of Myocardial Pathology, Cardiology Research Institute

111a, Kievskaya str., Tomsk, 634012

olgatukish@yandex.ruhttps://orcid.org/0000-0002-1747-9041КондратьевМ. Ю.KondratievM. Y.

Кондратьев Михаил Юрьевич, – младший научный сотрудник, отделение патологии миокарда

634012, Томск, ул. Киевская, 111а

Michael Y. Kondratiev, Junior Research Scientist, Department of Myocardial Pathology, Cardiology Research Institute

111a, Kievskaya str., Tomsk, 634012

kmu@cardio-tomsk.ruhttps://orcid.org/0000-0002-2629-6466ВиттК. Н.VittK. N.

Витт Карина Николаевна, младший научный сотрудник, отделение патологии миокарда

634012, Томск, ул. Киевская, 111а

Karina N. Vitt, Junior Research Scientist, Department of Myocardial Pathology, Cardiology Research Institute

111a, Kievskaya str., Tomsk, 634012

karinavitt@list.ruhttps://orcid.org/0000-0001-8753-7916ЧерновВ. И.ChernovV. I.

Чернов Владимир Иванович, д-р мед. наук, профессор, заместитель директора по научной работе и инновационной деятельности, заведующий отделением радионуклидной диагностики

634009, Томск, пер. Кооперативный, 5

Vladimir I. Chernov, Dr. Sci. (Med.), Professor, Deputy Director for Research and Innovation of Tomsk NRMC, Head of the Diagnostic Radiology Department, Oncology Research Institute

5, Kooperativny ln., Tomsk, 634009

chernov@tnimc.ruНаучно-исследовательский институт кардиологии, Томский национальный исследовательский медицинский центр Российской академии наукРоссияCardiology Research Institute, Tomsk National Research Medical Center, Russian Academy of SciencesRussian FederationНаучно-исследовательский институт онкологии, Томский национальный исследовательский медицинский центр Российской академии наукРоссияCancer Research Institute, Tomsk National Research Medical Center, Russian Academy of SciencesRussian Federation2022191020223731928Copyright © Кужелева Е.А., Гарганеева А.А., Тукиш О.В., Кондратьев М.Ю., Витт К.Н., Чернов В.И., 20222022Кужелева Е.А., Гарганеева А.А., Тукиш О.В., Кондратьев М.Ю., Витт К.Н., Чернов В.И.Kuzheleva E.A., Garganeeva A.A., Tukish O.V., Kondratiev M.Y., Vitt K.N., Chernov V.I.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.sibjcem.ru/jour/article/view/1499

Кардиотоксичность антрациклиновых химиопрепаратов является одной из основных междисциплинарных проблем в области кардиоонкологии. Как известно, высокая противоопухолевая эффективность антрациклиновых антибиотиков существенно нивелируется развитием инвалидизирующих и летальных поражений сердца. Вместе с тем патогенез токсического поражения сердца, а также диагностические критерии и маркеры антрациклин-индуцированной кардиомиопатии до конца не ясны. В статье приведен подробный обзор потенциальных предикторов антрациклиновой кардиотоксичности с позиции патогенеза заболевания. Предложена схема патогенетического развития антрациклин-индуцированной кардиомиопатии, отражены основные методы диагностики токсического повреждения сердца, используемые в настоящее время в клинических исследованиях отечественных и зарубежных ученых.

Cardiotoxicity of anthracycline chemotherapy drugs is one of the main interdisciplinary problems in the research area of cardio-oncology. As is known, the high antitumor efficacy of anthracycline antibiotics is significantly leveled by the development of disabling and lethal heart lesions. However, the pathogenesis of toxic heart disease, as well as diagnostic criteria and markers of anthracycline-induced cardiomyopathy are not fully understood. The article provides a detailed review of potential markers of anthracycline cardiotoxicity from the position of disease pathogenesis. The scheme of pathogenetic development of anthracycline-induced cardiomyopathy is proposed in this article. The main methods of diagnostics of toxic damage of the heart that are currently used in clinical researches of domestic and foreign scientists are reviewed.

кардиотоксичностькардиоонкологияантрациклиндоксорубицинкардиомиопатияхимиотерапияcardiotoxicitycardio-oncologyanthracyclinedoxorubicincardiomyopathychemotherapyИсследование проведено в рамках госзадания, тема ФНИ № 122020300045-5.ReferencesКаприн А.Д., Старинский В.В., Шахзадова А.О. Злокачественные новообразования в России в 2019 году (заболеваемость и смертность). М.: МНИОИ им. П.А. Герцена − филиал ФГБУ «НМИЦ радиологии» Минздрава России; 2020:252.Kaprin A.D., Starinskij V.V., Shahzadova A.O. Malignant tumors in Russia in 2019 (morbidity and mortality). Moscow: MNIOI im. P.A. Gercena − filial FGBU «NMIC radiologii» Minzdrava Rossii; 2020:252. (In Russ.).Patnaik J.L., Byers T., DiGuiseppi C., Dabelea D., Denberg T.D. Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: А retrospective cohort study. Breast Cancer Res. 2011;13(3):R64. DOI: 10.1186/bcr2901.Patnaik J.L., Byers T., DiGuiseppi C., Dabelea D., Denberg T.D. Cardiovascular disease competes with breast cancer as the leading cause of death for older females diagnosed with breast cancer: А retrospective cohort study. Breast Cancer Res. 2011;13(3):R64. DOI: 10.1186/bcr2901.Oliveira G., Al-Kindi S., Caimi P., Lazarus H. Maximizing anthracycline tolerability in hematologic malignancies: Treat to each heart’s content. Blood Reviews. 2016;30(3):169–178. DOI: 10.1016/j.blre.2015.11.001.Oliveira G., Al-Kindi S., Caimi P., Lazarus H. Maximizing anthracycline tolerability in hematologic malignancies: Treat to each heart’s content. Blood Reviews. 2016;30(3):169–178. DOI: 10.1016/j.blre.2015.11.001.Чазова И.Е., Тюляндин С.А., Виценя М.В., Овчинников А.Г., Полтавская М.Г., Гиляров М.Ю. и др. Руководство по диагностике, профилактике и лечению сердечно-сосудистых осложнений противоопухолевой терапии (часть I). Системные гипертензии. 2017;14(3):6−20. DOI: 10.26442/2075-082X_14.3.6-20.Chazova I.Ye., Tyulyandin S.A., Vitsenya M.V., Ovchinnikov A.G., Poltavskaja M.G., Giljarov M.Ju. et al. Clinical manual for diagnosis, prevention and treatment of cardiovascular complications of cancer therapy (part I). Systemic Hypertension. 2017;14(3):6−20. (In Russ.). DOI: 10.26442/2075-082X_14.3.6-20.Zamorano L.J., Lancellotti P., Muñoz D.R., Aboyans V., Asteggiano R., Galderisi M. et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur. Heart J. 2016;37(36):2768−2801. DOI: 10.1093/eurheartj/ehw211.Zamorano L.J., Lancellotti P., Muñoz D.R., Aboyans V., Asteggiano R., Galderisi M. et al. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: The Task Force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur. Heart J. 2016;37(36):2768−2801. DOI: 10.1093/eurheartj/ehw211.Gulati G., Heck S.L., Ree A.H., Hoff mann P., Schulz-Menger J., Fagerland M.W. et al. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Eur. Heart J. 2016;37(21):1671−1680. DOI: 10.1093/eurheartj/ehw022.Gulati G., Heck S.L., Ree A.H., Hoffmann P., Schulz-Menger J., Fagerland M.W. et al. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 × 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Eur. Heart J. 2016;37(21):1671−1680. DOI: 10.1093/eurheartj/ehw022.Gulati G., Heck S.L., Røsjø H., Ree A.H., Hoff mann P., Hagve T.A. et al. Neurohormonal Blockade and Circulating Cardiovascular Biomarkers During Anthracycline Therapy in Breast Cancer Patients: Results From the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) Study. J. Am. Heart Assoc. 2017;6(11):e006513. DOI: 10.1161/JAHA.117.006513.Gulati G., Heck S.L., Røsjø H., Ree A.H., Hoffmann P., Hagve T.A. et al. Neurohormonal Blockade and Circulating Cardiovascular Biomarkers During Anthracycline Therapy in Breast Cancer Patients: Results From the PRADA (Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy) Study. J. Am. Heart Assoc. 2017;6(11):e006513. DOI: 10.1161/JAHA.117.006513..Fridrik M.A., Jaeger U., Petzer A., Willenbacher W., Keil F., Lang A. et al. Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diff use large B-cell lymphoma: A randomised phase-III study from the Austrian Cancer Drug Therapy Working Group [Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT](NHL-14). Eur. J. Cancer. 2016;58:112−121. DOI: 10.1016/j.ejca.2016.02.004.Fridrik M.A., Jaeger U., Petzer A., Willenbacher W., Keil F., Lang A. et al. Cardiotoxicity with rituximab, cyclophosphamide, non-pegylated liposomal doxorubicin, vincristine and prednisolone compared to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone in frontline treatment of patients with diff use large B-cell lymphoma: A randomised phase-III study from the Austrian Cancer Drug Therapy Working Group [Arbeitsgemeinschaft Medikamentöse Tumortherapie AGMT](NHL-14). Eur. J. Cancer. 2016;58:112−121. DOI: 10.1016/j.ejca.2016.02.004.Крикунова О.В., Васюк Ю.А., Висков Р.В. Крикунов П.В., Иванова С.В., Коник В.А. Cердечные тропонины в выявлении кардиотоксичности у пациентов, подвергающихся химиотерапии. Российский кардиоло- гический журнал. 2015;12(128):119–125. DOI: 10.15829/1560-4071-2015-12-119-125.Krikunova O.V. , Vasyuk Yu. A., Viskov R.V., Krikunov P.V., Ivanova S.V., Konik V.A.. Chemotherapy cardiotoxicity screening with cardiac troponins. Russian Journal of Cardiology. 2015;12(128):119–125. (In Russ.). DOI: 10.15829/1560-4071-2015-12-119-125.Minotti G., Menna P., Camilli M., Salvatorelli E., Reggiardo G. Predictors of early or delayed diastolic dysfunction after anthracycline-based or nonanthracycline chemotherapy: A pharmacological appraisal. J. Pharmacol. Exp. Ther. 2021;376(2):231−239. DOI: 10.1124/jpet.120.000323.Minotti G., Menna P., Camilli M., Salvatorelli E., Reggiardo G. Predictors of early or delayed diastolic dysfunction after anthracycline-based or nonanthracycline chemotherapy: A pharmacological appraisal. J. Pharmacol. Exp. Ther. 2021;376(2):231−239. DOI: 10.1124/jpet.120.000323.Авалян А.А., Кириллова М.Ю., Шитов В.Н., Ощепкова Е.В., Саидова М.А., Стенина М.Б. и др. Поиск ранних маркеров кардиотоксичности противоопухолевого лечения у больных раком молочной железы в зависимости от уровня артериального давления. Системные гипертензии. 2017;14(3):21−27. DOI: 10.26442/2075-082X_14.3.21-27.Avalyan A.A., Kirillova M.Yu., Shitov V.N., Oshhepkova E.V., Saidova M.A., Stenina M.B. et al. Markers of early cardiotoxicity in patients with breast cancer undergoing chemotherapy depending on blood pressure level. Systemic Hypertension. 2017;14(3):21−27. (In Russ.). DOI: 10.26442/2075-082X_14.3.21-27.Curigliano G., Lenihan D., Fradley M., Ganatra S., Barac A., Blaes A. et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. 2020;31(2):171−190. DOI: 10.1016/j.annonc.2019.10.023.Curigliano G., Lenihan D., Fradley M., Ganatra S., Barac A., Blaes A. et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. 2020;31(2):171−190. DOI: 10.1016/j.annonc.2019.10.023.Herrmann J., Lenihan D., Armenian S., Barac A., Blaes A., Cardinale D. et al. Defi ning cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. Eur. Heart J. 2022;43(4):280–299. DOI: 10.1093/eurheartj/ehab674.Herrmann J., Lenihan D., Armenian S., Barac A., Blaes A., Cardinale D. et al. Defi ning cardiovascular toxicities of cancer therapies: an International Cardio-Oncology Society (IC-OS) consensus statement. Eur. Heart J. 2022;43(4):280–299. DOI: 10.1093/eurheartj/ehab674.Чернов В.И., Кравчук Т.Л., Зельчан Р.В., Гольдберг В.Е. Радионуклидные методы исследования в оценке кардиотоксичности антрациклина. Кардиология. 2015;55(7):57−62.Chernov V.I., Kravchuk T.L., Zelchan R.V., Goldberg V.E. Radionuclide methods in the assessment of anthracycline-induced cardiotoxicity. Kardiologiia. 2015;7:57–62. (In Russ.).Carvalho F.S., Burgeiro A., Garcia R., Moreno A.J., Carvalho R.A., Oliveira P.J. Doxorubicin‐induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med. Res. Rev. 2014;34(1):106–135. DOI: 10.1002/med.21280.Carvalho F.S., Burgeiro A., Garcia R., Moreno A.J., Carvalho R.A., Oliveira P.J. Doxorubicin‐induced cardiotoxicity: from bioenergetic failure and cell death to cardiomyopathy. Med. Res. Rev. 2014;34(1):106–135. DOI: 10.1002/med.21280.Nitiss K.C., Nitiss J.L. Twisting and ironing: doxorubicin cardiotoxicity by mitochondrial DNA damage. Clin. Cancer Res. 2014;20(18):4737–4739. DOI: 10.1158/1078-0432.CCR-14-0821.Nitiss K.C., Nitiss J.L. Twisting and ironing: doxorubicin cardiotoxicity by mitochondrial DNA damage. Clin. Cancer Res. 2014;20(18):4737–4739. DOI: 10.1158/1078-0432.CCR-14-0821.Голубцов О.Ю., Тыренко В.В., Лютов В.В., Масляков В.В., Макиев Р.Г. Кардиоваскулярные осложнения противоопухолевой терапии. Современные проблемы науки и образования. 2017;2:126.Golubtsov O.Y., Tyrenko V.V., Lyutov V.V., Masljakov V.V., Makiev R.G. Cardiovascular complications of anticancer therapy. Modern Problems of Science and Education. 2017;2:126. (In Russ.).McGowan J.V., Chung R., Maulik A., Piotrowska I., Walker J.M., Yellon D.M. Anthracycline chemotherapy and cardiotoxicity. Cardiovasc. Drugs Ther. 2017;31(1):63−75. DOI: 10.1007/s10557-016-6711-0.McGowan J.V., Chung R., Maulik A., Piotrowska I., Walker J.M., Yellon D.M. Anthracycline chemotherapy and cardiotoxicity. Cardiovasc. Drugs Ther. 2017;31(1):63−75. DOI: 10.1007/s10557-016-6711-0.Krajinovic M., Elbared J., Drouin S., Bertout L., Rezgui A., Ansari M. et al. Polymorphisms of ABCC5 and NOS3 genes infl uence doxorubicin cardiotoxicity in survivors of childhood acute lymphoblastic leukemia. Pharmacogenomics J. 2016;16(6):530–535. DOI: 10.1038/tpj.2015.63.Krajinovic M., Elbared J., Drouin S., Bertout L., Rezgui A., Ansari M. et al. Polymorphisms of ABCC5 and NOS3 genes infl uence doxorubicin cardiotoxicity in survivors of childhood acute lymphoblastic leukemia. Pharmacogenomics J. 2016;16(6):530–535. DOI: 10.1038/tpj.2015.63.Hellmann F., Völler S., Krischke M., Jamieson D., André N., Bisogno G. et al. Polymorphisms aff ecting cardiac biomarker concentrations in children with cancer: an Analysis from the “European Paediatric Oncology Off -patents Medicines Consortium” (EPOC) Trial. Eur. J. Drug Metab. Pharmacokinet. 2020;45(3):413−422. DOI: 10.1007/s13318-019-00592-6.Hellmann F., Völler S., Krischke M., Jamieson D., André N., Bisogno G. et al. Polymorphisms aff ecting cardiac biomarker concentrations in children with cancer: an Analysis from the “European Paediatric Oncology Off -patents Medicines Consortium” (EPOC) Trial. Eur. J. Drug Metab. Pharmacokinet. 2020;45(3):413−422. DOI: 10.1007/s13318-019-00592-6.Pedersen M.H., Hood B.L., Ehmsen S., Beck H.C., Conrads T.P., Bak M. et al. CYPOR is a novel and independent prognostic biomarker of recurrence-free survival in triple-negative breast cancer patients. Int. J. Cancer. 2019;144(3):631−640. DOI: 10.1002/ijc.31798.Pedersen M.H., Hood B.L., Ehmsen S., Beck H.C., Conrads T.P., Bak M. et al. CYPOR is a novel and independent prognostic biomarker of recurrence-free survival in triple-negative breast cancer patients. Int. J. Cancer. 2019;144(3):631−640. DOI: 10.1002/ijc.31798.Lubieniecka J.M., Graham J., Heff ner D., Mottus R., Reid R., Hogge D. et al. A discovery study of daunorubicin induced cardiotoxicity in a sample of acute myeloid leukemia patients prioritizes P450 oxidoreductase polymorphisms as a potential risk factor. Front. Genet. 2013;4:231. DOI: 10.3389/fgene.2013.00231.Lubieniecka J.M., Graham J., Heff ner D., Mottus R., Reid R., Hogge D. et al. A discovery study of daunorubicin induced cardiotoxicity in a sample of acute myeloid leukemia patients prioritizes P450 oxidoreductase polymorphisms as a potential risk factor. Front. Genet. 2013;4:231. DOI: 10.3389/fgene.2013.00231.Visscher H., Ross C.J., Rassekh S.R., Sandor G.S., Caron H.N., van Dalen E.C. et al. Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline‐induced cardiotoxicity in children. Pediatr. Blood Cancer. 2013;60(8):1375–1381. DOI: 10.1002/pbc.24505.Visscher H., Ross C.J., Rassekh S.R., Sandor G.S., Caron H.N., van Dalen E.C. et al. Validation of variants in SLC28A3 and UGT1A6 as genetic markers predictive of anthracycline‐induced cardiotoxicity in children. Pediatr. Blood Cancer. 2013;60(8):1375–1381. DOI: 10.1002/pbc.24505.Semsei A.F., Erdelyi D.J., Ungvari I., Csagoly E., Hegyi M.Z., Kiszel P.S. et al. ABCC1 polymorphisms in anthracycline‐induced cardiotoxicity in childhood acute lymphoblastic leukaemia. Cell Biol. Int. 2012;36(1):79–86. DOI: 10.1042/CBI20110264.Semsei A.F., Erdelyi D.J., Ungvari I., Csagoly E., Hegyi M.Z., Kiszel P.S. et al. ABCC1 polymorphisms in anthracycline‐induced cardiotoxicity in childhood acute lymphoblastic leukaemia. Cell Biol. Int. 2012;36(1):79–86. DOI: 10.1042/CBI20110264.Reichwagen A., Ziepert M., Kreuz M., Gödtel-Armbrust U., Rixecker T., Poeschel V. et al. Association of NADPH oxidase polymorphisms with anthracycline-induced cardiotoxicity in the RICOVER-60 trial of patients with aggressive CD20(+) B-cell lymphoma. Pharmacogenomics. 2015;16(4):361−372. DOI: 10.2217/pgs.14.179.Reichwagen A., Ziepert M., Kreuz M., Gödtel-Armbrust U., Rixecker T., Poeschel V. et al. Association of NADPH oxidase polymorphisms with anthracycline-induced cardiotoxicity in the RICOVER-60 trial of patients with aggressive CD20(+) B-cell lymphoma. Pharmacogenomics. 2015;16(4):361−372. DOI: 10.2217/pgs.14.179.Aminkeng F., Ross C.D.J., Rassekh S.R., Hwang S., Rieder M.J., Bhavsar A.P. et al. Recommendations for genetic testing to reduce the incidence of anthracycline-induced cardiotoxicity. Br. J. Clin. Pharmacol. 2016;82(3):683–695. DOI: 10.1111/bcp.13008.Aminkeng F., Ross C.D.J., Rassekh S.R., Hwang S., Rieder M.J., Bhavsar A.P. et al. Recommendations for genetic testing to reduce the incidence of anthracycline-induced cardiotoxicity. Br. J. Clin. Pharmacol. 2016;82(3):683–695. DOI: 10.1111/bcp.13008.Zhang S., Liu X., Bawa-Khalfe T., Lu L.S., Lyu Y.L., Liu L.F. et al. Identifi cation of the molecular basis of doxorubicin-induced cardiotoxicity. Nat. Med. 2012;18(11):1639–1642. DOI: 10.1038/nm.2919.Zhang S., Liu X., Bawa-Khalfe T., Lu L.S., Lyu Y.L., Liu L.F. et al. Identifi cation of the molecular basis of doxorubicin-induced cardiotoxicity. Nat. Med. 2012;18(11):1639–1642. DOI: 10.1038/nm.2919.Vejpongsa P., Yeh E.T.H. Topoisomerase 2β: A promising molecular target for primary prevention of anthracycline-induced cardiotoxicity. Clin. Pharmacol. Ther. 2014;95(1):45–52. DOI: 10.1038/clpt.2013.201.Vejpongsa P., Yeh E.T.H. Topoisomerase 2β: A promising molecular target for primary prevention of anthracycline-induced cardiotoxicity. Clin. Pharmacol. Ther. 2014;95(1):45–52. DOI: 10.1038/clpt.2013.201.Lyu Y.L., Kerrigan J.E., Lin C.P., Azarova A.M., Tsai Y.C., Ban Y. et al. Topoisomerase IIbeta mediated DNA double-strand breaks: Implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res. 2007;67(18):8839–8846. DOI: 10.1158/0008-5472.CAN-07-1649.Lyu Y.L., Kerrigan J.E., Lin C.P., Azarova A.M., Tsai Y.C., Ban Y. et al. Topoisomerase IIbeta mediated DNA double-strand breaks: Implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res. 2007;67(18):8839–8846. DOI: 10.1158/0008-5472.CAN-07-1649.Chung R., Maulik A., Hamarneh A., Hochhauser D., Hausenloy D.J., Walker J.M. et al. Effect of remote ischaemic conditioning in oncology patients undergoing chemotherapy: Rationale and design of the ERIC-ONC study-a single-center, blinded, Randomized Controlled Trial. Clin. Cardiol. 2016;39(2):72–82. DOI: 10.1002/clc.22507.Chung R., Maulik A., Hamarneh A., Hochhauser D., Hausenloy D.J., Walker J.M. et al. Eff ect of remote ischaemic conditioning in oncology patients undergoing chemotherapy: Rationale and design of the ERIC-ONC study-a single-center, blinded, Randomized Controlled Trial. Clin. Cardiol. 2016;39(2):72–82. DOI: 10.1002/clc.22507.Henninger C., Fritz G. Statins in anthracycline-induced cardiotoxicity: Rac and Rho, and the heartbreakers. Cell Death Dis. 2017;8(1):e2564. DOI: 10.1038/cddis.2016.418.Henninger C., Fritz G. Statins in anthracycline-induced cardiotoxicity: Rac and Rho, and the heartbreakers. Cell Death Dis. 2017;8(1):e2564. DOI: 10.1038/cddis.2016.418.Aminkeng F., Bhavsar A.P., Visscher H., Rassekh S.R., Li Y., Lee J.W. et al. A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat. Genet. 2015;47(9):1079−1084. DOI: 10.1038/ng.3374.Aminkeng F., Bhavsar A.P., Visscher H., Rassekh S.R., Li Y., Lee J.W. et al. A coding variant in RARG confers susceptibility to anthracycline-induced cardiotoxicity in childhood cancer. Nat. Genet. 2015;47(9):1079−1084. DOI: 10.1038/ng.3374.Lips J., Kaina B. DNA double-strand breaks trigger apoptosis in p53-deficient fibroblasts. Carcinogenesis. 2001;22(4):579–585. DOI: 10.1093/carcin/22.4.579.Lips J., Kaina B. DNA double-strand breaks trigger apoptosis in p53-defi cient fi broblasts. Carcinogenesis. 2001;22(4):579–585. DOI: 10.1093/carcin/22.4.579.Cunha-Oliveira T., Ferreira L.L., Coelho A.R., Deus C.M., Oliveira P.J. Doxorubicin triggers bioenergetic failure and p53 activation in mouse stem cell-derived cardiomyocytes. Toxicol. Appl. Pharmacol. 2018;348:1−13. DOI: 10.1016/j.taap.2018.04.009.Cunha-Oliveira T., Ferreira L.L., Coelho A.R., Deus C.M., Oliveira P.J. Doxorubicin triggers bioenergetic failure and p53 activation in mouse stem cell-derived cardiomyocytes. Toxicol. Appl. Pharmacol. 2018;348:1−13. DOI: 10.1016/j.taap.2018.04.009.Непомнящих Л.М. Регенераторно-пластическая недостаточность сердца: молекулярно-биологические механизмы и морфологические основы. Архив патологии. 2007;69(3):3–12.Nepomnyashchikh L.M. Regenerative and plastic heart failure: molecular biological mechanisms and morphological bases. Archives of Pathology. 2007;69(3):3–12. (In Russ.).Шилов С.Н., Тепляков А.Т., Попова А.А., Березикова Е.Н., Неупокоева Н.М., Гракова Е.В. и др. Прогностическое значение полиморфизма гена белка р53 в оценке риска развития антрациклин-индуцированной кардиотоксичности. Кардиология. 2019;59(7S):15–22. DOI: 10.18087/cardio.2571.Shilov S.N., Teplyakov A.T., Popova A.A., Berezikova E.N., Neupokoeva N.M., Grakova E.V. et al. Prognostic role of p53 gene polymorphism in risk assessment of anthracycline-induced cardiotoxicity. Kardiologiia. 2019;59(7S):15–22. (In Russ.). DOI: 10.18087/cardio.2571.Khiati S., Dalla Rosa I., Sourbier C., Ma X., Rao V.A., Neckers L.M. et al. Mitochondrial topoisomerase I (top1mt) is a novel limiting factor of doxorubicin cardiotoxicity. Clin. Cancer Res. 2014;20:4873–4881. DOI: 10.1158/1078-0432.CCR-13-3373.Khiati S., Dalla Rosa I., Sourbier C., Ma X., Rao V.A., Neckers L.M. et al. Mitochondrial topoisomerase I (top1mt) is a novel limiting factor of doxorubicin cardiotoxicity. Clin. Cancer Res. 2014;20:4873–4881. doi: 10.1158/1078-0432.CCR-13-3373.Васюк Ю.А., Школьник Е.Л., Несветов В.В., Школьник Л.Д., Варлан Г.В., Пильщиков А.В. Антрациклиновая кардиотоксичность: перспективы использования ивабрадина. Кардиосоматика. 2012;(3):65−69.Vasyuk Yu.A., Shkolnik E.L., Nesvetov V.V., Shkolnik L.D., Varlan G.V., Pilshhikov A.V. Anthracycline cardiotoxicity: Prospects for using ivabradine. Cardiosomatics. 2012;(3):65−69. (In Russ.).Delemasure S., Vergely C., Zeller M., Cottin Y., Rochette L. Preventing the cardiotoxic effects of anthracyclines: From basic concepts to clinical data. Ann. Cardiol. Angeiol. (Paris). 2006;55(2):104–112. (In French.). DOI: 10.1016/j.ancard.2006.02.005.Delemasure S., Vergely C., Zeller M., Cottin Y., Rochette L. Preventing the cardiotoxic eff ects of anthracyclines: From basic concepts to clinical data. Ann. Cardiol. Angeiol. (Paris). 2006;55(2):104–112. (In French.). DOI: 10.1016/j.ancard.2006.02.005.Pecoraro M., Rodríguez-Sinovas A., Marzocco S., Ciccarelli M., Iaccarino G., Pinto A. et al. Cardiotoxic effects of short-term doxorubicin administration: Involvement of connexin 43 in calcium impairment. Int. J. Mol. Sci. 2017;18(10):2121 DOI: 10.3390/ijms18102121.Pecoraro M., Rodríguez-Sinovas A., Marzocco S., Ciccarelli M., Iaccarino G., Pinto A. et al. Cardiotoxic eff ects of short-term doxorubicin administration: Involvement of connexin 43 in calcium impairment. Int. J. Mol. Sci. 2017;18(10):2121 DOI: 10.3390/ijms18102121.Hochster H.S. Clinical pharmacology of dexrazoxane. Semin. Oncol. 1998;25(4–10):37–42.Hochster H.S. Clinical pharmacology of dexrazoxane. Semin. Oncol. 1998;25(4–10):37–42.De Angelis A., Urbanek K., Cappetta D., Piegari E., Ciuffreda L.P., Rivellino A. et al. Doxorubicin cardiotoxicity and target cells: a broader perspective. Cardio-Oncology. 2016;2:2. DOI: 10.1186/s40959-016-0012-4.De Angelis A., Urbanek K., Cappetta D., Piegari E., Ciuff reda L.P., Rivellino A. et al. Doxorubicin cardiotoxicity and target cells: a broader perspective. Cardio-Oncology. 2016;2:2. DOI: 10.1186/s40959-016-0012-4.Kotamraju S., Chitambar C.R., Kalivendi S.V. Transferrin receptordependent iron uptake is responsible for doxorubicin-mediated apoptosis in endothelial cells: Role of oxidant-induced iron signaling in apoptosis. J. Biol. Chem. 2002;277(19):17179–17187. DOI: 10.1074/jbc.M111604200.Kotamraju S., Chitambar C.R., Kalivendi S.V. Transferrin receptordependent iron uptake is responsible for doxorubicin-mediated apoptosis in endothelial cells: Role of oxidant-induced iron signaling in apoptosis. J. Biol. Chem. 2002;277(19):17179–17187. DOI: 10.1074/jbc.M111604200.Ichikawa Y., Ghanefar M., Bayeva M., Wu R., Khechaduri A., Naga Prasad S.V. et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J. Clin. Invest. 2014;124(2):617–630. DOI: 10.1172/JCI72931.Ichikawa Y., Ghanefar M., Bayeva M., Wu R., Khechaduri A., Naga Prasad S.V. et al. Cardiotoxicity of doxorubicin is mediated through mitochondrial iron accumulation. J. Clin. Invest. 2014;124(2):617–630. DOI: 10.1172/JCI72931.Myers C.E., McGuire W.P., Liss R.H., Ifrim I., Grotzinger K., Young R.C. Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science. 1977;197(4299):165–167. DOI: 10.1126/science.877547.Myers C.E., McGuire W.P., Liss R.H., Ifrim I., Grotzinger K., Young R.C. Adriamycin: the role of lipid peroxidation in cardiac toxicity and tumor response. Science. 1977;197(4299):165–167. DOI: 10.1126/science.877547.Чернов В.И., Кравчук Т.Л., Зельчан Р.В., Подоплекин Д.М., Гольдберг В.Е. Возможности медикаментозной профилактики антрациклин-индуцированной кардиотоксичности. Сибирский онкологический журнал. 2015;1(1):19−25.Chernov V.I., Kravchuk T.L., Zelchan R.V., Podoplekin D.M., Gol’dberg V.E. Possibility of drug prevention anthracycline-induced cardiotoxicity. Siberian Journal of Oncology. 2015;1(1):19−25. (In Russ.).Hu K.Y., Yang Y., He L.H., Wang D.W., Jia Z.R., Li S.R. et al. Prevention against and treatment of doxorubicininduced acute cardiotoxicity by dexrazoxane and schisandrin B. Yao Xue Xue Bao. 2014;49(7):1007–1012. (In Chin.).Hu K.Y., Yang Y., He L.H., Wang D.W., Jia Z.R., Li S.R. et al. Prevention against and treatment of doxorubicininduced acute cardiotoxicity by dexrazoxane and schisandrin B. Yao Xue Xue Bao. 2014;49(7):1007–1012. (In Chin.).Sawyer D., Lenihan D. Managing heart failure in cancer patients. In: Mann D., Felker G. Heart Failure: A companion to braunwald’s heart disease; 3d ed. Philadelphia, Elsevier; 2016:689–696.Sawyer D., Lenihan D. Managing heart failure in cancer patients. In: Mann D., Felker G. Heart Failure: A companion to braunwald’s heart disease; 3d ed. Philadelphia, Elsevier; 2016:689–696.Barry E., Alvarez J.A., Scully R.E., Miller T.L., Lipshultz S.E. Anthracycline induced cardiotoxicity: course, pathophysiology, prevention, and management. Expert Opin. Pharmacother. 2007;8(8):1039–1058. DOI: 10.1517/14656566.8.8.1039.Barry E., Alvarez J.A., Scully R.E., Miller T.L., Lipshultz S.E. Anthracycline induced cardiotoxicity: course, pathophysiology, prevention, and management. Expert Opin. Pharmacother. 2007;8(8):1039–1058. DOI: 10.1517/14656566.8.8.1039.Cui L., Guo J., Zhang Q., Yin J., Li J., Zhou W. et al. Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicin-induced mitochondrial dysfunction and toxicity. Toxicol. Lett. 2017;275:28−38. DOI: 10.1016/j.toxlet.2017.04.018.Cui L., Guo J., Zhang Q., Yin J., Li J., Zhou W. et al. Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicin-induced mitochondrial dysfunction and toxicity. Toxicol. Lett. 2017;275:28−38. DOI: 10.1016/j.toxlet.2017.04.018.Gao J., Xiong Y., Ho Y.S., Liu X., Chua C.C., Xu X. et al. Glutathione peroxidase 1-deficient mice are more susceptible to doxorubicin-induced cardiotoxicity. Biochim. Biophys. Acta. 2008;1783(10):2020−2029. DOI: 10.1016/j.bbamcr.2008.05.027.Gao J., Xiong Y., Ho Y.S., Liu X., Chua C.C., Xu X. et al. Glutathione peroxidase 1-deficient mice are more susceptible to doxorubicin-induced cardiotoxicity. Biochim. Biophys. Acta. 2008;1783(10):2020−2029. DOI: 10.1016/j.bbamcr.2008.05.027.Rajic V., Aplenc R., Debeljak M., Prestor V.V., Karas-Kuzelicki N., Mlinaric-Rascan I. et al. Influence of the polymorphism in candidate genes on late cardiac damage in patients treated due to acute leukemia in childhood. Leuk. Lymphoma. 2009;50(10):1693–1698. DOI: 10.1080/10428190903177212.Rajic V., Aplenc R., Debeljak M., Prestor V.V., Karas-Kuzelicki N., Mlinaric-Rascan I. et al. Influence of the polymorphism in candidate genes on late cardiac damage in patients treated due to acute leukemia in childhood. Leuk. Lymphoma. 2009;50(10):1693–1698. DOI: 10.1080/10428190903177212.Hussain Shaik A., Rasool S.N., Abdul Kareem M., Krushna G.S., Akhtar P.M., Devi K.L. Maslinic acid protects against isoproterenol-induced cardiotoxicity in albino Wistar rats. J. Med. Food. 2012;15(8):741−746. DOI: 10.1089/jmf.2012.2191.Hussain Shaik A., Rasool S.N., Abdul Kareem M., Krushna G.S., Akhtar P.M., Devi K.L. Maslinic acid protects against isoproterenol- induced cardiotoxicity in albino Wistar rats. J. Med. Food. 2012;15(8):741−746. DOI: 10.1089/jmf.2012.2191.Torres V.M., Simic V.D. Doxorubicin-induced oxidative injury of cardiomyocytes – Do we have right strategies for prevention? In book: Cardiotoxicity of oncologic treatments. 2012. DOI: 10.5772/34692.Torres V.M., Simic V.D. Doxorubicin-induced oxidative injury of cardiomyocytes – Do we have right strategies for prevention? In book: Cardiotoxicity of oncologic treatments. 2012. DOI: 10.5772/34692.Abbas M., Kushwaha V.S., Srivastava K., Raza S.T., Banerjee M. Impact of GSTM1, GSTT1 and GSTP1 genes polymorphisms on clinical toxicities and response to concomitant chemoradiotherapy in cervical cancer. Br. J. Biomed. Sci. 2018;75(4):169−174. DOI: 10.1080/09674845.2018.1482734.Abbas M., Kushwaha V.S., Srivastava K., Raza S.T., Banerjee M. Impact of GSTM1, GSTT1 and GSTP1 genes polymorphisms on clinical toxicities and response to concomitant chemoradiotherapy in cervical cancer. Br. J. Biomed. Sci. 2018;75(4):169−174. DOI: 10.1080/09674845.2018.1482734.Bearzi C., Rota M., Hosoda T., Tillmanns J., Nascimbene A., De Angelis A. et al. Human cardiac stem cells. PNAS. 2007;104(35):14068–14073. DOI: 10.1073/pnas.0706760104.Bearzi C., Rota M., Hosoda T., Tillmanns J., Nascimbene A., De Angelis A. et al. Human cardiac stem cells. PNAS. 2007;104(35):14068–14073. DOI: 10.1073/pnas.0706760104.Smith R.R., Barile L., Cho H.C., Leppo M.K., Hare J.M., Messina E. et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation. 2007;115(7):896–908 DOI: 10.1161/CIRCULATIONAHA.106.655209.Smith R.R., Barile L., Cho H.C., Leppo M.K., Hare J.M., Messina E. et al. Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation. 2007;115(7):896–908 DOI: 10.1161/CIRCULATIONAHA.106.655209.Burridge P.W., Li Y.F., Matsa E., Wu H., Ong S.G., Sharma A. et al. Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat. Med. 2016;22(5):547–556. DOI: 10.1038/nm.4087.Burridge P.W., Li Y.F., Matsa E., Wu H., Ong S.G., Sharma A. et al. Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity. Nat. Med. 2016;22(5):547–556. DOI: 10.1038/nm.4087.Piegari E., Russo R., Cappetta D., Esposito G., Urbanek K., Dell’Aversana C. et al. MicroRNA-34a regulates doxorubicin-induced cardiotoxicity in rat. Oncotarget. 2016;7(38):62312−62326. DOI: 10.18632/oncotarget.11468.Piegari E., Russo R., Cappetta D., Esposito G., Urbanek K., Dell’Aversana C. et al. MicroRNA-34a regulates doxorubicin-induced cardiotoxicity in rat. Oncotarget. 2016;7(38):62312−62326. DOI: 10.18632/oncotarget.11468.

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