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Arrhythmogenic effects of doxorubicin

https://doi.org/10.17802/2306-1278-2020-9-3-69-80

Abstract

The article discusses the adverse arrhythmogenic effects of an antitumor drug – doxorubicin.

Doxorubicin has a significant effect on the action potentials and ion currents of cardiomyocytes, the dynamics of intracellular calcium concentration.

Oncological diseases are the leading causes of death and disability of the population, causing extremely high socio-economic damage. Among the many currently available drugs for the treatment of cancer, an important place is taken by the anthracycline antibiotic – doxorubicin. However, adverse concomitant effects on several organs and systems of the human body, in particular on the cardiovascular system, do not allow the full use of the high potential of doxorubicin`s antitumor effectiveness. Cardiotoxicity of doxorubicin is manifested in the form of electrocardiographic abnormalities and arrhythmias, degenerative cardiomyopathy and chronic heart failure. The authors consider the following arrhythmogenic effects of doxorubicin: the mechanisms of influence of doxorubicin on electrocardiographic parameters, the action potential of cardiomyocytes, cardiac ion currents and the dynamics of intracellular calcium concentration. The study and assessment of specific pathophysiological mechanisms of arrhythmogenic effects of doxorubicin is necessary for the development and justified use of cardioprotective measures.

About the Authors

A. M. Chaulin
Samara Regional Clinical Cardiology Dispensary; Samara State Medical University
Russian Federation

MD, assistant at the Histology and Embryology Department, 43, Aerodromnaya St., Samara, 443070;

pathologist at the Clinical and Diagnostic Laboratory, 89, Chapayevskaya St., Samara, 443099



D. V. Duplyakov
Samara Regional Clinical Cardiology Dispensary; Samara State Medical University
Russian Federation

PhD, Deputy Director for Medical Services, 43, Aerodromnaya St., Samara, 443070;

Professor at the Department of Cardiology and Cardiovascular Surgery, 89, Chapayevskaya St., Samara, 443099



References

1. Ferlay J., Soerjomataram I., Dikshit R., Eser S., Mathers C., Rebelo M., et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer. 2015; 136 (5): E359-386. doi: 10.1002/ijc.29210.

2. Tacar O., Sriamornsak P., Dass C.R. Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. The Journal Pharmacy and Pharmacology. 2013; 65 (2): 157-70. doi: 10.1111/j.2042-7158.2012.01567.x.

3. Simunek T., Sterba M., Popelova O., Adamcova M., Hrdina R., Gersl V. Anthracycline-induced cardiotoxicity: overview of studies examining the roles of oxidative stress and free cellular iron. Pharmacological Reports. 2009; 61 (1): 154- 71. doi: 10.1016/s1734-1140(09)70018-0.

4. Kim S.Y., Kim S.J., Kim B.J., Rah S.Y., Chung S.M., Im M.J., Kim U.H. Doxorubicin-induced reactive oxygen species generation and intracellular Ca2+ increase are reciprocally modulated in rat cardiomyocytes. Experimental & Molecular Medicine. 2006; 38 (5): 535-545. doi: 10.1038/emm.2006.63.

5. Seliverstova D.V., Evsina O.V. Cardiotoxicity of chemotherapy. Russian Heart Journal. 2016; 15 (1): 50-57. doi: 10.18087/rhj.2016.1.2115 (in Russian)

6. Chaulin A.M., Karslyan L.S., Grigoriyeva E.V., Nurbaltaeva D.A., Duplyakov D.V. Clinical and Diagnostic Value of Cardiac Markers in Human Biological Fluids. Kardiologiia. 2019;59(11):66– 75. doi:10.18087/cardio.2019.11.n414 (in Russian)

7. Jones M., O'Gorman P., Kelly C., Mahon N., Fitzgibbon M.C. High-sensitive cardiac troponin-I facilitates timely detection of subclinical anthracycline-mediated cardiac injury. Annals of Clinical Biochemistry. 2017; 54 (1): 149-157. doi: 10.1177/0004563216650464.

8. Chaulin A.M., Duplyakov D.V. Increased cardiac troponins, not associated with acute coronary syndrome. Part 1. Kardiologiya: novosti, mneniya, obuchenie [Cardiology: News, Opinions, Training]. 2019; 7 (2): 13–23. doi: 10.24411/2309-1908-2019-12002. (in Russian)

9. Chaulin A.M., Duplyakov D.V. Increased cardiac troponins, not associated with acute coronary syndrome. Part 2. Kardiologiya: novosti, mneniya, obuchenie [Cardiology: News, Opinions, Training]. 2019; 7 (2): 24–35. doi: 10.24411/2309-1908-2019-12003. (in Russian)

10. Chaulin A.M., Karslyan L.S., Grigorieva E.V., Nurbaltaeva D.A., Duplyakov D.V. Metabolism of cardiac troponins (literature review). Complex Issues of Cardiovascular Diseases. 2019; 8 (4): 103-115. doi: 10.17802/2306-1278-2019-8-4-103-115 (in Russian)

11. Armstrong G.T., Liu Q., Yasui Y., Neglia J.P., Leisenring W., Robison L.L., Mertens A.C. Late mortality among 5-year survivors of childhood cancer: a summary from the Childhood Cancer Survivor Study. Journal of Clinical Oncology. 2009; 27 (14): 2328-2338. doi:10.1200/jco.2008.21.1425.

12. Swain S.M., Whaley F.S., Ewer M.S. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003; 97 (11): 2869-2879. doi: 10.1002/cncr.11407.

13. Volkova M., Russell R.3rd. Anthracycline cardiotoxicity: prevalence, pathogenesis and treatment. Current Cardiology Reviews. 2011; 7 (4): 214-220. doi: 10.2174/157340311799960645.

14. 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. Medical Research Reviews. 2014; 34 (1): 106- 35. doi: 10.1002/med.21280.

15. Yin J., Guo J., Zhang Q., Cui L., Zhang L., Zhang T., et al. Doxorubicin-induced mitophagy and mitochondrial damage is associated with dysregulation of the PINK1/parkin pathway. Toxicol In Vitro. 2018; 51: 1-10. doi: 10.1016/j.tiv.2018.05.001.

16. Renu K., V. G. A., P. B. T.P., Arunachalam S. Molecular mechanism of doxorubicin-induced cardiomyopathy - An update. European Journal of Pharmacology. 2018; 818: 241- 253. doi: 10.1016/j.ejphar.2017.10.043.

17. Wagner S., Rokita A.G., Anderson M.E., Maier L.S. Redox regulation of sodium and calcium handling. Antioxidants & Redox Signaling. 2013; 18 (9): 1063-1077. doi: 10.1089/ars.2012.4818.

18. Larsen R.L., Jakacki R.I., Vetter V.L., Meadows A.T., Silber J.H., Barber G. Electrocardiographic changes and arrhythmias after cancer therapy in children and young adults. The American Journal of Cardiology. 1992; 70 (1): 73-77. doi: 10.1016/0002-9149(92)91393-i.

19. Kilickap S., Barista I., Akgul E., Aytemir K., Aksoy S., Tekuzman G. Early and late arrhythmogenic effects of doxorubicin. Southern Medical Journal. 2007; 100 (3): 262- 265. doi: 10.1097/01.smj.0000257382.89910.fe

20. Kilickap S., Akgul E., Aksoy S., Aytemir K., Barista I. Doxorubicin-induced second degree and complete atrioventricular block. Europace. 2005; 7 (3): 227-230. doi: 10.1016/j.eupc.2004.12.012

21. Rudzinski T., Ciesielczyk M., Religa W., Bednarkiewicz Z., Krzeminska-Pakula M. Doxorubicin-induced ventricular arrhythmia treated by implantation of an automatic cardioverter-defibrillator. Europace. 2007; 9 (5): 278-280. doi: 10.1093/europace/eum033

22. Markman T.M., Ruble K., Loeb D., Chen A., Zhang Y., Beasley G.S., et al. Electrophysiological effects of anthracyclines in adult survivors of pediatric malignancy. Pediatric Blood & Cancer. 2017; 64 (11). doi: 10.1002/pbc.26556

23. Amin A.S., Tan H.L., Wilde A.A. Cardiac ion channels in health and disease. Heart Rhythm. 2010; 7 (1): 117-126. doi: 10.1016/j.hrthm.2009.08.005

24. Antzelevitch C., Burashnikov A. Overview of Basic Mechanisms of Cardiac Arrhythmia. Cardiac Electrophysiology Clinics. 2011; 3 (1): 23-45. doi: 10.1016/j.ccep.2010.10.012

25. Killeen M.J., Sabir I.N., Grace A.A., Huang C.L. Dispersions of repolarization and ventricular arrhythmogenesis: lessons from animal models. Progress in Biophysics and Molecular Biology. 2008; 98 (2-3): 219-229. doi: 10.1016/j.pbiomolbio.2008.10.008.

26. Amioka M., Sairaku A., Ochi T., Okada T., Asaoku H., Kyo T., Kihara Y. Prognostic Significance of New-Onset Atrial Fibrillation in Patients With Non-Hodgkin's Lymphoma Treated With Anthracyclines. The American Journal of Cardiology. 2016; 118 (9): 1386-1389. doi: 10.1016/j.amjcard.2016.07.049

27. Purohit A., Rokita A.G., Guan X., Chen B., Koval O.M., Voigt N.. et al. Oxidized Ca(2+)/calmodulin-dependent protein kinase II triggers atrial fibrillation. Circulation. 2013; 128 (16): 1748-1757. doi:10.1161/circulationaha.113.003313.

28. Nousiainen T., Vanninen E., Rantala A., Jantunen E., Hartikainen J. QT dispersion and late potentials during doxorubicin therapy for non-Hodgkin's lymphoma. Journal of Internal Medicine. 1999; 245 (4): 359-364. doi: 10.1046/j.1365-2796.1999.00480.x.

29. Horacek J.M., Jakl M., Horackova J., Pudil R., Jebavy L., Maly J. Assessment of anthracycline-induced cardiotoxicity with electrocardiography. Experimental Oncology. 2009; 31 (2): 115-117. doi: https://www.ncbi.nlm.nih.gov/pubmed/19550402

30. Veronese P., Hachul D.T., Scanavacca M.I., Hajjar L.A., Wu T.C., Sacilotto L., et al. Effects of anthracycline, cyclophosphamide and taxane chemotherapy on QTc measurements in patients with breast cancer. PLoS One. 2018; 13 (5): e0196763. doi: 10.1371/journal.pone.0196763

31. Sarubbi B., Orditura M., Ducceschi V., De Vita F., Santangelo L., Ciaramella F., et al. Ventricular repolarization time indexes following anthracycline treatment. Heart and Vessels. 1997; 12 (6): 262-266. doi: 10.1007/bf02766801

32. Jensen R.A., Acton E.M., Peters J.H. Doxorubicin cardiotoxicity in the rat: comparison of electrocardiogram, transmembrane potential, and structural effects. Journal of Cardiovascular Pharmacology. 1984; 6 (1): 186-200. doi: https://www.ncbi.nlm.nih.gov/pubmed/6199603

33. Milberg P., Fleischer D., Stypmann J., Osada N., Monnig G., Engelen M.A., et al. Reduced repolarization reserve due to anthracycline therapy facilitates torsade de pointes induced by IKr blockers. Basic Research in Cardiology. 2007; 102 (1): 42- 51. doi: 10.1007/s00395-006-0609-0

34. Ducroq J., Moha ou Maati H., Guilbot S., Dilly S., Laemmel E., Pons-Himbert C., et al. Dexrazoxane protects the heart from acute doxorubicin-induced QT prolongation: a key role for I(Ks). British Journal of Pharmacology. 2010; 159 (1): 93-101. doi: 10.1111/j.1476-5381.2009.00371.x

35. Kharin S., Krandycheva V., Tsvetkova A., Strelkova M., Shmakov D. Remodeling of ventricular repolarization in a chronic doxorubicin cardiotoxicity rat model. Fundamental & Clinical Pharmacology. 2013; 27 (4): 364-372. doi: 10.1111/j.1472-8206.2012.01037.x

36. Agen C., Bernardini N., Danesi R., Della Torre P., Costa M., Del Tacca M. Reducing doxorubicin cardiotoxicity in the rat using deferred treatment with ADR-529. Cancer Chemotherapy and Pharmacology. 1992; 30 (2): 95-99. doi: 10.1007/bf00686399

37. He L., Xiao J., Fu H., Du G., Xiao X., Zhang C., et al. Effect of oxidative stress on ventricular arrhythmia in rabbits with adriamycin-induced cardiomyopathy. Journal of Huazhong University of Science and Technology. Medical Sciences. 2012; 32 (3): 334-339. doi: 10.1007/s11596-012-0058-y

38. Pye M.P., Cobbe S.M. Arrhythmogenesis in experimental models of heart failure: the role of increased load. Cardiovascular Research. 1996; 32 (2): 248-257. doi: 10.1016/0008-6363(96)00080-6

39. Pecoraro M., Rodríguez-Sinovas A., Marzocco S., Ciccarelli M., Iaccarino G., Pinto A., Popolo A. Cardiotoxic Effects of Short-Term Doxorubicin Administration: Involvement of Connexin 43 in Calcium Impairment. International Journal of Molecular Sciences. 2017; 18 (10). pii: E2121. doi: 10.3390/ij

40. Poelzing S., Rosenbaum D.S. Altered connexin43 expression produces arrhythmia substrate in heart failure. American Journal of Physiology. Heart and Circulatory Physiology. 2004; 287 (4): H1762-1770. doi: 10.1152/ajpheart.00346.2004

41. Xin Y., Zhang S., Gu L., Liu S., Gao H., You Z., et al. Electrocardiographic and biochemical evidence for the cardioprotective effect of antioxidants in acute doxorubicininduced cardiotoxicity in the beagle dogs. Biological & Pharmaceutical Bulletin. 2011; 34 (10): 1523-1526. doi: 10.1248/bpb.34.1523

42. Wu Y., Anderson M.E. CaMKII in sinoatrial node physiology and dysfunction. Frontiers in Pharmacology. 2014; 5: 48. doi: 10.3389/fphar.2014.00048

43. Sag C.M., Kohler A.C., Anderson M.E., Backs J., Maier L.S. CaMKII-dependent SR Ca leak contributes to doxorubicininduced impaired Ca handling in isolated cardiac myocytes. Journal of Molecular and Cellular Cardiology. 2011; 51 (5): 749-759. doi: 10.1016/j.yjmcc.2011.07.016

44. Tscheschner H., Meinhardt E., Schlegel P., Jungmann A., Lehmann L.H., Muller O.J., et al. CaMKII activation participates in doxorubicin cardiotoxicity and is attenuated by moderate GRP78 overexpression. PLoS One. 2019; 14 (4): e0215992. doi: 10.1371/journal.pone.0215992.

45. Xie L.H., Chen F., Karagueuzian H.S., Weiss J.N. Oxidative-stress-induced afterdepolarizations and calmodulin kinase II signaling. Circulation Research. 2009; 104 (1): 79-86. doi: 10.1161/CIRCRESAHA.108.183475

46. Venditti P., Balestrieri M., De Leo T., Di Meo S. Free radical involvement in doxorubicin-induced electrophysiological alterations in rat papillary muscle fibres. Cardiovasc Res. 1998; 38 (3): 695-702. doi: 10.1016/s0008-6363(98)00034-0

47. Lazarus M.L., Rossner K.L., Anderson K.M. Adriamycin-induced alterations of the action potential in rat papillary muscle. Cardiovascular Research. 1980; 14 (8): 446- 450. doi: 10.1093/cvr/14.8.446

48. Wang Y.X., Korth M. Effects of doxorubicin on excitation-contraction coupling in guinea pig ventricular myocardium. Circulation Research. 1995; 76 (4): 645-653. doi: 10.1161/01.res.76.4.645

49. Shenasa H., Calderone A., Vermeulen M., Paradis P., Stephens H., Cardinal R., et al. Chronic doxorubicin induced cardiomyopathy in rabbits: mechanical, intracellular action potential, and beta adrenergic characteristics of the failing myocardium. Cardiovascular Research. 1990; 24 (7): 591-604. doi: 10.1093/cvr/24.7.591

50. Binah O., Cohen I.S., Rosen M.R. The effects of adriamycin on normal and ouabain-toxic canine Purkinje and ventricular muscle fibers. Circulation Research. 1983; 53 (5): 655-662. doi: 10.1161/01.res.53.5.655

51. Earm Y.E., Ho W.K., So I. Effects of adriamycin on ionic currents in single cardiac myocytes of the rabbit. Journal of Molecular and Cellular Cardiology. 1994; 26 (2): 163-172. doi: 10.1006/jmcc.1994.1019

52. Boucek R.J. Jr., Olson R.D., Brenner D.E., Ogunbunmi E.M., Inui M., Fleischer S. The major metabolite of doxorubicin is a potent inhibitor of membrane-associated ion pumps. A correlative study of cardiac muscle with isolated membrane fractions. The Journal of Biological Chemistry. 1987; 262 (33): 15851-15856. doi: https://www.ncbi.nlm.nih.gov/pubmed/2890636

53. Keung E.C., Toll L., Ellis M., Jensen R.A. L-type cardiac calcium channels in doxorubicin cardiomyopathy in rats morphological, biochemical, and functional correlations. The Journal of Clinical Investigation. 1991; 87 (6): 2108-2113. doi: 10.1172/JCI115241

54. Liang H., Li X., Li S., Zheng M.Q., Rozanski G.J. Oxidoreductase regulation of Kv currents in rat ventricle. Journal of Molecular and Cellular Cardiology. 2008; 44 (6): 1062-1071. doi: 10.1016/j.yjmcc.2008.03.011.

55. Hanna A.D., Lam A., Tham S., Dulhunty A.F., Beard N.A. Adverse effects of doxorubicin and its metabolic product on cardiac RyR2 and SERCA2A. Molecular Pharmacology. 2014; 86 (4): 438-449. doi: 10.1124/mol.114.093849

56. Dolphin A.C. Voltage-gated calcium channels and their auxiliary subunits: physiology and pathophysiology and pharmacology. The Journal of Physiology. 2016; 594 (19): 5369-5390. doi:10.1113/jp272262

57. Song Y., Shryock J.C., Wagner S., Maier L.S., Belardinelli L. Blocking late sodium current reduces hydrogen peroxideinduced arrhythmogenic activity and contractile dysfunction. The Journal of Pharmacology and Experimental Therapeutics. 2006; 318 (1): 214-222. doi: 10.1124/jpet.106.101832

58. Wagner S., Ruff H.M., Weber S.L., Bellmann S., Sowa T., Schulte T., et al. Reactive oxygen species-activated Ca/ calmodulin kinase IIδ is required for late I(Na) augmentation leading to cellular Na and Ca overload. Circulation Research. 2011; 108 (5): 555-65. doi: 10.1161/CIRCRESAHA.110.221911

59. Bers D.M. Cardiac excitation-contraction coupling. Nature. 2002; 415 (6868): 198-205. doi: 10.1038/415198a

60. Llach A., Mazevet M., Mateo P., Villejouvert O., Ridoux A., Rucker-Martin C., et al. Progression of excitationcontraction coupling defects in doxorubicin cardiotoxicity. Journal of Molecular and Cellular Cardiology. 2019; 126: 129- 39. doi:10.1016/j.yjmcc.2018.11.019.

61. Olson R.D., Gambliel H.A., Vestal R.E., Shadle S.E., Charlier H.A. Jr., Cusack B.J. Doxorubicin cardiac dysfunction: effects on calcium regulatory proteins, sarcoplasmic reticulum, and triiodothyronine. Cardiovasc Toxicol. 2005; 5 (3): 269-83. doi: 10.1385/ct:5:3:269

62. Wagner S., Maier L.S., Bers D.M. Role of sodium and calcium dysregulation in tachyarrhythmias in sudden cardiac death. Circulation Research. 2015; 116 (12): 1956-1970. doi:10.1161/circresaha.116.304678.

63. Koval O.M., Guan X., Wu Y., Joiner M.L., Gao Z., Chen B. et al. CaV1.2 beta-subunit coordinates CaMKIItriggered cardiomyocyte death and afterdepolarizations. Proc. Natl. Acad. Sci U S A. 2010; 107 (11): 4996-5000. doi:10.1073/ pnas.0913760107.


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Chaulin A.M., Duplyakov D.V. Arrhythmogenic effects of doxorubicin. Complex Issues of Cardiovascular Diseases. 2020;9(3):69-80. (In Russ.) https://doi.org/10.17802/2306-1278-2020-9-3-69-80

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