Cardiovascular complications in patients with cancer: focus on anthracycline-induced cardiotoxicity

The article describes prevalence and risk factors of cardiovascular in patients with cancer. The problems of anthracycline-induced cardiotoxicity, the deleterious effects of doxorubicin on the heart, as well as the cardioprotective effects of beta-blockers and agents acting on the renin-angiotensin-aldosterone system pathway are discussed. By cardiotoxicity is implied the development of various adverse cardiovascular events against the background of drug therapy for cancer patients. Depending on the severity of myocardial damage, there are type I (anthracycline-mediated cardiotoxicity, myocardial damage is irreversible) and type II (trastuzumab-mediated cardiotoxicity, myocardial dysfunction is reversible) cardiotoxicity. Anthracycline-induced cardiotoxicity, in turn, is divided into acute, early-onset chronic and late-onset chronic. At the same time, the main mechanisms of anthracycline cytotoxicity in relation to healthy cardiomyocytes are stimulation of intracellular oxidative stress, a decrease in reduced glutathione concentration, inhibition of cell redox potential, and a change in iron metabolism. The article discusses in detail the risk factors (age, hypertension, diabetes, asymptomatic left ventricular dysfunction, documented cardiovascular diseases, heart failure, etc.), as well as the mechanisms and treatment of anthracycline-mediated cardiotoxicity.

1. Padegimas A, Clasen S, Ky B. Cardioprotective strategies to prevent breast cancer therapy-induced cardiotoxicity. Trends Cardiovasc Med. 2020;30:1:22-8. doi:10.1016/j.tcm.2019.01.006.

2. Global WHO. (In Russ.) Глобальный веб-сайт ВОЗ. https://www.who.int/ru/news-room/fact-sheets/detail/cancer.

3. Li W, Li Q, Wei L, et al. Rosmarinic Acid Analogue-11 Induces Apoptosis of Human Gastric Cancer SGC-7901 Cells via the Epidermal Growth Factor Receptor (EGFR)/Akt/Nuclear Factor kappa B (NF-kB) Pathway. Medical Sci Monit Basic Res. 2019;25:63-75. doi.10.12659/MSMBR.913331.

4. Gumerova KS, Sakhautdinova GM, Polyakova IM. Antitumour Drug Induced Cardiovascular Toxicity and Current Tumour Treatment Methods. Creative surgery and oncology. 2019;9(4):285-92. (In Russ.) doi:10.24060/2076-3093-2019-9-4-285-292.

5. Cancer incidence and mortality worldwide: IARC Cancer Base. http://gco.iarc.fr/tomorrow/home. Accessed 9 Dec 2019.

6. Gendlin GE, Emelina EI, Nikitin IG, Vasyuk YA. Modern view on cardiotoxicity of chemotherapeutics in oncology including anthracyclines. Russian Journal of Cardiology. 2017;(3):145-54. (In Russ.) doi:10.15829/1560-4071-2017-3-145-154.

7. Obrezan A, Kulikov N. Cardiovascular risk in patientsoncological diseases. Medical Alliance. 2019;7:3:100-4. (In Russ.) doi: 10.36422/2307-6348-2019-7-3-100-104.

8. Allison JD, Tanavin T, Yang Y, et al. Various Manifestations of 5-Fluorouracil Cardiotoxicity: A Multicenter Case Series and Review of Literature. Cardiovasc Toxicol. 2020;1-6. doi:10.1007/s12012-020-09562-w.

9. Shiga T, Hiraide M. Cardiotoxicities of 5-Fluorouracil and Other Fluoropyrimidines. Curr Treat Options Oncol. 2020;21(4):21-7. doi:10.1007/s11864-020-0719-1.

10. Herrmann J. Vascular toxic effects of cancer therapies. Nature Rev Cardiol. 2020;1-20. doi:10.1038/s41569-020-0347-2.

11. Ivanov VG. Epidemiological risk factors, early diagnosis of breast cancer. Practical Oncology. 2002;3:1:1-5. (In Russ.)

12. Bedritsky SA, Larionova VB, Snegovoy AV. Clinical guidelines for cardiovascular toxicity induced by chemotherapy and targeted drugs. Moscow. 2014. 10 р. (In Russ.) http://www.oncology.ru/association/clinical-guidelines/2014/14.pdf.

13. Chainikova TV. Frequency of risk factors for chemotherapy induced cardiotoxicity among patients of hemaological department of perm regional clinical hospital. Young Scientist. 2016;3:(107):337-41. (In Russ.)

14. Seliverstova DV, Evsina OV. Cardiotoxicity of chemotherapy. Russian Heart Journal. 2016; 15 (1):50-57 doi.10.18087/ rhj.2016.1.2115 (In Russ.) doi: 10.18087/rhj.2016.1.2115.

15. Vatutin NT, Sklyannaya EV, El-Khatib MA, Sologub IA. Risk factors and incidence of myocardial damage in patients with hemoblastosis receiving anthracyclin antibiotics. Oncohematology. 2017; 12(3):25-30. (In Russ.) doi:10.17650/1818-8346-2017-12-3-25-30.

16. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC committee for practice guidelines. Russian Journal of Cardiology. 2017;(3):105-139. (In Russ.) doi:10.15829/1560-4071-2017-3-105-139.

17. Snegovoy AV, Vitsenya MV, Kopp MV, et al. Practical recommendations for the correction of cardiovascular toxicity induced by chemotherapy and targeted drugs. Zlokachestvennye opukholi = Malignant tumors 2015;4:369-78. (In Russ.) doi:10.18027/2224-5057-2016-4s2-418-427.

18. Zamorano JL, Lancellotti P, Munoz DR, et al. ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines. Eur Heart J. 2016;37(36):2768-801. doi:10.1093/eurheartj/ehw211.

19. Curigliano G, Lenihan D, Fradley M, et al. Management of cardiac disease in cancer patients throughout oncological treatment: ESMO consensus recommendations. Ann Oncol. 2020;31:2:171-90. doi.10.1016/j.annonc.2019.10.023.

20. Swain SM, Whaley FS, Ewer MS. Congestive heart failure in patients treated with doxorubicin: a retrospective analysis of three trials. Cancer. 2003;97:11:2869-79. doi.10.1002/cncr.11407.

21. Danesi R, Fogli S, Gennari A, et al. Pharmacokinetic-pharmacodynamic relationships of the anthracycline anticancer drugs. Clin Pharmacokinet. 2002;41:6:431-44. doi:10.2165/00003088-200241060-00004.

22. Curigliano G, Cardinale D, Dent S, et al. Cardiotoxicity of anticancer treatments: epidemiology, detection, and management. CA Cancer J Clin. 2016;66:309-25. doi:10.3322/caac.21341.

23. Henriksen PA. Anthracycline cardiotoxicity: an update on mechanisms, monitoring and prevention. Heart. 2018; 104 (12):971-7 doi:10.1136/heartjnl-2017-312103.

24. Rocca C, Pasqua T, Cerra MC, Angelone T. Cardiac damage in anthracyclines therapy: focus on oxidative stress and inflammation. Antioxid Redox Signal. 2020;32:15:1081-97 doi:10.1089/ars.2020.8016.

25. Tajik R, Saadat H, Taherkhani M. Angina induced by 5-fluorouracil infusion in a patient with normal coronaries. Am 39. Heart Hosp J. 2010;8:2:E111-2.

26. Atar A, Korkmaz ME, Ozin B. Two cases of coronary vasospasm induced by 5-fluorouracil. Anadolu Kardiyol Derg. 2010;10:461-2. doi:10.5152/akd.2010.147.

27. 27 Shoemaker LK, Arora U, Rocha Lima, CM. 5-fluorouracil-induced coronary vasospasm. Cancer Control. 2004;11:46-9. doi:10.1177/107327480401100107.

28. Mikulyak NI, Minnigaleeva SD, Magdeyev RR, Mikulyak AI. Study of the nature and causes of cardiotoxic qualities of anthracycline antibiotics. The journal of scientific articles “Health & education millennium”. 2013; 15(1-4):184-6. (In Russ.)

29. Yandieva RA, Saribekyan EK, Mamedov MN. Cardiotoxicity of cancer therapy. International Heart and Vascular Disease Journal. 2018;17:3-10. (In Russ.) doi:10.15829/2311-1623-6-17

30. Cardinale D, Iacopo F, Cipolla CM. Cardiotoxicity of Anthra-cyclines. Front Cardiovasc Med. 2020;7:26. doi: 10.3389/fcvm.2020.00026.

31. Solomanina OO, Mikulyak NI, Kinzirsky AS. Studying the effect of probucol on some indicators of lipid peroxidation in rats with W-256 against experimental myocardial dystrophy treated with rubomycin Modern high technology. 2005;6:41-2. (In Russ.)

32. U. S. National Library of Medicine: National Institutes of Health. 2018. Available from: https://www.nih.gov.

33. Sara JD, Kaur J, Khodadadi R, et al. 5-fluorouracil and cardiotoxicity: a review. Ther Adv Med Oncol. 2018;10:1758835918780140. doi:10.1177/1758835918780140.

34. Shuykova KW, Emelina EI, Gendlin GE, Storozhakov GI. Cardiotoxicity of modern chemotherapeutic drugs. Atmosphere. Cardiology news. 2012:3:9-19. (In Russ.)

35. Herrmann J. Adverse cardiac effects of cancer therapies: cardiotoxicity and arrhythmia. Nature Reviews Cardiology. 2020;1-29. doi:10.1038/s41569-020-0348-1.

36. Brana I, Zamora E, Oristrell G, Tabernero J. Side effects of medical cancer therapy. Cardiotoxicity. 2018; 14:406. doi:10.1007/978-3-31970253-7_14.

37. Kaprin AD, Matskeplishvili ST, Potievskaya VI, et al. Cardiovascular diseases in cancer patients. P. A. Herzen Journal of Oncology = Onkologiya. Zhurnal imeni P. A. Gertsena. 2019;8(2):139-47 (In Russ.) doi:10.17116/onkolog20198021139.

38. Narayan V, Thompson EW, Demissei B, et al. Mechanistic Biomarkers Informative of Both Cancer and Cardiovascular Disease: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75: 21:2726-37 doi:10.1016/j.jacc.2020.03.067

39. Chazova IYe, Tyulyandin SA, Vitsenia MV, et al. Clinical manual for diagnosis, prevention and treatment of cardiovascular complications of cancer therapy. Parts VI-VII. Systemic Hypertension. 2018; 15( 1 ):6-20. (In Russ.). doi:10.26442/2075-082X_15.1.6-20.

40. Cardinale D, Sandri MT, Colombo A, et al. Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation. 2004;109:2749-54. doi:10.1161/01.CIR.0000130926.51766.CC

41. Seicean S, Seicean A, Alan N, et al. Cardioprotective effect of beta-adrenoceptor blockade in patients with breast cancer undergoing chemotherapy: follow-up study of heart failure. Circ Heart Fail. 2013;6:420-6. doi: 10.1161/CIRCHEARTFAILURE.112.000055.

42. Kaya MG, Ozkan M, Gunebakmaz O, et al. Protective effects of nebivolol against anthracycline-induced cardiomyopathy: a randomized control study. Int J Cardiol. 2013;167:2306-10. doi:10.1016/j.ijcard.2012.06.023.

43. Elitok A, Oz F, Cizgici AY, et al. Effect of carvedilol on silent anthracycline-induced cardiotoxicity assessed by strain imaging: a prospective randomized controlled study with six-month followup. Cardiol J. 2014;21:509-15. doi:10.5603/CJ.a2013.0150.

44. Cadeddu C, Piras A, Mantovani G, et al. Protective effects of the angiotensin II receptor blocker telmisartan on epirubicin-induced inflammation, oxidative stress, and early ventricular impairment. Am Heart J. 2010;160:3:487.e1-487.e7. doi:10.1016/j.ahj.2010.05.037.

45. Pituskin E, Mackey JR, Koshman S, et al. Multidisciplinary approach to novel therapies in cardio-oncology research (MANTICORE 101-Breast): a randomized trial for the prevention of trastuzumab-associated cardiotoxicity. J Clin Oncol. 2017;35:870-7 doi:10.1200/JCO.2016.68.7830.

46. Bosch X, Rovira M, Sitges M, et al. Enalapril and carvedilol for preventing chemotherapy-induced left ventricular systolic dysfunction in patients with malignant hemopathies: the OVERCOME trial (preventiOn of left Ventricular dysfunction with Enalapril and caRvedilol in patients submitted to intensive ChemOtherapy for the treatment of Malignant hEmo-pathies). J Am Coll Cardiol. 2013;61:2355-62. doi:10.1016/j.jacc.2013.02.072.

47. 47 Davis MK, Villa D, Tsang TSM, et al. Effect of eplerenone on diastolic function in women receiving anthracycline-based chemotherapy for breast cancer. J Am Coll Cardiol Cardio Onc. 2019;2:295-8. doi:10.1016/j.jaccao.2019.10.001.

48. Samura BB. The effect of atorvastatin therapy on heart function, heart rate variability in patients with remission of chronic lymphocytic leukemia. Actual nutrition of pharmaceutical and medical science and practice. 2019; 12:1:59-62. (In Russ.) doi:10.14739/2409-2932.2019.1.159131.

49. Gorbunova VA, Orel NF, Borisova TA, et al. Possibilities of using Taxotere for various solid tumors. Oncology. 2003;5(1):36-42. (In Russ.)