Course of arterial hypertension during breast cancer chemotherapy with anthracyclines

Aim. To study the characteristics of the course of arterial hypertension (AH) and subclinical cardiac damage during breast cancer chemotherapy with doxorubicin.

Materials and methods. The study included a total of 27 women with breast cancer (BC) and a history of controlled hypertension who were to receive chemotherapy with anthracyclines. Twelve women had stage 1 hypertension; 15 women had stage 2 hypertension. The patients received dual antihypertensive therapy according to clinical guidelines. All patients underwent echocardiography and 24-hour blood pressure monitoring at baseline, after the last course of chemotherapy, and 12 months after the end of chemotherapy. The control group included 35 women with BC without a history of AH, who also were to receive anthracycline chemotherapy.

Results. A significant relationship between pre-existing AH and the development of left ventricular systolic dysfunction 12 months after the completion of chemotherapy (p = 0.01) was found. According to 24-hour blood pressure monitoring, 15 women (55.6%) showed deterioration of blood pressure control after the completion of chemotherapy, which required modification of antihypertensive therapy by adding one more drug to the treatment regimen. At 12 months after the end of chemotherapy, in 13 women, hypertension control was reached with triple antihypertensive therapy. In two women, hypertension became resistant, which required prescription of a fourcomponent antihypertensive regimen.

Conclusion. Pre-existing AH plays an essential role in the development of anthracycline-induced cardiotoxicity, despite the quality of blood pressure control. Polychemotherapy with anthracyclines may deteriorate blood pressure control in patients with AH, which requires addition of antihypertensive drugs to the treatment regimen.

1. Муромцева Г.А., Концевая А.В., Константинов В.В., Артамонова Г.В., Гатагонова Т.М., Дупляков Д.В. и др. Распространенность факторов риска неинфекционных заболеваний в российской популяции в 2012–2013 гг. Результаты исследования ЭССЕ-РФ. Кардиоваскулярная терапия и профилактика. 2014;13(6):4–11. DOI: 10.15829/1728-88002014-6-4-11.

2. Sung H., Ferlay J., Siegel R.L., Laversanne M., Soerjomataram I., Jemal A., Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021;71(3):209–249. DOI: 10.3322/caac.21660.

3. Cohen J.B., Geara A.S., Hogan J.J., Townsend R.R. Hypertension in cancer patients and survivors: epidemiology, diagnosis, and management. ACC CardioOncol. 2019;1(2):238–251. DOI: 10.1016/j.jaccao.2019.11.009.

4. Jain M., Townsend R.R. Chemotherapy agents and hypertension: a focus on angiogenesis blockade. Curr. Hypertens. Rep. 2007;9(4):320–328. DOI: 10.1007/s11906-007-0058-7.

5. Васюк Ю.А., Гендлин Г.Е., Емелина Е.И., Шупенина Е.Ю., Баллюзек М.Ф., Баринова И.В. и др. Согласованное мнение российских экспертов по профилактике, диагностике и лечению сердечно-сосудистой токсичности противоопухолевой терапии. Российский кардиологический журнал. 2021;26(9):4703. DOI: 10.15829/1560-4071-2021-4703.

6. Lyon A.R., López-Fernández T., Couch L.S., Asteggiano R., Aznar M.C., Bergler-Klein J. et al. 2022 ESC Guidelines on Cardio-Oncology Developed in Collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS): Developed by the Task Force on Cardio-Oncology of the European Society of Cardiology (ESC). Eur. Heart J. 2022;43(41):4229–4361. DOI: 10.1093/eurheartj/ehac244.

7. Armstrong G.T., Oeffinger K.C., Chen Y., Kawashima T., Yasui Y., Leisenring W. et al. Modifiable risk factors and major cardiac events among adult survivors of childhood cancer. J. Clin. Oncol. 2013;31(29):3673–3680. DOI: 10.1200/JCO.2013.49.3205.

8. Kooijmans E.C., Bökenkamp A., Tjahjadi N.S., Tettero J.M., van Dulmen-den Broeder E., van der Pal H.J. et al. Early and late adverse renal effects after potentially nephrotoxic treatment for childhood cancer. Cochrane Database Syst. Rev. 2019;3(3):CD008944. DOI: 10.1002/14651858.CD008944.pub3.

9. Totzeck M., Mincu R.I., Mrotzek S., Schadendorf D., Rassaf T. Cardiovascular diseases in patients receiving small molecules with anti-vascular endothelial growth factor activity: A meta-analysis of approximately 29,000 cancer patients. Eur. J. Prev. Cardiol. 2018;25(5):482–494. DOI: 10.1177/2047487318755193.

10. Li W., Croce K., Steensma D.P., McDermott D.F., Ben-Yehuda O., Moslehi J. Vascular and metabolic implications of novel targeted cancer therapies: focus on kinase inhibitors. J. Am. Coll. Cardiol. 2015;66(10):1160–1178. DOI: 10.1016/j.jacc.2015.07.025.

11. Wojcik T., Szczesny E., Chlopicki S. Detrimental effects of chemotherapeutics and other drugs on the endothelium: A call for endothelial toxicity profiling. Pharmacol. Rep. 2015;67(4):811–817. DOI: 10.1016/j.pharep.2015.03.022.

12. Feng J., Wu Y. Endothelial-to-mesenchymal transition: potential target of doxorubicin-induced cardiotoxicity. Am. J. Cardiovasc. Drugs. 2023;23(3):231–246. DOI: 10.1007/s40256023-00573-w.

13. Sayed-Ahmed M.M., Khattab M.M., Gad M.Z., Osman A.M. Increased plasma endothelin-1 and cardiac nitric oxide during doxorubicin-induced cardiomyopathy. Pharmacol. Toxicol. 2001;89(3):140–144. DOI: 10.1034/j.1600-0773.2001.d01148.x.

14. Иванова Г.Т. Влияние доксорубицина на реактивность брыжеечных артерий крыс Вистар. Российский физиологический журнал им. И.М. Сеченова. 2022;108(11):1453– 1467. DOI: 10.31857/S0869813922110036.

15. Aldieri E., Bergandi L., Riganti C., Costamagna C., Bosia A., Ghigo D. Doxorubicin induces an increase of nitric oxide synthesis in rat cardiac cells that is inhibited by iron supplementation. Toxicol. Appl. Pharmacol. 2002;185(2):85–90. DOI: 10.1006/taap.2002.9527.

16. Deng S., Kruger A., Schmidt A., Metzger A., Yan T., Gödtel-Armbrust U. et al. Differential roles of nitric oxide synthase isozymes in cardiotoxicity and mortality following chronic doxorubicin treatment in mice. Naunyn Schmiedebergs Arch. Pharmacol. 2009;380(1):25–34. DOI: 10.1007/s00210-009-0407-y.

17. Bahadır A., Kurucu N., Kadıoğlu M., Yenilme E. The role of nitric oxide in doxorubicin-induced cardiotoxicity: experimental study. Turk. J. Haematol. 2014;31(1):68–74. DOI: 10.4274/Tjh.2013.0013.

18. Cao L., Huang C., Wang N., Li J. ET-1/NO: A controversial target for myocardial ischemia-reperfusion injury. Cardiology. 2014;127(2):140. DOI: 10.1159/000355536.

19. Yamashita J., Ogawa M., Shirakusa T. Plasma endothelin-1 As a marker for doxorubicin cardiotoxicity. Int. J. Cancer. 1995;62(5):542–547. DOI: 10.1002/ijc.2910620509.

20. Luu A.Z., Chowdhury B., Al-Omran M., Teoh H., Hess D.A., Verma S. Role of endothelium in doxorubicin-induced cardiomyopathy. ACC Basic Transl. Sci. 2018;3(6):861–870. DOI: 10.1016/j.jacbts.2018.06.005.

21. Vargas Vargas R.A., Varela Millán J.M., Fajardo Bonilla E. Renin-angiotensin system: Basic and clinical aspects-A general perspective. Endocrinol. Diabetes Nutr. (Engl. Ed.). 2022;69(1):52–62. DOI: 10.1016/j.endien.2022.01.005.

22. Zheng M., Kang Y.M., Liu W., Zang W.J., Bao C.Y., Qin D.N. Inhibition of cyclooxygenase-2 reduces hypothalamic excitation in rats with adriamycin-induced heart failure. PLoS One. 2012;7(11):e48771. DOI: 10.1371/journal.pone.0048771.

23. Arozal W., Watanabe K., Veeraveedu P.T., Thandavarayan R.A., Harima M., Sukumaran V. et al. Beneficial effects of angiotensin II receptor blocker, olmesartan, in limiting the cardiotoxic effect of daunorubicin in rats. Free Radic. Res. 2010;44(11):1369–1377. DOI: 10.3109/10715762.2010.509399.

24. Jones L.W., Haykowsky M., Peddle C.J., Joy A.A., Pituskin E.N., Tkachuk L.M. et al. Cardiovascular risk profile of patients with HER2/neu-positive breast cancer treated with anthracycline-taxane-containing adjuvant chemotherapy and/or trastuzumab. Cancer Epidemiol. Biomark. Prev. 2007;16(5):1026–1031. DOI: 10.1158/10559965.EPI-06-0870.

25. Rashikh A., Pillai K.K., Najmi A.K. Protective effect of a direct renin inhibitor in acute murine model of cardiotoxicity and nephrotoxicity. Fundam. Clin. Pharmacol. 2014;28(5):489– 500. DOI: 10.1111/fcp.12054.

26. Okumura K., Jin D., Takai S., Miyazaki M. Beneficial effects of angiotensinconverting enzyme inhibition in adriamycin-induced cardiomyopathy in hamsters. Jpn. J. Pharmacol. 2002;88(2):183–188. DOI: 10.1254/jjp.88.183.

27. Huang C.Y., Chen J.Y., Kuo C.H., Pai P.Y., Ho T.J., Chen T.S. et al. Mitochondrial ROS-induced ERK1/2 activation and HSF2-mediated AT1 R upregulation are required for doxorubicin-induced cardiotoxicity. J. Cell Physiol. 2018;233(1):463–475. DOI: 10.1002/jcp.25905.

28. Zong W.N., Yang X.H., Chen X.M., Huang H.J., Zheng H.J., Qin X.Y. et al. Regulation of angiotensin-(1–7) and angiotensin II type 1 receptor by telmisartan and losartan in adriamycin-induced rat heart failure. Acta Pharmacol. Sin. 2011;32(11):1345–1350. DOI: 10.1038/aps.2011.96.

29. Galán-Arriola C., Vílchez-Tschischke J.P., Lobo M., López G.J., de Molina-Iracheta A., Pérez-Martínez C. et al. Coronary microcirculation damage in anthracycline cardiotoxicity. Cardiovasc. Res. 2022;118(2):531–541. DOI: 10.1093/cvr/cvab053.

30. Gajalakshmi P., Priya M.K., Pradeep T., Behera J., Muthumani K., Madhuwanti S. et al. Breast cancer drugs dampen vascular functions by interfering with nitric oxide signaling in endothelium. Toxicol. Appl. Pharmacol. 2013;269(2):121– 131. DOI: 10.1016/j.taap.2013.03.011.

31. Тепляков А.Т., Шилов С.Н., Попова А.А., Гракова Е.В., Березикова Е.Н., Неупокоева М.Н., Молоков А.В., Копьева К.В., Калюжин В.В. Состояние сердечно-сосудистой системы у больных с антрациклиновой кардиомиопатией. Бюллетень сибирской медицины. 2017;16(3):127–136. DOI: 10.20538/1682-0363-2017-3-127-136.

32. Тепляков А.Т., Шилов С.Н., Попова А.А., Березикова Е.Н., Гракова Е.В., Неупокоева М.Н., Копьева К.В., Ратушняк Е.Т., Степачев Е.И. Роль провоспалительных цитокинов в развитии антрациклин-индуцированной сердечной недостаточности. Сибирский медицинский журнал. 2020. Т. 35, № 2. С. 66–74. DOI: 10.29001/2073-85522020-35-2-66-74.

33. Askarinejad A., Alizadehasl A., Jolfayi A.G., Adimi S. Hypertension in cardio-oncology clinic: an update on etiology, assessment, and management. Cardio-Оncology. 2023;9(1):46. DOI: 10.1186/s40959-023-00197-8.

34. Pedersen S.A., Gaist D., Schmidt S.A.J., Hölmich L.R., Friis S., Pottegård A. Hydrochlorothiazide use and risk of nonmelanoma skin cancer: A nationwide case-control study from Denmark. J. Am. Acad. Dermatol. 2018;78(4):673–681.e9. DOI: 10.1016/j.jaad.2017.11.042.

35. Rouette J., Yin H., Pottegård A., Nirantharakumar K., Azoulay L. Use of hydrochlorothiazide and risk of melanoma and nonmelanoma skin cancer. Drug Saf. 2021;44(2):245–254. DOI: 10.1007/s40264-020-01015-1.

36. Pottegard A., Pedersen S.A., Schmidt S.A.J., Lee C.N., Hsu C.K., Liao T.C. et al. Use of hydrochlorothiazide and risk of skin cancer: a nationwide Taiwanese case-control study. Br. J. Cancer. 2019;121(11):973–978. DOI: 10.1038/s41416019-0613-4.

37. Park E., Lee Y., Jue M.S. Hydrochlorothiazide use and the risk of skin cancer in patients with hypertensive disorder: a nationwide retrospective cohort study from Korea. Korean J. Intern. Med. 2020;35(4):917–928. DOI: 10.3904/kjim.2019.218.

38. Faconti L., Ferro A., Webb A.J., Cruickshank J.K., Chowienczyk P.J. Hydrochlorothiazide and the risk of skin cancer. A scientific statement of the British and Irish Hypertension society. J. Hum. Hypertens. 2019;33(4):257–258. DOI: 10.1038/s41371-019-0190-2.

39. Rachow T., Schiffl H., Lang S.M. Risk of lung cancer and renin-angiotensin blockade: a concise review. J. Cancer Res. Clin. Oncol. 2021;147(1):195–204. DOI: 10.1007/s00432020-03445-x.