THE ROLE OF POLYMORPHIC VARIANTS OF NO-SYNTHASE, RECEPTOR ENDOTHELIN-1 AND NADPH-OXIDASE IN THE DEVELOPMENT OF HEART FAILURE RESULTED FROM CHEMOTHERAPY-INDUCED CARDIOTOXICITY

Aim. To study the clinical and genetic aspects of the influence of polymorphic variants of the genes of endothelial NO-synthase (NOS3), the receptor of endothelin-1 type A (EDNRA) and NADPH-oxidase on the development of cardiotoxic remodeling of the left ventricle and heart failure during anthracycline-based regimens for patients with breast cancer.

Methods. 176 women with breast cancer receiving anthracycline antibiotics as part of multiple drug chemotherapy regimens were examined. According to the results of the examination, 12 months after the end of multiple drug chemotherapy, all the patients with the main disease in remission were divided into 2 groups: patients with cardiac remodeling caused by cardiotoxicity (Group 1 = 52) and those with preserved heart function (Group 2 = 124). All patients underwent echocardiographic assessment before chemotherapy, during the treatment regimen with anthracyclines and after the therapy. Genetic material (buccal cells) was collected from all patients for the subsequent typing of alleles of genes NOS3 (rs1799983), EDNRA (rs5335) and NADPH-oxidase (rs4673).

Results. Analysis of echocardiographic parameters in patients 12 months after the completion of multiple drug chemotherapy in comparison with those before treatment showed a statistically significant difference between end-systolic and end-diastolic dimensions, as well as a significant reduction in the left ventricular ejection fraction in the group of women who developed cardiotoxicity with anthracycline cardiotoxicity. An association between the development of cardiotoxic lesions with the presence of mutant allele of NOS3 rs1799983 and NADPH-oxidase rs4673 genes has been determined. The presence of the T/T genotype of the NOS3 rs1799983 gene was associated with myocardial damage during multiple drug chemotherapy, along with the T/T genotype of the NADPHoxidase gene rs4673. Importantly, the genotype G/G of the gene NOS3 rs1799983 was more frequently determined in Group 2, suggesting its protective effect against cardiotoxic myocardial damage.

Conclusion. The development of the strategy aimed at preventing or reducing the risk of cardiovascular complications in the treatment of cancer is a crucial problem. Genetic typing is an effective measure to predict the increased risk of cardiotoxic effects of anthracyclines.

1. Plana J.C., Galderisi M., Barac A. et al. Expert consensus for multimodality imaging evaluation of adult patients during after cancer-therapy: a report from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imagin. 2014; 15 (10): 1063-1093. doi: 10.1093/ehjci/jeu192

2. Tan-Chiu E., Yothers G., Romond E. et al. Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in nodepositive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. J Clin Oncol. 2005; 23 (31): 7811-7819. doi: 10.1200/JCO.2005.02.4091

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

4. Vasyuk Yu.A., Shkolnik E.L., Nesterov V.V. et al. Cardiooncology: current aspects of prevention of anthracycline toxicity. Kardiologiia. 2016; 56 (12): 72-79. (In Russian). doi: 10.18565/cardio.2016.12.72-79

5. Vasyuk Yu.A., Shkolnik E.L., Nesterov V.V. et al. Cardiooncology: Current aspects in diagnostics for cardiovascular complications of antitumor therapy . Russian Heart Failure Journal. 2016; 17 (6): 383–387. (In Russian). doi: 10.18087/rhfj.2016.6.2327

6. Bovelli D., Plataniotis G., Roila F. Cardiotoxicity of chemotherapeutic agents and radiotherapy-related heart disease: ESMO Clinical Practice Guidelines. Ann Oncol. 2010; 21 (5): 277-282. doi: 10.1093/annonc/mdq200

7. Walker J., Bhullar N., Fallah-Rad N. et al. Role of threedimensional echocardiography in breast cancer: comparison with two-dimensional echocardiography, multiple-gated acquisition scans, and cardiac magnetic resonance imaging. J Clin Oncol. 2010; 28 (21): 3429-3436. doi: 10.1200/JCO.2009.26.7294

8. Dorosz J.L., Lezotte D.C., Weitzenkamp D.A. et al. Performance of 3-dimensional echocardiography in measuring left ventricular volumes and ejection fraction: a systematic review and meta-analysis. J Am Coll Cardiol. 2012; 59 (20): 1799-1808. doi: 10.1016/j.jacc.2012.01.037

9. DeSantis C.E., Lin C.C., Maiotto A.B. et al. Cancer treatment and survivorship statistics, 2014. CA Cancer J Clin. 2014; 64: 252-271. doi: 10.3322/caac.21235

10. Bonow R. O., Bennett S., Casey D. E. et al. ACC/ AHA Clinical Performance Measures for Adults with Chronic Heart Failure: a report of the American College of Cardiology/ American Heart Association Task Force on Performance Measures (Writing Committee to Develop Heart Failure Clinical Performance Measures): endorsed by the Heart Failure Society of America. Circulation. 2005; 112 (12): 1853-1887. doi: 10.1161/CIRCULATIONAHA.105.170072

11. Teplyakov A.T., Shilov S.N., Popova A.A. et al. The cardiovascular system in patients with anthracycline cardiomiopathy. Bulletin of Siberian Medicine. 2017; 16 (3): 127– 136. (In Russian). doi: 10.20538/1682-0363-2017-3-127–136

12. Felker G. M., Thompson R. E., Hare J. M. et al. Underlying causes and long-term survival in patients with initially unexplained cardiomyopathy. N Engl J Med. 2000; 342 (15): 1077-1084. doi: 10.1056/NEJM200004133421502

13. Bovelli D., Plataniotis G., Roila F. Cardiotoxicity of chemotherapeutic agents and radiotherapy - related heart disease: ESMO Clinical Practice Guidelines. Ann Oncol. 2010; 21 (5): 277-582. doi: 10.1093/annonc/mdq200

14. Kuznecova T.Yu., Dudanov I.P., Gavrilov D.V. et al. Hronicheskaya serdechnaya nedostatochnost’ u pacientov s arterial’noj gipertenziej i polimorfizmy Glu298Asp gena ehndotelial’noj NO-sintazy i S242Tr22 phox gena NADPHoksidazy. Russian Heart Failure Journal. 2007; 8 (6); 274-277. (In Russian).

15. Brazhnik V.A., Zateyshchikov D.A., Sidorenko B.A. Hereditary factors and left ventricular hypertrophy. Kardiologiia. 2003; 43 (1): 78-86. (In Russian).

16. Minushkina L.O., Zateyshchikov D.A., Sidorenko B.A. Genetic aspects of the regulation of endothelial function in patients with essential hypertension. Kardiologiia. 2000; 40 (3): 68-76. (In Russian).

17. Shilov S.N. Hronicheskaya serdechnaya nedostatochnost’ pri IBS: kliniko-geneticheskie mekhanizmy razvitiya i vozmozhnosti uluchsheniya rannej diagnostiki, profilaktiki i medikamentoznoj terapii. [dissertation] Tomsk; 2011. (In Russian).

18. Teplyakov A.T., Shilov S.N., Mayanskaya S.D. Molekulyarno-geneticheskie mekhanizmy razvitiya serdechnoj nedostatochnosti. Novye personificirovannye tekhnologii v medicine. Tomsk: Izdatel’stvo Tomskogo universiteta; 2014. (In Russian).

19. Campedelli F.L., E Silva K.S.F., Rodrigues D.A. et al. Polymorphism of the gene eNOS G894T (Glu298Asp) in symptomatic patients with aterosclerosis. Genet Mol Res. 2017; 16 (2). doi: 10.4238/gmr16029550

20. Chen X.J., Qiu C.G., Kong X.D. et al. The association between an endothelial nitric oxide synthase gene polymorphism and coronary heart disease in young people and the underlying mechanism. Mol Med Rep. 2018; 17 (3): 3928-3934. doi: 10.3892/mmr.2017.8314

21. Gaо L., Wang W., Li Y.L. et al. Sympathoexcitation by central ANG II: roles for AT-1 receptor upregulation and NAD(P)H oxidase in RVLM. Am J Physiol Heart Circ Physiol. 2005; 288 (5): H 2271-2279. doi: 10.1152/ajpheart.00949.2004

22. Ito D., Murata M., Watanabe K. et al. C242T polymorphism of NADPH oxidase p22 PHOX gene and ischemic cerebrovascular disease in the Japanese population. Stroke. 2000; 31 (4): 936-939.

23. Wyche K.E., Wang S.S., Griendling K.K. et al. C242T CYBA polymorphism of NADPH oxidase is associated with reduced respiratory burst in human neutrophils. Hypertension. 2004; 43 960: 1246-1251. doi: 10.1161/01. HYP.0000126579.50711.62

24. Moreno M.U., Jose G.S., Fortuno A. et al. The C242T CYBA polymorphism of NADPH oxidase is associated with essential hypertension. J Hypertens. 2006; 24 (7): 1299-1306. doi: 10.1097/01.hjh.0000234110.54110.56

25. Böhm F., Pernow J. The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovasc Res. 2007;76 (1): 8-18. doi: 10.1016/j.cardiores.2007.06.004

26. Rubanyi G.M., Polokoff M.A. Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev. 1994; 46 (3): 325-415.

27. Rahman T., Baker M., Hall D.H. et al. Common genetic variation in the type A endothelin-1 receptor is associated with ambulatory blood pressure: a family study. J Hum Hypertens. 2008; 22 (4): 282-288. doi: 10.1038/sj.jhh.1002322.

28. Okan G., Yıldız Z., Gökdemir G. et al. G-231A and G+70C Polymorphisms of Endothelin Receptor Type-A Gene could Affect the Psoriasis Area and Severity Index Score and Endothelin 1 Levels. Indian J Dermatol. 2015; 60 (2): 211. doi: 10.4103/0019-5154.152561

29. Aydin A.F., Vural P., Oruc C.U. et al. The evaluation of endothelin 1 (EDN1) and endothelin receptor type A (EDNRA) gene polymorphisms in Hashimoto’s thyroiditis. Int Immunopharmacol. 2014; 21 (1): 181-185. doi: 10.1016/j.intimp.2014.04.023

30. Mareev V.Yu., Ageev F.T., Arutyunov G.P., Koroteev A.V., Mareev Yu.V., Ovchinnikov A.G. SEHF, RSC and RSMSIM national guidelines on CHF diagnostics and treatment (fourth revision). Russian Heart Failure Journal. 2013; 81 (7): 379-472. (in Russian).

31. Levis B.E., Binkley P.F., Shapiro C.L. Cardiotoxic effects of anthracycline-based therapy: what is the evidence and what are the potentialharms? Lancet Oncol. 2017; 18 (8): e445-e456. doi: 10.1016/S1470-2045(17)30535-1

32. Bird B.R., Swain S.M. Cardiac toxicity in breast cancer survivors: review of potential cardiac problems. Clin Cancer Res. 2008; 14 (1): 14-24. doi: 10.1158/1078-0432.CCR-07-1033

33. Radyukova I.M., Nechaeva G.I., Korennova O.Yu. et al. Еndothelial dysfunction as the pathogenetic factor of internal organ damage in polychemotherapy for the breast cancer. Siberian Medical Journal. 2012. 27 (1): 85-89. (In Russian).

34. Seidlerova J., Filipovsky J., Mayer O. et al. Association between endothelial NO synthase polymorphisms and arterial properties in the general population. Nitric Oxide. 2015; 44: 4751. doi: 10.1016/j.niox.2014.11.016