POLYMORPHISM OF GENES OF THE β-ADRENORECEPTION SYSTEM AND THE EFFECT OF LEVOTYROXINE ON THE COURSE OF HEART FAILURE IN PATIENTS WITH NON-TOXIC GOITER

Pyvovar S. M., Rudyk Yu. S., Lozyk T. V., Galchinska V. Yu., Bondar T. M.

CLINICAL AND EXPERIMENTAL MEDICINE

Scentific article

Heart failure (HF) is an important medical, social and economic problem. The incidence, occurance and mortality from this pathology are still high today, and the prognosis remains unfavorable. Optimizing existing and developing new treatment strategies is important for HF. The interest in the role of thyroid hormones in HF has increased over the last decade. Experimental and clinical studies have shown that thyroid hormones counteract the progression of HF, probably due to genomic and non-genomic effects in the myocardium, heart vessels and the whole body. In modern standards of HF treatment, the use of thyroid hormones, in the absence of hypothyroidism, is not recommended. In addition, at non-toxic goiter (NG), the most common thyroid pathology, levothyroxine (LT) is a recognized treatment strategy, even in the absence of organ hypofunction. This makes it possible to study the effects of LT in HF. Aim: to study the associations of gene polymorphisms of the β-adrenoreception system with the effect of levothyroxine on the course of heart failure in patients with non-toxic goiter. Object and research methods. In the study 218 patients with heart failure on the background of post-infarction cardiosclerosis were included. All patients were diagnosed with NG. 109 patients received LT in connection with NG. Genotyping was performed for 4 polymorphisms (Gly389Arg of the β1 -receptor gene (β1 -АR), Ser49Gly of the β1 -АR gene, Gln27Glu of the β2 -АR gene and Ser275 of the β3-subunit of G-protein (GNβ3 )) using polymerase chain reaction. Echocardioscopy and ultrasound of the thyroid gland were performed. We studied the course of heart failure for 2 years. Results. Use of LT in connection with NG reduces the risk of re-hospitalization (RH) of patients with heart failure (Odds ratio (OR) = 0.490 (0.281-0.857), p = 0.018). A tendentious decrease in the risk of achieving a combinedendpoint was revealed (by 27.9%, p = 0.074). The analysis did not reveal any reliable associations of the effect of the use of LT on the frequency of RH with the polymorphism of genes of the β-adrenoreception system. The division of patients into groups by LT dose (according to the ROC analysis) revealed that the use of the drug at a dose of > 0.53 μg/kg in homozygous carriers of the C-allele of Gln27Glu polymorphism (c.79C> G) of the β2-AR gene leads to reduce the risk of RH over two years (OR = 0.09 (0.02-0.48)). In the subgroup of patients with a heterozygous (C / G) genotype, an increase in the risk of an adverse course of heart failure (an increase in the incidence of RH, OR = 3.82 (1.29-11.31), p = 0.0087) was detected in the absence of LT treatment. No reliable association of LT effect on the course of heart failure with other polymorphisms of the β-adrenoreceptor system genes were revealed. Conclusions. Congenital genetic differences in the pathways of β-adrenoreception may modulate effects of levothyroxine. The use of this drug at a dose of > 0.53 μg/kg in homozygous carriers of the C allele of the Gln27Glu polymorphism (c.79C> G) of the β2-adrenoreceptor gene reduces the risk of re-hospitalization due to decompensation of the heart failure for two years.

heart failure, non-toxic goiter, gene, polymorphism, β-adrenoreceptors, levothyroxine.

1. Garganeyeva AA, Bauer VA, Borel' KN. Pandemiya XXI veka: khronicheskaya serdechnaya nedostatochnost' – bremya sovremennogo obshchestva. Epidemiologicheskiye aspekty. Sibirskiy meditsinskiy zhurnal. 2014;3(29):8-12. [in Russian].
2. Pingitore A, Galli E, Barison A, Iervasi A, Scarlattini M, NucciPingitore DA, et al. Acute effects of triiodothyronine (T3) replacement therapy in patients with chronic heart failure and low-T3 syndrome: a randomized, placebo-controlled study. J Clin Endocrinol Metab. 2008;93:1351-8.
3. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2016. The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC) Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. European Heart Journal. 2016;8:2129-200. DOI: 10.1093/eurheartj/ehw128
4. Silva JE. Catecholamines and the sympathoadrenal system in thyrotoxicosis. In: Werner & Ingbar’s The thyroid. A fundamental and clinical text. Braverman LE, Utiger RD, editors. Philadelphia: Lippincott Willians & Wilkins; 2000. p. 642-51.
5. Dillmann WH. Cellular action of thyroid hormone on the heart. Thyroid. 2002;12:447-52.
6. Hesse С, Eisenach JH. Genetic variation in the β2-adrenergic receptor: impact on intermediate cardiovascular phenotypes. Curr Pharmacogenomics Person Med. 2008;6(3):160-70.
7. Dayem Ullah AZ, Lemoine NR, Chelala C. SNPnexus: a web server for functional annotation of novel and publicly knowngenetic variants (2012 update). Nucleic Acids Res. 2012;40(Web Server issue):65-70. DOI: 10.1093/nar/gks364
8. Xu Z, Taylor JA. SNPinfo: integrating GWAS and candidate gene information into functional SNP selection for genetic association studies. Nucleic Acids Res. 2009;37(Web Server issue):600-5. DOI: 10.1093/nar/gkp290
9. Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, Mandel SJ, et al. Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2009;19:1167-214. DOI: 10.1089/thy.2009.0110
10. Knobel M. Etiopathology, clinical features, and treatment of diffuse and mul-tinodular nontoxic goiters. J Endocrinol Invest. 2016;39:357-73. DOI: 10.1007/ s40618-015-0391-7
11. Sole X, Guino E, Valls J, Iniesta R, Moreno V. SNPStats: a web tool for the analysis of association studies. Bioinformatics. 2006;22:1928-9. DOI: 10.1093/bioinformatics/btl268
12. Dillmann Wolfgang H. Mechanism of Action of Thyroid Hormone on the Cardiac Vascular System. Thyroid and Heart Failure. Springer-Verlag: Italia; 2009. р. 45-54.
13. Naga Prasad SV, Nienaber J, Rockman HA. Beta-adrenergic axis and heart disease. Trends Genet. 2001;17:44-9.
14. Xiao RP. Beta-adrenergic signaling in the heart: dual coupling of the beta2-adrenergic receptor to G(s) and G(i) proteins. Sci STKE. 2001;2001:RE15.
15. Carvalho-Bianco K, Reed Larsen. Thyroid Hormone and Adrenergic Signaling. Arq Bras Endocrinol Metab. 2004;48(1):171-5.
16. Bilezekian JP, Loeb JN. The influence of hyperthyroidism and hypothyroidism on the a- and b-adrenergic receptor system and adrenergic responsiveness. Endocr Rev. 1983;4:378-88.
17. Pracyk JB, Slotkin TA. Thyroid hormone differentially regulates development of beta-adrenergic receptors, adenylate cyclase and ornithine decarboxylase in rat heart and kidney. J Dev Physiol. 1991;16:251-61.
18. Hoit BD, Khoury SF, Shao Y, Gabel M, Liggett SB, Walsh RA. Effects of thyroid hormone on cardiac beta-adrenergic responsiveness in conscious baboons. Circulation. 1997;96:592-8.
19. Novotny J, Bourova L, Malkova O, Svoboda P, Kolar F. G-proteins, beta-adrenoreceptors and beta-adrenergic responsiveness in immature and adult rat ventricular myocardium: influence of neonatal hypo- and hyperthyroidism. J Mol Cell Cardiol. 1999;31:761-72.
20. Bahouth SW. Thyroid hormones transcriptionally regulate the beta 1-adrenergic receptor gene in cultured ventricular myocytes. J Biol Chem. 1991;266:15863-9.
21. Bahouth SW, Cui X, Beauchamp MJ, Park EA. Thyroid hormone induces beta1-adrenergic receptor gene transcription through a direct repeat separated by five nucleotides. J Mol Cell Cardiol. 1997;29:3223-37.
22. Zolk O, Kilter H, Flesch M, Mansier P, Swynghedauw B, Schnabel P, et al. Functional coupling of overexpressed beta 1-adrenoceptors in the myocardium of transgenic mice. Biochem Biophys Res Commun. 1998;248:801-5.
23. Heubach JF, Trebess I, Wettwer E, Himmel HM, Michel MC, Kaumann AJ, et al. L-type calcium current and contractility in ventricular myocytes from mice overexpressing the cardiac beta 2-adrenoceptor. Cardiovasc Res. 1999;42:173-82.
24. Covolo L, Gelatti U, Metra M, Nodari S, Piccichè A, Pezzali N, et al. Role of beta1- and beta2-adrenoceptor polymorphisms in heart failure: a case-control study. Eur Heart J. 2004;25:1534-41. DOI: 10.1016/ j.ehj.2004. 06.015
25. Aquilante CL, Yarandi NH, Cavallari LH, Andrisin TE, Terra SG, Lewis JF, et al. β-Adrenergic receptor gene polymorphisms and hemodynamic response to dobutamine during dobutamine stress echocardiography. The Pharmacogenomics J. 2008;8:408-15. DOI: 10.1038/sj.tpj.6500490
26. Levin M, Marullo S, Muntaner O, Andersson B, Magnusson Y. The myocardium pro-tective Gly 49 variant of the beta1 adrenergic receptor exhibits of constitutive activity and increased desensitization and down regulation. J Biol Chemistry. 2002;277:30429-35. DOI: 10.1074/jbc. M200681200
27. Zhu WZ, Zheng M, Koch WJ, Lefkowitz RJ, Kobilka BK, Xiao RP. Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes. Proc Natl Acad Sci USA. 2001;98:1607-12.
28. Matkovich SJ, Van Booven DJ, Hindes A, Kang MY, Druley TE, Vallania FL, et al. Cardiac signaling genes exhibit unexpected sequence diversity in sporadic cardiomyopathy, revealing HSPB7 polymorphisms associated with disease. J Clin Invest. 2010;120:280-9. DOI: 10.1172/ jci39085
29. Sheppard R, Hsich E, Damp J, Elkayam U, Kealey A, Ramani G, et al. Investigators GNB3 C825T Polymorphism and Myocardial Recovery in Peripartum Cardiomyopathy. Results of the Multicenter Investigations of Pregnancy-Associated Cardiomyopathy Study. Circulation: Heart Failure. 2016;9. DOI: 10.1161/ CIRCHEARTFAILURE. 115.002683

«Bulletin of problems biology and medicine» Issue 4 Part 2 (154), 2019 year, 181-188 pages, index UDK 616.12-008.46-085:575.174.015.3:616.441-006.5

10.29254/2077-4214-2019-4-2-154-181-188