THE RABBIT’S CARDIOMYOCYTES ULTRASTRUCTURE AT THE EXPERIMENTAL HYPOTHYROIDISM MANIFESTATION

Hypothyroidism is one of the most frequently endocrine diseases caused by dysfunction of the thyroid gland. Hypothyroidism is accompanied by reactive changes in all organs and tissues, which is due to the presence of many targets for the thyroid hormones thyroxine and triiodothyronine and the role of these hormones in the animals and human's body. Striated cardiac muscle tissue is one of the most often involved in the reactive process during hypofunction of the thyroid gland in human, and the developing changes in the myocardium are of important clinical significance. The purpose of the study is ultrastructural changes in rabbit's cardiomyocytes with experimental hypothyroidism at the manifest stage of obvious signs. Male Soviet Chinchilla kind rabbits aged 12-14 months and weighing 3.1-3.5 kg (n=10) were used as the object of the study. The animals were divided into 2 equal groups: 1) experimental (n=5), in which experimental modeling of hypothyroidism was carried out through oral administration of the antithyroid drug thiamazole (10 mg/kg for 4 weeks), which inhibits the formation of thyroid glands hormones; 2) control (n=5), who received placebo and were in a physiological state. Electron microscopy was used to study ultrastructural changes in cardiomyocytes. According to the results of the study, numerous ultrastructural changes were revealed in all compartments of cardiomyocytes: in the nucleus (wrinkling, uneven contours of the nucleus and the appearance of invaginations of the nuclear membrane, chromatin condensation), in the contractile apparatus (thinning of myofibrils, the appearance of areas of excess contraction of myofibrils with contractures), in the energy apparatus ( change in the shape of mitochondria from oval to round, swelling of mitochondria, signs of destruction of the outer and inner membranes of mitochondria), in the sarcoplasmic system (expansion of the cisterns of the sarcoplasmic reticulum), in supporting apparatus (deformation of the intercalary discs between cardiomyocytes). These changes in the ultrastructure of cardiomyocytes probably underlie the impairment of myocardial contractile functions, apoptosis of cardiomyocytes and the gradual development of heart failure against the background of hypothyroidism.

1. Chaker L, Bianco AC, Jonklaas J, Peeters RP. Hypothyroidism. Lancet. 2017 Sep 23;390(10101):1550-1562. https://doi.org/10.1016/S0140-6736(17)30703-1

2. Petunina N.A. Sindrom gipotireoza. Russian Medical Journal. 2005;6:295. In Russian

3. Verbovoy AF, Dolgikh YuA, Verbovaya NI. Gipotireos - mezhdistziplinarnaya problema. Russian Medical Inquiry. 2022;6(9):509–515. In Russian. https://doi.org/10.32364/2587-6821-2022-6-9-509-515

4. Kannan L, Shaw PA, Morley MP, et al. Thyroid Dysfunction in Heart Failure and Cardiovascular Outcomes. Circ Heart Fail. 2018 Dec;11(12):e005266. https://doi.org/10.1161/CIRCHEARTFAILURE.118.005266

5. Curotto-Grasiosi J, Parquet C, Peressotti B, et. al. Insuficiencia cardiaca por hipotiroidismo primario. Revisión a propósito de un caso. Rev Med Inst Mex Seguro Soc. 2020;58(2):206-211. In Spanish. https://doi.org/10.24875/RMIMSS.M20000019

6. Ono Y, Fujita M, Ono S, Ogata S, et al. A rabbit model of fatal hypothyroidism mimicking "myxedema coma" established by microscopic total thyroidectomy. Endocr J. 2016;63(6):523-32. https://doi.org/10.1507/endocrj.EJ16-0005

7. Botasheva VS, Samoylova NI. Structural changes in myocardium of rats with experimental hypothyroidism. Medical alphabet. 2018;1(4):42-45. In Russian

8. Chaulin AM, Grigorieva JV, Suvorova GN. Experimental’nye modeli gypotireoza. Morphologicheskie vedomosti - Morphological newsletter. 2021;29(1):69-76. In Russian. https://doi.org/10.20340/mv-mn.2021.29(1).69-76

9. Botasheva VS, Dolgashova MA, Samoylova NI. Rezul'taty gistologicheskogo issledovaniya kardioprotektornogo effekta al'fa-tokoferola pri eksperimental'nom gipotireoze. Zurnak nauchnykh statey «Zdorov’e i obrazovanie v XXI veke» – The journal of scientific articles «Health and Education Millenium». 2019;21(1):31-46. https://doi.org/10.26787/nydha-2226-7425-2019-21-1-31-36

10. Usenko V, Lepekhin E, Lyzogubov V, et al. The influence of low doses 131I-induced maternal hypothyroidism on the development of rat embryos. Exp Toxicol Pathol. 1999;51(3):223–227. https://doi.org/10.1016/s0940-2993(99)80100-6

11. Kashchenko SA, Mosin DV. Strukturnye i organometricheskie izmeneniya shchitovidnoy zhelezy krys v usloviyakh immunosupressii i immunomodulyatsii na rannikh srokakh vozdeystviya. Ulyanovsky medico-biologichesky zhurnal. 2019;1:110–118. In Russian. https://doi.org/10.34014/2227-1848-2019-1-110-118

12. Paschou SA, Bletsa E, Stampouloglou PK, et al. Thyroid disorders and cardiovascular manifestations: an update. Endocrine. 2022;75(3):672-683. https://doi.org/10.1007/s12020-022-02982-4

13. Chaulin AM, Grigorieva JV. Sovremennye predstavleniya o serdechno-sosudistykh effektakh gipo- i gipertireoza.Sovremennye problem nauki I obrazovaniya. 2021(6):163. In Russian. https://doi.org/10.17513/spno.31202

14. Gluvic ZM, Zafirovic SS, Obradovic MM, et al. Hypothyroidism and Risk of Cardiovascular Disease. Curr Pharm Des. 2022;28(25):2065-2072. https://doi.org/10.2174/1381612828666220620160516

15. Ozmen O, Topsakal S. Examination of skin lesions in rats with induced hyperthyroidism and hypothyroidism. Biotech Histochem. 2020;95(6):438-444. https://doi.org/10.1080/10520295.2020.1714731

16. Silva TS, Faro GBA, Cortes MGB, Rego VRPA. Primary hypothyroidism with exuberant dermatological manifestations. An Bras Dermatol. 2020;95(6):721-723. https://doi.org/10.1016/j.abd.2019.07.010

17. Williams GR, Bassett JHD. Thyroid diseases and bone health. J Endocrinol Invest. 2018;41(1):99-109. https://doi.org/10.1007/s40618-017-0753-4

18. Rossmeisl JH, Duncan RB, Inzana KD, et al. Longitudinal study of the effects of chronic hypothyroidism on skeletal muscle in dogs. Am J Vet Res. 2009;70(7):879-889. https://doi.org/10.2460/ajvr.70.7.879

19. La Vignera S, Vita R, Condorelli RA, et al. Impact of thyroid disease on testicular function. Endocrine. 2017;58(3):397-407. https://doi.org/10.1007/s12020-017-1303-8

20. Sun J, Hui C, Xia T, Xu M, et al. Effect of hypothyroidism on the hypothalamic-pituitary-ovarian axis and reproductive function of pregnant rats. BMC Endocr Disord. 2018;18(1):30. https://doi.org/10.1186/s12902-018-0258-y

21. Hantson P. Mechanisms of toxic cardiomyopathy. Clin Toxicol (Phila). 2019;57(1):1-9. https://doi.org/10.1080/15563650.2018.1497172

22. Wang P, Xu TY, Guan YF, et al. Vascular smooth muscle cell apoptosis is an early trigger for hypothyroid atherosclerosis. Cardiovasc Res. 2014;102(3):448-459. https://doi.org/10.1093/cvr/cvu056

23. Huang XW, Zhao ZY, Ji C. Effects of hypothyroidism on apoptosis and the expression of Bcl-2 and Bax gene in the neonatal rat hippocampus neurons. Zhonghua Er Ke Za Zhi. 2005;43(1):48-52. In Chinese

24. Singh R, Upadhyay G, Godbole MM. Hypothyroidism alters mitochondrial morphology and induces release of apoptogenic proteins during rat cerebellar development. J Endocrinol. 2003;176(3):321-329. https://doi.org/10.1677/joe.0.1760321

25. Mishra J, Vishwakarma J, Malik R, et al. Hypothyroidism Induces Interleukin-1-Dependent Autophagy Mechanism as a Key Mediator of Hippocampal Neuronal Apoptosis and Cognitive Decline in Postnatal Rats. Mol Neurobiol. 2021;58(3):1196-1211. https://doi.org/10.1007/s12035-020-02178-9

26. Upadhyay G, Singh R, Kumar A, et al. Severe hyperthyroidism induces mitochondria-mediated apoptosis in rat liver. Hepatology. 2004;39(4):1120-1130. https://doi.org/10.1002/hep.20085

27. Yousefzadeh N, Jeddi S, Alipour MR. Effect of Fetal Hypothyroidism on Cardiac Myosin Heavy Chain Expression in Male Rats. Arq Bras Cardiol. 2016;107(2):147-153. https://doi.org/10.5935/abc.20160099

28. Yousefzadeh N, Jeddi S, Ghiasi R, Alipour MR. Effect of fetal hypothyroidism on MyomiR network and its target gene expression profiles in heart of offspring rats. Mol Cell Biochem. 2017;436(1-2):179-187. https://doi.org/10.1007/s11010-017-3089-7

29. Butler-Browne GS, Herlicoviez D, Whalen RG. Effects of hypothyroidism on myosin isozyme transitions in developing rat muscle. FEBS Lett. 1984;166(1):71-75. https://doi.org/10.1016/0014-5793(84)80047-2

30. Rubinstein NA, Lyons GE, Kelly AM. Hormonal control of myosin heavy chain genes during development of skeletal muscles. Ciba Found Symp. 1988;138:35-51. https://doi.org/10.1002/9780470513675.ch4

31. Chen YD, Hoch FL. Mitochondrial inner membrane in hypothyroidism. Arch Biochem Biophys. 1976;172(2):741-744. https://doi.org/10.1016/0003-9861(76)90132-6

32. Paradies G, Ruggiero FM, Dinoi P, et al. Decreased cytochrome oxidase activity and changes in phospholipids in heart mitochondria from hypothyroid rats. Arch Biochem Biophys. 1993;307(1):91-95. https://doi.org/10.1006/abbi.1993.1565

33. Venditti P, De Rosa R, Di Meo S. Effect of thyroid state on susceptibility to oxidants and swelling of mitochondria from rat tissues. Free Radic Biol Med. 2003;35(5):485-494. https://doi.org/10.1016/s0891-5849(03)00331-9

34. Cavallo A, Taurino F, Damiano F, Siculella L, et al. Acute administration of 3,5-diiodo-L-thyronine to hypothyroid rats stimulates bioenergetic parameters in liver mitochondria. J Bioenerg Biomembr. 2016;48(5):521-529. https://doi.org/10.1007/s10863-016-9686-4

35. Delitala AP, Fanciulli G, Maioli M, Delitala G. Subclinical hypothyroidism, lipid metabolism and cardiovascular disease. Eur J Intern Med. 2017;38:17-24. https://doi.org/10.1016/j.ejim.2016.12.015

36. Marrakchi S, Kanoun F, Idriss S, et al. Arrhythmia and thyroid dysfunction. Herz. 2015;40(Suppl 2):101-109. https://doi.org/10.1007/s00059-014-4123-0