TH Treatment in Patients with Cardiac Disorders: General Aspects and Rationale

  • Laura SabatinoEmail author


Thyroid hormones (TH) are the principal modulators of cardiovascular homeostasis in both physiological and pathological conditions, mainly regulating heart rate, cardiac contractility, and vascular resistance, by genomic and non-genomic activities. In the present chapter, are discussed the most important events characterizing the TH regulation of the cardiac muscle at molecular and cellular levels. In particular, are considered the TH reduction observed in some pathological conditions and the switch from beneficial to progressively harmful effects. Moreover, is evaluated the importance of epigenetic modifications related to TH signaling in a cardiac context. Based on these observations, the possible cardiac role of TH and its potential clinical and therapeutical relevance will be discussed.


Thyroid hormones Cardiovascular system Cardiovascular homeostasis Cardiac remodeling Epigenetic 


  1. 1.
    Razvi S, Jabbar A, Pingitore A, Danzi S, Biondi B, Klein I, et al. Thyroid hormones and cardiovascular function and diseases. JACC. 2018;71:1781–96. Scholar
  2. 2.
    Sabatino L, Iervasi G, Pingitore A. Thyroid hormone and heart failure: from myocardial protection to systemic regulation. Expert Rev Cardiovasc Ther. 2014;12:1227–36. Scholar
  3. 3.
    Pantos C, Xinaris C, Mourouzis I, Malliopoulou V, Kardami E, Cokkinos DV. Thyroid hormone changes cardiomyocyte shape and geometry via ERK signaling pathway: potential therapeutic implications in reversing cardiac remodeling? Mol Cell Biochem. 2007;297:65–72. Scholar
  4. 4.
    Pantos C, Mourouzis I, Cokkinos DV. Thyroid hormone as a therapeutic option for treating ischaemic heart disease: from early reperfusion to late remodelling. Vascul Pharmacol. 2010;52(3–4):157–65. Scholar
  5. 5.
    Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev. 2008;29:898–938. Scholar
  6. 6.
    Friesema ECH, Jansen J, Jachtenberg J-W, Visser WE, Kester MHA, Visser TJ. Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10. Mol Endocrinol. 2008;22:1357–69. Scholar
  7. 7.
    Everts ME, Verhoeven FA, Bezstarosti K, Moerings EP, Hennemann G, Visser TJ, et al. Uptake of thyroid hormones in neonatal rat cardiac myocytes. Endocrinology. 1996;137:4235–42. Scholar
  8. 8.
    Sabatino L, Iervasi G, Ferrazzi P, Francesconi D, Chopra IJ. A study of iodothyronine 5′-monodeiodinase activities in normal and pathological tissues in man and their comparison with activities in rat tissues. Life Sci. 2000;68:191–202. Scholar
  9. 9.
    Sabatino L, Chopra IJ, tanavoli S, Iacconi P, Iervasi G. A radioimmunoassay for type I iodothyronine 5′-monodeiodinase in human tissues. Thyroid. 2001;11:733–9. Scholar
  10. 10.
    Wassen FW, Schiel AE, Kuiper GG, Kaptein E, Bakker O, Visser TJ, Simonides WS. Induction of thyroid hormone-degrading deiodinase in cardiac hypertrophy and failure. Endocrinology. 2002;143:2812–5. Scholar
  11. 11.
    Simonides WS, Mulcahey MA, Redout EM, et al. Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats. J Clin Invest. 2008;118:975–83. Scholar
  12. 12.
    Lazar MA. Thyroid hormone action: a binding contract. J Clin Invest. 2003;112:497–9. Scholar
  13. 13.
    Davis PJ, Shih A, Lin H-Y, Martino LJ, Davis FB. Thyroxine promotes Association of mitogen-activated protein kinase and nuclear thyroid hormone receptor (TR) and causes serine phosphorylation of TR. J Biol Chem. 2000;275:38032–9. Scholar
  14. 14.
    Balzan S, Del Carratore R, Nardulli C, Sabatino L, Lubrano V, Iervasi G. The stimulative effect of T3 and T4 on human myocardial endothelial cell proliferation, migration and angiogenesis. J Clin Exp Cardiolog. 2013;4:12. Scholar
  15. 15.
    Sabatino L, Kusmic C, Nicolini G, Amato R, Casini G, Iervasi G, et al. T3 enhances Ang2 in rat aorta in myocardial I/R: comparison with left ventricle. J Mol Endocrinol. 2016;57:139–49. Scholar
  16. 16.
    Pantos C, Mourouzis I, Galanopoulos G, Gavra M, Perimenis P, Spanou D, et al. Thyroid hormone receptor alpha1 downregulation in postischemic heart failure progression: the potential role of tissue hypothyroidism. Horm Metab Res. 2010;42:718–24. Scholar
  17. 17.
    Kinugawa K, Yonekura K, Ribeiro RC, Eto Y, Aoyagi T, Baxter JD, et al. Regulation of thyroid hormone receptor isoforms in physiological and pathological cardiac hypertrophy. Circ Res. 2001;89:591–8.CrossRefGoogle Scholar
  18. 18.
    Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med. 2001;344:501–9. Scholar
  19. 19.
    Marin-Garcia J. Thyroid hormone and myocardial mitochondrial biogenesis. Vascul Pharmacol. 2010;52:120–30. Scholar
  20. 20.
    Ojamaa K, Klemperer JD, Klein I. Acute effects of thyroid hormone on vascular smooth muscle. Thyroid. 1996;6(5):505–12. Scholar
  21. 21.
    Mizuma H, Murakami M, Mori M. Thyroid hormone activation in human vascular smooth muscle cells: expression of type II iodothyronine deiodinase. Circ Res. 2001;88:313–8.CrossRefGoogle Scholar
  22. 22.
    Sabatino L, Lubrano V, Balzan S, Kusmic C, Del Turco S, Iervasi G. Thyroid hormone deiodinases D1, D2, and D3 are expressed in human endothelial dermal microvascular line: effects of thyroid hormones. Mol Cell Biochem. 2015;399:87–94. Scholar
  23. 23.
    Carrillo-Sapulveda MA, Ceravolo GS, Fortes Z, Carvalho MH, Tostes RC, Laurindo FR, et al. Thyroid hormone stimulates NO production via activation of the PI3K/Akt pathway in vascular myocytes. Cardiovasc Res. 2010;3:560–70. Scholar
  24. 24.
    Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L. Low-grade systemic inflammation causes endothelial dysfunction in patients with Hashimoto’s thyroiditis. J Clin Endocrinol Metab. 2006;91:5076–82. Scholar
  25. 25.
    Taddei S, Caraccio N, Virdis A, Dardano A, Versari D, Ghiadoni L. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J Clin Endocrinol Metab. 2003;88:3731–7. Scholar
  26. 26.
    Rajagopalan V, Gerdes AM. Role of thyroid hormones in ventricular remodeling. Curr Heart Fail Rep. 2015;12:141–9. Scholar
  27. 27.
    de Castro AL, Fernandes RO, Ortiz VD, Campos C, Bonetto JH, Fernandes TR, et al. Thyroid hormones improve cardiac function and decrease expression of pro-apoptotic proteins in the heart of rats 14 days after infarction. Apoptosis. 2016;21:184–94. Scholar
  28. 28.
    Kahaly GJ, Dillman WH. Thyroid hormone action in the heart. Endocr Rev. 2005;26:704–28. Scholar
  29. 29.
    Pantos C, Xinaris C, Mourouzis I. Thyroid hormone receptor α1: a switch to cardiac cell “metamorphosis”? J Physiol Pharmacol. 2008;59:253–69. Scholar
  30. 30.
    Kenessey A, Ojamaa K. Thyroid hormone stimulates protein synthesis in the cardiomyocyte by activating the Akt-mTOR and p70S6K pathways. J Biol Chem. 2006;281:20666–72. Scholar
  31. 31.
    Gerdes AM, Iervasi G. Thyroid replacement therapy and heart failure. Circulation. 2010;122:385–93. Scholar
  32. 32.
    Hoshijima M. Mechanical stress-strain sensors embedded in cardiac cytoskeleton: Z disk, titin, and associated structures. Am J Physiol Heart Circ Physiol. 2006;290:H1313–25. Scholar
  33. 33.
    Mayer SC, Gilsbach R, Preissl S, Monroy Ordonez EB, Schnick T, Beetz N, et al. Adrenergic repression of the epigenetic reader MeCP2 facilitates cardiac adaptation in chronic heart failure. Circ Res. 2015;117:622–33. Scholar
  34. 34.
    Gil-Cayuela C, Roselló-LLetía E, Tarazóna E, Ortega A, Sandoval J, Martínez-Dolzh L. Thyroid hormone biosynthesis machinery is altered in the ischemic myocardium: an epigenomic study. Int J Cardiol. 2017;243:27–33. Scholar
  35. 35.
    Janssen R, Muller A, Simonides WS. Cardiac thyroid hormone metabolism and heart failure. Eur Thyroid J. 2017;6:130–7. Scholar
  36. 36.
    Haddad F, Jiang W, Bodell PW, Qin AX, Baldwindoi KM. Cardiac myosin heavy chain gene regulation by thyroid hormone involves altered histone modifications. Am J Physiol Heart Circ Physiol. 2010;299:H1968–80. Scholar
  37. 37.
    Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683–92. Scholar
  38. 38.
    Nagao H, Imazu T, Hayashi H, Takahashi K, Minato K. Influence of thyroidectomy on thyroxine metabolism and turnover rate in rats. J Endocrinol. 2011;210:117–23. Scholar
  39. 39.
    Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in development and physiology: implications for disease and therapy. Nat Rev Genet. 2009;10:32–42. Scholar
  40. 40.
    Clayton AL, Hazzalin CA, Mahadevan LC. Enhanced histone acetylation review and transcription: a dynamic perspective. Mol Cell. 2006;23:289–96. Scholar
  41. 41.
    Catalucci D, Latronico MV, Condorelli G. MicroRNAs control gene expression: importance for cardiac development and pathophysiology. Ann N Y Acad Sci. 2008;1123:20–9. Scholar
  42. 42.
    Janssen R, Zuidwijk MJ, Muller A, van Mil A, Dirkx E, Oudejans CBM, et al. MicroRNA 214 is a potential regulator of thyroid hormone levels in the mouse heart following myocardial infarction, by targeting the thyroid-hormone-inactivating enzyme deiodinase type III. Front Endocrinol. 2016;7:22. Scholar
  43. 43.
    Morkin E. Control of cardiac myosin heavy chain gene expression. Microsc Res Tech. 2000;50:522–31. Scholar
  44. 44.
    Callis TE, Pandya K, Seok HY, Tang RH, Tatsuguchi M, Huang ZP, et al. MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J Clin Invest. 2009;119:2772–86. Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Institute of Clinical Physiology CNRPisaItaly

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