Skip to main content

Advertisement

SpringerLink
Log in

New insights into the role of thyroid hormone in cardiac remodeling: time to reconsider?

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

Chronic ischemia or pressure overload decreases thyroid hormone (TH) signaling and activates the fetal gene program in the heart. While these features are of physiologic importance in the developing heart, their respective roles in the postnatal heart are debated. Administration of TH can prevent the changes of the fetal gene program and rebuild the heart after an “index event” such as ischemia. TH affects cardiac remodeling by limiting reperfusion injury, and, at later states, by inducing distinct changes in cardiac chamber geometry in a time-dependent manner. Furthermore, administration of TH can convert pathologic to physiologic hypertrophy. These effects are the result of favorable cellular remodeling. While preliminary clinical studies provide encouraging results, the potential and efficacy of TH in the treatment of heart disease still await evaluation in large clinical trials.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. Swynghedauw B (1999) Molecular mechanisms of myocardial remodeling. Physiol Rev 79:215–262

    PubMed  CAS  Google Scholar 

  2. Pantos C, Mourouzis I, Saranteas T et al (2005) Thyroid hormone receptors alpha1 and beta1 are downregulated in the post-infarcted rat heart: consequences on the response to ischaemia–reperfusion. Basic Res Cardiol 100:422–432

    PubMed  CAS  Google Scholar 

  3. Pantos C, Mourouzis I, Cokkinos DV (2007) Protection of the abnormal heart. Heart Fail Rev 12:319–330

    PubMed  Google Scholar 

  4. Jopling C, Sleep E, Raya M et al (2010) Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464:606–609

    PubMed  CAS  Google Scholar 

  5. Furlow JD, Yang HY, Hsu M et al (2004) Induction of larval tissue resorption in Xenopus laevis tadpoles by the thyroid hormone receptor agonist GC-1. J Biol Chem 279:26555–26562

    PubMed  CAS  Google Scholar 

  6. Heikkila JJ (2010) Heat shock protein gene expression and function in amphibian model systems. Comp Biochem Physiol A Mol Integr Physiol 156:19–33

    PubMed  Google Scholar 

  7. Morvan-Dubois G, Demeneix BA, Sachs LM (2008) Xenopus laevis as a model for studying thyroid hormone signalling: from development to metamorphosis. Mol Cell Endocrinol 293:71–79

    PubMed  CAS  Google Scholar 

  8. Kress E, Samarut J, Plateroti M (2009) Thyroid hormones and the control of cell proliferation or cell differentiation: paradox or duality? Mol Cell Endocrinol 313:36–49

    PubMed  CAS  Google Scholar 

  9. Mai W, Janier MF, Allioli N et al (2004) Thyroid hormone receptor alpha is a molecular switch of cardiac function between fetal and postnatal life. Proc Natl Acad Sci USA 101:10332–10337

    PubMed  CAS  Google Scholar 

  10. Pantos C, Xinaris C, Mourouzis I et al (2008) Thyroid hormone receptor alpha 1: a switch to cardiac cell “metamorphosis”? J Physiol Pharmacol 59:253–269

    PubMed  CAS  Google Scholar 

  11. De Groot LJ (1999) Dangerous dogmas in medicine: the nonthyroidal illness syndrome. J Clin Endocrinol Metab 84:151–164

    PubMed  Google Scholar 

  12. Hennemann G (2005) Notes on the history of cellular uptake and deiodination of thyroid hormone. Thyroid 15:753–756

    PubMed  CAS  Google Scholar 

  13. Bianco AC, Salvatore D, Gereben B et al (2002) Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev 23:38–89

    PubMed  CAS  Google Scholar 

  14. Bianco AC, Kim BW (2006) Deiodinases: implications of the local control of thyroid hormone action. J Clin Invest 116:2571–2579

    PubMed  CAS  Google Scholar 

  15. Lanni A, Moreno M, Lombardi A et al (2005) 3,5-Diiodo-l-thyronine powerfully reduces adiposity in rats by increasing the burning of fats. FASEB J 19:1552–1554

    PubMed  CAS  Google Scholar 

  16. Scanlan TS, Suchland KL, Hart ME et al (2004) 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat Med 10:638–642

    PubMed  CAS  Google Scholar 

  17. Nicoll JB, Gwinn BL, Iwig JS et al (2003) Compartment-specific phosphorylation of rat thyroid hormone receptor alpha1 regulates nuclear localization and retention. Mol Cell Endocrinol 205:65–77

    PubMed  CAS  Google Scholar 

  18. Kinugawa K, Yonekura K, Ribeiro RC et al (2001) Regulation of thyroid hormone receptor isoforms in physiological and pathological cardiac hypertrophy. Circ Res 89:591–598

    PubMed  CAS  Google Scholar 

  19. Flamant F, Samarut J (2003) Thyroid hormone receptors: lessons from knockout and knock-in mutant mice. Trends Endocrinol Metab 14:85–90

    PubMed  CAS  Google Scholar 

  20. Kinugawa K, Jeong MY, Bristow MR et al (2005) Thyroid hormone induces cardiac myocyte hypertrophy in a thyroid hormone receptor alpha1-specific manner that requires TAK1 and p38 mitogen-activated protein kinase. Mol Endocrinol 19:1618–1628

    PubMed  CAS  Google Scholar 

  21. Pantos C, Mourouzis I, Malliopoulou V et al (2005) Dronedarone administration prevents body weight gain and increases tolerance of the heart to ischemic stress: a possible involvement of thyroid hormone receptor alpha1. Thyroid 15:16–23

    PubMed  CAS  Google Scholar 

  22. Pantos C, Mourouzis I, Paizis I et al (2007) Pharmacological inhibition of TRalpha1 receptor potentiates the thyroxine effect on body weight reduction in rats: potential therapeutic implications in controlling body weight. Diabetes Obes Metab 9:136–138

    PubMed  CAS  Google Scholar 

  23. Gullberg H, Rudling M, Salto C et al (2002) Requirement for thyroid hormone receptor beta in T3 regulation of cholesterol metabolism in mice. Mol Endocrinol 16:1767–1777

    PubMed  CAS  Google Scholar 

  24. Forrest D, Hanebuth E, Smeyne RJ et al (1996) Recessive resistance to thyroid hormone in mice lacking thyroid hormone receptor beta: evidence for tissue-specific modulation of receptor function. EMBO J 15:3006–3015

    PubMed  CAS  Google Scholar 

  25. Tavi P, Sjogren M, Lunde PK et al (2005) Impaired Ca2+ handling and contraction in cardiomyocytes from mice with a dominant negative thyroid hormone receptor alpha1. J Mol Cell Cardiol 38:655–663

    PubMed  CAS  Google Scholar 

  26. Luidens MK, Mousa SA, Davis FB et al (2010) Thyroid hormone and angiogenesis. Vascul Pharmacol 52:142–145

    PubMed  CAS  Google Scholar 

  27. Wikstrom L, Johansson C, Salto C et al (1998) Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. EMBO J 17:455–461

    PubMed  CAS  Google Scholar 

  28. Venero C, Guadano-Ferraz A, Herrero AI et al (2005) Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor alpha1 can be ameliorated by T3 treatment. Genes Dev 19:2152–2163

    PubMed  CAS  Google Scholar 

  29. Kress E, Rezza A, Nadjar J et al (2008) The thyroid hormone receptor-alpha (TRalpha) gene encoding TRalpha1 controls deoxyribonucleic acid damage-induced tissue repair. Mol Endocrinol 22:47–55

    PubMed  CAS  Google Scholar 

  30. Belakavadi M, Saunders J, Weisleder N et al (2010) Repression of cardiac phospholamban gene expression is mediated by thyroid hormone receptor-{alpha}1 and involves targeted covalent histone modifications. Endocrinology 151:2946–2956

    PubMed  CAS  Google Scholar 

  31. Esaki T, Suzuki H, Cook M et al (2004) Cardiac glucose utilization in mice with mutated alpha- and beta-thyroid hormone receptors. Am J Physiol Endocrinol Metab 287:E1149–E1153

    PubMed  CAS  Google Scholar 

  32. White P, Burton KA, Fowden AL et al (2001) Developmental expression analysis of thyroid hormone receptor isoforms reveals new insights into their essential functions in cardiac and skeletal muscles. FASEB J 15:1367–1376

    PubMed  CAS  Google Scholar 

  33. Chassande O (2003) Do unliganded thyroid hormone receptors have physiological functions? J Mol Endocrinol 31:9–20

    PubMed  CAS  Google Scholar 

  34. Li Q, Sachs L, Shi YB et al (1999) Modification of chromatin structure by the thyroid hormone receptor. Trends Endocrinol Metab 10:157–164

    PubMed  CAS  Google Scholar 

  35. Zhang J, Lazar MA (2000) The mechanism of action of thyroid hormones. Annu Rev Physiol 62:439–466

    PubMed  CAS  Google Scholar 

  36. Flamant F, Poguet AL, Plateroti M et al (2002) Congenital hypothyroid Pax8(−/−) mutant mice can be rescued by inactivating the TRalpha gene. Mol Endocrinol 16:24–32

    PubMed  CAS  Google Scholar 

  37. Morte B, Manzano J, Scanlan T et al (2002) Deletion of the thyroid hormone receptor alpha 1 prevents the structural alterations of the cerebellum induced by hypothyroidism. Proc Natl Acad Sci USA 99:3985–3989

    PubMed  CAS  Google Scholar 

  38. Kaneshige M, Suzuki H, Kaneshige K et al (2001) A targeted dominant negative mutation of the thyroid hormone alpha 1 receptor causes increased mortality, infertility, and dwarfism in mice. Proc Natl Acad Sci USA 98:15095–15100

    PubMed  CAS  Google Scholar 

  39. Tinnikov A, Nordstrom K, Thoren P et al (2002) Retardation of post-natal development caused by a negatively acting thyroid hormone receptor alpha1. EMBO J 21:5079–5087

    PubMed  CAS  Google Scholar 

  40. Cody V, Davis PJ, Davis FB (2007) Molecular modeling of the thyroid hormone interactions with alpha v beta 3 integrin. Steroids 72:165–170

    PubMed  CAS  Google Scholar 

  41. Hiroi Y, Kim HH, Ying H et al (2006) Rapid nongenomic actions of thyroid hormone. Proc Natl Acad Sci USA 103:14104–14109

    PubMed  CAS  Google Scholar 

  42. Alpert NR, Brosseau C, Federico A et al (2002) Molecular mechanics of mouse cardiac myosin isoforms. Am J Physiol Heart Circ Physiol 283:H1446–H1454

    PubMed  CAS  Google Scholar 

  43. Pantos C, Mourouzis I, Xinaris C et al (2008) Thyroid hormone and “cardiac metamorphosis”: potential therapeutic implications. Pharmacol Ther 118:277–294

    PubMed  CAS  Google Scholar 

  44. Pantos C, Xinaris C, Mourouzis I et al (2008) TNF-alpha administration in neonatal cardiomyocytes is associated with differential expression of thyroid hormone receptors: a response prevented by T3. Horm Metab Res 40:731–734

    PubMed  CAS  Google Scholar 

  45. Simonides WS, Mulcahey MA, Redout EM et al (2008) Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats. J Clin Invest 118:975–983

    PubMed  CAS  Google Scholar 

  46. Ojamaa K, Kenessey A, Shenoy R et al (2000) Thyroid hormone metabolism and cardiac gene expression after acute myocardial infarction in the rat. Am J Physiol Endocrinol Metab 279:E1319–E1324

    PubMed  CAS  Google Scholar 

  47. Olivares EL, Marassi MP, Fortunato RS et al (2007) Thyroid function disturbance and type 3 iodothyronine deiodinase induction after myocardial infarction in rats a time course study. Endocrinology 148:4786–4792

    PubMed  CAS  Google Scholar 

  48. Pol CJ, van Deel ED, Muller A et al (2008) Left ventricular myocardial infarction in mice induces sustained cardiac deiodinase type III activity. J Mol Cell Cardiol 44:722–723

    Google Scholar 

  49. Wassen FW, Schiel AE, Kuiper GG et al (2002) Induction of thyroid hormone-degrading deiodinase in cardiac hypertrophy and failure. Endocrinology 143:2812–2815

    PubMed  CAS  Google Scholar 

  50. Pantos C, Mourouzis I, Xinaris C et al (2007) Time-dependent changes in the expression of thyroid hormone receptor {alpha}1 in the myocardium after acute myocardial infarction: possible implications in cardiac remodelling. Eur J Endocrinol 156:415–424

    PubMed  CAS  Google Scholar 

  51. Pantos C, Mourouzis I, Galanopoulos G et al (2010) Thyroid hormone receptor α1 down-regulation in postischemic heart failure progression: the potential role of tissue hypothyroidism. Horm Metab Res (in press). doi:10.1055/s-0030-1255035

  52. Pantos C, Malliopoulou V, Mourouzis I et al (2003) Propylthiouracil-induced hypothyroidism is associated with increased tolerance of the isolated rat heart to ischaemia–reperfusion. J Endocrinol 178:427–435

    PubMed  CAS  Google Scholar 

  53. Mourouzis I, Dimopoulos A, Saranteas T et al (2009) Ischemic preconditioning fails to confer additional protection against ischemia-reperfusion injury in the hypothyroid rat heart. Physiol Res 58:29–38

    PubMed  CAS  Google Scholar 

  54. Pantos C, Mourouzis I, Tsagoulis N et al (2009) Thyroid hormone at supra-physiological dose optimizes cardiac geometry and improves cardiac function in rats with old myocardial infarction. J Physiol Pharmacol 60:49–56

    PubMed  CAS  Google Scholar 

  55. Kalofoutis C, Galanopoulos G, Mourouzis I et al (2010) Post-ischemic cardiac remodeling is accelerated in diabetic rats due to tissue hypothyroidism. Journal of Molecular and Cellular Cardiology 48:S133 (abstract)

    Google Scholar 

  56. Trivieri MG, Oudit GY, Sah R et al (2006) Cardiac-specific elevations in thyroid hormone enhance contractility and prevent pressure overload-induced cardiac dysfunction. Proc Natl Acad Sci USA 103:6043–6048

    PubMed  CAS  Google Scholar 

  57. Belke DD, Gloss B, Swanson EA et al (2007) Adeno-associated virus-mediated expression of thyroid hormone receptor isoforms-alpha1 and -beta1 improves contractile function in pressure overload-induced cardiac hypertrophy. Endocrinology 148:2870–2877

    PubMed  CAS  Google Scholar 

  58. Khalife WI, Tang YD, Kuzman JA et al (2005) Treatment of subclinical hypothyroidism reverses ischemia and prevents myocyte loss and progressive LV dysfunction in hamsters with dilated cardiomyopathy. Am J Physiol Heart Circ Physiol 289:H2409–H2415

    PubMed  CAS  Google Scholar 

  59. Ferrari R (1999) The role of TNF in cardiovascular disease. Pharmacol Res 40:97–105

    PubMed  CAS  Google Scholar 

  60. Chung ES, Packer M, Lo KH et al (2003) Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF therapy against congestive heart failure (ATTACH) trial. Circulation 107:3133–3140

    Google Scholar 

  61. Shannon R, Chaudhry M (2006) Effect of alpha1-adrenergic receptors in cardiac pathophysiology. Am Heart J 152:842–850

    PubMed  CAS  Google Scholar 

  62. Xiao L, Pimental DR, Amin JK et al (2001) MEK1/2-ERK1/2 mediates alpha1-adrenergic receptor-stimulated hypertrophy in adult rat ventricular myocytes. J Mol Cell Cardiol 33:779–787

    PubMed  CAS  Google Scholar 

  63. Barron AJ, Finn SG, Fuller SJ (2003) Chronic activation of extracellular-signal-regulated protein kinases by phenylephrine is required to elicit a hypertrophic response in cardiac myocytes. Biochem J 371:71–79

    PubMed  CAS  Google Scholar 

  64. Proud CG (2004) Ras, PI3-kinase and mTOR signaling in cardiac hypertrophy. Cardiovasc Res 63:403–413

    PubMed  CAS  Google Scholar 

  65. Dorn GW II, Force T (2005) Protein kinase cascades in the regulation of cardiac hypertrophy. J Clin Invest 115:527–537

    PubMed  CAS  Google Scholar 

  66. Miki T, Miura T, Tanno M et al (2007) Impairment of cardioprotective PI3K-Akt signaling by post-infarct ventricular remodeling is compensated by an ERK-mediated pathway. Basic Res Cardiol 102:163–170

    PubMed  CAS  Google Scholar 

  67. Kehat I, Molkentin JD (2010) Extracellular signal-regulated kinase 1/2 (ERK1/2) signaling in cardiac hypertrophy. Ann N Y Acad Sci 1188:96–102

    PubMed  CAS  Google Scholar 

  68. Weigel NL (1996) Steroid hormone receptors and their regulation by phosphorylation. Biochem J 319(Pt 3):657–667

    PubMed  CAS  Google Scholar 

  69. Pantos C, Mourouzis I, Markakis K et al (2008) Long-term thyroid hormone administration reshapes left ventricular chamber and improves cardiac function after myocardial infarction in rats. Basic Res Cardiol 103:308–318

    PubMed  CAS  Google Scholar 

  70. Frost RJ, van Rooij E (2010) miRNAs as therapeutic targets in ischemic heart disease. J Cardiovasc Transl Res 3:280–289

    PubMed  Google Scholar 

  71. van Rooij E, Sutherland LB, Qi X et al (2007) Control of stress-dependent cardiac growth and gene expression by a microRNA. Science 316:575–579

    PubMed  Google Scholar 

  72. Callis TE, Pandya K, Seok HY et al (2009) MicroRNA-208a is a regulator of cardiac hypertrophy and conduction in mice. J Clin Invest 119:2772–2786

    PubMed  CAS  Google Scholar 

  73. Pantos C, Mourouzis I, Markakis K et al (2007) Thyroid hormone attenuates cardiac remodeling and improves hemodynamics early after acute myocardial infarction in rats. Eur J Cardiothorac Surg 32:333–339

    PubMed  Google Scholar 

  74. Hambleton M, Hahn H, Pleger ST et al (2006) Pharmacological- and gene therapy-based inhibition of protein kinase C alpha/beta enhances cardiac contractility and attenuates heart failure. Circulation 114:574–582

    PubMed  CAS  Google Scholar 

  75. Scruggs SB, Walker LA, Lyu T et al (2006) Partial replacement of cardiac troponin I with a non-phosphorylatable mutant at serines 43/45 attenuates the contractile dysfunction associated with PKCepsilon phosphorylation. J Mol Cell Cardiol 40:465–473

    PubMed  CAS  Google Scholar 

  76. Kim YK, Suarez J, Hu Y et al (2006) Deletion of the inducible 70-kDa heat shock protein genes in mice impairs cardiac contractile function and calcium handling associated with hypertrophy. Circulation 113:2589–2597

    PubMed  CAS  Google Scholar 

  77. Lembcke A, Dushe S, Dohmen PM et al (2006) Early and late effects of passive epicardial constraint on left ventricular geometry: ellipsoidal re-shaping confirmed by electron-beam computed tomography. J Heart Lung Transplant 25:90–98

    PubMed  Google Scholar 

  78. Pantos C, Xinaris C, Mourouzis I et al (2007) Thyroid hormone changes cardiomyocyte shape and geometry via ERK signaling pathway: potential therapeutic implications in reversing cardiac remodeling? Mol Cell Biochem 297:65–72

    PubMed  CAS  Google Scholar 

  79. Kenessey A, Ojamaa K (2006) Thyroid hormone stimulates protein synthesis in the cardiomyocyte by activating the Akt-mTOR and p70S6K pathways. J Biol Chem 281:20666–20672

    PubMed  CAS  Google Scholar 

  80. Ziegelhoffer-Mihalovicova B, Briest W, Baba HA et al (2003) The expression of mRNA of cytokines and of extracellular matrix proteins in triiodothyronine-treated rat hearts. Mol Cell Biochem 247:61–68

    PubMed  Google Scholar 

  81. Yao J, Eghbali M (1992) Decreased collagen gene expression and absence of fibrosis in thyroid hormone-induced myocardial hypertrophy. Response of cardiac fibroblasts to thyroid hormone in vitro. Circ Res 71:831–839

    PubMed  CAS  Google Scholar 

  82. Wong K, Boheler KR, Petrou M et al (1997) Pharmacological modulation of pressure-overload cardiac hypertrophy: changes in ventricular function, extracellular matrix, and gene expression. Circulation 96:2239–2246

    PubMed  CAS  Google Scholar 

  83. Wang X, Zheng W, Christensen LP et al (2003) DITPA stimulates bFGF, VEGF, angiopoietin, and Tie-2 and facilitates coronary arteriolar growth. Am J Physiol Heart Circ Physiol 284:H613–H618

    PubMed  CAS  Google Scholar 

  84. Bergh JJ, Lin HY, Lansing L et al (2005) Integrin alphaVbeta3 contains a cell surface receptor site for thyroid hormone that is linked to activation of mitogen-activated protein kinase and induction of angiogenesis. Endocrinology 146:2864–2871

    PubMed  CAS  Google Scholar 

  85. Mousa SA, O’Connor L, Davis FB et al (2006) Proangiogenesis action of the thyroid hormone analog 3,5-diiodothyropropionic acid (DITPA) is initiated at the cell surface and is integrin mediated. Endocrinology 147:1602–1607

    PubMed  CAS  Google Scholar 

  86. Mousa SA, Davis FB, Mohamed S et al (2006) Pro-angiogenesis action of thyroid hormone and analogs in a three-dimensional in vitro microvascular endothelial sprouting model. Int Angiol 25:407–413

    PubMed  CAS  Google Scholar 

  87. Mousa SA, O’Connor LJ, Bergh JJ et al (2005) The proangiogenic action of thyroid hormone analogue GC-1 is initiated at an integrin. J Cardiovasc Pharmacol 46:356–360

    PubMed  CAS  Google Scholar 

  88. Makino A, Suarez J, Wang H et al (2009) Thyroid hormone receptor-beta is associated with coronary angiogenesis during pathological cardiac hypertrophy. Endocrinology 150:2008–2015

    PubMed  CAS  Google Scholar 

  89. Sirlak M, Yazicioglu L, Inan MB et al (2004) Oral thyroid hormone pretreatment in left ventricular dysfunction. Eur J Cardiothorac Surg 26:720–725

    PubMed  Google Scholar 

  90. Pantos CI, Tzilalis V, Giannakakis S et al (2001) Phenylephrine induced aortic vasoconstriction is attenuated in hyperthyroid rats. Int Angiol 20:181–186

    PubMed  CAS  Google Scholar 

  91. Pappas M, Mourouzis K, Karageorgiou H et al (2009) Thyroid hormone modulates the responsiveness of rat aorta to a1-adrenergic stimulation: an effect due to increased activation of b2-adrenergic signaling. Int Angiol 28:474–478

    PubMed  CAS  Google Scholar 

  92. Pantos C, Mourouzis I, Cokkinos DV (2006) Myocardial ischemia: basic concepts. In: Cokkinos DV, Pantos C, Heusch G, Taegtmeyer H (eds) Myocardial ischemia: from mechanisms to therapeutic potentials. Springer, New York, pp 11–77

    Google Scholar 

  93. Skyschally A, van Caster P, Iliodromitis EK et al (2009) Ischemic postconditioning: experimental models and protocol algorithms. Basic Res Cardiol 104:469–483

    PubMed  Google Scholar 

  94. Heusch G, Boengler K, Schulz R (2010) Inhibition of mitochondrial permeability transition pore opening: the Holy Grail of cardioprotection. Basic Res Cardiol 105:151–154

    PubMed  Google Scholar 

  95. Ovize M, Baxter GF, Di Lisa F et al (2010) Postconditioning and protection from reperfusion injury: where do we stand?: position paper from the working group of cellular biology of the heart of the european society of cardiology. Cardiovasc Res. doi:10.1093/cvr/cvq1129

  96. Klemperer JD, Zelano J, Helm RE et al (1995) Triiodothyronine improves left ventricular function without oxygen wasting effects after global hypothermic ischemia. J Thorac Cardiovasc Surg 109:457–465

    PubMed  CAS  Google Scholar 

  97. Walker JD, Crawford FA Jr, Spinale FG (1995) 3,5,3′ Triiodo-l-thyronine pretreatment with cardioplegic arrest and chronic left ventricular dysfunction. Ann Thorac Surg 60:292–299

    PubMed  CAS  Google Scholar 

  98. Liu Q, Clanachan AS, Lopaschuk GD (1998) Acute effects of triiodothyronine on glucose and fatty acid metabolism during reperfusion of ischemic rat hearts. Am J Physiol 275:E392–E399

    PubMed  CAS  Google Scholar 

  99. Spinale FG (1999) Cellular and molecular therapeutic targets for treatment of contractile dysfunction after cardioplegic arrest. Ann Thorac Surg 68:1934–1941

    PubMed  CAS  Google Scholar 

  100. Zinman T, Shneyvays V, Tribulova N et al (2006) Acute, nongenomic effect of thyroid hormones in preventing calcium overload in newborn rat cardiocytes. J Cell Physiol 207:220–231

    PubMed  CAS  Google Scholar 

  101. Buser PT, Wikman-Coffelt J, Wu ST et al (1990) Postischemic recovery of mechanical performance and energy metabolism in the presence of left ventricular hypertrophy. A 31P-MRS study. Circ Res 66:735–746

    PubMed  CAS  Google Scholar 

  102. Pantos CI, Malliopoulou VA, Mourouzis IS et al (2001) Long-term thyroxine administration increases heat stress protein-70 mRNA expression and attenuates p38 MAP kinase activity in response to ischaemia. J Endocrinol 170:207–215

    PubMed  CAS  Google Scholar 

  103. Pantos CI, Malliopoulou VA, Mourouzis IS et al (2002) Long-term thyroxine administration protects the heart in a pattern similar to ischemic preconditioning. Thyroid 12:325–329

    PubMed  CAS  Google Scholar 

  104. Pantos C, Malliopoulou V, Mourouzis I et al (2003) Thyroxine pretreatment increases basal myocardial heat-shock protein 27 expression and accelerates translocation and phosphorylation of this protein upon ischaemia. Eur J Pharmacol 478:53–60

    PubMed  CAS  Google Scholar 

  105. Pantos C, Malliopoulou V, Mourouzis I et al (2003) Involvement of p38 MAPK and JNK in heat stress-induced cardioprotection. Basic Res Cardiol 98:158–164

    PubMed  CAS  Google Scholar 

  106. Kuzman JA, Gerdes AM, Kobayashi S et al (2005) Thyroid hormone activates Akt and prevents serum starvation-induced cell death in neonatal rat cardiomyocytes. J Mol Cell Cardiol 39:841–844

    PubMed  CAS  Google Scholar 

  107. Pantos C, Malliopoulou V, Mourouzis I et al (2006) Hyperthyroid hearts display a phenotype of cardioprotection against ischemic stress: a possible involvement of heat shock protein 70. Horm Metab Res 38:308–313

    PubMed  CAS  Google Scholar 

  108. Pantos CI, Mourouzis IS, Tzeis SM et al (2000) Propranolol diminishes cardiac hypertrophy but does not abolish acceleration of the ischemic contracture in hyperthyroid hearts. J Cardiovasc Pharmacol 36:384–389

    PubMed  CAS  Google Scholar 

  109. Pantos CI, Cokkinos DD, Tzeis SM et al (1999) Hyperthyroidism is associated with preserved preconditioning capacity but intensified and accelerated ischaemic contracture in rat heart. Basic Res Cardiol 94:254–260

    PubMed  CAS  Google Scholar 

  110. Pantos C, Paizis I, Mourouzis I et al (2005) Blockade of angiotensin II type 1 receptor diminishes cardiac hypertrophy, but does not abolish thyroxin-induced preconditioning. Horm Metab Res 37:500–504

    PubMed  CAS  Google Scholar 

  111. Speechly-Dick ME, Mocanu MM, Yellon DM (1994) Protein kinase C. Its role in ischemic preconditioning in the rat. Circ Res 75:586–590

    PubMed  CAS  Google Scholar 

  112. Zhao J, Renner O, Wightman L et al (1998) The expression of constitutively active isotypes of protein kinase C to investigate preconditioning. J Biol Chem 273:23072–23079

    PubMed  CAS  Google Scholar 

  113. Maizels ET, Peters CA, Kline M et al (1998) Heat-shock protein-25/27 phosphorylation by the delta isoform of protein kinase C. Biochem J 332(Pt 3):703–712

    PubMed  CAS  Google Scholar 

  114. Pantos C, Malliopoulou V, Paizis I et al (2003) Thyroid hormone and cardioprotection: study of p38 MAPK and JNKs during ischaemia and at reperfusion in isolated rat heart. Mol Cell Biochem 242:173–180

    PubMed  CAS  Google Scholar 

  115. Martin JL, Mestril R, Hilal-Dandan R et al (1997) Small heat shock proteins and protection against ischemic injury in cardiac myocytes. Circulation 96:4343–4348

    PubMed  CAS  Google Scholar 

  116. Venditti P, Di Meo S (2006) Thyroid hormone-induced oxidative stress. Cell Mol Life Sci 63:414–434

    PubMed  CAS  Google Scholar 

  117. Downey JM, Davis AM, Cohen MV (2007) Signaling pathways in ischemic preconditioning. Heart Fail Rev 12:181–188

    PubMed  CAS  Google Scholar 

  118. Novitzky D, Cooper DK, Swanepoel A (1989) Inotropic effect of triiodothyronine (T3) in low cardiac output following cardioplegic arrest and cardiopulmonary bypass: an initial experience in patients undergoing open heart surgery. Eur J Cardiothorac Surg 3:140–145

    PubMed  CAS  Google Scholar 

  119. Dyke CM, Yeh T Jr, Lehman JD et al (1991) Triiodothyronine-enhanced left ventricular function after ischemic injury. Ann Thorac Surg 52:14–19

    PubMed  CAS  Google Scholar 

  120. Novitzky D, Matthews N, Shawley D et al (1991) Triiodothyronine in the recovery of stunned myocardium in dogs. Ann Thorac Surg 51:10–16; discussion 16–17

    Google Scholar 

  121. Holland FW II, Brown PS Jr, Clark RE (1992) Acute severe postischemic myocardial depression reversed by triiodothyronine. Ann Thorac Surg 54:301–305

    PubMed  Google Scholar 

  122. Dyke CM, Ding M, Abd-Elfattah AS et al (1993) Effects of triiodothyronine supplementation after myocardial ischemia. Ann Thorac Surg 56:215–222

    PubMed  CAS  Google Scholar 

  123. Kadletz M, Mullen PG, Ding M et al (1994) Effect of triiodothyronine on postischemic myocardial function in the isolated heart. Ann Thorac Surg 57:657–662

    PubMed  CAS  Google Scholar 

  124. Klemperer JD, Klein I, Gomez M et al (1995) Thyroid hormone treatment after coronary-artery bypass surgery. N Engl J Med 333:1522–1527

    PubMed  CAS  Google Scholar 

  125. Ranasinghe AM, Quinn DW, Pagano D et al (2006) Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting. Circulation 114:I245–I250

    PubMed  Google Scholar 

  126. Pantos C, Mourouzis I, Tzeis S et al (2003) Dobutamine administration exacerbates postischaemic myocardial dysfunction in isolated rat hearts: an effect reversed by thyroxine pretreatment. Eur J Pharmacol 460:155–161

    PubMed  CAS  Google Scholar 

  127. Chen YF, Kobayashi S, Chen J et al (2008) Short term triiodo-l-thyronine treatment inhibits cardiac myocyte apoptosis in border area after myocardial infarction in rats. J Mol Cell Cardiol 44:180–187

    PubMed  CAS  Google Scholar 

  128. Forini F, Lionetti V, Ardehali H et al (2010) Early long-term L-T3 replacement rescues mitochondria and prevents ischemic cardiac remodeling in rats. J Cell Mol Med (in press). doi:10.1111/j.1582-4934.2010.01014

  129. Marin-Garcia J (2010) Thyroid hormone and myocardial mitochondrial biogenesis. Vascul Pharmacol 52:120–130

    PubMed  CAS  Google Scholar 

  130. Chang KC, Figueredo VM, Schreur JH et al (1997) Thyroid hormone improves function and Ca2+ handling in pressure overload hypertrophy. Association with increased sarcoplasmic reticulum Ca2+-ATPase and alpha-myosin heavy chain in rat hearts. J Clin Invest 100:1742–1749

    Google Scholar 

  131. Thomas TA, Kuzman JA, Anderson BE et al (2005) Thyroid hormones induce unique and potentially beneficial changes in cardiac myocyte shape in hypertensive rats near heart failure. Am J Physiol Heart Circ Physiol 288:H2118–H2122

    PubMed  CAS  Google Scholar 

  132. Ito K, Kagaya Y, Shimokawa H (2010) Thyroid hormone and chronically unloaded hearts. Vascul Pharmacol 52:138–141

    PubMed  CAS  Google Scholar 

  133. Minatoya Y, Ito K, Kagaya Y et al (2007) Depressed contractile reserve and impaired calcium handling of cardiac myocytes from chronically unloaded hearts are ameliorated with the administration of physiological treatment dose of T3 in rats. Acta Physiol (Oxf) 189:221–231

    CAS  Google Scholar 

  134. Klein I, Ojamaa K (2001) Thyroid hormone-targeting the heart. Endocrinology 142:11–12

    PubMed  CAS  Google Scholar 

  135. Abo-Zenah HA, Shoeb SA, Sabry AA et al (2008) Relating circulating thyroid hormone concentrations to serum interleukins-6 and 10 in association with non-thyroidal illnesses including chronic renal insufficiency. BMC Endocr Disord 8:1–7

    PubMed  Google Scholar 

  136. Kimura T, Kanda T, Kotajima N et al (2000) Involvement of circulating interleukin-6 and its receptor in the development of euthyroid sick syndrome in patients with acute myocardial infarction. Eur J Endocrinol 143:179–184

    PubMed  CAS  Google Scholar 

  137. Eber B, Schumacher M, Langsteger W et al (1995) Changes in thyroid hormone parameters after acute myocardial infarction. Cardiology 86:152–156

    PubMed  CAS  Google Scholar 

  138. Holland FW II, Brown PS Jr, Weintraub BD et al (1991) Cardiopulmonary bypass and thyroid function: a “euthyroid sick syndrome”. Ann Thorac Surg 52:46–50

    PubMed  Google Scholar 

  139. Friberg L, Werner S, Eggertsen G et al (2002) Rapid down-regulation of thyroid hormones in acute myocardial infarction: is it cardioprotective in patients with angina? Arch Intern Med 162:1388–1394

    PubMed  CAS  Google Scholar 

  140. Iervasi G, Pingitore A, Landi P et al (2003) Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation 107:708–713

    PubMed  Google Scholar 

  141. Pingitore A, Iervasi G, Barison A et al (2006) Early activation of an altered thyroid hormone profile in asymptomatic or mildly symptomatic idiopathic left ventricular dysfunction. J Card Fail 12:520–526

    PubMed  CAS  Google Scholar 

  142. Pantos C, Dritsas A, Mourouzis I et al (2007) Thyroid hormone is a critical determinant of myocardial performance in patients with heart failure: potential therapeutic implications. Eur J Endocrinol 157:515–520

    PubMed  CAS  Google Scholar 

  143. Moruzzi P, Doria E, Agostoni PG et al (1994) Usefulness of l-thyroxine to improve cardiac and exercise performance in idiopathic dilated cardiomyopathy. Am J Cardiol 73:374–378

    PubMed  CAS  Google Scholar 

  144. Moruzzi P, Doria E, Agostoni PG (1996) Medium-term effectiveness of l-thyroxine treatment in idiopathic dilated cardiomyopathy. Am J Med 101:461–467

    PubMed  CAS  Google Scholar 

  145. Pingitore A, Galli E, Barison A et al (2008) 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 93:1351–1358

    PubMed  CAS  Google Scholar 

  146. Liu Z, Wu J, Zhang YY et al (2009) Therapeutic effect of low-dose thyroxin in elderly patients with refractory heart failure and euthyroid sick syndrome. Nan Fang Yi Ke Da Xue Xue Bao 29:1848–1850

    PubMed  CAS  Google Scholar 

  147. Goldman S, McCarren M, Morkin E et al (2009) DITPA (3,5-diiodothyropropionic acid), a thyroid hormone analog to treat heart failure: phase II trial veterans affairs cooperative study. Circulation 119:3093–3100

    PubMed  CAS  Google Scholar 

  148. Pantos C, Mourouzis I, Saranteas T et al (2009) Thyroid hormone improves postischaemic recovery of function while limiting apoptosis: a new therapeutic approach to support hemodynamics in the setting of ischaemia–reperfusion? Basic Res Cardiol 104:69–77

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank the S. Niarchos Foundation for support.

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Athens, 75 Mikras Asias Ave., 11527, Goudi, Athens, Greece

    Constantinos Pantos & Iordanis Mourouzis

  2. Onassis Cardiac Surgery Center, 356 Sygrou Ave., 17674, Kallithea, Athens, Greece

    Dennis V. Cokkinos

  3. Biomedical Research Foundation, Academy of Athens, Athens, Greece

    Dennis V. Cokkinos

Authors
  1. Constantinos Pantos
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Iordanis Mourouzis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dennis V. Cokkinos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Constantinos Pantos.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pantos, C., Mourouzis, I. & Cokkinos, D.V. New insights into the role of thyroid hormone in cardiac remodeling: time to reconsider?. Heart Fail Rev 16, 79–96 (2011). https://doi.org/10.1007/s10741-010-9185-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10741-010-9185-3

Keywords

Search

Navigation