Skip to main content
SpringerLink
Log in

Rebuilding the post-infarcted myocardium by activating ‘physiologic’ hypertrophic signaling pathways: the thyroid hormone paradigm

  • Published:
Heart Failure Reviews Aims and scope Submit manuscript

Abstract

Viable myocardium undergoes several changes in the course of cardiac remodeling following myocardial infarction aiming to adapt the heart to the hemodynamic compromise. This response is characterized by reactivation of the fetal transcriptional program and results in cardiac dysfunction. Changes in thyroid hormone (TH)-TH receptors (TRs) axis occur in the course of post-infarction cardiac remodeling and seem to contribute to cardiac fetal phenotype. TH can “rebuild” the post-infarcted heart by preventing the fetal-like pattern of contractile proteins expression, normalizing wall tension, and optimizing cardiac chamber geometry. This effect seems to be attributed to TH pleiotropic cellular actions; TH promotes tissue growth and differentiation and favorably remodels cardiac cell while increases cellular survival upon stress. TH may constitute a new therapeutic option for mending the ischemic myocardium.

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

Similar content being viewed by others

References

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

    CAS  PubMed  Google Scholar 

  2. Rajabi M, Kassiotis C, Razeghi P et al (2007) Return to the fetal gene program protects the stressed heart: a strong hypothesis. Heart Fail Rev 12:331–343. doi:10.1007/s10741-007-9034-1

    Article  CAS  PubMed  Google Scholar 

  3. Pantos C, Mourouzis I, Xinaris C et al (2008) Thyroid hormone and “cardiac metamorphosis”: potential therapeutic implications. Pharmacol Ther 118:277–294. doi:10.1016/j.pharmthera.2008.02.011

    Article  CAS  PubMed  Google Scholar 

  4. 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

    CAS  PubMed  Google Scholar 

  5. 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. doi:10.1210/en.2007-0043

    Article  CAS  PubMed  Google Scholar 

  6. 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. doi:10.1007/s00395-005-0545-4

    Article  CAS  PubMed  Google Scholar 

  7. 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. doi:10.1530/EJE-06-0707

    Article  CAS  PubMed  Google Scholar 

  8. 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. doi:10.1096/fj.00-0725com

    Article  CAS  PubMed  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. doi:10.1073/pnas.0401843101

    Article  CAS  PubMed  Google Scholar 

  10. Torre-Amione G (2005) Immune activation in chronic heart failure. Am J Cardiol 95:3C–8C, discussion 38C–40C. doi:10.1016/j.amjcard.2005.03.006

    Google Scholar 

  11. 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. doi:10.1042/BJ20021395

    Article  CAS  PubMed  Google Scholar 

  12. Pantos C, Xinaris C, Mourouzis I et al (2008) Thyroid hormone receptor α1: a switch to cardiac cell “metamorphosis”? J Physiol Pharmacol 59(2):253–269

    CAS  PubMed  Google Scholar 

  13. 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. doi:10.1210/me.2004-0503

    Article  CAS  PubMed  Google Scholar 

  14. 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. doi:10.1016/j.yjmcc.2005.02.008

    Article  CAS  PubMed  Google Scholar 

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

  16. Wang B, Ouyang J, Xia Z (2006) Effects of triiodo-thyronine on angiotensin-induced cardiomyocyte hypertrophy: reversal of increased beta-myosin heavy chain gene expression. Can J Physiol Pharmacol 84:935–941. doi:10.1139/Y06-043

    Article  CAS  PubMed  Google Scholar 

  17. Kenessey A, Sullivan EA, Ojamaa K (2006) Nuclear localization of protein kinase C-alpha induces thyroid hormone receptor-alpha1 expression in the cardiomyocyte. Am J Physiol Heart Circ Physiol 290:H381–H389. doi:10.1152/ajpheart.00576.2005

    Article  CAS  PubMed  Google Scholar 

  18. Klein I, Ojamaa K (2001) Thyroid hormone and the cardiovascular system. N Engl J Med 344:501–509. doi:10.1056/NEJM200102153440707

    Article  CAS  PubMed  Google Scholar 

  19. 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. doi:10.1186/1472-6823-8-1

    Article  PubMed  CAS  Google Scholar 

  20. 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. doi:10.1530/eje.0.1430179

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  22. Holland FW 2nd, Brown PS Jr, Weintraub BD et al (1991) Cardiopulmonary bypass and thyroid function: a “euthyroid sick syndrome”. Ann Thorac Surg 52:46–50

    Article  PubMed  Google Scholar 

  23. 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. doi:10.1001/archinte.162.12.1388

    Article  CAS  PubMed  Google Scholar 

  24. 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. doi:10.1161/01.CIR.0000048124.64204.3F

    Article  PubMed  Google Scholar 

  25. 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. doi:10.1016/j.cardfail.2006.05.009

    Article  CAS  PubMed  Google Scholar 

  26. 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. doi:10.1530/EJE-07-0318

    Article  CAS  PubMed  Google Scholar 

  27. Klein I, Hong C (1986) Effects of thyroid hormone on cardiac size and myosin content of the heterotopically transplanted rat heart. J Clin Invest 77:1694–1698. doi:10.1172/JCI112488

    Article  CAS  PubMed  Google Scholar 

  28. 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. doi:10.1097/00005344-200009000-00015

    Article  CAS  PubMed  Google Scholar 

  29. 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. doi:10.1055/s-2005-870317

    Article  CAS  PubMed  Google Scholar 

  30. Kenessey A, Ojamaa K (2006) Thyroid hormone stimulates protein synthesis in the cardiomyocyte by activating the Akt-mTOR and p70S6 K pathways. J Biol Chem 281:20666–20672. doi:10.1074/jbc.M512671200

    Article  CAS  PubMed  Google Scholar 

  31. 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. doi:10.1023/A:1024153003249

    Article  PubMed  Google Scholar 

  32. 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

    CAS  PubMed  Google Scholar 

  33. 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

    CAS  PubMed  Google Scholar 

  34. 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. doi:10.1007/s11010-006-9323-3

    Article  CAS  PubMed  Google Scholar 

  35. Xinaris C, Mourouzis I, Carageorgiou H et al (2006) Differential activation of stress kinase signaling by phenylephrine and thyroid hormone in neonatal cardiomyocytes. J Mol Cell Cardiol 40:999

    Google Scholar 

  36. Xinaris C, Mourouzis I, Pantos C et al (2006) Thyroid hormone promotes cardiac myocyte plasticity via activation of stress kinase signalling. J Mol Cell Cardiol 40:218 Abstract

    Google Scholar 

  37. Pantos C, Mourouzis I, Markakis K et al (2008) Long-term thyroid hormone administration re-shapes left ventricular chamber and improves cardiac function after myocardial infarction in rats. Basic Res Cardiol 103(4):308–318

    Article  CAS  PubMed  Google Scholar 

  38. 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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  40. 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. doi:10.1074/jbc.273.36.23072

    Article  CAS  PubMed  Google Scholar 

  41. 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

    CAS  PubMed  Google Scholar 

  42. 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. doi:10.1089/10507250252949469

    Article  CAS  PubMed  Google Scholar 

  43. 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. doi:10.1016/j.ejphar.2003.08.030

    Article  CAS  PubMed  Google Scholar 

  44. 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

    CAS  PubMed  Google Scholar 

  45. 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. doi:10.1161/CIRCULATIONAHA.105.598409

    Article  CAS  PubMed  Google Scholar 

  46. 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. doi:10.1002/jcp.20562

    Article  CAS  PubMed  Google Scholar 

  47. 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. doi:10.1677/joe.0.1700207

    Article  CAS  PubMed  Google Scholar 

  48. 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. doi:10.1055/s-2006-925404

    Article  CAS  PubMed  Google Scholar 

  49. Venditti P, Di Meo S (2006) Thyroid hormone-induced oxidative stress. Cell Mol Life Sci 63:414–434. doi:10.1007/s00018-005-5457-9

    Article  CAS  PubMed  Google Scholar 

  50. Downey JM, Davis AM, Cohen MV (2007) Signaling pathways in ischemic preconditioning. Heart Fail Rev 12:181–188. doi:10.1007/s10741-007-9025-2

    Article  CAS  PubMed  Google Scholar 

  51. 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. doi:10.1016/j.ejcts.2007.05.004

    Article  PubMed  Google Scholar 

  52. Gay R, Gustafson TA, Goldman S et al (1987) Effects of L-thyroxine in rats with chronic heart failure after myocardial infarction. Am J Physiol 253:H341–H346

    CAS  PubMed  Google Scholar 

  53. Gay RG, Graham S, Aguirre M et al (1988) Effects of 10- to 12-day treatment with L-thyroxine in rats with myocardial infarction. Am J Physiol 255:H801–H806

    CAS  PubMed  Google Scholar 

  54. Hambleton M, Hahn H, Pleger ST et al (2006) Pharmacological- and gene therapy-based inhibition of protein kinase Calpha/beta enhances cardiac contractility and attenuates heart failure. Circulation 114:574–582. doi:10.1161/CIRCULATIONAHA.105.592550

    Article  CAS  PubMed  Google Scholar 

  55. 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. doi:10.1016/j.yjmcc.2005.12.009

    Article  CAS  PubMed  Google Scholar 

  56. 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. doi:10.1677/joe.0.1780427

    Article  CAS  PubMed  Google Scholar 

  57. Wong SP, French JK, Lydon AM et al (2004) Relation of left ventricular sphericity to 10-year survival after acute myocardial infarction. Am J Cardiol 94:1270–1275. doi:10.1016/j.amjcard.2004.07.110

    Article  PubMed  Google Scholar 

  58. 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. doi:10.1016/j.healun.2005.02.025

    Article  PubMed  Google Scholar 

  59. 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. doi:10.1016/1010-7940(89)90092-4

    Article  CAS  PubMed  Google Scholar 

  60. 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. doi:10.1016/S0014-2999(02)02927-8

    Article  CAS  PubMed  Google Scholar 

  61. Pantos C, Cokkinos DV (2006) Hormones signaling and myocardial ischemia. In: Cokkinos DV, Pantos C, Heusch G, Taegtmeyer H (eds) Myocardial ischemia: from mechanisms to theurapeutic potentials. Springer, New York, pp 11–77

    Google Scholar 

  62. 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. doi:10.1016/j.yjmcc.2007.09.009

    Article  CAS  PubMed  Google Scholar 

  63. 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 

  64. Mahaffey KW, Raya TE, Pennock GD et al (1995) Left ventricular performance and remodeling in rabbits after myocardial infarction. Effects of a thyroid hormone analogue. Circulation 91:794–801

    CAS  PubMed  Google Scholar 

  65. Tomanek RJ, Zimmerman MB, Suvarna PR et al (1998) A thyroid hormone analog stimulates angiogenesis in the post-infarcted rat heart. J Mol Cell Cardiol 30:923–932. doi:10.1006/jmcc.1998.0671

    Article  CAS  PubMed  Google Scholar 

  66. Litwin SE, Zhang D, Roberge P et al (2000) DITPA prevents the blunted contraction-frequency relationship in myocytes from infarcted hearts. Am J Physiol Heart Circ Physiol 278:H862–H870

    CAS  PubMed  Google Scholar 

  67. Pennock GD, Spooner PH, Summers CE et al (2000) Prevention of abnormal sarcoplasmic reticulum calcium transport and protein expression in post-infarction heart failure using 3, 5-diiodothyropropionic acid (DITPA). J Mol Cell Cardiol 32:1939–1953. doi:10.1006/jmcc.2000.1225

    Article  CAS  PubMed  Google Scholar 

  68. Spooner PH, Thai HM, Goldman S et al (2004) Thyroid hormone analog, DITPA, improves endothelial nitric oxide and beta-adrenergic mediated vasorelaxation after myocardial infarction. J Cardiovasc Pharmacol 44:453–459. doi:10.1097/01.fjc.0000140206.81804.33

    Article  CAS  PubMed  Google Scholar 

  69. Zheng W, Weiss RM, Wang X et al (2004) DITPA stimulates arteriolar growth and modifies myocardial postinfarction remodeling. Am J Physiol Heart Circ Physiol 286:H1994–H2000. doi:10.1152/ajpheart.00991.2003

    Article  CAS  PubMed  Google Scholar 

  70. Morkin E, Pennock GD, Spooner PH et al (2002) Clinical and experimental studies on the use of 3, 5-diiodothyropropionic acid, a thyroid hormone analogue, in heart failure. Thyroid 12:527–533. doi:10.1089/105072502760143935

    Article  CAS  PubMed  Google Scholar 

  71. Klein I (2003) Thyroid hormone and cardiac contractility. Am J Cardiol 91:1331–1332. doi:10.1016/S0002-9149(03)00433-8

    Article  PubMed  Google Scholar 

  72. Tomanek RJ, Doty MK, Sandra A (1998) Early coronary angiogenesis in response to thyroxine: growth characteristics and upregulation of basic fibroblast growth factor. Circ Res 82:587–593

    CAS  PubMed  Google Scholar 

  73. Pantos C, Malliopoulou V, Varonos DD et al (2004) Thyroid hormone and phenotypes of cardioprotection. Basic Res Cardiol 99:101–120. doi:10.1007/s00395-003-0449-0

    Article  CAS  PubMed  Google Scholar 

  74. Naito H, Melnychenko I, Didie M et al (2006) Optimizing engineered heart tissue for therapeutic applications as surrogate heart muscle. Circulation 114:I72–I78. doi:10.1161/CIRCULATIONAHA.105.001560

    Article  PubMed  Google Scholar 

  75. Ronald A, Dunning J (2006) Does perioperative thyroxine have a role during adult cardiac surgery? Interact Cardiovasc Thorac Surg 5:166–178. doi:10.1510/icvts.2006.128363

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, University of Athens, School of Medicine, 75 Mikras Asias Avenue, 11527, Goudi, Athens, Greece

    Constantinos Pantos & Iordanis Mourouzis

  2. 1st Cardiology Department, Onassis Cardiac Surgery Center, 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. Rebuilding the post-infarcted myocardium by activating ‘physiologic’ hypertrophic signaling pathways: the thyroid hormone paradigm. Heart Fail Rev 15, 143–154 (2010). https://doi.org/10.1007/s10741-008-9111-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10741-008-9111-0

Keywords

Search

Navigation