Physiological Role of Thyroid Hormone in the Developing and Mature Heart

  • Grazia RutiglianoEmail author
  • Giorgio Iervasi


The first notion of a connection between the thyroid and the heart dates back to 1786, when Caleb Hillier Parry, an English physician, described a woman with goitre and palpitations whose “each systole shook the whole thorax” [1]. At the other end of the thyroid function spectrum, a century later, William Greenfield reported about obvious autoptic cardiovascular alterations—“much serous effusion in the pericardium (…) the heart was large (…) the arteries were everywhere thickened, the larger ones atheromatous”—in a middle-aged woman with myxoedema [2]. It took until 1949 to eventually identify and synthesize the specific hormones produced by the thyroid gland, levothyroxine (T4) and triiodothyronine (T3) [3]. Nowadays, the role of the thyroid hormone (TH) in the cardiovascular system is broadly recognized. For TH, receptors have been detected in the myocardium and peripheral vessels, and a broad range of effects have been described in the maintenance of cardiovascular homeostasis in adult life [4]. Furthermore, TH is the first morphogen ever described and critically drives the transition from a foetal to a mature gene expression profile in the postnatal heart. This chapter will present the current knowledge about the physiological effects of TH in the developing and mature heart.


Cardiac growth Myofibril Ion channel Sarcoplasmic reticulum Ca2+ ATPase Phospholamban Contraction/relaxation Foetal reprogramming Gene expression 


  1. 1.
    Klein I, Danzi S. Thyroid disease and the heart. Curr Probl Cardiol. 2016;41(2):65–92. Scholar
  2. 2.
    Ord WM. On myxoedema, a term proposed to be applied to an essential condition in the “Cretinoid” affection occasionally observed in middle-aged women. Med Chir Trans. 1878;61:57–78.5.CrossRefGoogle Scholar
  3. 3.
    Slater S. The discovery of thyroid replacement therapy. Part 3: a complete transformation. J R Soc Med. 2011;104(3):100–6. Scholar
  4. 4.
    Jabbar A, Pingitore A, Pearce SH, Zaman A, Iervasi G, Razvi S. Thyroid hormones and cardiovascular disease. Nat Rev Cardiol. 2017;14(1):39–55. Scholar
  5. 5.
    Robbins J, Rall JE. The interaction of thyroid hormones and protein in biological fluids. Recent Prog Horm Res. 1957;13:161–202; discussion 202–168.PubMedGoogle Scholar
  6. 6.
    Everts ME, Verhoeven FA, Bezstarosti K, Moerings EP, Hennemann G, Visser TJ, Lamers JM. Uptake of thyroid hormones in neonatal rat cardiac myocytes. Endocrinology. 1996;137(10):4235–42. Scholar
  7. 7.
    Friesema EC, Jansen J, Visser TJ. Thyroid hormone transporters. Biochem Soc Trans. 2005;33(Pt 1):228–32. Scholar
  8. 8.
    Hennemann G, Docter R, Friesema EC, de Jong M, Krenning EP, Visser TJ. Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr Rev. 2001;22(4):451–76. Scholar
  9. 9.
    Accorroni A, Saponaro F, Zucchi R. Tissue thyroid hormones and thyronamines. Heart Fail Rev. 2016;21(4):373–90. Scholar
  10. 10.
    Bonen A, Heynen M, Hatta H. Distribution of monocarboxylate transporters MCT1-MCT8 in rat tissues and human skeletal muscle. Appl Physiol Nutr Metab. 2006;31(1):31–9. Scholar
  11. 11.
    Jansen J, Friesema EC, Kester MH, Schwartz CE, Visser TJ. Genotype-phenotype relationship in patients with mutations in thyroid hormone transporter MCT8. Endocrinology. 2008;149(5):2184–90. Scholar
  12. 12.
    Visser WE, Friesema EC, Visser TJ. Minireview: thyroid hormone transporters: the knowns and the unknowns. Mol Endocrinol. 2011;25(1):1–14. Scholar
  13. 13.
    Visser WE, Wong WS, van Mullem AA, Friesema EC, Geyer J, Visser TJ. Study of the transport of thyroid hormone by transporters of the SLC10 family. Mol Cell Endocrinol. 2010;315(1–2):138–45. Scholar
  14. 14.
    Fujiwara K, Adachi H, Nishio T, Unno M, Tokui T, Okabe M, et al. Identification of thyroid hormone transporters in humans: different molecules are involved in a tissue-specific manner. Endocrinology. 2001;142(5):2005–12. Scholar
  15. 15.
    Grube M, Kock K, Oswald S, Draber K, Meissner K, Eckel L, et al. Organic anion transporting polypeptide 2B1 is a high-affinity transporter for atorvastatin and is expressed in the human heart. Clin Pharmacol Ther. 2006;80(6):607–20. Scholar
  16. 16.
    Dentice M, Morisco C, Vitale M, Rossi G, Fenzi G, Salvatore D. The different cardiac expression of the type 2 iodothyronine deiodinase gene between human and rat is related to the differential response of the Dio2 genes to Nkx-2.5 and GATA-4 transcription factors. Mol Endocrinol. 2003;17(8):1508–21. Scholar
  17. 17.
    Bianco AC, Salvatore D, Gereben B, Berry MJ, Larsen PR. Biochemistry, cellular and molecular biology, and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev. 2002;23(1):38–89. Scholar
  18. 18.
    Yonemoto T, Nishikawa M, Matsubara H, Mori Y, Toyoda N, Gondou A, et al. Type 1 iodothyronine deiodinase in heart --effects of triiodothyronine and angiotensin II on its activity and mRNA in cultured rat myocytes. Endocr J. 1999;46(5):621–8.PubMedCrossRefGoogle Scholar
  19. 19.
    Olivares EL, Marassi MP, Fortunato RS, da Silva AC, Costa-e-Sousa RH, Araujo IG, et al. Thyroid function disturbance and type 3 iodothyronine deiodinase induction after myocardial infarction in rats a time course study. Endocrinology. 2007;148(10):4786–92. Scholar
  20. 20.
    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(7):2812–5. Scholar
  21. 21.
    Brown DD, Cai L. Amphibian metamorphosis. Dev Biol. 2007;306(1):20–33. Scholar
  22. 22.
    Breall JA, Rudolph AM, Heymann MA. Role of thyroid hormone in postnatal circulatory and metabolic adjustments. J Clin Invest. 1984;73(5):1418–24. Scholar
  23. 23.
    Nilsson M, Fagman H. Development of the thyroid gland. Development. 2017;144(12):2123–40. Scholar
  24. 24.
    Chassande O. Do unliganded thyroid hormone receptors have physiological functions? J Mol Endocrinol. 2003;31(1):9–20.PubMedCrossRefGoogle Scholar
  25. 25.
    Pantos C, Mourouzis I, Xinaris C, Papadopoulou-Daifoti Z, Cokkinos D. Thyroid hormone and “cardiac metamorphosis”: potential therapeutic implications. Pharmacol Ther. 2008a;118(2):277–94. Scholar
  26. 26.
    Mai W, Janier MF, Allioli N, Quignodon L, Chuzel T, Flamant F, Samarut J. Thyroid hormone receptor alpha is a molecular switch of cardiac function between fetal and postnatal life. Proc Natl Acad Sci U S A. 2004;101(28):10332–7. Scholar
  27. 27.
    Hadj-Sahraoui N, Seugnet I, Ghorbel MT, Demeneix B. Hypothyroidism prolongs mitotic activity in the post-natal mouse brain. Neurosci Lett. 2000;280(2):79–82.PubMedCrossRefGoogle Scholar
  28. 28.
    Sirsat TS, Crossley DA 2nd, Crossley JL, Dzialowski EM. Thyroid hormone manipulation influences development of cardiovascular regulation in embryonic Pekin duck, Anas platyrhynchos domestica. J Comp Physiol B. 2018;188(5):843–53. Scholar
  29. 29.
    Esaki T, Suzuki H, Cook M, Shimoji K, Cheng SY, Sokoloff L, Nunez J. Cardiac glucose utilization in mice with mutated alpha- and beta-thyroid hormone receptors. Am J Physiol Endocrinol Metab. 2004;287(6):E1149–53. Scholar
  30. 30.
    Wikstrom L, Johansson C, Salto C, Barlow C, Campos Barros A, Baas F, et al. Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. EMBO J. 1998;17(2):455–61. Scholar
  31. 31.
    Jonker SS, Zhang L, Louey S, Giraud GD, Thornburg KL, Faber JJ. Myocyte enlargement, differentiation, and proliferation kinetics in the fetal sheep heart. J Appl Physiol (1985). 2007;102(3):1130–42. Scholar
  32. 32.
    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(30):20666–72. Scholar
  33. 33.
    Kinugawa K, Jeong MY, Bristow MR, Long CS. 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. 2005;19(6):1618–28. Scholar
  34. 34.
    Pantos C, Xinaris C, Mourouzis I, Perimenis P, Politi E, Spanou D, Cokkinos DV. Thyroid hormone receptor alpha 1: a switch to cardiac cell "metamorphosis"? J Physiol Pharmacol. 2008b;59(2):253–69.Google Scholar
  35. 35.
    Burrell JH, Boyn AM, Kumarasamy V, Hsieh A, Head SI, Lumbers ER. Growth and maturation of cardiac myocytes in fetal sheep in the second half of gestation. Anat Rec A Discov Mol Cell Evol Biol. 2003;274(2):952–61. Scholar
  36. 36.
    Chattergoon NN, Giraud GD, Louey S, Stork P, Fowden AL, Thornburg KL. Thyroid hormone drives fetal cardiomyocyte maturation. FASEB J. 2012;26(1):397–408. Scholar
  37. 37.
    Khait L, Birla RK. Effect of thyroid hormone on the contractility of self-organized heart muscle. In Vitro Cell Dev Biol Anim. 2008;44(7):204–13. Scholar
  38. 38.
    Bedada FB, Chan SS, Metzger SK, Zhang L, Zhang J, Garry DJ, et al. Acquisition of a quantitative, stoichiometrically conserved ratiometric marker of maturation status in stem cell-derived cardiac myocytes. Stem Cell Rep. 2014;3(4):594–605. Scholar
  39. 39.
    Gassanov N, Er F, Michels G, Zagidullin N, Brandt MC, Hoppe UC. Divergent regulation of cardiac KCND3 potassium channel expression by the thyroid hormone receptors alpha1 and beta1. J Physiol. 2009;587(Pt 6):1319–29. Scholar
  40. 40.
    Guo W, Kamiya K, Hojo M, Kodama I, Toyama J. Regulation of Kv4.2 and Kv1.4 K+ channel expression by myocardial hypertrophic factors in cultured newborn rat ventricular cells. J Mol Cell Cardiol. 1998;30(7):1449–55. Scholar
  41. 41.
    Wickenden AD, Kaprielian R, Parker TG, Jones OT, Backx PH. Effects of development and thyroid hormone on K+ currents and K+ channel gene expression in rat ventricle. J Physiol. 1997;504(Pt 2):271–86.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Cernohorsky J, Kolar F, Pelouch V, Korecky B, Vetter R. Thyroid control of sarcolemmal Na+/Ca2+ exchanger and SR Ca2+-ATPase in developing rat heart. Am J Phys. 1998;275(1 Pt 2):H264–73.Google Scholar
  43. 43.
    Liu B, Huang F, Gick G. Regulation of Na,K-ATPase beta 1 mRNA content by thyroid hormone in neonatal rat cardiac myocytes. Cell Mol Biol Res. 1993;39(3):221–9.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Reed TD, Babu GJ, Ji Y, Zilberman A, Ver Heyen M, Wuytack F, Periasamy M. The expression of SR calcium transport ATPase and the Na(+)/Ca(2+)Exchanger are antithetically regulated during mouse cardiac development and in hypo/hyperthyroidism. J Mol Cell Cardiol. 2000;32(3):453–64. Scholar
  45. 45.
    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):147–53. Scholar
  46. 46.
    Janssen R, Muller A, Simonides WS. Cardiac thyroid hormone metabolism and heart failure. Eur Thyroid J. 2017;6(3):130–7. Scholar
  47. 47.
    Saba A, Chiellini G, Frascarelli S, Marchini M, Ghelardoni S, Raffaelli A, et al. Tissue distribution and cardiac metabolism of 3-iodothyronamine. Endocrinology. 2010;151(10):5063–73. Scholar
  48. 48.
    Weltman NY, Ojamaa K, Schlenker EH, Chen YF, Zucchi R, Saba A, et al. Low-dose T(3) replacement restores depressed cardiac T(3) levels, preserves coronary microvasculature and attenuates cardiac dysfunction in experimental diabetes mellitus. Mol Med. 2014;20:302–12. Scholar
  49. 49.
    Samuels HH, Tsai JS, Casanova J, Stanley F. Thyroid hormone action: in vitro characterization of solubilized nuclear receptors from rat liver and cultured GH1 cells. J Clin Invest. 1974;54(4):853–65. Scholar
  50. 50.
    Gloss B, Trost S, Bluhm W, Swanson E, Clark R, Winkfein R, et al. Cardiac ion channel expression and contractile function in mice with deletion of thyroid hormone receptor alpha or beta. Endocrinology. 2001;142(2):544–50. Scholar
  51. 51.
    Johansson C, Vennstrom B, Thoren P. Evidence that decreased heart rate in thyroid hormone receptor-alpha1-deficient mice is an intrinsic defect. Am J Phys. 1998;275(2 Pt 2):R640–6.Google Scholar
  52. 52.
    Schwartz HL, Lazar MA, Oppenheimer JH. Widespread distribution of immunoreactive thyroid hormone beta 2 receptor (TR beta 2) in the nuclei of extrapituitary rat tissues. J Biol Chem. 1994;269(40):24777–82.PubMedGoogle Scholar
  53. 53.
    Kushnir A, Marks AR. The ryanodine receptor in cardiac physiology and disease. Adv Pharmacol. 2010;59:1–30. Scholar
  54. 54.
    Koss KL, Kranias EG. Phospholamban: a prominent regulator of myocardial contractility. Circ Res. 1996;79(6):1059–63.PubMedCrossRefGoogle Scholar
  55. 55.
    Carr AN, Kranias EG. Thyroid hormone regulation of calcium cycling proteins. Thyroid. 2002;12(6):453–7. Scholar
  56. 56.
    Ojamaa K, Kenessey A, Klein I. Thyroid hormone regulation of phospholamban phosphorylation in the rat heart. Endocrinology. 2000;141(6):2139–44. Scholar
  57. 57.
    Kahaly GJ, Dillmann WH. Thyroid hormone action in the heart. Endocr Rev. 2005;26(5):704–28. Scholar
  58. 58.
    Shenoy R, Klein I, Ojamaa K. Differential regulation of SR calcium transporters by thyroid hormone in rat atria and ventricles. Am J Physiol Heart Circ Physiol. 2001;281(4):H1690–6. Scholar
  59. 59.
    Bluhm WF, Meyer M, Sayen MR, Swanson EA, Dillmann WH. Overexpression of sarcoplasmic reticulum Ca(2+)-ATPase improves cardiac contractile function in hypothyroid mice. Cardiovasc Res. 1999;43(2):382–8.PubMedCrossRefGoogle Scholar
  60. 60.
    Kiss E, Brittsan AG, Edes I, Grupp IL, Grupp G, Kranias EG. Thyroid hormone-induced alterations in phospholamban-deficient mouse hearts. Circ Res. 1998;83(6):608–13.PubMedCrossRefGoogle Scholar
  61. 61.
    Boerth SR, Artman M. Thyroid hormone regulates Na(+)-Ca2+ exchanger expression during postnatal maturation and in adult rabbit ventricular myocardium. Cardiovasc Res. 1996;31:E145–52.PubMedCrossRefGoogle Scholar
  62. 62.
    Hojo Y, Ikeda U, Tsuruya Y, Ebata H, Murata M, Okada K, Saito T, Shimada K. Thyroid hormone stimulates Na(+)-Ca2+ exchanger expression in rat cardiac myocytes. J Cardiovasc Pharmacol 1997;29(1), 75–80.PubMedCrossRefGoogle Scholar
  63. 63.
    Arai M, Otsu K, MacLennan DH, Alpert NR, Periasamy M. Effect of thyroid hormone on the expression of mRNA encoding sarcoplasmic reticulum proteins. Circ Res. 1991;69(2):266–76.PubMedCrossRefGoogle Scholar
  64. 64.
    Dillmann WH. Cellular action of thyroid hormone on the heart. Thyroid. 2002;12(6):447–52. Scholar
  65. 65.
    Reiser PJ, Moss RL, Giulian GG, Greaser ML. Shortening velocity in single fibers from adult rabbit soleus muscles is correlated with myosin heavy chain composition. J Biol Chem. 1985;260(16):9077–80.PubMedGoogle Scholar
  66. 66.
    Morkin E, Flink IL, Goldman S. Biochemical and physiologic effects of thyroid hormone on cardiac performance. Prog Cardiovasc Dis. 1983;25(5):435–64.PubMedCrossRefGoogle Scholar
  67. 67.
    Danzi S, Klein S, Klein I. Differential regulation of the myosin heavy chain genes alpha and beta in rat atria and ventricles: role of antisense RNA. Thyroid. 2008;18(7):761–8. Scholar
  68. 68.
    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(2):592–8.CrossRefGoogle Scholar
  69. 69.
    Le Bouter S, Demolombe S, Chambellan A, Bellocq C, Aimond F, Toumaniantz G, et al. Microarray analysis reveals complex remodeling of cardiac ion channel expression with altered thyroid status: relation to cellular and integrated electrophysiology. Circ Res. 2003;92(2):234–42.PubMedCrossRefGoogle Scholar
  70. 70.
    Watanabe H, Ma M, Washizuka T, Komura S, Yoshida T, Hosaka Y, et al. Thyroid hormone regulates mRNA expression and currents of ion channels in rat atrium. Biochem Biophys Res Commun. 2003;308(3):439–44.PubMedCrossRefGoogle Scholar
  71. 71.
    Renaudon B, Lenfant J, Decressac S, Bois P. Thyroid hormone increases the conductance density of f-channels in rabbit sino-atrial node cells. Receptors Channels. 2000;7(1):1–8.PubMedGoogle Scholar
  72. 72.
    Davis PJ, Goglia F, Leonard JL. Nongenomic actions of thyroid hormone. Nat Rev Endocrinol. 2016;12(2):111–21. Scholar
  73. 73.
    Davis PJ, Davis FB, Lawrence WD. Thyroid hormone regulation of membrane Ca2(+)-ATPase activity. Endocr Res. 1989;15(4):651–82.PubMedCrossRefGoogle Scholar
  74. 74.
    Lin HY, Tang HY, Davis FB, Mousa SA, Incerpi S, Luidens MK, Meng R, Davis PJ. Nongenomic regulation by thyroid hormone of plasma membrane ion and small molecule pumps. Discov Med. 2012;14(76):199–206.Google Scholar
  75. 75.
    Schmidt BM, Martin N, Georgens AC, Tillmann HC, Feuring M, Christ M, Wehling M. Nongenomic cardiovascular effects of triiodothyronine in euthyroid male volunteers. J Clin Endocrinol Metab. 2002;87(4):1681–6. Scholar
  76. 76.
    Rudinger A, Mylotte KM, Davis PJ, Davis FB, Blas SD. Rabbit myocardial membrane Ca2+−adenosine triphosphatase activity: stimulation in vitro by thyroid hormone. Arch Biochem Biophys. 1984;229(1):379–85.PubMedCrossRefGoogle Scholar
  77. 77.
    Horowitz B, Hensley CB, Quintero M, Azuma KK, Putnam D, McDonough AA. Differential regulation of Na,K-ATPase alpha 1, alpha 2, and beta subunit mRNA and protein levels by thyroid hormone. J Biol Chem. 1990;265(24):14308–14.PubMedGoogle Scholar
  78. 78.
    Watanabe H, Washizuka T, Komura S, Yoshida T, Hosaka Y, Hatada K, et al. Genomic and non-genomic regulation of L-type calcium channels in rat ventricle by thyroid hormone. Endocr Res. 2005;31(1):59–70.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Harris DR, Green WL, Craelius W. Acute thyroid hormone promotes slow inactivation of sodium current in neonatal cardiac myocytes. Biochim Biophys Acta. 1991;1095(2):175–81.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Dudley SC Jr, Baumgarten CM. Bursting of cardiac sodium channels after acute exposure to 3,5,3′-triiodo-L-thyronine. Circ Res. 1993;73(2):301–13.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Huang CJ, Geller HM, Green WL, Craelius W. Acute effects of thyroid hormone analogs on sodium currents in neonatal rat myocytes. J Mol Cell Cardiol. 1999;31(4):881–93. Scholar
  82. 82.
    Sen L, Sakaguchi Y, Cui G. G protein modulates thyroid hormone-induced Na(+) channel activation in ventricular myocytes. Am J Physiol Heart Circ Physiol. 2002;283(5):H2119–29. Scholar
  83. 83.
    Sakaguchi Y, Cui G, Sen L. Acute effects of thyroid hormone on inward rectifier potassium channel currents in Guinea pig ventricular myocytes. Endocrinology. 1996;137(11):4744–51. Scholar
  84. 84.
    Felzen B, Sweed Y, Binah O. Electrophysiological effects of thyroid hormones in Guinea-pig ventricular muscle: time course and relationships to blood levels. J Mol Cell Cardiol. 1989;21(11):1151–61.PubMedCrossRefGoogle Scholar
  85. 85.
    Carrillo-Sepulveda MA, Ceravolo GS, Fortes ZB, 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;85(3):560–70. Scholar
  86. 86.
    Park KW, Dai HB, Ojamaa K, Lowenstein E, Klein I, Sellke FW. The direct vasomotor effect of thyroid hormones on rat skeletal muscle resistance arteries. Anesth Analg. 1997;85(4):734–8.CrossRefGoogle Scholar
  87. 87.
    Kuzman JA, Gerdes AM, Kobayashi S, Liang Q. Thyroid hormone activates Akt and prevents serum starvation-induced cell death in neonatal rat cardiomyocytes. J Mol Cell Cardiol. 2005;39(5):841–4. Scholar
  88. 88.
    Incerpi S, Scapin S, D'Arezzo S, Spagnuolo S, Leoni S. Short-term effects of thyroid hormone in prenatal development and cell differentiation. Steroids. 2005;70(5–7):434–43. Scholar
  89. 89.
    Silva JE. Thyroid hormone control of thermogenesis and energy balance. Thyroid. 1995;5(6):481–92. Scholar
  90. 90.
    Resnick LM, Laragh JH. PLasma renin activity in syndromes of thyroid hormone excess and deficiency. Life Sci. 1982;30(7–8):585–6.PubMedCrossRefGoogle Scholar
  91. 91.
    Fukuyama K, Ichiki T, Takeda K, Tokunou T, Iino N, Masuda S, et al. Downregulation of vascular angiotensin II type 1 receptor by thyroid hormone. Hypertension. 2003;41(3):598–603. Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Institute of Life Sciences, Scuola Superiore Sant’AnnaPisaItaly
  2. 2.Institute of Clinical Physiology (IFC), National Research Council (CNR)PisaItaly
  3. 3.Department of PathologyUniversity of PisaPisaItaly

Personalised recommendations