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  • Review Article
  • Published:

Thyroid hormones and cardiovascular disease

Key Points

  • Thyroid hormones have a direct effect on the heart

  • Patients with hypothyroidism or hyperthyroidism have increased risk of cardiovascular disease

  • Treatment with thyroid hormones in patients with hypothyroidism improves cardiovascular risk factors, but the effect on cardiovascular events has not been assessed in randomized, controlled trials

  • In experimental settings, thyroid hormones influence myocardial remodelling and function after myocardial infarction, but the utility of thyroid hormone replacement therapy in patients with acute cardiac events is yet to be elucidated

  • Intracellular and circulating thyroid hormone concentrations (mainly T3) decrease after acute myocardial infarction and in chronic heart failure, and this reduction is associated with poor outcomes

  • Small studies showed that treatment with thyroid hormones is safe and beneficial in patients with chronic heart failure; however, larger, adequately powered trials are required to confirm safety and assess efficacy

Abstract

Myocardial and vascular endothelial tissues have receptors for thyroid hormones and are sensitive to changes in the concentrations of circulating thyroid hormones. The importance of thyroid hormones in maintaining cardiovascular homeostasis can be deduced from clinical and experimental data showing that even subtle changes in thyroid hormone concentrations — such as those observed in subclinical hypothyroidism or hyperthyroidism, and low triiodothyronine syndrome — adversely influence the cardiovascular system. Some potential mechanisms linking the two conditions are dyslipidaemia, endothelial dysfunction, blood pressure changes, and direct effects of thyroid hormones on the myocardium. Several interventional trials showed that treatment of subclinical thyroid diseases improves cardiovascular risk factors, which implies potential benefits for reducing cardiovascular events. Over the past 2 decades, accumulating evidence supports the association between abnormal thyroid function at the time of an acute myocardial infarction (MI) and subsequent adverse cardiovascular outcomes. Furthermore, experimental studies showed that thyroid hormones can have an important therapeutic role in reducing infarct size and improving myocardial function after acute MI. In this Review, we summarize the literature on thyroid function in cardiovascular diseases, both as a risk factor as well as in the setting of cardiovascular diseases such as heart failure or acute MI, and outline the effect of thyroid hormone replacement therapy for reducing the risk of cardiovascular disease.

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Figure 1: Effect of thyroid hormones on the cardiomyocyte via genomic and nongenomic actions.
Figure 2: Cardiac 31P spectra in subclinical hypothyroidism and euthyroid state.
Figure 3: Thyroid hormones and cardioprotection.

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References

  1. Mozaffarian, D. et al. Heart disease and stroke statistics — 2015 update: a report from the American Heart Association. Circulation 131, e29–e322 (2015).

    PubMed  Google Scholar 

  2. World Health Organization. Global status report on noncommunicable diseases. WHO http://www.who.int/nmh/publications/ncd_report_full_en.pdf (2010).

  3. Townsend, N., Nichols, M., Scarborough, P. & Rayner, M. Cardiovascular disease in Europe 2015: epidemiological update. Eur. Heart J. 36, 2673–2674 (2015).

    Article  PubMed  Google Scholar 

  4. Klein, I. & Ojamaa, K. Thyroid hormone and the cardiovascular system. N. Engl. J. Med. 344, 501–509 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Allahabadia, A., Razvi, S., Abraham, P. & Franklyn, J. Diagnosis and treatment of primary hypothyroidism. BMJ 338, b725 (2009).

    Article  PubMed  Google Scholar 

  6. Hak, A. E. et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam Study. Ann. Intern. Med. 132, 270–278 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Walsh, J. P. et al. Subclinical thyroid dysfunction as a risk factor for cardiovascular disease. Arch. Intern. Med. 165, 2467–2472 (2005).

    Article  PubMed  Google Scholar 

  8. Razvi, S., Weaver, J. U., Vanderpump, M. P. & Pearce, S. H. The incidence of ischemic heart disease and mortality in people with subclinical hypothyroidism: reanalysis of the Whickham Survey cohort. J. Clin. Endocrinol. Metab. 95, 1734–1740 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Parle, J. V., Maisonneuve, P., Sheppard, M. C., Boyle, P. & Franklyn, J. A. Prediction of all-cause and cardiovascular mortality in elderly people from one low serum thyrotropin result: a 10-year cohort study. Lancet 358, 861–865 (2001).

    Article  CAS  PubMed  Google Scholar 

  10. Cappola, A. R. et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA 295, 1033–1041 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Canaris, G. J., Manowitz, N. R., Mayor, G. & Ridgway, E. C. The Colorado thyroid disease prevalence study. Arch. Intern. Med. 160, 526–534 (2000).

    Article  CAS  PubMed  Google Scholar 

  12. Laurberg, P. et al. Iodine intake and the pattern of thyroid disorders: a comparative epidemiological study of thyroid abnormalities in the elderly in Iceland and in Jutland, Denmark. J. Clin. Endocrinol. Metab. 83, 765–769 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. Vadiveloo, T., Donnan, P. T., Cochrane, L. & Leese, G. P. The Thyroid Epidemiology, Audit, and Research Study (TEARS): the natural history of endogenous subclinical hyperthyroidism. J. Clin. Endocrinol. Metab. 96, E1–E8 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Ord, W. M. 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. 61, 57–78.5 (1878).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kocher, T. Ueber Kropfexstirpation und ihre Folgen. Arch. Klin. Chir. 29, 254–337 (in German) (1883).

    Google Scholar 

  16. Hun, H. & Prudden, T. M. Myxoedema. Four cases, with two autopsies. With a report of the microscopical examination. Am. J. Med. Sci. 96, 1–24 (1888).

    Article  Google Scholar 

  17. Murray, G. R. Note on the treatment of myxoedema by hypodermic injections of an extract of the thyroid gland of a sheep. Br. Med. J. 2, 796–797 (1891).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Slater, S. The discovery of thyroid replacement therapy. Part 3: a complete transformation. J. R. Soc. Med. 104, 100–106 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Barnes, B. O. Prophylaxis of ischaemic heart-disease by thyroid therapy. Lancet 2, 149–152 (1959).

    Article  CAS  PubMed  Google Scholar 

  20. Barnes, B. O. On the genesis of atherosclerosis. J. Am. Geriatr. Soc. 21, 350–354 (1973).

    Article  CAS  PubMed  Google Scholar 

  21. Kountz, W. B. Vascular degeneration in hypothyroidism. AMA Arch. Pathol. 50, 765–777 (1950).

    CAS  PubMed  Google Scholar 

  22. Utiger, R. D. Radioimmunoassay of human plasma thyrotropin. J. Clin. Invest. 44, 1277–1286 (1965).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Vanhaelst, L., Neve, P. & Bastenie, P. A. Coronary-artery disease in myxoedema. Lancet 2, 1257–1258 (1967).

    Article  CAS  PubMed  Google Scholar 

  24. Vanhaelst, L., Neve, P., Chailly, P. & Bastenie, P. A. Coronary-artery disease in hypothyroidism. Observations in clinical myxoedema. Lancet 2, 800–802 (1967).

    Article  CAS  PubMed  Google Scholar 

  25. Tunbridge, W. M. et al. The spectrum of thyroid disease in a community: the Whickham survey. Clin. Endocrinol. (Oxf.) 7, 481–493 (1977).

    Article  CAS  Google Scholar 

  26. The Coronary Drug Project Research Group. The coronary drug project. Findings leading to further modifications of its protocol with respect to dextrothyroxine. JAMA 220, 996–1008 (1972).

  27. Brenta, G., Danzi, S. & Klein, I. Potential therapeutic applications of thyroid hormone analogs. Nat. Clin. Pract. Endocrinol. Metab. 3, 632–640 (2007).

    Article  CAS  PubMed  Google Scholar 

  28. Stamler, J. The coronary drug project — findings with regard to estrogen, dextrothyroxine, clofibrate and niacin. Adv. Exp. Med. Biol. 82, 52–75 (1977).

    CAS  PubMed  Google Scholar 

  29. Pingitore, A., Chen, Y., Gerdes, A. M. & Iervasi, G. Acute myocardial infarction and thyroid function: new pathophysiological and therapeutic perspectives. Ann. Med. 44, 745–757 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Ladenson, P. W. et al. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N. Engl. J. Med. 362, 906–916 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Sjouke, B. et al. Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled phase 3 study. Lancet Diabetes Endocrinol. 2, 455–463 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Samuels, H. H., Tsai, J. S., Casanova, J. & Stanley, F. Thyroid hormone action: in vitro characterization of solubilized nuclear receptors from rat liver and cultured GH1 cells. J. Clin. Invest. 54, 853–865 (1974).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Davis, P. J., Davis, F. B., Mousa, S. A., Luidens, M. K. & Lin, H. Y. Membrane receptor for thyroid hormone: physiologic and pharmacologic implications. Annu. Rev. Pharmacol. Toxicol. 51, 99–115 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Gereben, B. et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr. Rev. 29, 898–938 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Croteau, W., Davey, J. C., Galton, V. A. & St Germain, D. L. Cloning of the mammalian type II iodothyronine deiodinase. A selenoprotein differentially expressed and regulated in human and rat brain and other tissues. J. Clin. Invest. 98, 405–417 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Salvatore, D., Bartha, T., Harney, J. W. & Larsen, P. R. Molecular biological and biochemical characterization of the human type 2 selenodeiodinase. Endocrinology 137, 3308–3315 (1996).

    Article  CAS  PubMed  Google Scholar 

  38. Pol, C. J. et al. Left-ventricular remodeling after myocardial infarction is associated with a cardiomyocyte-specific hypothyroid condition. Endocrinology 152, 669–679 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Cooper, D. S. & Biondi, B. Subclinical thyroid disease. Lancet 379, 1142–1154 (2012).

    Article  PubMed  Google Scholar 

  40. Brent, G. A. Mechanisms of thyroid hormone action. J. Clin. Invest. 122, 3035–3043 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Cheng, S. Y., Leonard, J. L. & Davis, P. J. Molecular aspects of thyroid hormone actions. Endocr. Rev. 31, 139–170 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Brent, G. A. The molecular basis of thyroid hormone action. N. Engl. J. Med. 331, 847–853 (1994).

    Article  CAS  PubMed  Google Scholar 

  43. He, H. et al. Overexpression of the rat sarcoplasmic reticulum Ca2+ ATPase gene in the heart of transgenic mice accelerates calcium transients and cardiac relaxation. J. Clin. Invest. 100, 380–389 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Holt, E., Sjaastad, I., Lunde, P. K., Christensen, G. & Sejersted, O. M. Thyroid hormone control of contraction and the Ca2+-ATPase/phospholamban complex in adult rat ventricular myocytes. J. Mol. Cell. Cardiol. 31, 645–656 (1999).

    Article  CAS  PubMed  Google Scholar 

  45. Kaasik, A., Paju, K., Vetter, R. & Seppet, E. K. Thyroid hormones increase the contractility but suppress the effects of β-adrenergic agonist by decreasing phospholamban expression in rat atria. Cardiovasc. Res. 35, 106–112 (1997).

    Article  CAS  PubMed  Google Scholar 

  46. Nadal-Ginard, B. & Mahdavi, V. Molecular basis of cardiac performance. Plasticity of the myocardium generated through protein isoform switches. J. Clin. Invest. 84, 1693–1700 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fazio, S., Palmieri, E. A., Lombardi, G. & Biondi, B. Effects of thyroid hormone on the cardiovascular system. Recent Prog. Horm. Res. 59, 31–50 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Ojamaa, K., Klemperer, J. D. & Klein, I. Acute effects of thyroid hormone on vascular smooth muscle. Thyroid 6, 505–512 (1996).

    Article  CAS  PubMed  Google Scholar 

  49. Kranias, E. G. & Hajjar, R. J. Modulation of cardiac contractility by the phospholamban/SERCA2a regulatome. Circ. Res. 110, 1646–1660 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kiss, E., Jakab, G., Kranias, E. G. & Edes, I. Thyroid hormone-induced alterations in phospholamban protein expression. Regulatory effects on sarcoplasmic reticulum Ca2+ transport and myocardial relaxation. Circ. Res. 75, 245–251 (1994).

    Article  CAS  PubMed  Google Scholar 

  51. Hoit, B. D. et al. Effects of thyroid hormone on cardiac beta-adrenergic responsiveness in conscious baboons. Circulation 96, 592–598 (1997).

    Article  CAS  PubMed  Google Scholar 

  52. Kuzman, J. A., Gerdes, A. M., Kobayashi, S. & Liang, Q. Thyroid hormone activates Akt and prevents serum starvation-induced cell death in neonatal rat cardiomyocytes. J. Mol. Cell. Cardiol. 39, 841–844 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  54. Madathil, A. et al. Levothyroxine improves abnormal cardiac bioenergetics in subclinical hypothyroidism: a cardiac magnetic resonance spectroscopic study. J. Clin. Endocrinol. Metab. 100, E607–E610 (2015).

    Article  CAS  PubMed  Google Scholar 

  55. Park, K. W. et al. The direct vasomotor effect of thyroid hormones on rat skeletal muscle resistance arteries. Anesth. Analg. 85, 734–738 (1997).

    Article  CAS  PubMed  Google Scholar 

  56. Silva, J. E. Thyroid hormone control of thermogenesis and energy balance. Thyroid 5, 481–492 (1995).

    Article  CAS  PubMed  Google Scholar 

  57. Feldman, T., Borow, K. M., Sarne, D. H., Neumann, A. & Lang, R. M. Myocardial mechanics in hyperthyroidism: importance of left ventricular loading conditions, heart rate and contractile state. J. Am. Coll. Cardiol. 7, 967–974 (1986).

    Article  CAS  PubMed  Google Scholar 

  58. Klemperer, J. D. et al. Thyroid hormone treatment after coronary-artery bypass surgery. N. Engl. J. Med. 333, 1522–1527 (1995).

    Article  CAS  PubMed  Google Scholar 

  59. Resnick, L. M. & Laragh, J. H. Plasma renin activity in syndromes of thyroid hormone excess and deficiency. Life Sci. 30, 585–586 (1982).

    Article  CAS  PubMed  Google Scholar 

  60. Nakazawa, H. K., Sakurai, K., Hamada, N., Momotani, N. & Ito, K. Management of atrial fibrillation in the post-thyrotoxic state. Am. J. Med. 72, 903–906 (1982).

    Article  CAS  PubMed  Google Scholar 

  61. Biondi, B. Mechanisms in endocrinology: heart failure and thyroid dysfunction. Eur. J. Endocrinol. 167, 609–618 (2012).

    Article  CAS  PubMed  Google Scholar 

  62. Franklyn, J. A., Sheppard, M. C. & Maisonneuve, P. Thyroid function and mortality in patients treated for hyperthyroidism. JAMA 294, 71–80 (2005).

    Article  CAS  PubMed  Google Scholar 

  63. Marvisi, M. et al. Pulmonary hypertension is frequent in hyperthyroidism and normalizes after therapy. Eur. J. Intern. Med. 17, 267–271 (2006).

    Article  PubMed  Google Scholar 

  64. Suk, J. H. et al. Prevalence of echocardiographic criteria for the diagnosis of pulmonary hypertension in patients with Graves' disease: before and after antithyroid treatment. J. Endocrinol. Invest. 34, e229–e234 (2011).

    CAS  PubMed  Google Scholar 

  65. Al Husseini, A. et al. Thyroid hormone is highly permissive in angioproliferative pulmonary hypertension in rats. Eur. Respir. J. 41, 104–114 (2013).

    Article  CAS  PubMed  Google Scholar 

  66. Davis, F. B. et al. Proangiogenic action of thyroid hormone is fibroblast growth factor-dependent and is initiated at the cell surface. Circ. Res. 94, 1500–1506 (2004).

    Article  CAS  PubMed  Google Scholar 

  67. Surks, M. I. et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 291, 228–238 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Gharib, H. et al. Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society. J. Clin. Endocrinol. Metab. 90, 581–585 (2005).

    Article  CAS  PubMed  Google Scholar 

  69. Biondi, B. & Cooper, D. S. The clinical significance of subclinical thyroid dysfunction. Endocr. Rev. 29, 76–131 (2008).

    Article  CAS  PubMed  Google Scholar 

  70. Bahn, R. S. et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocr. Pract. 17, 456–520 (2011).

    Article  PubMed  Google Scholar 

  71. Parle, J. V., Franklyn, J. A., Cross, K. W., Jones, S. R. & Sheppard, M. C. Thyroxine prescription in the community: serum thyroid stimulating hormone level assays as an indicator of undertreatment or overtreatment. Br. J. Gen. Pract. 43, 107–109 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Okosieme, O. E., Belludi, G., Spittle, K., Kadiyala, R. & Richards, J. Adequacy of thyroid hormone replacement in a general population. QJM 104, 395–401 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Taylor, P. N. et al. Falling threshold for treatment of borderline elevated thyrotropin levels-balancing benefits and risks: evidence from a large community-based study. JAMA Intern. Med. 174, 32–39 (2014).

    Article  PubMed  Google Scholar 

  74. Vadiveloo, T., Donnan, P. T., Cochrane, L. & Leese, G. P. The Thyroid Epidemiology, Audit, and Research Study (TEARS): morbidity in patients with endogenous subclinical hyperthyroidism. J. Clin. Endocrinol. Metab. 96, 1344–1351 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. Biondi, B. et al. Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J. Clin. Endocrinol. Metab. 85, 4701–4705 (2000).

    CAS  PubMed  Google Scholar 

  76. Sgarbi, J. A., Villaca, F. G., Garbeline, B., Villar, H. E. & Romaldini, J. H. The effects of early antithyroid therapy for endogenous subclinical hyperthyroidism in clinical and heart abnormalities. J. Clin. Endocrinol. Metab. 88, 1672–1677 (2003).

    Article  CAS  PubMed  Google Scholar 

  77. Pearce, E. N., Yang, Q., Benjamin, E. J., Aragam, J. & Vasan, R. S. Thyroid function and left ventricular structure and function in the Framingham Heart Study. Thyroid 20, 369–373 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Dorr, M. et al. Subclinical hyperthyroidism is not associated with progression of cardiac mass and development of left ventricular hypertrophy in middle-aged and older subjects: results from a 5-year follow-up. Clin. Endocrinol. (Oxf.) 73, 821–826 (2010).

    Article  Google Scholar 

  79. Volzke, H. et al. Thyroid function and carotid wall thickness. J. Clin. Endocrinol. Metab. 89, 2145–2149 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Dorr, M. et al. Low serum thyrotropin is associated with high plasma fibrinogen. J. Clin. Endocrinol. Metab. 91, 530–534 (2006).

    Article  CAS  PubMed  Google Scholar 

  81. Iervasi, G. et al. Association between increased mortality and mild thyroid dysfunction in cardiac patients. Arch. Intern. Med. 167, 1526–1532 (2007).

    Article  PubMed  Google Scholar 

  82. Sawin, C. T. Subclinical hyperthyroidism and atrial fibrillation. Thyroid 12, 501–503 (2002).

    Article  PubMed  Google Scholar 

  83. Auer, J. & Eber, B. Subclinical hyperthyroidism and atrial fibrillation. Acta Med. Austriaca 30, 98–99 (in German) (2003).

    CAS  PubMed  Google Scholar 

  84. Gammage, M. D. et al. Association between serum free thyroxine concentration and atrial fibrillation. Arch. Intern. Med. 167, 928–934 (2007).

    Article  CAS  PubMed  Google Scholar 

  85. Collet, T. H. et al. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch. Intern. Med. 172, 799–809 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Rodondi, N. et al. Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure: the Cardiovascular Health Study. J. Am. Coll. Cardiol. 52, 1152–1159 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Chaker, L. et al. Normal thyroid function and the risk of atrial fibrillation: the Rotterdam Study. J. Clin. Endocrinol. Metab. 100, 3718–3724 (2015).

    Article  CAS  PubMed  Google Scholar 

  88. Cappola, A. R. et al. Thyroid function in the euthyroid range and adverse outcomes in older adults. J. Clin. Endocrinol. Metab. 100, 1088–1096 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Heeringa, J. et al. High-normal thyroid function and risk of atrial fibrillation: the Rotterdam Study. Arch. Intern. Med. 168, 2219–2224 (2008).

    Article  PubMed  Google Scholar 

  90. Flynn, R. W. et al. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J. Clin. Endocrinol. Metab. 95, 186–193 (2010).

    Article  CAS  PubMed  Google Scholar 

  91. van den Beld, A. W., Visser, T. J., Feelders, R. A., Grobbee, D. E. & Lamberts, S. W. Thyroid hormone concentrations, disease, physical function, and mortality in elderly men. J. Clin. Endocrinol. Metab. 90, 6403–6409 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Biondi, B. et al. The 2015 European Thyroid Association guidelines on diagnosis and treatment of endogenous subclinical hyperthyroidism. Eur. Thyroid J. 4, 149–163 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Tunbridge, W. M. et al. Lipid profiles and cardiovascular disease in the Whickham area with particular reference to thyroid failure. Clin. Endocrinol. (Oxf.) 7, 495–508 (1977).

    Article  CAS  Google Scholar 

  94. Klein, I. & Danzi, S. Thyroid disease and the heart. Circulation 116, 1725–1735 (2007).

    Article  PubMed  Google Scholar 

  95. Cappola, A. R. & Ladenson, P. W. Hypothyroidism and atherosclerosis. J. Clin. Endocrinol. Metab. 88, 2438–2444 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Hamilton, T. E., Davis, S., Onstad, L. & Kopecky, K. J. Thyrotropin levels in a population with no clinical, autoantibody, or ultrasonographic evidence of thyroid disease: implications for the diagnosis of subclinical hypothyroidism. J. Clin. Endocrinol. Metab. 93, 1224–1230 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Hollowell, J. G. et al. Serum TSH, T4, and thyroid antibodies in the United States population (1988 to 1994): National Health and Nutrition Examination Survey (NHANES III). J. Clin. Endocrinol. Metab. 87, 489–499 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. Parle, J. V., Franklyn, J. A., Cross, K. W., Jones, S. C. & Sheppard, M. C. Prevalence and follow-up of abnormal thyrotrophin (TSH) concentrations in the elderly in the United Kingdom. Clin. Endocrinol. (Oxf.) 34, 77–83 (1991).

    Article  CAS  Google Scholar 

  99. Monzani, F. et al. Effect of levothyroxine on cardiac function and structure in subclinical hypothyroidism: a double blind, placebo-controlled study. J. Clin. Endocrinol. Metab. 86, 1110–1115 (2001).

    Article  CAS  PubMed  Google Scholar 

  100. Biondi, B. et al. Left ventricular diastolic dysfunction in patients with subclinical hypothyroidism. J. Clin. Endocrinol. Metab. 84, 2064–2067 (1999).

    Article  CAS  PubMed  Google Scholar 

  101. Ripoli, A. et al. Does subclinical hypothyroidism affect cardiac pump performance? Evidence from a magnetic resonance imaging study. J. Am. Coll. Cardiol. 45, 439–445 (2005).

    Article  PubMed  Google Scholar 

  102. Brenta, G. et al. Assessment of left ventricular diastolic function by radionuclide ventriculography at rest and exercise in subclinical hypothyroidism, and its response to l-thyroxine therapy. Am. J. Cardiol. 91, 1327–1330 (2003).

    Article  CAS  PubMed  Google Scholar 

  103. Kahaly, G. J. Cardiovascular and atherogenic aspects of subclinical hypothyroidism. Thyroid 10, 665–679 (2000).

    Article  CAS  PubMed  Google Scholar 

  104. Owen, P. J., Sabit, R. & Lazarus, J. H. Thyroid disease and vascular function. Thyroid 17, 519–524 (2007).

    Article  CAS  PubMed  Google Scholar 

  105. Boekholdt, S. M. et al. Initial thyroid status and cardiovascular risk factors: the EPIC-Norfolk prospective population study. Clin. Endocrinol. (Oxf.) 72, 404–410 (2010).

    Article  CAS  Google Scholar 

  106. McQuade, C. et al. Hypothyroidism and moderate subclinical hypothyroidism are associated with increased all-cause mortality independent of coronary heart disease risk factors: a PreCIS database study. Thyroid 21, 837–843 (2011).

    Article  PubMed  Google Scholar 

  107. Rodondi, N. et al. Subclinical hypothyroidism and the risk of heart failure, other cardiovascular events, and death. Arch. Intern. Med. 165, 2460–2466 (2005).

    Article  PubMed  Google Scholar 

  108. Rodondi, N. et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA 304, 1365–1374 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Jabbar, A. & Razvi, S. Thyroid disease and vascular risk. Clin. Med. (Lond.) 14, s29–s32 (2014).

    Article  Google Scholar 

  110. Razvi, S., Shakoor, A., Vanderpump, M., Weaver, J. U. & Pearce, S. H. The influence of age on the relationship between subclinical hypothyroidism and ischemic heart disease: a metaanalysis. J. Clin. Endocrinol. Metab. 93, 2998–3007 (2008).

    Article  CAS  PubMed  Google Scholar 

  111. Razvi, S., Weaver, J. U., Butler, T. J. & Pearce, S. H. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch. Intern. Med. 172, 811–817 (2012).

    CAS  PubMed  Google Scholar 

  112. Pearce, S. H. et al. 2013 ETA guideline: management of subclinical hypothyroidism. Eur. Thyroid J. 2, 215–228 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Parle, J. V., Franklyn, J. A., Cross, K. W., Jones, S. R. & Sheppard, M. C. Circulating lipids and minor abnormalities of thyroid function. Clin. Endocrinol. (Oxf.) 37, 411–414 (1992).

    Article  CAS  Google Scholar 

  114. Duntas, L. H. Thyroid disease and lipids. Thyroid 12, 287–293 (2002).

    Article  CAS  PubMed  Google Scholar 

  115. Ineck, B. A. & Ng, T. M. Effects of subclinical hypothyroidism and its treatment on serum lipids. Ann. Pharmacother. 37, 725–730 (2003).

    Article  CAS  PubMed  Google Scholar 

  116. Hueston, W. J. & Pearson, W. S. Subclinical hypothyroidism and the risk of hypercholesterolemia. Ann. Fam. Med. 2, 351–355 (2004).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Asvold, B. O., Vatten, L. J., Nilsen, T. I. & Bjoro, T. The association between TSH within the reference range and serum lipid concentrations in a population-based study. The HUNT Study. Eur. J. Endocrinol. 156, 181–186 (2007).

    Article  CAS  PubMed  Google Scholar 

  118. Pandak, W. M. et al. Hormonal regulation of cholesterol 7α-hydroxylase specific activity, mRNA levels, and transcriptional activity in vivo in the rat. J. Lipid Res. 38, 2483–2491 (1997).

    CAS  PubMed  Google Scholar 

  119. Razvi, S. et al. The beneficial effect of l-thyroxine on cardiovascular risk factors, endothelial function, and quality of life in subclinical hypothyroidism: randomized, crossover trial. J. Clin. Endocrinol. Metab. 92, 1715–1723 (2007).

    Article  CAS  PubMed  Google Scholar 

  120. Caraccio, N., Ferrannini, E. & Monzani, F. Lipoprotein profile in subclinical hypothyroidism: response to levothyroxine replacement, a randomized placebo-controlled study. J. Clin. Endocrinol. Metab. 87, 1533–1538 (2002).

    Article  CAS  PubMed  Google Scholar 

  121. Monzani, F. et al. Effect of levothyroxine replacement on lipid profile and intima-media thickness in subclinical hypothyroidism: a double-blind, placebo- controlled study. J. Clin. Endocrinol. Metab. 89, 2099–2106 (2004).

    Article  CAS  PubMed  Google Scholar 

  122. Jaeschke, R. et al. Does treatment with l-thyroxine influence health status in middle-aged and older adults with subclinical hypothyroidism? J. Gen. Intern. Med. 11, 744–749 (1996).

    Article  CAS  PubMed  Google Scholar 

  123. Kong, W. M. et al. A 6-month randomized trial of thyroxine treatment in women with mild subclinical hypothyroidism. Am. J. Med. 112, 348–354 (2002).

    Article  CAS  PubMed  Google Scholar 

  124. Danese, M. D., Ladenson, P. W., Meinert, C. L. & Powe, N. R. Clinical review 115: effect of thyroxine therapy on serum lipoproteins in patients with mild thyroid failure: a quantitative review of the literature. J. Clin. Endocrinol. Metab. 85, 2993–3001 (2000).

    CAS  PubMed  Google Scholar 

  125. Villar, H. C., Saconato, H., Valente, O. & Atallah, A. N. Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst. Rev. 3, CD003419 (2007).

    Google Scholar 

  126. Iqbal, A., Jorde, R. & Figenschau, Y. Serum lipid levels in relation to serum thyroid-stimulating hormone and the effect of thyroxine treatment on serum lipid levels in subjects with subclinical hypothyroidism: the Tromsø study. J. Intern. Med. 260, 53–61 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Danzi, S. & Klein, I. Thyroid hormone and blood pressure regulation. Curr. Hypertens. Rep. 5, 513–520 (2003).

    Article  PubMed  Google Scholar 

  128. Ching, G. W. et al. Cardiac hypertrophy as a result of long-term thyroxine therapy and thyrotoxicosis. Heart 75, 363–368 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Volzke, H. et al. Subclinical hyperthyroidism and blood pressure in a population-based prospective cohort study. Eur. J. Endocrinol. 161, 615–621 (2009).

    Article  CAS  PubMed  Google Scholar 

  130. Cai, Y., Ren, Y. & Shi, J. Blood pressure levels in patients with subclinical thyroid dysfunction: a meta-analysis of cross-sectional data. Hypertens. Res. 34, 1098–1105 (2011).

    Article  PubMed  Google Scholar 

  131. Volzke, H. et al. The association between subclinical hyperthyroidism and blood pressure in a population-based study. J. Hypertens. 24, 1947–1953 (2006).

    Article  CAS  PubMed  Google Scholar 

  132. Walsh, J. P. et al. Subclinical thyroid dysfunction and blood pressure: a community-based study. Clin. Endocrinol. (Oxf.) 65, 486–491 (2006).

    Article  CAS  Google Scholar 

  133. Osman, F., Franklyn, J. A., Holder, R. L., Sheppard, M. C. & Gammage, M. D. Cardiovascular manifestations of hyperthyroidism before and after antithyroid therapy: a matched case-control study. J. Am. Coll. Cardiol. 49, 71–81 (2007).

    Article  CAS  PubMed  Google Scholar 

  134. Saito, I., Ito, K. & Saruta, T. Hypothyroidism as a cause of hypertension. Hypertension 5, 112–115 (1983).

    Article  CAS  PubMed  Google Scholar 

  135. Fommei, E. & Iervasi, G. The role of thyroid hormone in blood pressure homeostasis: evidence from short-term hypothyroidism in humans. J. Clin. Endocrinol. Metab. 87, 1996–2000 (2002).

    Article  CAS  PubMed  Google Scholar 

  136. Iqbal, A., Figenschau, Y. & Jorde, R. Blood pressure in relation to serum thyrotropin: the Tromsø study. J. Hum. Hypertens. 20, 932–936 (2006).

    Article  CAS  PubMed  Google Scholar 

  137. Dart, A. M. et al. Aortic distensibility in patients with isolated hypercholesterolaemia, coronary artery disease, or cardiac transplant. Lancet 338, 270–273 (1991).

    Article  CAS  PubMed  Google Scholar 

  138. Laurent, S. et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 37, 1236–1241 (2001).

    Article  CAS  PubMed  Google Scholar 

  139. Dernellis, J. & Panaretou, M. Effects of thyroid replacement therapy on arterial blood pressure in patients with hypertension and hypothyroidism. Am. Heart J. 143, 718–724 (2002).

    Article  CAS  PubMed  Google Scholar 

  140. Obuobie, K. et al. Increased central arterial stiffness in hypothyroidism. J. Clin. Endocrinol. Metab. 87, 4662–4666 (2002).

    Article  CAS  PubMed  Google Scholar 

  141. Nagasaki, T. et al. Increased pulse wave velocity in subclinical hypothyroidism. J. Clin. Endocrinol. Metab. 91, 154–158 (2006).

    Article  CAS  PubMed  Google Scholar 

  142. Nagasaki, T. et al. Changes in brachial-ankle pulse wave velocity in subclinical hypothyroidism during normalization of thyroid function. Biomed. Pharmacother. 61, 482–487 (2007).

    Article  PubMed  Google Scholar 

  143. Nagasaki, T. et al. Decrease of brachial-ankle pulse wave velocity in female subclinical hypothyroid patients during normalization of thyroid function: a double-blind, placebo-controlled study. Eur. J. Endocrinol. 160, 409–415 (2009).

    Article  CAS  PubMed  Google Scholar 

  144. Lerman, A. & Zeiher, A. M. Endothelial function: cardiac events. Circulation 111, 363–368 (2005).

    Article  PubMed  Google Scholar 

  145. Lekakis, J. et al. Flow-mediated, endothelium-dependent vasodilation is impaired in subjects with hypothyroidism, borderline hypothyroidism, and high-normal serum thyrotropin (TSH) values. Thyroid 7, 411–414 (1997).

    Article  CAS  PubMed  Google Scholar 

  146. Taddei, S. et al. Impaired endothelium-dependent vasodilatation in subclinical hypothyroidism: beneficial effect of levothyroxine therapy. J. Clin. Endocrinol. Metab. 88, 3731–3737 (2003).

    Article  CAS  PubMed  Google Scholar 

  147. Taddei, S. et al. Low-grade systemic inflammation causes endothelial dysfunction in patients with Hashimoto's thyroiditis. J. Clin. Endocrinol. Metab. 91, 5076–5082 (2006).

    Article  CAS  PubMed  Google Scholar 

  148. Kvetny, J., Heldgaard, P. E., Bladbjerg, E. M. & Gram, J. Subclinical hypothyroidism is associated with a low-grade inflammation, increased triglyceride levels and predicts cardiovascular disease in males below 50 years. Clin. Endocrinol. (Oxf.) 61, 232–238 (2004).

    Article  CAS  Google Scholar 

  149. Turemen, E. E., Cetinarslan, B., Sahin, T., Canturk, Z. & Tarkun, I. Endothelial dysfunction and low grade chronic inflammation in subclinical hypothyroidism due to autoimmune thyroiditis. Endocr. J. 58, 349–354 (2011).

    Article  CAS  PubMed  Google Scholar 

  150. Cikim, A. S. et al. Evaluation of endothelial function in subclinical hypothyroidism and subclinical hyperthyroidism. Thyroid 14, 605–609 (2004).

    Article  PubMed  Google Scholar 

  151. Marazuela, M., Sanchez-Madrid, F., Acevedo, A., Larranaga, E. & de Landazuri, M. O. Expression of vascular adhesion molecules on human endothelia in autoimmune thyroid disorders. Clin. Exp. Immunol. 102, 328–334 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Suarez, J. et al. In vivo selective expression of thyroid hormone receptor α1 in endothelial cells attenuates myocardial injury in experimental myocardial infarction in mice. Am. J. Physiol. Regul. Integr. Comp. Physiol. 307, R340–R346 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Carrillo-Sepulveda, M. A. et al. Thyroid hormone stimulates NO production via activation of the PI3K/Akt pathway in vascular myocytes. Cardiovasc. Res. 85, 560–570 (2010).

    Article  CAS  PubMed  Google Scholar 

  154. Wang, X., Zheng, W., Christensen, L. P. & Tomanek, R. J. DITPA stimulates bFGF, VEGF, angiopoietin, and Tie-2 and facilitates coronary arteriolar growth. Am. J. Physiol. Heart Circ. Physiol. 284, H613—H618 (2003).

    Google Scholar 

  155. Tomanek, R. J., Doty, M. K. & Sandra, A. Early coronary angiogenesis in response to thyroxine: growth characteristics and upregulation of basic fibroblast growth factor. Circ. Res. 82, 587–593 (1998).

    Article  CAS  PubMed  Google Scholar 

  156. Erem, C. Blood coagulation, fibrinolytic activity and lipid profile in subclinical thyroid disease: subclinical hyperthyroidism increases plasma factor X activity. Clin. Endocrinol. (Oxf.) 64, 323–329 (2006).

    Article  CAS  Google Scholar 

  157. Franchini, M., Lippi, G. & Targher, G. Hyperthyroidism and venous thrombosis: a casual or causal association? A systematic literature review. Clin. Appl. Thromb. Hemostasis 17, 387–392 (2011).

    Article  Google Scholar 

  158. Dorr, M. et al. The association of thyroid function with carotid artery plaque burden and strokes in a population-based sample from a previously iodine-deficient area. Eur. J. Endocrinol. 159, 145–152 (2008).

    Article  CAS  PubMed  Google Scholar 

  159. Muller, B. et al. Haemostatic profile in hypothyroidism as potential risk factor for vascular or thrombotic disease. Eur. J. Clin. Invest. 31, 131–137 (2001).

    Article  CAS  PubMed  Google Scholar 

  160. Canturk, Z. et al. Hemostatic system as a risk factor for cardiovascular disease in women with subclinical hypothyroidism. Thyroid 13, 971–977 (2003).

    Article  CAS  PubMed  Google Scholar 

  161. Viswanathan, G. et al. Blood thrombogenicity is independently associated with serum TSH levels in post-non-ST elevation acute coronary syndrome. J. Clin. Endocrinol. Metab. 99, E1050–E1054 (2014).

    Article  CAS  PubMed  Google Scholar 

  162. Squizzato, A., Gerdes, V. E., Brandjes, D. P., Buller, H. R. & Stam, J. Thyroid diseases and cerebrovascular disease. Stroke 36, 2302–2310 (2005).

    Article  CAS  PubMed  Google Scholar 

  163. Erem, C. et al. Blood coagulation and fibrinolytic activity in hypothyroidism. Int. J. Clin. Pract. 57, 78–81 (2003).

    CAS  PubMed  Google Scholar 

  164. Nitu-Whalley, I. C. & Lee, C. A. Acquired von Willebrand syndrome — report of 10 cases and review of the literature. Haemophilia 5, 318–326 (1999).

    Article  CAS  PubMed  Google Scholar 

  165. Michiels, J. J., Schroyens, W., Berneman, Z. & van der Planken, M. Acquired von Willebrand syndrome type 1 in hypothyroidism: reversal after treatment with thyroxine. Clin. Appl. Thromb. Hemostasis 7, 113–115 (2001).

    Article  CAS  Google Scholar 

  166. Gullu, S., Sav, H. & Kamel, N. Effects of levothyroxine treatment on biochemical and hemostasis parameters in patients with hypothyroidism. Eur. J. Endocrinol. 152, 355–361 (2005).

    Article  CAS  PubMed  Google Scholar 

  167. Chadarevian, R. et al. Components of the fibrinolytic system are differently altered in moderate and severe hypothyroidism. J. Clin. Endocrinol. Metab. 86, 732–737 (2001).

    Article  CAS  PubMed  Google Scholar 

  168. Virtanen, V. K., Saha, H. H., Groundstroem, K. W., Salmi, J. & Pasternack, A. I. Thyroid hormone substitution therapy rapidly enhances left-ventricular diastolic function in hypothyroid patients. Cardiology 96, 59–64 (2001).

    Article  CAS  PubMed  Google Scholar 

  169. Tielens, E. T., Pillay, M., Storm, C. & Berghout, A. Changes in cardiac function at rest before and after treatment in primary hypothyroidism. Am. J. Cardiol. 85, 376–380 (2000).

    Article  CAS  PubMed  Google Scholar 

  170. Aghini-Lombardi, F. et al. Early textural and functional alterations of left ventricular myocardium in mild hypothyroidism. Eur. J. Endocrinol. 155, 3–9 (2006).

    Article  CAS  PubMed  Google Scholar 

  171. Yazici, M. et al. Effects of thyroxin therapy on cardiac function in patients with subclinical hypothyroidism: index of myocardial performance in the evaluation of left ventricular function. Int. J. Cardiol. 95, 135–143 (2004).

    Article  PubMed  Google Scholar 

  172. Simonides, W. S. et al. Hypoxia-inducible factor induces local thyroid hormone inactivation during hypoxic-ischemic disease in rats. J. Clin. Invest. 118, 975–983 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Diano, S. & Horvath, T. L. Type 3 deiodinase in hypoxia: to cool or to kill? Cell Metab. 7, 363–364 (2008).

    Article  CAS  PubMed  Google Scholar 

  174. Silva-Tinoco, R. et al. Developing thyroid disorders is associated with poor prognosis factors in patient with stable chronic heart failure. Int. J. Cardiol. 147, e24–e25 (2011).

    Article  PubMed  Google Scholar 

  175. Passino, C. et al. Prognostic value of combined measurement of brain natriuretic peptide and triiodothyronine in heart failure. J. Card. Fail. 15, 35–40 (2009).

    Article  CAS  PubMed  Google Scholar 

  176. Iacoviello, M. et al. Prognostic role of sub-clinical hypothyroidism in chronic heart failure outpatients. Curr. Pharm. Design 14, 2686–2692 (2008).

    Article  CAS  Google Scholar 

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

    Article  PubMed  Google Scholar 

  178. Pingitore, A. et al. Triiodothyronine levels for risk stratification of patients with chronic heart failure. Am. J. Med. 118, 132–136 (2005).

    Article  CAS  PubMed  Google Scholar 

  179. Chuang, C. P., Jong, Y. S., Wu, C. Y. & Lo, H. M. Impact of triiodothyronine and N-terminal pro-B-type natriuretic peptide on the long-term survival of critically ill patients with acute heart failure. Am. J. Cardiol. 113, 845–850 (2014).

    Article  CAS  PubMed  Google Scholar 

  180. Hamilton, M. A. et al. Safety and hemodynamic effects of intravenous triiodothyronine in advanced congestive heart failure. Am. J. Cardiol. 81, 443–447 (1998).

    Article  CAS  PubMed  Google Scholar 

  181. Pingitore, A. et al. 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 (2008).

    Article  CAS  PubMed  Google Scholar 

  182. James, S. R. et al. The effects of acute triiodothyronine therapy on myocardial gene expression in brain stem dead cardiac donors. J. Clin. Endocrinol. Metab. 95, 1338–1343 (2010).

    Article  CAS  PubMed  Google Scholar 

  183. Holmager, P. et al. Long-term L-triiodothyronine (T3) treatment in stable systolic heart failure patients: a randomised, double-blind, cross-over, placebo-controlled intervention study. Clin. Endocrinol. (Oxf.) 83, 931–937 (2015).

    Article  CAS  Google Scholar 

  184. Moruzzi, P., Doria, E., Agostoni, P. G., Capacchione, V. & Sganzerla, P. Usefulness of l-thyroxine to improve cardiac and exercise performance in idiopathic dilated cardiomyopathy. Am. J. Cardiol. 73, 374–378 (1994).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  186. Yu, J. & Koenig, R. J. Regulation of hepatocyte thyroxine 5′-deiodinase by T3 and nuclear receptor coactivators as a model of the sick euthyroid syndrome. J. Biol. Chem. 275, 38296–38301 (2000).

    Article  CAS  PubMed  Google Scholar 

  187. Lim, A. S., Paz-Pacheco, E., Reyes, M. & Punzalan, F. Pericardial decompression syndrome in a patient with hypothyroidism presenting as massive pericardial effusion: a case report and review of related literature. BMJ Case Rep. http://dx.doi.org/10.1136/bcr.04.2011.4117 (2011).

  188. Kabadi, U. M. & Kumar, S. P. Pericardial effusion in primary hypothyroidism. Am. Heart J. 120, 1393–1395 (1990).

    Article  CAS  PubMed  Google Scholar 

  189. Sachdev, Y. & Hall, R. Effusions into body cavities in hypothyroidism. Lancet 1, 564–566 (1975).

    Article  CAS  PubMed  Google Scholar 

  190. Iacobellis, G. & Sharma, A. M. Epicardial adipose tissue as new cardio-metabolic risk marker and potential therapeutic target in the metabolic syndrome. Curr. Pharm. Design 13, 2180–2184 (2007).

    Article  CAS  Google Scholar 

  191. Jeong, J. W. et al. Echocardiographic epicardial fat thickness and coronary artery disease. Circ. J. 71, 536–539 (2007).

    Article  PubMed  Google Scholar 

  192. Baker, A. R. et al. Human epicardial adipose tissue expresses a pathogenic profile of adipocytokines in patients with cardiovascular disease. Cardiovasc. Diabetol. 5, 1 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Yazici, D. et al. Effects of restoration of the euthyroid state on epicardial adipose tissue and carotid intima media thickness in subclinical hypothyroid patients. Endocrine 48, 909–915 (2015).

    Article  CAS  PubMed  Google Scholar 

  194. Asik, M. et al. Evaluation of epicardial fat tissue thickness in patients with Hashimoto thyroiditis. Clin. Endocrinol. (Oxf.) 79, 571–576 (2013).

    Article  CAS  Google Scholar 

  195. Robuschi, G. et al. Cardiopulmonary bypass: a low T4 and T3 syndrome with blunted thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH). Horm. Res. 23, 151–158 (1986).

    Article  CAS  PubMed  Google Scholar 

  196. Holland, F. W., 2nd, Brown, P. S. Jr, Weintraub, B. D. & Clark, R. E. Cardiopulmonary bypass and thyroid function: a “euthyroid sick syndrome”. Ann. Thorac. Surg. 52, 46–50 (1991).

    Article  PubMed  Google Scholar 

  197. Novitzky, D. et al. Impact of triiodothyronine on the survival of high-risk patients undergoing open heart surgery. Cardiology 87, 509–515 (1996).

    Article  CAS  PubMed  Google Scholar 

  198. Cerillo, A. G. et al. The low triiodothyronine syndrome: a strong predictor of low cardiac output and death in patients undergoing coronary artery bypass grafting. Ann. Thorac. Surg. 97, 2089–2095 (2014).

    Article  PubMed  Google Scholar 

  199. Klemperer, J. D. et al. Triiodothyronine therapy lowers the incidence of atrial fibrillation after cardiac operations. Ann. Thorac. Surg. 61, 1323–1327 (1996).

    Article  CAS  PubMed  Google Scholar 

  200. Haas, N. A., Camphausen, C. K. & Kececioglu, D. Clinical review: thyroid hormone replacement in children after cardiac surgery — is it worth a try? Crit. Care 10, 213 (2006).

    Article  PubMed  PubMed Central  Google Scholar 

  201. Portman, M. A. et al. Triiodothyronine Supplementation in Infants and Children Undergoing Cardiopulmonary Bypass (TRICC): a multicenter placebo-controlled randomized trial: age analysis. Circulation 122, S224–S233 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Chowdhury, D. et al. A prospective randomized clinical study of thyroid hormone treatment after operations for complex congenital heart disease. J. Thorac. Cardiovasc. Surg. 122, 1023–1025 (2001).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  204. Li, L. et al. Negative association between free triiodothyronine level and international normalized ratio in euthyroid subjects with acute myocardial infarction. Acta Pharmacol. Sin. 32, 1351–1356 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Ozcan, K. S. et al. Sick euthyroid syndrome is associated with poor prognosis in patients with ST segment elevation myocardial infarction undergoing primary percutaneous intervention. Cardiol. J. 21, 238–244 (2014).

    Article  PubMed  Google Scholar 

  206. Ertugrul, O. et al. Prevalence of subclinical hypothyroidism among patients with acute myocardial infarction. ISRN Endocrinol. 2011, 810251 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Olivares, E. L. et al. Thyroid function disturbance and type 3 iodothyronine deiodinase induction after myocardial infarction in rats a time course study. Endocrinology 148, 4786–4792 (2007).

    Article  CAS  PubMed  Google Scholar 

  208. Van den Berghe, G. Non-thyroidal illness in the ICU: a syndrome with different faces. Thyroid 24, 1456–1465 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  210. Zhang, B., Peng, W., Wang, C., Li, W. & Xu, Y. A low fT3 level as a prognostic marker in patients with acute myocardial infarctions. Intern. Med. 51, 3009–3015 (2012).

    Article  CAS  PubMed  Google Scholar 

  211. Friberg, L., Drvota, V., Bjelak, A. H., Eggertsen, G. & Ahnve, S. Association between increased levels of reverse triiodothyronine and mortality after acute myocardial infarction. Am. J. Med. 111, 699–703 (2001).

    Article  CAS  PubMed  Google Scholar 

  212. Kimur, T. et al. Correlation of circulating interleukin-10 with thyroid hormone in acute myocardial infarction. Res. Commun. Mol. Pathol. Pharmacol. 110, 53–58 (2001).

    CAS  PubMed  Google Scholar 

  213. Lymvaios, I. et al. Thyroid hormone and recovery of cardiac function in patients with acute myocardial infarction: a strong association? Eur. J. Endocrinol. 165, 107–114 (2011).

    Article  CAS  PubMed  Google Scholar 

  214. Pingitore, A. et al. Cardioprotection and thyroid hormones. Heart Failure Rev. 21, 391–399 (2016).

    Article  CAS  Google Scholar 

  215. Columbano, A. et al. The thyroid hormone receptor-β agonist GC-1 induces cell proliferation in rat liver and pancreas. Endocrinology 147, 3211–3218 (2006).

    Article  CAS  PubMed  Google Scholar 

  216. Naqvi, N. et al. A proliferative burst during preadolescence establishes the final cardiomyocyte number. Cell 157, 795–807 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Forini, F. et al. Early long-term L-T3 replacement rescues mitochondria and prevents ischemic cardiac remodelling in rats. J. Cell. Mol. Med. 15, 514–524 (2011).

    Article  CAS  PubMed  Google Scholar 

  218. Dixon, J. A. & Spinale, F. G. Pathophysiology of myocardial injury and remodeling: implications for molecular imaging. J. Nucl. Med. 51, 102S–106S (2010).

    Article  PubMed  Google Scholar 

  219. Gerdes, A. M. et al. Structural remodeling of cardiac myocytes in patients with ischemic cardiomyopathy. Circulation 86, 426–430 (1992).

    Article  CAS  PubMed  Google Scholar 

  220. Pfeffer, M. A. Left ventricular remodeling after acute myocardial infarction. Annu. Rev. Med. 46, 455–466 (1995).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  222. Henderson, K. K. et al. Physiological replacement of T3 improves left ventricular function in an animal model of myocardial infarction-induced congestive heart failure. Circ. Heart Fail. 2, 243–252 (2009).

    Article  PubMed  Google Scholar 

  223. Katzeff, H. L., Powell, S. R. & Ojamaa, K. Alterations in cardiac contractility and gene expression during low-T3 syndrome: prevention with T3 . Am. J. Physiol. 273, E951–E956 (1997).

    CAS  PubMed  Google Scholar 

  224. Willis, B. C. et al. Impaired oxidative metabolism and calcium mishandling underlie cardiac dysfunction in a rat model of post-acute isoproterenol-induced cardiomyopathy. Am. J. Physiol. Heart Circ. Physiol. 308, H467–H477 (2015).

    Article  CAS  PubMed  Google Scholar 

  225. Rybin, V. & Steinberg, S. F. Thyroid hormone represses protein kinase C isoform expression and activity in rat cardiac myocytes. Circ. Res. 79, 388–398 (1996).

    Article  CAS  PubMed  Google Scholar 

  226. Pantos, C. et al. 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 (2009).

    Article  CAS  PubMed  Google Scholar 

  227. Pantos, C. et al. 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 (2003).

    Article  CAS  PubMed  Google Scholar 

  228. Mourouzis, I. et al. Dose-dependent effects of thyroid hormone on post-ischemic cardiac performance: potential involvement of Akt and ERK signalings. Mol. Cell. Biochem. 363, 235–243 (2012).

    Article  CAS  PubMed  Google Scholar 

  229. Forini, F. et al. Triiodothyronine prevents cardiac ischemia/reperfusion mitochondrial impairment and cell loss by regulating miR30a/p53 axis. Endocrinology 155, 4581–4590 (2014).

    Article  CAS  PubMed  Google Scholar 

  230. de Castro, A. L. et al. Thyroid hormones improve cardiac function and decrease expression of pro-apoptotic proteins in the heart of rats 14 days after infarction. Apoptosis 21, 184–194 (2016).

    Article  CAS  PubMed  Google Scholar 

  231. Matsumoto, S. et al. Circulating p53-responsive microRNAs are predictive indicators of heart failure after acute myocardial infarction. Circ. Res. 113, 322–326 (2013).

    Article  CAS  PubMed  Google Scholar 

  232. Eckle, T., Kohler, D., Lehmann, R., El Kasmi, K. & Eltzschig, H. K. Hypoxia-inducible factor-1 is central to cardioprotection: a new paradigm for ischemic preconditioning. Circulation 118, 166–175 (2008).

    Article  CAS  PubMed  Google Scholar 

  233. Moeller, L. C., Dumitrescu, A. M. & Refetoff, S. Cytosolic action of thyroid hormone leads to induction of hypoxia-inducible factor-1α and glycolytic genes. Mol. Endocrinol. 19, 2955–2963 (2005).

    Article  CAS  PubMed  Google Scholar 

  234. Chen, Y. F. et al. Improvement of left ventricular remodeling after myocardial infarction with eight weeks l-thyroxine treatment in rats. J. Transl Med. 11, 40 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Rajagopalan, V. et al. Safe oral triiodo-l-thyronine therapy protects from post-infarct cardiac dysfunction and arrhythmias without cardiovascular adverse effects. PLoS ONE 11, e0151413 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. De Vito, P. et al. Thyroid hormones as modulators of immune activities at the cellular level. Thyroid 21, 879–890 (2011).

    Article  CAS  PubMed  Google Scholar 

  237. Plow, E. F., Haas, T. A., Zhang, L., Loftus, J. & Smith, J. W. Ligand binding to integrins. J. Biol. Chem. 275, 21785–21788 (2000).

    Article  CAS  PubMed  Google Scholar 

  238. Siddiqi, A., Burrin, J. M., Wood, D. F. & Monson, J. P. Tri-iodothyronine regulates the production of interleukin-6 and interleukin-8 in human bone marrow stromal and osteoblast-like cells. J. Endocrinol. 157, 453–461 (1998).

    Article  CAS  PubMed  Google Scholar 

  239. Mascanfroni, I. et al. Control of dendritic cell maturation and function by triiodothyronine. FASEB J. 22, 1032–1042 (2008).

    Article  CAS  PubMed  Google Scholar 

  240. Wong, G. H. & Goeddel, D. V. Induction of manganous superoxide dismutase by tumor necrosis factor: possible protective mechanism. Science 242, 941–944 (1988).

    Article  CAS  PubMed  Google Scholar 

  241. Nakano, M., Knowlton, A. A., Yokoyama, T., Lesslauer, W. & Mann, D. L. Tumor necrosis factor-alpha-induced expression of heat shock protein 72 in adult feline cardiac myocytes. Am. J. Physiol. 270, H1231–H1239 (1996).

    CAS  PubMed  Google Scholar 

  242. Finkel, M. S. et al. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 257, 387–389 (1992).

    Article  CAS  PubMed  Google Scholar 

  243. Lubrano, V., Pingitore, A., Carpi, A. & Iervasi, G. Relationship between triiodothyronine and proinflammatory cytokines in chronic heart failure. Biomed. Pharmacother. 64, 165–169 (2010).

    Article  CAS  PubMed  Google Scholar 

  244. Kimura, T. et al. 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 (2000).

    Article  CAS  PubMed  Google Scholar 

  245. Chen, Y. F. et al. 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 (2008).

    Article  CAS  PubMed  Google Scholar 

  246. Gerdes, A. M. & Iervasi, G. Thyroid replacement therapy and heart failure. Circulation 122, 385–393 (2010).

    Article  PubMed  Google Scholar 

  247. Jabbar, A., Ingoe, L., Pearce, S., Zaman, A. & Razvi, S. Thyroxine in acute myocardial infarction (ThyrAMI) — levothyroxine in subclinical hypothyroidism post-acute myocardial infarction: study protocol for a randomised controlled trial. Trials 16, 115 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Mourouzis, I., Forini, F., Pantos, C. & Iervasi, G. Thyroid hormone and cardiac disease: from basic concepts to clinical application. J. Thyroid Res. 2011, 958626 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

S.R. is supported by a National Institute for Health Research (NIHR) Career Development Fellowship. The work of S.H.S.P. on subclinical hyperthyroidism was funded by MRC Grant G0500783. This report is independent research supported by the National Institute for Health Research Career Development Fellowship CDF−2012–05–231. The views expressed in this publication are those of the author(s) and not necessarily those of the National Health Service, the NIHR, or the Department of Health.

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Jabbar, A., Pingitore, A., Pearce, S. et al. Thyroid hormones and cardiovascular disease. Nat Rev Cardiol 14, 39–55 (2017). https://doi.org/10.1038/nrcardio.2016.174

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