Abstract
Thyroid hormone action is modulated by the interaction between circulating levels of thyroid hormone and the cellular and nuclear signal translation mechanisms leading to a fine time- and cell-specific regulation of the hormonal signal. The peripheral metabolism of thyroid hormone is responsible for the activation or degradation of thyroid hormone and plays a pivotal role in regulating the circulating levels of T3 in hypothyroidism. Additionally acute and chronic cardiovascular disease are associated with a decrease in circulating levels of T3, possibly maladaptive, prompting the hypothesis that T3 replacement may hasten myocardial recovery. The design of therapy aimed to restore circulating and tissue levels of T3 during cardiovascular disease should take in account the pharmacokinetics characteristics of T3 and the potential for clinically relevant rapid non-genomic effects of thyroid hormone.
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References
Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations in serum T(4) and T(3) in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab. 2002;87(3):1068–72.
Vella KR, Hollenberg AN. The actions of thyroid hormone signaling in the nucleus. Mol Cell Endocrinol. 2017;458:127–35.
Abdalla SM, Bianco AC. Defending plasma T3 is a biological priority. Clin Endocrinol (Oxf). 2014;81(5):633–41.
Bianco AC, da Conceicao RR. The deiodinase trio and thyroid hormone signaling. Methods Mol Biol. 1801;2018:67–83.
Pilo A, Iervasi G, Vitek F, Ferdeghini M, Cazzuola F, Bianchi R. Thyroidal and peripheral production of 3,5,3′-triiodothyronine in humans by multicompartmental analysis. Am J Physiol. 1990;258(4 Pt 1):E715–26.
Wassner AJ, Jugo RH, Dorfman DM, Padera RF, Maynard MA, Zavacki AM, et al. Myocardial induction of type 3 deiodinase in dilated cardiomyopathy. Thyroid. 2017;27(5):732–7.
Janssen R, Muller A, Simonides WS. Cardiac thyroid hormone metabolism and heart failure. Eur Thyroid J. 2017;6(3):130–7.
Friberg L, Drvota V, Bjelak AH, Eggertsen G, Ahnve S. Association between increased levels of reverse triiodothyronine and mortality after acute myocardial infarction. Am J Med. 2001;111(9):699–703.
Peeters RP, Wouters PJ, Kaptein E, van Toor H, Visser TJ, Van den Berghe G. Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients. J Clin Endocrinol Metab. 2003;88(7):3202–11.
Coceani M, Iervasi G, Pingitore A, Carpeggiani C, L’Abbate A. Thyroid hormone and coronary artery disease: from clinical correlations to prognostic implications. Clin Cardiol. 2009;32(7):380–5.
Jonklaas J, Bianco AC, Bauer AJ, Burman KD, Cappola AR, Celi FS, et al. Guidelines for the treatment of hypothyroidism: prepared by the American Thyroid Association Task Force on thyroid hormone replacement. Thyroid. 2014;24(12):1670–751.
Biondi B, Wartofsky L. Combination treatment with T4 and T3: toward personalized replacement therapy in hypothyroidism? J Clin Endocrinol Metab. 2012;97(7):2256–71.
Cappola AR, Desai AS, Medici M, Cooper LS, Egan D, Sopko G, et al. Thyroid and cardiovascular disease: research agenda for enhancing knowledge, prevention, and treatment. Thyroid. 2019;29(6):760–77.
Kannan L, Shaw PA, Morley MP, Brandimarto J, Fang JC, Sweitzer NK, et al. Thyroid dysfunction in heart failure and cardiovascular outcomes. Circ Heart Fail. 2018;11(12):e005266.
Collet TH, Bauer DC, Cappola AR, Asvold BO, Weiler S, Vittinghoff E, et al. Thyroid antibody status, subclinical hypothyroidism, and the risk of coronary heart disease: an individual participant data analysis. J Clin Endocrinol Metab. 2014;99(9):3353–62.
Gencer B, Collet TH, Virgini V, Bauer DC, Gussekloo J, Cappola AR, et al. Subclinical thyroid dysfunction and the risk of heart failure events: an individual participant data analysis from 6 prospective cohorts. Circulation. 2012;126(9):1040–9.
Rodondi N, den Elzen WP, Bauer DC, Cappola AR, Razvi S, Walsh JP, et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality. JAMA. 2010;304(12):1365–74.
Rodondi N, Bauer DC, Cappola AR, Cornuz J, Robbins J, Fried LP, et al. Subclinical thyroid dysfunction, cardiac function, and the risk of heart failure. The cardiovascular health study. J Am Coll Cardiol. 2008;52(14):1152–9.
Novitzky D, Human PA, Cooper DK. Inotropic effect of triiodothyronine following myocardial ischemia and cardiopulmonary bypass: an experimental study in pigs. Ann Thorac Surg. 1988;45(1):50–5.
Novitzky D, Cooper DK, Swanepoel A. 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. 1989;3(2):140–5.
Klemperer JD, Zelano J, Helm RE, Berman K, Ojamaa K, Klein I, et al. Triiodothyronine improves left ventricular function without oxygen wasting effects after global hypothermic ischemia. J Thorac Cardiovasc Surg. 1995;109(3):457–65.
Klemperer JD, Klein I, Gomez M, Helm RE, Ojamaa K, Thomas SJ, et al. Thyroid hormone treatment after coronary-artery bypass surgery. N Engl J Med. 1995;333(23):1522–7.
Bennett-Guerrero E, Jimenez JL, White WD, D’Amico EB, Baldwin BI, Schwinn DA. Cardiovascular effects of intravenous triiodothyronine in patients undergoing coronary artery bypass graft surgery. A randomized, double-blind, placebo- controlled trial. Duke T3 study group. JAMA. 1996;275(9):687–92.
Mullis-Jansson SL, Argenziano M, Corwin S, Homma S, Weinberg AD, Williams M, et al. A randomized double-blind study of the effect of triiodothyronine on cardiac function and morbidity after coronary bypass surgery. J Thorac Cardiovasc Surg. 1999;117(6):1128–34.
Klemperer JD, Klein IL, Ojamaa K, Helm RE, Gomez M, Isom OW, et al. Triiodothyronine therapy lowers the incidence of atrial fibrillation after cardiac operations. Ann Thorac Surg. 1996;61(5):1323–7; discussion 8–9.
Bettendorf M, Schmidt KG, Grulich-Henn J, Ulmer HE, Heinrich UE. Tri-iodothyronine treatment in children after cardiac surgery: a double-blind, randomised, placebo-controlled study. Lancet. 2000;356(9229):529–34.
Mackie AS, Booth KL, Newburger JW, Gauvreau K, Huang SA, Laussen PC, et al. A randomized, double-blind, placebo-controlled pilot trial of triiodothyronine in neonatal heart surgery. J Thorac Cardiovasc Surg. 2005;130(3):810–6.
Flores S, Loomba RS, Checchia PA, Graham EM, Bronicki RA. Thyroid hormone (triiodothyronine) therapy in children after congenital heart surgery: a meta-analysis. Semin Thorac Cardiovasc Surg. 2019;S1043–0679(19):30168–6.
Zhang JQ, Yang QY, Xue FS, Zhang W, Yang GZ, Liao X, et al. Preoperative oral thyroid hormones to prevent euthyroid sick syndrome and attenuate myocardial ischemia-reperfusion injury after cardiac surgery with cardiopulmonary bypass in children: a randomized, double-blind, placebo-controlled trial. Medicine (Baltimore). 2018;97(36):e12100.
Vavouranakis I, Sanoudos G, Manios A, Kalogeropoulou K, Sitaras K, Kokkinos C. Triiodothyronine administration in coronary artery bypass surgery: effect on hemodynamics. J Cardiovasc Surg (Torino). 1994;35(5):383–9.
Chaker L, van den Berg ME, Niemeijer MN, Franco OH, Dehghan A, Hofman A, et al. Thyroid function and sudden cardiac death: a prospective population-based cohort study. Circulation. 2016;134(10):713–22.
Collet TH, Gussekloo J, Bauer DC, den Elzen WP, Cappola AR, Balmer P, et al. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med. 2012;172(10):799–809.
Hiroi Y, Kim HH, Ying H, Furuya F, Huang Z, Simoncini T, et al. Rapid nongenomic actions of thyroid hormone. Proc Natl Acad Sci U S A. 2006;103(38):14104–9.
Cao X, Kambe F, Yamauchi M, Seo H. Thyroid-hormone-dependent activation of the phosphoinositide 3-kinase/Akt cascade requires Src and enhances neuronal survival. Biochem J. 2009;424(2):201–9.
Vicinanza R, Coppotelli G, Malacrino C, Nardo T, Buchetti B, Lenti L, et al. Oxidized low-density lipoproteins impair endothelial function by inhibiting non-genomic action of thyroid hormone-mediated nitric oxide production in human endothelial cells. Thyroid. 2013;23(2):231–8.
Rees-Jones RW, Rolla AR, Larsen PR. Hormonal content of thyroid replacement preparations. JAMA. 1980;243(6):549–50.
Razvi S, Weaver JU, Butler TJ, Pearce SH. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch Intern Med. 2012;172(10):811–7.
Villar HC, Saconato H, Valente O, Atallah AN. Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev. 2007;(3):CD003419.
Parle J, Roberts L, Wilson S, Pattison H, Roalfe A, Haque MS, et al. A randomized controlled trial of the effect of thyroxine replacement on cognitive function in community-living elderly subjects with subclinical hypothyroidism: the Birmingham elderly thyroid study. J Clin Endocrinol Metab. 2010;95(8):3623–32.
Stott DJ, Rodondi N, Kearney PM, Ford I, Westendorp RGJ, Mooijaart SP, et al. Thyroid hormone therapy for older adults with subclinical hypothyroidism. N Engl J Med. 2017;376(26):2534–44.
Gullo D, Latina A, Frasca F, Le Moli R, Pellegriti G, Vigneri R. Levothyroxine monotherapy cannot guarantee euthyroidism in all athyreotic patients. PLoS One. 2011;6(8):e22552.
Woeber KA. Levothyroxine therapy and serum free thyroxine and free triiodothyronine concentrations. J Endocrinol Invest. 2002;25(2):106–9.
Escobar-Morreale HF, del Rey FE, Obregon MJ, de Escobar GM. Only the combined treatment with thyroxine and triiodothyronine ensures euthyroidism in all tissues of the thyroidectomized rat. Endocrinology. 1996;137(6):2490–502.
Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ Jr. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med. 1999;340(6):424–9.
Rodriguez T, Lavis VR, Meininger JC, Kapadia AS, Stafford LF. Substitution of liothyronine at a 1:5 ratio for a portion of levothyroxine: effect on fatigue, symptoms of depression, and working memory versus treatment with levothyroxine alone. Endocr Pract. 2005;11(4):223–33.
Walsh JP, Shiels L, Lim EM, Bhagat CI, Ward LC, Stuckey BG, et al. Combined thyroxine/liothyronine treatment does not improve well-being, quality of life, or cognitive function compared to thyroxine alone: a randomized controlled trial in patients with primary hypothyroidism. J Clin Endocrinol Metab. 2003;88(10):4543–50.
Appelhof BC, Fliers E, Wekking EM, Schene AH, Huyser J, Tijssen JG, et al. Combined therapy with levothyroxine and liothyronine in two ratios, compared with levothyroxine monotherapy in primary hypothyroidism: a double-blind, randomized, controlled clinical trial. J Clin Endocrinol Metab. 2005;90(5):2666–74.
Sawka AM, Gerstein HC, Marriott MJ, MacQueen GM, Joffe RT. Does a combination regimen of thyroxine (T4) and 3,5,3′-triiodothyronine improve depressive symptoms better than T4 alone in patients with hypothyroidism? Results of a double-blind, randomized, controlled trial. J Clin Endocrinol Metab. 2003;88(10):4551–5.
Bunevicius R, Jakuboniene N, Jurkevicius R, Cernicat J, Lasas L, Prange AJ Jr. Thyroxine vs thyroxine plus triiodothyronine in treatment of hypothyroidism after thyroidectomy for Graves’ disease. Endocrine. 2002;18(2):129–33.
Clyde PW, Harari AE, Getka EJ, Shakir KM. Combined levothyroxine plus liothyronine compared with levothyroxine alone in primary hypothyroidism: a randomized controlled trial. JAMA. 2003;290(22):2952–8.
Escobar-Morreale HF, Botella-Carretero JI, Gomez-Bueno M, Galan JM, Barrios V, Sancho J. Thyroid hormone replacement therapy in primary hypothyroidism: a randomized trial comparing L-thyroxine plus liothyronine with L-thyroxine alone. Ann Intern Med. 2005;142(6):412–24.
Fadeyev VV, Morgunova TB, Melnichenko GA, Dedov II. Combined therapy with L-thyroxine and L-triiodothyronine compared to L-thyroxine alone in the treatment of primary hypothyroidism. Hormones (Athens). 2010;9(3):245–52.
Nygaard B, Jensen EW, Kvetny J, Jarlov A, Faber J. Effect of combination therapy with thyroxine (T4) and 3,5,3′-triiodothyronine versus T4 monotherapy in patients with hypothyroidism, a double-blind, randomised cross-over study. Eur J Endocrinol. 2009;161(6):895–902.
Saravanan P, Simmons DJ, Greenwood R, Peters TJ, Dayan CM. Partial substitution of thyroxine (T4) with tri-iodothyronine in patients on T4 replacement therapy: results of a large community-based randomized controlled trial. J Clin Endocrinol Metab. 2005;90(2):805–12.
Siegmund W, Spieker K, Weike AI, Giessmann T, Modess C, Dabers T, et al. Replacement therapy with levothyroxine plus triiodothyronine (bioavailable molar ratio 14:1) is not superior to thyroxine alone to improve well-being and cognitive performance in hypothyroidism. Clin Endocrinol (Oxf). 2004;60(6):750–7.
Valizadeh M, Seyyed-Majidi MR, Hajibeigloo H, Momtazi S, Musavinasab N, Hayatbakhsh MR. Efficacy of combined levothyroxine and liothyronine as compared with levothyroxine monotherapy in primary hypothyroidism: a randomized controlled trial. Endocr Res. 2009;34(3):80–9.
Hoang TD, Olsen CH, Mai VQ, Clyde PW, Shakir MK. Desiccated thyroid extract compared with levothyroxine in the treatment of hypothyroidism: a randomized, double-blind, crossover study. J Clin Endocrinol Metab. 2013;98(5):1982–90.
Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, et al. Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Thyroid. 2012;22(12):1200–35.
Pearce SH, Brabant G, Duntas LH, Monzani F, Peeters RP, Razvi S, et al. 2013 ETA guideline: management of subclinical hypothyroidism. Eur Thyroid J. 2013;2(4):215–28.
Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP. 2012 ETA guidelines: the use of L-T4 + L-T3 in the treatment of hypothyroidism. Eur Thyroid J. 2012;1(2):55–71.
Oddie TH, Fisher DA, Rogers C. Whole-body counting of I-131-labeled thyroxine. J Clin Endocrinol Metab. 1964;24:628–37.
Nicoloff JT, Low JC, Dussault JH, Fisher DA. Simultaneous measurement of thyroxine and triiodothyronine peripheral turnover kinetics in man. J Clin Invest. 1972;51(3):473–83.
Cavalieri RR, Steinberg M, Searle GL. Metabolic clearance rate of L-triiodothyronine in man: a comparison of results by single-injection and constant infusion methods. J Clin Endocrinol Metab. 1971;33(4):624–9.
Fisher DA, Oddie TH. Whole-body counting of 131-I-labeled triiodothyronine. J Clin Endocrinol Metab. 1964;24:733–9.
Woeber KA, Sobel RJ, Ingbar SH, Sterling K. The peripheral metabolism of triiodothyronine in normal subjects and in patients with hyperthyroidism. J Clin Invest. 1970;49(4):643–9.
Saberi M, Utiger RD. Serum thyroid hormone and thyrotropin concentrations during thyroxine and triiodothyronine therapy. J Clin Endocrinol Metab. 1974;39(5):923–7.
Lieblich J, Utiger RD. Triiodothyronine radioimmunoassay. J Clin Invest. 1972;51(1):157–66.
Surks MI, Schadlow AR, Oppenheimer JH. A new radioimmunoassay for plasma L-triiodothyronine: measurements in thyroid disease and in patients maintained on hormonal replacement. J Clin Invest. 1972;51(12):3104–13.
Celi FS, Zemskova M, Linderman JD, Babar NI, Skarulis MC, Csako G, et al. The pharmacodynamic equivalence of levothyroxine and liothyronine: a randomized, double blind, cross-over study in thyroidectomized patients. Clin Endocrinol (Oxf). 2010;72(5):709–15.
Celi FS, Zemskova M, Linderman JD, Smith S, Drinkard B, Sachdev V, et al. Metabolic effects of liothyronine therapy in hypothyroidism: a randomized, double-blind, crossover trial of liothyronine versus levothyroxine. J Clin Endocrinol Metab. 2011;96(11):3466–74.
Jonklaas J, Burman KD, Wang H, Latham KR. Single-dose T3 administration: kinetics and effects on biochemical and physiological parameters. Ther Drug Monit. 2015;37(1):110–8.
Celi GF, Linderman JD, Smith S, Yavuz S, Pucino F, Van Tassel N. Pharmacokinetics of liothyronine during thyroid hormone therapy withdrawal. In: Society TE, editor. Endocrine Society ENDO 2019 Annual Meeting; New Orleans LA 2019.
LeBoff MS, Kaplan MM, Silva JE, Larsen PR. Bioavailability of thyroid hormones from oral replacement preparations. Metabolism. 1982;31(9):900–5.
Saravanan P, Siddique H, Simmons DJ, Greenwood R, Dayan CM. Twenty-four hour hormone profiles of TSH, free T3 and free T4 in hypothyroid patients on combined T3/T4 therapy. Exp Clin Endocrinol Diabetes. 2007;115(4):261–7.
Ladenson PW, Sherman SI, Baughman KL, Ray PE, Feldman AM. Reversible alterations in myocardial gene expression in a young man with dilated cardiomyopathy and hypothyroidism. Proc Natl Acad Sci U S A. 1992;89(12):5251–5.
Klein I, Ojamaa K. Thyroid hormone and the cardiovascular system. N Engl J Med. 2001;344(7):501–9.
Biondi B, Cooper DS. The clinical significance of subclinical thyroid dysfunction. Endocr Rev. 2008;29(1):76–131.
Sun J, Yao L, Fang Y, Yang R, Chen Y, Yang K, et al. Relationship between subclinical thyroid dysfunction and the risk of cardiovascular outcomes: a systematic review and meta-analysis of prospective cohort studies. Int J Endocrinol. 2017;2017:8130796.
Flynn RW, Bonellie SR, Jung RT, MacDonald TM, Morris AD, Leese GP. Serum thyroid-stimulating hormone concentration and morbidity from cardiovascular disease and fractures in patients on long-term thyroxine therapy. J Clin Endocrinol Metab. 2010;95(1):186–93.
Rothberger GD, Gadhvi S, Michelakis N, Kumar A, Calixte R, Shapiro LE. Usefulness of serum triiodothyronine (T3) to predict outcomes in patients hospitalized with acute heart failure. Am J Cardiol. 2017;119(4):599–603.
Liu J, Wu X, Lu F, Zhao L, Shi L, Xu F. Low T3 syndrome is a strong predictor of poor outcomes in patients with community-acquired pneumonia. Sci Rep. 2016;6:22271.
Slag MF, Morley JE, Elson MK, Crowson TW, Nuttall FQ, Shafer RB. Hypothyroxinemia in critically ill patients as a predictor of high mortality. JAMA. 1981;245(1):43–5.
Hamilton MA, Stevenson LW, Fonarow GC, Steimle A, Goldhaber JI, Child JS, et al. Safety and hemodynamic effects of intravenous triiodothyronine in advanced congestive heart failure. Am J Cardiol. 1998;81(4):443–7.
Pingitore A, Galli E, Barison A, Iervasi A, Scarlattini M, Nucci D, 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. 2008;93(4):1351–8.
Holmager P, Schmidt U, Mark P, Andersen U, Dominguez H, Raymond I, 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). 2015;83(6):931–7.
Pingitore A, Mastorci F, Piaggi P, Aquaro GD, Molinaro S, Ravani M, et al. Usefulness of triiodothyronine replacement therapy in patients with ST elevation myocardial infarction and borderline/reduced triiodothyronine levels (from the THIRST study). Am J Cardiol. 2019;123(6):905–12.
Wimmer BC, Cross AJ, Jokanovic N, Wiese MD, George J, Johnell K, et al. Clinical outcomes associated with medication regimen complexity in older people: a systematic review. J Am Geriatr Soc. 2017;65(4):747–53.
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Celi, F.S. (2020). Modalities of Thyroid Hormone Administration and Correlates Between Blood and Tissue Levels. In: Iervasi, G., Pingitore, A., Gerdes, A., Razvi, S. (eds) Thyroid and Heart . Springer, Cham. https://doi.org/10.1007/978-3-030-36871-5_26
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