Deciphering the roles of triiodothyronine (T3) and thyroid-stimulating hormone (TSH) on cardiac electrical remodeling in clinical and experimental hypothyroidism.
Arrhythmia
Cardiac electrophysiology
Electrical remodeling
Endocrine disease
Journal
Journal of physiology and biochemistry
ISSN: 1877-8755
Titre abrégé: J Physiol Biochem
Pays: Spain
ID NLM: 9812509
Informations de publication
Date de publication:
29 Nov 2023
29 Nov 2023
Historique:
received:
15
06
2023
accepted:
20
11
2023
medline:
29
11
2023
pubmed:
29
11
2023
entrez:
29
11
2023
Statut:
aheadofprint
Résumé
Hypothyroidism is the most frequent endocrine pathology. Although clinical or overt hypothyroidism has been traditionally associated to low T3 / T4 and high thyrotropin (TSH) circulating levels, other forms exist such as subclinical hypothyroidism, characterized by normal blood T3 / T4 and high TSH. In its different forms is estimated to affect approximately 10% of the population, especially women, in a 5:1 ratio with respect to men. Among its consequences are alterations in cardiac electrical activity, especially in the repolarization phase, which is accompanied by an increased susceptibility to cardiac arrhythmias. Although these alterations have traditionally been attributed to thyroid hormone deficiency, recent studies, both clinical trials and experimental models, demonstrate a fundamental role of TSH in cardiac electrical remodeling. Thus, both metabolic thyroid hormones and TSH regulate cardiac ion channel expression in many and varied ways. This means that the different combinations of hormones that predominate in different types of hypothyroidism (overt, subclinic, primary, central) can generate different forms of cardiac electrical remodeling. These new findings are raising the relevant question of whether serum TSH reference ranges should be redefined.
Identifiants
pubmed: 38019451
doi: 10.1007/s13105-023-01000-z
pii: 10.1007/s13105-023-01000-z
doi:
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Ministerio de Ciencia e Innovación
ID : PID2020-118814RB-I00
Organisme : Gobierno Vasco
ID : IT1707-22
Informations de copyright
© 2023. The Author(s).
Références
Akirov A, Gimbel H, Grossman A, Shochat T, Shimon I (2017) Elevated TSH in adults treated for hypothyroidism is associated with increased mortality. Eur J Endocrinol 176:57–66
pubmed: 27760792
doi: 10.1530/EJE-16-0708
Alonso H, Fernandez-Ruocco J, Gallego M, Malagueta-Vieira LL, Rodríguez-de-Yurre A, Medei E, Casis O (2015) Thyroid stimulating hormone directly modulates cardiac electrical activity. J Mol Cel Cardiol 89:280–286
doi: 10.1016/j.yjmcc.2015.10.019
Altun A, Altun G, Ozbay G (1999) QT dispersion in hypothyroidism. Int J Cardiol 72:93–95
pubmed: 10636640
doi: 10.1016/S0167-5273(99)00178-3
Aweimer A, Schiedat F, Schöne D, Landgrafe-Mende G, Bogossian H, Mügge A, Patsalis PC, Gotzmann M, Akin I, El-Battrawy I, Dietrich JW (2021) Abnormal cardiac repolarization in thyroid diseases: results of an observational study. Front Cardiovasc Med 8:738–517. https://doi.org/10.3389/fcvm.2021.738517
doi: 10.3389/fcvm.2021.738517
Ayala A, Mark D, Ladenson MD (2000) When to treat mild hypothyroidism. Endocrinol Metabol Clin North Am 29:399–415
doi: 10.1016/S0889-8529(05)70139-0
Bagchy N, Brown T, Parish F (1990) Thyroid dysfunction in adults over age 55 years. A study in an urban US community. Arch Intern Med 150:785–787
doi: 10.1001/archinte.1990.00390160053012
Bakiner O, Ertorer M, Haydardedeoglu F, Bozkirli E, Tutuncu N, Demirag N (2008) Subclinical hypothyroidism is characterized by increased QT interval dispersion among women. Med Princ Pract 17:390–394
pubmed: 18685279
doi: 10.1159/000141503
Bosch RF, Wang Z, Li GR, Nattel S (1999) Electrophysiological mechanisms by which hypothyroidism delays repolarization in guinea pig hearts. Am J Physiol 277:211–220
Casula S, Ettleson MD, Bianco AC (2023) Are we restoring thyroid hormone signaling in levothyroxine-treated patients with residual symptoms of hypothyroidism? Endocr Pract 29(7):581–588. https://doi.org/10.1016/j.eprac.2023.04.003
doi: 10.1016/j.eprac.2023.04.003
pubmed: 37419565
Ciulla M, Paliotti R, Cortelazzi D, Tortora G, Barelli M, Buonamici V, Magrini F, Beck-Peccoz P (2001) Effects of thyroid hormones on cardiac structure: a tissue characterization study in patients with thyroid disorders before and after treatment. Thyroid 7:613–619
doi: 10.1089/105072501750362673
Chacón I, Barrio V (2013) Nota de prensa de la Sociedad Española de Endocrinología y Nutrición
Davies T, Marians R, Latif R (2002) The TSH receptor reveals itself. J Clin Invest 110:161–164
pubmed: 12122107
pmcid: 151075
doi: 10.1172/JCI0216234
Dillmann WH (1989) Diabetes and thyroid-hormone-induced changes in cardiac function and their molecular basis. Annu Rev Med 40:373–394
pubmed: 2658757
doi: 10.1146/annurev.me.40.020189.002105
Drvota V, Janson A, Norman C, Sylven C, Haggblad J, Bronnegard M, Marcus C (1995) Evidence for the presence of functional thyrotropin receptor in cardiac muscle. Biochem Biophys Res 211:426–431
doi: 10.1006/bbrc.1995.1831
Fernandez-Ruocco J, Gallego M, Rodriguez-de-Yurre A, Zayas-Arrabal J, Echeazarra L, Alquiza A, Fernandez-Lopez V, Rodriguez-Robledo JM, Brito O, Schleier Y, Sepulveda M, Oshiyama NF, Vila-Petroff M, Bassani RA, Medei EH, Casis O (2019) High thyrotropin is critical for cardiac electrical remodeling and arrhythmia vulnerability in hypothyroidism. Thyroid 29:934–945
pubmed: 31084419
pmcid: 6648210
doi: 10.1089/thy.2018.0709
Ferrer T, Arín R, Casis E, Torres-Jacome J, Sanchez-Chapula JA, Casis O (2012) Mechanisms responsible for the altered cardiac repolarization dispersion in experimental hypothyroidism. Acta Physiol (Oxf) 204:502–512
pubmed: 21933354
doi: 10.1111/j.1748-1716.2011.02364.x
Ferrer T, Gallego M, Madrigal R, Torres J, Navarro R, Casis O, Sánchez-Chapula JA (2006) DITPA restores the repolarizing potassium currents Itof and Iss in cardiac ventricular myocytes of diabetic rats. Life Sci 79:883–889
pubmed: 16616210
doi: 10.1016/j.lfs.2006.03.014
Fitzgerald SP, Bean NG, Falhammar H, Tuke J (2020) Clinical parameters are more likely to be associated with thyroid hormone levels than with thyrotropin levels: a systematic review and meta-analysis. Thyroid 30(12):1695–1709. https://doi.org/10.1089/thy.2019.0535
doi: 10.1089/thy.2019.0535
pubmed: 32349628
pmcid: 7757573
Fitzgerald SP, Falhammar H (2022) Redefinition of successful treatment of patients with hypothyroidism. Is TSH the best biomarker of euthyroidism? Front Endocrinol (Lausanne) 13:854–920. https://doi.org/10.3389/fendo.2022.920854
doi: 10.3389/fendo.2022.920854
Galetta F, Franzoni F, Fallahi P, Tocchini L, Braccini L, Santoro G, Antonelli A (2008) Changes in heart rate variability and QT dispersion in patients with overt hypothyroidism. Eur J Endocrinol 158:85–90
pubmed: 18166821
doi: 10.1530/EJE-07-0357
Galetta F, Franzoni F, Fallahi P, Tocchini L, Graci F, Gaddeo C, Rossi M, Cini G, Carpi A, Santoro G, Antonelli A (2010) Changes in autonomic regulation and ventricular repolarization induced by subclinical hyperthyroidism. Biomed Pharmacother 64:546–549
pubmed: 20650598
doi: 10.1016/j.biopha.2009.10.001
Garber JR, Cobin RH, Gharib H, Hennessey JV, Klein I, Mechanick JI, Woeber KA (2012) Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocrine Practice 18(6):989–1028
doi: 10.4158/EP12280.GL
Gascó E, Serna MC, Vázquez A, Peremiquel M, Ibarz M, Serra L (1999) The prevalence of thyroid functional disorders in the province of Lleida. Aten Primaria 24:460–475
Gupta V, Lee M (2011) Central hypothyroidism. Indian. J. Endocrinol Metab 15:S99–S106
Horváth B, Szentandrássy N, Almássy J, Dienes C, Kovács ZM, Nánási PP, Banyasz T (2022) Late sodium current of the heart: where do we stand and where are we going? Pharmaceuticals (Basel) 15(2):231. https://doi.org/10.3390/ph15020231
doi: 10.3390/ph15020231
pubmed: 35215342
Huang W, Xu J, Jing F et al (2014) Functional thyrotropin receptor expression in the ventricle and the effects on ventricular BNP secretion. Endocrine 46:328–339
pubmed: 24065308
doi: 10.1007/s12020-013-0052-6
Huber G, Staub J, Meier C, Mitrache C, Guglielmetti M, Huber P, Braverman LE (2002) Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve and thyroid antibodies. J Clin Endocrinol Metab 87:3221–3226
pubmed: 12107228
doi: 10.1210/jcem.87.7.8678
Inoue K, Tsujimoto T, Saito J, Sugiyama T (2016) Association between serum thyrotropin levels and mortality among euthyroid adults in the United States. Thyroid 10:1457–1465
doi: 10.1089/thy.2016.0156
Jonklaas J, Bianco AC, Cappola AR, Celi FS, Fliers E, Heuer H, McAninch EA, Moeller LC, Nygaard B, Sawka AM, Watt T, Dayan CM (2021) Evidence-based use of levothyroxine/liothyronine combinations in treating hypothyroidism: a consensus document. Thyroid 31(2):156–182. https://doi.org/10.1089/thy.2020.0720
doi: 10.1089/thy.2020.0720
pubmed: 33276704
pmcid: 8035928
Kahaly GJ, Dillmann WH (2005) Thyroid hormone action in the heart. Endocr Rev 26:704–728
pubmed: 15632316
doi: 10.1210/er.2003-0033
Keating MT, Sanguinetti MC (2001) Molecular and cellular mechanisms of cardiac arrhythmias. Cell 104:569–580
pubmed: 11239413
doi: 10.1016/S0092-8674(01)00243-4
Kim WG, Kim WB, Woo G, Kim H, Cho Y, Kim TY et al (2017) Thyroid stimulating hormone reference range and prevalence of thyroid dysfunction in the Korean population: Korea National Health and Nutrition Examination Survey 2013 to 2015. Endocrinol Metab (Seoul) 32:106–114
pubmed: 28116874
doi: 10.3803/EnM.2017.32.1.106
Le-Bouter S, Demolombe S, Chambellan A, Bellocq C, Aimond F, Toumaniantz G, Lande G, Siavoshian S, Baró I, Pond AL, Nerbonne JM, Léger JJ, Escande D, Charpentier F (2003) Microarray analysis reveals complex remodeling of cardiac ion channel expression with altered thyroid status: relation to cellular and integrated electrophysiology. Circ Res 92:234–242
pubmed: 12574152
doi: 10.1161/01.RES.0000053185.75505.8E
Leung AM (2016) Mortality risks among individuals with high-normal serum TSH concentrations were increased as compared with those with midnormal TSH concentrations. Clin Thyroidol 28:287–289
doi: 10.1089/ct.2016;28.287-289
Li GY, Elimam AM, Lo LW, Lin YJ, Chang SL, Hu YF, Chung FP, Chao TF, Lin CY, Liu CM, Liao JN, Ton AK, Yugo D, Lin L, Tuan TC, Kao PH, Liu SH, Chhay C, Kuo L et al (2023) Factors predicting the progression from paroxysmal to persistent atrial fibrillation despite an index catheter ablation. J Cardiovasc Electrophysiol. https://doi.org/10.1111/jce.16100
Liu GX, Choi BR, Koren G (2012) Differential conditions for early after-depolarizations and triggered activity in cardiomyocytes derived from transgenic LQT1 and LQT2 rabbits. J Physiol 590:1171–1180
pubmed: 22183728
doi: 10.1113/jphysiol.2011.218164
Lorenzo Gómez T, Cardelle Pérez F, De Las Heras Liñero E (2010) The high prevalence of thyroid dysfunction in psychiatric inpatients. Rev Psiquiatr Salud Ment 3:23-26
McDermott MT, Ridgway EC (2001) Subclinical hypothyroidism is mild thyroid failure and should be treated. J Clin Endocrinol Metab 86:4585–4590
pubmed: 11600507
doi: 10.1210/jcem.86.10.7959
Mendes D, Alves C, Silverio N, Batel Marques F (2019) Prevalence of undiagnosed hypothyroidism in Europe: a systematic review and meta-analysis. European Thyroid Journal 8(3):130–143
pubmed: 31259155
pmcid: 6587201
doi: 10.1159/000499751
Montalvo D, Pérez-Treviño P, Madrazo-Aguirre K, González-Mondellini FA, Miranda-Roblero HO, Ramonfaur-Gracia D, Jacobo-Antonio M, Mayorga-Luna M, Norma L, Gómez-Víquez N, García N, Altamirano J (2018) Underlying mechanism of the contractile dysfunction in atrophied ventricular myocytes from a murine model of hypothyroidism. Cell Calcium 72:26–38
pubmed: 29748131
doi: 10.1016/j.ceca.2018.01.005
Moss AJ, Kass RS (2005) Long QT syndrome: from channels to cardiac arrhythmias. J. Clin. Invest 115:2018–2024
pubmed: 16075042
pmcid: 1180552
doi: 10.1172/JCI25537
Müller P, Leow MK, Dietrich JW (2022) Minor perturbations of thyroid homeostasis and major cardiovascular endpoints-physiological mechanisms and clinical evidence. Front Cardiovasc Med 9:942–971. https://doi.org/10.3389/fcvm.2022.942971
doi: 10.3389/fcvm.2022.942971
Nygren A, Fiset C, Firek L, Clark JW, Lindblad DS, Clark RB, Giles WR (1998) Mathematical model of an adult human atrial cell: the role of K+ currents in repolarization. Circ Res 82(1):63–81. https://doi.org/10.1161/01.res.82.1.63
doi: 10.1161/01.res.82.1.63
pubmed: 9440706
O'Hara T, Virág L, Varró A, Rudy Y (2011) Simulation of the undiseased human cardiac ventricular action potential: model formulation and experimental validation. PLoS Comput Biol 7(5):e1002061. https://doi.org/10.1371/journal.pcbi.1002061
doi: 10.1371/journal.pcbi.1002061
pubmed: 21637795
pmcid: 3102752
Ojamaa K, Kenessey A, Shenoy R, Klein I (2000) Thyroid hormone metabolism and cardiac gene expression after acute myocardial infarction in the rat. Am J Physiol Endocrinol Metab 279:E1319–E1324
pubmed: 11093920
doi: 10.1152/ajpendo.2000.279.6.E1319
Pearce EN, Yang Q, Benjamin EJ, Aragam J, Vasan RS (2010) Thyroid function and left ventricular structure and function in the Framingham Heart Study. Thyroid 20(4):369–373
pubmed: 20210671
pmcid: 2867586
doi: 10.1089/thy.2009.0272
Pereira L, Bare DJ, Galice S, Shannon TR, Bers DM (2017) β-Adrenergic induced SR Ca2+ leak is mediated by an Epac-NOS pathway. J Mol Cell Cardiol 108:8–16
pubmed: 28476660
pmcid: 5523849
doi: 10.1016/j.yjmcc.2017.04.005
Persani L, Ferretti E, Borgato S et al (2000) Circulating thyrotropin bioactivity in sporadic central hypothyroidism. J Clin Endocrinol Metab 85:3631–3635. https://doi.org/10.1210/jcem.85.10.6895
doi: 10.1210/jcem.85.10.6895
pubmed: 11061514
Rajagopalan V, Zhang Y, Ojamaa K, Chen YF, Pingitore A, Pol CJ, Saunders D, Balasubramanian K, Towner RA, Gerdes AM (2016) Safe oral triiodo-L-thyronine therapy protects from post-infarct cardiac dysfunction and arrhythmias without cardiovascular adverse effects. PLoS One 11(3):151–413. https://doi.org/10.1371/journal.pone.0151413
doi: 10.1371/journal.pone.0151413
Roberts CG, Ladenson PW (2004) Hypothyroidism. Lancet 363:793–803
pubmed: 15016491
doi: 10.1016/S0140-6736(04)15696-1
Shakir MKM, Brooks DI, McAninch EA, Fonseca TL, Mai VQ, Bianco AC, Hoang TD (2021) Comparative effectiveness of levothyroxine, desiccated thyroid extract, and levothyroxine+liothyronine in hypothyroidism. J Clin Endocrinol Metab 106(11):4400–4413. https://doi.org/10.1210/clinem/dgab478
doi: 10.1210/clinem/dgab478
Shimoni Y, Fiset C, Clark RB, Dixon JE, McKinnon D, Giles WR (1997) Thyroid hormone regulates postnatal expression of transient K+ channel isoforms in rat ventricle. J Physiol 500:65–73
pubmed: 9097933
pmcid: 1159359
doi: 10.1113/jphysiol.1997.sp021999
Shimoni Y, Severson DL (1995) Thyroid status and potassium currents in rat ventricular myocytes. Am J Physiol 268:H576–H583
pubmed: 7864182
Souza DS, Marques LP, Costa AD, Cruz JS, Rhana P, Santos-Miranda A, Joviano-Santos JV, Durço AO, Vasconcelos CML, Roman-Campos D (2022) Experimental hypothyroidism induces cardiac arrhythmias and ranolazine reverts and prevents the phenotype. Life Sci 308:120–945. https://doi.org/10.1016/j.lfs.2022.120945
doi: 10.1016/j.lfs.2022.120945
Spaulding SW (2017) Sequential TSH determinations may help in assessing the adequacy of treatment for overt hypothyroidis in older patients. Clin Thyroidol 29:48–51
doi: 10.1089/ct.2017;29.48-51
Sun Z, Ojamaa K, Coetzee W, Artman M, Klein I (2000) Effects of thyroid hormone on action potential and repolarizing currents in rat ventricular myocytes. Am J Physiol Endocrinol Metab 278:E302–E307
pubmed: 10662715
doi: 10.1152/ajpendo.2000.278.2.E302
Takawale A, Aguilar M, Bouchrit Y, Hiram R (2022) Mechanisms and management of thyroid disease and atrial fibrillation: impact of atrial electrical remodeling and cardiac fibrosis. Cells 11(24):40–47. https://doi.org/10.3390/cells11244047
doi: 10.3390/cells11244047
Tang Y, Kuzman J, Said S, Anderson B, Wang X, Gerdes A (2005) Low thyroid function leads to cardiac atrophy with chamber dilatation, impaired myocardial blood flow, loss of arterioles, and severe systolic dysfunction. Circulation 112:3122–3130
pubmed: 16275864
doi: 10.1161/CIRCULATIONAHA.105.572883
Ulivieri A, Lavra L, Magi F et al (2022) Thyroid hormones regulate cardiac repolarization and QT-interval related gene expression in hiPSC cardiomyocytes. Sci Rep 12:568
pubmed: 35022468
pmcid: 8755773
doi: 10.1038/s41598-021-04659-w
Unal O, Erturk E, Ozkan H, Kiyici S, Guclu M, Ersoy C, Yener F, Imamoglu S (2007) Effect of levothyroxine treatment on QT dispersion in patients with subclinical hypothyroidism. Endocr Pract 13:711–715
pubmed: 18194926
doi: 10.4158/EP.13.7.711
Van Uytfanghe K, Ehrenkranz J, Halsall D, Hoff K, Ping Loh T, Spencer CA, Köhrle J, ATA Thyroid Function Tests Writing Group (2023) Thyroid stimulating hormone and thyroid hormones (triiodothyronine and thyroxine): an American Thyroid Association-commissioned review of current clinical and laboratory status. Thyroid 33:1013–1028
pubmed: 37655789
pmcid: 10517335
Vieira IH, Rodrigues D, Paiva I (2022) The Mysterious Universe of the TSH Receptor. Front Endocrinol (Lausanne) 13:715–944
doi: 10.3389/fendo.2022.944715
Wang L, Wada Y, Ballan N, Schmeckpeper J, Huang J, Rau CD, Wang Y, Gepstein L, Knollmann BC (2021) Triiodothyronine and dexamethasone alter potassium channel expression and promote electrophysiological maturation of human-induced pluripotent stem cell-derived cardiomyocytes. J Mol Cell Cardiol 161:130–138
pubmed: 34400182
pmcid: 9809541
doi: 10.1016/j.yjmcc.2021.08.005
Watanabe H, Washizuka T, Komura S, Yoshida T, Hosaka Y, Hatada K, Aizawa Y, Chinushi M, Yamamoto T, Ma M, Watanabe K (2005) Genomic and non-genomic regulation of L-type calcium channels in rat ventricle by thyroid hormone. Endocr Res 31:59–70
pubmed: 16238192
doi: 10.1080/07435800500229227
Wickenden AD, Kaprielian R, Parker TG, Jones OT, Backx PH (1997) Effects of development and thyroid hormone on K+ currents and K+ channel gene expression in rat ventricle. J Physiol 504:271–286
pubmed: 9365903
pmcid: 1159909
doi: 10.1111/j.1469-7793.1997.271be.x
Wickenden A, Kaprielian R, You X, Backx P (2000) The thyroid hormone analog DITPA restores I(to) in rats after myocardial infarction. Am J Physiol Heart Circ Physiol 278:H1105–H1116
pubmed: 10749704
doi: 10.1152/ajpheart.2000.278.4.H1105
Yamakawa H, Kato TS, Noh JY, Yuasa S, Kawamura A, Fukuda K, Aizawa Y (2021) Thyroid hormone plays an important role in cardiac function: from bench to bedside. Front. Physiol 12:606–931. https://doi.org/10.3389/fphys.2021.606931
doi: 10.3389/fphys.2021.606931
Yang X, Rodriguez M, Pabon L, Fischer KA, Reinecke H, Regnier M, Sniadecki NJ, Ruohola-Baker H, Murry CE (2014) Tri-iodo-l-thyronine promotes the maturation of human cardiomyocytes-derived from induced pluripotent stem cells. J Mol Cell Cardiol 72:296–304. https://doi.org/10.1016/j.yjmcc.2014.04.005
doi: 10.1016/j.yjmcc.2014.04.005
pubmed: 24735830
pmcid: 4041732
Zhang Y, Dedkov EI, Teplitsky D, Weltman NY, Pol CJ, Rajagopalan V, Lee B, Gerdes AM (2013) Both hypothyroidism and hyperthyroidism increase atrial fibrillation inducibility in rats. Circ Arrhythm Electrophysiol 6(5):952–959. https://doi.org/10.1161/CIRCEP.113.000502
doi: 10.1161/CIRCEP.113.000502
pubmed: 24036190
pmcid: 3973490