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Pro-Arrhythmic Signaling of Thyroid Hormones and Its Relevance in Subclinical Hyperthyroidism

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Pro-Arrhythmic Signaling of Thyroid Hormones and Its Relevance in Subclinical Hyperthyroidism International Journal of Molecular Sciences Review Pro-Arrhythmic Signaling of Thyroid Hormones and Its Relevance in Subclinical Hyperthyroidism Narcis Tribulova 1,* , Lin Hai Kurahara 2, Peter Hlivak 3, Katsuya Hirano 2 and Barbara Szeiffova Bacova 1,* 1 Centre of Experimental Medicine, Slovak Academy of Sciences, Institute for Heart Research, 84104 Bratislava, Slovakia 2 Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, Kagawa 76 0793, Japan; [email protected] (L.H.K.); [email protected] (K.H.) 3 Department of Arrhythmias and Pacing, National Institute of Cardiovascular Diseases, Pod Krásnou Hôrkou 1, 83348 Bratislava, Slovakia; [email protected] * Correspondence: [email protected] (N.T.); [email protected] (B.S.B.); Tel.: +421-2-32295-423 (B.S.B.) Received: 13 March 2020; Accepted: 17 April 2020; Published: 19 April 2020 Abstract: A perennial task is to prevent the occurrence and/or recurrence of most frequent or life-threatening cardiac arrhythmias such as atrial fibrillation (AF) and ventricular fibrillation (VF). VF may be lethal in cases without an implantable cardioverter defibrillator or with failure of this device. Incidences of AF, even the asymptomatic ones, jeopardize the patient’s life due to its complication, notably the high risk of embolic stroke. Therefore, there has been a growing interest in subclinical AF screening and searching for novel electrophysiological and molecular markers. Considering the worldwide increase in cases of thyroid dysfunction and diseases, including thyroid carcinoma, we aimed to explore the implication of thyroid hormones in pro-arrhythmic signaling in the pathophysiological setting. The present review provides updated information about the impact of altered thyroid status on both the occurrence and recurrence of cardiac arrhythmias, predominantly AF. Moreover, it emphasizes the importance of both thyroid status monitoring and AF screening in the general population, as well as in patients with thyroid dysfunction and malignancies. Real-world data on early AF identification in relation to thyroid function are scarce. Even though symptomatic AF is rare in patients with thyroid malignancies, who are under thyroid suppressive therapy, clinicians should be aware of potential interaction with asymptomatic AF. It may prevent adverse consequences and improve the quality of life. This issue may be challenging for an updated registry of AF in clinical practice. Thyroid hormones should be considered a biomarker for cardiac arrhythmias screening and their tailored management because of their multifaceted cellular actions. Keywords: thyroid diseases; thyroid hormone signaling; cardiac arrhythmias 1. Introduction Atrial fibrillation (AF) and ventricular fibrillation (VF) are clinically relevant and potentially life-threatening arrhythmias. Despite some differences, both AF and VF have been assumed to occur due to abnormalities in the electrical activity involved in impulse initiation and impulse propagation [1–9]. The former is due to an enhanced automaticity of the cardiomyocytes (i.e., pacemaker-like activity) or triggered activity expressed as early after-depolarization (EAD) or delayed after-depolarization (DAD). The latter is associated with a conduction block promoting a re-entrant excitation (most likely due to an electrical uncoupling), disorders at the intercellular connexin (Cx) channels, myocardial structural remodeling (hypertrophy and/or fibrosis, adiposity), and variations in the refractory periods. Int. J. Mol. Sci. 2020, 21, 2844; doi:10.3390/ijms21082844 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 2844 2 of 19 2 of 19 As mentioned in this review and depicted in Figure1, thyroid hormones (TH) can be involved in all of theseinvolved mechanisms, in all of these as well mechanisms as in the, modulationas well as in ofthe the modulation autonomous of the nervous autonomous system nervous (ANS) and system the renin–angiotensin–aldosterone(ANS) and the renin–angiotensin system–aldosterone (RAAS) system that aff ect(RAAS) arrhythmogenesis. that affect arrhythmogenesis. FigureFigure 1. AnAn excess excess of thyroid of thyroid hormones hormones (TH) (TH)promote promotess the occurrence the occurrence of the main of the factors main involved factors involvedin cardiac in arrhythmogenesis: cardiac arrhythmogenesis: Substrate, Substrate,triggers, autonomous triggers, autonomous nervous system nervous (ANS system), and (ANS),renin– andangiotensin renin–angiotensin–aldosterone–aldosterone system (RAAS system) imbalance. (RAAS) imbalance. TheThe thyroidthyroid glandgland producesproduces thyroxinethyroxine (T(T44),), whichwhich isis a relatively inactive prohormone,prohormone, andand lowerlower amountsamounts ofof thethe activeactive hormone,hormone, triiodothyroninetriiodothyronine (T (T33).). AboutAbout 20%20% ofof TT33 isis mademade byby thethe thyroidthyroid glandgland andand thethe otherother 80% 80% comes comes from from T T4 4upon upon conversion conversion by by type type 1 1 iodothyronine iodothyronine deiodinases deiodinases (IDs), (IDs which), which is widelyis widely distributed. distributed. Type Type 2 ID 2 ID catalyzes catalyze thes the inactivation inactivation of FTof 4FTand4 and FT FT3 while3 while type type 3 ID3 ID acts acts like like type type 1 ID,1 ID, and and is expressedis expressed in in skeletal skeletal and and cardiac cardiac muscles, muscles, thus thus providing providing local local intracellular intracellular production production of Tof3 [T103 [10]]. TheThe releaserelease of of TH TH from from the the thyroid thyroid gland gland is controlled is controlled by the by thyrotrophin-releasingthe thyrotrophin-releasing hormone hormone from thefrom hypothalamus the hypothalamus in the brainin the and brain by and the thyroid-stimulating by the thyroid-stimulating hormone hormone (TSH) produced (TSH) produced by the pituitary by the gland.pituitary This gland. forms This part forms of a feedbackpart of a loopfeedback known loop as known the hypothalamic–pituitary–thyroid as the hypothalamic–pituitary axis–thyroid [11]. Theaxis thyroid[11]. The gland thyroid can become gland overactivecan become in hyperthyroidismoveractive in hyperthyroidism or underactive inor hypothyroidism.underactive in Thehypothyroidism. latter is often accompaniedThe latter is often by an accomp enlargementanied of by the an thyroid enlargement gland knownof the thyroid as goiter. gland Thyrotoxicosis known as maygoiter. be Thyrotoxicosis the result of may hyperthyroidism be the result asof inhyperthyroidism Graves’ disease as (autoimmunein Graves’ disease hyperthyroidism), (autoimmune inflammationhyperthyroidism) of the, inflammation thyroid, benign of the thyroid thyroid, tumor, benign or thyroid due to tumor factors, or that due atoffect factors hypothalamic, that affect pituitary,hypothala ormic, thyroid pituitary function, or thyroid [12]. function Hyperthyroidism [12]. Hyperthyroidism can also be can caused also bybe caused an acquired by an immuneacquired deficiencyimmune deficiency syndrome syndrome along with along anti-retroviral with anti-retroviral therapy [ 13therapy]. Moreover, [13]. Moreover, a not-so-infrequent a not-so-infrequent cause of hyperthyroidismcause of hyperthyroidism in clinical in practice clinical ispractice an iatrogenic is an iatrogenic one due toone the due adverse to the actionadverse of action drugs, of namely drugs, amiodarone.namely amiodarone. Apart from Apart that, from various that, gastrointestinal various gastrointestinal disorders disorders may impede may the impede absorption the absorption of T4 and increaseof T4 and the increase risk of the developing risk of developing iatrogenic iatrogenic hyperthyroidism hyperthyroidism [14]. [14]. BothBoth overtovert andand subclinicalsubclinical (latent)(latent) hyperthyroidismhyperthyroidism areare endocrineendocrine disordersdisorders thatthat occuroccur asas aa resultresult ofof excessiveexcessive TH TH secretion. secretion. TSH isTSH a sensitive is a indicatorsensitive of indicator thyroid function. of thyroid Subclinical function. hyperthyroidism Subclinical ishyperthyroidism common in the generalis common population in the general and its frequencypopulation is and variable, its frequency depending is variable, on age, sex, depending and iodine on statusage, sex [15, –and17], iodine and has status been [15 defined–17], and as lower has been serum defined TSH levels as lower (<0.10 serum mlU TSH/L), whilelevels the (<0.10 free mlU/L), T4 and Twhile3 concentrations the free T4 and are T within3 concentration the references are within range. the The reference euthyroid range. status The is euthyroid defined as status the conditionis defined whereinas the condition the TSH levelwherein is within the TSH the rangelevel is from within 0.45 the to 4.49 range mlU fr/omL. In 0.45 the to National 4.49 mlU/L. Health In and the Nutrition National ExaminationHealth and Nu Survey,trition 2.5% Examination of the population Survey, 2.5 had% of a serumthe population TSH below had the a serum lower limitTSH below of the referencethe lower rangelimit of [18 the]. reference range [18]. THTH aaffectffect heartheart metabolism,metabolism, electricalelectrical properties,properties, andand functionfunction throughthrough thethe interplayinterplay ofof genomicgenomic andand non-genomicnon-genomic mechanismsmechanisms ofof actionaction [[17,1917,19––2222]].. Accordingly, chronicchronic andand acuteacute changeschanges inin thethe 2+ circulatingcirculating THTH have
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