Thyroid Hormone & Cardiovascular Vascular Pharmacology 52 (2010) 102–112 Contents lists available at ScienceDirect Vascular Pharmacology j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / v p h Review Thyroid hormones and cardiac arrhythmias Narcis Tribulova a,⁎, Vladimir Knezl b, Asher Shainberg c, Shingo Seki d, Tomas Soukup e a Institute for Heart Research, Slovak Academy of Sciences, Bratislava, Slovak Republic Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Bratislava, Slovak Republic c Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel d Division of Cardiology, Department of Internal Medicine, Jikei University, Tokyo, Japan e Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic b a r t i c l e i n f o Article history: Received 26 August 2009 Accepted 5 October 2009 Keywords: Thyroid hormone Arrhythmias Ion channels Connexin-43 Ca2+ handling a b s t r a c t Thyroid hormone plays an important role in cardiac electrophysiology and Ca2+ handling through both genomic and nongenomic mechanisms of action, while both actions can interfere. Chronic changes in the amount of circulating thyroid hormone due to thyroid dysfunction or systemic disease result in structural, electrophysiological and Ca2+ handling remodeling, while acute changes may affect basal activity of cardiac cells membrane systems. Consequently, long-term or rapid modulation of sarcolemmal ion channels, Ca2+ cycling proteins and intercellular communicating channels by thyroid hormone may affect heart function as well as susceptibility of the heart to arrhythmias. This aspect including pro- and anti-arrhythmic potential of thyroid hormone is highlighted in this review. © 2009 Elsevier Inc. All rights reserved. Contents 1. 2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Arrhythmogenic and anti-arrhythmic effects of thyroid hormones on the heart . . 2.1. Incidence of atrial fibrillation due to the overt or subclinical hyperthyroidism 2.2. Incidence of ventricular arrhythmias due to altered thyroid status . . . . . 2.3. Anti-arrhythmic actions of TH . . . . . . . . . . . . . . . . . . . . . . 3. Molecular basis of TH actions . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. Genomic (nuclear) TH-mediated effects . . . . . . . . . . . . . . . . . . 3.2. Nongenomic (non-nuclear) TH-mediated effects . . . . . . . . . . . . . . 4. Mechanisms potentially involved in pro- and anti-arrhythmic effects of TH . . . . 4.1. Modulation of ion channels expression and function . . . . . . . . . . . . 4.2. Modulation of Ca2+ handling and intracellular free Ca2+ concentration . . . . 4.3. Modulation of Cx43 expression and phosphorylation . . . . . . . . . . . 5. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1. Introduction Thyroid hormone (TH) excess and deficiency are common as well as readily diagnosed and treated. Even mildly altered thyroid status may affect heart rhythm and rate, ventricular function, risk of coronary artery disease and cardiovascular mortality (Arnold et al., ⁎ Corresponding author. Institute for Heart Research, Slovak Academy of Sciences, 840 05 Bratislava, Dubravska cesta 9, POBox 104, Slovak Republic. Tel.: +421 2 54774405; fax: +421 2 54776637. E-mail address: narcisa.tribulova@savba.sk (N. Tribulova). 1537-1891/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.vph.2009.10.001 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102 103 103 104 105 105 105 105 106 106 107 108 109 109 109 2006; Aronow, 1995; Danzi and Klein, 2002; Ladenson, 1993; Toft and Boon, 2000). Overt hyperthyroidism is a pathological syndrome in which tissue is exposed to excessive amounts of circulating TH, while its defficiency is associated with overt hypothyroidism. Moreover, thyroid dysfunction can result in subclinical hyper- or hypothyroidism that are characterized by decreased or increased levels of thyroid stimulating hormone (TSH) while normal serum T3 and T4 concentrations are present. There is an increasing prevalence of overt thyroid disease with aging and prevalence of subclinical thyroid dysfunction in young adults (Biondi et al., 2000) and in elderly with cardiac disease (Burmeister and Flores, 2002; Cappola et al., 2006). A variety of abnormalities in the electrocardiogram have been associated with pathology of the thyroid gland. Sinus tachycardia, atrial flutter and atrial fibrillation (AF) are commonly found in patients suffering from overt or subclinical hyperthyroidism (Fadel et al., 2000; Hennersdorf and Strauer, 2000; Sawin, 2002; Shimizu et al., 2002; Shimoyama et al., 1993). Less frequent manifestations include first degree atrioventricular block, shortening of the Q–T interval and various nonspecific T wave abnormalities (Klein and Ojamaa, 2001; Toft and Boon, 2000). TH can also increase the occurrence of re-entrant AV nodal tachycardia (Biondi et al., 1998). Recent data suggest that subclinical hyperthyroidism can represent a novel risk factor for the development of AF (Auer et al., 2001). On the other hand, hypothyroidism (which is prevalent in the elderly) is characterized by combination of sinus bradycardia, low QRS complexes, prolongation of Q–T interval and lowering or inversion of the T wave (Osborn et al., 1999). Subclinical hypothyroidism is a common disorder with prevalence of about 7–8% in women over 50 years. Importantly, overt or subclinical hypothyroidism enhances a risk rather for atherosclerosis and myocardial infarction than for arrhythmias (Hak et al., 2000; Walsh et al., 2005). In addition, there are data indicating both pro- and anti-arrhythmic potential of TH (Feng et al., 2007; Knezl et al., 2008; Klemperer, 2002; Tribulova et al., 2004b; Wickenden et al., 2000). Electrophysiological studies performed at the cellular levels revealed that the sinus tachycardia and bradycardia associated with hyper- and hypothyroidism could be directly related to the effect of TH on the rate of diastolic depolarization in sinoatrial cells via modulation of the conductance of f-channels (Renaudon et al., 2000; Sun et al., 2001). It suggests direct effect of TH on electrogenesis in the myocardial membrane. Unlike chronotropic actions of TH its effects on the development of malignant arrhythmias such as atrial (AF) and ventricular fibrillations (VF) are more complex. The general classification of cardiac arrhythmias assumed that all disturbances of rhythm result from one of two primary abnormalities in electrical activity. The first is an abnormality in impulse initiation and the second, an abnormality in cell-to-cell impulse propagation, whereby both may co-exist (Hoffman and Rosen, 1981). The former is associated particularly with abnormal automaticity and/or triggered activity, whereas the latter with a block of conduction and reentry. Abnormal automaticity is rapid pacemaker-like rhythmic beating in cells that do not usually demonstrate such behavior. Triggered activity is induced by early (EAD) or delayed afterdepolarizations (DAD) and is capable of initiating and maintaining cardiac arrhythmias. Re-entrant excitation is continuous excitation in an electrical circuit without independent triggering of each beat. Heterogeneity in the electrophysiological properties of tissue in the circuit, notably differences in refractory periods or in conduction velocity, facilitates reentry. Events promoting heart rhythm disorders, notable AF and VF that are leading causes of death and disability, are demonstrated in Fig. 1. Possible implications of TH in these processes are noted in following chapters. 103 persistent that can deteriorate to permanent form. Likewise to human the hyperthyroidism in experimental animals (rats) increases propensity of the heart to inducible AF (see Fig. 2). Subclinical hyperthyroidism (Burmeister and Flores, 2002) is more common than overt hyperthyroidism in the population, with the prevalence in iodine repleted areas, reported to range from 0.5% to 3.9% in adults and 11.8% in the elderly (Osman et al., 2002a,b). It is defined as a low serum TSH concentration in an asymptomatic subject with normal serum T3 and T4 concentrations. A low serum TSH is generally a sensitive marker of thyroid hormone excess and has been reported to be associated with a 3-fold higher risk of developing AF (Auer et al., 2001; Sawin et al., 1994). However, it should be noted that in older euthyroid subjects with normal TSH levels, increased serum free T4 concentration was independently associated with AF as well (Gammage et al., 2007). In general, there is a prevalence of AF in men (6.6%) compared to women (3.1%). A shortening of the atrial refractory period due to electrical remodeling has been considered as the main mechanism for the risk of AF in hyperthyroidism (Komiya et al., 2002). Moreover, TH can activate electrical triggers such as abnormal supraventricular depolarizations (Wustman et al., 2008; Waktare et al., 2001) that often arise from the cardiomyocytes of pulmonary veins (Haissaguerre et al., 1998; Honjo et al., 2003; Chen et al., 1999). Increased automaticity and enhanced triggered activity may increase the arrhythmogenic activity due to higher incidence of delayed afterdepolarization (DAD) (Chen et al., 2002). The latter often initiates atrial tachycardia or AF. In the clinic, electrically-induced premature atrial stimulation is the most usual method to evaluate “atrial vulnerability”. In addition to enhanced automaticity and triggered activity, an elevation of left atrial pressure and size (Colkesen et al., 2008) (due to the hyperdynamic cardiovascular state) predicts paroxysmal AF. It is likely because of the presence of structural arrhythmogenic substrates linked with electrical abnormalities in impulse initiation and propagation. Indeed, alterations of myocardial architecture associated with aging and accompanied by abnormalities in cell-to-cell coupling have been shown to facilitate the development of AF and its persistence (Kostin et al., 2002; Tribulova et al., 1999). Moreover, very recent data suggest that atria of hyperthyroid rats that were susceptible to electrically inducible AF, exhibited alterations of cell-to-cell coupling protein (Mitasikova et al., 2009). These 2. Arrhythmogenic and anti-arrhythmic effects of thyroid hormones on the heart 2.1. Incidence of atrial fibrillation due to the overt or subclinical hyperthyroidism Thyroid hormones exert direct effects on the myocardium predisposing to dysrrhythmias, especially supraventricular AF, which is well known to be an independent risk factor for cerebrovascular events (often fatal). Growing lines of evidence suggest that AF is the most common cardiac arrhythmia encountered in hyperthyroidism and occurs in 10–15% of hyperthyroid patients (Katircibasi et al., 2007; Sawin et al., 1994; Vergara et al., 2007; Woeber, 1992). This incidence increases with age irrespective of whether there is associated heart disease. In human, the AF can be manifested as a transient paroxysmal or Fig. 1. Events and mechanisms involved in cardiac arrhythmias development. Increased automaticity, triggered activity and reentry are considered as crucial mechanisms implicated in development of malignant arrhythmias. These are facilitated in the heart exhibiting arrhythmogenic substrates such as electrical, structural or metabolic remodeling while arrhythmias susceptibility is modulated by acute or chronic abnormalities in autonomic tone, thyroid status or severity of ischemia. EAD-induced triggered responses are traditionally thought to be involved in the generation of ventricular arrhythmias under long Q–T conditions and are precipitated by bradycardia. In contrast DAD-induced triggered activity commonly underlies arrhythmias precipitated by tachycardia particularly in short Q–T conditions. EAD and DAD-induced afterdepolarizations resulting in ventricular premature beats can initiate malignant arrhythmias particularly in the setting promoting conduction block and reentry, i.e. in myocarium with abnormal cell-to-cell coupling. Thyroid Hormone & Cardiovascular N. Tribulova et al. / Vascular Pharmacology 52 (2010) 102–112 Thyroid Hormone & Cardiovascular 104 N. Tribulova et al. / Vascular Pharmacology 52 (2010) 102–112 Fig. 2. Duration of electrically-induced AF in isolated Langendorff-mode perfused male and female Wistar rat hearts. Rats treated for two weeks with 50 microgram/100g/day of TH (W-T3) were much prone to inducible AF and its duration was significantly increased when compared to untreated (W). conditions likely affect P wave duration and may increase P wave dispersion that has been reported to carry an increased risk of AF (Katircibasi et al., 2007). In order to prevent permanent AF, an improved detection of supraventricular dysrhythmias and therapeutic interventions as well as monitoring of the thyroid status should be considered. Management of AF usually includes restoration of basal TH levels, anti-arrhythmic medication and even invasive electrophysiological procedure, such as catheter radiofrequency ablation of atrial or pulmonary vein arrhythmogenic foci (Chen et al., 1999). The reversion rate, however, decreases with age and duration of AF. It should be noted that different from hyperthyroidism, the incidence of AF in hypothyroidism is rare (Makusheva and Kileinikov, 2008; Fazio et al., 2004) and associated rather with subclinical hypothyroidism, as reported in patients that underwent coronary bypass grafting (Park et al., 2009). Furthermore, a body of data indicates that cardiovascular disorders both acute (due to infarction, open heart surgery) and chronic (due to systemic illness, heart failure) may alter the metabolisms of TH resulting in reduction of circulating T4 and/or T3 levels (Ascheim and Hryniewicz, 2002; Friberg et al., 2002; Holland et al., 1991). This status termed as “euthyroid sick syndrome” or “low T3 syndrome” (i.e. decreased serum T3 levels due to impaired conversion from T4, which is in normal level) is considered a risk factor for AF in patients undergoing cardiac surgery (Cerillo et al., 2003; Danzi and Klein, 2002; Kokkonen et al., 2005). AF episodes commonly disappear upon normalization of serum T3 (Klemperer, 2002) and after pharmacological treatment or omega-3 fatty acid administration (Ninio et al., 2005, Savelieva and Camm, 2008). 2.2. Incidence of ventricular arrhythmias due to altered thyroid status In contrast to high incidence of atrial arrhythmias in the hyperthyroid status, the ventricular arrhythmias are uncommon and found with a frequency similar to that in the normal population (Colzani et al., 2001; Davison and Davison, 1995; Osman et al., 2002a,b; Sarma et al., 1990; Von Olshausen et al., 1989). It is likely because VF is exceptional in those with elevated TH without cardiomyopathy (Aronow, 1995; Jao et al., 2004, Nadkarni et al., 2008; Wheatley et al., 1988). Thus, the occurrence of ventricular arrhythmias in thyrotoxic subjects during and after antithyroid therapy is rare (Osman et al., 2002a; Von Olshausen et al., 1989). However, VF may occur in those with associated heart disease or heart failure of various etiology (Polikar et al., 1993). The difference between the prevalence of arrhythmias arising in the atria and ventricles may be owing to a difference in tissue properties. These can include chamber differences in thyroid hormone-induced expression and/or regulation of crucial cellular proteins potentially involved in arrhythmogenesis, such as sarcolemmal and intercellular channels, Ca2+-cycling proteins, βadrenoreceptors, etc. (Bokník et al., 1999; Crozatier et al., 1991; Golf et al., 1985; Ma et al., 2003; Mitasikova et al., 2009; Ojamaa et al., 1999; Shenoy et al., 2001; Shimoni et al., 1992). Nevertheless, the shortening of the Q–T interval and the effect of TH on the autonomic nervous system may affect ventricular arrhythmogenesis (Biondi et al., 1998; Kollai and Kollai, 1988). TH interacts with the sympathetic nervous system by altering responsiveness to sympathetic stimulation presumably by modulating adrenergic receptor function and/or density (Polikar et al., 1993). The density of myocardial adrenergic binding sites has been shown enhanced by chronic as well as acute treatment with TH while reduced in hypothyroidism (Gross and Lues, 1985; Tielens et al., 1996). TH, in addition, induces a rate-dependent lengthening of the Purkinje fiber action potential while ventricular action potential shortens (Jaeger et al., 1981). Consequently, these differences can enhance dispersion of myocardial repolarization and facilitate re-entrant arrhythmias including VF (Qu and Weiss, 2006). It should also be noted that hyperthyroidism may affect myocardial electrical stability (Meo et al., 1994) due to increased excitability linked to triggered activity (Buscemi et al., 2007) resulting in ventricular premature beats (VPB) (Polikar et al., 1986) that often initiate malignant arrhythmias. In animal (rat, mouse, rabbit, dog and cat) models of hyperthyroidism caused by overdose of TH, the thyreotoxicosis always results in cardiomyopathy that is characterized by myocardial electrical, structural, metabolic and Ca2+ handling remodeling. This predisposes the heart to ventricular arrhythmias and VF develops upon acute exposure of the heart to hypokalemia, post-ischemic reperfusion (Feng et al., 2007; Knezl et al., 2008; Tribulova et al., 2004b; Xia et al., 2006a,b) or a burst of electrical stimulation (Lin et al., 2008). Excess of TH is known to induce left ventricular hypertrophy that is termed a “physiological hypertrophy” since there is no shift of ventricular myosin heavy chain (MHC) expression α (or V1) to β (or V3) prevalence. The latter predominates in “pathological hypertrophy” of various etiology (e.g. hypertension, infarction), which is known to increase vulnerability of the heart to malignant arrhythmias (Severs, 2001; Tribulova et al., 2003). In this context it is interesting to note that animals with predominant V1 expression exhibit transient (spontaneously terminated) VF, while those with predominant V3 exhibit sustained VF (for details see Manoach et al., 2007). This might explain partially the lower incidence of VF in human hyperthyroidism, which suppresses V3 (prevalent MHC isoform in human) and upregulates V1 MHC in ventricular myocardium. Moreover, it can be expected that TH due to its potency to convert V3 to V1 (Brik and Shainberg, 1990) and hence pathological to physiological hypertrophy can affect ability of the heart for self-termination of VF even in clinical conditions (Qu and Weiss, 2006). Many patients with overt hypothyroidism have Q–T interval lengthening, which reflects the prolonged ventricular action potential due to electrical remodeling (Di Meo et al., 1997; Bosch et al., 1999; Klein and Ojamaa 2000; Ojamaa et al., 1999). It renders the heart prone to ventricular arrhythmias, such as potentially lethal polymorphic tachycardia “Torsade de Pointes” (Schenck et al., 2006). The incidence of arrhythmia precedes the occurrence of EAD usually triggered in the setting of hypokalemia. EAD-induced triggered responses are traditionally thought to be involved in the generation of ventricular arrhythmias under long Q–T conditions. Dispersion of ventricular refractoriness resulting from heterogeneous myocardial structural remodeling (Freudlund and Olsson, 1983) predisposes to Q–T dispersion and consequently to ventricular arrhythmias particularly in patients with subclinical hypothyroidism that are treated with L-thyroxine (Unal et al., 2007). Furthermore, in hypothyroidism an atrioventricular block of different degrees may occur (Lee and Lewis, 1962). Nevertheless, the VF incidence is reduced in hypothyroidism (Chess-Williams and Coker, 1989) and depression of TH levels seems to be beneficial in patients with angina and acute myocardial infarction (Friberg et al., 2002). Experimental studies suggest that hypothyroidism accompanied by the decreased heart rate and excitability rather protects the diseased heart against arrhythmias (Liu et al., 1996; Venkatesh et al., 1991; Zhang et al., 2002). 2.3. Anti-arrhythmic actions of TH Taken into consideration the incidence of cardiac arrhythmias in relation to the altered thyroid status (Osman et al., 2002a,b) it appears that hypothyroidism is mostly associated with reduced probability of cardiac arrhythmias unlike hyperthyroidism that increases a risk notably for atrial and to a lesser extent ventricular arrhythmias (that occur particularly in a cardiomyopathic heart). Some clinical and experimental studies, in addition, suggest antiarrhythmic or both pro- and anti-arrhythmic effects of TH. T3 treatment lowered the prevalence of AF in post-coronary artery bypass graft patients likely due to the prompt response of certain voltage gated potassium channels (Klemperer et al., 1996). The TH analog DITPA (3,5-diiodothyropropionic acid) restored repolarization-related potassium current and APD in rats after myocardial infarction (Wickenden et al., 2000). It has also been reported (Knezl et al., 2008; Tribulova et al., 2004b) that administration of a pharmacological dose of T4 for two weeks to old and young rats suppressed significantly in both the hypokalemia-induced ventricular premature beats (VPB) and increased the time to the onset of VPB when compared to untreated controls (Fig. 3). Because bradycardia and prolongation of repolarization due to hypokalemia play an important role in the occurrence of VPB triggered by EAD (Tribulova et al., 2003), it is likely that shortening of repolarization by TH would suppress their incidence. Moreover, the treatment of old rats with T4 facilitated termination of hypokalemia-induced VF and spontaneous sinus rhythm restoration upon returning to normokalemic conditions (Fig. 4B). Furthermore, the post-fibrillation recovery of mechanical function was much better in both young and old rat hearts likely due 105 to positive chrono- and inotropic actions of TH. It is also interesting to note that the incidence of hypokalemia-induced VF was not increased in T4-treated old rats (Fig. 4A), while young rats were more susceptible to such treatment compared to untreated controls. It points out age-related differences in response to TH and that treatment of old individuals by TH may be safe. Notably, a very recent experimental study (Knezl et al., 2008) demonstrated that even acute administration of TH can protect by a dose-dependent manner the heart against electrically-induced malignant arrhythmias. Accordingly, T3 in the range of 1–100 nmol/l delayed significantly the occurrence of VF, while in the higher concentration (1000 nmol/l and more) facilitated it (Fig. 5A). Furthermore, T3 in lower (100 nmol/l and less) concentration accelerated the termination of VF and sinus rhythm restoration, while in the higher concentration (1000 nmol/l and more) had the opposite effect (Fig. 5B). Thus, experimental studies suggest that TH can modulate the susceptibility of the heart to VF and its ability to restore the sinus rhythm by long-term (genomic) and acute (nongenomic) actions. Both, anti- and proarrhythmic potentials of TH appear to be age- and dose-dependent. Beneficial effects of TH administration were observed clinically in the setting of correcting either chronic (heart failure) or acute (due to cardiac surgery) hypothyroid states as well as during resuscitation from myxedema-associated cardiogenic shock (Hamilton et al., 1998; Factor et al., 1993; MacKerrow et al., 1992; Morkin et al., 2002; Pantos et al., 2008; Salter et al., 1992). Likewise to experimental conditions clinical data suggest that the cardioprotective and antiarrhythmic actions of TH depend on tailored treatment and provide a relatively “narrow therapeutic window”. 3. Molecular basis of TH actions 3.1. Genomic (nuclear) TH-mediated effects The biologically active hormone T3 mediates TH genomic action. Once inside the cardiomyocyte, T3 enters the nucleus and binds to the nuclear receptors that are bound to DNA response elements of target genes. The nuclear TH receptor has a much higher affinity for T3 than any other analog and thyroxine (T4) has almost no measurable action. T3-responsive genes encode both structural and regulatory proteins in the heart (Dillman, 2002; Yen, 2001). Numerous cardiac genes are regulated by TH at transcriptional and post-transcriptional levels. Table 1 summarizes these that encode cardiac proteins that might be potentially involved in anti- or pro- arrhythmic effects of TH. 3.2. Nongenomic (non-nuclear) TH-mediated effects Fig. 3. Time to the onset (A) and number of hypokalemia-induced ventricular premature beats (B) in the isolated hearts of young (Y, n = 6) and old (O, n = 6) rats treated with 50 microgram/100g/day of L-thyroxine (T4) for two weeks. Note that TH suppressed significantly the incidence of VPB recorded during 5 min of hypokalemic perfusion in both young and old rat hearts as well as the onset of VPB in the latter ones. The results are expressed as means ± S.E.M, p < 0.05 (Adapted from Tribulova et al., 2004b). Nongenomic actions of TH have long been recognized, although the specific targets and mechanisms that mediate these actions have been difficult to demonstrate (Davis and Davis, 1993). Different to nuclear effects that are delayed in onset, TH exerts non-nuclear rapid actions on the heart (Davis and Davis, 2002; Klemperer et al., 1996). These effects are not altered by inhibition of protein synthesis and are mediated by TH binding to plasma membrane (receptors), sarcoplasmic reticulum, cytoskeleton, mitochondria or contractile elements (Davis and Davis, 1993, 2002). In addition, acute actions of TH are thought to be mediated by direct binding to the target proteins or TH affects intracellular signaling (Rybin and Steinberg, 1996) that regulate gating of the protein channels (e.g. via PKA, PKC phosphorylation). Numerous nongenomic mechanisms are modulated by phosphorylation–dephosphorylation of substrate proteins. Interestingly, for nongenomic effects T4 is often more active than T3. Other TH analogs that have been thought to be inactive biologically, such as reverse T3 and T2 have been shown to be active occasionally (Davis and Davis, 2002). Some of nongenomic effects that might be implicated in the modulation of cardiac arrhythmias susceptibility are summarized in Table 2. Thyroid Hormone & Cardiovascular N. Tribulova et al. / Vascular Pharmacology 52 (2010) 102–112 Thyroid Hormone & Cardiovascular 106 N. Tribulova et al. / Vascular Pharmacology 52 (2010) 102–112 Table 1 Regulation of genes by TH in the heart. Positive regulation Negative regulation α-myosin heavy chaina SR Ca ATPase (SERCA2)b Na,K ATPasec β1-adrenergic receptorsd Ryanodine receptorsf K+ channels (Kv1.5, Kv4.2, Kv4.3)h Connexin-40j, connexin-43k β-myosin heavy chaina Phospholambanb Na/Ca exchangerb α1-adrenergic receptorse Ca2+ channelsg K+ channels (Kv 1.2, Kv 1.4)i PKC-εl For more details see aMorkin, 1993; bShenoy et al., 2001; Kiss et al., 1994; Brik and Shainberg, 1990; cAwais et al., 2000; Brik and Shainberg, 1990; dDisatnik and Shainberg, 1991; Golf et al., 1985; Gross and Lues, 1985; Hammond et al., 1987; Hoit et al., 1997; e Gross and Lues, 1985; fXia et al., 2006a,b; gWatanabe et al., 2005; hShimoni and Banno, 1993; Watanabe et al., 2003, 2005; iSunagawa et al., 2005; jAlmeida et al., 2009; kStock and Sies, 2000; lHamasaki et al., 2000; Mitasikova et al., 2009; Rybin and Steinberg, 1996. 4. Mechanisms potentially involved in pro- and anti-arrhythmic effects of TH Fig. 4. Time to hypokalemia-induced VF (A) and time to the spontaneous sinus rhythm restoration (B) due to normokalemia in the isolated hearts of young (Y) and old (O) rats treated with 50 microgram/100g/day of L-thyroxine (T4) for two weeks. Note that TH significantly (p < 0.05) facilitated the occurrence of VF in young, but not in old rat hearts (A) in which, in addition, TH accelerated the termination of VF and sinus rhythm restoration (SSR) (B). (Adapted from Tribulova et al., 2004b). Generally, there are direct and indirect actions of TH that may be involved in the modulation of cardiac arrhythmia susceptibility. The former include genomic or nongenomic regulation of “target proteins”, while the latter include activation or suppression of target proteins, which consequently affect proteins implicated in arrhythmogenesis. Available data suggest that crucial target proteins include cell membrane ion channels, intercellular communicating channels and Ca2+ transporting systems. Target proteins can be tuned by THinduced activation of various intracellular signaling pathways (Bahouth, 1995; Barros et al., 1998) including protein kinases (Lin et al., 2008; Mitasikova et al., 2009; Rybin and Steinberg, 1996). 4.1. Modulation of ion channels expression and function Ion currents contributing to action potential in human atrial and ventricular tissues include fast sodium current (INa), transient outward potassium current (Ito), L-type calcium current (ICa), slow delayed-rectifier potassium current (IKs) rapid delayed-rectifier potassium current (IKr) and inward rectifier potassium current (IK1). In addition, ultra-rapid delayed-rectifier potassium current (IKur) and acetylcholine-regulated potassium current (IKAch) are present in the atrial tissue only (Ehrlich et al., 2008). TH plays an important role in cardiac electrophysiology through both genomic and nongenomic mechanisms of action (Davis and Davis, 1993; Sun et al., 2000). TH selectively and differentially regulates transcript expression for at least nine ion channel alpha- and beta-subunits (Le Bouter et al., 2003). Available evidence indicates that TH can affect expression and function of several ion channels, such as voltage-activated K+ channel genes including Kv.4.2, Kv4.3 (Ito), Kv1.2, Kv1.4 and Kv1.5 (IKur) (Ojamaa et al., 1999; Shimoni et al., 1995, 1997; Wickenden et al., 1997; Ma et al., 2003). Hyperthyroidism markedly up-regulated expression of Kv1.5 mRNA and its increase was greater in the atrium than ventricle. Furthermore, TH decreased Kv1.2 and Kv1.4 (in both atria and ventricles) as well as the L-type Ca2+ channels in the atria (Sunagawa et al., 2005), while the Kv2.1 and Kv4.2 mRNA did not Table 2 Non-nuclear acute TH actions in the heart. Fig. 5. Acute dose-dependent effects of triiodotyronine (T3) on the occurrence of electrically-induced VF (A) and spontaneous sinus rhythm restoration (B) in isolated guinea pig hearts. Note that T3 in range of 1–100 nmol/l delayed, while in the higher (1 µmol/l) concentration facilitated the occurrence of VF (A). In addition, T3 accelerated the termination of VF and sinus rhythm restoration that was significant upon 100 nmol/ l, while the (1 µmol/l) higher concentration had the opposite effect (B). (Adapted from Knezl et al., 2008). Stimulation of sarcolemmal and SR Ca ATPase activitya Activation of SR Ca2+ release channel (RyR)b Suppression of Ca2+ channelc Activation of Na+ channeld Activation of K+ channele Activation of β adrenergic receptorsf For more details see aWatanabe et al., 2005; Segal, 1990 Segal et al., 1996; bConnely et al., 1994; cConnely et al., 1994; Gøotzsche, 1994, Han et al., 1994; Watanabe et al., 2005; dDudley and Baumgarten, 1993; Harris et al., 1991; Wang et al., 2003; eDavis and Davis, 1993, 2002; fTielens et al., 1996. change (Ma et al., 2003; Watanabe et al., 2003). The shortening of APD in hyperthyroid rat atria was linked with remarkably increased IKur currents (Ma et al., 2003), whereas Ito currents were unchanged and ICa currents were decreased. APD shortening was greater in right than left atria (Hu et al., 2006). In the atrium the dominant currents of repolarization are considered to be Ito, IKs, IKr. Hence any changes in the expression of channels carrying these currents can affect APD and contribute to proarrhythmic electrophysiological remodeling. T3induced increase of the outward currents and decrease of the inward currents may provide an electrophysiological arrhythmogenic substrate due to shortening of APD associated with decreased refractoriness, which facilitates occurrence of AF. Thus, thyreotoxicosis could induce the shortening of APD by alterations in current density of both I(Ca(L)) and I(K(delay)) in rat atrial myocytes (Sunagawa et al., 2005). Moreover, there was an increase of maximal rate of rise AP amplitude (Max dV/dt) attributed most likely to enhanced INa current since sodium channel blocker inhibited it (Yamakawa et al., 2005). It suggests that Na+ channel activity can also be regulated by TH likely via bursting the Na+ channel activity (Dudley and Baumgarten, 1993) as well as by promoting slow inactivation kinetics in Na+ channels (Harris et al., 1991). Increase of INa enhances excitability and conductivity that can facilitate AF by stabilizing of re-entrant foci. Moreover, cellular stretch due to the increase of left atrial pressure can activate stretch-activated nonselective cation channels (SACs) that alter myocardial electrical activity by promoting DAD (Ehrlich et al., 2008). Ventricular cardiomyocytes from hypothyroid rat showed a significant decrease in the mRNA of Kv 1.2 and Kv 1.4 and this was associated with marked prolongation of APD (Nishiyama et al., 1998). Exposure to T3 significantly shortened it (Sun et al., 2000). However, transient outward current Ito was not affected by the acute application of T3. Ito was shown to be reduced in hypothyroid rat heart ventricle thereby prolonging APD and consequently the effective refractory period. It can contribute to lower incidence of VF despite of a risk for malignant arrhythmia in the setting of hypokalemia. In contrast, Ito density and Kv 1.5 and Kv 2.1 mRNA expression were significantly increased in hyperthyroid cardiomyocytes (Nishiyama et al., 1998) resulting in proarrhythmic APD and refractoriness shortening (Shimoni et al., 1992). In this context it should be noted that TH analog DITPA abolished Ito downregulation in rats after myocardial infarction and consequently normalized APD (Wickenden et al., 2000). In addition, acute T3 caused a shortening of APD in guinea pig ventricular myocytes by increasing Ik1 current via increasing the open probability (Sakaguchi et al., 1996). Neither the number of channels nor the unit amplitude of single Ik1 was changed by T3. There was no acute effect of T3 on APD in euthyroid rat unlike guinea pig ventricles, where T3 shortened it. This difference may reflect the longer APD in the euthyroid guinea pigs compared to the euthyroid rats. In the rat cardiomyocytes, two primary depolarization-activated outward currents are important in regulating APD, i.e. Ito and slowly inactivating IK. They are present also in human atrial and ventricular cardiomyocytes. Several studies have shown that TH is involved in regulation of specific K+ channels via activation of certain protein kinases (Barros et al., 1998; Nakamura et al., 1997). It is interesting to note that L-type Ca2+ current was increased by TH despite a decrease of Ca2+ channel gene expression (Gøotzsche, 1994; Mager et al., 1992; Watanabe et al., 2005). These effects likely coincide with TH-induced regulation of myocardial Ca2+ cycling proteins. 4.2. Modulation of Ca2+ handling and intracellular free Ca2+ concentration TH has multiple direct effects on the heart affecting its mechanical function. Alterations of the myocardial Ca2+ handling due to the longterm effect of pharmacological dose of TH and/or of hyperthyroidism are well established. TH regulates transcription of Ca2+ cycling proteins (Cappola et al., 2002), i.e. the sarcoplasmic reticulum Ca2+ATPase 107 (SERCA2) and Ca2+ release channel of SR, ryanodine receptors (RyR) are up-regulated, whereas Na+/Ca2+ exchanger as well as phospholamban are down-regulated (Aronow, 1995; Cernohorsky et al., 1998; Connely et al., 1994; Kiss et al., 1994; Khoury et al., 1996; Shenoy et al., 2001; Xia et al., 2006a,b). Furthermore, phosphorylation of phospholamban is increased (Ojamaa et al., 2000). Consequently, hyperthyroidism is associated with increased Ca2+ influx and greater Ca2+ efflux rate (Kim and Smith, 1985) due to activation of sarcolemmal Ca2+ channels (Watanabe et al., 2005) and stimulation of Ca2+ ATPase activity (Mylotte et al., 1985). PKC-ε has been shown involved in the regulation of Ca2+ channels (Hu et al., 2000) and its supression by TH (Hamasaki et al., 2000; Mitasikova et al., 2009; Rybin and Steinberg, 1996) likely promotes activation of Ca2+ channels. Although Ca2+ fluxes are increased the mean intracellular free Ca2+ ([Ca2+]i) in resting cardiomyocytes is not significantly different from euthyroid ones (Beekman et al., 1988). On the other hand, SERCA2 mRNA and protein levels are down-regulated in hypothyroidism, whereas phospholamban and Na+/Ca2+ exchanger are up-regulated (Dillmann, 1990; Reed et al., 2000; Shenoy et al., 2001). It should be noted that in addition to genomic effects of TH on Ca2+ cycling proteins there are rapid nongenomic TH responses (Connely et al., 1994; Gøotzsche, 1994; Han et al., 1994; Segal, 1990; Segal et al., 1996; Watanabe et al., 2005) that modulate activity of Ca2+ cycling proteins and hence intracellular [Ca2+]i. Taken together, it appears that TH controls Ca2+ homeostasis particularly due to regulation of SR function. Nevertheless, it can be expected that longterm or acute changes in basal levels of circulating TH (due to thyroid dysfunction or systemic disease) might induce disorders in Ca2+ homeostasis because of altered (abnormal) Ca2+ handling. The latter may facilitate the development of Ca2+ overload in various nonphysiological conditions (such as heavy exercise, emotional stress, high frequency tachycardia) as well as in the pathophysiological setting (e.g., acute hypokalemia or ischemia) and hence increase risk for cardiac arrhythmias (Kihara and Mogan, 1991; Merrilat et al., 1990; Tribulova et al., 2001, 2002, 2008; Van Heerden et al., 1985). Although the mechanisms for abnormal automaticity and triggered activity such as EAD or DAD are not completely understood, the evidence supports a prominent role for abnormal Ca2+ cycling and Ca2+ overload. EAD and DAD have been shown capable of initiating cardiac arrhythmias likely due to spontaneous release of Ca2+ from overloaded SR (Lakatta and Guarnieri, 1993). The latter activates transient inward current (Iti) that largely comprises inward Na+/Ca2+ exchange (INa–Ca) and Ca-activated chloride (ICa(Cl)) currents (Burashnikov and Antzelevitch, 2006). Consequently, it leads to either EAD or DAD followed by premature or after-contractions. Moreover, an acute exposure to TH increased INa current resulting in increase of [Ca2+]i likely via reverse mode of Na+/Ca2+ exchanger in cat atrial myocytes (Wang et al., 2003). DAD may occur during high rates as it is tachycardia in hyperthyroidism, while EAD can occur in conditions of decreased heart rate and prolonged Q–T interval (features of hypothyroidism). EAD are often triggered by augmentation of ICa(Cl) or late sodium current (INa) usually associated with reduction of Ikr and Iks currents (Burashnikov and Antzelevitch, 2006). These conditions increase a risk for Torsade de pointes in the setting of hypokalemia (Freudlund and Olsson, 1983; Tribulova et al., 2002). High diastolic [Ca2+]i, in addition, has been shown to be a key arrhythmogenic factor involved in the initiation and maintenance of AF and VF (Kihara and Mogan, 1991; Merrilat et al., 1990; Tribulova et al., 2002, 2008). Underlying mechanisms appear to be Ca2+ overloadinduced cell-to-cell electrical uncoupling (Kurebayashi et al., 2008) that impairs myocardial conductivity and leads to conduction block and consequently promotes re-entrant excitation (Kleber, 1990). Thus, it can be expected that TH may modulate the arrhythmia susceptibility via modulation of [Ca2+]i. It could explain, in part, increased incidence of AF and VF in young hyperthyroid rats. In addition, increased susceptibility of the heart to AF may be partially attributed to the differences in the expression of Ca2+ cycling proteins. It has been shown that ratio of SERCA2 to PLB (due to decreased expression of PLB) is significantly Thyroid Hormone & Cardiovascular N. Tribulova et al. / Vascular Pharmacology 52 (2010) 102–112 Thyroid Hormone & Cardiovascular 108 N. Tribulova et al. / Vascular Pharmacology 52 (2010) 102–112 higher in human and rat atria compared to ventricle, suggesting that PLB may play a minor role in regulation of SERCA2 function in atria. Moreover, the expression of Na+/Ca2+ protein showed greater response to TH treatment in atrial than in ventricular tissue (Shenoy et al., 2001). Acute modulation of [Ca2+]i by TH has been shown by several studies. Accordingly, TH in physiological concentration (1 nmol/l and 10 nmol/lmol/l) caused rapid but transient increase in [Ca2+]i (Lomax et al., 1991). Moreover, TH in a supra-physiological concentration (10 nmol/l and 100 nmol/l) rapidly attenuated a Ca2+ overload in a neonatal heart-cell culture, however, higher concentration enhanced it (Zinman et al., 2006). In whole heart preparation, TH in concentration of 10 µmol/l decreased a previously elevated [Ca2+]i although in higher concentration (100 µmol/l) further Ca2+ increase was detected (Fig. 6). It was followed by transient arrhythmias, including VT and VF (Tribulova et al., 2004a). Furthermore, TH attenuated post-ischemia related Ca2+ overload in diabetic rats (Oshiro et al., 2001). These findings indicate rapid dose-dependent modulation of [Ca2+]i by TH that may be implicated in the protection against cardiac arrhythmias as well as in their spontaneous termination (Tribulova et al., 2009). 4.3. Modulation of Cx43 expression and phosphorylation It has been reported that some hormones, including TH, may regulate intercellular communication ensured by gap junction channels in various tissues and cell types (Decker, 1976). Intercellular coupling at the gap junction connexin channels is essential for normal electro-mechanical function of the heart, i.e. for cell-to-cell electrical impulse propagation and direct intercellular signalling. Cardiomyocytes are interconnected by channels consisting of three types of connexin proteins; Cx43 is a major cardiac connexin expressed in the ventricles and atria, while Cx40 is expressed in atrial tissues only and Cx45 expression predominates in conducting cells (Salameh and Dhein, 2005). Growing lines of evidence indicate that abnormal gap junctions distribution (remodeling) as well as alterations in the expression and/or phosphorylation of connexins in diseased heart can Fig. 6. Original records of fura-2 fluorescence ratio (indicating [Ca2+]i) and left ventricular pressure (LVP, indicating contractility) during perfusion of the isolated guinea pig heart with oxygenated HEPES-buffered Tyrode solution. Basal state (A) was followed by increase in [Ca2+]i) and LVP due to the elevation of external Ca2+ from 2 to 3 mmol/l (B). T3 administration (in range 10 nmol/l–10 µmol/l) caused dose-dependent decrease of elevated diastolic [Ca2+]i within a few minutes (see part C in panel a) that was accompanied by decrease of elevated LVP. Ca2+ overload, however, was not abolished due to higher 100 µmol/l concentration of T3, (see part C panel b) instead further increase of [Ca2+]i was detected. It was sporadically accompanied by incidence of transient arrhythmias, such as VPB and VT (not shown). result in defects of cell-to-cell electrical signal propagation and consequently promote occurrence of re-entrant malignant arrhythmias (Kleber, 1992; Kostin et al., 2002; Lin et al., 2008; Severs, 2001; Tribulova et al., 1999, 2001, 2002, 2008). Recent results (Stock and Sies, 2000) suggest that thyroid hormone receptors bind to an element in the Cx43 promoter. This indicates that regulatory signals of TH that modify expression of nuclear genes can directly regulate Cx43 mRNA synthesis. Stimulation of both Cx43 mRNA expression and gap junctional communication by TH has been found in rat liver epithelial cells (Stock et al., 1998). However, no induction of myocardial Cx43 mRNA occurred in the adult rat after a single exposure to T3 (Stock and Sies, 2000) presumably due to the extremely high basal expression of Cx43 in the heart. Unlike Cx43, the Cx40 mRNA was positively regulated in hyperthyroid mice atria, while down-regulated in hypothyroid status (Almeida et al., 2009). The Cx43 protein levels have been shown enhanced in neonatal cultured cardiomyocytes exposed to TH for two–three days (Tribulova et al., 2004c). Furthermore, recent studies (Lin et al., 2008; Mitasikova et al., 2009) have demonstrated chamberrelated differences in total Cx43 protein levels in adult male rats treated with TH, i.e. enhanced Cx43 expression in heart atria (Fig. 7), whereas no significant change in ventricles (Fig. 8). It is not known yet, whether alterations in myocardial Cx43 protein result from transcriptional or post-transcriptional modulation of Cx43 expression by TH that seems to be age and specific tissue-related. It should be also taken into consideration that total amount of Cx43 protein is affected by its synthesis and degradation (Salameh and Dhein, 2005). Thus, Fig. 7. A representative Western blot (upper panel) and densitometric quantification of Cx43 immunoblots (bottom panel) in the atria of normal (N), T3-treated (T3, 10micrograms/ 100g/day), diabetic (D) and diabetic T3-treated (DT3) rats. Note the significant decrease of the Cx43 phosphorylated (P1 +P2) to unphosphorylated (P0) ratio in T3-treated and diabetic rat heart atria. Interestingly, the Cx43 phopshorylation is not suppressed in T3 treated diabetic rats. The total Cx43 levels are increased in T3-treated as well as diabetic rat heart atria and partly in diabetic T3-treated rats. Data (n =6) are means+ SD and ⁎p<0.05 vs N, #p<005 vs D. (Adapted from Mitasikova et al., 2009). 109 Steinberg, 1996) and its elevated expression was suppressed in diabetic rat heart ventricles (Lin et al., 2008). The latter was linked with suppression of myocardial Cx43 phosphorylation and increased susceptibility of diabetic rat hearts to VF. Noteworthy, decreased phosphorylation of Cx43 by PKC-ε in hyperthyroid rat heart was associated with increased myocardial conduction velocity (Lin et al., 2008). TH, in addition, decreased conduction time in specialized cells of conducting system (El Shahawy et al., 1975). These findings fit very well with decreased cell-to-cell resistance of atrial tissues from TH treated rats (Sunagawa et al., 2005). Conduction velocity is determined predominantly by the level of cell-to-cell coupling at the connexin channels and by the maximal rate of rise (Max dV/dt) of AP that was increased due to TH as well. Thus, it appears that modulation of Cx43 phosphorylation and myocardial conduction velocity by TH might be implicated in cardiac arrhythmias susceptibility. 5. Concluding remarks TH regulation consists of an integrated network of both nuclear and extra-nuclear processes to maintain myocardial tissue homeostasis and heart function. While incidence of cardiac arrhythmia is rare in hypothyroidism, the thyreotoxicosis may increase a risk particularly for AF and VF may occur in cardiomyopathic heart. Disorders in [Ca2+]i due to altered Ca2+ handling, in conjunction with electrophysiological remodeling and cell-to-cell coupling alterations, seem to play a crucial arrhythmogenic role. On the other hand, antiarrhythmic potential of TH appears to be linked with the prevention and/or attenuation of Ca2+ overload and its harmful consequences. Further studies are needed to examine whether the application of TH could lead to new therapies designed to enhance the cardiac contractile function and limit the arrhythmogenic substrates. Fig. 8. A representative Western blot (upper panel) and densitometric quantification of Cx43 immunoblots (bottom panel) in the ventricles of normal (N), T3-treated (T3, 10micrograms/100g/day), diabetic (D) and diabetic T3-treated (DT3) rats. Note the significant decrease of the Cx43 phosphorylated (P1 + P2) to unphosphorylated (P0) ratio in T3-treated, while an increase in diabetic rat heart ventricles. The Cx43 phopshorylation was suppressed in T3 treated diabetic rats. The total Cx43 levels are significantly decreased in T3-treated rats only. Data (n = 6) are means ± SD and ⁎p < 0.05 vs N, #p < 005 vs D. (Adapted from Lin et al., 2008). Acknowledgements further studies are needed to examine whether the latter might be modulated by TH. Potential mechanisms controlling the level of connexin channels mediated intercellular communication in the heart include both, a regulation of Cx43 expression and phosphorylation. Importantly, phosphorylated isoforms of Cx43 were markedly suppressed in both atria (Fig. 7) and ventricles (Fig. 8) of hyperthyroid rats when compared to untreated controls (Lin et al., 2008; Mitasikova et. al., 2009). Decreased phosphorylation of Cx43 due to TH may affect the Cx43 channel function (Stagg and Flechter, 1990) and consequently influence cardiac arrhythmia susceptibility. Indeed, decline of myocardial Cx43 phosphorylation was associated with an increased susceptibility of T3treated rats to both VF (Lin et al., 2008) and AF (Fig. 2). Interestingly, neither ventricular Cx43 expression and phosphorylation nor VF susceptibility was significantly altered in aged female rats treated by TH when compared to untreated ones (Tribulova et al., 2004b; Tribulová et al., 2005). It suggests age-related differences in response to TH. In this context it should be stressed that TH may affect phosphorylation status of Cx43 most likely via modulation of protein kinase expression and/or activity. In the Cx43 phosphorylation, several protein kinases, such as PKA, PKG, MAPK and PKC, have been implicated. Consequently, PKA increases Cx43 channel conduction, while PKG and MAPK decrease it and effects of PKC are isoformspecific (Bowling et al., 2001; Doble et al., 2000; Salameh and Dhein, 2005). Cardiac expression of PKC-ε has been found to be decreased by TH (Hamasaki et al., 2000; Mitasikova et al., 2009; Rybin and Almeida, N.A., Cordeiro, A., Machado, D.S., Souza, L.L., Ortiga-Carvalho, T.M., Camposde-Carvalho, A.C., Wondisford, F.E., Pazos-Moura, C.C., 2009. Connexin40 messenger ribonucleic acid is positively regulated by thyroid hormone (TH) acting in cardiac atria via the TH receptor. Endocrinology 150, 546–554. 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