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Experimental Physiology 89.5 pp 629-636
DOI: 10.1113/expphysiol.2004.027607
© The Physiological Society 2004
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L-thyroxine increases susceptibility of adult rats to low K+-induced ventricular fibrillation, and sinus rhythm restoration in old rats

Narcis Tribulova1, Vladimir Knezl2, Ludmila Okruhlicova1, Jan Drimal2, Dalma Lamosova3, Jan Slezak1 and Jan Styk1

1 Institute for Heart Research2 Institute of Experimental Pharmacology3 Institute of Animal Biochemistry and Genetics, Slovak Academy of Sciences, Bratislava, Slovak Republic


   Abstract
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 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Hypokalaemia increases the risk for life-threatening arrhythmias; however, data about interaction with thyroid status are lacking. The aim of this study was to investigate vulnerability of L-thyroxine (T4)-treated adult and old rats to low K+-induced ventricular fibrillation (VF) as well as the ability of the heart to recover sinus rhythm. The experiments were performed on isolated heart preparations using the heart of 4- and 20-month-old female Wistar rats without and with feeding with T4 50 µg (100 g day)–1 over a period of 2 weeks. Perfusion of the isolated heart with oxygenated Krebs–Henseleit solution at constant pressure was followed by perfusion with K+-deficient solution until occurrence of VF (< 10 min). After 2 min of sustained VF, the heart was perfused with normal solution for 10 min, during which sinus rhythm was restored. ECG, left ventricular pressure (LVP) and coronary flow were continuously monitored. The results showed that compared with untreated rats, the onset of low K+-induced ventricular premature beats was delayed and their number was significantly decreased in both T4-treated groups. Nevertheless, VF occurred earlier in T4-treated than in non-treated adult rats (6.78 ± 0.28 vs. 9.59 ± 0.55 min, P < 0.05), whereas the difference was not significant in aged animals. Furthermore, sinus rhythm appeared earlier in old T4-treated rats compared with non-treated rats (7.18 ± 0.57 vs. 8.94 ± 0.64 min, P < 0.05), whereas in adult hearts it set in at practically the same time regardless of treatment. In conclusion, our results indicate that administration of a pharmacological dose of T4 can increase the risk of low K+-induced VF in adult but not in old animals; in the latter it even facilitated restoration of sinus rhythm. Moreover, enhanced mechanical function was observed in both adult and old T4-treated hearts.

(Received 4 March 2004; accepted after revision 8 July 2004; first published online 15 July 2004)
Corresponding author N. Tribulova: Institute for Heart Research, Slovak Academy of Sciences, Dubravska cesta 9, 840 05 Bratislava 45, PO Box 104, Slovak Republic. Email: narcisa.tribulova{at}savba.sk


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
The cardiovascular system is sensitive to the effects of thyroid hormones, and deficiency or excess in thyroid status may significantly alter cardiac function (Cernohorsky et al. 1998; Biondi et al. 2000). Cardiovascular manifestations of hyperthyroidism are decreased vascular resistance and hyperdynamic systolic function with mild hypertrophy, while thyrotoxic heart disease may lead to overt congestive heart failure (Ladenson, 1993). Thyroid hormone has been shown to modulate expression of cardiac potassium channels involved in myocardial repolarization. Accordingly, the reduction of Kv1.2, Kv1.4 and Kv1.5 mRNA levels were associated with cardiac hypetrophy induced by triiodothyronine, T3 (Ma et al. 2003). Nevertheless, there are conflicting data as to thyrotoxicosis-associated changes in ventricular repolarization. Both lengthening in humans (Colzani et al. 2001) as well as shortening in animals were reported (Binah et al. 1987).

Several cardiovascular conditions and some drugs can interfere with thyroid hormone metabolism, which may or may not be manifested in hormone levels (Fadel et al. 2000). Furthermore, starvation and ageing or amiodarone therapy are associated with a decrease and/or variations in thyroid hormone levels (Cizza et al. 1992; Webber & MacDonald, 1994; Doggrell, 2001). By contrast, the therapeutic potential of thyroid hormone as a cardioactive agent was addressed recently (Klemperer, 2002).

The aforementioned as well as other pathophysiological events are associated with electrolyte disturbances, whereby both elevation and depletion of extracellular potassium were reported to increase vulnerability to lethal arrhythmias (Curtis et al. 1993). We previously demonstrated in whole heart preparation that K+ deficiency increased intracellular free Ca2+ (Tribulova et al. 2002a), prolonged action potential duration and consequently promoted triggered activity due to early after-depolarizations followed by premature impulses (Tribulova et al. 2003a). The risk for life-threatening low K+-induced arrhythmias increases in the diseased heart (Tribulova et al. 2002a, 2003a) or in the course of therapy (Helfant, 1998), and susceptibility is increased with ageing itself (Manoach et al. 1986; Carbonin et al. 1992; Tribulova et al. 2002b). Moreover, these conditions were associated with impairment of intercellular junctions and coupling (Tribulova et al. 2001). The latter can contribute to alterations in myocardial synchronization, promoting ventricular re-entry arrhythmias such as ventricular tachycardia and fibrillation (Peters et al. 1997).

The incidence of ventricular arrhythmias in the clinic is usually not attributable to hyperthyroidism alone, whereas atrial fibrillation is the most common dysrhythmia, especially in elderly patients (Aronow, 1995). In most cases the cardiovascular changes associated with thyroid dysfunction are completely reversible (Kienle et al. 1994) and even 56% of atrial fibrillation spontaneously reverted to sinus rhythm when the serum thyroid hormone declined (Shimizu et al. 2002). Because thyroid hormones affect myocardial potassium currents, they can probably interfere with hypokalaemia-related changes and the incidence of ventricular arrhythmias.

Based on clinical case reports, data in the literature and our previous studies, we hypothesized that compared with the adult heart, the aged heart may differ in its susceptibility to low K+-induced VF and its ability to recover sinus rhythm, and this can be affected by the thyroid state. Therefore, this study aimed to examine whether short-term administration of thyroid hormone would have adverse or beneficial effects on the hearts of old and adult rats, with regard to occurrence of VF and restoration of sinus rhythm.


   Materials and methods
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 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
All the experiments were performed in accordance with the Proclamation of the Ministry of Agriculture of the Slovak Republic (1998) for the Care and Use of Laboratory Animals (Law no. 231/1998 in the Digest of Laws of the Slovak Republic). Four- (n= 14) and 20-month-old (n= 14) female Wistar rats were fed with small pieces of apple containing 50 µg (100 g day)–1 T4 (Sigma, St Louis, MO, USA) over two consecutive weeks. These rats as well as age-matched controls (n= 12) were anaesthetized with ether and heparinized (500 IU I.V.). Rapid thoracotomy was performed, the aorta was cannulated in situ and the isolated heart was mounted on to Langendorff apparatus for non-recirculating mode perfusion. The heart was perfused at constant pressure (85 mmHg) with Krebs–Henseleit solution containing: 118.00 mmol L–1 NaCl, 4.70 mmol L–1 KCl, 1.66 mmol L–1 MgSO4, 1.18 mmol L–1 KH2PO4, 2.00 mmol L–1 CaCl2, 25.00 mmol L–1 NaHCO3 and 11.00 mmol L–1 glucose, saturated with 95% O2 plus 5% CO2 (pH 7.4, 37°C). Coronary flow was measured by a timed collection of coronary effluent. Left ventricular pressure was measured by insertion of a thin latex balloon into the left ventricle. Electrical activity of the heart was recorded through two stainless steel electrodes attached to the left ventricular wall on an electrocardiograph (6 NEK 401, RFT, Germany) for heart rate and arrhythmia analysis.

Following stabilization for 30 min, the heart was perfused with K+-deficient (1.2 mmol l–1) Krebs–Henseleit solution until VF occurred (< 10 min). Two minutes of sustained VF were followed by perfusion with normal solution for 10 min, during which sinus rhythm was restored.

Ultrastructure examination of T4-treated and non-treated rat hearts was performed on the intact left ventricular myocardium taken at the end of stabilization and taken at the end of the experiment (n= 6 for each group). Small 1–2 mm tissue blocks were fixed in buffered 2.5% glutaraldehyde, postfixed with 1% osmium tetroxide and routinely processed for preparing thin sections (Tribulova et al. 2002a), which were then analysed by electron microscopy (Tesla 500, Brno, Czech Republic).

Blood samples were collected from the aorta at the time of chest opening and serum T4 and T3 concentrations were measured in all groups using a radioimmunoassay kit.

All data were expressed as mean ±S.E.M. and Student's unpaired t test was performed to compare treated and untreated rats. Statistical significance was determined at P < 0.05.


   Results
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 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
Two weeks of treatment with L-thyroxine resulted in a significant increase in left ventricular weight and left ventricular weight to body weight ratio both in adult and in old T4-treated rats. Unlike adult rats, a moderate decrease in body weight due to T4 treatment was found in the group of old animals (Table 1). The serum levels of the active form of thyroid hormone, T3, were significantly (P < 0.05) elevated in adult (1.35 ± 0.1 vs. 0.80 ± 0.03 ng ml–1) as well as old (1.15 ± 0.03 vs. 0.56 ± 0.05 ng ml–1) T4-treated rats. There were no significant changes in T4 between groups.


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  		Table 1.  LVW, body weight (BW) and LVW to BW ratio of T4- treated (n= 14) and control (n= 12) rats
 
Effects of T4 on functional parameters of the heart during normal and low K+ perfusion

Characteristic haemodynamic data taken at the end of a stabilization period, at low potassium perfusion before the onset of sustained VF and after 10 min of recovery at normal potassium levels are summarized in Table 2.


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  		Table 2.  Haemodynamic parameters of isolated T4-treated and non-treated rat hearts at the end of the stabilization period, at low potassium perfusion before the onset of VF and after 10 min recovery at normokalaemia
 
No difference in heart rate was detected between the T4-treated and untreated rat heart during normal perfusion and neither did we detect a significant difference in coronary flow among the groups. However, a considerable increase in LVP was observed in adult T4-treated rat hearts (Table 2). This parameter was also increased but to a lesser extent in old T4-treated rat hearts. A rapid and pronounced decline in heart rate due to perfusion with K+ deficient Krebs–Henseleit solution was observed in all groups until the occurrence of VF (Table 2). Furthermore, there was an abrupt temporary decrease in coronary flow within the first minute of low K+ perfusion, which recovered thereafter almost to baseline levels, with the exception of adult T4-treated rat hearts. In parallel with changes in coronary flow, a transient and abrupt decline in LVP detected within 1 min of low K+ perfusion (data not shown). LVP soon returned practically to its basal level in all groups (Table 2).

Effects of T4 on incidence of low K+-related arrhythmias

Compared with T4-treated hearts, low K+ perfusion-induced ventricular premature beats occurred earlier and their number was significantly higher in non-treated hearts (Fig. 1A and B). There was no apparent group-related difference in the incidence of transient arrhythmias, such as bigeminy, ventricular tachycardia and VF (not shown) preceding sustained VF. The time to sustained VF, however, was significantly shorter in adult T4-treated than in non-treated rats heart (6.78 ± 0.28 vs. 9.59 ± 0.55 min, Fig. 2A). The difference was, however, not significant in old T4-treated and untreated rat hearts (6.31 ± 0.69 vs. 7.18 ± 0.67 min, Fig. 2A).



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  		Figure 1.  Time to the onset and number of ventricular premature beats in young adult and old non-treated and T4-treated rat hearts
A, time to the onset of ventricular premature beats; and B, number of these arrhythmias in young adult ({blacksquare}) and old ({square}) non-treated as well as T4-treated (T4) rat hearts. *P < 0.05.

 


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  		Figure 2.  Time to the onset of VF and restoration of sinus rhythm in young adult and old non-treated and T4-treated rat hearts
A, time to the onset of VF; and B, time to restoration of sinus rhythm in young adult ({blacksquare}) and old ({square}) non-treated as well as T4-treated (T4) rat hearts. *P < 0.05.

 
Effect of T4 on spontaneous sinus rhythm restoration and recovery of functional parameters

After 2 min of sustained VF, perfusion with normokalaemic Krebs–Henseleit solution was started, and this resulted in a marked increase in coronary flow (data not shown). Normokalaemia resulted in spontaneous recovery of sinus rhythm within a period of less than 10 min in all hearts examined. However, unlike adult T4-treated and non-treated rats in which sinus rhythm occurred at a similar time, in old T4-treated rat hearts there was a significantly shorter time to sinus rhythm reversion compared with non-treated hearts (Fig. 2B). Upon sinus rhythm recovery, coronary flow returned virtually to its baseline levels and heart rate did not differ from initial values (Table 2). It is noteworthy that sinus rhythm restoration was accompanied by apparently better recovery of LVP in all T4-treated rat hearts compared with age-matched controls (Table 2).

Effect of T4 on subcellular myocardial alterations

Regardless of the treatment, electron microscopic examination revealed age-related myocardial alterations that consisted of intracellular lipid accumulation, widened intercellular junctions and interstitial fibrosis in the heart of old T4-treated as well as non-treated rats (Fig. 3A and B). Either in old or in adult rat hearts, administration of T4 did not cause apparent cellular changes of cardiomyocytes, indicating a progressive (characterized by abundance of polyribosomes, neoformation of myofilaments, translocation of mitochondria to subsarcolemmal area, etc.) but rather moderate process of cell growth. However, T4-treated rat hearts exhibited apparently more electron-dense mitochondria with irregular shape of cristae (Fig. 3B, D and F) compared with less electron-dense mitochondria of controls with flattened and tightly packed cristae (Fig. 3A, C and E).



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  		Figure 3.  Electron micrographs of the ultrastructure of cardiomyocytes in non-treated and T4-treated rats
A, C and F, ultrastructure of cardiomyocytes in non-treated rats; and B, D and F, in T4-treated rats at the beginning (A and B) and at the end of the experiments (C–F). Note more electron-dense mitochondria in the myocardium of T4-treated adult (F) and old (B,D) rats compared with more electrolucent mitochondria in the myocardium of untreated adult (E) and old (A,C) rats. Moreover, there are various degrees of subcellular alterations due to low K+ perfusion and incidence of VF, such as overcontraction of myofibrils, impairment of intercellular junctions and injury of mitochondria. The majority of cardiomyocytes, however, were only slightly altered. Magnification 25 000 x.

 
Ultrastructural examination of the myocardium taken at the end of experiments revealed marked heterogeneity of injury due to low K+-related changes and incidence of arrhythmias in all groups. Common features of subcellular alterations were observed, such as mitochondrial swelling and rupture or clamping of their cristae (Fig. 3C–F), focal hypercontraction bands of myofibres and non-uniform patterns of sarcomeres, as well as dehiscence of intercellular junctions. The degree of heart tissue damage was more pronounced when VF lasted for a longer time. There was no apparent difference regarding features of myocardial subcellular alterations between T4-treated and untreated rats. However, the irreversibly injured cardiomyocytes were found more often in the hearts of young T4-treated rats (Fig. 3F) than in other groups.


   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The main findings of the present study can be summarized as follows. (1) Short-term L-thyroxine admimistration increased the propensity of adult but not of old rats hearts to low K+-induced VF. (2) Both L-thyroxine-treated groups exhibited a delay in the occurrence and decrease in the number of ventricular premature beats compared with non-treated animals. (3) Restoration of spontaneous sinus rhythm due to perfusion of the heart with normokalaemic solution occurred earlier in the old T4-treated rats compared with non-treated ones, whereas there was no difference between adult T4-treated and non-treated rats. (4) Sinus rhythm restoration was followed by significantly better recovery of mechanical function in all hearts of T4-treated rats.

Short-term oral administration of a pharmacological dosage of T4 used in our study resulted in a mild degree of hyperthyroidism, as evidenced by a moderate increase in serum T3 levels, mild cardiac hypertrophy, and essentially unchanged heart rate (monitored ex vivo) and body weight. However, it considerably increased LVP in adult rat hearts, indicating hyperdynamic systolic function comparable with that seen in moderate hyperthyroidism (Aronow, 1995). Increased heart rate, left ventricular mass index and contractility can be observed, as reported recently, during subclinical thyrotoxicosis (Burmeister & Flores, 2002). An increase in cardiac output was found as a result of chronic elevation of T3 (Yen, 2001), and permanent elevation is thought to contribute to atrial fibrillation (Ladenson, 1993).

According to ultrastructural examination, both groups of T4-treated rat hearts exhibited a higher energetic state of mitochondria. This was indicated by an increased electron density and irregular shape of cristae (Munn, 1974) compared with less dense mitochondria with flattened and tightly packed cristae observed in the myocardium of untreated rats. However, regardless of the treatment, there were apparent age-related myocardial alterations, such as widened adhesive intercellular junctions and interstitial fibrosis in old rat hearts. These changes can partially explain the less pronounced increase in heart function in the old T4-tretaed rat hearts despite the fact that ventricular tissue mass was augmented to the same degree as in adult T4-treated rats.

Hypokalaemia is known to increase the risk for arrhythmias and VF due to prolongation and dispersion of myocardial repolarization (Helfant, 1998; Tribulova et al. 2003a) as well as due to elevation of intracellular free calcium and Ca2+ overload (Tribulova et al. 2002a). These conditions and decrease in heart rate promote both triggered activity and re-entry, i.e. crucial mechanisms involved in the development of VF (Helfant, 1998; Tribulova et al. 2001, 2002a). In agreement with this, we showed previously that low K+-related triggered activity followed by ventricular premature beats occurred earlier and more often in young rats suffering from hypertension, exhibiting prolongation of action potential duration (Tribulova et al. 2001; Tribulova et al. 2003). By contrast, a delay in the occurrence and a decrease in the number of ventricular premature beats were found in all T4-treated rats. Because prolongation of repolarization due to hypokalaemia plays an important role in the mechanisms of these arrhythmias, it can be expected that shortening of repolarization by thyroid hormone (Binah et al. 1987) would suppress their incidence. Nevertheless, it is very interesting that despite comparable significant suppression of triggered activity in both adult and old T4-treated rats, they differed in susceptibility to VF. The latter was increased in adult but not in old T4-treated rats, compared with non-treated animals, suggesting that neither the time of onset of premature beats nor their prevalence can be considered predictors of susceptibility to VF. Taking into consideration another important risk factor for the occurrence of hypokalaemia-related VF, i.e. decrease in heart rate, it should be noted that this was far more pronounced in T4-treated rats compared with non-treated rats. This can partially explain the higher vulnerability of adult T4-treated rats to VF. Why is this not the case in old T4-treated rats? We can only speculate that their lower basal heart rate and less pronounced hypokalaemia-induced decline compared with adult rats may affect their susceptibility to VF.

Results of this study indicate a higher susceptibility of adult T4-treated rat hearts to low K+-induced VF compared with non-treated rats. In agreement with this, an unusual case of thyrotoxicosis and hypokalaemic periodic paralysis presenting with ventricular tachycardia was reported in a young man (Davison & Davison, 1995). Adverse thyroid hormone-induced effects can contribute to atrial fibrillation in humans (Shimizu et al. 2002) and they most likely contribute to the higher vulnerability of adult T4-treated rats to low K+-induced VF. These effects were associated with ion-channel remodelling and Ca2+ cycling protein alterations, such as potassium current down-regulation (Ma et al. 2003) and Na+/Ca2+ exchanger up-regulation (Carr & Kranias, 2002) as well as with a functional hyperdynamic state.

Note that thyroid hormones can also affect myocardial expression of intercellular gap junction channel proteins. These are crucial for electrical coupling and consequently for maintenance of myocardial synchronization, whereas dysfunction of gap junctions facilitates the occurrence of malignant arrhythmias (Peters et al. 1997). Our latest data suggest that thyroid hormone can up-regulate gap junction proteins in neonatal rat myocytes (Tribulova et al. 2004). Thyroid hormone may do so also in old rat cardiomyocytes, which exhibit a lower number of gap junctions compared with adult cardiomyocytes (Tribulova et al. 2002b). By contrast, application of thyroid hormone to adult animals down-regulates gap junction protein, connexin43, and increases their susceptibility to electrically induced VF (results in preparation). This suggests a distinct, age-dependent effect of thyroid hormone on intercellular channel protein expression.

Hypokalaemia and consequent VF lead to heterogeneously distributed structural alterations of the myocardium and this feature persisted even after sinus rhythm restoration (as demonstrated in Fig. 3). The majority of cardiomyocytes in all groups exhibited reversible alterations, whereas irreversibly altered cardiomyocytes were more often found in young adult T4 -treated rat hearts, which exhibited highest vulnerability to VF.

Our results indicate a beneficial effect of T4 administration to old rats resulting in facilitation of sinus rhythm restoration. A clear beneficial effect of thyroid hormone replacement was used clinically in the setting of correcting both chronic (e.g. heart failure) and acute (due to cardiac surgery) hypothyroid states or during resuscitation (MacKerrow et al. 1992; Klemperer, 2002). Enhancement of intercellular coupling and communication at the gap junction by thyroid hormone (Tribulova et al. 2003a,b) in old animals may be involved in this process. However, further studies are necessary to prove this hypothesis.

It is noteworthy that both old and adult T4-treated rat hearts exhibited significantly better mechanical recovery upon restoration of sinus rhythm compared with non-treated groups. Improvement of haemodynamic function after VF can most likely be attributed to the positive inotropic effects of T4 observed in experimental as well as in clinical settings (Klemperer, 2002). Because this effect is associated with acceleration of Ca2+ uptake by sarcoplasmic reticulum, it can help in the recovery from cardio-depression resulting from VF-induced Ca2+ overload.

In conclusion, the results of this study indicate age-dependently diverse effects of T4 administration causing increased susceptibility of adult (but not old) rat hearts to hypokalaemia-induced VF and increased ability of the old heart to restore sinus rhythm. Moreover, T4 administration enhanced mechanical function upon sinus rhythm recovery in both adult and old rat hearts.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Aronow WS (1995). The heart and thyroid disease. Clin Geriatr Med 11, 219–229.[Medline]

Binah O, Rubinstein I & Gilat E (1987). Effects of thyroid hormone on the action potential and membrane currents of guinea pig ventricular myocytes. Pflugers Arch 409, 214–216.[CrossRef][Medline]

Biondi B, Palmieri EA, Fazio S, Cosco C, Nocera M, Sacca L, Filetti S, Lombardi G & Perticone F (2000). Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J Clin Endocrinol Metab 85, 4701–4705.[Abstract/Free Full Text]

Burmeister LA & Flores A (2002). Subclinical thyrotoxicosis and the heart. Thyroid 12, 495–499.[CrossRef][Medline]

Carbonin PU, Pahor M & Olivetti G (1992). Increased incidence of arrhythmias with aging in normal and pathological rat hearts. Ann NY Acad Sci 673, 311–320.[CrossRef][Medline]

Carr AN & Kranias EG (2002). Thyroid hormone regulation of calcium cycling proteins. Thyroid 12, 453–457.[CrossRef][Medline]

Cernohorsky J, Kolar F, Pelouch V, Korecky B & Vetter R (1998). Thyroid control sarcolemmal Na/Ca exchanger and SR Ca-ATPase in developing rat heart. Am J Physiol 275, H264–H273.

Cizza G, Brady LS, Calogero AE, Bagdy G, Lynn AB, Kling MA, Blackman MR, Chrousos GP & Gold PW (1992). Central hypothyroidism is associated with advanced age in male Fischer 344/A rats: in vivo and in vitro studies. Endocrinology 131, 2672–2680.[Abstract]

Colzani RM, Emdin M, Conforti F, Passino C, Scarlattini M & Iervasi G (2001). Hyperthyroidism is associated with lengthening of ventricular repolarization. Clin Endocrinol 55, 27–32.[CrossRef][Medline]

Curtis MJ, Pugsley MK & Walker MJA (1993). Endogenous chemical mediator of ventricular arrhythmias in ischaemic heart disease. Cardiovasc Res 27, 703–719.[Free Full Text]

Davison ET & Davison MJ (1995). Triiodothyronine (T3) toxicosis with hypokalemic periodic paralysis and ventricular tachycardia. J Electrocardiol 28, 161–164.[CrossRef][Medline]

Doggrell SA (2001). Amiodarone – waxed and waned and waxed again. Expert Opin Pharmacother 2, 1877–1890.[CrossRef][Medline]

Fadel BM, Ellahham S, Ringel MD, Lindsay J Jr, Wartofsky L & Burman KD (2000). Hyperthyroid heart disease. Clin Cardiol 23, 402–408.[Medline]

Helfant RH (1998). Hypokalemia and arrhythmias. Am J Med 80, 13–22.

Kienle RD, Bruyette D & Pion PD (1994). Effects of thyroid hormone and thyroid dysfunction on the cardiovascular system. Vet Clin North Am Small Anim Pract 24, 495–507.[Medline]

Klemperer JD (2002). Thyroid hormone and cardiac surgery. Thyroid 12, 517–521.[CrossRef][Medline]

Ladenson PW (1993). Thyrotoxicosis and the heart: something old and something new. J Clin Endocrinol Metab 77, 332–333.[CrossRef][Medline]

Ma ML, Watanabe K, Watanabe H, Hosala Y, Komura S, Aizawa Y & Yamamoto T (2003). Different gene expression of potassium channels by thyroid hormone and antithyrpid drug between the atrium and ventricle of rats. Jpn Heart J 44, 101–110.[CrossRef][Medline]

MacKerrow SD, Osborn LA, Levy H, Eaton RP & Economou P (1992). Myxedema-associated cardiogenic shock treated with intravenous triiodothyronine. Ann Intern Med 117, 1014–1015.

Manoach M, Netz H, Varon D, Amitzur G, Weinstock M, Kauli A & Assaeli M (1986). Factors influencing spontaneous initiation and termination of ventricular fibrillation. Jap Heart J 27, 365–375.[Medline]

Munn EA (1974). The Structure of Mitochondria. Academic Press, London.

Peters NS, Coromilas J, Severs NJ & Wit AL (1997). Disturbed connexin-43 gap junction distribution correlates with location of circuits in the epicardial border zone of healing canine infarct that cause ventricular tachycardia. Circulation 95, 988–996.[Abstract/Free Full Text]

Shimizu T, Koide S, Noh JY, Sugino K, Ito K & Nakazawa H (2002). Hyperthyroidism and the management of atrial fibrillation. Thyroid 12, 489–493.[CrossRef][Medline]

Tribulova N, Manoach M, Varon D, Okruhlicova L, Zinman T & Shainberg A (2001). Dispersion of cell-to-cell uncoupling precedes low K+-induced ventricular fibrillation. Physiol Res 50, 247–259.[Medline]

Tribulova N, Okruhlicova L, Imanaga I, Hirosava N, Manoach M, Ogawa K & Weismann P (2003a). Factors involved in the susceptibility of spontaneously hypertensive rats to low K+-induced arrhythmias. Gen Physiol Biophys 22, 369–382.[Medline]

Tribulova N, Okruhlicova L, Novakova S, Pancza D, Bernatova I, Pechanova O, Weismann P, Manoach M, Seki S & Mochizuki M (2002a). Hypertension-related intermyocyte junctions remodeling is associated with higher incidence of low K+-induced lethal arrhythmias, in isolated rat heart. Exp Physiol 82, 195–205.[CrossRef]

Tribulova N, Okruhlicova L, Varon D, Manoach M, Pechanova O, Bernatova I, Weismann P, Barancik M, Styk J & Slezak J (2002b). Structural substrates involved in the development of severe arrhythmias in hypertensive rat and aged guinea pig hearts. In Cardiac Remodeling and Failure, ed. Dhalla N & Singal P, pp. 377–398. Kluwer Academic Publishers, Boston.

Tribulova N, Shneyvays V, Mamedova LK, Zinman T, Moshel S, Shainberg A, Manoach M, Weismann P & Kostin S (2004). Enhanced connexin 43 and alfa sarcomeric actin expression in cultured heart myocytes exposed to triiodo-1-thyronine. Histochem J 35, (in press).

Webber J & MacDonald IA (1994). The cardiovascular, metabolic and hormonal changes accompanying acute starvation in men and women. Br J Nutr 71, 437–447.[CrossRef][Medline]

Yen PM (2001). Physiological and molecular basis of thyroid hormone action. Physiol Rev 81, 1097–1142.[Abstract/Free Full Text]


   Acknowledgements
 
We wish to thank to Professor M. Manoach, Tel Aviv University, Israel, for critical review of this paper. We are also grateful to Mrs A. Brichtova, A. Maczaliova and T. Ottova for excellent technical assistance. This work was supported by VEGA grants no. 2/3124/22, 2/2064/22, 2/20/65/22, 1/8216/22, 2/2055/22 and APVT grant no. 51-020802.





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