Reentrant Atrioventricular Nodal Tachycardia Induced by Levothyroxine

Bernadette Biondi, Serafino Fazio, Fernando Coltorti, Emiliano Antonio Palmieri, Carlo Carella, Gaetano Lombardi and Luigi Saccà

Departments of Internal Medicine (S.F., F.C., E.A., L.S.) and Endocrinology of University "Federico II" (B.B., G.L.); and Department of Endocrinology of the 2nd University (C.C.) Naples, Italy

Address all correspondence and requests for reprints to: Luigi Saccà, Medicina Interna, via Pansini, 5, 80131 Naples, Italy.


    Introduction
 Top
 Introduction
 Clinical presentation
 Discussion
 References
 
SINUS tachycardia, atrial premature beats and, in some cases, atrial fibrillation are frequent complications of overt hyperthyroidism (1, 2, 3). Only recently these alterations of cardiac rhythm also have been reported in patients with subclinical hyperthyroidism. This condition may be the consequence of levothyroxine (L-T4) treatment (exogenous hyperthyroidism) or may be of endogenous origin, usually because of autonomously functioning thyroid adenoma or multinodular goiter. Subclinical hyperthyroidism induced by exogenous administration of L-T4 has been shown to increase the average 24-h heart rate and the number of atrial premature beats. Palpitations occur in some patients, and they may be alleviated by the administration of a ß-adrenergic blocking drug (4, 5). Sawin et al. (6), in a large group of 2007 people 60 yr of age or older, documented a 3-fold higher risk of atrial fibrillation in the presence of low serum TSH concentrations caused by endogenous or exogenous subclinical thyrotoxicosis (6).

Our report shows the possibility that thyroid hormones may also induce other kinds of supraventricular arrhythmias not yet described in hyperthyroid patients, such as reentrant atrioventricular (A-V) nodal tachycardia.


    Clinical presentation
 Top
 Introduction
 Clinical presentation
 Discussion
 References
 
We observed five women during the last 2 yr complaining of increasingly frequent and prolonged episodes of palpitations during substitutive L-T4 therapy (1.2–1.5 µg/kg per day) for multinodular nontoxic goiter. Before the initiation of L-T4 therapy, the patients had a normal thyroid function as assessed by serum free T4 (FT4), free T3 (FT3), and TSH levels in the normal range, and by a normal TSH response to TRH. The age of the patients ranged from 34–52 yr. They had no evidence of cardiac disease except for the anamnestic remark of previous episodes of palpitations in two patients, even before L-T4 therapy. Assessment of cardiac rhythm and thyroid function was performed to evaluate a possible relationship between the presence of palpitations and L-T4 therapy.

The evaluation was performed by standard and 24-h ambulatory electrocardiogram (ECG) monitoring (Holter ECG), transoesophageal electrophysiological study, and thyroid hormone and TSH assays during L-T4 therapy and 2 months after L-T4 withdrawal. The patients took no medication other than L-T4 during their evaluation.

Serum levels of FT4 and FT3 were in the normal range, although they were higher during L-T4 therapy than after L-T4 withdrawal, whereas TSH was lower during L-T4 therapy than after withdrawal (Table 1Go).


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Table 1. TSH, FT3, and FT4 serum levels during L-T4 therapy and 2 months after therapy withdrawal (W)

 
Four patients had abnormal conduction pathway as demonstrated by a shortened P-R interval at the standard 12 lead ECG, both during L-T4 therapy and after L-T4 withdrawal.

Holter ECG showed a clear increase of mean 24-h heart rate (82 ± 5 vs. 72 ± 6 beats/min) and atrial premature beats (1435 ± 512 vs. 453 ± 145 beats/24 h) and evidenced a greater number of episodes of reentrant A-V nodal tachycardia (47 ± 33 vs. 9 ± 9 min/24 h) during L-T4 therapy. These episodes were observed in all five patients during therapy and persisted in only two patients after discontinuation of therapy. In addition, they were started by atrial premature beats.

Transoesophageal electrophysiological study was performed in only three patients who gave their informed consent. A reentrant A-V nodal tachycardia (diagnosed on the basis of a ventriculo-atrial interval less than 70 ms) (Fig. 1Go) was inducible in all the three patients evaluated, both during L-T4 therapy and after L-T4 withdrawal, although it was less easily induced in the latter case. Furthermore, the effective refractory A-V nodal period was significantly shortened during L-T4 therapy (230 ± 10 vs. 257 ± 6; P = 0.015), as was the Wenckebach point (307 ± 6 vs. 333 ± 8; P = 0.004) (Table 2Go).



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Figure 1. Reentrant A-V nodal tachycardia triggered by three consecutive electrical extrastimuli during transoesophageal electrophysiological study.

 

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Table 2. Transoesophageal electrophysiological study

 

    Discussion
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 Introduction
 Clinical presentation
 Discussion
 References
 
It is well known that thyroid hormones have electrophysiological actions that are important in triggering supraventricular arrhythmias. Indeed, thyroid hormones have direct positive chronotropic effect because of a reduced time of repolarization phase of the action potential, which results in shortening of the effective refractory period (7, 8, 9, 10, 11). Recent data on sodium and potassium ion channel currents have demonstrated that thyroid hormones up-regulate Kv 1.5 messenger RNA levels in the rat heart (12). Kv 1.5 is an ion channel for IKur current that was also observed in the human atrial cells (13). The molecular cloning of an individual cardiac ion channel has provided important new information on the molecular basis of cardiac excitability. The preferential atrial arrhythmogenic effect of thyroid hormones could also be caused by the increased atrial ß-adrenergic receptor density (14) in the presence of reduced parasympathetic tone (15, 16). Thus, it is conceivable that ß-adrenergic blockade might reduce the arrhythmogenic effect of thyroid hormone in patients predisposed to supraventricular tachycardia, when L-T4 treatment is considered indispensable.

This report also shows that reentrant A-V nodal tachycardia may be triggered by thyroid hormone in predisposed subjects. The reentrant A-V nodal tachycardia is a relatively common cause of regular, narrow QRS complex tachycardia, and it is more prevalent in women (7:3) than in men (17, 18). Epidemiologically, it must be emphasized that both thyroid disease and reentrant A-V nodal tachycardia are highly prevalent in females. The symptoms of this arrhythmia are generally mild and are described by patients as rapid heart beat, palpitation, and dizziness, whereas older subjects may complain of presyncope.

In patients with reentrant A-V nodal tachycardia, at least two functionally distinct A-V nodal conduction patterns are demonstrable (19, 20). One pathway, referred to as the fast pathway, is characterized by rapid conduction velocity and relatively long refractoriness. The second or slow pathway typically shows slow conduction velocity and short refractoriness. During sinus rhythm, the electric impulse is expected to reach the His bundle and the ventricle preferentially over the faster-conducting pathway with the frequent evidence of a short P-R interval at the ECG. A-V nodal reentry of the common type (slow-fast) is typically initiated by an atrial premature beat that conducts down only through the slow pathway because of functional block of the fast pathway, and reenters back through the fast pathway because of recovery of its excitability (Fig. 2Go).



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Figure 2. Schematic description of induction of A-V nodal reentry following an atrial premature beat in a subject with two distinct functional pathways.

 
Conceivably, thyroid hormones might increase the occurrence of reentrant A-V nodal tachycardia in predisposed subjects because of the enhancement of atrial excitability, with consequent increase of the number of atrial premature beats and the shortening of the refractory period of the conducting tissues. Thus, reentrant A-V nodal tachycardia might be triggered in patients in whom L-T4 is exogenously administered to lower TSH. On this basis, a standard ECG may be considered before starting L-T4 therapy to identify the subjects with a short P-R interval who might be predisposed to this kind of arrhythmia, and consequently, L-T4 therapy should be given with caution to these patients.

Received February 11, 1998.

Revised March 26, 1998.

Accepted April 21, 1998.


    References
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 Introduction
 Clinical presentation
 Discussion
 References
 

  1. Olshausen KV, Bischoff S, Kahaly G, et al. 1998 Cardiac arrhythmias and heart rate in hyperthyroidism. Am J Cardiol. 63:930–933.
  2. Presti CF, Hart RG. 1989 Thyrotoxicosis, atrial fibrillation and embolism, revisited. Am Heart J. 117:976–977.[Medline]
  3. Forfar JC, Miller HC, Toft AD. 1979 Occult thyrotoxicosis: a correctable cause of "idiopathic" atrial fibrillation. 44:9–12.
  4. Biondi B, Fazio S, Carella C, et al. 1993 Cardiac effects of long-term thyrotropin-suppressive therapy with levothyroxine. J Clin Endocrinol Metab. 77:334–338.[Abstract]
  5. Biondi B, Fazio S, Carella C, et al. 1994 Control of adrenergic overactivity by beta-blockade improves quality of life in patients on long-term suppressive therapy with levothyroxine. J Clin Endocrinol Metab. 78:1028–1033.[Abstract]
  6. Sawin CT, Geller A, Walf PA, et al. 1994 Low serum thyrotropin concentration as a risk factor for atrial fibrillation in older persons. N Engl J Med. 331:1249–1252.[Abstract/Free Full Text]
  7. Klein I, Hong C. 1986 Effects of thyroid hormone on cardiac size and myosin content of the heterotopically transplanted rat heart. J Clin Invest. 77:1694–1698.[Medline]
  8. Valente M, De Santo C, de Martino Rosaroll P, Di Maio V, Di Meo S, De Leo T. 1988 The direct effect of thyroid hormone on cardiac chronotropism. Arch Int Physiol Biochim. 97:431–440.
  9. Freedberg AS, Papp JG, Vougham Williams EM. 1970 The effect of altered thyroid state on atrial intracellular potential. J Physiol. 207:357–369.[Medline]
  10. Johnson PN, Freedberg AS, Marshall SM. 1973 Action of thyroid hormone on the transmembrane potential from sinoatrial node cells and atrial muscle cells in isolated atria of rabbits. Cardiology. 58:273–289.[Medline]
  11. Arnsdorf MF, Childers RW. 1970 Atrial electrophysiology in experimental hyperthyroidism in rabbits. Circ Res. 26:575–581.[Medline]
  12. Nishiyama A, Kambe F, Kamiya K, Yamaguchi S, Murata Y, Seo H, et al. 1997 Effects of thyroid and glucocorticoid hormones on Kv 1.5 potassium channel gene expression in the rat left ventricle. Biochem Biophys Res Commun. 237:521–526.[CrossRef][Medline]
  13. Wang Z, Fermini B, Nattel S. 1993 Sustained depolarization-induced outward current in human atrial myocytes. Evidence for a novel delayed rectifier K+ current similar to Kv 1.5 cloned channel currents. Circ Res. 73:1061–1076.[Abstract]
  14. Golf S, Lovstad R, Hansson V. 1985 ß-Adrenoreceptor density and relative number of ß-adrenoreceptor subtypes in biopsies from human right atrial, left ventricular and right ventricular myocardium. Cardiovasc Res. 19:636–641.[Medline]
  15. Klein I, Levey GS. 1996 The cardiovascular system in thyeotoxicosis. In: Brawerman LE, Utiger RD, eds. Werner and Ingbar’s the thyroid, 7th ed. Philadelphia: Lippincott Raven; 607–615.
  16. Cacciatori V, Bellavere F, Pezzarossa A, et al. 1996 Power spectral analysis of heart rate in hyperthyroidism. J Clin Endocrinol Metab. 81:2828–2835.[Abstract]
  17. Ganz LI, Friedman PL. 1995 Supraventricular tachycardia. N Engl J Med. 332:162–172.[Free Full Text]
  18. Akhtar M, Jazayeri MR, Sra J, Blanck Z, Deshpande S, Dhala A. 1993 Atrioventricular nodal re-entry. Clinical, electrophysiological, and therapeutic considerations. Circulation. 88:282–295.[Abstract]
  19. Denes P, Wu P, Dhingra RC, Chuquimia R, Rosen KM. 1973 Demonstration of a dual A-V nodal pathway in patients with paroxysmal supraventricular tachycardia. Circulation. 48:549–555.[Medline]
  20. Rosen KM, Metha A, Miller RA. 1974 Demonstration of dual atrioventricular nodal pathway in man. Am J Cardiol. 33:291–294.[Medline]