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Cardiovascular Research 2000 48(2):188-190; doi:10.1016/S0008-6363(00)00181-4
© 2000 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Acquired delayed rectifier channelopathies: how heart disease and antiarrhythmic drugs mimic potentially-lethal congenital cardiac disorders

Stanley Nattel*

Research Center and Department of Medicine, Montreal Heart Institute, 5000 Belanger Street E., Montreal, Quebec H1T 1C8; and University of Montreal, Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada

* Tel.: +1-514-376-3330; fax: +1-514-593-2521 nattel{at}icm.umontreal.ca

Received 28 June 2000; accepted 28 June 2000

See article by Tsuji et al. [10] (pages 300–309) in this issue.

The discovery of the molecular bases of the congenital long QT syndromes (LQTSs) [1–5] has created an explosion of insight, not only into these relatively rare congenital abnormalities, but also into the broader function of delayed rectifier channels in the heart. Recent reviews have covered the pathophysiology of these syndromes in detail [6,7] with arrhythmogenesis due to defects at the level of the density of repolarizing current and/or abnormal kinetics. The evolving knowledge has highlighted the role of the rapid component (IKr) of delayed rectifier current (IK) as a primary repolarizing current in ventricular tissue (including the human heart) and of the slower component (IKs) as an important ‘safety factor’ in the presence of adrenergic stimulation [8] or prolonged action potentials (APs) [9].

The article by Tsuji et al. in the present issue [10] is part of a rapidly-evolving body of knowledge that points to acquired conditions that may predispose to potentially lethal ventricular tachyarrhythmias while recreating ionic abnormalities associated with congenital LQTSs. Tsuji et al. show that congestive heart failure (CHF) results in downregulation of a variety of ionic currents in ventricular myocytes, including L-type Ca2+ current (ICa), Ca2+-independent transient outward K+ current (Ito) and IK [10]. Decreased Ito is well-known to occur in a range of cardiac conditions, including CHF [11], the post-myocardial infarction state [12], and tachycardia-induced atrial remodeling [13]. Reductions in ICa have been reported to occur in CHF by some investigators [14] but not others [11,15]. Less has been known about changes in IK in cardiac disease states.

An important novel contribution of the Tsuji paper is the convincing demonstration that ventricular IK is downregulated by CHF. This observation may be very important for a number of reasons. Patients with CHF are at increased risk of sudden cardiac death due to ventricular tachyarrhythmias [16], with abnormalities in cardiac repolarization believed to play a prominent role [17]. At least two arrhythmogenic mechanisms might be implicated in the ventricular tachyarrhythmia-promoting effects of delayed repolarization.

First, arrhythmogenic early afterdepolarizations (EADs) occur in the setting of delayed repolarization and can lead to potentially-lethal ventricular arrhythmias [18]. In the congenital and acquired LQTSs, EADs typically lead to Torsades de Pointes (TdP) morphologies. Ventricular tachyarrhythmias associated with CHF do not typically have TdP morphologies. However, the characteristic TdP morphology in the LQTS is believed to be due to a specific transmural distribution of QT prolongation, greatest in midmyocardial M cells and less in other layers [19]. In CHF, AP prolongation has a different distribution, tending to reduce (rather than exaggerate) transmural AP duration (APD) disparities [20]. Therefore, EAD-related ventricular tachyarrhythmias in patients with CHF may not have the typical features of TdP.

Second, the Na+,Ca2+-exchanger (NCX) is up-regulated by CHF [21]. Enhanced NCX activity is an important potential mechanism of arrhythmogenic delayed afterdepolarizations (DADs) [22]. The NCX carries an inward current when Ca2+ that has entered the cell during depolarization is exchanged in a 1:3 molar ratio for Na+ (thus carrying a net inward current) upon repolarization. By delaying repolarization, reduced IK indirectly increases Ca2+ entry during the prolonged AP [23], resulting in a larger intracellular Ca2+ load, increasing the amount of Ca2+ to be exchanged for Na+ and functionally increasing the potentially arrhythmogenic current carried by the NCX.

In addition to its potential contribution to primary ventricular tachyarrhythmias in CHF, the decreased IK in CHF may be quite important in sensitizing patients with CHF to the proarrhythmic effects of antiarrhythmic drugs. The presence of CHF is known to be an important risk factor for drug-induced TdP [24]. Tsuji et al. show that CHF-induced downregulation is particularly important for IKs, with IKr also significantly decreased but to a lesser extent [10]. The CHF-induced decrease in IKs may make the cell critically dependent on the remaining IKr for repolarization, exposing the heart to a greater risk of TdP upon exposure to IKr-reducing agents like most clinically-available class III drugs. This type of pathophysiology is suggested by a dog model of cardiac hypertrophy associated with increased susceptibility to drug-induced TdP [25], in which ventricular myocyte IKs downregulation is prominent [26]. The results of Tsuji et al. suggest that both IKs and IKr may be decreased in the ventricles by CHF [10], with a relatively greater decrease in IKs. Combined dysfunction of IKs and IKr has been described as causing a particularly malignant form of congenital LQTS [27]. Thus, if the results of the Tsuji study can be extrapolated to man, one could imagine that a relatively small additional drug-induced reduction in IKr could be enough to trigger potentially-lethal ventricular tachyarrhythmias in CHF patients.

The paper by Tsuji et al. is the first full publication in the literature to demonstrate downregulation of the components of ventricular IK in CHF. Decreases in IKs in a canine CHF model have been described in abstract form [20]. A previous study has shown decreases in ventricular IKr in cardiomyopathic hamsters [28], but IKs could not be detected and it was unclear whether the IKr deficiency was a result of the underlying cardiomyopathic process or was secondary to CHF per se. Downregulation of IKs in CHF may not be limited to ventricular myocytes— it appears to occur in atrial myocytes of animals with CHF [29]. Previous publications have emphasized the importance of decreased Ito [11] and increased NCX [21,30] in the AP prolongation typically associated with CHF. The report by Tsuji et al. emphasizes that changes in IK must also be seriously considered in evaluating the mechanisms responsible for AP abnormalities in CHF. The transmural distribution of IKs, believed to be less dense in M cells compared to subendocardial and subepicardial layers [31], fits with the distribution of CHF-induced APD prolongation, which is less in M cells than in other regions [20].

Tsuji et al. evaluated changes in Ito, IK1, ICa and IK in rabbits with tachycardia-induced CHF. They elegantly correlated in vivo hemodynamic and electrocardiographic findings with recordings of APs and ionic currents from isolated cells— important correlations too often lacking in voltage-clamp studies. These investigators are to be congratulated for succeeding in recording IK and separating it into its constituent components in a species in which IK is notoriously small and in which until recently there was even doubt as to the existence of the IKs component [32]. The similarity in activation kinetics between IKr and IKs in their study is a bit disturbing, suggesting either that IKr kinetics in the rabbit are different from those reported in other species or that there may be some contamination of their E-4031 sensitive component by IKs rundown. This limitation does not affect their conclusions that total IK and the IKs component are reduced by CHF. Previous observations regarding changes in IKr in cardiac hypertrophy and failure have varied. Li et al. found no change in atrial IKr of dogs with CHF [29]. In a model of arrhythmogenic ventricular hypertrophy, Volders et al. noted a decreased IKr in the right, but not left, ventricle [26]. A more detailed characterization of the changes in IKr in CHF by further electrophysiological studies, along with molecular evaluations of changes in the expression of HERG protein and mRNA levels, would be helpful to shed further light on this issue.

Among the clinical predictors of class III antiarrhythmic drug-induced TdP, CHF is prominent [24]. The report by Tsuji et al. indicates that IK is reduced in the ventricles of rabbits with CHF. In conjunction with the nicely-demonstrated role of IK reductions in a chronic dog model of TdP [25,26], these observations raise the interesting possibility that some naturally-occurring cardiac diseases predispose to ventricular tachyarrhythmias and to drug-induced TdP by reproducing pathophysiologic features of congenital LQTSs. Clearly, CHF and myocardial hypertrophy alter several important ionic currents in addition to IK, and their arrhythmogenic properties cannot be considered a simple mimicking of LQTS. On the other hand, the loss of IK and its critical repolarization-promoting function should not be overlooked as a potentially important contributor to the arrhythmic manifestations of these cardiac disease states. Along with the IKr-blocking class III agents, which clearly mimic important pathophysiological aspects of the LQT2 form of LQTS [1], these conditions involving significant acquired abnormalities in IK function may merit consideration as a class of acquired delayed rectifier channelopathies. Whether or not this specific terminology is applied, the potential importance of acquired abnormalities of cardiac IK function need to be considered in understanding the arrhythmogenic consequences, not only of repolarization-delaying drugs, but also of cardiac disease processes and of disease/drug combinations.


   Acknowledgements
 
The author thanks the Medical Research Council of Canada and the Quebec Heart Foundation for financial support, and Luce Bégin for secretarial help with the manuscript.


   References
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