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Am J Physiol Heart Circ Physiol 291: H2597-H2605, 2006. First published July 28, 2006; doi:10.1152/ajpheart.00393.2006
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Computational Analyses in Ion Channelopathies

Electrophysiological mechanisms of ventricular arrhythmias in relation to Andersen-Tawil syndrome under conditions of reduced IK1: a simulation study

Ruey J. Sung,1,2 Sheng-Nan Wu,3,4 Jiun-Shian Wu,3 Han-Dong Chang,3 and Ching-Hsing Luo5

Departments of 1Medicine and 3Physiology and Institutes of 4Basic Medical Sciences and 5Electrical Engineering, Colleges of Medicine and Engineering, National Cheng Kung University, Tainan, Taiwan; and 2Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, California

Submitted 14 April 2006 ; accepted in final form 26 June 2006


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
Patients with Andersen-Tawil syndrome (ATS) mostly have mutations on the KCNJ2 gene, producing loss of function or dominant-negative suppression of the inward rectifier K+ channel Kir2.1. However, clinical manifestations of ATS including dysmorphic features, periodic paralysis (hypo-, hyper-, or normokalemic), long QT, and ventricular arrhythmias (VAs) are considerably variable. Using a modified dynamic Luo-Rudy simulation model of cardiac ventricular myocytes, we attempted to elucidate mechanisms of VA in ATS by analyzing effects of the inward rectifier K+ channel current (IK1) on the action potential (AP). During pacing at 1.0 Hz with extracellular K+ concentration ([K+]o) at 4.5 mM, a stepwise 10% reduction of Kir2.1 channel conductance progressively prolonged the terminal repolarization phase of the AP along with gradual depolarization of the resting membrane potential (RMP). At 90% reduction, early afterdepolarizations (EADs) became inducible and RMP was depolarized to –52.0 mV (control: –89.8 mV), followed by emergence of spontaneous APs. Both EADs and spontaneous APs were facilitated by a decrease in [K+]o and suppressed by an increase in [K+]o. Simulated beta-adrenergic stimulation enhanced delayed afterdepolarizations (DADs) and could also facilitate EADs as well as spontaneous APs in the setting of low [K+]o and reduced Kir2.1 channel conductance. In conclusion, the spectrum of VAs in ATS may include 1) triggered activity mediated by EADs and/or DADs and 2) abnormal automaticity manifested as spontaneous APs. These VAs can be aggravated by a decrease in [K+]o and beta-adrenergic stimulation and may potentially induce torsade de pointes and cause sudden death. In patients with ATS, the hypokalemic form of periodic paralysis should have the highest propensity to VAs, especially during physical activity.

Andersen syndrome; long QT

ANDERSEN-TAWIL SYNDROME (ATS) is a rare autosomal dominant disorder characterized by clinical manifestations of periodic paralysis, long QT, ventricular arrhythmias, and multiple skeletal dysmorphic features (3, 7, 33, 36, 40, 50). These clinical manifestations are considerably variable, suggesting that ATS is a genetically heterogeneous disease. Since its original description of genetic defects in 2001 (33), more than 20 mutations have been identified on the KCNJ2 gene (chromosome 17q23), which encodes the {alpha}-subunit of the inward rectifier K+ (Kir2.1) channel (1, 2, 5, 6, 10, 13, 20, 33, 41). Functional analyses have revealed that the Kir2.1 channel is present in the heart, skeletal muscle, and neural tissue (11, 19), and most KCNJ2 gene mutations cause loss of function and dominant-negative suppression of the Kir2.1 channel, thereby abolishing or reducing the inward rectifier K+ channel current (IK1) (1, 2, 5, 6, 10, 13, 20, 33, 41).

In patients with ATS, dizziness, syncope, cardiac arrest, and, rarely, sudden death (9, 10, 41, 50) have been reported, and ventricular arrhythmias such as frequent ventricular premature beats, ventricular tachycardia, and torsade de pointes have been documented (1–3, 5–7, 9, 10, 13, 20, 33, 36, 40, 41, 50). Since IK1 plays a major role in setting the resting membrane potential (RMP) and in contributing to the terminal phase of cardiac repolarization (11, 19, 23, 46), the cause of ventricular arrhythmias in ATS is generally attributed to dysfunction of the K+ channel Kir2.1 with resultant alteration of cardiac excitability (11, 19, 23, 46). Nevertheless, the detailed mechanisms of ventricular arrhythmias in this clinical setting have not been clearly defined. This is further confounded by the fact that attacks of periodic paralysis can be associated with either hypo- or hyperkalemia (36, 41, 50), both of which have been shown to be arrhythmogenic (39). Consequently, an interplay between serum K+ concentrations and the extent of dysfunction of the K+ channel Kir2.1 is expected to affect clinical manifestations of ventricular arrhythmias in patients with ATS.

In the present study, we used a modified dynamic Luo-Rudy (LRd) simulation model of the cardiac ventricular myocyte (24, 44, 49) in an attempt to delineate potential mechanisms of ventricular arrhythmias related to various degrees of reduction of Kir2.1 K+ channel conductance associated with various forms (hypo-, hyper-, and normokalemic) of periodic paralysis. Furthermore, we evaluated potential effects of beta-adrenergic stimulation on the inducibility of ventricular arrhythmias so as to identify modes of the onset of ventricular arrhythmias in patients with ATS.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 GRANTS
 REFERENCES
 
The simulation used in this study was primarily conducted with the theoretical LRd model of a mammalian ventricular action potential (24) with subsequent modifications. In this model, the action potential was mathematically reconstructed from ionic processes that were formulated on the basis of experimental data obtained mostly from the guinea pig (24). Of importance in this formulation was a linkage between sarcolemmal Ca2+ entry during the action potential upstroke and the Ca2+ release process of junctional sarcoplasmic reticulum that allows relationships between the action potential time course and Ca2+ homeostasis to be considered from a theoretical standpoint (24, 44, 49). Because of the extent to which formulations of ion currents and model predictions have been validated, this model has been extensively applied for simulation studies. The program source code in the C++ format for a single LRd model cell is available from http://rudylab.wustl.edu/old.rudylab/research/cell/methodology/cellmodels/LRd/code.htm. Numerical integration was performed with forward Euler schemes with a fixed time step of 0.002 ms.

Over the years, with advances in the understanding of cellular and molecular cardiac electrophysiology, the LRd model of cardiac ventricular myocyte has been revised repeatedly (24, 44, 49). Observations made with this LRd model have been shown to correlate well with results of cellular electrophysiology (44, 49). In the present study, we set the extracellular K+ concentration ([K+]o) at 4.5 mM and examined the effect of KCNJ2 mutations on the cardiac ventricular action potential. Various ion channel activities and parameters were analyzed. These included action potential duration (APD) at various percentages of repolarization (e.g., APD50, APD70, APD90), phase 3 repolarization rate (voltage at APD50 – voltage at APD90)/(APD90 – APD50), RMP, Na+ channel current (INa), L-type Ca2+ channel current (ICa,L), the rapidly and slowly delayed rectifying K+ currents (IKr and IKs), IK1, Na+/Ca2+ exchanger current (INCX), Ca2+-release channel current from the sarcoplasmic reticulum (Irel), intracellular Ca2+ transient ([Ca2+]i), Ca2+ transient of the junctional sarcoplasmic reticulum ([Ca2+]JSR), Ca2+ transient of the net sarcoplasmic reticulum ([Ca2+]NSR), and appearance of early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs). The pacing was set at 1.0 Hz for 40 beats or, at times, more to see whether there was development of EADs, DADs, or an abnormal rhythm. To examine the effects of heart rate, the pacing frequency was increased or decreased to 0.5 or 2.0 Hz, respectively, and to assess influence of beta-adrenergic stimulation (38), we arbitrarily increased ICa,L, and IKs each by 30% along with an increase in the pacing frequency from 1.0 to 2.0 Hz.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 GRANTS
 REFERENCES
 
Effects of reduction of Kir2.1 channel conductance on APD and RMP. We reduced Kir2.1 channel conductance stepwise by 10%. During pacing at a frequency of 1.0 Hz, prolongation of the terminal phase of repolarization along with depolarization of RMP became clearly discernible at 50% reduction of Kir2.1 channel conductance (Fig. 1). Table 1 summarizes representative values of APD50, APD70, APD90, phase 3 repolarization rate, and RMP in response to reduction of Kir2.1 channel conductance by 50–90%. For example, when 80% reduction of Kir2.1 channel conductance was reached, APD50 and APD70 remained relatively unchanged compared with the control (100.3 vs. 102.6 ms and 116.3 vs. 116.4 ms, respectively), whereas APD90 increased from 139.0 to 226.2 ms. The phase 3 repolarization rate measured from APD50 to APD90 was reduced from 1.45 to 0.38 mV/ms. Correspondingly, RMP was depolarized from –89.8 to –77.8 mV. Further reduction of Kir2.1 channel conductance to 90% resulted in marked prolongation of APD along with appearance of EADs, interrupting cardiac repolarization (Fig. 1). Continuous pacing at 1.0 Hz produced a pattern of bigeminal rhythm with either an early or a late phase 3 EAD and that of couplets with both early and late phase 3 EADs (Fig. 2).


Figure 1
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  		Fig. 1. Responses of action potential to 10% stepwise reduction of Kir2.1 channel conductance. Note that there is gradual prolongation of the terminal repolarization phase of the action potential along with gradual depolarization (becoming less negative) of the resting membrane potential (RMP) between 50% and 80% reduction of Kir2.1 channel conductance. When reduction of conductance reaches 90%, there is marked increase in the action potential duration followed by induction of an early afterdepolarization (EAD, arrow). Pacing cycle length: 1.0 Hz. IK1, inward rectifier K+ channel current.

 

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  		Table 1. Changes of APD50, APD70, APD90, phase 3 RR, and RMP with reduction of Kir2.1 channel conductance

 

Figure 2
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  		Fig. 2. Induction of EADs in patterns of bigeminy and couplets with 90% reduction of Kir2.1 channel conductance during pacing at 1.0 Hz. Portions of tracing in A (indicated by bars) are amplified in B to show early phase 3 EAD in bigeminy (1), late phase 3 EAD in bigeminy (2), and both early and late EADs in couplets (3).

 
Before pacing, the pivotal role of the Kir2.1 channel in stabilizing RMP was evident because RMP was progressively depolarized after each stepwise reduction of channel conductance (Fig. 3). Within 17.7 s, RMP was depolarized –82.4 and –79.5 mV, respectively, at 70% and 80% reduction of Kir2.1 channel conductance. Of note, at 90% reduction RMP was further depolarized to –52.0 mV (activation potential), at which time there was emergence of spontaneous action potentials with a cycle length of 753.0 ms.


Figure 3
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  		Fig. 3. Development of spontaneous action potentials (abnormal automaticity) with reduction of Kir2.1 channel conductance. The RMP is gradually depolarized to –82.4 and –79.5 mV, respectively, at 70% and 80% reduction of channel conductance. Note that at 90% reduction the RMP is markedly depolarized to –52.0 mV (activation potential) in 17.7 s, at which time spontaneous action potentials with a cycle length of 753.0 ms emerge. [K+]o, extracellular K+ concentration.

 
Effects of Kir2.1 channel conductance on IK1 and subsequent changes in ICa,L, INCX, [Ca2+]i, Irel, [Ca2+]JSR, and [Ca2+]NSR. Stepwise reduction of Kir2.1 channel conductance caused a progressive decrease in its current (IK1) in the unclamped cells (Fig. 4). At 50% reduction the peak amplitude of IK1 decreased from 2.55 to 1.47 µA/µF, and at 80% reduction it measured 0.56 µA/µF. After further reduction to reach 90% reduction of Kir2.1 channel conductance, it became barely visible at 0.06 µA/µF. Notably, because IK1 is a function of the membrane potential, the time course of this current during reduction of Kir2.1 channel conductance was altered (i.e., a more slowly rising phase) because of a prolongation of late repolarization.


Figure 4
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  		Fig. 4. Dynamic alteration of IK1, L-type Ca2+ channel current (ICa,L), and Na+/Ca2+ exchange current (INCX) corresponding to changes of the action potential in response to reduction of Kir2.1 channel conductance by 50%, 80%, and 90%. The transmembrane potential (A) is expressed in mV, and IK1 (B), ICa,L (C), and INCX (D) are expressed in µA/µF. Note that the induction of EAD (arrow in A) coincides with reactivation of the ICa,L channel (inward current indicated by upward arrow in C), during which the INCX exchanger is functioning in reverse mode (outward current indicated by downward arrow in D). Pacing cycle length: 1.0 Hz.

 
Subsequent oscillations of the cell affected ICa,L, INCX, [Ca2+]i, Irel, [Ca2+]JSR, and [Ca2+]NSR. Of these, the development of EAD was related to reactivation of the ICa,L channel during which the INCX channel was functioning in reverse mode (outward current) corresponding to the appearance of an EAD (Fig. 4, C and D). Changes of ICa,L and INCX with EADs in bigeminy and in couplets (Fig. 2), and during spontaneous action potentials (Fig. 3), were also analyzed. Both early and late phase 3 EADs were also related to inward currents caused by reactivation of the ICa,L channel rather than activation of the INCX exchanger functioning in forward mode (not shown). Notably, the onset of spontaneous action potentials was associated with activation of the ICa,L channel when depolarization of RMP reached –52.0 mV (activation potential), during which the voltage-dependent INa channel was almost totally inactivated (Fig. 5).


Figure 5
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  		Fig. 5. Intracellular ionic events underlying spontaneous action potentials with extracellular K+ concentration ([K+]o) at 4.5 mM and 90% reduction of Kir2.1 channel conductance. Trace at top (transmembrane potentials) is the same as that shown in Fig. 3. Note that spontaneous action potentials under this setting are caused by activation of the ICa,L channel (inward currents), during which the INCX exchanger is functioning in reverse mode (outward currents) and the Na+ channel current (INa) channel is inactivated.

 
Effects of changes in [K+]o with reduction of Kir2.1 channel conductance. To investigate how [K+]o might affect the inducibility of ventricular arrhythmias in the setting of reduced Kir2.1 channel conductance, we reset [K+]o from the control level of 4.5 mM to various concentrations. As shown in Table 2, decreasing [K+]o to 3.5 and 3.0 mM hyperpolarized RMP and the corresponding APD50, APD70, and APD90 were significantly prolonged. When compared with effects of stepwise reduction of Kir2.1 channel conductance that involved only the terminal repolarization phase (Fig. 1 and Table 1), low-[K+]o-induced prolongation of APD affected both phases 2 and 3 (Table 2). Further decreasing [K+]o to 2.5 mM hyperpolarized RMP to –99.5 mV, and the ventricular myocyte became inexcitable (not shown). In contrast, increasing [K+]o to 6.0 and 8.0 mM resulted in depolarization of RMP, and the corresponding APD50, APD70, and APD90 were significantly shortened. Also of note, the high-[K+]o-induced shortening of APD was not limited to the terminal repolarization phase of APD (Table 2).


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  		Table 2. Changes of APD50, APD70, APD90, and RMP at various [K+]o

 
Changes in [K+]o as described above were then applied during stepwise reduction of Kir2.1 channel conductance. Decreasing [K+]o along with reduction of Kir2.1 channel conductance produced more prolongation of APD compared with either one alone. However, the hyperpolarizing effect of low [K+]o tended to minimize the depolarizing effect of reduced Kir2.1 channel conductance on RMP (Table 3). At 60% reduction of Kir2.1 channel conductance with [K+]o of 4.5 mM, APD90 and RMP were 181.6 ms and –87.3 mV, respectively. At the same degree of reduced Kir2.1 channel conductance, decreasing [K+]o to 3.5 mM further prolonged APD90 to 275.4 ms but reverted RMP to –91.2 mV, very close to that of control (–89.8 mV). Nevertheless, the combination of both low [K+]o and reduced Kir2.1 channel conductance seemed to facilitate induction of EADs (not shown). For example, EADs were not inducible until reduction of Kir2.1 channel conductance reached 90% with [K+]o at 4.5 mM, but they became inducible at 80% and 70% reduction of channel conductance when [K+]o was decreased to 3.5 and 3.0 mM, respectively. In contrast, increasing [K+]o to 6.0 and 8.0 mM, respectively, shortened APD, counteracting the APD-prolonging effect of reduced Kir2.1 channel conductance, but its depolarizing effect on RMP appeared to be additive to that of reduced Kir2.1 channel conductance (not shown). Of note, increasing [K+]o tended to suppress EADs, because EADs became noninducible with [K+]o at 8 mM, even when the reduction of Kir2.1 channel conductance reached 90%. With regard to the abnormal automaticity that expressed as spontaneous action potentials resulting from depolarization of RMP, decreasing [K+]o facilitated whereas increasing [K+]o delayed or suppressed its onset (Fig. 6). Notably, under these circumstances, the occurrence of spontaneous action potentials was also initiated by activation (inward currents) of the ICa,L channel rather than the forward-mode INCX exchanger (not shown).


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  		Table 3. Changes of APD90 and RMP with different [K+]o at varying degrees of reduced Kir2.1 channel conductance

 

Figure 6
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  		Fig. 6. Effects of [K+]o on the onset of spontaneous action potentials with 90% reduction of Kir2.1 channel conduction. At control [K+]o of 4.5 mM, the onset of spontaneous action potentials occurs in 17.7 s, when depolarization of the RMP reaches the activation potential of –51.4 mV. Note that decreasing [K+]o to 3.5 and 3.0 mM shortens the onset of spontaneous action potentials to 11.4 and 9.2 s, respectively, and increasing [K+]o to 6 mM delays the onset of spontaneous action potentials to 31.6 s; further increasing [K+]o to 8 mM suppresses the onset of spontaneous action potentials during an observation period of 40 s.

 
Influences of simulated beta-adrenergic stimulation. To study potential influences of beta-adrenergic stimulation, we first observed effects of the pacing cycle length by changing it from 1.0 Hz to 0.5 and 2.0 Hz. A cycle length of 0.5 Hz prolonged APD and enhanced induction of EADs, whereas a cycle length of 2.0 Hz shorted APD and did not allow development of EADs (not shown). To simulate effects of beta-adrenergic stimulation, we kept the pacing cycle length at 2.0 Hz and arbitrarily increased conductance of ICa,L and IKs channels, each by 30%. In the presence of normal Kir2.1 channel conductance, beta-adrenergic stimulation induced DADs of small amplitude but not EADs (Fig. 7). Although there was no induction of EADs with up to 90% reduction of Kir2.1 channel conductance, beta-adrenergic stimulation could enhance DADs to reach the activation potential, manifesting as a triggered action potential at 30% reduction of Kir2.1 channel conductance. The intracellular event underlying DADs appeared different from that of EADs. Specifically, its onset was triggered by a transient inward current produced by the forward-mode INCX exchanger (a role of a nonselective cation channel could not be excluded) followed by activation of INa and ICa,L channels (Fig. 7).


Figure 7
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  		Fig. 7. Induction of delayed afterdepolarizations (DADs) with simulated beta-adrenergic stimulation. While [K+]o is maintained at 4.5 mM, beta-adrenergic stimulation is simulated by pacing at 2.0 Hz along with increasing slowly delayed rectifying K+ current (IKs) and ICa,L channel conductance, each by 30%. beta-Adrenergic stimulation (red dashed lines) prolongs action potential duration at 90% repolarization from 181.5 to 189.5 ms without affecting the RMP and induces DAD (solid arrow) after discontinuation of pacing for 19.5 s. However, with 30% reduction of Kir 2.1 channel conductance, beta-adrenergic stimulation-induced DAD attains the excitation threshold and manifests as an action potential (blue dotted lines). Note that the initiation of DAD and the triggered action potential are related to a transient inward current (dashed arrow) generated by the INCX exchanger functioning in forward mode (a role of a nonselective cation channel cannot be excluded) followed by activation of INa and ICa,L channels.

 
Simulated beta-adrenergic stimulation also facilitated onset of spontaneous action potentials. At 90% reduction of Kir2.1 channel conductance, beta-adrenergic stimulation accelerated the onset of spontaneous action potentials with [K+]o at 4.5, 3.5, and 3.0 mM from 17.7 to 14.3, 11.4 to 8.4, and 9.2 to 6.3 s, respectively (not shown), compared with the situation when there was no intervention with beta-adrenergic stimulation (Fig. 6). In addition, it was noted that beta-adrenergic stimulation induced more EADs in both patterns of bigeminy and couplets, especially in the setting of low [K+]o (not shown). Of interest, intracellular mechanisms of EADs and spontaneous action potentials induced by beta-adrenergic stimulation in the setting of low [K+]o and reduced Kir2.1 channel conductance appeared identical to those documented in Figs. 4 and 5, respectively.


   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
GRANTS
 REFERENCES
 
In this modified dynamic LRd model of cardiac ventricular myocyte, we demonstrated potential electrophysiological mechanisms underlying ventricular arrhythmias in patients with ATS: 1) development of EADs associated with APD prolongation and 2) induction of spontaneous action potentials (abnormal automaticity) due to depolarization of RMP, both of which were caused by reduction of inward rectifier K+ channel Kir2.1 conductance. Hypokalemia tended to facilitate both EADs and spontaneous action potentials, and, in contrast, hyperkalemia seemed to suppress both of them. beta-Adrenergic stimulation enhanced DADs and could facilitate EADs and spontaneous action potentials, especially in the setting of both hypokalemia and reduced conductance of the Kir2.1 channel.

To date, more than 20 mutations including 2 deletions on the KCNJ2 gene have been described (1, 2, 5, 6, 9, 10, 13, 20, 33, 41, 50). Since prolongation of the QT interval was the most common individual electrocardiographic finding in KCNJ2-associated ATS patients, Tristani-Firouzi et al. (41) proposed that ATS be referred to as a form of long QT syndrome—LQT7. In patients with ATS, expression of the triad of clinical traits is highly variable. Sporadic cases do occur, and no KCNJ2 gene abnormalities can be found in ~40% of patients with ATS (2, 33, 41). In KCJN2 mutation carriers, the frequency of periodic paralysis is 64%, long QT 71%, ventricular arrhythmias 64%, and multiple skeletal dysmorphic features 78%. The inward rectifier K+ channel Kir2.1, a member of the Kir2.x subfamily, is the critical {alpha}-subunit of the cardiac IK1 (11, 19, 46). Molecular studies have shown that Kir2.1 subunits coassemble to form tetrameric (homo- or heteromeric) inward rectifier K+ channels (21, 22, 54) in many cell types and are the major determinant of IK1 (23, 47, 48). On the other hand, functional analyses have revealed that the majority of KCJN2 mutations causes loss of function and dominant-negative suppression of Kir2.1 channel function, leading to a loss or reduction of IK1 (1, 2, 5, 6, 9, 10, 13, 20, 33, 41). Moreover, differential tetramerization or heteromultimerization of the mutant allele of Kir2.1 with wild-type Kir2.x (Kir2.1, Kir2.2, and Kir2.3) channels can exhibit variable extents of a dominant-negative effect between different mutants (34, 51). These observations provide, to some extent, the molecular basis of "genotype-phenotype mismatch" as well as variable penetrance and expressivity of ATS phenotypes. To mimic a variety of clinical circumstances, accordingly, we systemically reduced conductance of the Kir2.1 channel stepwise by 10% in our study design.

To study the role of IK1 in cardiac excitability, Miake et al. (28, 29) applied the technique of in vivo gene transfer in the guinea pig ventricular myocyte. They first (28) demonstrated that cells with transduced dominant-negative Kir2.1-AAA mutated gene showed ~80% reduction of IK1 and manifested either APD prolongation or spontaneous action potentials. Those cells showing spontaneous action potentials resembled "genuine pacemaker cells," because these cells exhibited a relatively depolarized maximal RMP (–60.7 ± 2.1 mV), spontaneous initiation with a slow upstroke, and response to beta-adrenergic stimulation. These latter findings support the notion that intrinsic pacemaker activity of adult myocytes is suppressed by IK1 (48) and suggest that this technique might have therapeutic implications. Subsequently, also by applying the gene transfer technique, Miake et al. (29) pursued a quantitative approach to achieve IK1 enhancement (overexpression) and suppression. They noted that Kir2.1 enhancement by 100% significantly shortened APD, accelerated phase 3 repolarization, and hyperpolarized RMP. In contrast, dominant-negative Kir2.1-AAA mutated gene reduced IK1 by 50–90%; those cells with <80% reduction of IK1 exhibited APD prolongation with decelerated phase 3 repolarization and depolarization of RMP. Further reduction of IK1 (by >80%) led to development of spontaneous action potentials. Notably, of the five Kir2.1 AAA-transduced animals, three maintained sinus rhythm despite significant QT prolongation and the remaining two with more severe IK1 reduction manifested ventricular arrhythmias. In terms of changes of APD and RMP and emergence of spontaneous action potentials, the results of our simulation study were very much in line with the cellular findings resulting from IK1 suppression described by Miake et al. (28, 29).

Various simulation models (15, 30, 41) have been deployed to elucidate functional characteristics of the Kir2.1 channel. With the use of a modified LRd simulation model of cardiac ventricular myocyte, our study has extended preliminary observations made in these simulation studies. Although most of our findings are confirmatory of those obtained in cellular and in vivo animal experiments (27, 28, 29, 48), our study provides expanded information suggestive of more detailed mechanisms of an arrhythmogenic propensity related to ATS. Specifically, with a ≥50% reduction of Kir2.1 channel conductance, prolongation of the terminal repolarization phase of APD is discernible, and with a >80% reduction, EADs become inducible and depolarization of RMP can lead to spontaneous action potentials (abnormal automaticity). These simulation results are compatible with previous observations showing that cesium chloride could block Kir channel conduction, thereby causing prolongation of cardiac APD and induction of EADs and spontaneous action potentials (14, 21). Hypokalemia further enhances these arrhythmogenic properties, and beta-adrenergic stimulation potentiates DADs, facilitates spontaneous action potentials, and may also enhance EADs. To some extent, these findings may explain why patients with ATS manifest various electrocardiographic phenotypes—absence of prolonged QT, QT prolongation with no arrhythmias, and prolonged QT with ventricular arrhythmias including torsade de pointes.

Furthermore, we have demonstrated that both early and late phase 3 EADs could be related to reactivation of the ICa,L channel associated with APD prolongation (Fig. 4), whereas DADs could be related to triggering of the forward-mode INCX exchanger causing transient inward currents (ITi), albeit not excluding a possible contribution from the nonselective cation channel (Fig. 7). Both DADs and EADs have been attributed to abnormal intracellular Ca2+ homeostasis due to Ca2+ overload (8, 17, 25, 32, 45). With regard to the genesis of EADs, the underlying mechanism remains controversial (4, 25, 32, 37, 45). A reduction of IK1 is expected to alter the rate of repolarization in the voltage range between –30 and –80 mV (30). Normally, the membrane potential must be in the range of –40 to 0 mV to reactivate the ICa,L window current (31); therefore, it has been suggested that late phase 3 EADs might be generated under the condition of intracellular Ca2+ overload similar to that of DADs, a phenomenon being evoked by a secondary rise of [Ca2+]i that triggers ITi through activation of the forward-mode INCX exchanger followed by reactivation of the ICa,L or INa channel (25, 32, 45). Hence, EADs may be comprised of different types with different mechanisms, at least one being primarily caused by reactivation of the ICa,L channel and the other by activation of the forward-mode INCX exchanger.

[K+]o has been demonstrated to affect all K+ channels possessing inward rectifying properties (30, 31, 35). This is evidenced by changes of the overall repolarization phase of APD (not limited to the terminal phase of repolarization) with a decrease or an increase in [K+]o as illustrated in our study (Table 2). We have also observed that low [K+]o, by providing an additive effect on APD prolongation, enhances induction of EADs in the presence of reduced Kir2.1 channel conductance, and high [K+]o, with an opposite effect on APD prolongation, suppresses induction of EADs. However, low [K+]o, despite its hyperpolarizing effects, and high [K+]o, despite its depolarizing effects on RMP, have been shown to facilitate and suppress onset of spontaneous action potentials, respectively (Fig. 6). In general, prolongation of APD may increase Ca2+ entry via the ICa,L channel during the plateau phase, causing accumulation of Ca2+ in the sarcoplasmic reticulum and its spontaneous Ca2+ release; the resultant increase in [Ca2+]i alters intracellular Ca2+ homeostasis and may thereby depolarize myocytes via Ca2+-dependent currents favoring not only EADs and DADs but also abnormal automaticity (25, 26, 32, 45). Low [K+]o and high [K+]o seem to exert opposite effects by virtue of their disparate effects on APD and RMP as seen in the present study. Since all these arrhythmias are directly or indirectly linked to disturbances of intracellular Ca2+ homeostasis, it is no surprise that calcium channel blockers such as verapamil may be effective as an antiarrhythmic in some clinical situations (16, 50). Further studies at the subcellular level along with testing of various classes of antiarrhythmic drugs are required to unravel detailed mechanisms underlying these phenomena.

As has been demonstrated in congenital and acquired long QT syndromes (38), the initiation of ventricular arrhythmias may be related to the status of autonomic tone. Bradycardia, as in enhanced vagotonia, prolongs APD and the QT interval, whereas tachycardia, as in increased adrenergic tone, shortens APD and the QT interval (12, 43). Consequently, spontaneous torsade de pointes is more likely to occur in association with bradycardia (38, 43). Nevertheless, high adrenergic tone along with its induced sinus tachycardia enhances Ca2+ entry into cardiac myocytes, resulting in an increase of Ca2+ in the sarcoplasmic reticulum and its spontaneous Ca2+ release (12 38, 43). This in turn favors induction of both EADs and DADs and their mediated triggered activity (25, 32, 45). Furthermore, beta-adrenergic stimulation abbreviates APD much more in the epicardium and endocardium than in the midmyocardium, which intrinsically contains less IKs (38). Consequently, beta-adrenergic stimulation can markedly increase transmural dispersion of refractoriness, favoring induction of torsade de pointes. In addition, beta-adrenergic stimulation reversibly depolarizes RMP by activating an inward Cl– current (ICl) or inhibiting the inwardly rectifying IK1 or both (18) and may thereby facilitate spontaneous action potentials as observed in the present study. As a result, physical activities may trigger an onset of ventricular arrhythmias in patients with ATS (1, 2, 3, 5–7, 9, 10, 13, 20, 31, 36, 40, 41, 50). It is worthy of mention that, despite a relatively high prevalence of ventricular arrhythmias, the rare incidence of sudden cardiac death may be attributed to a lack of significant increase in transmural dispersion of repolarization induced by isolated reduction of Kir2.1 channel conductance (42).

Thus, in light of the results of the present study, it is anticipated that ATS patients with the hypokalemic form of periodic paralysis are at a higher risk of more serious ventricular arrhythmias, especially during physical activity. From the arrhythmia standpoint, various clinical phenotypes of ATS may be deduced from observations made in the present study, and future research should be directed to risk stratification, targeted pharmacotherapy, selection of patients to receive implantable cardioverter/defibrillators, and the feasibility of corrective gene therapy at an early age.

Limitations of study. The major limitation inherent to the present study design is that no attempt was made to account for either transmural heterogeneities of APD or the homogenizing effect of electrically coupled cardiac myocytes in a three-dimensional network of the myocardium. Nonetheless, observations made in the present study should provide a basis for future simulation studies aimed in these directions. We also realize that >80% reduction of Kir2.1 channel conductance may not be compatible with life. Furthermore, our study may have underestimated the arrhythmogenic effects of hyperkalemia, particularly at the tissue level. Fourth, beta-adrenergic stimulation affects many ion channel currents (18), making it difficult to simulate; increasing ICa,L and IKs each by 30% actually produces opposing effects on APD, QT interval, and genesis of EADs (4, 45). Besides, alteration of autonomic tone is dynamic and individual sensitivity varies greatly. As a result, the effects of beta-adrenergic stimulation may not be predictable under various clinical settings. In our study, the arbitrary application of increasing ICa,L and IKs each by 30% along with pacing at 2.0 Hz is understandably an oversimplification. Finally, the ICl channel was not included in this model. Inclusion of ICl could have affected the interpretation of the present data.


   GRANTS
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 ABSTRACT
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This work was in part supported by grants from the National Science Council (NSC-94-2314-B-006-110) and the Program for Promoting Academic Excellence & Developing World Class Research Centers, Ministry of Education, Taiwan.


   FOOTNOTES
 

Address for reprint requests and other correspondence: R. J. Sung, Dept. of Medicine, College of Medicine, National Cheng Kung Univ., 1 University Road, Tainan, Taiwan, 704 (e-mail: rsung{at}mail.ncku.edu.tw; rsung{at}cvmed.stanford.edu)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.


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 ABSTRACT
 METHODS
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 DISCUSSION
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 REFERENCES
 

  1. Ai T, Fujiwara Y, Tsuji K, Otani H, Nakono S, Kubo Y, and Horie M. Novel KCJN2 mutation in familial periodic paralysis with ventricular dysrhythmia. Circulation 105: 2592–2594, 2002.[Abstract/Free Full Text]
  2. Andelfinger G, Tapper AR, Welch RC, Vanoye CG, George AL Jr, and Benson DW. KCJN2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet 71: 663–668, 2002.[CrossRef][Web of Science][Medline]
  3. Andersen ED, Krasilnikoff PA, and Overvad H. Intermittent muscular weakness, extrasystoles and multiple developmental abnormalities: a new syndrome? Acta Paediatr Scand 60: 559–564, 1971.[Web of Science][Medline]
  4. Antzelevitch C and Sicouri S. Clinical relevance of cardiac arrhythmias generated by afterdepolarizations: role of M cells in the generation of U waves, triggered activity and torsade de pointes. J Am Coll Cardiol 23: 259–277, 1994.[Abstract]
  5. Bendahhou S, Donaldson MR, Plaster NM, Tristani-Firouzi M, Fu YH, and Ptacek LJ. Defective potassium channel Kir2.1 trafficking underlies Andersen-Tawil syndrome. J Biol Chem 278: 51779–51785, 2003.[Abstract/Free Full Text]
  6. Bendahhou S, Fournier E, Sternberg D, Bassez G, Furby A, Sereni C, Donaldson MR, Larroque MM, Fontaine B, and Baehanin J. In vivo and in vitro functional characterization of Andersen's syndrome mutations. J Physiol 565: 731–741, 2005.[Abstract/Free Full Text]
  7. Canun S, Perez N, and Beirana LG. Andersen syndrome: autosomal dominant in three generations. Am J Med Genet 85: 147–156, 1999.[CrossRef][Web of Science][Medline]
  8. Choi BR, Burton F, and Salama G. Cytosolic Ca2+ triggers early afterdepolarizations and torsade de pointes in rabbit hearts with type 2 long QT syndrome. J Physiol 543: 615–631, 2002.[Abstract/Free Full Text]
  9. Chun TU, Epstein MR, Dick M II, Andelfinger G, Ballester L, Vanoye CG, George AL Jr, and Benson DW. Polymorphic ventricular tachycardia and KCNJ2 mutations. Heart Rhythm 1: 235–241, 2004.[CrossRef][Web of Science][Medline]
  10. Donaldson MR, Jensen JL, Tristani-Firouzi M, Tawil R, Bendahhou S, Suarez WA, Cobo AM, Poza JJ, Behr E, Wagstaff J, Szepetowski P, Pereira S, Mozaffar T, Escolar DM, Fu YH, and Ptacek LJ. PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology 60: 1811–1816, 2003.[Abstract/Free Full Text]
  11. Doupnik CA, Davidson N, and Lester HA. The inward rectifier potassium channel family. Curr Opin Neurobiol 5: 268–277, 1995.[CrossRef][Web of Science][Medline]
  12. Faber GM and Rudy Y. Action potential and contractility changes in [Na]i overload cardiac myocytes: a simulation study. Biophys J 78: 2392–2404, 2000.[Web of Science][Medline]
  13. Hosaka Y, Hanawa H, Washizuka T, Chiunshi M, Yamashita F, Yoshita T, Komura S, Watanabe H, and Aizawa Y. Function, subcellular localization and assembly of a novel mutation of KCNJ2 in Andersen's syndrome. J Mol Cell Cardiol 35: 409–415, 2003.[CrossRef][Web of Science][Medline]
  14. Isenberg G. Cardiac Purkinje fibers: cesium as a tool to block inward rectifying potassium currents. Pflügers Arch 365: 99–106, 1976.[CrossRef][Web of Science][Medline]
  15. Jongsma HJ and Wilders R. Channelopathies: Kir2.1 mutations jeopardize many cell functions. Curr Biol 11: R747–R750, 2001.[CrossRef][Web of Science][Medline]
  16. Kannankeril PJ, Roden DM, and Fish FA. Suppression of bidirectional ventricular tachycardia and unmasking of prolong QT interval with verapamil in Andersen's syndrome. J Cardiovasc Electrophysiol 15: 119, 2004.[Web of Science][Medline]
  17. Katra RP and Laurita KR. Cellular mechanism of calcium-mediated triggered activity in the heart. Circ Res 96: 535–542, 2005.[Abstract/Free Full Text]
  18. Koumi SI, Backer CL, Arentzen CE, and Sato R. beta-Adrenergic modulation of the inwardly rectifying potassium channel in isolated human ventricular myocytes. Alteration in channel response to beta-adrenergic stimulation in failing human hearts. J Clin Invest 96: 2870–2881, 1995.[Web of Science][Medline]
  19. Kubo Y, Baldwin TJ, Jan YN, and Jan LN. Primary structure and functional expression of a mouse inward rectifier potassium channel. Nature 362: 127–133, 1993.[CrossRef][Medline]
  20. Lange PS, Er F, Gassanov N, and Hoppe UC. Andersen mutations of KCNJ2 suppress the native inward rectifier current IK1 in a dominant-negative fashion. Cardiovasc Res 59: 321–327, 2003.[Abstract/Free Full Text]
  21. Levine JH, Spear JF, Guarnieri T, Weisfeldt ML, de Langen CDJ, Becker LC, and Moore EN. Cesium chloride-induced long QT syndrome: demonstration of afterdepolarizations and triggered activity in vivo. Circulation 72: 1092–1103, 1985.[Abstract/Free Full Text]
  22. Liu GX, Derst C, Schlichthorl G, Heinen S, Seebohm G, Bruggermann A, Kummer W, Veh RW, Daut J, and Preisig-Muller R. Comparison of cloned Kir2 channels with native inward rectifier K+ channels from guinea-pig cardiomyocytes. J Physiol 532: 115–126, 2001.[Abstract/Free Full Text]
  23. Lopatin AN and Nichols CG. Inward rectifiers in the heart: an update on IK1. J Mol Cell Cardiol 33: 625–638, 2001.[CrossRef][Web of Science][Medline]
  24. Luo CH and Rudy Y. A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. Circ Res 74: 1071–1096, 1994.[Abstract/Free Full Text]
  25. Marban E, Robinson SW, and Wier WG. Mechanisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle. J Clin Invest 78: 1185–1192, 1986.[Web of Science][Medline]
  26. Mazzanti M and DiFrancesco D. Intracellular Ca modulates K-inward rectification in cardiac myocytes. Pflügers Arch 413: 322–324, 1989.[CrossRef][Web of Science][Medline]
  27. McLerie M and Lopatin A. Dominant-negative suppression of IK1 in the mouse heart leads to altered cardiac excitability. J Mol Cell Cardiol 35: 367–378, 2003.[CrossRef][Web of Science][Medline]
  28. Miake M, Marban E, and Nuss HB. Biological pacemaker created by gene transfer. Nature 419: 132–133, 2002.[Medline]
  29. Miake M, Marban E, and Nuss HB. Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression. J Clin Invest 111: 1529–1536, 2003.[CrossRef][Web of Science][Medline]
  30. Nichols CG, Makhina EN, Pearson WL, Sha Q, and Lopatin AN. Inward rectification and implications for cardiac excitability. Circ Res 78: 1–7, 1996.[Abstract/Free Full Text]
  31. Noble D. Ionic mechanisms in cardiac electrical activity. In: Cardiovascular Electrophysiology, edited by Zipes DP and Jalife J. Philadelphia, PA: Saunders, 1995.
  32. Nuss HB, Kabb S, Kass DA, Tomaselli GF, and Marban E. Cellular basis of ventricular arrhythmias and abnormal automaticity in heart failure. Am J Physiol Heart Circ Physiol 277: H80–H91, 1999.[Abstract/Free Full Text]
  33. Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL Jr, Fish A, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu YH, and Ptacek LJ. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome. Cell 105: 511–519, 2001.[CrossRef][Web of Science][Medline]
  34. Preisig-Muller R, Schlichthorl G, George T, Heinen S, Bruggemann A, Rajan S, Derst C, Veh RW, and Daut J. Heteromerization of Kir2.x potassium channels contribute to the phenotype of Andersen's syndrome. Proc Natl Acad Sci USA 99: 7774–7779, 2002.[Abstract/Free Full Text]
  35. Sanguinetti MC and JurkiewiczK. Role of external Ca2+ and K+ in gating of cardiac delayed rectifier currents. Pflügers Arch 420: 180–186, 1992.[CrossRef][Web of Science][Medline]
  36. Sansone V, Griggs RC, Meola G, Ptacek LJ, Barohn R, Innaccone S, Bryan W, Baker N, Janas SJ, Scott W, Ririe D, and Tawil R. Andersen's syndrome: a distinct periodic paralysis. Ann Neurol 42: 305–312, 1997.[CrossRef][Web of Science][Medline]
  37. el-Sherif N, Caref EB, Yin H, and Restivo M. The electrophysiological mechanism of ventricular arrhythmias in the long QT syndrome: tridimensional mapping of activation and recovery patterns. Circ Res 79: 474–492, 1996.[Abstract/Free Full Text]
  38. Shimizu W and Antzelevitch C. Cellular basis for the electrocardiographic features of the LQT1 form of the long QT syndrome: effects of beta-adrenergic agonists, antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes. Circulation 98: 2314–2322, 1998.[Abstract/Free Full Text]
  39. Surawicz B. Electrolytes, hormones, temperature, and miscellaneous factors. In: Electrophysiologic Basis of ECG and Cardiac Arrhythmias. New York: Williams & Wilkins, 1995, p. 426–453.
  40. Tawil R, Ptacek LJ, Pavlakis SG, DeVivo DC, Penn AS, Ozdemir C, and Griggs RC. Andersen's syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann Neurol 35: 326–330, 1994.[CrossRef][Web of Science][Medline]
  41. Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, Ptacek LJ, and Tawil R. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest 11: 381–388, 2002.
  42. Tsuboi M and Antzelevitch C. Cellular basis for electrocardiographic and arrhythmic manifestations of Andersen-Tawil syndrome (LQT7). Heart Rhythm 3: 328–335, 2006.[CrossRef][Web of Science][Medline]
  43. Tsuji Y, Zicha S, Qi XY, Kodama I, and Nattel S. Potassium channel subunit remodeling in rabbits exposed to long term bradycardia or tachycardia. Discrete arrhythmogenic consequences related to differential delayed-rectifier changes. Circulation 113: 345–355, 2006.[Abstract/Free Full Text]
  44. Viswanathan P, Shaw R, and Rudy Y. Effects of IKr and IKs heterogeneity on action potential duration and its rate dependence: a simulation study. Circulation 99: 2466–2474, 1999.[Abstract/Free Full Text]
  45. Volders PGA, Vos MA, Szabo B, Sipido KR, de Groot M, Gorgels APM, Wellens HJJ, and Lazarra R. Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts. Cardiovasc Res 46: 376–392, 2000.[Free Full Text]
  46. Yang J, Jan YN, and Jan LY. Determination of the subunit stoichiometry of an inwardly rectifying potassium channel. Neuron 15: 1441–1447, 1995.[CrossRef][Web of Science][Medline]
  47. Zaritsky JJ, Eckman DM, Wellman GC, Nelson MT, and Schwarz TL. Targeted disruption of Kir2.1 and Kir22 genes reveals the essential role of the inwardly rectifying K+ current in K+-mediated vasodilation. Circ Res 87: 160–166, 2000.[Abstract/Free Full Text]
  48. Zaritsky JJ, Redell JB, Tempel BL, and Schwarz TL. The consequences of disrupting cardiac inwardly rectifying K+ current (IK1) as revealed by the targeted deletion of murine Kir2.1 and Kir22 genes. J Physiol 533: 697–710, 2001.[Abstract/Free Full Text]
  49. Zeng J, Laurita KR, Rosenbaum DS, and Rudy Y. Two components of the delayed rectifier K+ currents in ventricular myocytes of the guinea pig type. Theoretical formulation and their role in repolarization. Circ Res 77: 140–152, 1995.[Abstract/Free Full Text]
  50. Zhang L, Benson DW, Tristani-Firouzi M, Ptacek LJ, Tawil R, Schwartz P, George AL, Horie M, Andelfinger G, Snow GL, Fu YH, Ackerman MJ, and Vincent M. Electrocardiographic features in Andersen-Tawil syndrome patients with KCNJ2 mutations. Characteristic T-U-wave patterns predict the KCNJ2 genotype. Circulation 111: 2720–2726, 2005.[Abstract/Free Full Text]
  51. Zoble C, Cho HC, Nguyen TT, Pekhletski R, Diaz RJ, Wilson GJ, and Backx PH. Molecular dissection of the inward rectifier potassium current (IK1) in rabbit cardiomyocytes: evidence for heteromeric co-assembly of Kir2.1 and Kir22. J Physiol 550: 365–372, 2003.[Abstract/Free Full Text]



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