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Data
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Simulation study of Andersen-Tawil syndrome (Sung et al 2006)
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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
(VA) are considerably variable. Using a modified dynamic Luo-Rudy simulation model of cardiac ventricular myocyte, we
elucidate the mechanisms of VA in ATS. We adopted a kinetic model of KCNJ2 in which channel block by Mg(+2) and
spermine was incorporated. In this study, we attempt to examine the effects of KCNJ2 mutations on the ventricular action
potential (AP), single-channel Markovian models were reformulated and incorporated into the dynamic Luo-Rudy model
for rapidly and slowly delayed rectifying K(+) currents and KCNJ2 channel. During pacing at 1.0 Hz with [K(+)]o at 5.4
mM, a stepwise 10% reduction of Kir2.1 channel conductance progressively prolonged the terminal repolarization phase
of AP along with gradual depolarization of the resting membrane potential (RMP). At 90% reduction, early after-
depolarizations (EADs) became inducible and RMP was depolarized to -55.0 mV (control: -90.1 mV) followed by
emergence of spontaneous action potentials (SAP). Both EADs and SAP were facilitated by a decrease in [K(+)]o and
suppressed by increase in [K(+)]o. beta-adrenergic stimulation enhanced delayed after-depolarizations (DADs) and could
also facilitate EADs as well as SAP in the setting of low [K(+)]o and reduced Kir2.1 channel conductance. In conclusion,
the spectrum of VA in ATS includes (1) triggered activity mediated by EADs and/or DADs, and (2) abnormal automaticity
manifested as SAP. These VA can be aggravated by a decrease in [K(+)]o and beta-adrenergic stimulation, and may
potentially induce torsades de pointes and cause sudden death. In patients with ATS, the hypokalemic form of periodic
paralysis should have the highest propensity to VA especially during physical activities.
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Sung RJ, Wu SN, Wu JS, Chang HD, Luo CH (2006) Show
Other
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snwu@mail.ncku.edu.tw
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Han-Dong Chang
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