Arrhythmogenesis in the Short-QT Syndrome Associated With Combined HERG Channel Gating Defects

Abstract

he short-QT syndrome constitutes a new primary electrical abnormality associated with sudden cardiac death. 1,2 A part of the disorder has been linked to gain of function mutations in the cardiac channel of rapidly activating delayed rectifier currents (IKr), HERG (KCNH2). 3 Heterogeneous abbreviation of the action potential duration (APD) in different cell types spanning the ventricular wall seems to create the substrate for the genesis of ventricular arrhythmia in the short-QT syndrome, as is proposed for the long-QT syndrome and Brugada syndrome. [4][5][6][7][8] Brugada et al identified the first mutation associated with the short-QT syndrome. 3 The missense mutation (N588K) involving a substitution of lysine for asparagine in position 588 of KCNH2 was found to cause a remarkable gain of function in the IKr. We studied how the gain of function mutation N588K in the KCNH2 could affect APD in different cell types of the ventricular walls, and how it could be associated with life-threatening arrhythmia in the LuoRudy (LRd) theoretical model of the cardiac ventricular action potential (AP). 4,5,7,9 Unexpectedly, although the gain of function of KCNH2 resulted in shortening of the APD, arrhythmogenesis was associated not only with the gain of function, but also with accelerated deactivation of the N588K HERG channel. MethodsTo evaluate the electrophysiological consequences of the N588K mutation associated with the short-QT syndrome at the level of the cardiac AP, we constructed a Markov model of the N588K mutant channel, based on the experimental data of voltage-clamp recordings of IKr heterologously expressed in TSA 201 cells. 3 The wild-type (WT) and N588K Markov models were then integrated into the LRd theoretical model of the cardiac ventricular AP. 5 The simulation programs were encoded in C++ and implemented on a personal computer running Windows XP or an HP AlphaServer running Tru64 UNIX. Background This study aimed to show the mechanism how the HERG channel gating defects causes lifethreatening arrhythmia in the short-QT syndrome, using a simulation model of ventricular action potentials (APs). Methods and ResultsTo evaluate the electrophysiological consequences of the short-QT syndrome at the level of the cardiac AP, the Markov model of wild-type (WT) KCNH2 channel was modified to obtain a model of the KCNH2 channel with the N588K mutation associated with the short-QT syndrome. Two parameters ( i and ) were changed to reconstruct the N588K mutant Markov model, which successfully reproduced the experimental results of voltage-clamp recordings. The WT and mutant models were then integrated into the LuoRudy theoretical model of the cardiac ventricular AP. Unexpectedly, 1 parameter change alone, which caused gain of function, could shorten the AP duration (APD) but failed to induce early after-depolarizations (EADs).Only the condition with the combined gating defects could lead to EAD. Conclusions Although the gain of function for KCNH2 shortened APD in the short-QT syndrome, this simulation study suggested t...

Biophysical Characterization of the Short QT Mutation hERG-N588K Reveals a Mixed Gain-and Loss-of-Function

“…It is also interesting to notice how the reversal potential is shifted to more positive potentials in N588K compared to WT channels. This is consistent with earlier findings and in silico simulations have demonstrated how such a change in selectivity increase the chance of evoking early after depolarisations (EAD's) [14,21,25]. Since it is still an open question whether the β-subunit KCNE2 is a part of native I Kr current co-expression experiments with HERG-N588K and KCNE2 were also performed.…”

hERG K+Channels: Structure, Function, and Clinical Significance

“…An alternative to animal models is to use in silico models of the N588K mutation (283,681,712). These models have reproduced the shorter action potential duration and QT interval; however, the earlier models did not reproduce the altered dispersion of repolarization or the taller T-waves typical of SQTS1.…”

The Short QT Syndrome

“…Computer simulations that mimic the major kinetic changes to I Kr , I Ks and I K1 of the major SQT1-3 mutations have shown accelerated repolarisation convincingly at cell and tissue levels [26,27,60,[75][76][77], though with changes to T-wave morphology more accurately reproduced for SQT2 [60] and SQT3 [27] variants than for SQT1 [75,76]. At the single cell level, AP shortening in simulated SQT1 and SQT2 is heterogeneous, with mid-myocardial AP repolarisation more greatly affected than that in epicardial or endocardial cells [60,75,76].…”

“…This is attributable to differences in AP morphology between the two cell types and may lead to increased heterogeneity between ventricular and Purkinje fibre repolarisation in SQT1, which could feasibly contribute to prominent U-waves seen in some SQTS patients [47,49,52]. One simulation study has suggested that hERG gating defects due to the N588K mutation might facilitate early after-depolarisations in SQT1 [77], with reduced hERG 'tail currents' [78] and altered response to 'premature' stimuli in vitro [52]. Our most detailed simulation work to-date has been for V307L-KCNQ1-linked SQT2.…”