J Korean Med Sci.  2020 Jul;35(29):e238. 10.3346/jkms.2020.35.e238.

Proarrhythmogenic Effect of the L532P and N588K KCNH2 Mutations in the Human Heart Using a 3D Electrophysiological Model

• Heikhmakhtiar AK
• Abrha AT
• Jeong DU
• Lim KM

• KMID: 2504700
• DOI: http://doi.org/10.3346/jkms.2020.35.e238

Abstract

Background
Atrial arrhythmia is a cardiac disorder caused by abnormal electrical signaling and transmission, which can result in atrial fibrillation and eventual death. Genetic defects in ion channels can cause myocardial repolarization disorders. Arrhythmia-associated gene mutations, including KCNH2 gene mutations, which are one of the most common genetic disorders, have been reported. This mutation causes abnormal QT intervals by a gain of function in the rapid delayed rectifier potassium channel (IKr). In this study, we demonstrated that mutations in the KCNH2 gene cause atrial arrhythmia.
Methods
The N588K and L532P mutations were induced in the Courtemanche-Ramirez-Nattel (CRN) cell model, which was subjected to two-dimensional and three-dimensional simulations to compare the electrical conduction patterns of the wild-type and mutant-type genes.
Results
In contrast to the early self-termination of the wild-type conduction waveforms, the conduction waveform of the mutant-type retained the reentrant wave (N588K) and caused a spiral break-up, resulting in irregular wave generation (L532P).
Conclusion
The present study confirmed that the KCNH2 gene mutation increases the vulnerability of the atrial tissue for arrhythmia.

Keyword

KCNH2 Gene Mutation; L532P Mutation; N588K Mutation; Three-dimensional Heart Modeling

Figure

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  Fig. 1 CRN cell model diagram (A), N588K and L532P mutations in the S5 sub-unit of the IKr channel and in the S4 voltage sensor, respectively (B).CRN = Courtemanche-Ramirez-Nattel.

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  Fig. 2 IKr current profiles (A), Action potential (B).

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  Fig. 3 Mesh of the 3D atrial model.

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  Fig. 4 Description of the S1-S2 protocol in the 2D (A) and 3D (B) models.

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  Fig. 5 Spiral wave activity and action potential shape observed in the 2D tissue model. WT (A), N588K mutation (B), and L532P mutation (C).

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  Fig. 6 Spiral wave activity and action potential shape observed in the 3D atrial model. WT (A), N588K mutation (B), and L532P mutation (C).

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  Fig. 7 “Vulnerability to re-entry” grid constructed by summarizing the outcomes at varying S10th and S11th intervals.F = failure to initiate S11th stimulus, P = normal propagation of S2 beat, R = re-entry.

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