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. 2020 Jul 27;35(29):e238.
doi: 10.3346/jkms.2020.35.e238.

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

Aulia Khamas Heikhmakhtiar  1   2 , Abebe Tekle Abrha  3 , Da Un Jeong  3 , Ki Moo Lim  4
Affiliations

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

Aulia Khamas Heikhmakhtiar et al. J Korean Med Sci. .

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.

Keywords: KCNH2 Gene Mutation; L532P Mutation; N588K Mutation; Three-dimensional Heart Modeling.

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Conflict of interest statement

The authors have no potential conflicts of interest to disclose.

Figures

Fig. 1
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.
Fig. 2
Fig. 2. IKr current profiles (A), Action potential (B).
Fig. 3
Fig. 3. Mesh of the 3D atrial model.
Fig. 4
Fig. 4. Description of the S1-S2 protocol in the 2D (A) and 3D (B) models.
Fig. 5
Fig. 5. Spiral wave activity and action potential shape observed in the 2D tissue model. WT (A), N588K mutation (B), and L532P mutation (C).
Fig. 6
Fig. 6. Spiral wave activity and action potential shape observed in the 3D atrial model. WT (A), N588K mutation (B), and L532P mutation (C).
Fig. 7
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.
See this image and copyright information in PMC

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