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Influence of the KCNQ1 S140G Mutation on Human Ventricular Arrhythmogenesis and Pumping Performance: Simulation Study

Authors :
Da Un Jeong
Ki Moo Lim
Source :
Frontiers in Physiology, Vol 9 (2018)
Publication Year :
2018
Publisher :
Frontiers Media S.A., 2018.

Abstract

The KCNQ1 S140G mutation, which is involved in IKs current, affects atrial fibrillation. However, little is known about its effect on the mechanical behavior of the heart. Therefore, we assessed the influence of the KCNQ1 S140G mutation on ventricular electrophysiological stability and mechanical pumping performance using a multi-scale model of cardiac electromechanics. An image-based electromechanical model was used to assess the effect on electrical propagation and arrhythmogenesis of the KCNQ1 S140G mutation. In addition, it was used to compare the mechanical response under the wild-type (WT) and S140G mutation conditions. The intracellular calcium transient obtained from the electrophysiological model was applied as an input parameter to a mechanical model to implement excitation–contraction coupling. The IKs current equation was modified to account for expression of the KCNQ1 S140G mutation, and it included a scaling factor (ϕ) for mutant expressivity. The WT and S140G mutation conditions were compared at the single-cell and three-dimensional (3D) tissue levels. The action potential duration (APD) was reduced by 60% by the augmented IKs current under the S140G mutation condition, which resulted in shorter QT interval. This reduced the 3D sinus rhythm wavelength by 60% and the sustained re-entry by 56%. However, pumping efficiency of mutant ventricles was superior in sinus rhythm condition. In addition, the shortened wavelength in cardiac tissue allowed a re-entrant circuit to form and increased the probability of sustaining ventricular tachycardia and ventricular fibrillation. In contrast, under the WT condition, a normal wavelength (20.8 cm) was unlikely to initiate and sustain re-entry in the cardiac tissue. Subsequently, the S140G mutant ventricles developed a higher dominant frequency distribution range (2.0–5.3 Hz) than the WT condition (2.8–3.7 Hz). In addition, stroke volume of mutant ventricles was reduced by 65% in sustained re-entry compared to the WT condition. In conclusion, signs of the S140G mutation might be difficult to identify in sinus rhythm even though the mutant ventricles show shortened QT interval. This suggests that the KCNQ1 S140G mutation increases the risk of death by sudden cardiac arrest. In addition, the KCNQ1 S140G mutation can induce ventricular arrhythmia and lessen ventricular contractility under re-entrant conditions.

Details

Language :
English
ISSN :
1664042X
Volume :
9
Database :
Directory of Open Access Journals
Journal :
Frontiers in Physiology
Publication Type :
Academic Journal
Accession number :
edsdoj.713ff15b2b1a4daea80fe2f075fb9e29
Document Type :
article
Full Text :
https://doi.org/10.3389/fphys.2018.00926