Proarrhythmia in KCNJ2 E299V-linked Short QT Syndrome: A Simulation Study

Cunjin Luo1, Tong Liu2, Ying He3, Kuanquan Wang4, Henggui Zhang5
1University of Essex, 2Tianjin Medical University, 3De montfort University, 4Harbin Institute of Technology, 5The University of Machester


Background. The KCNJ2 mutations induce short QT syndrome(SQT3) by increasing the inward recitfier potassium current (IK1). There have been many studies on the mutations such as the KCNJ2 D172N that cause SQT3. However, the KCNJ2 E299V mutation is distinguished from other representative mutations that can induce SQT3. The electrophysiological effects of E299V mutations on myocardial cells and tissue are limited. Therefore, this study investigated the mechanisms by which the KCNJ2 E299V mutation facilitates and maintains the ventricualr re-entrant arrhythmias.

Methods and Results. We performed simulations using a human ventricular model of electrophysiological properties developed by ten Tusscher et al. The simulations were performed under normal condition (WT), heterogeneous mutation condition (WT-E299V), and homozygous mutation condition (E299V). First, a single-cell simulation was performed in three types of ventricular cells (endocardial, midmyocardial, and epicardial). Then, in one-dimensional simulations, we conpared electrical changes and the corresponding ECG changes caused by the expression level of E299V mutation. Finally, in two-dimensional simulations, we observed the electrophysiological properties of the E299V mutation during ventricular arrhythmias. The KCNJ2 E299V mutation acclerated and increased IK1 current, resulting in a decrease in action potential duration (APD). Accordingly the QT interval was reduced to 176 ms under WT-E299V and 130 ms under E299V conditions compared to the WT condition (413 ms). Re-entrant waves were sustained under the mutant WT-E299V and E299V condtions compared to the WT condition,

Conclusions. Increased IK1 due to the KCNJ2 E299V mutation facilitates initiation and maintenance of ventricular re-entrant arrhythmias.