Computational Analysis of the Effects of KCNJ2-linked E299V Mutation Short QT Syndrome and Its Potential Therapeutic Targets

Cunjin Luo1, Ying He2, Kuanquan Wang3, Henggui Zhang4
1University of Essex, 2University of Nottingham, 3Harbin Instituteo of Technology, 4University of Manchester


Short QT syndrome (SQTS) is a rare genetic disease associated with sudden cardiac death (SCD), characterized by short QT intervals on the ECGs. The KCNJ2 gene mutations induce short QT syndrome variant 3 (SQT3) by directly increasing the IK1 current. To date, there have been many studies on the pathological effects of mutations such as KCNJ2 E299V mutation that cause the SQT3. However, the studies of the pharmacological effects on myocardial cells associated with KCNJ2 E299V mutation are limited. Therefore, in this study, we investigated the potential therapeutic targets for SQTS. Ten Tusscher et al. models were used to simulate human action potentials in endocardial, mid-myocardial, and epicardial ventricular myocytes. The simulations were performed under normal condition (WT), heterogeneous mutation condition (WT-E299V), and homogeneous mutation condition (E299V). In simulations, three types of ventricular cells were performed to confirm the electrophysiological changes in action potentials and pseudo-ECGs caused by the KCNJ2 E299V mutation. Computational simulations identified IK1 and ICaL blockade as a beneficial pharmacologic target for prolonging the action potential and QT intevals on the ECGs, and reducing the transmutal action potential duration heterogeneity associated with KCNJ2 E299V mutation. In conclusion, computational simulations identified IK1 and ICaL blockers as potential therapeutic targets for SQT3.