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

Short QT syndrome (SQTS) is a cardiac disorder characterized by arrhythmia and even sudden cardiac death (SCD). SQTS variant 3 (SQT3) has been linked to the KCNJ2 gene mutations, which directly increasing the inward rectifier K+ current $\left({{I_{{\mathrm{K}}1}}} \right)$. There have been many studies on the effects of the mutation KCNJ2 D172N that cause the SQT3, but the potential effect of the mutation KCNJ2 E299V is little known. Therefore, we aim to predict and compare the potential effects of ion channels blocking under the E299V mutation. In this study, a biophysically detailed computer model of the heart which was developed by was coupled with the KCNJ2 E299V mutant IK1 patch clamp data. Effects of a combined action of blocking of ${I_{\text{K1}}}$ and ICaL was also simulated under the E299V mutant condition. Our simulation data showed that a combined action of blocking of ${I_{\text{K1}}}$ and ${I_{\text{CaL}}}$ prolonged the cardiac cell action potential duration (APD) and QT interval under SQT3 E299V condition, and demonstrated that blocking of ${I_{\text{K1}}}$ and ${I_{\text{CaL}}}$ produced a therapeutic effect under SQT3 E299V. This study provides new evidence that blocking of ${I_{\text{K1}}}$ and ${I_{\text{CaL}}}$ may be a potential treatment for SQTS patients.