Effects of propafenone on KCNH2-linked short QT syndrome: A modelling study

Abstract

The identified genetic short QT syndrome (SQTS) is associated with an increased risk of arrhythmia and sudden death. This study was to investigate the potential effects of propafenone on KCNH2-linked short QT syndrome (SQT1) using a multi-scale biophysically detailed model of the heart developed by ten Tusscher and Panfilov. The ion electrical conductivities were reduced by propafenone in order to simulate the pharmacological effects in healthy and SQT1 cells. Based on the experimental data of McPate et al., the pharmacological effect of propafenone was modelled by dose-dependent IKr blocking. Action potential (AP) profiles and 1D tissue level were analyzed to predict the effects of propafenone on SQT1. Both low- and high- dose of propafenone prolonged APD and QT interval in SQT1 cells. It suggests the superior efficacy of high dose of propafenone on SQT1. However, propafenone did not significantly alter the healthy APD or QT interval at low dose, whereas markedly shortened them at high dose. Our simulation data show that propafenone has a dose-dependently anti-arrhythmic effect on SQT1, and a pro-arrhythmic effect on healthy cells. These computer simulations help to better understand the underlying mechanisms responsible for the initiation or termination of arrhythmias in healthy or SQT1 patients using propafenone.