Modelling the Effects of Propafenone on Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome

Abstract

The N588K mutation to the human Ether-à-go-go-Related Gene (hERG) underlies short QT syndrome variant 1 (SQT1), which is associated with atrial fibrillation (AF). However, mechanisms and management of AF in the context of SQT1 remain poorly understood. In this study, multi-scale computational modelling was used to investigate pharmacotherapeutic effects of the class Ic drug propafenone for SQT1-mediated human atrial patho-electrophysiology. A Markov chain formulation of rapid delayed rectifier potassium current, IKr, describing wild type (WT) and N588K mutant currents was incorporated into a recent model of the human atrial action potential (AP), which was integrated into multi-scale tissue models. Effects of multi-channel block by propafenone were simulated on single- and multi-cellular electrophysiology models. At the single cell level, propafenone prolonged the AP duration under SQT1 (heterozygous N588K) conditions in a dose-dependent manner. In tissue, propafenone prolonged the effective refractory period and excitation wavelength, whilst reducing the conduction velocity. In 2D sheet simulations, propafenone demonstrated efficacy in pharmacological conversion of re-entry. Our findings suggest that propafenone shows efficacy in reversing AF associated with hERG-linked short QT syndrome.