Pharmacotherapeutic Effects of Quinidine on Short QT Syndrome by Using Purkinje-Ventricle Model: A Simulation Study

Short QT syndrome (SQTS) arises due to gene mutations leading to accelerated ventricular repolarization, and increased risk of cardiac arrhythmias and sudden cardiac death (SCD). The SQT1, SQT2 and SQT3 variants of the SQTS result from inherited gain-of-function mutations (e.g. N588K, V307L and D172N, respectively) to potassium channels. However, the effective management of SQTS remains a challenge, and is incompletely understood. In this study, computational modelling was used to investigate pharmacotherapeutic effects of selected class I drug quinidine on SQT1, SQT2 and SQT3 variants.

The biophysically-detailed Stewart et al. model of Purkinje fibre cell action potentials and the ten Tusscher et al. model of ventricular cell action potentials were coupled together into a heterogeneous two-dimensional (2D) tissue model. Previously validated I_Kr, I_Ks and I_K1 channel formulations for SQT1, SQT2 and SQT3 were incorporated in ventricular cell and tissue models. The channel-blocking effects of quinidine on ionic currents were modelled by using Hill coefficient and IC₅₀ values from the literature. At the 10 μM concentration tested in this study, quinidine effectively prolonged the action potential duration (APD) under all the SQT1, SQT2 and SQT3 conditions. In 2D simulations, quinidine prolonged the ventricular repolarization process and prolonged the QT intervals under all SQTS variants conditions.

Our findings provide a rational basis for the pursuit of pharmacotherapeutic agent quinidine in the treatment of all SQTS variants.