Modelling the effects of quinidine, disopyramide, and E-4031 on short QT syndrome variant 3 in the human ventricles

Objective: Short QT syndrome (SQTS) is an inherited cardiac channelopathy, but at present little information is available on its pharmacological treatment. SQT3 variant (linked to the inward rectifier potassium current I _K1) of SQTS, results from a gain-of-function mutation (Kir2.1 D172N) in the KCNJ2-encoded channels, which is associated with ventricular fibrillation (VF). Using biophysically-detailed human ventricular computer models, this study investigated the potential effects of quinidine, disopyramide, and E-4031 on SQT3. Approach: The ten Tusscher et al model of human ventricular myocyte action potential (AP) was modified to recapitulate the changes in I _K1 due to heterozygous and homozygous forms of the D172N mutation. Wild-type (WT) and mutant WT-D172N and D172N formulations were incorporated into one-dimensional (1D) and 2D tissue models with transmural heterogeneities. Effects of drugs on channel-blocking activity were modelled using half-maximal inhibitory concentration (IC₅₀) and Hill coefficient (nH) values. Effects of drugs on AP duration (APD), effective refractory period (ERP) and QT interval of pseudo-ECGs were quantified, and both temporal and spatial vulnerability to re-entry was measured. Re-entry was simulated in the 2D ventricular tissue. Main results: At the single cell level, the drugs quinidine, disopyramide, and E-4031 prolonged APD at 90% repolarization (APD₉₀), and decreased maximal transmural voltage heterogeneity (δV); this caused the decreased transmural dispersion of APD₉₀. Quinidine prolonged the QT interval and decreased the T-wave amplitude. Furthermore, quinidine increased ERP and reduced temporal vulnerability and increased spatial vulnerability, resulting in a reduced susceptibility to arrhythmogenesis in SQT3. In the 2D tissue, quinidine was effective in terminating and preventing re-entry associated with the heterozygous D172N condition. Quinidine exhibited significantly better therapeutic effects on SQT3 than disopyramide and E-4031. Significance: This study substantiates a causal link between quinidine and QT interval prolongation in SQT3 Kir2.1 mutations and highlights possible pharmacological agent quinidine for treating SQT3 patients.