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

Luo, Cunjin and Wang, Kuanquan and Zhang, Henggui (2017) 'Modelling the effects of quinidine, disopyramide, and E-4031 on short QT syndrome variant 3 in the human ventricles.' Physiological Measurement, 38 (10). pp. 1859-1873. ISSN 0967-3334

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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 IK1) 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 IK1 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.

Item Type: Article
Uncontrolled Keywords: short QT syndrome; computational modelling; arrhythmia; quinidine; disopyramide; E-4031
Divisions: Faculty of Science and Health
Faculty of Science and Health > Computer Science and Electronic Engineering, School of
SWORD Depositor: Elements
Depositing User: Elements
Date Deposited: 03 Mar 2021 10:37
Last Modified: 23 Sep 2022 19:39

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