Abstract
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.
Highlights
Short QT syndrome (SQTS) is a disorder in the electrical function of the heart, and it is associated with high risk of arrhythmias and of sudden cardiac death (SCD) (Gussak et al 2000, Gaita et al 2003, Schimpf et al 2005)
Using biophysically-detailed human ventricular computer models, this study investigated the potential effects of quinidine, disopyramide, and E-4031 on SQT3
The ten Tusscher et al human ventricular cell model incorporating SQT3 IK1 formulations (Adeniran et al 2012) gave action potential (AP) characteristics which were in excellent agreement with experimental data from human ventricular myocytes (Priori et al 2005)
Summary
Short QT syndrome (SQTS) is a disorder in the electrical function of the heart, and it is associated with high risk of arrhythmias and of sudden cardiac death (SCD) (Gussak et al 2000, Gaita et al 2003, Schimpf et al 2005). The basis for SQTS associated with various mutations in 6 different genes have been found: KCNH2 (Brugada et al 2004), KCNQ1 (Bellocq et al 2004), KCNJ2 (Priori et al 2005), CACNA1C (Antzelevitch et al 2007), CACNB2b (Antzelevitch et al 2007), and CACNA2D1 (Templin et al 2011). Among these mutations, either a gain-in-function of the potassium channel (linked to KCNH2, KCNQ1, and KCNJ2 gene) or a loss-in-function of the calcium channel (linked to CACNA1C, CACNB2b, and CACNA2D1 gene) has been observed. Previous studies have been shown that increased IK1 in SQT3 shortened the action potential duration (APD) and the effective refractory period (ERP), and stabilized rotors in computational models of human ventricular electrophysiology (Adeniran et al 2012)
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