Effects of amiodarone on short QT syndrome variant 3 in human ventricles: a simulation study

Cunjin Luo,Henggui Zhang,Kuanquan Wang

doi:10.1186/s12938-017-0369-0

Cunjin Luo, Henggui Zhang + Show 1 more

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https://doi.org/10.1186/s12938-017-0369-0

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Abstract

BackgroundShort QT syndrome (SQTS) is a newly identified clinical disorder associated with atrial and/or ventricular arrhythmias and increased risk of sudden cardiac death (SCD). The SQTS variant 3 is linked to D172N mutation to the KCNJ2 gene that causes a gain-of-function to the inward rectifier potassium channel current (IK1), which shortens the ventricular action potential duration (APD) and effective refractory period (ERP). Pro-arrhythmogenic effects of SQTS have been characterized, but less is known about the possible pharmacological treatment of SQTS. Therefore, in this study, we used computational modeling to assess the effects of amiodarone, class III anti-arrhythmic agent, on human ventricular electrophysiology in SQT3.MethodsThe ten Tusscher et al. model for the human ventricular action potentials (APs) was modified to incorporate IK1 formulations based on experimental data of Kir2.1 channels (including WT, WT-D172N and D172N conditions). The modified cell model was then implemented to construct one-dimensional (1D) and 2D tissue models. The blocking effects of amiodarone on ionic currents were modeled using IC50 and Hill coefficient values from literatures. Effects of amiodarone on APD, ERP and pseudo-ECG traces were computed. Effects of the drug on the temporal and spatial vulnerability of ventricular tissue to genesis and maintenance of re-entry were measured, as well as on the dynamic behavior of re-entry.ResultsAmiodarone prolonged the ventricular cell APD and decreased the maximal voltage heterogeneity (δV) among three difference cells types across transmural ventricular wall, leading to a decreased transmural heterogeneity of APD along a 1D model of ventricular transmural strand. Amiodarone increased cellular ERP, prolonged QT interval and decreased the T-wave amplitude. It reduced tissue’s temporal susceptibility to the initiation of re-entry and increased the minimum substrate size necessary to sustain re-entry in the 2D tissue.ConclusionsAt the therapeutic-relevant concentration of amiodarone, the APD and ERP at the single cell level were increased significantly. The QT interval in pseudo-ECG was prolonged and the re-entry in tissue was prevented. This study provides further evidence that amiodarone may be a potential pharmacological agent for preventing arrhythmogenesis for SQT3 patients.

Highlights

Short QT syndrome (SQTS) is a newly identified clinical disorder associated with atrial and/or ventricular arrhythmias and increased risk of sudden cardiac death (SCD)
It is of particular note that with the use of amiodarone in the WT-D172N condition, mimicking the effects on the heterozygous state of the proband, we found that the simulated QT interval extended from 322 to 341 ms in the low-dose amiodarone condition and 340 ms in the high-dose condition
Our simulation results indicate that the amiodarone (i) extended the A PD90 in the SQTS variant 3 (SQT3) condition and decreased susceptibility to arrhythmia; (ii) extended the QT interval on the pseudo-ECG and reduced the T-wave amplitude; (iii) decreased the maximal voltage heterogeneity during action potentials (APs), which contributed to the decreased T-wave amplitude; (iv) prolonged cell APD90 across the 1D strand and decreased maximal dispersion of APD90, which subsequently led to the decreased T-wave amplitude; (v) prevented re-entrant excitation waves and increased the minimum substrate size of tissue required to maintain re-entrant excitation waves

Summary

Introduction

Short QT syndrome (SQTS) is a newly identified clinical disorder associated with atrial and/or ventricular arrhythmias and increased risk of sudden cardiac death (SCD). Short QT syndrome (SQTS) is a potentially lethal cardiac ion channelopathy associated with a variety of signs and symptoms, from dizziness and fainting (syncope) to cardiac arrest and sudden death [1,2,3,4,5,6]. SQTS with various mutations is genetically heterogeneous, involving the KCNH2 [4], KCNQ1 [3], KCNJ2 [2], CACNA1C [7], CACNB2b [7] and CACNA2D1 [8] genes These identified gene mutations in membrane ion channels alter the electrical activity of the heart, leading to arrhythmic characteristic of SQTS. Either a gain-in-function of the potassium channel or a loss-in-function of the calcium channel across the membrane of cardiac muscle cells has been observed [2,3,4, 7, 8]

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