Modeling the effects of amiodarone on short QT syndrome variant 2 in the human ventricles

Aims: The short QT syndrome (SQTS) is a new genetic disorder associated with atrial and ventricular arrhythmias and sudden death. The SQT2, SQTS variant, results from a gain-of-function mutation (V307L) in the KCNQ1-encoded potassium channel. Although pro-arrhythmogenic effects of SQTS have been characterized, less is known about the pharmacology of SQTS. Therefore, this study aims to assess the effects of amiodarone on SQT2. Methods and Results: The ten Tusscher et al. model of the human ventricular action potential (AP) was modified to incorporate changes to IKs based on experimental data. Cell models were incorporated into heterogeneous one-dimensional (1D) tissue to compute the pseudo-ECG and the corresponding QT interval. The blocking effects of amiodarone on IKs, INa, INaK, ICaL, INaCa, and IKr were modeled using nH (Hill coefficient) and IC50 values from the literature. At the cellular level, amiodarone both at low and high doses prolonged the SQT2 AP duration (APD); at the tissue level, amiodarone at a high dose caused QT prolongation to the physiological range, but failed at a low dose. Conclusions: Amiodarone at a high dose produced better therapeutic effects on SQT2 than at a low dose. This study provides new evidence that amiodarone at a high dose may be a potential pharmacological treatment for SQT2.