Effects of Quinidine on Short QT Syndrome Variant 2 in the Human Ventricles: a Modelling Study

The short QT syndrome (SQTS) is a rare cardiac disorder associated with an abnormally short QT interval and an increased risk of ventricular arrhythmias and sudden cardiac death (SCD). Gain-of-function mutation to potassium channels mediating the slow delayed rectifier current, I Ks , underlie KCNQ1-linked SQTS variant 2 (SQT2), in which treatment with sodium, calcium and potassium channel blocking class Ia antiarrhythmic agents has demonstrated some efficacy. This study used computational modelling and simulation to gain mechanistic insights into the actions the clinical drug, quinidine, in the setting of SQT2. The ten Tusscher et al. human ventricle model was modified to incorporate KCNQ1 V307L mutation-induced changes to I Ks based on experimentally observed data: wild type (WT) and SQT2 mutant conditions were studied. Actions of quinidine were simulated by implementing a simple pore block theory to simulate the drug blocking effects on I Kr , I Ks , I to , I Na , I CaL , I NaCa and I NaL , which were modelled using IC 50 and Hill coefficient. Cell models were incorporated into onedimensional (1D) model that considered the intrinsic electrical heterogeneity in the left ventricle. At a clinically therapeutic concentration of 10M quinidine, the action potential duration (APD) was significantly increased, and the QT interval on the pseudo-ECG was prolonged. This study helps to better understand the underlying mechanisms of pharmacological therapy, and provides further evidence that quinidine is a suitable treatment for the SQT2 phenotype.