Session S45.2

Mechanistic Insights to Pro-Arrhythmogenesis of Short-QT Syndrome Associated with KCNQ1 Gene Mutation

H Zhang*, S Kharche, P Stewart, JC Hancox

The University of Manchester
Manchester, UK

Idiopathic short QT (SQT) syndrome is a recently identified, genetically heterogeneous condition characterized by abbreviated QT intervals and an increased susceptibility to arrhythmia and sudden death. In this computer simulation study, we identify the mechanisms by which cellular electrophysiological changes in the SQT syndrome associated with KCNQ1 gene mutation increase arrhythmia-risk. Experimental data on changes of slowly activated delay rectifier potassium channel (IKs) kinetics due to V307L mutation of the KCNQ1 subunit were incorporated into a computer model of electrical action potential (AP) of human ventricular myocytes developed by ten Tusscher et al.. Modified single cell models were then incorporated into multicellular tissue models of transmural ventricular tissues in 1D and 2D. Incorporating the V307L mutation into simulations reproduced defining features of the SQTS - abbreviation of the QT-interval, and increases in T-wave amplitude and T(peak)-T(end) duration. In the single cell model, the V307L mutation abbreviated ventricular cell AP duration at 90% repolarization (APD90) and increased the maximal transmural voltage heterogeneity (Delta V) during APs; this resulted in augmented transmural heterogeneity of APD90 and of the effective refractory period (ERP). In the intact tissue model, the vulnerable window for uni-directional conduction block was also increased. In 2D tissue the V307L mutation facilitated and maintained reentrant excitation. Thus, the V307L mutation increases in transmural heterogeneity of APD, Delta V, ERP and an increased vulnerable window for uni-directional conduction block generate an electrical substrate favorable to re-entrant arrhythmia. This study provided novel mechanistic insights toward understandings of pro-arrhythmogenesis in patients with SQT syndrome associated with V307L gene mutation.

(Abstract Control Number: 127)