Increased Vulnerability of Human Ventricle to Re-entrant Excitation in hERG-linked Variant 1 Short QT Syndrome

• Published in: PLoS computational biology Vol. 7; no. 12; p. e1002313
• Main Authors: Adeniran, Ismail, McPate, Mark J., Witchel, Harry J., Hancox, Jules C., Zhang, Henggui
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.12.2011; Public Library of Science (PLoS)
• Subjects: Action Potentials; Arrhythmia; Biology; Cardiac arrhythmia; Computer Science; Electrocardiography; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels - genetics; Ether-A-Go-Go Potassium Channels - physiology; Experiments; Gene mutations; Genetic aspects; Geometry; Heart - physiology; Heart Ventricles - metabolism; Humans; Long QT syndrome; Markov analysis; Markov Chains; Models, Cardiovascular; Mutation; Physics; Risk factors; Ventricular Function; United Kingdom; Action Potentials; Heart; Heart Ventricles; Markov Chains; Models, Cardiovascular; Humans; Ventricular Function; Electrocardiography; Ether-A-Go-Go Potassium Channels; Mutation
• ISSN: 1553-7358; 1553-734X; 1553-7358
• DOI: 10.1371/journal.pcbi.1002313

The short QT syndrome (SQTS) is a genetically heterogeneous condition characterized by abbreviated QT intervals and an increased susceptibility to arrhythmia and sudden death. This simulation study identifies arrhythmogenic mechanisms in the rapid-delayed rectifier K(+) current (I(Kr))-linked SQT1 variant of the SQTS. Markov chain (MC) models were found to be superior to Hodgkin-Huxley (HH) models in reproducing experimental data regarding effects of the N588K mutation on KCNH2-encoded hERG. These ionic channel models were then incorporated into human ventricular action potential (AP) models and into 1D and 2D idealised and realistic transmural ventricular tissue simulations and into a 3D anatomical model. In single cell models, the N588K mutation abbreviated ventricular cell AP duration at 90% repolarization (APD(90)) and decreased the maximal transmural voltage heterogeneity (δV) during APs. This resulted in decreased transmural heterogeneity of APD(90) and of the effective refractory period (ERP): effects that are anticipated to be anti-arrhythmic rather than pro-arrhythmic. However, with consideration of transmural heterogeneity of I(Kr) density in the intact tissue model based on the ten Tusscher-Noble-Noble-Panfilov ventricular model, not only did the N588K mutation lead to QT-shortening and increases in T-wave amplitude, but δV was found to be augmented in some local regions of ventricle tissue, resulting in increased tissue vulnerability for uni-directional conduction block and predisposing to formation of re-entrant excitation waves. In 2D and 3D tissue models, the N588K mutation facilitated and maintained re-entrant excitation waves due to the reduced substrate size necessary for sustaining re-entry. Thus, in SQT1 the N588K-hERG mutation facilitates initiation and maintenance of ventricular re-entry, increasing the lifespan of re-entrant spiral waves and the stability of scroll waves in 3D tissue.