title: Increased vulnerability of human ventricle to re-entrant excitation in hERG-linked variant 1 short QT syndrome.
abstract: 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.
authors.affiliation: Biological Physics Group, School of Physics & Astronomy, The University of Manchester, Manchester, UK.
authors.forename: Ismail
authors.initials: I
authors.lastname: Adeniran
authors.forename: Mark J
authors.initials: MJ
authors.lastname: McPate
authors.forename: Harry J
authors.initials: HJ
authors.lastname: Witchel
authors.forename: Jules C
authors.initials: JC
authors.lastname: Hancox
authors.forename: Henggui
authors.initials: H
authors.lastname: Zhang
mesh_terms: D000200:Action Potentials; D000072237:ERG1 Potassium Channel; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics / Q000502:physiology*; D006321:Heart / Q000502:physiology*; D006352:Heart Ventricles / Q000378:metabolism; D006801:Humans; D008390:Markov Chains; D008955:Models, Cardiovascular; D009154:Mutation; D016276:Ventricular Function
chemical_list: D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human