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

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 (IKr)-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 (APD90) and decreased the maximal transmural voltage heterogeneity (δV) during APs. This resulted in decreased transmural heterogeneity of APD90 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 IKr 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. Author Summary: Sudden cardiac death may arise in individuals with diseased heart tissue, or in apparently healthy subjects who suffer from genetic defects in ‘ion channel’ proteins, which increase cardiac arrhythmia risk and are associated with significant morbidity and mortality. One rare, though serious, genetic condition is the ‘short QT syndrome’ (SQTS). Although it is now known that the KCNH2-encoded N588K-hERG mutation is associated with the main (SQT1) variant of the SQTS, the mechanisms by which ventricular arrhythmia is initiated and sustained are still unclear due to lack of genotypically accurate experimental models. In this study, we used sophisticated multi-scale computer models of human ventricles in order to investigate the pro-arrhythmic effects of the N588K hERG mutation. It was found that the mutation accelerated the ventricular repolarization process, produced augmented electrical heterogeneity in some local regions of the tissue, leading to increased risk of arrhythmia genesis. It was also found that accelerated ventricular repolarization reduced the substrate size of the tissue required to sustain re-entrant circuits in both two and three dimensions. This study provides new mechanistic insight into understanding of how changes to hERG channel function in SQT1 lead to exacerbated ventricular arrhythmia risk in this inherited arrhythmia syndrome.