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 (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.

Shortening of the Short Refractory Periods in Short QT Syndrome

“…The authors reported that the mutation accelerated the ventricular repolarization, shortened the AP duration and the effective ventricular RP while increasing electrical heterogeneity at some local areas, leading to increased risk of re‐entrant arrhythmia. Shortening of the RP was associated with a reduction of the tissue size required to sustain re‐entrant circuits in both 2 and 3 dimensions 26. On the basis of these results, a shortening of ventricular RP may be directly correlated to an increased risk of ventricular arrhythmia in SQTS, although shorter RPs were not linked to the induction of ventricular fibrillation nor to the outcome in our study.…”

Computer-based Assessment of the Effects of Amiodarone on Short QT Syndrome Variant 1 in Human Ventricles

“…The parameters of I Kr equations in the original model were replaced with a Markov chain (MC) model of the wildtype (WT) and N588K I Kr [4,5].…”

Modelling the Effects of Disopyramide on Short QT Syndrome Variant 1 in the Human Ventricles

“…The conductance of IKr was chosen based on the APD prolongation observed under experimental IKr block in the human ventricles [12], and the conductances of IKs and IK1 adjusted accordingly. An IKr scaling factor ratio of 1.5:1 in epicardial (EPI) to endocardial (ENDO) cells, respectively, was applied as suggested in the study of Adeniran et al [4], in order to generate a tall, symmetrical T-wave in the pseudo-ECG of the SQT1 phenotype, as seen clinically [2].…”

“…Eq (2) was discretised in space using the finite difference method and a spatial step of 0.15 mm. The 1D transmural model of human ventricle had a size of 15 mm, comprising 25 ENDO, 35 MCELL, and 40 EPI cells, with isotropic diffusion except for a 5-fold decrease in D at the MCELL:EPI border, as described in [4]. A stimulus was applied at the endocardial surface, eliciting a plane wave which propagated transmurally towards the epicardial surface.…”

“…The N588K-hERG channel mutation causes a gain-of-function to IKr through severely impaired inactivation over the physiological range of membrane potentials [3]. In a prior computational study from our group, this was shown to profoundly reduce ventricular effective refractory period (ERP), decreasing the minimal substrate size necessary to sustain re-entry and increasing the lifespan of re-entrant excitation waves [4]. Whereas multiple proarrhythmogenic effects of SQT1 in the human ventricles have been extensively characterised, less is known about the pharmacology of SQT1.…”