Abstract
Atrial fibrillation (AF) and sinus bradycardia have been reported in patients with short QT syndrome variant 2 (SQT2), which is underlain by gain-of-function mutations in KCNQ1 encoding the α subunit of channels carrying slow delayed rectifier potassium current, IKs. However, the mechanism(s) underlying the increased atrial arrhythmogenesis and impaired cardiac pacemaking activity arising from increased IKs remain unclear. Possible pharmacological interventions of AF in the SQT2 condition also remain to be elucidated. Using computational modelling, we assessed the functional impact of SQT2 mutations on human sinoatrial node (SAN) pacemaking, atrial repolarisation and arrhythmogenesis, and efficacy of the anti-arrhythmic drug quinidine. Markov chain formulations of IKs describing two KCNQ1 mutations – V141M and V307L – were developed from voltage-clamp experimental data and then incorporated into contemporary action potential (AP) models of human atrial and SAN cells, the former of which were integrated into idealised and anatomically detailed tissue models. Both mutations shortened atrial AP duration (APD) through distinct IKs ‘gain-of-function’ mechanisms, whereas SAN pacemaking rate was slowed markedly only by the V141M mutation. Differences in APD restitution steepness influenced re-entry dynamics in tissue – the V141M mutation promoted stationary and stable spiral waves whereas the V307L mutation promoted non-stationary and unstable re-entrant waves. Both mutations shortened tissue excitation wavelength through reduced effective refractory period but not conduction velocity, which served to increase the lifespan of re-entrant excitation in a 3D anatomical human atria model, as well as the dominant frequency (DF), which was higher for the V141M mutation. Quinidine was effective at terminating arrhythmic excitation waves associated with the V307L but not V141M mutation, and reduced the DF in a dose-dependent manner under both mutation conditions. This study provides mechanistic insights into different AF/bradycardia phenotypes in SQT2 and the efficacy of quinidine pharmacotherapy.
Highlights
The short QT syndrome (SQTS) is a rare but important cardiac disorder characterised by a shortened QT interval, increased incidence of ventricular and atrial arrhythmias, and risk of sudden death in affected patients (Schimpf et al, 2005)
In the 3D anatomical human atria model, scroll waves self-terminated in the wild type (WT) condition, whereas all SQTS variant 2 (SQT2) mutation conditions favoured sustenance of re-entry; (5) Quinidine exerted an anti-arrhythmic decrease in the dominant frequency (DF) of reentrant excitation in heterozygous forms of the SQT2 mutations, but was effective at terminating scroll waves associated with the V307L mutation only
In the FS human sinoatrial node (SAN) model, the homozygous form of the V141M mutation abolished pacemaking, whereas the heterozygous form reduced the spontaneous beating rate from 73 bpm in the WT condition to 50 bpm. This is in good agreement with 40–60 bpm (Villafañe et al, 2014) and 50 bpm (Righi et al, 2016) heart rates reported in SQT2 probands with the KCNQ1 V141M mutation
Summary
The short QT syndrome (SQTS) is a rare but important cardiac disorder characterised by a shortened QT interval, increased incidence of ventricular and atrial arrhythmias, and risk of sudden death in affected patients (Schimpf et al, 2005). Upregulation of IKs has been identified in patients with chronic atrial fibrillation (AF) (Caballero et al, 2010; González de la Fuente et al, 2013), and mutations to KCNQ1 have been shown to underlie lone AF (Chen et al, 2003; Lundby et al, 2007; Das et al, 2009). These findings suggest that enhanced IKs may play a role in the pathogenesis of AF. The SQTS represents a valuable paradigm for investigating the role of K+ channels in AF
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