Human Atrial Arrhythmogenesis and Sinus Bradycardia in KCNQ1-Linked Short QT Syndrome: Insights From Computational Modelling

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.

Learning from studying very rare cardiac conditions: the example of short QT syndrome

“…In a recent simulation study of atrial arrhythmia substrates in SQT2, simulated quinidine application increased atrial ERP for both V307L and V141M KCNQ1 mutations. However, it was not effective at restoring APD in the V141M setting [78] though it decreased the dominant frequency of excitation for both mutations, consistent with a potential role for rate if not rhythm control. The in silico observations regarding lack of effectiveness of quinidine for rhythm control with V141M correspond well to clinical findings in which recurrent AF associated with the V141M KCNQ1 mutation failed to respond to antiarrhythmic agents including quinidine [77].…”

“…This mutation results in an instantaneous component of I Ks current and initial modelling (using a human ventricular model and rabbit sinoatrial node model) showed abbreviation of ventricular APs and abolition of pacemaking [49]. Our recent human atrial and sinus node simulations have shown that the distinct changes to I Ks produced by the two mutations can account for their different phenotypes in respect of sinus bradycardia [78]. Only the V141M mutation exerted a marked effect on simulated sinoatrial node pacemaking rate, due to its greater effect in increasing I Ks over the diastolic membrane potential range (the increased I Ks resulting in a slowed diastolic depolarisation) [78].…”

“…Our recent human atrial and sinus node simulations have shown that the distinct changes to I Ks produced by the two mutations can account for their different phenotypes in respect of sinus bradycardia [78]. Only the V141M mutation exerted a marked effect on simulated sinoatrial node pacemaking rate, due to its greater effect in increasing I Ks over the diastolic membrane potential range (the increased I Ks resulting in a slowed diastolic depolarisation) [78]. The V141M mutation also produced a greater effect on atrial AP duration than did V307L and whilst both mutations shortened atrial tissue excitation wavelength for re-entry, V141M led to more stationary spiral wave dynamics than did V307L [78].…”

“…Simulations of the I560T hERG mutation, which produces a more modest attenuation of inactivation than N588K, have also shown susceptibility to sustained spiral wave re-entry [15]. Simulations of KCNQ1 mutations in SQT2 have shown abbreviation of ERP and reduction of the tissue substrate required to support reentry, for both ventricular and atrial tissue [74,75,78].…”

Modelling the Effects of Propafenone on Human Atrial Patho-Electrophysiology Associated With hERG-Linked Short QT Syndrome

“…Equation (1) was solved using a finite difference PDE solver based on the explicit forward Euler method and Strang splitting scheme. Effects of the N588K-hERG mutation and its modulation by propafenone on effective refractory period (ERP), conduction velocity (CV), excitation wavelength (WL; given by WL = CV × ERP), and spiral wave dynamics were determined using 1D and 2D atrial tissue models with spatial step, Δx = 0.25 mm, as described previously [17], [18]. Re-entry in the 2D sheet was initiated using an S1-S2 cross-shock protocol.…”