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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 ? subunit of channels carrying slow delayed rectifier potassium current, I Ks. However, the mechanism(s) underlying the increased atrial arrhythmogenesis and impaired cardiac pacemaking activity arising from increased I Ks 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 I Ks 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 I Ks '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.

SUBMITTER: Whittaker DG

PROVIDER: S-EPMC6180159 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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

Whittaker Dominic G DG Colman Michael A MA Ni Haibo H Hancox Jules C JC Zhang Henggui H

Frontiers in physiology 20181004

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, I Ks. However, the mechanism(s) underlying the increased atrial arrhythmogenesis and impaired cardiac pacemaking activity arising from increased I Ks remain unclear. Possible pharmacological int ...[more]

PMID: 30337886

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Project description:Short QT syndrome variant 1 (SQT1) arises due to gain-of-function mutations to the human Ether-à-go-go-Related Gene (hERG), which encodes the α subunit of channels carrying rapid delayed rectifier potassium current, I Kr. In addition to QT interval shortening and ventricular arrhythmias, SQT1 is associated with increased risk of atrial fibrillation (AF), which is often the only clinical presentation. However, the underlying basis of AF and its pharmacological treatment remain incompletely understood in the context of SQT1. In this study, computational modeling was used to investigate mechanisms of human atrial arrhythmogenesis consequent to a SQT1 mutation, as well as pharmacotherapeutic effects of selected class I drugs-disopyramide, quinidine, and propafenone. A Markov chain formulation describing wild type (WT) and N588K-hERG mutant I Kr was incorporated into a contemporary human atrial action potential (AP) model, which was integrated into one-dimensional (1D) tissue strands, idealized 2D sheets, and a 3D heterogeneous, anatomical human atria model. Multi-channel pharmacological effects of disopyramide, quinidine, and propafenone, including binding kinetics for I Kr/hERG and sodium current, I Na, were considered. Heterozygous and homozygous formulations of the N588K-hERG mutation shortened the AP duration (APD) by 53 and 86 ms, respectively, which abbreviated the effective refractory period (ERP) and excitation wavelength in tissue, increasing the lifespan and dominant frequency (DF) of scroll waves in the 3D anatomical human atria. At the concentrations tested in this study, quinidine most effectively prolonged the APD and ERP in the setting of SQT1, followed by disopyramide and propafenone. In 2D simulations, disopyramide and quinidine promoted re-entry termination by increasing the re-entry wavelength, whereas propafenone induced secondary waves which destabilized the re-entrant circuit. In 3D simulations, the DF of re-entry was reduced in a dose-dependent manner for disopyramide and quinidine, and propafenone to a lesser extent. All of the anti-arrhythmic agents promoted pharmacological conversion, most frequently terminating re-entry in the order quinidine > propafenone = disopyramide. Our findings provide further insight into mechanisms of SQT1-related AF and a rational basis for the pursuit of combined I Kr and I Na block based pharmacological strategies in the treatment of SQT1-linked AF.

Dataset Information

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

Publications

Human Atrial Arrhythmogenesis and Sinus Bradycardia in <i>KCNQ1</i>-Linked Short QT Syndrome: Insights From Computational Modelling.

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