Atrial arrhythmogenicity of KCNJ2 mutations in short QT syndrome: Insights from virtual human atria.

Dominic G Whittaker,Haibo Ni,Aziza El Harchi,Henggui Zhang,Jules C Hancox,Alexander V Panfilov

doi:10.1371/journal.pcbi.1005593

Dominic G Whittaker, Haibo Ni + Show 4 more

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https://doi.org/10.1371/journal.pcbi.1005593

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Abstract

Gain-of-function mutations in KCNJ2-encoded Kir2.1 channels underlie variant 3 (SQT3) of the short QT syndrome, which is associated with atrial fibrillation (AF). Using biophysically-detailed human atria computer models, this study investigated the mechanistic link between SQT3 mutations and atrial arrhythmogenesis, and potential ion channel targets for treatment of SQT3. A contemporary model of the human atrial action potential (AP) was modified to recapitulate functional changes in IK1 due to heterozygous and homozygous forms of the D172N and E299V Kir2.1 mutations. Wild-type (WT) and mutant formulations were incorporated into multi-scale homogeneous and heterogeneous tissue models. Effects of mutations on AP duration (APD), conduction velocity (CV), effective refractory period (ERP), tissue excitation threshold and their rate-dependence, as well as the wavelength of re-entry (WL) were quantified. The D172N and E299V Kir2.1 mutations produced distinct effects on IK1 and APD shortening. Both mutations decreased WL for re-entry through a reduction in ERP and CV. Stability of re-entrant excitation waves in 2D and 3D tissue models was mediated by changes to tissue excitability and dispersion of APD in mutation conditions. Combined block of IK1 and IKr was effective in terminating re-entry associated with heterozygous D172N conditions, whereas IKr block alone may be a safer alternative for the E299V mutation. Combined inhibition of IKr and IKur produced a synergistic anti-arrhythmic effect in both forms of SQT3. In conclusion, this study provides mechanistic insights into atrial proarrhythmia with SQT3 Kir2.1 mutations and highlights possible pharmacological strategies for management of SQT3-linked AF.

Highlights

The cardiac inward rectifier potassium current (IK1) is responsible for stabilising the resting membrane potential (RMP) and contributes to terminal repolarisation of both atrial and ventricular action potentials (APs) [1]
The Colman et al (CZ) human atrial cell model updated with our WT IK1 formulation gave AP characteristics which were in excellent agreement with experimental data from human atrial myocytes (Supplemental S1 and S2 Figs)
The D172N mutation resulted in shortening of APD90 and hyperpolarisation of the resting membrane potential (RMP) (Fig 3Ai), with the homozygous condition exerting a more profound effect than the heterozygous condition

Summary

Introduction

The cardiac inward rectifier potassium current (IK1) is responsible for stabilising the resting membrane potential (RMP) and contributes to terminal repolarisation of both atrial and ventricular action potentials (APs) [1]. Gain-of-function KCNJ2 mutations are potentially lifethreatening, underlying variant 3 of the short QT syndrome (SQT3) [4,5,6], as well as familial atrial fibrillation (AF) [7]. The first reported SQT3 mutation, D172N Kir2.1 [4], was shown to increase significantly outward IK1 at potentials between −75 mV and −45 mV. The proband and her father exhibited significantly shortened QTc intervals (315 ms and 320 ms, respectively) and presented with a history of presyncopal events and palpitations [4]. The proband presented with an extremely short QT interval (200 ms) which showed no rate-adaptation, and recurring episodes of paroxysmal AF [6]

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