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

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 I _K1 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 I _K1 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 I _K1 and I _Kr was effective in terminating re-entry associated with heterozygous D172N conditions, whereas I _Kr block alone may be a safer alternative for the E299V mutation. Combined inhibition of I _Kr and I _Kur 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.

Author summary

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and is characterised by complex and irregular electrical activation of the upper chambers of the heart. One rare, genetic condition associated with increased risk of AF is the short QT syndrome (SQTS), which is caused by mutations in genes involved in normal electrical function of the heart. Underlying mechanisms by which SQTS-related gene mutations facilitate development of arrhythmias in the human atria are not well understood. In this study, sophisticated computer models representing ‘virtual’ human atria, incorporating detailed electrophysiological data at the ‘ion channel’ protein level into both idealised and realistic multi-scale tissue geometries, were used to dissect mechanisms by which two mutations in the KCNJ2 gene responsible for SQTS variant 3 (SQT3) promote initiation and sustenance of arrhythmias. It was found that the D172N and E299V mutations to KCNJ2 accelerated the repolarisation process at the cellular level through distinct mechanisms. This, along with the way the mutations affected heterogeneity in electrical behaviour at the organ level, mediated stability of arrhythmias and response to simulated ion channel block. This study improves understanding of mechanisms underlying increased AF risk associated with D172N and E299V KCNJ2 mutations, and outlines potential therapeutic strategies.