In silico assessment of genetic variation in KCNA5 reveals multiple mechanisms of human atrial arrhythmogenesis.

Michael A Colman,Haibo Ni,Nicole Schmitt,Henggui Zhang,Bo Liang,Alexander V Panfilov

doi:10.1371/journal.pcbi.1005587

Abstract

A recent experimental study investigating patients with lone atrial fibrillation identified six novel mutations in the KCNA5 gene. The mutants exhibited both gain- and loss-of-function of the atrial specific ultra-rapid delayed rectifier K+ current, IKur. The aim of this study is to elucidate and quantify the functional impact of these KCNA5 mutations on atrial electrical activity. A multi-scale model of the human atria was updated to incorporate detailed experimental data on IKur from both wild-type and mutants. The effects of the mutations on human atrial action potential and rate dependence were investigated at the cellular level. In tissue, we assessed the effects of the mutations on the vulnerability to unidirectional conduction patterns and dynamics of re-entrant excitation waves. Gain-of-function mutations shortened the action potential duration in single cells, and stabilised and accelerated re-entrant excitation in tissue. Loss-of-function mutations had heterogeneous effects on action potential duration and promoted early-after-depolarisations following beta-adrenergic stimulation. In the tissue model, loss-of-function mutations facilitated breakdown of excitation waves at more physiological excitation rates than the wild-type, and the generation of early-after-depolarisations promoted unidirectional patterns of excitation. Gain- and loss-of-function IKur mutations produced multiple mechanisms of atrial arrhythmogenesis, with significant differences between the two groups of mutations. This study provides new insights into understanding the mechanisms by which mutant IKur contributes to atrial arrhythmias. In addition, as IKur is an atrial-specific channel and a number of IKur-selective blockers have been developed as anti-AF agents, this study also helps to understand some contradictory results on both pro- and anti-arrhythmic effects of blocking IKur.

Highlights

Mutations in genes encoding the proteins involved in cardiac electrophysiology can result in alterations of the electrical action potential (AP) and tissue excitability, which may affect cardiac output and predispose to arrhythmias, such as atrial fibrillation (AF) [1,2].AF, the world’s most common cardiac arrhythmia [3], is characterised by complex and rapid electrical activation of the upper chambers of the heart, impairing cardiac function and significantly increasing the risk of heart failure, stroke and death [4]
In simulations using the Colman et al [13] and Courtemanche et al [21] single cell models mapped onto the 3D reconstruction of human atrial anatomy, all three gain-of-function mutations promoted stable, higher frequency re-entrant scroll waves compared to the WT in all models (Fig 1B, Figure A in S3 Text)
Re-entry could be sustained at larger values of the diffusion coefficient (D), closer to control, indicating an increased susceptibility to re-entry in the structurally normal atria, or atria with a normal electrical coupling (Table A in S3 Text). chronic AF (cAF) remodelling accelerated and stabilised re-entrant excitation in all mutations and WT compared to the lone AF condition and in all mutations compared to the WT (Fig 1Bi,ii)

Summary

Introduction

Mutations in genes encoding the proteins involved in cardiac electrophysiology can result in alterations of the electrical action potential (AP) and tissue excitability, which may affect cardiac output and predispose to arrhythmias, such as atrial fibrillation (AF) [1,2]. AF, the world’s most common cardiac arrhythmia [3], is characterised by complex and rapid electrical activation of the upper chambers of the heart, impairing cardiac function and significantly increasing the risk of heart failure, stroke and death [4]. The ultra-rapid potassium current (IKur) plays an important role in repolarisation of the atrial action potential in human and other animals [2,10]. All mutations resulted in alterations of the channel’s maximum current density and kinetics [2], which is likely to manifest as modifications to AP morphology and duration

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Conclusion