Colman Michael A, Ni Haibo, Liang Bo, Schmitt Nicole, Zhang Henggui
Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester, United Kingdom.
School of Biomedical Sciences, Faculty of Biological Sciences, University of Leeds, Leeds, United Kingdom.
PLoS Comput Biol. 2017 Jun 16;13(6):e1005587. doi: 10.1371/journal.pcbi.1005587. eCollection 2017 Jun.
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.
最近一项针对孤立性房颤患者的实验研究在KCNA5基因中发现了六个新突变。这些突变体表现出心房特异性超快速延迟整流钾电流（IKur）的功能获得和功能丧失。本研究的目的是阐明并量化这些KCNA5突变对心房电活动的功能影响。更新了人类心房的多尺度模型，以纳入来自野生型和突变体的关于IKur的详细实验数据。在细胞水平上研究了这些突变对人类心房动作电位和频率依赖性的影响。在组织中，我们评估了这些突变对单向传导模式易感性和折返性兴奋波动态的影响。功能获得性突变缩短了单细胞中的动作电位持续时间，并稳定和加速了组织中的折返性兴奋。功能丧失性突变对动作电位持续时间有不同的影响，并在β肾上腺素能刺激后促进早期后去极化。在组织模型中，功能丧失性突变比野生型更容易在更生理的兴奋频率下促进兴奋波的破裂，并且早期后去极化的产生促进了单向兴奋模式。功能获得性和功能丧失性IKur突变产生了多种心房心律失常发生机制，两组突变之间存在显著差异。本研究为理解突变型IKur导致心房心律失常的机制提供了新的见解。此外，由于IKur是一种心房特异性通道并且已经开发了许多IKur选择性阻滞剂作为抗房颤药物，本研究也有助于理解关于阻断IKur的促心律失常和抗心律失常作用的一些矛盾结果。
