Biological Physics Group, School of Physics and Astronomy, University of Manchester, Manchester M13 9PL, UK.
J Physiol. 2012 Sep 15;590(18):4501-14. doi: 10.1113/jphysiol.2012.229146. Epub 2012 Apr 16.
Functional analysis has shown that the missense gain-in-function KCNQ1 S140G mutation associated with familial atrial fibrillation produces an increase of the slow delayed rectifier potassium current (I(Ks)). Through computer modelling, this study investigated mechanisms by which the KCNQ1 S140G mutation promotes and perpetuates atrial fibrillation. In simulations, Courtemanche et al.'s model of human atrial cell action potentials (APs) was modified to incorporate experimental data on changes of I(Ks) induced by the KCNQ1 S140G mutation. The cell models for wild type (WT) and mutant type (MT) I(Ks) were incorporated into homogeneous multicellular 2D and 3D tissue models. Effects of the mutation were quantified on AP profile, AP duration (APD) restitution, effective refractory period (ERP) restitution, and conduction velocity (CV) restitution.Temporal and spatial vulnerabilities of atrial tissue to genesis of re-entry were computed. Dynamic behaviours of re-entrant excitation waves (lifespan (LS), tip meandering patterns and dominant frequency) in 2D and 3D models were characterised. It was shown that the KCNQ1 S140G mutation abbreviated atrial APD and ERP and flattened APD and ERP restitution curves. It reduced atrial CV at low excitation rates, but increased it at high excitation rates that facilitated the conduction of high rate atrial excitation waves. Although it increased slightly tissue temporal vulnerability for initiating re-entry, it reduced markedly the minimal substrate size necessary for sustaining re-entry (increasing the tissue spatial vulnerability). In the 2D and 3D models, the mutation also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained re-entry. In the 3D model, scroll waves under the mutation condition MT conditions also degenerated into persistent and erratic wavelets, leading to fibrillation. In conclusion, increased I(Ks) due to the KCNQ1 S140G mutation increases atrial susceptibility to arrhythmia due to increased tissue vulnerability, shortened ERP and altered atrial conduction velocity, which, in combination, facilitate initiation and maintenance of re-entrant excitation waves.
功能分析表明，与家族性心房颤动相关的错义获得功能 KCNQ1 S140G 突变会增加缓慢延迟整流钾电流 (I(Ks)))。通过计算机建模，本研究探讨了 KCNQ1 S140G 突变促进和维持心房颤动的机制。在模拟中，Courtemanche 等人的人类心房细胞动作电位 (AP) 模型被修改，以纳入 KCNQ1 S140G 突变引起的 I(Ks)变化的实验数据。WT 和 MT I(Ks)的细胞模型被整合到同质的二维和三维组织模型中。量化了突变对 AP 轮廓、APD 复极恢复、ERP 复极恢复和传导速度 (CV) 复极恢复的影响。计算了心房组织对折返发生的时空易损性。在二维和三维模型中，对折返兴奋波的动态行为（寿命 (LS)、尖端蜿蜒模式和主导频率）进行了特征描述。结果表明，KCNQ1 S140G 突变缩短了心房 APD 和 ERP，并使 APD 和 ERP 复极恢复曲线变平。它降低了低兴奋率时的心房 CV，但增加了高兴奋率时的 CV，从而促进了高频心房兴奋波的传导。尽管它略微增加了组织产生折返的时间易损性，但它显著减少了维持折返所需的最小基质大小（增加了组织空间易损性）。在二维和三维模型中，突变还稳定并加速了折返兴奋波，导致快速和持续的折返。在 3D 模型中，突变条件下的 scroll 波也退化成为持续和不稳定的小波，导致纤维颤动。总之，由于 KCNQ1 S140G 突变导致 I(Ks)增加，增加了组织易感性心律失常，因为组织易损性增加，ERP 缩短，心房传导速度改变，这三者共同促进了折返兴奋波的启动和维持。
