Proarrhythmia in KCNJ2-linked short QT syndrome: insights from modelling
Proarrhythmia in KCNJ2-linked short QT syndrome: insights from modelling
复制标题
KCNJ2 相关短 QT 综合征中的致心律失常：来自建模的见解
DOI：
10.1093/cvr/cvs082
复制
发表时间：
2012-04-01
影响因子：
10.8
通讯作者：
Zhang, Henggui
中科院分区：
文献类型：
--
作者：
Adeniran, Ismail;El Harchi, Aziza;Zhang, Henggui
短QT综合征（SQT 3）的一种形式与Kir2.1的D172 N功能增益突变有关，该突变优先增加通过负责内向整流K电流（I-K1）的通道的外向电流。本研究探讨了Kir2.1 D172 N突变促进和维持室性心律失常的机制。Tusscher等人基于实验观察到的Kir2.1功能变化，对人心室动作电位（AP）模型进行了修改，以纳入I-K1的变化：研究了杂合（WT-D172 N）和纯合（D172 N）突变情况。将细胞模型合并到异质一维（1D）、二维组织和三维模型中，以计算AP持续时间（APD-R）、有效不应期（ERP-R）和传导速度（CV）的恢复曲线。心室组织的时间和空间的脆弱性，以再入测量和动态行为的再入激励波（寿命和主频）在2D和3D模型的人心室的特点。D172 N突变体I-K1使APD和ERP缩短，APD-R和ERP-R曲线变陡。它在低兴奋率下降低组织兴奋性，但在高兴奋率下增加组织兴奋性。它增加了组织的时间脆弱性，启动重返，但减少了最小的基板大小所需的维持重返。SQT 3突变体I-K1还稳定和加速折返兴奋波，导致持续快速折返。由于Kir2.1 D172 N突变而增加的I-K1增加了心律失常风险，这是由于组织脆弱性增加、ERP缩短和兴奋性改变，其组合促进折返回路的启动和维持。
One form of the short QT syndrome (SQT3) has been linked to the D172N gain-in-function mutation to Kir2.1, which preferentially increases outward current through channels responsible for inward rectifier K current (I-K1). This study investigated mechanisms by which the Kir2.1 D172N mutation facilitates and perpetuates ventricular arrhythmias.The ten Tusscher et al. model for human ventricular action potentials (APs) was modified to incorporate changes to I-K1 based on experimentally observed changes to Kir2.1 function: both heterozygous (WT-D172N) and homozygous (D172N) mutant scenarios were studied. Cell models were incorporated into heterogeneous one-dimensional (1D), 2D tissue, and 3D models to compute the restitution curves of AP duration (APD-R), effective refractory period (ERP-R), and conduction velocity (CV). Temporal and spatial vulnerability of ventricular tissue to re-entry was measured and dynamic behaviour of re-entrant excitation waves (lifespan and dominant frequency) in 2D and 3D models of the human ventricle was characterized. D172N omutant' I-K1 led to abbreviated APD and ERP, as well as steeper APD-R and ERP-R curves. It reduced tissue excitability at low excitation rates but increased it at high rates. It increased tissue temporal vulnerability for initiating re-entry, but reduced the minimal substrate size necessary to sustain re-entry. SQT3 omutant' I-K1 also stabilized and accelerated re-entrant excitation waves, leading to sustained rapid re-entry.Increased I-K1 due to the Kir2.1 D172N mutation increases arrhythmia risk due to increased tissue vulnerability, shortened ERP, and altered excitability, which in combination facilitate initiation and maintenance of re-entrant circuits.