Biological Physics Group, School of Physics and Astronomy, The University of Manchester, Manchester M60 1QD, UK.
Cardiovasc Res. 2012 Apr 1;94(1):66-76. doi: 10.1093/cvr/cvs082. Epub 2012 Feb 2.
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 'mutant' 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 'mutant' 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.
短 QT 综合征（SQT3）的一种形式与 Kir2.1 的 D172N 获得性功能突变有关，该突变优先增加负责内向整流钾（I（K1））电流的通道的外向电流。本研究旨在探讨 Kir2.1 D172N 突变促进和维持室性心律失常的机制。
采用 ten Tusscher 等人的人类心室动作电位（AP）模型，根据 Kir2.1 功能的实验观察结果对 I（K1）进行了修改：研究了杂合（WT-D172N）和纯合（D172N）突变情况。细胞模型被整合到异质一维（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。测量了心室组织对折返的时间和空间易感性，并对二维和三维人类心室模型中的折返兴奋波的动态行为（寿命和主导频率）进行了表征。D172N“突变”I（K1）导致 APD 和 ERP 缩短，以及 APD-R 和 ERP-R 曲线更陡峭。它降低了低激发率下的组织兴奋性，但增加了高激发率下的兴奋性。它增加了组织发起折返的时间易感性，但减少了维持折返所需的最小基质大小。SQT3“突变”I（K1）还稳定并加速了折返兴奋波，导致持续快速折返。
由于 Kir2.1 D172N 突变导致 I（K1）增加，从而增加了组织易感性、ERP 缩短和兴奋性改变，这些因素共同促进了折返电路的发起和维持，从而增加了心律失常的风险。
