Bai Jieyun, Lu Yaosheng, Lo Andy, Zhao Jichao, Zhang Henggui
Department of Electronic Engineering, College of Information Science and Technology, Jinan University, Guangzhou 510632, China.
Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand.
Ann Transl Med. 2020 Mar;8(5):191. doi: 10.21037/atm.2020.01.90.
Functional analysis has shown that the paired-like homeodomain transcription factor 2 (PITX2) overexpression associated with atrial fibrillation (AF) leads to the slow delayed rectifier K current ( ) increase and the L-type Ca current ( ) reduction observed in isolated right atrial myocytes from chronic AF (CAF) patients. Through multiscale computational models, this study aimed to investigate the functional impact of the PITX2 overexpression on atrial electrical activity.
The well-known Courtemanche-Ramirez-Nattel (CRN) model of human atrial action potentials (APs) was updated to incorporate experimental data on alterations in and due to the PITX2 overexpression. These cell models for sinus rhythm (SR) and CAF were then incorporated into homogeneous multicellular one-dimensional (1D), two-dimensional (2D), and three-dimensional (3D) tissue models. The proarrhythmic effects of the PITX2 overexpression were quantified with ion current profiles, AP morphology, AP duration (APD) restitution, conduction velocity restitution (CVR), wavelength (WL), vulnerable window (VW) for unidirectional conduction block, and minimal substrate size required to induce re-entry. Dynamic behaviors of spiral waves were characterized by measuring lifespan (LS), tip patterns and dominant frequencies.
The increase and the decrease arising from the PITX2 overexpression abbreviated APD and flattened APD restitution (APDR) curves in single cells. It reduced WL and increased CV at high excitation rates at the 1D tissue level. Although it had no effects on VW for initiating spiral waves, it decreased the minimal substrate size necessary to sustain re-entry. It also stabilized and accelerated spiral waves in 2D and 3D tissue models.
Electrical remodeling ( and ) due to the PITX2 overexpression increases susceptibility to AF due to increased tissue vulnerability, abbreviated APD, shortened WL and altered CV, which, in combination, facilitate initiation and maintenance of spiral waves.
功能分析表明，与心房颤动（AF）相关的配对样同源结构域转录因子2（PITX2）过表达导致慢性AF（CAF）患者分离的右心房肌细胞中缓慢延迟整流钾电流（ ）增加和L型钙电流（ ）减少。通过多尺度计算模型，本研究旨在探讨PITX2过表达对心房电活动的功能影响。
更新了著名的人类心房动作电位（APs）的Courtemanche-Ramirez-Nattel（CRN）模型，纳入了因PITX2过表达导致的 和 改变的实验数据。然后将这些窦性心律（SR）和CAF的细胞模型纳入均匀的多细胞一维（1D）、二维（2D）和三维（3D）组织模型。通过离子电流分布、AP形态、AP持续时间（APD）恢复、传导速度恢复（CVR）、波长（WL）、单向传导阻滞的易损窗口（VW）以及诱导折返所需的最小基质大小来量化PITX2过表达的促心律失常作用。通过测量寿命（LS）、尖端模式和主导频率来表征螺旋波的动态行为。
PITX2过表达引起的 增加和 减少缩短了单细胞的APD并使APD恢复（APDR）曲线变平。在一维组织水平上，它降低了WL并在高刺激频率下增加了CV。虽然它对引发螺旋波的VW没有影响，但它降低了维持折返所需的最小基质大小。它还使二维和三维组织模型中的螺旋波稳定并加速。
由于PITX2过表达导致的电重构（ 和 ）增加了组织易损性，缩短了APD，缩短了WL并改变了CV，从而增加了对AF的易感性，这些因素共同促进了螺旋波的起始和维持。
