Bai Jieyun, Lu Yaosheng, Lo Andy, Zhao Jichao, Zhang Henggui
Department of Electronic Engineering, College of Information Science and Technology, Jinan University, Guangzhou, China.
Auckland Bioengineering Institute, The University of Auckland, Auckland, New Zealand.
Front Physiol. 2019 Oct 22;10:1314. doi: 10.3389/fphys.2019.01314. eCollection 2019.
Functional analysis has shown that the p.Met207Val mutation was linked to atrial fibrillation and caused an increase in transactivation activity of PITX2c, which caused changes in mRNA synthesis related to ionic channels and intercellular electrical coupling. We assumed that these changes were quantitatively translated to the functional level. This study aimed to investigate the potential impact of the PITX2c p.Met207Val mutation on atrial electrical activity through multiscale computational models. The well-known Courtemanche-Ramirez-Nattel (CRN) model of human atrial cell action potentials (APs) was modified to incorporate experimental data on the expected p.Met207Val mutation-induced changes in ionic channel currents ( , , and ) and intercellular electrical coupling. The cell models for wild-type (WT), heterozygous (Mutant/Wild type, MT/WT), and homozygous (Mutant, MT) PITX2c cases were incorporated into homogeneous multicellular 1D and 2D tissue models. Effects of this mutation-induced remodeling were quantified as changes in AP profile, AP duration (APD) restitution, conduction velocity (CV) restitution and wavelength (WL). Temporal and spatial vulnerabilities of atrial tissue to the genesis of reentry were computed. Dynamic behaviors of re-entrant excitation waves (Life span, tip trajectory and dominant frequency) in a homogeneous 2D tissue model were characterized. Our results suggest that the PITX2c p.Met207Val mutation abbreviated atrial APD and flattened APD restitution curves. It reduced atrial CV and WL that facilitated the conduction of high rate atrial excitation waves. It increased the tissue's temporal vulnerability by increasing the vulnerable window for initiating reentry and increased the tissue spatial vulnerability by reducing the substrate size necessary to sustain reentry. In the 2D models, the mutation also stabilized and accelerated re-entrant excitation waves, leading to rapid and sustained reentry. In conclusion, electrical and structural remodeling arising from the PITX2c p.Met207Val mutation may increase atrial susceptibility to arrhythmia due to shortened APD, reduced CV and increased tissue vulnerability, which, in combination, facilitate initiation and maintenance of re-entrant excitation waves.
功能分析表明，p.Met207Val突变与心房颤动相关，并导致PITX2c的反式激活活性增加，进而引起与离子通道和细胞间电偶联相关的mRNA合成变化。我们假设这些变化在功能水平上得到了定量转化。本研究旨在通过多尺度计算模型研究PITX2c p.Met207Val突变对心房电活动的潜在影响。对著名的人类心房细胞动作电位（AP）的Courtemanche-Ramirez-Nattel（CRN）模型进行了修改，纳入了关于预期的p.Met207Val突变引起的离子通道电流（ 、 和 ）和细胞间电偶联变化的实验数据。将野生型（WT）、杂合型（突变体/野生型，MT/WT）和纯合型（突变体，MT）PITX2c病例的细胞模型纳入均匀的多细胞1D和2D组织模型。将这种突变诱导的重塑效应量化为AP形态、AP持续时间（APD）恢复、传导速度（CV）恢复和波长（WL）的变化。计算了心房组织对折返发生的时间和空间易损性。对均匀2D组织模型中折返激发波的动态行为（寿命、尖端轨迹和主导频率）进行了表征。我们的结果表明，PITX2c p.Met207Val突变缩短了心房APD并使APD恢复曲线变平。它降低了心房CV和WL，促进了高速率心房激发波的传导。它通过增加引发折返的易损窗口增加了组织的时间易损性，并通过减小维持折返所需的底物大小增加了组织的空间易损性。在2D模型中，该突变还使折返激发波稳定并加速，导致快速且持续的折返。总之，PITX2c p.Met207Val突变引起的电和结构重塑可能由于APD缩短、CV降低和组织易损性增加而增加心房对心律失常的易感性，这些因素共同促进了折返激发波的起始和维持。
