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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Physiol. | doi: 10.3389/fphys.2019.01314

Proarrhythmia in the p.Met207Val PITX2c-linked familial atrial fibrillation-insights from modelling

  • 1Jinan University, China
  • 2Auckland Bioengineering Institute, University of Auckland, New Zealand
  • 3School of Physics & Astronomy, Faculty of Science and Engineering, University of Manchester, United Kingdom
  • 4Qingdao National Laboratory for Marine Science and Technology, China

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 (INaL, IKs and IKr) 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 remodelling 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, ion channel remodelling and conduction remodelling 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.

Keywords: Atrial Fibrillation, PITX2c, Modelling and simulation, Human atrial action potential model, Ion channel remodelling, Conduction remodelling

Received: 26 Jun 2019; Accepted: 30 Sep 2019.

Copyright: © 2019 Bai, Lu, Lo, Zhao and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Jieyun Bai, Jinan University, Guangzhou, China, bai_jieyun@126.com
Dr. Jichao Zhao, Auckland Bioengineering Institute, University of Auckland, Auckland, 1142, Auckland, New Zealand, j.zhao@auckland.ac.nz
Prof. Henggui Zhang, School of Physics & Astronomy, Faculty of Science and Engineering, University of Manchester, Manchester, M13 9PL, United Kingdom, henggui.zhang@manchester.ac.uk