Atrial Fibrillation Arising from Impaired Pitx2: Insight from a 3D Human Atrial Model

Jieyun Bai1, Yijie Zhu1, Yaosheng Lu1, Andy Lo2, Jichao Zhao3
1Department of Electronic Engineering, College of Information Science and Technology, Jinan University, 2Auckland Bioengineering Institute, The University of Auckland, 3The University of Auckland


The paired like homeodomain 2 (Pitx2) plays an important role in the determination of the left-right asymmetry of the atria. Genome-wide association studies have shown that impaired Pitx2 contributes to the genesis of atrial fibrillation (AF), but mechanisms underlying Pitx2-induced AF remain incomplete. Using a biophysically detailed model of human atria, we investigated mechanisms by which Pitx2-induced electrical remodelling promotes and perpetuates AF. Our action potential (AP) model for human right atrial cells was modified to consider intrinsic electrophysiological heterogeneities to generate regional AP models for the control condition by scaling maximum conductances of ionic currents (including ICaL, IKur, Ito, IK1, IKs, INaCa, Jrel and Jup). Based on various experimental data sets on Pitx2-induced electrical remodelling (INa, ICaL, IK1, IKs, Jrel and Jup), the single-cell models for the AF condition were developed. These cellular models for control and AF conditions were incorporated into a realistic 3D model of human atria to investigate electrical waves. Effects of the Pitx2-induced electrical remodelling were quantified as the changes of AP and the inducibility of electrical waves. In our simulations, Pitx2-induced electrical remodelling abbreviated AP duration in the left atrium, increased tissue vulnerability to re-entry initiation at these junctions between right and left atriums, and promoted triggered activities in pulmonary vein cells. Under the AF condition, the ectopic atrial activity generated in pulmonary veins and degenerated into re-entrant scroll waves, leading to AF. In conclusion, AF due to impaired Pitx2 may be resulted from triggered activity, regionally heterogeneous, and shortened APD.