PITX2 Overexpression Leads to Atrial Electrical Remodeling Linked to Atrial Fibrillation

摘要

Although functional analysis has shown that electrical remodelling in Atrial fibrillation (AF) patients is related to PITX2 overexpression, this link between PITX2 overexpression and the likelihood of atrial arrhythmias remains to be demonstrated directly. Therefore, utilizing computer modelling, this study was to quantify the pro-arrhythmogenic effects of PITX2 overexpression in the human atrium at cell and tissue levels. In simulations, Courtemanche et al.'s model of human atrial cell AP was modified to incorporate experimental data on changes of IKs and ICaL induced by PITX2 overexpression. The cell models for normal and AF type ionic currents (IKs and ICaL) were incorporated into the homogeneous multicellular 2D tissue model. Effects of electrical remodelling induced by PITX2 overexpression were quantified on ionic currents, AP profile and AP duration (APD). Dynamic behaviors of re‐entrant excitation waves in the 2D model were characterized. It was shown that the PITX2 overexpression abbreviated atrial APD. In the 2D model, the PITX2 overexpression also stabilized and accelerated re‐entrant excitation waves, leading to rapid and sustained re‐entry. In conclusion, increased IKs and reduced ICaL due to the PITX2 overexpression increases atrial susceptibility to arrhythmia due to increased tissue vulnerability, shortened APD and abbreviated wavelength.