PITX2 upregulation increases the risk of chronic atrial fibrillation in a dose-dependent manner by modulating IKs and ICaL—insights from human atrial modelling

Abstract

Background: 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 (I Ks) increase and the L-type Ca 2+ current (I CaL) 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. Methods: The well-known Courtemanche-Ramirez-Nattel (CRN) model of human atrial action potentials (APs) was updated to incorporate experimental data on alterations in I Ks and I CaL 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. Results: The I Ks increase and the I CaL 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. Conclusions: Electrical remodeling (I Ks and I CaL) 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.