No abstract

Transcription factors TBX5 and PITX2 involve in the regulation of gene expression of ion channels and are closely associated with atrial fibrillation (AF), the most common cardiac arrhythmia in developed countries. The exact cellular and molecular mechanisms underlying the increased susceptibility to AF in patients with TBX5/PITX2 insufficiency remain unclear. In this study, we have developed and validated a novel human left atrial cellular model (TPA) based on the ten Tusscher-Panfilov ventricular cell model to systematically investigate how electrical remodeling induced by TBX5/PITX2 insufficiency leads to AF. Using our TPA model, we have demonstrated that spontaneous diastolic depolarization observed in atrial myocytes with TBX5-deletion can be explained by altered intracellular calcium handling and suppression of inward-rectifier potassium current (IK1). Additionally, our computer simulation results shed new light on the novel cellular mechanism underlying AF by indicating that the imbalance between suppressed outward current IK1 and increased inward sodium-calcium exchanger current (INCX) resulted from SR calcium leak leads to spontaneous depolarizations. Furthermore, our simulation results suggest that these arrhythmogenic triggers can be potentially suppressed by inhibiting sarcoplasmic reticulum (SR) calcium leak and reversing remodeled IK1. More importantly, this study has clinically significant implications on the drugs used for maintaining SR calcium homeostasis, whereby drugs such as dantrolene may confer significant improvement for the treatment of AF patients with TBX5/PITX2 insufficiency.

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is a major cause of stroke and morbidity. Recent genome-wide association studies have shown that pairedlike homeodomain transcription factor 2 (Pitx2) to be strongly associated with AF. However, the mechanisms underlying Pitx2 modulated arrhythmogenesis and variable effectiveness of antiarrhythmic drugs (AADs) in patients in the presence or absence of impaired Pitx2 expression remain unclear. We have developed multi-scale computer models, ranging from a single cell to tissue level, to mimic control and Pitx2-knockout atria by incorporating recent experimental data on Pitx2-induced electrical and structural remodeling in humans, as well as the effects of AADs. The key findings of this study are twofold. We have demonstrated that shortened action potential duration, slow conduction and triggered activity occur due to electrical and structural remodelling under Pitx2 deficiency conditions. Notably, the elevated function of calcium transport ATPase increases sarcoplasmic reticulum Ca 2+ concentration, thereby enhancing susceptibility to triggered activity. Furthermore, heterogeneity is further elevated due to Pitx2 deficiency: 1) Electrical heterogeneity between left and right atria increases; and 2) Increased fibrosis and decreased cell-cell coupling due to structural remodelling slow electrical propagation and provide obstacles to attract re-entry, facilitating the initiation of re-entrant circuits. Secondly, our study suggests that flecainide has antiarrhythmic effects on AF due to impaired Pitx2 by preventing spontaneous calcium release and increasing wavelength. Furthermore, our study suggests that Na + channel effects alone are insufficient to explain the efficacy of flecainide. Our study may provide the mechanisms underlying Pitx2-induced AF and possible explanation behind the AAD effects of flecainide in patients with Pitx2 deficiency.

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.