Proarrhythmia in the p.Met207Val PITX2c-Linked Familial Atrial Fibrillation-Insights From Modeling

Abstract

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 remodeling 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, electrical and structural remodeling 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.

In silico study of the effects of anti-arrhythmic drug treatment on sinoatrial node function for patients with atrial fibrillation

“…was developed to simulate electrical waves under the AF-induced SND condition in the presence of drugs. In the 1D cable model, the mathematical model of the human atrial myocyte developed in our previous study [47][48][49][50][51][52] was used, and AF was simulated by introducing electrical remodelling based on experimental data [53][54][55][56][57][58][59][60][61][62] (listed in the Supplementary Table 8). The membrane potential is described by:…”

In silico investigation of the mechanisms underlying atrial fibrillation due to impaired Pitx2

“…Pitx2 encodes 3 isoforms (Pitx2a, Pitx2b and Pitx2c) and the Pitx2c isoform promotes the embryonic development of cardiac left-right asymmetry, with levels in right and left atriums being 1:100 [10]. The atrial-selective transcription factor Pitx2 is an upstream transcriptional regulator of atrial electric function and cardiogenesis [11,12]. Complete loss of Pitx2 function can result in malformation of the pulmonary veins that are wellknown sites for ectopic activity promoting spontaneous AF [9].…”

In Silico Assessment of Class I Antiarrhythmic Drugs Effects on Pitx2-induced Atrial Fibrillation: Insights from Populations of Electrophysiological Models of Human Atrial Cells and Tissues

“…To obtain human AF myocytes models that reproduced the experimentally observed changes in the mRNA levels corresponding to key proteins under Pitx2-induced electrical remodelling conditions, we assumed that these changes in mRNA expression are quantitatively reflected at the final functional level of ion channels [29] and incorporated alterations in the maximal conductances of ionic currents due to Pitx2-induced electrical remodelling into the Bai et al (or the Grandi et al) model. These Pitx2-induced changes in the ionic channel properties have been well characterized in many experimental studies [17,18,[23][24][25][26]61].…”

“…Gene expression analyses highlighted that Pitx2 regulated genes of ion channels [11,12,17,22,23,25,26] in a dose-dependent manner. Based on these experimental data on changes in expression of ion channels, we constructed multi-scale models of human atrial electrophysiology to investigate mechanisms by which Pitx2-induced remodelling promotes AF in our previous studies [27][28][29][30][31][32][33]. However, effective management of AF remains a challenge, and is incompletely understood in the context of Pitx2-induced AF.…”

“…Although the efficacy of disopyramide, quinidine, and propafenone on human atrial pathoelectrophysiology associated with hERG-linked short QT syndrome has been investigated using a multi-scale computational model [37], mechanisms by which short QT mutations promote AF may be different from that underlying Pitx2-induced AF [27][28][29][30][31][32]36]. Also, both clinical [34] and theoretical [36] studies of pharmacotherapy for Pitx2-induced AF often ignored inter-subject variability in atrial electrophysiology properties.…”