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

Jieyun Bai,Andy Lo,Jichao Zhao,Henggui Zhang,Yaosheng Lu

doi:10.3389/fphys.2019.01314

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.

Highlights

The most common arrhythmia atrial fibrillation (AF) increases with age and is associated with adverse events (Heijman et al, 2018)
Genome-wide association studies suggested genetic variation contributes to AF susceptibility, with >100 AF-associated loci reported to date (Nielsen et al, 2018), including the atrial-selective transcription factor Paired like homeodomain-2 (PITX2) that regulates membrane effector genes associated with AF (Gudbjartsson et al, 2007; Chinchilla et al, 2011; Kirchhof et al, 2011; Qiu et al, 2014; Tao et al, 2014; Lozano-Velasco et al, 2015; Pérez-Hernández et al, 2015; Bai et al, 2018; Mechakra et al, 2019)
The measured APD values at 90% repolarization (APD90) was 260.62 ms for the WT condition, which was shortened to 197.58 ms for the Mutant/Wild type PITX2 c isoform (PITX2c) (MT/WT) condition and to 170.14 ms under the MT condition

Summary

Introduction

The most common arrhythmia atrial fibrillation (AF) increases with age and is associated with adverse events (such as heart failure, stroke, hypertension and diabetes) (Heijman et al, 2018) These cardiac disorders are thought to promote AF which is characterized by uncoordinated patterns of atrial electrical activation and a fast and irregular heartbeat (Hansen et al, 2015). Genome-wide association studies suggested genetic variation contributes to AF susceptibility, with >100 AF-associated loci reported to date (Nielsen et al, 2018), including the atrial-selective transcription factor PITX2 (paired like homeodomain-2) that regulates membrane effector genes associated with AF (Gudbjartsson et al, 2007; Chinchilla et al, 2011; Kirchhof et al, 2011; Qiu et al, 2014; Tao et al, 2014; Lozano-Velasco et al, 2015; Pérez-Hernández et al, 2015; Bai et al, 2018; Mechakra et al, 2019). Functional analysis of the transactivation activity of wild-type and variant PITX2c revealed a gain-of-function of PITX2c (the PITX2 c isoform), leading to an increase in the mRNA level of KCNH2 (the α subunit of IKr), KCNQ1 (the α subunit of IKs), SCN1B (the β1 subunit of sodium channels that modulates INaL), GJA5 (Cx40), and GJA1 (Cx43) (Mechakra et al, 2019)

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