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 (I _NaL , I _Ks , and I _Kr ) 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.

Keywords: PITX2c; atrial fibrillation; electrical and structural remodeling; gene regulation; human atrial action potential model; modeling and simulation; single nucleotide polymorphism; transcription factors.

Figure 1

A schematic overview of human atrial myocyte model and its corresponding action potentials (APs). (A) The original myocyte model (Original CRN) was improved to include the I_NaLmodel (marked in red). (B) APs obtained from the Original CRN model and the Modified CRN model.

Figure 2

Effects of the p.Met207Val PITX2c mutation on atrial electrophysiological properties at the cellular and subcellular levels. There are three conditions (Wild type: WT, homozygous p.Met207Val mutation: MT and heterozygous p.Met207Val mutation: MT/WT). (A) Relative changes (%) in the Cx43/[Cx40+Cx43] ratio, I_NaL, I_Ks, and I_Kr. (B) AP profiles. (C) APD restitution curves. (D) Measured maximum slopes of APD restitution curves.

Figure 3

Effects of the p.Met207Val PITX2c mutation on electrical conduction at the one-dimensional tissue level. (A) Conduction velocity (CV) restitution curves for WT, MT, and MT/WT conditions, respectively. (B) Measured wavelengths at a basic cycle length (BCL) of 1,000 ms in the three cases.

Figure 4

Effects of the p.Met207Val PITX2c mutation on the temporal vulnerability of atrial tissue in the 1D cable model with 375 nodes. (A) Electrical waves at different S1-S2 intervals, illustrating bidirectional conduction block (left), unidirectional conduction block (middle) and bidirectional conduction (right) for WT, MT, and MT/WT conditions, respectively. (B) Vulnerable windows of atrial tissue vulnerability to unidirectional conduction block under WT, MT, and MT/WT conditions, respectively.

Figure 5

Effects of the p.Met207Val PITX2c mutation on the spatial vulnerability of atrial tissue in the 2D tissue model with 750 × 750 nodes. (A) Electrical waves following an S2 stimulus at different time intervals, illustrating the minimal substrate size required to induce a pair of re-entrant circuits under WT, MT, and MT/WT conditions, respectively. (B) Minimal substrate sizes of atrial tissue vulnerability to the genesis of re-entrant excitation waves under WT, MT, and MT/WT conditions, respectively.

Figure 6

Effects of the p.Met207Val PITX2c mutation on the maintenance of spiral waves in the 2D sheet model with 375 × 375 nodes. (A) Snapshots of electrical waves, for WT, MT, and MT/WT conditions, at time = 50, 400, 1,000, 2,000, 3,000, and 4,000 ms. (B) Tip trajectories of re-entrant waves under WT, MT, and MT/WT conditions. (C) Membrane potential traces of localized electrical excitations (marked with red points in (A). (D) Dominant frequencies under WT, MT, and MT/WT conditions.

Figure 7

Effects of the p.Met207Val PITX2c mutation on action potential shape and action potential duration (APD) obtained from the Grandi model. AP profiles (A), APDs (B), APD restitution curves (C), and measured maximum slopes (D) of APD restitution curves, for WT, MT, and MT/WT conditions, respectively.