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

Abstract

Electrical remodelling as a result of homeodomain transcription factor 2 (Pitx2)-dependent gene regulation was linked to atrial fibrillation (AF) and AF patients with single nucleotide polymorphisms at chromosome 4q25 responded favorably to class I antiarrhythmic drugs (AADs). The possible reasons behind this remain elusive. The purpose of this study was to assess the efficacy of the AADs disopyramide, quinidine, and propafenone on human atrial arrhythmias mediated by Pitx2-induced remodelling, from a single cell to the tissue level, using drug binding models with multi-channel pharmacology. Experimentally calibrated populations of human atrial action po-tential (AP) models in both sinus rhythm (SR) and Pitx2-induced AF conditions were constructed by using two distinct models to represent morphological subtypes of AP. Multi-channel pharmaco-logical effects of disopyramide, quinidine, and propafenone on ionic currents were considered. Simulated results showed that Pitx2-induced remodelling increased maximum upstroke velocity (dVdtmax), and decreased AP duration (APD), conduction velocity (CV), and wavelength (WL). At the concentrations tested in this study, these AADs decreased dVdtmax and CV and prolonged APD in the setting of Pitx2-induced AF. Our findings of alterations in WL indicated that disopyramide may be more effective against Pitx2-induced AF than propafenone and quinidine by prolonging WL.

Keywords: Pitx2; action potential; atrial fibrillation; class I antiarrhythmic drugs; disopyramide; flecainide; in silico model; population of models; propafenone; quinidine.

Figure 1

A flow chart illustrating the process for in silico assessment of class I antiarrhythmic drug effects on Pitx2-induced atrial fibrillation (AF). Note: There are two distinct morphological subtypes of human atrial action potential (AP) [58] and therefore the Bai et al. model with a notch-and-dome AP morphology [27] and the Grandi et al. model with a triangular AP shape [59] were used in the present study. Class I antiarrhythmic drugs assessed include quinidine, disopyramide, and propafenone. Abbreviations: Pitx2: Homeodomain transcription factor 2, SR: Sinus rhythm; dVdt_max: Maximum upstroke velocity, RMP: Resting membrane potential, APD₅₀ and APD₉₀: AP duration at 50% and 90%, respectively, CV: Conduction velocity, and WL: Wavelength.

Figure 2

The experimentally calibrated populations constructed with the Bai et al. model for sinus rhythm (SR, blue) and atrial fibrillation (AF, red) conditions. (a,b) Representative traces of action potential (AP) models in SR and Pitx2-induced AF conditions. (c,d) Distributions of AP biomarkers (including dVdt_max, RMP, APD₅₀, and APD₉₀) under SR and Pitx2-induced AF conditions.

Figure 3

The experimentally calibrated populations constructed with the Grandi et al. model for sinus rhythm (SR, blue) and atrial fibrillation (AF, red) conditions. (a,b) Representative traces of action potential (AP) models in SR and Pitx2-induced AF conditions. (c,d) Distributions of AP biomarkers (including dVdt_max, RMP, APD₅₀, and APD₉₀) under SR and Pitx2-induced AF conditions.

Figure 4

Partial correlation coefficients (PPCs) between biomarkers (dVdt_max or APD₉₀) and parameters associated with Pitx2-induced electrical remodelling (G_Na, G_CaL, G_Ks, G_K1, G_rel, and G_up) or actions (G_Na, G_CaL, G_to, G_Ks, G_Kr, G_Kur, G_KATP, G_KAch,Ado, and G_K1) of antiarrhythmic drugs. PPCs between dVdt_max and G_Na, G_CaL, G_Ks, G_K1, G_Kr, G_to, G_Kur, G_KATP, G_KAch,Ado, G_rel, or G_up for the virtual atrial myocytes created by the Bai et al. model in SR (a, blue) and AF (b, red) are compared to those for virtual atrial myocytes in the SR (c, blue) and AF (d, red) populations created by the Grandi et al. model. PPCs of APD₉₀ for virtual atrial SR (e, blue) and AF (f, red) myocyte populations created by the Bai et al. model are compared to those for the virtual atrial myocytes created by the Grandi et al. model in SR (g, blue) and AF (h, red).

Figure 5

Effects of low (L), medium (M), and high (H) doses of disopyramide (Diso), quinidine (Quin), and propafenone (Prop) on the atrial fibrillation (AF) population. Using the Bai et al. model, simulated changes in APD90 (a) and dVdtmax (b) following the application of drugs at different doses in comparison to the drug-free conditions in the AF population or in the normal population for sinus rhythm (SR). Using the Grandi et al. model, ranges of APD90 (c) and dVdtmax (d) in conditions of drug-free SR, drug-free AF, AF in the presence of disopyramide at low (Diso_L), medium (Diso_M), and high (Diso_H) doses, AF in the presence of quinidine at low (Quin_L), medium (Quin_M), and high (Quin_H) doses, and AF in the presence of propafenone at low (Prop_L), medium (Prop_M), and high (Prop_H) doses. Each boxplot represents the range covered by the ionic conductances: The edges of the box are the 1st and 3rd quartiles, the whiskers extend to the most extreme datapoints, the estimated median physiological value is the central horizontal line and the notch around the median is the 5% significance level (Mann–Whitney U test: * p < 0.05; ** p < 0.01; *** p < 0.001).

Figure 6

Effects of low (L), medium (M), and high (H) doses of disopyramide (Diso), quinidine (Quin), and propafenone (Prop) on the virtual tissue population for atrial fibrillation (AF). Using the Bai et al. model, simulated changes in conduction velocity (CV, a) and wavelength (WL, b) following the applications of drugs at different doses in comparison to the drug-free conditions in the AF population or in the normal population for sinus rhythm (SR). Using the Grandi et al. model, ranges of CV (c) and WL (d) in conditions of drug-free SR, drug-free AF, AF in the presence of disopyramide at low (Diso_L), medium (Diso_M), and high (Diso_H) doses, AF in the presence of quinidine at low (Quin_L), medium (Quin_M), and high (Quin_H) doses, and AF in the presence of propafenone at low (Prop_L), medium (Prop_M), and high (Prop_H) doses. Each boxplot represents the range covered by the ionic conductances: The edges of the box are the 1st and 3rd quartiles, the whiskers extend to the most extreme datapoints, the estimated median physiological value is the central horizontal line and the notch around the median is the 5% significance level (Mann–Whitney U test: * p < 0.05; ** p < 0.01; *** p < 0.001).