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Article

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

by
Jieyun Bai
1,*,†,
Yijie Zhu
1,†,
Andy Lo
2,
Meng Gao
3,*,
Yaosheng Lu
1,*,
Jichao Zhao
2 and
Henggui Zhang
4
1
Department of Electronic Engineering, College of Information Science and Technology, Jinan University, Guangzhou 510632, China
2
Auckland Bioengineering Institute, University of Auckland, Auckland 1010, New Zealand
3
Department of Computer Science and Technology, College of Electrical Engineering and Information, Northeast Agricultural University, Harbin 150030, China
4
Biological Physics Group, School of Physics and Astronomy, The University of Manchester, Manchester M13 9PL, UK
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2021, 22(3), 1265; https://doi.org/10.3390/ijms22031265
Submission received: 23 November 2020 / Revised: 17 January 2021 / Accepted: 18 January 2021 / Published: 27 January 2021
(This article belongs to the Special Issue Electrophysiology)
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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: action potential; atrial fibrillation; in silico model; population of models; class I antiarrhythmic drugs; flecainide; disopyramide; quinidine; propafenone; Pitx2 action potential; atrial fibrillation; in silico model; population of models; class I antiarrhythmic drugs; flecainide; disopyramide; quinidine; propafenone; Pitx2
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MDPI and ACS Style

Bai, J.; Zhu, Y.; Lo, A.; Gao, M.; Lu, Y.; Zhao, J.; Zhang, H. 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. Int. J. Mol. Sci. 2021, 22, 1265. https://doi.org/10.3390/ijms22031265

AMA Style

Bai J, Zhu Y, Lo A, Gao M, Lu Y, Zhao J, Zhang H. 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. International Journal of Molecular Sciences. 2021; 22(3):1265. https://doi.org/10.3390/ijms22031265

Chicago/Turabian Style

Bai, Jieyun, Yijie Zhu, Andy Lo, Meng Gao, Yaosheng Lu, Jichao Zhao, and Henggui Zhang. 2021. "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" International Journal of Molecular Sciences 22, no. 3: 1265. https://doi.org/10.3390/ijms22031265

APA Style

Bai, J., Zhu, Y., Lo, A., Gao, M., Lu, Y., Zhao, J., & Zhang, H. (2021). 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. International Journal of Molecular Sciences, 22(3), 1265. https://doi.org/10.3390/ijms22031265

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