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.

Jieyun Bai,Yijie Zhu,Yaosheng Lu,Henggui Zhang,Meng Gao,Andy Lo,Jichao Zhao

doi:10.3390/ijms22031265

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.

Highlights

Atrial fibrillation (AF) incidence increases with age, and with the context of concomitant cardiac pathologies [1], population-based genome-wide association studies (GWASs) showed that one-third of atrial fibrillation (AF) patients carry common genetic variants, suggesting that AF has a heritable component [2]
Many AF-associated loci were identified in GWASs [3,4,5,6,7,8,9] and the most common AF susceptibility locus first identified in European, Chinese, and Japanese populations is located on chromosome 4q25 [10]
Our models developed by the Bai et al model or the Grandi et al model predicted that all drugs reduced dVdtmax and APD90 to different extents

Summary

Introduction

Atrial fibrillation (AF) incidence increases with age, and with the context of concomitant cardiac pathologies [1], population-based genome-wide association studies (GWASs) showed that one-third of AF patients carry common genetic variants, suggesting that AF has a heritable component [2]. Many AF-associated loci were identified in GWASs [3,4,5,6,7,8,9] and the most common AF susceptibility locus first identified in European, Chinese, and Japanese populations is located on chromosome 4q25 [10]. Pitx suppresses left atrial automaticity and the formation of “sinus node-like structures” in the left atrium [21] and contributes to the formation of the pulmonary vein myocardium [13]. Pitx is mainly expressed in the left atrium and pulmonary vein [11]. Experimental studies of Pitx2-induced AF have indicated that the downregulation of Pitx creates a predisposition to AF without marked structural changes in the atria [11,15,18,22] via shortened atrial repolarisation [22], a more depolarised resting membrane potential (RMP) [18], and abnormalities in calcium cycling [17,23,24]

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