Department of Electronic Engineering, College of Information Science and Technology, Jinan University, Guangzhou 510632, China.
Auckland Bioengineering Institute, University of Auckland, Auckland 1010, New Zealand.
Int J Mol Sci. 2021 Jan 27;22(3):1265. doi: 10.3390/ijms22031265.
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.
电重构是同源结构域转录因子 2（Pitx2）依赖性基因调节的结果，与心房颤动（AF）有关，并且在 4q25 染色体上具有单核苷酸多态性的 AF 患者对 I 类抗心律失常药物（AADs）反应良好。其背后的可能原因仍不清楚。本研究的目的是使用具有多通道药理学的药物结合模型，从单细胞到组织水平，评估 AAD 地尔硫卓、奎尼丁和普罗帕酮对由 Pitx2 诱导的重构介导的人类心房心律失常的疗效。通过使用两种不同的模型来代表动作电位（AP）的形态亚型，构建了窦性节律（SR）和 Pitx2 诱导的 AF 条件下的人类心房动作电位（AP）模型的实验校准群体。考虑了地尔硫卓、奎尼丁和普罗帕酮对离子电流的多通道药理作用。模拟结果表明，Pitx2 诱导的重构增加了最大上升速度（dVdtmax），并降低了 AP 持续时间（APD）、传导速度（CV）和波长（WL）。在本研究中测试的浓度下，这些 AAD 在 Pitx2 诱导的 AF 中降低了 dVdtmax 和 CV 并延长了 APD。我们对 WL 变化的发现表明，与普罗帕酮和奎尼丁相比，地尔硫卓可能通过延长 WL 对 Pitx2 诱导的 AF 更有效。
