Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and an important contributor to morbidity and mortality. Endothelial dysfunction has been postulated to be an important contributing factor in cardiovascular events in patients with AF. However, how vascular endothelial cells respond to arrhythmic flow is not fully understood, mainly due to the limitation of current in vitro systems to mimic arrhythmic flow conditions. To address this limitation, we developed a microfluidic system to study the effect of arrhythmic flow on the mechanobiology of human aortic endothelial cells (HAECs). The system utilises a computer-controlled piezoelectric pump for generating arrhythmic flow with a unique ability to control the variability in both the frequency and amplitude of pulse waves. The flow rate is modulated to reflect physiological or pathophysiological shear stress levels on endothelial cells. This enabled us to systematically dissect the importance of variability in the frequency and amplitude of pulses and shear stress level on endothelial cell mechanobiology. Our results indicated that arrhythmic flow at physiological shear stress level promotes endothelial cell spreading and reduces the plasma membrane-to-cytoplasmic distribution of β-catenin. In contrast, arrhythmic flow at low and atherogenic shear stress levels does not promote endothelial cell spreading or redistribution of β-catenin. Interestingly, under both shear stress levels, arrhythmic flow induces inflammation by promoting monocyte adhesion via an increase in ICAM-1 expression. Collectively, our microfluidic system provides opportunities to study the effect of arrhythmic flows on vascular endothelial mechanobiology in a systematic and reproducible manner.

中文翻译：

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研究心律失常血流对内皮细胞影响的微流体模型

心房颤动（AF）是最常见的心律失常类型，也是导致发病率和死亡率的重要因素。内皮功能障碍被认为是 AF 患者心血管事件的重要影响因素。然而，血管内皮细胞如何响应心律失常血流尚不完全清楚，这主要是由于当前体外系统模拟心律失常血流条件的限制。为了解决这一限制，我们开发了一种微流体系统来研究心律失常血流对人主动脉内皮细胞（HAEC）力学生物学的影响。该系统利用计算机控制的压电泵来产生心律失常流量，具有控制脉搏波频率和幅度变化的独特能力。调节流速以反映内皮细胞上的生理或病理生理剪切应力水平。这使我们能够系统地剖析脉冲频率和幅度以及剪切应力水平的可变性对内皮细胞力学生物学的重要性。我们的结果表明，生理剪切应力水平下的心律失常流动促进内皮细胞扩散并减少β-连环蛋白的质膜到细胞质的分布。相反，低水平和致动脉粥样化剪切应力水平下的心律失常血流不会促进内皮细胞扩散或β-连环蛋白的重新分布。有趣的是，在两种剪切应力水平下，心律失常血流通过增加ICAM-1 表达来促进单核细胞粘附，从而诱发炎症。总的来说，我们的微流体系统提供了以系统和可重复的方式研究心律失常流动对血管内皮力学生物学影响的机会。