Mechanisms Underpinning Afterload-Induced Atrial Fibrillation

项目总结 房颤是成人最常见的持续性心律失常。房颤时，心房功能不全 心肌细胞(ACM)和房壁内的纤维化导致异常的脉冲产生和组织紊乱 波前传播，阻止协调的心房收缩，最终增加 血栓栓塞性中风和心力衰竭患者。高血压使患者容易发生房颤，原因是 增加后负荷，或心脏必须抵抗的压力。此外，NLRP3炎症性小体已经 然而，在房颤患者中显示出持续的激活，然而，激活的机制尚未解释。 尽管房颤的患病率越来越高，但治疗仍然不足。临床上可用的抗凝剂和 抗心律失常药物有危险的副作用，无法解决房颤的致病机制，包括 ACM功能障碍和纤维化。预防性策略仅限于管理潜在情况。 鉴于房颤本质上是渐进性的，预防易感患者的发病可能会产生更好的结果 并显著提高患者的存活率。因此，我们的目标是研究电学背后的机制 以及在后负荷诱发的房颤中所见的结构重构，以确定可能的上游靶点。整体而言 假说是，凝胶细胞EHT平台中升高的后负荷将概括为压力超负荷 见于慢性高血压和心力衰竭。我们EHT上后负荷的增加将激活 NLRP3炎症小体，导致CF激活，促纤维化信号级联，以及 房颤发生过程中的电生理和结构重构。为了实现这一点，我们将利用 新的生理相关房颤模型。由脱细胞的人心房组成的工程化心脏组织 用hPSC来源的ACM和心脏成纤维细胞再细胞组织，将概括异质性， 天然心房心肌的复杂结构和功能。这种组织将被包裹在一层坚硬的聚乙烯薄膜中 酒精水凝胶会对其施加多轴应力。这将模拟高血压所见的增加的后负荷。 这一新的平台将为该领域提供一种新的、相关的人房颤体外模型。我们会观察到 加载对照工程组织中的房颤样重塑以及NLRP3-/-组织。这些实验将 确定后负荷和NLRP3炎症小体在房颤发生中的关键作用。这项研究可能 阐明房颤发病率的稳步上升，并积极努力降低其患病率。

PROJECT SUMMARY Atrial Fibrillation (AF) is the most common sustained arrhythmia among adults. In AF, dysfunctional atrial cardiomyocytes (aCMs) and fibrosis within the atrial wall result in abnormal impulse generation and disorganized wave front propagation, preventing a coordinated atrial contraction, ultimately increasing the risk of thromboembolic stroke and heart failure in patients. Hypertension predisposes patients to AF due to the increased afterload, or pressure the heart must work against. In addition, the NLRP3 inflammasome has been shown to be consistently activated in AF patients, however, the mechanism of activation has yet to be explained. Despite its growing prevalence, AF treatments remain inadequate. Clinically available anticoagulants and antiarrhythmic drugs have dangerous side effects and fail to address the causal mechanisms of AF, including the dysfunctional aCMs and fibrosis. Preventative strategies are limited to managing underlying conditions. Given that AF is progressive in nature, preventing its onset in susceptible patients may yield better outcomes and significantly improve patient survival. Therefore, we aim to investigate the mechanisms underlying electrical and structural remodeling seen in afterload-induced AF to identify possible upstream targets. The overall hypothesis is that elevated afterload in the cell-in-gel EHT platform will recapitulate pressure overload seen in chronic hypertension and heart failure. The increase in afterload on our EHT will activate the NLRP3 inflammasome, resulting in CF activation, pro-fibrotic signaling cascades, and electrophysiological and structural remodeling seen in AF development. To achieve this, we will utilize a novel physiologically relevant model of AF. Engineered heart tissue, composed of decellularized human atrial tissue recellularized with hiPSC derived aCMs and cardiac fibroblasts, will recapitulate the heterogeneity, complex structure, and functionality of native atrial myocardium. This tissue will be encased within a stiff polyvinyl alcohol hydrogel that will apply multiaxial stress to it. This will mimic the increased afterload seen in hypertension. This novel platform will provide the field with a new and relevant in vitro model of human AF. We will observe AF-like remodeling in loaded control engineered tissue along with an NLRP3-/- tissue. These experiments will determine the critical roles of afterload and the NLRP3 inflammasome in AF development. This research could elucidate the steady rise in AF occurrence and actively work to curtail its prevalence.