Mechanisms Underpinning Afterload-Induced Atrial Fibrillation

后负荷诱发心房颤动的机制

基本信息

批准号：
10679796
负责人：
Daphne Agostina Diloretto
金额：
$ 4万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10679796
关键词：
3-Dimensional Action Potentials Address Adhesions Adult Affect Animal Model Anti-Arrhythmia Agents Anticoagulants Arrhythmia Atrial Fibrillation Biochemical Biomedical Engineering CRISPR/Cas technology Cardiac Cardiac Myocytes Cell Line Cell model Cells Chronic Clinical Clustered Regularly Interspaced Short Palindromic Repeats Complex Cues Dangerousness Development Diabetes Mellitus Electrophysiology (science)Extracellular Matrix Fibroblasts Fibrosis Gel Gene Silencing Generations Goals Heart Heart Atrium Heart failure Heterogeneity Human Human Engineering Hypertension Image Inflammasome Inflammation Knowledge Mechanical Stress Mediating Mentors Mentorship Modeling Morphology Myocardial Myocardial Ischemia Myocardium Nature Obesity Outcome Pathway interactions Patients Persons Physicians Physiologic intraventricular pressure Physiological Physiology Play Polyvinyl Alcohol Predisposition Prevalence Prevention strategy Profibrotic signal Rattus Research Risk Role Scientist Stress Stretching Structure Techniques Testing Thrombosis Tissue Engineering Tissues Training Work cardiac tissue engineering comorbidity experimental study graduate student human embryonic stem cell human model human pluripotent stem cell human tissue improved in vitro Model induced pluripotent stem cell insight mechanical load mechanical signal multidisciplinary novel polyvinyl alcohol hydrogel pressure prevent side effect therapeutic target three dimensional cell culture thromboembolic stroke

项目摘要

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.

项目概要心房颤动（AF）是成人中最常见的持续性心律失常。在 AF 中，心房功能障碍心肌细胞 (aCM) 和心房壁内的纤维化导致异常脉冲产生和紊乱波前传播，阻止协调的心房收缩，最终增加风险患者的血栓栓塞性中风和心力衰竭。高血压使患者容易发生房颤，因为后负荷增加，或心脏必须抵抗的压力。此外，NLRP3 炎症小体已被研究显示在 AF 患者中持续激活，但激活机制尚未得到解释。尽管房颤的患病率不断上升，但房颤治疗仍然不足。临床可用的抗凝剂和抗心律失常药物具有危险的副作用，并且无法解决 AF 的因果机制，包括功能失调的 aCM 和纤维化。预防策略仅限于管理潜在的条件。鉴于房颤本质上是进行性的，预防易感患者发生房颤可能会产生更好的结果并显着提高患者的生存率。因此，我们的目标是研究电学的潜在机制以及在后载引起的 AF 中观察到的结构重塑，以识别可能的上游目标。整体假设凝胶细胞 EHT 平台中后负荷升高将重现压力过载见于慢性高血压和心力衰竭。 EHT 上后载的增加将激活 NLRP3 炎症小体，导致 CF 激活、促纤维化信号级联反应，以及房颤发展过程中出现的电生理学和结构重塑。为了实现这一目标，我们将利用 AF 的新型生理相关模型。工程心脏组织，由脱细胞人心房组成用 hiPSC 衍生的 aCM 和心脏成纤维细胞进行再细胞化的组织将重现异质性，天然心房心肌的复杂结构和功能。该组织将被包裹在坚硬的聚乙烯内酒精水凝胶将对其施加多轴应力。这将模仿高血压中所见的后负荷增加。这个新颖的平台将为该领域提供一种新的、相关的人类房颤体外模型。我们将观察负载对照工程组织以及 NLRP3-/- 组织中的 AF 样重塑。这些实验将确定后负荷和 NLRP3 炎症小体在 AF 发展中的关键作用。这项研究可以阐明房颤发生率的稳步上升并积极努力遏制其患病率。