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.

项目摘要房颤（AF）是成年人中最常见的持续性心律失常。在AF中，功能失调的心房心房壁内的心肌细胞（ACM）和纤维化导致异常脉冲产生和混乱波前传播，防止了协调的心房收缩，最终增加了患者的血栓栓塞中风和心力衰竭。高血压使患者患有AF 增加后负载或压力必须对抗。此外，NLRP3炎性体已经然而，证明在AF患者中持续激活，激活机制尚未解释。尽管越来越普遍，AF治疗仍然不足。临床上可用的抗凝剂和抗心律失常药物具有危险的副作用，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基本条件。鉴于AF本质上是渐进的，因此防止易感患者的发作可能会产生更好的结果并显着改善患者的生存。因此，我们旨在研究电气的基础机制以及在后载引起的AF中看到的结构重塑，以识别可能的上游目标。总体假设是，在电池内电池EHT平台中的升高将概括压力超负荷在慢性高血压和心力衰竭中可见。 EHT上载荷的增加将激活 NLRP3炎性体，导致CF激活，促纤维化信号级联和电生理和结构重塑在AF发育中可见。为了实现这一目标，我们将利用新型AF的生理相关模型。设计的心脏组织，由脱细胞的人心房组成用hipsc衍生的ACM和心脏成纤维细胞对组织进行覆盖，将概括异质性，本地心肌的复杂结构和功能。该组织将被包裹在刚性的聚乙烯基中酒精水凝胶将施加多轴应力。这将模仿高血压中看到的后负荷增加。这个新颖的平台将为该领域提供人类AF的新型体外模型。我们会观察与NLRP3 - / - 组织一起在负载控制的组织组织中进行AF状重塑。这些实验会确定后负载的关键作用和NLRP3炎症体在AF发育中。这项研究可以阐明AF发生的稳定上升，并积极努力降低其流行率。