Mechanisms Underpinning Afterload-Induced Atrial Fibrillation

后负荷诱发心房颤动的机制

• 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
• 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

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 心房颤动（AF）是成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）和纤维化导致异常冲动产生和紊乱 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， 增加后负荷或心脏必须对抗的压力。此外，NLRP3炎性小体已经被发现， 在房颤患者中被持续激活，然而，激活机制尚未得到解释。 尽管其患病率不断增加，但AF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，并且未能解决AF的因果机制，包括 功能失调的aCM和纤维化预防性策略仅限于管理潜在的条件。 鉴于房颤本质上是进行性的，在易感患者中预防其发作可能会产生更好的结局 并显著提高患者生存率。因此，我们的目标是研究潜在的机制， 以及后负荷诱导的房颤中观察到的结构重塑，以确定可能的上游靶点。整体 假设细胞-凝胶EHT平台的后负荷升高将重现压力超负荷 见于慢性高血压和心力衰竭。EHT后负荷的增加将激活 NLRP3炎性体，导致CF活化，促纤维化信号级联，和 在AF发展中观察到的电生理和结构重塑。为了实现这一目标，我们将利用 AF的新生理相关模型。工程化心脏组织，由脱细胞人心房肌组成 用hiPSC衍生的aCM和心脏成纤维细胞再细胞化的组织，将重现异质性， 复杂的结构和天然心房心肌的功能。这块组织将被包裹在一个坚硬的聚乙烯 酒精水凝胶将施加多轴应力。这将模拟高血压中所见的后负荷增加。 这种新的平台将为该领域提供一种新的相关的人类AF体外模型。 负载对照工程化组织中的AF样重塑沿着NLRP 3-/-组织。这些实验将 确定后负荷和NLRP 3炎性体在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，并积极努力降低其患病率。