The role of inflammation in the pathogenesis of atrial fibrillation: Implications for atrial remodeling pathophysiology and for early atrial arrhythmia recurrences following radiofrequency ablation and pulsed field ablation

炎症在心房颤动发病机制中的作用：对心房重塑病理生理学以及射频消融和脉冲场消融后早期房性心律失常复发的影响

• 批准号: 514892030
• 负责人: Dr. Miruna-Andreea Popa
• 金额: --
• 依托单位: Klinik für Herz- und Kreislauferkrankungen
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 财政年份: 2023
• 资助国家: 德国
• 起止时间: 2022-12-31 至 2023-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/514892030?language=en
• 关键词: role; inflammation; pathogenesis; atrial; fibrillation

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. AF is associated with significant morbidity and mortality and correlates with an increased risk for ischaemic stroke and heart failure. Despite recent advances in the management of AF, the mechanisms of AF initiation and perpetuation remain incompletely understood. Electrical and structural remodeling of the left atrium represents a hallmark of AF progression and is characterized by a shortened refractory period, left atrial enlargement and fibrosis. Increasing evidence supports the role of inflammation in AF pathophysiology. However, causal links between inflammatory pathways, AF progression and atrial remodeling remain to be defined. This project aims to investigate the role of inflammation in AF pathogenesis by addressing two major aspects of AF initiation and progression. The first part focusses on characterizing systemic and local inflammatory pathways involved in atrial remodeling. For this purpose, biomarkers of systemic inflammation associated with clinical AF progression and the significance of platelet-monocyte-interactions as a potential link between thrombosis and inflammation will be investigated in blood samples of AF patients. In addition, histopathologic examination of immune cell infiltrates in atrial tissue derived from an animal model of AF progression will allow mechanistic insights into how the local inflammatory environment contributes to electroanatomic remodeling. These findings will help define specific inflammatory pathways causally involved in the pathophysiology of atrial fibrosis and thus identify potential novel targets for AF prevention and therapy. The second part of the project addresses the effect of post-ablation inflammation on early recurrence of atrial tachyarrhythmia (ERAT). Catheter ablation is an established and effective AF therapy. However, ERAT is very common after ablation, being caused by transient inflammatory processes. Pulsed field ablation (PFA) is a novel non-thermal ablation modality which is currently studied in clinical trials with promising efficacy and safety results. The inflammatory response following PFA has not been described so far. PFA is tissue-selective and generates more homogeneous ablation lesions as compared to conventional radiofrequency ablation (RFA). Therefore, PFA may elicit a reduced inflammatory reaction which could translate into lower ERAT rates. In order to test this hypothesis, plasma levels of inflammatory biomarkers and the incidence of ERAT will be compared after PFA and RFA in a clinical study. Furthermore, histopathologic evaluation of inflammatory cells in ablation lesions will be conducted in an animal model following PFA and RFA. Defining the inflammatory response and early recurrence rate of PFA will contribute to establishing this novel ablation modality as a clinical standard.

心房颤动（AF）是最常见的持续性心律失常。房颤与显著的发病率和死亡率相关，并与缺血性卒中和心力衰竭的风险增加相关。尽管最近在房颤的治疗方面取得了进展，但房颤的发生和持续的机制仍然不完全清楚。左心房电和结构重构是房颤进展的标志，其特征是不应期缩短、左心房增大和纤维化。越来越多的证据支持炎症在房颤病理生理中的作用。然而，炎症途径、房颤进展和心房重构之间的因果关系仍有待明确。本项目旨在通过解决房颤发生和进展的两个主要方面来研究炎症在房颤发病机制中的作用。第一部分的重点是表征系统性和局部炎症途径参与心房重构。为此，将在房颤患者的血液样本中研究与临床房颤进展相关的全身性炎症的生物标志物，以及血小板-单核细胞相互作用作为血栓和炎症之间潜在联系的意义。此外，对AF进展动物模型中心房组织免疫细胞浸润的组织病理学检查将有助于了解局部炎症环境如何促进电解剖重构的机制。这些发现将有助于确定与心房纤维化病理生理相关的特定炎症途径，从而确定房颤预防和治疗的潜在新靶点。该项目的第二部分探讨消融后炎症对房性心动过速（ERAT）早期复发的影响。导管消融是一种成熟有效的房颤治疗方法。然而，ERAT在消融后非常常见，是由短暂的炎症过程引起的。脉冲场消融（PFA）是一种新型的非热消融方式，目前正在临床试验中，具有良好的疗效和安全性。PFA后的炎症反应至今未见报道。与传统射频消融（RFA）相比，PFA具有组织选择性，产生更均匀的消融病变。因此，PFA可能引起炎症反应的减少，这可能转化为更低的ERAT率。为了验证这一假设，将在临床研究中比较PFA和RFA后的血浆炎症生物标志物水平和ERAT发生率。此外，将在PFA和RFA后的动物模型中对消融病变中的炎症细胞进行组织病理学评估。明确PFA的炎症反应和早期复发率将有助于将这种新型消融方式建立为临床标准。