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

房颤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，并与缺血性中风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不完全清楚。左房的电性和结构重构是房颤进展的标志，其特征是不应期缩短、左房增大和纤维化。越来越多的证据支持炎症在房颤病理生理学中的作用。然而，炎症通路、房颤进展和心房重构之间的因果联系仍有待确定。本项目旨在通过研究房颤的发生和发展的两个主要方面来探讨炎症在房颤发病中的作用。第一部分集中于描述参与心房重构的全身和局部炎症途径。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炎症的生物标志物以及作为血栓形成和炎症之间潜在联系的血小板-单核细胞相互作用的意义。此外，从房颤进展的动物模型中提取的心房组织中免疫细胞渗透的组织病理学检查将有助于从机制上深入了解局部炎症环境如何促进电解剖重构。这些发现将有助于确定与心房纤维化的病理生理学密切相关的特定炎症通路，从而确定预防和治疗房颤的潜在新靶点。该项目的第二部分阐述了消融后炎症对房性快速性心律失常(ERAT)早期复发的影响。导管消融是一种公认的有效的房颤治疗方法。然而，消融后ERAT非常常见，是由一过性炎症过程引起的。脉冲场消融(PFA)是一种新型的非热消融方式，目前正在进行临床试验研究，取得了良好的疗效和安全性。PFA后的炎症反应到目前为止还没有被描述。与传统的射频消融(RFA)相比，PFA具有组织选择性，可产生更均匀的消融损伤。因此，PFA可能会导致炎症反应减少，从而降低ERAT发生率。为了验证这一假说，在一项临床研究中，将比较PFA和RFA后血浆炎症生物标志物的水平和ERAT的发生率。此外，在PFA和RFA之后，将在动物模型中进行消融损伤中炎性细胞的组织病理学评估。明确PFA的炎症反应和早期复发率将有助于建立这种新的消融方式作为临床标准。

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.