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

心房颤动（AF）是最常见的持续性心律失常。AF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。尽管最近在房颤的管理方面取得了进展，但房颤发生和持续的机制仍不完全清楚。左心房的电重构和结构重构代表AF进展的标志，其特征在于不应期缩短、左心房增大和纤维化。越来越多的证据支持炎症在AF病理生理学中的作用。然而，炎症途径、AF进展和心房重塑之间的因果关系仍有待确定。本项目旨在通过解决房颤起始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。第一部分着重于表征心房重构中涉及的全身和局部炎症通路。为此，将在AF患者的血液样本中研究与临床AF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形成和炎症之间潜在联系的意义。此外，房颤进展动物模型心房组织中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。这些发现将有助于确定心房纤维化病理生理学中涉及的特定炎症通路，从而确定房颤预防和治疗的潜在新靶点。该项目的第二部分讨论了消融后炎症对房性快速性心律失常（ERAT）早期复发的影响。导管消融术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，由短暂的炎症过程引起。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进行研究，具有良好的疗效和安全性。PFA后的炎症反应迄今尚未被描述。PFA具有组织选择性，与传统射频消融（RFA）相比，可产生更均匀的消融损伤。因此，PFA可能引起炎症反应减少，这可能转化为较低的ERAT率。为了检验这一假设，将在临床研究中比较PFA和RFA后炎症生物标志物的血浆水平和ERAT的发生率。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价。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确立为临床标准。

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.