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

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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.