Department of Medicine I / Cardiology

Atrial fibrillation (AF) is the most common arrhythmia worldwide and is associated with significant morbidity and mortality (1-3). A number of known risk factors such as obesity or hypertension predispose to AF. Current therapy options for AF are limited (4). Anti-arrhythmic drug therapy has limited efficacy and may cause ventricular arrhythmia. Ablation therapies are effective in only 50% of patients with persistent AF and entail significant procedural risks (4). After cardioversion therapy or AF ablation, relapse is common, especially if there is underlying atrial enlargement and fibrosis. At present, there is no safe, efficient therapeutic that can prevent AF relapse, most likely since current treatment options are rather symptomatic than targeting causal mechanisms (5-7). However, developing causal therapies is a major challenge since the pathophysiology of AF is still incompletely understood (5-8).

AF is often associated with inflammatory conditions, i.e. it frequently occurs post cardiac surgery or in the context of comorbidities with chronic inflammatory response such as diabetes (9-11). These findings suggest that local immune cells may be important players in AF, especially since a growing body of evidence suggests cardiac macrophages as key mediators in electrophysiology, both in regulating the physiologic electrical conduction and proarrhythmogenic remodeling leading to arrhythmias (13-21). A recent study by Hulsmans et al. (13) showed that in patients with AF a large portion of cells in the atria are macrophages which was further confirmed in a novel mouse model for AF. In this model (HOMER model) they combined arterial hypertension, obesity and mitral valve regurgitation and could demonstrate a macrophage-mediated mechanism underlying the increased susceptibility for AF.

Although mouse models as the above mentioned HOMER mouse model are invaluable in basic cardiovascular research, they have several limitations, most importantly, these findings cannot be directly applied to human patients. For this purpose other large animal models (e.g. pigs) are needed that better resemble the human situation (22-27). Thus, we established the HOMER model in pigs and could confirm a strong AF phenotype in this novel preclinical model.

With the proposed project we want to (i) confirm findings from the HOMER mouse model in the HOMER pig model and (ii) to further investigate cellular mechanisms underlying arrhythmogenesis in HOMER pigs. Healthy control pigs, pigs with individual comorbidities (obesity, mitral valve regurgitation) or pigs with combined comorbidities (HOMER model) will be studied in vivo (e.g. ECG, implantable loop recorders, electrophysiology study to assess conduction properties, monophasic action potentials). Flow cytometry will be used to determine the number of immune cells (with focus on monocytes/macrophages) in the heart. Furthermore, primary cells will be isolated (cardiomyocytes and cardiac macrophages) for further cellular electrophysiology experiments (e.g. action potential measurements, calcium transient measurements), gene and protein expression studies (e.g. qPCR, western blot) and histologic analyses (e.g. fibrosis staining, immunofluorescence stainings) will be performed. This will allow a comprehensive characterization of proarrhythmogenic structural, electrical and immunological remodeling processes in this innovative close-to-human pig model.