Deciphering inheritable drivers of atrial arrhythmia, from cellular microdomains in models to phenotypes in patients

Background and Aim: Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is a frequent symptom of inheritable cardiac arrhythmia syndromes. The clinical picture of AF develops due to a multitude of mechanisms which are aggravated by external factors and comorbidities, complicating explanatory research. Hence, studying inheritable drivers of atrial arrhythmia represents a valuable approach to pinpoint molecular pathomechanisms of AF. Aim of this thesis therefore was to gain knowledge on atrial arrhythmia mechanisms driven by genetic predisposition. Additionally, we set out to investigate the impact of elevated androgenic steroid concentrations as an extrinsic factor. Methods: Clinical observations were used as a basis for murine experimental study designs. Employing two murine models, one for arrhythmogenic right ventricular cardiomyopathy (ARVC) and one for familial AF, enabled us to study atrial arrhythmia mechanisms at different scale, from in vivo to ex vivo, from the living animal to ion channels in atrial cardiomyocytes. Effects of the mutations and interventions on atrial structure, function and electrophysiology were revealed by a variety of methods, including echocardiography, electrocardiograms (ECGs), optical mapping, monophasic action potential recordings, histology, RNA sequencing and super-resolution microscopy. Moreover, atrial involvement in human ARVC was studied in digital patient ECGs. Results and Conclusions: Atrial arrhythmias are a common clinical feature of ARVC and are accompanied by impaired conduction, observed in both, patients and the murine model. Vulnerable desmosomes and increased concentrations of androgenic steroids jointly impair atrial conduction and cardiac sodium current. The studied point mutation of the cardiac sodium channel alpha-subunit Nav1.5, associated with familial AF, leads to a gain-of-function and atria show a blunted response to the clinically used sodium channel blocker flecainide. Our findings underline that murine models represent a valuable tool to decipher drivers of atrial arrhythmia seen in patients.