Excerpt

Atrial fibrillation (AF) is the most frequent arrhythmia in the clinical setting and is associated with substantial cardiac morbidity and mortality [19]. Current drug interventions have limited efficacy and are accompanied by significant risk of proarrhythmic events [9]. The generally poor outcome with current antiarrhythmic drugs likely reflects the fact that most of the used agents were developed in the absence of precise understanding of pro- and anti-arrhythmic drug actions and the arrhythmogenic disease-specific cardiac substrate. Conceptually, AF induction requires a vulnerable substrate and a trigger that acts on the substrate to initiate the arrhythmia [25, 35]. Once AF is initiated, the rapid-atrial rate creates progressive AF-related changes in atrial electrical and structural properties (atrial remodeling). Electrical remodeling involves a shortening of the atrial effective refractory period (AERP) and abnormal atrial Ca²⁺ signaling, whereas increased atrial fibrosis and heterogeneous conduction slowing are typical characteristics of structural remodeling. Atrial remodeling can promote ectopic (triggered) activity and facilitate reentry, thereby contributing to AF perpetuation and the progression from short-lasting (paroxysmal) to long-standing persistent AF [7, 10, 25, 26, 35], which makes AF more resistant to both pharmacological and non-pharmacological therapeutic approaches. Therefore, it is assumed that a better understanding of the molecular mechanisms underlying AF maintenance will help to design novel drugs with improved efficacy and safety profiles [8]. …