Mapping the maze: advancing atrial fibrillation models and therapies

Abstract

This thesis addresses atrial fibrillation (AF), the most common cardiac arrhythmia and a major contributor to morbidity, mortality, and healthcare costs. AF arises from complex interactions between electrical triggers and an arrhythmogenic atrial substrate, and current rhythm-control strategies are insufficient for many patients, particularly those with long-standing persistent AF. The clinical component of this work evaluates thoracoscopic epicardial ablation as a treatment strategy in this challenging population. Thoracoscopic ablation proved effective in restoring sinus rhythm, with comparable short-term outcomes between clamping and non-clamping devices. Long-term follow-up demonstrated durable rhythm control up to five years, especially when complemented by selective endocardial touch-up procedures, resulting in substantial reductions in AF burden and antiarrhythmic drug use. In addition, this thesis aims to improve human in vitro models of AF. While human atrial tissue slices showed high variability and limited culture success, a novel conditional immortalization strategy enabled the generation of human immortalized atrial myocytes (hiAMs). These cells closely resemble primary human atrial myocytes, exhibit signs of electrophysiological maturity, and support reproducible modeling and pharmacological termination of fibrillatory activity, providing a powerful platform for translational AF research.