Multiplatform modeling of atrial fibrillation identifies phospholamban as central regulator of cardiac rhythm.

Atrial fibrillation (AF) is a common and genetically inheritable form of cardiac arrhythmia; however, it is currently not known how these genetic predispositions contribute to the initiation and/or maintenance of AF-associated phenotypes. One major barrier to progress is the lack of experimental systems enabling to rapidly explore gene function on rhythm parameters in models with human atrial and whole organ relevance. Here, we assembled a multi-model platform enabling 1) the high-throughput characterization of gene function on action potential duration and rhythm parameters using human iPSC-derived atrial-like cardiomyocytes and the Drosophila heart model, and 2) the validation of the findings using computational models of human adult atrial myocytes and tissue. As proof of concept, we screened 20 AF-associated genes and identified Phospholamban loss of function as a top conserved hit that shortens action potential duration and increases the incidence arrhythmia phenotypes upon stress. Mechanistically, our study reveals that Phospholamban regulates rhythm homeostasis by functionally interacting with L-type calcium channels and NCX. In summary, our study illustrates how a multi-model system approach paves the way for the discovery and molecular delineation of gene regulatory networks controlling atrial rhythm with application to AF.