Atrial remodeling during persistent AF (PsAF) underlies differential adaptative changes in non-myocyte populations, which depend on the functional relevance of individual-specific atrial regions to drive the overall arrhythmia.Driver regions underlie a phenotypic shift towards cardiac resident macrophages with an associated transcriptomic and proteomic profile favoring cardiomyocyte homeostasis and cell survival within a substrate prone to reentry.