Regional specific changes in cardiac resident 1 macrophages and 2 fibroblasts modulate long-term atrial fibrillation maintenance

Most of the mechanistic insights into atrial fibrillation (AF) pathophysiology have been reported on cardiomyocytes, and it is commonly assumed that such apply in the same manner to the atria as a whole. This study shows that 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. Radiofrequency delivery at driver regions can terminate the arrhythmia in pigs and achieve long-term arrhythmia AF-free survival in patients. Importantly, driver regions show overt compositional shifts in fibroblasts and myeloid populations that are highly consistent across pig models and patients. More specifically, 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. In fibroblasts, PTX3 represented a transcriptional hallmark exclusively present in driver regions, which supports their role on modulating the immune response of the surrounding tissue.