Atrial remodelling and atrial fibrillation self-sustaining: the role of circulating circDGCR8

Abstract Aims The prediction of atrial fibrillation (AF) progression and post-ablation recurrence is currently based on empirical estimates, leading to suboptimal predictive accuracy. This study investigates whether atrial remodelling, a key factor in the severity of atrial cardiomyopathy, could serve as a shared substrate influencing both AF progression and recurrence. We aimed to identify circular RNAs (circRNAs) associated with atrial remodelling and to evaluate their ability to predict AF progression and recurrence. Methods and results We assessed the differential expression of plasma circRNAs between paroxysmal (PAF) and persistent AF (PsAF) patients using microarray analysis. Selected candidate circRNAs were validated through qPCR following rigorous statistical and bioinformatics analysis. circDGCR8 was consistently found to be up-regulated in PsAF compared with PAF patients. Additionally, circDGCR8 was significantly up-regulated in human atrial fibroblasts treated with angiotensin II (AngII). Gain- and loss-of-function studies suggested that circDGCR8 could promote atrial remodelling at cellular level by enhancing collagen production and fibroblast proliferation. Overexpression of circDGCR8 in human cardiac fibroblasts significantly altered the gene expression spectrum, impacting pathways including IL-17 signalling and TNF signalling. Moreover, circDGCR8 levels were positively correlated with atrial fibrosis, as indicated by increased percentages of low voltage zones. The predictive value of circDGCR8 was evaluated in two cohorts: (i) PAF patients monitored for 36 months with progression to PsAF as the endpoint, and (ii) AF patients who underwent radiofrequency ablation followed for 12 months to assess recurrence. In both cohorts, higher level of circDGCR8 was associated with increased risks of AF progression and post-ablation recurrence. Conclusion Our results suggest that circDGCR8, associated with atrial remodelling, holds potential as a predictive biomarker for both AF progression and post-ablation recurrence.