Rationale Electrogram-based catheter ablation, targeting complex fractionated atrial electrograms (CFAEs), is empirically known to be effective in halting persistent/permanent atrial fibrillation (AF). However, the mechanisms underlying CFAEs and electrogram-based ablation remain unclear. Objective Because atrial fibrosis is associated with persistent/permanent AF, we hypothesized that electrotonic interactions between atrial myocytes and fibroblasts play an important role in CFAE genesis and electrogram-based catheter ablation. Methods and Results We used a human atrial tissue model in heart failure and simulated propagation and spiral wave reentry with and without regionally proliferated fibroblasts. Coupling of fibroblasts to atrial myocytes resulted in shorter action potential duration, slower conduction velocity, and lower excitability. Consequently, heterogeneous fibroblast proliferation in the myocardial sheet resulted in frequent spiral wave breakups, and the bipolar electrograms recorded at the fibroblast proliferation area exhibited CFAEs. The simulations demonstrated that ablation targeting such fibroblast-derived CFAEs terminated AF, resulting from the ablation site transiently pinning the spiral wave and then pushing it out of the fibroblast proliferation area. CFAEs could not be attributed to collagen accumulation alone. Conclusions Fibroblast proliferation in atria might be responsible for the genesis of CFAEs during persistent/ permanent AF. Our findings could contribute to better understanding of the mechanisms underlying CFAE-targeted AF ablation.

BackgroundEffects of nonparoxysmal atrial fibrillation (non‐PAF) ablation targeting complex fractionated atrial electrogram (CFAE) areas and/or low voltage areas (LVAs) are still controversial.Methods and ResultsA recently developed online real‐time phase mapping system (ExTRa Mapping) was used to conduct LVA mapping and simultaneous ExTRa and CFAE mapping in 28 non‐PAF patients after pulmonary vein isolation (PVI). Nonpassively activated areas, in the form of meandering rotors and/or multiple wavelets assumed to contain non‐PAF drivers, partly overlapped with CFAE/LVAs but not always coincided with them.ConclusionReal‐time rotor imaging, rather than conventional indirect indicators only, might be very useful for detecting non‐PAF drivers.