The Role of Fibroblasts in Complex Fractionated Electrograms During Persistent/Permanent Atrial Fibrillation

Abstract

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.

Not all rotors, effective ablation targets for nonparoxysmal atrial fibrillation, are included in areas suggested by conventional indirect indicators of atrial fibrillation drivers: ExTRa Mapping project

“…Combined with the timing of the action potential onset determined by the intra‐atrial signals, the in silico part calculated the virtual atrial action potentials based on the in silico model of human non‐PAF 5. Therefore, the virtual action potentials during non‐PAF could faithfully reproduce the restitution properties of human atria under structural remodeling.…”

Fibroblast Inward-Rectifier Potassium Current Upregulation in Profibrillatory Atrial Remodeling

“…14,15 Although the importance of fibroblast-cardiomyocyte coupling in vivo is still controversial, mathematical modeling work suggests that it may account for complex fractionated electrogram properties in fibrotic tissues. 16 We have recently evaluated the effects of fibroblast ion channel remodeling on the potential electric and arrhythmogenic interactions between coupled fibroblasts and cardiomyocytes, finding that if fibroblasts were well coupled to cardiomyocytes, fibroblast Kv current downregulation would suppress the AFsubstrate, whereas Kir current upregulation would enhance it. 17 We have also obtained evidence for a profibrotic role of Kv current downregulation, although the underlying mechanism is unclear.…”

Principles of Cardiac Electric Propagation and Their Implications for Re-entrant Arrhythmias

“…Interestingly, although focal ablation at a rotor core does not produce circuit transection and direct termination, it has been shown that focal ablation can increase the range over which a rotor core meanders. 23 This can ultimately produce rotor collision with a tissue boundary and, therefore, circuit interruption; thus, focal ablation can indirectly result in rotor annihilation.…”