Latent drivers for atrial fibrillation and specific patterns of localized fibrosis

This editorial refers to ‘‘Trapped re-entry’ as source of acute focal atrial arrhythmias’, by T. De Coster et al., https://doi.org/10.1093/cvr/cvad179. The mechanisms for atrial fibrillation (AF) are uncertain but likely reflect an interplay between initiating triggers and sustaining mechanisms, which are often dichotomized in the literature.1 AF triggers represent rapid firing from the pulmonary veins, which are an established and predominant target for ablation therapy, and other sites. AF-sustaining mechanisms are less established and may comprise globally disorganized reentry or ‘chaotic’ beats, or a smaller number of localized drivers in the form of foci or reentrant sources that cause AF in surrounding tissue. Support for localized AF drivers is increasing, based on optical mapping of human atria,2 clinical studies,3 and emerging randomized trials,4 although mapping technologies remain suboptimal1 and clinical results mixed. Therapy of patients with AF could be advanced by better understanding how activity in localized arrhythmogenic sources could escape to ‘drive’ AF and by defining robust signatures for their identification. In this issue of Cardiovascular Research, De Coster et al. 5 show how reentry may be ‘trapped’ within localized fibrotic regions they term ‘electrically isolated conduction pathways (EICPs)’ and demonstrate conditions under which it ‘escapes’ to drive atrial arrhythmia. The authors used optogenetic stimulation of light-gated depolarizing ion channels in murine atrial monolayers and illumination to create specific patterns of non-conducting regions that model fibrotic isthmuses. These results showed reentry within EICPs ‘surrounded by’ sinus rhythm. Globally reducing sodium conductance (GNa) and narrower isthmuses promoted trapping, while reducing gap junctional coupling and wider isthmuses promoted escape. In a realistic 3D model of human atria with fibrosis, sites of ‘trapped reentry’ exhibited fractionated unipolar pseudoelectrograms. Escape of activation resulted in the acute onset of global tachyarrhythmias. The authors should be congratulated for identifying EICPs as potentially detectable substrates for latent arrhythmia sources, which blur the distinction between trigger and substrate. One immediate clinical implication is that EICP could be identified during AF ablation to provide a more targeted strategy. This extends ongoing efforts to map localized AF drivers6 by considering fibrotic signatures of EICP as well as electrical patterns of rotational activity. The ∼2 mm resolution of atrial MRI could obfuscate such efforts,7 and efforts should be made to identify their electrical signatures.8 An intriguing question is whether EICP could serve as latent triggers and be detected in sinus rhythm. Although latent reentries were not observed in optical mapping of human atria2 or preclinical models,1 those studies focused less on sinus rhythm than on AF. Certainly, fractionated electrograms in sinus rhythm are often seen in AF patients,8 and while they are assumed to indicate slow conduction, high-resolution mapping could probe if such sites could represent localized reentry. Indeed, localized AF has been reported as ‘an island within sinus rhythm’,9 and continuously fractionated electrical signals have been observed.8 Finally, these in vitro and modelling studies could be applied to the ventricle, where they could be implicated in ventricular arrhythmia storm. As with all innovative studies, certain limitations must be acknowledged as avenues for further research. Without clinical validation, it remains unclear if these elegant experimental mechanisms are generalizable to patients with AF. Moreover, ablation of these sites may not improve outcomes. The notion of preventing escape of localized reentrant sources has been modelled in human AF,10 although it remains unclear how this could be achieved. If higher pacing rates are expected to suppress the escape of trapped reentry from EICP, one might expect a reduction in AF episodes in patients with implanted pacemakers, which has not been widely observed11 but could be present in subsets. The authors should be congratulated for this exciting and provocative study showing that trapped reentry within EICP could be latent, localized sources for arrhythmias during sinus rhythm. In the case of AF, this blurs the distinction between triggers and substrates and could improve mapping for mechanistic ablation targets in patients in whom pulmonary vein isolation alone is unsuccessful. The next challenge is to develop methods to translate these concepts into clinical tools for mapping to design optimal pharmacological or ablative strategies for their elimination. No new data were generated or analysed in support of this editorial statement.