Trapped re-entry: a dormant source of arrhythmia
Authors: De Coster T , Teplenin AS , Feola I , Van Brakel T , Zeppenfeld K , Ypey D , Panfilov AV , De Vries AAF , Pijnappels DA 
Published: May 2022

Funding Acknowledgements

Type of funding sources: Public grant(s) – EU funding. Main funding source(s): This study was supported by the European Research Council (Starting grant 716509) to D.A. Pijnappels.

Background

Diseased atria are characterized by functional and structural heterogeneities (e.g. dense fibrotic regions), which add to abnormal impulse generation and propagation, like ectopy and block. These heterogeneities are thought to play a role in the origin of complex fractionated atrial electrograms (CFAEs) under sinus rhythm (SR) in patients with atrial fibrillation (AF), but also in the onset and perpetuation (e.g. re-entry) of this disorder. The underlying mechanisms, however, remain incompletely understood.

Objective

To test the hypothesis that dense local fibrotic regions can create an electrically isolated conduction pathway in which re-entry can be established via ectopy and block to become "trapped" (giving rise to CFAEs under SR), only to be "released" under dynamic tissue changes at a connecting isthmus (causing acute onset of arrhythmia).

Methods

The geometry of such a pathway, under which re-entry could be trapped and released, was explored in vitro using optogenetics by creating conduction blocks of any shape by means of light-gated depolarizing ion channels (CatCh) and patterned illumination. Insight from these studies was used for complementary investigation in a digital twin of the human atria to assess clinical relevance.

Results

Optical mapping studies, in monolayers of CatCh-activated neonatal rat atrial cardiomyocytes, revealed that re-entry can be established and trapped by creating an electrically isolated pathway with a bulk-connecting isthmus causing source-sink mismatch. A tachyarrhythmia was shown to exist locally with SR prevailing in the bulk of the monolayer. Next, conditions were found under which re-entry could escape this pathway, thereby converting a local dormant arrhythmic source into an active driver with global impact. Escape could be established by overcoming the source-sink mismatch through widening of the isthmus or a reduction of the gap junctional coupling. In a digital twin of the human atria, it was revealed that the conditions for "trapped re-entry" and its release can be realized as well. Unipolar pseudo-electrograms derived from these complementary computational 3D studies showed CFAEs at the site of "trapped re-entry" in coexistence with normal electrograms of SR in the bulk of the atria. Upon release of the re-entry, acute arrhythmia onset occurred, affecting the complete atria as evidenced by wave front and electrogram visualization.

Conclusion

This study reveals that "trapped re-entry", a previously undesignated phenomenon, can explain the observation of two designated ones: CFAEs under SR and acute arrhythmia onset. Further exploration of the concept of "trapped re-entry" may not only expand our understanding of AF initiation and perpetuation, but also termination, including ablation strategies by site-directed targeting.