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. 2022 Jul 15;24(6):1015-1024.
doi: 10.1093/europace/euac026.

Endomysial fibrosis, rather than overall connective tissue content, is the main determinant of conduction disturbances in human atrial fibrillation

Bart Maesen  1   2 , Sander Verheule  2   3 , Stef Zeemering  2   3 , Mark La Meir  4 , Jan Nijs  4 , Stijn Lumeij  3 , Dennis H Lau  3 , Mathieu Granier  3 , Harry Jgm Crijns  2   5 , Jos G Maessen  1   2 , Stefan Dhein  6 , Ulrich Schotten  2   3
Affiliations

Endomysial fibrosis, rather than overall connective tissue content, is the main determinant of conduction disturbances in human atrial fibrillation

Bart Maesen et al. Europace. .

Abstract

Aims: Although in persistent atrial fibrillation (AF) a complex AF substrate characterized by a high incidence of conduction block has been reported, relatively little is known about AF complexity in paroxysmal AF (pAF). Also, the relative contribution of various aspects of structural alterations to conduction disturbances is not clear. In particular, the contribution of endomysial fibrosis to conduction disturbances during progression of AF has not been studied yet.

Methods and results: During cardiac surgery, epicardial high-density mapping was performed in patients with acutely induced (aAF, n = 11), pAF (n = 12), and longstanding persistent AF (persAF, n = 9) on the right atrial (RA) wall, the posterior left atrial wall (pLA) and the LA appendage (LAA). In RA appendages, overall and endomysial (myocyte-to-myocyte distances) fibrosis and connexin 43 (Cx43) distribution were quantified. Unipolar AF electrogram analysis showed a more complex pattern with a larger number of narrower waves, more breakthroughs and a higher fractionation index (FI) in persAF compared with aAF and pAF, with no differences between aAF and pAF. The FI was consistently higher at the pLA compared with the RA. Structurally, Cx43 lateralization increased with AF progression (aAF = 7.5 ± 8.9%, pAF = 24.7 ± 11.1%, persAF = 35.1 ± 11.4%, P < 0.001). Endomysial but not overall fibrosis correlated with AF complexity (r = 0.57, P = 0.001; r = 0.23, P = 0.20; respectively).

Conclusions: Atrial fibrillation complexity is highly variable in patients with pAF, but not significantly higher than in patients with acutely induced AF, while in patients with persistent AF complexity is higher. Among the structural alterations studied, endomysial fibrosis, but not overall fibrosis, is the strongest determinant of AF complexity.

Keywords: AF complexity; AF substrate; Atrial fibrillation; Endomysial fibrosis; Epicardial mapping; Fibrosis.

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Figures

Figure 1
Figure 1
Examples of the epicardial 256-channel (A) and 64-channel (B) mapping electrode. (C) Diagram of the atria with locations of electrode application. Larger electrode cartoons represent the 256 electrode, smaller electrode cartoon represents the 64 electrode (D). Illustrative view on the mapping procedure during cardiac surgery.
Figure 2
Figure 2
Representative isochrone maps of 1 AF beat in the posterior left atrium and the corresponding electrograms of patients with aAF, pAF, and persAF. Separate waves are coloured different shades of green for aAF, yellow for pAF and red for persAF. Electrograms are preceded by numbered asterisks that corresponds to the asterisks on the map. Four-way arrow symbols represent breakthrough conduction. AF, atrial fibrillation; aAF, acutely induced AF; pAF, paroxysmal AF; persAF, longstanding persistent AF.
Figure 3
Figure 3
(A) Representative pictures of Sirius red staining after exclusion of pericardial and perivascular fibrosis for aAF, pAF, and persAF. (B) Total amount of fibrosis (%) in the right atrial appendage. (C) Correlation between total amount of fibrosis (%) and AF complexity. AF, atrial fibrillation; aAF, acutely induced AF; pAF, paroxysmal AF; persAF, longstanding persistent AF.
Figure 4
Figure 4
(A) Representative pictures of haematoxylin and eosin (H&E) staining with endomysial fibrosis (i.e. myocyte-to-myocyte distance) for aAF, pAF, and persAF. (B) Endomysial fibrosis in the right atrial appendage. (C) Correlation between endomysial fibrosis and AF complexity. AF, atrial fibrillation; aAF, acutely induced AF; pAF, paroxysmal AF; persAF, longstanding persistent AF.
Figure 5
Figure 5
(A) Representative pictures of immunostaining for Cx43 for aAF, pAF, and persAF. In aAF, Cx43 is mainly localized at the longitudinal junction between myocytes. In persAF, distribution of Cx43 is more lateralized than in aAF. (B) Amount of polar Cx43, lateral Cx43, and Cx43 ratio in right atrial appendages. (C) Correlation between the Cx43 ratio and AF complexity. AF, atrial fibrillation; aAF, acutely induced AF; Cx43, connexin 43; pAF, paroxysmal AF; persAF, longstanding persistent AF.
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