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

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.