Chronic Atrial Overload Contributes to the Slow Decay of Intramural Fibrosis in the Human Atrium: Assessment by High‐Resolution 3D Histology

Abstract

BackgroundThe intramural distribution of fibrosis is considered one of the most important factors in the formation of a substrate for atrial fibrillation. Chronic atrial stretch is known to play a mechanistic role in this structural remodeling process. However, the distribution of fibrosis through the entire atrial wall is poorly characterized as well as its relationship with chronic atrial stretch. Based on these premises, this study aimed at assessing the intramural profile of fibrosis in the human atrium in patients with different degrees of atrial dilatation and arrhythmic profiles by high‐resolution 3D histology.Methods and ResultsSerial vibratome‐cut longitudinal slices, encompassing the whole atrial wall at a resolution of 5 μm, were obtained from right atrial appendage samples from cardiac surgery patients. Serial slices were stained in Picrosirius red, imaged by polarized light microscopy, and analyzed with a custom‐made computer program. In all patients the intramural fibrotic content followed a progressive decreasing profile along tissue depth, passing from the epicardium to the endocardium. On average it decreased from 69 ± 12 % to 34 ± 16 % within the first 20% of atrial tissue depth, undergoing a further slight decrease to 21 ± 14 % at 40% of tissue depth. Finally, in deeper mid‐wall to subendocardial layers, the average fibrotic content slightly varied around low values of 10–13%. Distinct intramural fibrotic profiles were observed in sinus rhythm patients with normal atria with respect to patients with dilated atria, who showed, respectively, rapid and slow exponential decays (decay constant: 80.9 ± 24.4 μm versus 171.2 ± 54.5 μm, p<0.005). Similar to patients with atrial dilatation, patients with atrial fibrillation showed a slow fibrotic decrease with decay constant of 142.9 ± 41.7 μm. The decay rate of intramural fibrosis correlated with the degree of atrial dilatation (r=0.69, p<0.001).ConclusionsThe quantification of the intramural profile of fibrosis in the human atrium is feasible by combining slice‐to‐slice histology with computerized image analysis. Our results showed a deeper penetration of fibrosis in the atrial wall closely related with the presence of atrial dilatation. The stretch‐related intramural penetration of fibrosis may contribute to epiendocardial dissociation of electrical activity and the formation of an arrhythmic substrate.Support or Funding InformationThis work was supported by Fondazione Cassa di Risparmio di Trento e Rovereto.