Histopathological substrate for chronic atrial fibrillation in humans

Heart Rhythm. 2009 Apr;6(4):454-60. doi: 10.1016/j.hrthm.2009.01.010. Epub 2009 Jan 16.


Background: There is a lack of understanding of the substrate for microreentrant circuits and triggered activity of the pulmonary vein (PV) muscle sleeves and atria in patients with atrial fibrillation (AF).

Objective: This study sought to examine the histological substrate of patients with chronic AF.

Methods: We stained 23 biopsies taken from the PV-left atrium (LA) junction and right atrial appendage from 5 chronic AF patients and 3 sinus rhythm (SR) patients undergoing mitral valve surgery using periodic acid-Schiff (PAS) test, and antibodies to hyperpolarization-activated cyclic nucleotide-gated potassium channel 4 (HCN4), CD117/c-kit, myoglobin, tyrosine hydroxylase (TH), growth-associated protein 43, cholineacetyltransferase, and synaptophysin, as well as trichrome.

Results: As opposed to being clustered together in the subendocardial layer in SR patients, PAS-positive cells were separated from each other by inflammatory infiltrate and collagen fibers in AF patients. These cells stained positively for HCN4 and myoglobin, indicating they were cardiomyocytes that might have a potential pacemaking function, but different from CD117/c-kit-positive interstitial Cajal-like cells (ICLC). In AF patients, the intercellular space was occupied by a lymphomononuclear infiltrate (100% vs 33% in SR patients, P = .002), and a greater amount of interstitial fibrosis (37% +/- 5.6% vs 7.4% +/- 2.8%, P = .009). Nerve densities did not differ between AF and SR patients. However, the density of sympathetic nerve twigs in AF patients was significantly greater as compared to the others nerves (P = .03).

Conclusion: HCN4-/PAS-positive cardiomyocytes and CD117/c-kit-positive ICLC scattered among abundant inflammatory infiltrate, fibrous tissue, and sympathetic nerve structures in the atria and at the PV-LA junctions might be a substrate for the maintenance of chronic AF.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Analysis of Variance
  • Atrial Appendage / cytology
  • Atrial Appendage / innervation
  • Atrial Appendage / pathology*
  • Atrial Fibrillation / pathology*
  • Biopsy
  • Chi-Square Distribution
  • Chronic Disease
  • Female
  • Fibrosis / pathology
  • Heart Atria / cytology
  • Heart Atria / innervation
  • Heart Atria / pathology*
  • Heart Conduction System / pathology
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Pulmonary Veins / innervation
  • Pulmonary Veins / pathology*
  • Staining and Labeling
  • Sympathetic Nervous System / pathology