Right atrial appendages of 163 patients were excised during heart surgery and grouped according to rhythm (SR vs. AF) and AF duration. Five groups were defined: SR, paroxysmal/chronic persistent AF (< 6 months), chronic permanent AF (CAF) of 7–24 months, 25–60 months, and > 60 months duration. Collagen content of atria, determined morphometrically, revealed a steady and significant increase in patients with SR (14.6 ± 8.9 % ) up to patients with CAF of > 60 months (28.1 ± 7.1 % ). Likewise, expression of TGF-β1 mRNA and protein, TGF-β-receptor-II protein, profibrotic phospho-Smad-2 and -4 proteins increased. However, the TGF-β1 effect appeared to decline with increasing AF duration, characterized by a decrease in TGF-β-receptor-I protein, increases of TGF-β inhibiting Smad-7 protein and a reduction of ph-Smad-2.
Human atrial fibrogenesis in patients with atrial fibrillation is accompanied by a biphasic response, an early increase and later loss of responsiveness to TGF-β1. It appears that fibrosis progresses despite compensatory changes in the TGF-β-signaling pathway. The sequential changes in the contribution of different profibrotic processes during the establishment of AF may offer the opportunity to selectively interfere with the atrial remodeling process at different stages.