Molecular basis of selective atrial fibrosis due to overexpression of transforming growth factor-β1.

Animal studies show that transforming growth factor-1 (TGF-1) is an important mediator of atrial fibrosis and atrial fibrillation (AF). This study investigated the role of TGF-1 in human AF and the mechanism of atrial-selective fibrosis. Atrial specimens from 17 open heart surgery patients and left atrial and ventricular specimens from 17 explanted hearts were collected to assess the relationship between TGF-1, AF, and differential atrial vs. ventricular TGF-1 levels. A transgenic mouse model overexpressing active TGF-1 was used to study the mechanisms underlying the resultant atrial-selective fibrosis. Higher right atrial total TGF-1 levels (2.58 0.16-fold, P 0.0001) and active TGF-1 (3.7 0.7-fold, P 0.013) were observed in those that developed post-operative AF. Although no ventricular differences were observed, 11 explanted heart failure hearts exhibited higher atrial TGF-1 levels than 6 non-failing hearts (2.30 0.87 fold higher, P 0.001). In the transgenic mouse, TGF-1 receptor-1 kinase blockade resulted in decreased atrial expression of fibrosis-related genes. By RNA microarray analyses in that model, 80 genes in the atria and only 2 genes in the ventricle were differentially expressed. Although these mice atria, but not the ventricles, exhibited increased expression of fibrosis-related genes and phosphorylation of Smad2, there were no differences in TGF-1 receptor levels or Smads in the atria compared with the ventricles. TGF-1 mediates selective atrial fibrosis in AF that occurs via TGF- Receptor 1/2 and the classical Smad pathway. The differential atrial vs. ventricular fibrotic response occurs at the level of TGF-1 receptor binding or phosphorylation.