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Cardiovasc Res. 2013 Sep 1;99(4):769-79. doi: 10.1093/cvr/cvt074. Epub 2013 Apr 23.

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

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Division of Cardiology, University of California, San Francisco, CA 94143, USA.



Animal studies show that transforming growth factor-β1 (TGF-β1) is an important mediator of atrial fibrosis and atrial fibrillation (AF). This study investigated the role of TGF-β1 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-β1, AF, and differential atrial vs. ventricular TGF-β1 levels. A transgenic mouse model overexpressing active TGF-β1 was used to study the mechanisms underlying the resultant atrial-selective fibrosis. Higher right atrial total TGF-β1 levels (2.58 ± 0.16-fold, P < 0.0001) and active TGF-β1 (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-β1 levels than 6 non-failing hearts (2.30 ± 0.87 fold higher, P < 0.001). In the transgenic mouse, TGF-β1 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-β1 receptor levels or Smads in the atria compared with the ventricles.


TGF-β1 mediates selective atrial fibrosis in AF that occurs via TGF-β Receptor 1/2 and the classical Smad pathway. The differential atrial vs. ventricular fibrotic response occurs at the level of TGF-β1 receptor binding or phosphorylation.


Atrial fibrillation; Cardiac fibrosis; Gene expression; Heart failure; Transforming growth factor-beta1

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