Upregulated in Human Persistent Atrial Fibrillation with Underlying Valve Disease Brundel, Short title: Endothelin system in atrial fibrillation

Background: Activation of the endothelin system is an important compensatory mechanism that is activated during left ventricular dysfunction. Whether this system also plays a role at the atrial level during AF has not been thoroughly examined. The purpose of this study was to investigate mRNA and protein expression levels of the endothelin system in AF patients with and without concomitant underlying heart disease. Metods and results: Right atrial appendages of 36 patients with either paroxysmal or persistent AF were compared with 36 controls in sinus rhythm. The mRNA amounts of pro-endothelin1 (ET-1), endothelin receptors A (ET-A) and B (ET-B) were studied by semi-quantitative PCR. Protein amounts of the receptors were investigated by slot-blot analysis. The endogenous mRNA production of pro-ET-1 was induced (+ 40%, p=0.002) in patients with persistent AF and underlying valve disease. Furthermore, the ET-A and ET-B receptor protein amounts were significantly reduced in paroxysmal AF (-39% and –47%, respectively) and persistent AF with (-28% and –30%, respectively) and without (-20% and –40%, respectively) underlying valve disease. Moreover, the mRNA amounts for proET-1 and ET-A were not different in AF patients, in contrast to ET-B mRNA amounts which were significantly reduced in persistent AF with (-30%, p<0.001) and without (30%, p=0.04) underlying valve disease. Conclusions: Alterations in gene expression of the endothelin system occur in the atria during AF, especially in the presence of underlying valve disease. These results suggest that the endothelin system might play a role in adaptive mechanisms in these patients.