The role of angiotensin in electrophysiological gap junction remodeling in human atrial fibrillation

Objective: Atrial fibrillation (AF) is a progressive disease and associated with electrical remodeling in the atria. Because of positive clinical effects of ACE-inhibitors we wanted to elucidate, whether angiotensin and AT-receptors may be involved in the gap junction remodelling of the gap junction proteins (connexins) Cx43 and Cx40 in AF in the human left and right atria.

Methods: Left and right atrial tissue from patients with AF or sinusrhythm (SR), both with mitral valve disease were examined for AT1, AT2, Cx43 and Cx40 expression by Western Blotting and immunhistochemistry.

Results: Left atrium: In AF, CX43 expression was significantly increased (2,27±0,25; p<0,05) compared to SR (1,38±0,19). CX40 expression exhibited a slight increase in AF (1,15±0,15; p=0,11) compared to SR (0,70±0,10). The analysis of angiotensin-II-receptors revealed an increase of AT1 (1,51±0,20; p=0,01) vs. SR (0,67±0,07) and a decrease of AT2 (1,44±0,14; p<0,01) vs. SR (2,34±0,32). Right atrium: There was an increase of CX40 expression in patients with AF (0,63±0,02; p=0,10) vs. SR (0,43±0,08), whereras CX43, AT1 and AT2 remained unchanged in patients with AF vs. SR. We observed an increased heterogeneity and lateralization of CX40 and CX43 in both atria. In-vitro data showed that this lateralization led to enhanced transverse conduction and reduced anisotropy. Angiotensin induced Cx43 but not Cx40 expression in cultured cardiomyocytes suppressable by losartan.

Conclusions: AF is associated with gap junctional remodeling leading to altered biophysics of the tissue which can help to explain the chronification of AF. Angiotensin seems to be involved in this process in left atrium via AT1-receptors.