METHODS AND RESULTS: Tissue microarrays were used to screen right atrial tissue specimens obtained from 320 consecutive patients for differences in atrial expression of the prothrombogenic
proteins VCAM-1,
ICAM-1,
thrombomodulin,
plasminogen activator inhibitor-1, and
von Willebrand factor. An in vitro organotypic human atrial tissue model and a pig model of rapid atrial pacing were used to determine the therapeutic impact of
angiotensin II receptor blockade. Immunohistochemical analyses showed that all prothrombogenic
proteins are expressed by endocardial cells. Using multivariable analysis, only the intensity of
VCAM-1 expression was increased in patients with AF (P=0.03). Increased atrial
VCAM-1 expression was confirmed by Western blotting in patients with persistent and paroxysmal AF (persistent AF 207+/-42% versus sinus rhythm 100+/-16%, P=0.028; paroxysmal AF 193+/-42%, P=0.024 versus sinus rhythm). In vitro pacing of ex vivo human atrial tissue slices confirmed that rapid activation causes
VCAM-1 upregulation (
mRNA and
protein levels). Pacing-induced
VCAM-1 expression was abolished by
olmesartan. To confirm this finding in vivo,
VCAM-1 expression was determined in 14 pigs after rapid atrial pacing (600 bpm). Atrial
tachycardia caused an upregulation of
VCAM-1 expression, which was prevented by
irbesartan, consistent with the observed increase in plasma levels of
angiotensin II. Alterations in the in vivo
VCAM-1 expression were more pronounced in the left atrium (>5-fold compared with
sham) than in the right atrium (3.5-fold compared with
sham).
CONCLUSIONS: AF and rapid atrial pacing both increase endocardial
VCAM-1 expression, which can be attenuated by
angiotensin II receptor blockade. This provides evidence that
angiotensin II plays a pathophysiological role in prothrombotic endocardial remodeling.