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(Circulation. 2008;117:732-742.)
© 2008 American Heart Association, Inc.

Arrhythmia/Electrophysiology

Angiotensin II Receptor Blockade Reduces Tachycardia-Induced Atrial Adhesion Molecule Expression

Andreas Goette, MD^*; Alicja Bukowska, PhD^*; Uwe Lendeckel, PhD^*; Michaela Erxleben, MD; Matthias Hammwöhner, MD; Denis Strugala, MS; Jan Pfeiffenberger, MS; Friedrich-Wilhelm Röhl, PhD; Christof Huth, MD; Matthias P.A. Ebert, MD; Helmut U. Klein, MD; Christoph Röcken, MD

From the Division of Cardiology (A.G., M.E., M.H., D.S., J.P., H.U.K.), Institute of Experimental Internal Medicine (A.B., U.L.), Institute of Biometrics (F.-W.R.), and Department of Cardiovascular Surgery (C.H.), Otto von Guericke University Hospital Magdeburg, Magdeburg, Germany; Department of Medicine II (M.P.A.E.), Klinikum rechts der Isar, Technical University of Munich, Germany; and Institute of Pathology, Charité University Hospital, Berlin, Germany (C.R.).

Correspondence to Andreas Goette, MD, Division of Cardiology, University Hospital Magdeburg, Leipzigerstraße 44, 39120 Magdeburg, Germany. E-mail andreas.goette{at}med.ovgu.de

Received July 30, 2007; accepted November 14, 2007.

Background— Increased levels of inflammatory markers are predictors of thromboembolic events during atrial fibrillation (AF). Increased endocardial expression of adhesion molecules (ie, vascular cell adhesion molecule [VCAM] and intercellular adhesion molecule [ICAM]) could be an important link between initiation of inflammatory and prothrombogenic mechanisms responsible for thrombus development at the atrial endocardium (endocardial remodeling).

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.

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CLINICAL PERSPECTIVE

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Clinical Summaries
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