title: Angiotensin II receptor blockade reduces tachycardia-induced atrial adhesion molecule expression.
abstract: 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).
  
  
  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.
authors.affiliation: Division of Cardiology, Otto von Guericke University Hospital Magdeburg, Magdeburg, Germany. andreas.goette@med.ovgu.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Goette
authors.forename: Alicja
authors.initials: A
authors.lastname: Bukowska
authors.forename: Uwe
authors.initials: U
authors.lastname: Lendeckel
authors.forename: Michaela
authors.initials: M
authors.lastname: Erxleben
authors.forename: Matthias
authors.initials: M
authors.lastname: Hammwöhner
authors.forename: Denis
authors.initials: D
authors.lastname: Strugala
authors.forename: Jan
authors.initials: J
authors.lastname: Pfeiffenberger
authors.forename: Friedrich-Wilhelm
authors.initials: FW
authors.lastname: Röhl
authors.forename: Christof
authors.initials: C
authors.lastname: Huth
authors.forename: Matthias P A
authors.initials: MP
authors.lastname: Ebert
authors.forename: Helmut U
authors.initials: HU
authors.lastname: Klein
authors.forename: Christoph
authors.initials: C
authors.lastname: Röcken
mesh_terms: D000368:Aged; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001281:Atrial Fibrillation / Q000188:drug therapy / Q000378:metabolism*; D015153:Blotting, Western; D002304:Cardiac Pacing, Artificial; D006348:Cardiac Surgical Procedures; D005260:Female; D006325:Heart Atria / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000096:biosynthesis; D013552:Swine; D013610:Tachycardia / Q000188:drug therapy / Q000378:metabolism*; D046888:Tissue Array Analysis; D046509:Tissue Culture Techniques; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D057911:Angiotensin Receptor Antagonists; D012333:RNA, Messenger; D019010:Vascular Cell Adhesion Molecule-1