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). 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 (Pϭ0.03). Increased atrial VCAM-1 expression was confirmed by Western blotting in patients with persistent and paroxysmal AF (persistent AF 207Ϯ42% versus sinus rhythm 100Ϯ16%, Pϭ0.028; paroxysmal AF 193Ϯ42%, Pϭ0.024 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 (Ͼ5-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. (Circulation. 2008;117:732-742.)

Soluble Cell Adhesion Molecules – Does Estimating sVCAM-1 and sICAM-1 Concentration Provide Additional Information About Cardiovascular Risk in Patients with Coronary Artery Disease?

“…In our analysis, after 6 months following ACS and optimal medical therapy, sVCAM-1 concentration increased (p = 0.01). There are studies heralding the role of VCAM-1 in the optimization of CAD therapy, as it was shown that a decrease in the expression of VCAM-1 can be observed along with the administration of antioxidants and polyunsaturated fatty acids as well as in patients chronically treated with ACE inhibitors, statins and fibrates [13][14][15][16]. The elevation of sVCAM-1 seen in our study following the six-month-long optimal medical therapy might require further explanation.…”

EHRA/HRS/APHRS/SOLAECE expert consensus on atrial cardiomyopathies: definition, characterization, and clinical implication

“…305 Endocardial thrombogenic alterations in diseased atria, which appear to be related to oxidative stress, appear to contribute to clot formation, particularly in the left atrial appendage. [306][307][308][309][310] Thus, the impact and the relation between EHRAS Classses and the extend of endocardial thrombogenic alterations have to be assessed in future studies. Interestingly, duration of AF does not correlate with the extent of abserved endocardial changes.…”

Dabigatran for prophylaxis of thromboembolic events in patients with atrial fibrillation

“…Soluble VCAM-1 levels appear to be an independent predictor of atrial thrombi in multivariate analysis of variance. 6,15,18,23,24 Recently, in ex vivo experiments using organotypic human atrial tissue cultures and in vivo experiments, we found increased atrial expression of VCAM-1 in patients with paroxysmal and persistent atrial fibrillation. Importantly, it was shown that increased expression of atrial adhesion molecules and reduced levels of nitric oxide occur within hours of rapid atrial pacing and is related to increased oxidative stress and generation of reactive oxygen species.…”

“…6,7,14,15 The remodeling processes mentioned earlier affect myocardial cells and the atrial endothelium ("endocardial remodeling"). Endothelial damage and prothrombotic endothelial alteration are present in fibrillating atria.…”

“…Importantly, it was shown that increased expression of atrial adhesion molecules and reduced levels of nitric oxide occur within hours of rapid atrial pacing and is related to increased oxidative stress and generation of reactive oxygen species. 12,14,15 In addition to age and reduced left ventricular function, soluble VCAM-1 was an independent predictor of mortality in patients with atrial fibrillation. 25 It is of note that irbesartan and olmesartan therapy reduced adhesion molecule expression in atrial tissue during rapid pacing.…”