Adhesion Molecules in Atrial Fibrillation - Adhesion Molecules - page 415

in vitro model we were able to show that rapid atrial pacing increased amounts of
phospho-IκB-α substantially. Nuclear accumulation of NF-κB p50 was observed
in atrial tissue from patients with AF and in paced atrial tissue slices. In line with
the activation of NF-κB signaling, we observed an increase of pro-inl ammatory
and prothrombotic adhesion molecules such as ICAM-1 and VCAM-1, but also
LOX-1 in atrial tissue from patients with AF and in in vitro paced atrial tissue
slices (Bukowska et al. 2008) (Fig. 4) . Interestingly, LOX-1 ligation itself was also
shown to increase expression of adhesion molecules such as ICAM-1, VCAM-1,
P-selectin, and E-selectin.
h ese i ndings strongly imply that oxidative stress in atrial tissue activates NF-
κB signaling, which accounts for endocardial activation followed by an increased
risk of atrial thrombus formation during AF. Tachycardia-associated factors
(activated compounds of the RAS and Ca 2+ signaling pathway) are involved in this
response, which are directly or indirectly linked to oxidative stress. Accordingly,
AT1R blockade, inhibition of L-type calcium channels, inhibition of NADPH
oxidase, applications of antioxidants, and inhibition of NF-κB activation were all
found to abolish or decrease the pacing-dependent changes in the atrial tissue
(Figs. 3 and 4) .
PROTHROMBOTIC ENDOCARDIAL REMODELING
h rombus formation within the vascular system depends on pathological
endothelial changes. h e remodeling processes mentioned earlier af ect myocardial
cells and the atrial endothelium ('endocardial remodeling'). Endothelial damage
and prothrombotic endothelial alteration are present in i brillating atria. h ey are
a prerequisite for the development of atrial clots, since atrial thrombi always start
to grow from the atrial wall.
Virchow's triad dei nes circumstances under which thrombus formation
is likely. It also applies to atrial thrombus formation during AF. Accordingly,
thrombi develop in the presence of reduced blood velocities ( circulatory stasis ),
when the activity of the clotting system is increased ( hypercoagulable state ), and
in the presence of endothelial alterations ( endothelial injury ). While the loss of
regular atrial contractions reduces blood l ow velocities particularly in the atrial
appendages, AF is also associated with an activation of the plasmatic clotting
system and of platelets (Sohara et al. 1997, Goette et al. 2000a). However, until
now, the contribution of endothelial alterations to atrial thrombogenesis has not
yet been fully understood.
Numerous studies have shown that AF is associated with an inl ammatory
response measurable by systemic inl ammatory markers (Conway et al. 2004).
In turn, increased inl ammatory markers and increased leukocyte-platelet
interactions are predictors of atrial thrombus formation and thromboembolic
stroke (Kawamura et al. 2006). An increased endothelial expression of adhesion