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Mueller et al. Vessel Plus 2018;2:13 I http://dx.doi.org/10.20517/2574-1209.2018.19 Page 7 of 10

controls. Furthermore, in the present study the analysis of the plasmatic levels of RANTES between patients
with and without a lesion on MRI showed no statistical significant difference. Also correlation to TBR persisted
even in patients without a stroke lesion. RANTES may therefore be a marker of inflammation in atherosclerosis
and be less influenced by ischemic damage in stroke [Table 5]. In the present study, we found higher levels of
ICAM-1 in MES+ patients, but not in patients with higher TBR values. These results possibly reflect different
plaque components; in fact FDG-PET-CT mainly depicts the inflammatory state of the whole carotid plaque
18
whereas presence of MES reflects surface abnormalities such as ulceration and/or plaque thrombus [7,10] .
Although a significant correlation between presence of symptoms and MES could be demonstrated in our
cohort [Table 1], no difference was found between symptomatic and asymptomatic patients with respect to
ICAM-1 levels, again giving more strength to the link between biomarkers and thrombotically active plaques
per se [Table 5]. Cellular adhesion molecules, including ICAM-1, VCAM-1 and E-selectin promote recruitment
of inflammatory cells into the arterial wall where they interact with lipid particles leading subsequently to
plaque formation . In the Atherosclerosis Risk In Communities (ARIC) study, the relationship of ICAM-
[28]
1 and E-selectin with coronary heart disease and carotid artery atherosclerosis was independent of other
known risk factors . Cellular adhesion molecules have also been implicated in the destabilisation of
[29]
atherosclerotic plaques. In a recent study including human carotid endarterectomy (CEA) specimens from
asymptomatic (n = 30) and symptomatic (n = 30) patients, expression of VCAM-1 on the endothelium of CEA
specimens from symptomatic patients was 2.4-fold greater than that from asymptomatic patients (P < 0.01) .
[30]
In another study performed upon 40 patients undergoing carotid endarterectomy it was possible to determine
the influence of surgery on the levels of adhesion molecules. A statistically significant decrease of the ICAM-1
levels 1 h and 6 h after the endarterectomy compared to levels before the operation was found suggesting
that decrease of ICAM-1 could be a possible marker of endothelial de-activation after plaque removal .
[31]
Only very few studies investigated the relationship between biomarkers and presence of MES [32,33] . One study
including 104 controls and 118 patients found increased values of CXCL16 in stroke and in MES+ patients .
[33]
Other studies reported the following biomarker candidates for MES:P-selectin, fibrinogen, high neutrophil
count, reduced ratio of CD4+CD25, high regulatory T cells and the C allele of TNF receptor superfamily
member . At present ICAM-1 has never been reported in association with MES. However, as this biomarker
[32]
may be involved in the process of plaque destabilization, its relationship to MES is nevertheless very likely.
Interestingly in our cohort MMP-2 levels were significantly more important in patients with lower TBR values
and MMP-3 and P-selectin in those who were MES-. There was also a trend of MMP-2 levels to be higher in
MES- patients. MMPs are a class of proteases involved in extracellular matrix degradation, which appear to
play a key role in the process of vascular remodeling during the course of vascular disease [34,35] . Numerous
studies suggest that MMPs and in particular MMP-3, MMP-7, MMP-9 and MMP-12, may be involved in the
process of plaque destabilization [36,37] . However there are conflicting results in particular regarding MMP-3.
The correlation between MMP-3 blood levels and carotid atherosclerotic disease has been reported in several
studies. Lien et al. showed in a study including 433 patients that MMP-3 was significantly associated with the
[38]
presence of higher carotid plaques scores reflecting more unstable plaques. On the other hand, experimental
studies show that MMP-3 is required for efficient neointima formation after carotid ligation and for smooth
cell migration, supporting the fact that MMP-3 acts on plaque stability . The relationship between MMP-2
[39]
and stable plaques has been already described by Sluijter et al. who showed in a study including 150 subjects
[40]
that there was an increased activity of MMP-2 in association with the presence of smooth muscle cells and a
fibrous phenotype. This finding suggested that MMP-2 may be considered as a marker of a stable plaque. The
correlation between P-selectin and stable plaques has been less well documented. In the study reported by
Yin et al. , P-selectin was increased in MES+ patients. On the opposite, in our cohort there was a significant
[32]
increase of P-selectin levels in MES- patients with an inverse correlation between the number of MES and the
plasmatic levels of P-selectin.

To conclude, in the present study ICAM-1 was associated with the presence of thrombotically active
atherosclerotic plaques, while RANTES mainly correlated with the inflammatory process. MMP-2, MMP-3