Supplementary Material for: Molecular Imaging of Carotid Plaque Vulnerability

Background: Carotid endarterectomy (CEA) has been shown
to be beneficial in patients with high-grade symptomatic carotid artery
stenosis. Patients with high-grade asymptomatic stenosis may only
exceptionally benefit from CEA during periods of increased plaque
vulnerability. Imaging modalities to characterize unstable, vulnerable
plaques are strongly needed for better risk stratification in these
patients. Summary: Contrast-enhanced ultrasound (CEUS) is a
novel and noninvasive technique capable to identify several surrogate
markers of vulnerable carotid plaques. The use of specific ultrasound
microbubbles allows a reliable detection of microulcerations due to an
optimized visualization of the plaque-lumen border. As microbubbles are
strictly intravascular tracers, the detection of individual microbubbles
within the plaque corresponds to intraplaque neovessels. The accuracy
of CEUS in the visualization of newly formed microvessels has been
confirmed in histological studies on carotid endarterectomy specimens.
Together with the formation of adventitial vasa vasorum, intraplaque
neovascularization is a strong predictor for symptomatic disease. The
phenomenon of late phase contrast enhancement is based on the adherence
of microbubble-containing monocytes on inflamed endothelium. Recent
studies suggest that late phase contrast enhancement may reflect
endothelial inflammation or activation within carotid plaques. The
development of conjugated microbubbles that bind to specific ligands
such as thrombotic material or neovessels has led to the term ‘molecular
imaging'. CEUS with microbubbles targeted to P-selectin and VCAM-1, key
molecules in leukocyte trafficking, was used to detect an inflammatory
plaque phenotype, whereas microbubbles coupled to the VEGF-receptor may
allow for a detection of neovascularization. Even though imaging with
targeted microbubbles is yet in an experimental stage, this technique
can visualize active plaque reorganization with increased vulnerability
leading to generation of arterio-arterial embolism. Key Messages:
The use of contrast-enhanced ultrasound can be recommended to assess
atherosclerotic carotid lesions at risk for rupture. Prospective
clinical studies are needed to validate the use of CEUS in patients with
high risks of recurrent large artery strokes. In particular, this
applies to the detection of intraplaque neovascularization, a
well-established marker in preclinical and observational studies, while
the clinical significance of late phase contrast enhancement still needs
to be determined.