Abstract
PurposeAs atherosclerotic plaque ruptures are the primary cause of ischaemic events, their preventive identification by imaging remains a clinical challenge. Matrix metalloproteinases (MMP) are involved in plaque progression and destabilisation and are therefore promising targets to characterize rupture-prone unstable plaques. This study aims at evaluating MMP imaging to discriminate unstable from stable plaque phenotypes.MethodsApoE deficient mice (ApoE-/-) on a high cholesterol diet underwent implantation of a tapered cuff around the right common carotid artery (CCA) inducing a highly inflamed atherosclerotic plaque upstream (US) and a more stable plaque phenotype downstream (DS) of the cuff. 8 weeks after surgery, the MMP inhibitor-based photoprobe Cy5.5-AF443 was administered i.v. 3h prior to in situ and ex vivo fluorescence reflectance imaging of the CCAs. Thereafter, CCAs were analysed regarding plaque size, presence of macrophages, and MMP-2 and MMP-9 concentrations by immunohistochemistry and ELISA.ResultsWe found a significantly higher uptake of Cy5.5-AF443 in US as compared to DS plaques in situ (1.29 vs. 1.06 plaque-to-background ratio; p<0.001), which was confirmed by ex vivo measurements. Immunohistochemistry revealed a higher presence of macrophages, MMP-2 and MMP-9 in US compared to DS plaques. Accordingly, MMP-2 concentrations were significantly higher in US plaques (47.2±7.6 vs. 29.6±4.6 ng/mg; p<0.05).ConclusionsIn the ApoE-/- cuff model MMP-2 and MMP-9 activities are significantly higher in upstream low shear stress-induced unstable atherosclerotic plaques as compared to downstream more stable plaque phenotypes. MMP inhibitor-based fluorescence molecular imaging allows visualization of these differences in shear stress-induced atherosclerosis.
Highlights
Cardiovascular diseases are common in populations worldwide and mostly originate from atherosclerosis, a chronic inflammation of the arterial vessel wall [1]
In the ApoE-/- cuff model Matrix metalloproteinases (MMP)-2 and MMP-9 activities are significantly higher in upstream low shear stress-induced unstable atherosclerotic plaques as compared to downstream more stable plaque phenotypes
A plaque characterisation by means of molecular imaging is urgently needed to detect rupture prone atherosclerosis, which causes life threatening events. In this experimental model of atherosclerosis, we successfully prove and visualize overexpression of MMP-2 and MMP-9 in unstable upstream low oscillatory shear stress plaques as compared to the high laminar shear stress-induced downstream plaques and control carotids
Summary
Cardiovascular diseases are common in populations worldwide and mostly originate from atherosclerosis, a chronic inflammation of the arterial vessel wall [1]. Life-threatening clinical complications of atherosclerosis impend when stable plaques transform into unstable or vulnerable phenotypes, characterized by fragile fibrous caps and a high degree of inflammation. These might suddenly rupture, triggering an immediate occlusion of the plaque-carrying artery with hypoperfusion and hypoxia of the flow-dependent organs, such as the heart or the brain. An urgent clinical need exists for novel, non-invasive vascular imaging techniques to discriminate high-risk, unstable plaques from stable ones These imaging modalities should be able to describe the broad variety of known or emerging inflammatory processes and mechanisms that contribute to plaque vulnerability
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