Abstract
Identification of patients with high-risk asymptomatic carotid plaques remains a challenging but crucial step in stroke prevention. Inflammation is the key factor that drives plaque instability. Currently, there is no imaging tool in routine clinical practice to assess the inflammatory status within atherosclerotic plaques. We have developed a molecular magnetic resonance imaging (MRI) tool to quantitatively report the inflammatory activity in atherosclerosis using dual-targeted microparticles of iron oxide (DT-MPIO) against P-selectin and VCAM-1 as a smart MRI probe. A periarterial cuff was used to generate plaques with varying degree of phenotypes, inflammation and risk levels at specific locations along the same single carotid artery in an Apolipoprotein-E-deficient mouse model. Using this platform, we demonstrated that in vivo DT-MPIO-enhanced MRI can (i) target high-risk vulnerable plaques, (ii) differentiate the heterogeneity (i.e. high vs intermediate vs low-risk plaques) within the asymptomatic plaque population and (iii) quantitatively report the inflammatory activity of local plaques in carotid artery. This novel molecular MRI tool may allow characterisation of plaque vulnerability and quantitative reporting of inflammatory status in atherosclerosis. This would permit accurate risk stratification by identifying high-risk asymptomatic individual patients for prophylactic carotid intervention, expediting early stroke prevention and paving the way for personalised management of carotid atherosclerotic disease.
Highlights
Stroke is the second leading cause of death and long-term disability globally [1]
In vivo MR angiography (MRA) of carotid arteries was carried out to determine if dual-targeted microparticles of iron oxide (DT-microparticles of iron oxide (MPIO)) can target and discriminate the high-risk vulnerable plaques from the lowrisk stable ones
The most controversial issue is the growing body of evidence that the stroke risk among medically treated asymptomatic patients has reduced across all stenosis severities, attributable to advances in medical therapy, such as statins, antiplatelets and, more recently, dual pathway inhibition with low-dose rivaroxaban [17, 18]
Summary
Stroke is the second leading cause of death and long-term disability globally [1]. Atherosclerosis, defined by persistent inflammation and accumulation of lipid-rich plaquesThe advancements in molecular imaging techniques have helped to shift the emphasis from imaging plaque structure alone, to directly reporting the pathophysiological activities of atherosclerosis at the molecular and cellular levels [5].1 3 Vol.:(0123456789)Translational Stroke ResearchMolecular MRI aims to concurrently image the precise anatomy and biological processes in vivo by acquiring different contrast weightings, enabling co-registration of molecular with anatomical information into a single imaging modality [6]. Iron oxide contrast agents augment sensitivity and enhance diagnosis by reducing T2 and T2* relaxation times to generate hypointense (dark) signals on T2- and T2*-weighted MRI [6]. Molecular MRI encompasses ‘passive’ and ‘active’ targeting strategies. ‘Passive’ targeting strategy, for example utilising the non-specific uptake of ultrasmall superparamagnetic particles of iron oxide (USPIO) by plaque macrophages as surrogate markers of intraplaque inflammation, has been reported in both animals [7] and human [8]. With higher iron oxide content, MPIO augments MR signal to enhance direct reporting of molecular targets in vivo. ‘Active’ molecular imaging can be attained through conjugating MPIO to specific targeting antibodies against inflammatory antigens expressed by ‘active’ vascular endothelium [9,10,11]
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