Abstract
BackgroundPlaque vulnerability to rupture has emerged as a critical correlate to risk of adverse coronary events but there is as yet no clinical method to assess plaque stability in vivo. In the search to identify biomarkers of vulnerable plaques an association has been found between macrophages and plaque stability—the density and pattern of macrophage localization in lesions is indicative of probability to rupture. In very unstable plaques, macrophages are found in high densities and concentrated in the plaque shoulders. Therefore, the ability to map macrophages in plaques could allow noninvasive assessment of plaque stability. We use a multimodality imaging approach to noninvasively map the distribution of macrophages in vivo. The use of multiple modalities allows us to combine the complementary strengths of each modality to better visualize features of interest. Our combined use of Positron Emission Tomography and Magnetic Resonance Imaging (PET/MRI) allows high sensitivity PET screening to identify putative lesions in a whole body view, and high resolution MRI for detailed mapping of biomarker expression in the lesions.Methodology/Principal FindingsMacromolecular and nanoparticle contrast agents targeted to macrophages were developed and tested in three different mouse and rat models of atherosclerosis in which inflamed vascular plaques form spontaneously and/or are induced by injury. For multimodal detection, the probes were designed to contain gadolinium (T1 MRI) or iron oxide (T2 MRI), and Cu-64 (PET). PET imaging was utilized to identify regions of macrophage accumulation; these regions were further probed by MRI to visualize macrophage distribution at high resolution. In both PET and MR images the probes enhanced contrast at sites of vascular inflammation, but not in normal vessel walls. MRI was able to identify discrete sites of inflammation that were blurred together at the low resolution of PET. Macrophage content in the lesions was confirmed by histology.Conclusions/SignificanceThe multimodal imaging approach allowed high-sensitivity and high-resolution mapping of biomarker distribution and may lead to a clinical method to predict plaque probability to rupture.
Highlights
Atherosclerosis is a progressive disease characterized by the formation of arterial plaques
For the probe uptake (PET) imaging, the axial and transaxial field-of views (FOVs) were 4.9 cm and 8.5 cm, with an energy window of 250–750 keV, a timing window of 6 ns, a scan time of 60 minutes, and a fully 3D maximum a posterioi (MAP) reconstruction was performed resulting in a spatial resolution of 0.460.460.58 mm3 for a 1286128683 matrix[28]
Positive contrast macromolecular and negative contrast nanoparticulate multimodal probes were synthesized that are targeted to macrophages through the macrophage scavenger receptor A type 1 (SRA), a cell surface receptor found on macrophages [20,26]
Summary
Atherosclerosis is a progressive disease characterized by the formation of arterial plaques. The ability to image plaques at high resolution to determine macrophage content and distribution could provide a means to noninvasively assess plaque vulnerability and degree of risk to rupture in inflamed arteries. The recognition that the majority of clots leading to acute coronary events occur in plaques that are not highly stenotic [12] highlighted the need for alternative imaging methods that can directly image the vessel wall. There are a number of alternative techniques to image plaques including invasive modalities such as intravascular ultrasound, angioscopy, thermography, optical coherence tomography, raman spectroscopy, near infra-red spectroscopy and intravascular MRI[12,13,14,15] These invasive techniques involve intravascular transceivers that must be threaded into the vessel being examined and are unsuitable for exploratory imaging to assess overall plaque burden in the patient.
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
