Molecular imaging of inflammation in atherosclerosis

Abstract

Acute rupture of vulnerable plaques frequently leads to myocardial infarction and stroke. Within the last decades, several cellular and molecular players have been identified that promote atherosclerotic lesion formation, maturation and plaque rupture. It is now widely recognized that inflammation of the vessel wall and distinct leukocyte subsets are involved throughout all phases of atherosclerotic lesion development. The mechanisms that render a stable plaque unstable and prone to rupture, however, remain unknown and the identification of the vulnerable plaque remains a major challenge in cardiovascular medicine. Imaging technologies used in the clinic offer minimal information about the underlying biology and potential risk for rupture. New imaging technologies are therefore being developed, and in the preclinical setting have enabled new and dynamic insights into the vessel wall for a better understanding of this complex disease. Molecular imaging has the potential to track biological processes, such as the activity of cellular and molecular biomarkers in vivo and over time. Similarly, novel imaging technologies specifically detect effects of therapies that aim to stabilize vulnerable plaques and silence vascular inflammation. Here we will review the potential of established and new molecular imaging technologies in the setting of atherosclerosis, and discuss the cumbersome steps required for translating molecular imaging approaches into the clinic.

Keywords: Atherosclerosis; Inflammation; Molecular imaging.

Fig 1

Tools and targets for molecular imaging of atherosclerosis. Figure demonstrates schematic evolution of atherosclerotic plaques and potential targets for molecular imaging.

Fig 2

MR Imaging of endothelial permeability. Uptake of gadofosveset in regions of the brachiocephalic artery of control (Panel A-E) and atherosclerotic mice after 4 (Panel F-J) and 12 weeks (Panel K-O) of high-fat diet is associated with endothelial permeability. After 12 weeks significant increase in R1 relaxivity is observed in the inflamed vessel wall following gadofosveset injection (Panel P). Image courtesy of Alkystis Phinikaridou and René M. Botnar, King's College London.

Fig 3

MR Imaging of vascular inflammation using very small superparamagnetic nanoparticles (VSOP). VSOPs target inflammatory macrophages in high-fat diet induced atherosclerosis in mice, inducing shortening of T2* relaxation in the vessel wall in HFD fed mice (lower row) as compared to controls (upper row). Imaging findings are corroborated by histology (A4-A6 and B4-B6). EvG=Elastica van Gieson, HFD=high-fat diet, SGM=susceptibility gradient mapping. TOF=Time-of-Flight angiography. Image courtesy of René M. Botnar, King's College London.

Fig 4

Imaging of the vulnerable plaques in human coronary atherosclerosis. Representative images of ¹⁸F-FDG PET (A), CT (B), PET/CT (C), and coronary angiography (D) from patient with good suppression with coronary ¹⁸F-FDG uptake (arrows). Reprinted with the permission of the Society of Nuclear Medicine from Wykrzykowska et al.

Fig 5

Molecular Imaging of atherosclerosis by hybrid PET-CT and MR-PET. Inflammation in plaques of hypercholesterolemic rabbits can be assessed and quantified by 18F-FDG PET and co-localized to carotid artery by simultaneously acquired MRI. Panel A: TOF angiography, Panel B, contrast enhanced fat-suppressed T1 weighted MRI (delayed enhancement), Panel C: MR-PET fusion showing increase tracer accumulation around the left carotid artery. Images demonstrate good correlation of PET signal and contrast-enhanced MRI but also show limited spatial resolution of PET technology. Hybrid Molecular Imaging in a patient with large-vessel vasculitis (Panels D-L). Increased 18F-FDG uptake can be visualized by whole-body PET and correctly co-localized to the aortic arch by the subsequently performed contrasted enhanced CT (Panels D-G: PET-CT). Similar co-localization can be performed using hybrid MR-PET (Panels H-J). Whole body MRA (Panel K) and CTA (Panel L) can be routinely performed during hybrid image acquisition. Images courtesy of Isabel Dregely, Stefan Nekolla and Ambros J. Beer from the Munich PET/MR consortium of TUM and LMU (funded by DFG).

Fig 6

Myeloperoxidase (MPO) - targeted MRI of vascular inflammation. MPO-Gd MR imaging of atherosclerosis in a rabbit model fed high cholesterol diet for 24 months. MPO-Gd imaging identifies areas of high MPO activity and content (red circles) that are corroborated by MPO immunostaining. Images courtesy of John W. Chen, Massachusetts General Hospital, Harvard Medical School.

Fig 7

Imaging of Vascular Remodeling. Vascular remodeling can be assessed with an Elastin-targeted Magnetic Resonance Agent (=ESMA). Panels A and B show ESMA-enhanced MR images of the aortic arch and supraaortic vessels in swine wit increased SNR and CNR compared to non-targeted Gd-DTPA (Panel C and D). A similar approach is able to detect vascular injury following coronary stent implantation. Magnetic Resonance Angiography (MRA, Panel E), delayed-enhancement MRI after injection of ESMA (Panel F) and fusion of E and F (Panel G). Quantification of Elastin by MRI yields good correlation with Histology (Panel H). Images courtesy of Marcus Makowski and René M. Botnar, Kings College London and Christian von Bary, Universität Regensburg.

Fig 8

Fibrin-targeted molecular MRI of thrombus formation. 3D TOF images of the aortic arch in a control (Panel A) and ApoE^-/- mice (Panel C). The subsequently performed imaging sequences (delayed enhancement and T1 mapping sequences) were aligned perpendicular to the brachiocephalic artery. Atherosclerotic plaques were imaged prior to FTCA in control (B1) and 12 week HFD ApoE^-/- mice (D1), and 2 hours after an injection of FTCA (B2-3, D2-3). Delayed enhancement (white arrows) is seen selectively as a white hotspot on the post-contrast images (D2) whilst the signal from the surrounding blood and tissues is suppressed. Fusion of the TOF and late enhancement images confirm signal localization in the vessel wall of the BCA (D3, E). Transmission electron microscopy (F) and mapping of gadolinium distribution (G) in an engineered thrombus. For colocalization experiments thrombus samples were incubated with FTCA. Good colocalization of signal from Gd with the fibrin mesh was found (H). aA: ascending aorta, dA: descending aorta, BC: brachiocephalic artery, IR: inversion recovery, SC: subclavian artery, CA: carotid artery, FTCA: Fibrin targeted contrast agent. Images courtesy of René M. Botnar, King's College London.