Molecular and Nonmolecular Imaging of Macrophages in Atherosclerosis

Abstract

Atherosclerosis is a major cause of ischemic heart disease, and the increasing medical burden associated with atherosclerotic cardiovascular disease has become a major public health concern worldwide. Macrophages play an important role in all stages of the dynamic progress of atherosclerosis, from its initiation and lesion expansion increasing the vulnerability of plaques, to the formation of unstable plaques and clinical manifestations. Early imaging can identify patients at risk of coronary atherosclerotic disease and its complications, enabling preventive measures to be initiated. Recent advances in molecular imaging have involved the noninvasive and semi-quantitative targeted imaging of macrophages and their related molecules in vivo, which can detect atheroma earlier and more accurately than conventional imaging. Multimodal imaging integrates vascular structure, function, and molecular imaging technology to achieve multi-dimensional imaging, which can be used to comprehensively evaluate blood vessels and obtain clinical information based on anatomical structure and molecular level. At the same time, the rapid development of nonmolecular imaging technologies, such as intravascular imaging, which have the unique advantages of having intuitive accuracy and providing rich information to identify macrophage inflammation and inform targeted personalized treatment, has also been seen. In this review, we highlight recent methods and research hotspots in molecular and nonmolecular imaging of macrophages in atherosclerosis that have enormous potential for rapid clinical application.

Keywords: atherosclerosis; macrophage; molecular imaging; multimodal imaging; optical coherence tomography.

Figure 1

Macrophage evolution in progressive stages and the role of matrix metalloproteinases (MMP) in the late stages of atherosclerosis.

Figure 2

Examples of surface-enhanced Raman spectroscopy and optical imaging for macrophages in atherosclerosis. (A) SERS probe GNR techniques for detection of adhesion molecules expressed on the surface of macrophage cells (Raw264.7) [adapted from (14)]. (B) SERS spectra detected from Raw264.7 cells treated with LPS for different lengths of time (1, 3, and 5 h). The SERS spectra were averaged from ~80 to 235 spectra detected for each condition [adapted from (14)]. (C) Bioluminescence metabolic imaging showed energy metabolism in shoulder region of human atherosclerotic lesion in the common carotid artery [adapted from (16)]. (D) An aorta explanted from an Apoe^−/− Cx3cr1GFP/+CD11cYFP mouse fed WD and imaged with two-photon microscopy shows GFP, DP, and YFP cells in the wall [adapted from (17)]. (E) NIRF imaging of atherosclerotic plaques in ApoE KO mice. P-ICG2-PS-Lip was intravenously injected into ApoE KO mice via a tail vein, and the images were obtained by using a Maestro fluorescence imaging system [adapted from (18)]. (G) Ex vivo imaging with GB123 in human carotid plaque (above: unstable plaque + inhibitor, middle: unstable plaque, below: stable plaque) revealed high cathepsin activity, in yellow, was found in probe-treated unstable plaques [adapted from (19)]. (H) NIR fluorescence images of collected aorta from ApoE KO mice after 24 h injection of IONP-cRGD-NC, IONP-Col IV-tg-NC, IONP-NC [adapted from (20)].

Figure 3

Examples of MRI and nuclear imaging for macrophages in atherosclerosis. (A) Pre- and post-MPO-Gd and DTPA-Gd T1-TSE imaging in TS Apoe^−/− mice. Representative as-acquired (2-cm field-of-view) MR images and higher-magnification images of unstable plaque (R), plaque-free artery (L) and stable plaque (BA) before and 60 min after probe administration, with corresponding time-course of CNR (MPO-Gd, filled symbols; DTPA-Gd, open symbols) in L (squares), R (circles), and BA (triangles) [adapted from (53)]. (B) Representative PET/CT images of several experiments in ApoE^−/− and wild-type control mice after IV Macroflor injection. (C) Cardiac PET images with respective agents (above: Macroflor, below: [18F] FDG) [adapted from (54)].

Figure 4

Examples of nonmolecular imaging for macrophages in atherosclerosis. (A,B) OCT cross-section images of the atherosclerotic vessel lumen, the location indicated by the white arrow is the macrophage. (C,D) Macrophages with robust NIRF signals on OCT-NIRF, and its content can be judged by red signal intensity; Focal plaque with surface infiltration of lipid-laden macrophages [adapted from (70)].