## 3 Cardiovascular Disease
### Atherosclerotic Arterial Disease
#### 3.2.3 Imaging Atherosclerosis
(**c**,**d**) Scatter plots showing significant (\(p<0.05\)) correlation between morphometric PAMV measurements (**c**) and lumen CSA measurements (**d**) on high-resolution DE-MRI (Delayed enhancement magnetic resonance imaging) images and on corresponding EvG-stained histological sections (n = 15). Scale bars: white, 250 \(\upmu\)m; black, 100 \(\upmu\)m. Values are expressed as means \(\pm\) s.d. MRI—magnetic resonance imaging, HFD—high fat diet, TOF—time of flight, PAMV—percentage atheroma/media volume, CSA—cross-sectional area. Reproduced with permission from [PERSON] et al., 2011 [57]. Figure 8: In vivo magnetic resonance imaging (MRI) comparison of vessel wall enhancement using the elastin (elastin-specific magnetic resonance contrast agent [ESMA]) and tropoelastin (TESMA) binding contrast agents in mice. (**A**), Fused maximum intensity projection (MIP) reconstructed magnetic resonance angiography and delayed-enhanced-MRI after administration of Gd-TESMA show focal uptake of Gd-TESMA in the brachiocephalic artery (BCA) of an atherosclerotic apolipoprotein E–deficient mouse. (**B–E**), MRI of the BCA acquired from a control animal, scanned 24 h apart, showed vessel wall uptake of Gd-ESMA (**B**,**C**), but no uptake of Gd-TESMA (**D**,**E**) because of the lack of tropoelastin in the absence of disease. (**F–M**), MRI of the BCA acquired from 2 different diseased animals showed enhancement of the vessel wall after administration of both agents because of the presence of both cross-linked elastin and tropoelastin in the atherosclerotic lesion. Ao indicates aortic; and L., left. Reproduced with permission from [PERSON] et al., 2018 [61]. Figure 7: (**A**,**E**), Cross-sectional pre-contrast MR images. (**B**,**F**), Corresponding DE MR images obtained after administration of elastin-specific contrast agent. (**C**,**G**), DE MR images fused with angiographic images. (**D**,**H**), Corresponding R1 maps obtained after administration of elastin-specific contrast agent. Uptake of elastin-specific contrast agent and R1 values are higher in diseased compared with control aortas. Reproduced with permission from [PERSON] et al., 2014 [60]. Collagen  
The differential expression of various collagen sub-types within atherosclerotic plaque and at different stages of plaque progression makes it an attractive target for atherosclerosis imaging. Type I collagen is the most abundant sub-type and accounts for up to two thirds of all collagen [62]. In an ex vivo immunoblotting study, [PERSON] et al. investigated the abundance of different subtypes of collagen in atherosclerotic carotid arteries in patients presenting with diabetes. They demonstrated significant accumulation of type III collagen in diabetic vessels and found that type III collagen was more predominant than type I [63]. [PERSON] et al. developed a Gd-DTPA-based MRI probe that binds to type I collagen (EP-3533) for molecular imaging of fibrosis [64]. More recently, [PERSON] et al. extended this approach by conjugating high density lipoprotein (HDL) based nanoparticles with EP-3533 and used it to image collagen in atherosclerotic plaque progression and regression in mice in vivo (Figure 9) [65]. Molecular imaging of collagen using EP-3533 has been extensively discussed in a review article by [PERSON] et al. [12]. Using a different approach, a collagen binding adhesion protein found in _Staphylococcus aureus_, called CNA35, was shown to selectively bind to type I and type II collagen [66; 67]. Healthy and atherosclerotic arteries have been imaged with both gadolinium and fluorescently labelled liposomes conjugated with CNA35 [68; 69]. Using positron emission tomography (PET), [PERSON] et al. demonstrated the feasibility of a novel platelet-collagen-receptor-glycoprotein (GP) VI radiotracer to target and selectively visualise collagen type I and III ex vivo in human carotid atherosclerotic plaques and in vivo in an ApoE\({}^{-/-}\) mouse model [70].