## 3 Cardiovascular Disease
### Matrix Metalloproteinases  
Matrix metalloproteinases (MMPs) have an important role in extracellular matrix and plaque remodelling and are associated with the thinning of the fibrous cap and the destabilization of atherosclerotic plaques [80; 81]. [PERSON] et al. introduced a novel gadolinium-based MRI contrast agent (P947) to target MMPs in atherosclerotic plaques [82]. P947 was evaluated in vivo using ApoE- mice and ex vivo in hyperlipidaemic rabbits and human carotid artery endarterectomy specimens. This study demonstrated the preferential accumulation of P947 in atherosclerotic lesions  
Figure 11: In vivo MRI of Gd-labelled fibrinogen clots. (**A,D**), Coronary MRA before (**A**) and after (**D**) thrombus delivery. On both scans, no apparent thrombus is visible (circle). (**B,E**), Black-blood inversion recovery TFE scans before (**B**) and after (**E**) clot delivery (same view as (**A,D**). After thrombus delivery (**E**), three bright areas are readily visible (arrows and circle), consistent with location of thrombus. No apparent thrombus was visible on prethrombus (**B**) images (arrow and circle). (**C**), X-ray angiogram confirming MR finding of thrombus in mid-LAD (circle). (**F**), Magnified view of (**C**). LM indicates left main; LAD indicates left anterior descending artery; LCX indicates left circumflex artery. Reproduced with permission from [PERSON] et al., 2004 [77]. Figure 12: (**a**) Molecular MR imaging of thrombus in the descending thoracic aorta in an 82-year-old female patient using inversion recovery black-blood gradient-echo imaging (IR). In this patient, parasagittal IR post-contrast imaging was also performed to demonstrate the extent of the clot. The high local signal amplification allows for white spot imaging of the clot (arrow). (**b**) Corresponding multiplanar reconstruction from contrast-enhanced multislice CT demonstrating corresponding plaque in the aortic wall. At the cranial end of the plaque a small calcification is also visible (arrowhead). Reproduced with permission from [PERSON] et al., 2008 [78]. compared with non-targeted Gd-DOTA (Figure 13). This contrast agent has also been shown to distinguish dietary-induced variations in MMP-related enzymatic activity within plaques in an atherosclerotic model, supporting its utility as a clinical imaging tool for in vivo detection of arterial wall remodelling [83]. [PERSON] et al. have systematically reviewed alternative applications of the P947 probe for imaging the ECM [12]. In a more recent study, fluorescent-labelled activatable cell penetrating peptides (ACPPs) designed to target MMPs were tested in a rabbit model of plaque rupture [84]. Fluorescence enhancement was significantly higher in ruptured plaques ex vivo, suggesting that ACPP probes can selectively differentiate unstable from stable plaques (Figure 14). Taking advantage of the higher sensitivity of single photon emission computed tomography (SPECT), [PERSON] et al. proposed a technetium-99m-labelled monoclonal antibody targeted to MMP-1, for imaging atherosclerosis in a rabbit model [85]. Probe uptake was significantly higher in atherosclerotic arteries compared with control arteries, with further increased uptake in grade IV atheroma in comparison with neointimal or more stable lesions. In another study, technetium-99m-labelling of the broad MMP inhibitor (MPI) enabled ex vivo quantification of the reduction of MMP after dietary modification or statin therapy in atherosclerotic rabbit aortas [86]. In a further study, [PERSON] et al. used a novel indium \({}^{111}\)In-labelled tracer (RP782) with specificity for activated MMPs for molecular imaging of MMP activation in injury-induced vascular remodelling in ApoE-\({}^{/-}\) mice [87] using micro SPECT/CT. Figure 13: In vivo MRI of an ApoE-\({}^{/-}\) mouse before (arrow) and after P947 injection (arrowhead). After injection, significant contrast-enhancement appears in the atherosclerotic aortic wall as shown on the inset images of the aorta.