Articles in PresS. Am J Physiol Heart Circ Physiol (October 12, 2012). doi:10.1152/ajpheart.00583.2012 ͳ Advances in Molecular Imaging of Atherosclerosis and Myocardial Infarction: Shedding New ʹ Light on In-vivo Cardiovascular Biology ͵ Ͷ Alkystis Phinikaridou1,4, Marcelo Andia1,2,4, Ajay M. Shah3,4, and René M. Botnar 1,4,5 ͷ 1 Division of Imaging Science and Biomedical Engineering, King’s College London, London, UK 2 Radiology Department, School of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile ͺ 3 ͻ Cardiovascular Division, King’s College London, United Kingdom 4 ͳͲ 5 BHF Centre of Excellence, King’s College London, United Kingdom Wellcome Trust and EPSRC Medical Engineering Center, King’s College London, United Kingdom ͳͳ ͳʹ ͳ͵ ͳͶ Correspondence address: ͳͷ Alkystis Phinikaridou, PhD ͳ King’s College London, Division of Imaging Sciences and Biomedical Engineering ͳ The Rayne Institute, 4th Floor, Lambeth Wing, St Thomas’ Hospital ͳͺ London SE1 7EH, United Kingdom ͳͻ Tel: 020 7188 8386 ʹͲ Fax: 020 7188 5442 ʹͳ Email: [email protected] ʹʹ ʹ͵ ʹͶ ʹͷ ʹ ʹ ʹͺ ʹͻ ͵Ͳ ͵ͳ ͵ʹ ͳ Copyright © 2012 by the American Physiological Society. ͵͵ Abstract ͵Ͷ Molecular imaging of the cardiovascular system heavily relies on the development of new imaging ͵ͷ probes and technologies to facilitate visualization of biological processes underlying or preceding ͵ disease. Molecular imaging is a highly active research discipline that has seen tremendous growth ͵ over the past decade. It has broadened our understanding of oncologic, neurologic, and ͵ͺ cardiovascular diseases (CVD) by providing new insights into the in vivo biology of disease ͵ͻ progression and therapeutic interventions. As it allows for the longitudinal evaluation of biological ͶͲ processes it is ideally suited for monitoring treatment response. In this review, we will concentrate on Ͷͳ the major accomplishments and advances in the field of molecular imaging of atherosclerosis and Ͷʹ myocardial infarction, with a special focus on magnetic resonance imaging (MRI). Ͷ͵ ͶͶ PART A: Imaging of Atherosclerosis Ͷͷ Atherosclerosis related cardiovascular complications, primarily myocardial infarction and stroke, are Ͷ estimated to become the leading cause of death worldwide by the year 2020 (117). As “high-risk Ͷ vulnerable plaques” are often undetected until they cause life-threatening adverse events, an Ͷͺ increasing effort has been made to better understand plaque biology and vulnerability with a special Ͷͻ focus on the development of new targeted molecular imaging agents. Such agents may allow in vivo: ͷͲ 1) monitoring of plaque progression, 2) detecting of vulnerable plaque, 3) monitoring of the ͷͳ effectiveness of interventions, and 4) guiding of patient-specific medical treatment. Currently, a ͷʹ plethora of targeted imaging agents are available for the visualization of the major biological ͷ͵ processes involved in atherosclerosis both for experimental and clinical utilization. Some of these ͷͶ applications are summarized in Figure 1. ͷͷ ͷ Endothelial permeability and activation ͷ Increased endothelial cell permeability, dysfunction, and expression of surface adhesion molecules ͷͺ (E- and P-selectin) are considered to be the initiating events in atherogenesis. Increased endothelial ͷͻ leakage allows circulating low-density lipoprotein particles (LDL) (73) to passively diffuse into the ʹ Ͳ vessel wall whereas expression of adhesion molecules is responsible for the receptor-mediated ͳ recruitment of leukocytes (30). Additionally, endothelial dysfunction defined as the decrease in the ʹ bioavailability of nitric oxide promotes platelet activation and smooth muscle cell (SMC) proliferation ͵ (30). Functionally, endothelial dysfunction is associated with a paradoxical vasoconstriction in Ͷ response to acetylcholine both in humans (98) and ApoE-/- mice (7, 28). It precedes angiographic ͷ evidence of coronary artery disease (207) and is a predictor of future cardiovascular events (52). Recently, contrast-enhanced MRI with gadofosveset has been used to image endothelial permeability in an ApoE-/- mouse model of accelerated atherosclerosis (139) (Figure 1). Gadofosveset is a ͺ clinically approved gadolinium-based contrast agent that reversibly binds to serum albumin, resulting ͻ in a prolonged vascular presence and a 5-10 fold increase in relaxivity (r1) (16, 92). Gadofosveset Ͳ uptake was associated with mechanically damaged endothelium in a swine model of coronary injury ͳ (138), atherosclerosis-associated endothelial damage in ApoE-/- mice (139) (Figure 1), and leaky ʹ neovessels in human carotid and rabbit aortic plaque (96, 97). Furthermore, VHSPNKK-modified ͵ magnetofluorescent particles (VNP) targeting the VCAM-1 receptor (74, 121) and microparticles of Ͷ iron oxide (MPIO) (103, 104) (Figure 1) targeting the VCAM-1 receptor and/or P-selectin have been ͷ used to image activated endothelium in murine atherosclerotic plaque. Imaging of VCAM-1 leucocyte recruitment has also been achieved with a hybrid positron emission tomography/computed tomography (PET-CT) system using an ͺ has also been used to assess endothelial vasomotor responses in humans before and after ͻ administration of endothelial stressors (55, 128, 185). Interestingly, the extent of endothelial ͺͲ dysfunction correlated with local plaque burden (55, 185). 18 F-labeled small VCAM-1 affinity ligand (122). Finally, MRI ͺͳ ͺʹ Macrophage, metabolism and lipoproteins ͺ͵ Inflammatory macrophages participate in all phases of atherogenesis, including lesion initiation, ͺͶ progression, and complications (105). Initially recruited to the vessel wall as monocytes, resident ͺͷ macrophages uptake oxidized LDL via the scavenger receptor and subsequently transform into foam ͺ cells contributing to atheroma expansion. Macrophages also secrete several proteolytic enzymes and ͵ ͺ extracellular matrix proteins (e.g., elastin) that both increase plaque burden and destabilize the lesion. ͺͺ Finally, macrophage apoptosis (programmed cell death) leads to the development of an acellular lipid ͺͻ core. The ability of macrophages to endocytose foreign objects has been used as the basis of their ͻͲ imaging. Iron-oxide based magnetic nanoparticles (MNP) of variable size (SPIO, USPIO, VSOP) and ͻͳ stabilized with different surface coating materials (e.g. dextran or citrate) have been shown to be non- ͻʹ specifically endocytosed by macrophages in hyperlipidemic rabbits (35, 57, 66, 88, 114, 152, 155, ͻ͵ 158, 164, 214), mice (Figure 1) (100) and human carotid plaques (64, 87, 181, 182, 188-190), and ͻͶ are used to image macrophage density. These nanoparticles are biocompatible and able to exert a ͻͷ strong T2 and T2* effect (R2>R1) resulting in a signal drop visible on T2-weighted (T2W) and T2*- ͻ weighted (T2*W) MR images 24-48h after administration. Histological correlation showed co- ͻ localization of the MNPs with macrophage-rich regions of the plaque whereas little uptake was ͻͺ observed in SMCs and endothelial cells. Magenotofluorescent nanoparticles that combine MRI with ͻͻ optical imaging properties by additionally carrying a fluorescent moiety (e.g., near-infrared fluorescent, ͳͲͲ [NIRF]) are also available and have been used to quantify the cellular distribution of nanoparticles ͳͲͳ (70). ͳͲʹ (N1177) for CT imaging (65) of macrophages. Receptor-based macrophage imaging has also been ͳͲ͵ achieved by using gadolinium-loaded micelles targeting the macrophage scavenger receptor (Figure ͳͲͶ 1) (3), the cannabinoid receptor (CB2-R), and neutrophil gelatinase-associated lipocalin 2 (NGAL) in ͳͲͷ murine plaques (3, 116, 183, 184). 64 Cu-labeled nanoparticles allowed for PET/CT imaging (127) and crystalline iodinated particles ͳͲ On a functional level, the glucose analogue [18]-fluorodeoxyglucose (18FDG), that competes ͳͲ with glucose for uptake into metabolically active cells, has been used to image inflammatory cell ͳͲͺ activity non-invasively by PET, with or without complementary CT or MRI scans, in humans (151, 159) ͳͲͻ and rabbits (13). Experiments in humans showed that the net ͳͳͲ (plaque/integral plasma) in symptomatic lesions was 27% higher than in the contralateral ͳͳͳ asymptomatic lesions. There was no measurable ͳͳʹ arteries. Autoradiography of excised plaques confirmed accumulation of deoxyglucose in ͳͳ͵ macrophage-rich areas of the plaque. Ͷ 18 FDG accumulation rate 18 FDG uptake in angiographically normal carotid ͳͳͶ Imaging plaque lipids is also essential as lipid-rich plaques are more likely to rupture. ͳͳͷ labeled LDL particles have been used to image subjects with large tendon xanthomas secondary to ͳͳ homozygous familial hypercholesterolemia or sitosterolemia over 20 years ago (47). On the molecular ͳͳ level, gadolinium-loaded LDL-based nanoparticles (GdDO3A-OA-LDL) (Figure 1) (213) and ͳͳͺ recombinant HDL-like nanoparticles (Figure 1) (25, 41) have also been developed to image ͳͳͻ atherosclerosis in mice. Furthermore, the oxidized LDL receptor (LOX-1) and oxidized plaque LDL ͳʹͲ particles have been imaged using antibodies that bind to the LOX-1 receptor (94) and oxidation ͳʹͳ specific epitopes (11, 186, 191) using single photon emission computed tomography (SPECT), CT, ͳʹʹ and MRI. Finally, diffusion weighted imaging (DWI) that generates endogenous contrast between ͳʹ͵ plaque components based on the characteristic diffusion coefficients of water molecules has been ͳʹͶ used to visualize plaque components including lipids both in vivo and ex vivo (Figure 1) (143, 187). 99m Tc- ͳʹͷ ͳʹ Enzymatic activity and apoptosis ͳʹ Matrix metalloproteinases (MMPs) degrade extracellular matrix proteins including elastin and ͳʹͺ collagen and therefore participate in plaque destabilization (43, 50, 163, 179). MMP expression was ͳʹͻ show to be increased in vulnerable atherosclerotic plaque undergoing positive arterial remodeling ͳ͵Ͳ (136, 156). In vivo SPECT using a ͳ͵ͳ to the active catalytic site of MMPs (58) demonstrated focal signal enhancement of carotid plaque in ͳ͵ʹ atherosclerotic ApoE-/- mice (154). In vivo and ex vivo MRI for the detection of MMP-rich plaques was ͳ͵͵ achieved with the use of a gadolinium-based MMP sensitive contrast agent (P947) (91). Gadolinium ͳ͵Ͷ quantification and MRI showed a preferential accumulation of P947 in rabbit atherosclerotic lesions ͳ͵ͷ compared ͳ͵ endarterectomy specimens, P947 facilitated discrimination between histologically defined MMP-rich ͳ͵ and MMP-poor plaques. with the 123 non-targeted I- or 125 I-radiolabeled agent derived from a compound that binds compound, Gd-DOTA. Moreover, using human carotid ͳ͵ͺ Myeloperoxidase (MPO) is secreted by activated macrophages at multiple stages of plaque ͳ͵ͻ development and generates the oxidant species hydrochlorous acid (10, 29, 129, 177, 178) that ͳͶͲ modifies LDL, activates MMPs, induces endothelial cell apoptosis, inactivates nitric oxide, and triggers ͷ ͳͶͳ tissue factor release. In vivo MR imaging of MPO has been achieved with the development of a ͳͶʹ gadolinium-based MO sensor bis-5HT-DTPA(Gd) [MPO(Gd)] in rabbit atherosclerotic plaques (Figure ͳͶ͵ 1) (144, 150). ͳͶͶ Cathepsins expressed by plaque macrophages, endothelial cells, and SMCs, can also ͳͶͷ degrade extracellular matrix proteins via their elastase and/or collagenase properties and promote ͳͶ plaque destabilization (180). In vivo imaging of cathepsin B was achieved with protease-activated ͳͶ NIRF probes (20, 130, 206). NIRF imaging, using this probe, and in combination with MRI showed ͳͶͺ that murine atherosclerotic lesions were fluorescently labeled 24h post injection and the signal ͳͶͻ colocalized with cathepsin B and macrophage immunopositive regions. Recently, a new 2D ͳͷͲ intravascular NIRF pullback catheter combined with a cysteine protease-activatable probe (ProSense) ͳͷͳ provided high-resolution in vivo mapping of arterial inflammation in coronary-sized arteries and ͳͷʹ revealed increased inflammation in atheromata and in stent-induced arterial injury (69). ͳͷ͵ Lastly, cellular apoptosis is also a key feature of plaque progression and stability. Imaging of ͳͷͶ apoptosis is mainly based on targeting annexinA5 that binds to phosphatidylserine, a membrane ͳͷͷ phospholipid that becomes externalized on the extracellular leaflet of the cell membrane in apoptotic ͳͷ cells. Apoptosis has been visualized ex vivo with 99mTc-annexin injected in atherosclerotic rabbits (86). ͳͷ Quantitative annexin uptake was 9.3-fold higher in lesion versus non-lesion areas and the uptake ͳͷͺ paralleled lesion severity and macrophage burden. No correlation was observed with SMCs. In vivo ͳͷͻ detection of plaque instability using ͳͲ atherosclerosis 6h post injection of the tracer (77). Higher tracer uptake correlated with ͳͳ histopathological features characteristic of unstable plaque, including substantial macrophage ͳʹ infiltration and intraplaque hemorrhage. Immunohistochemical analysis demonstrated specific binding ͳ͵ of annexinA5 to macrophage cell membranes. Recently, MRI and fluorescence imaging of apoptosis ͳͶ has been achieved using annexinA5-functionalized bimodal nanoparticles in murine atherosclerotic ͳͷ plaques (Figure 1) (196). In vivo T1-weighted (T1W) MRI of the abdominal aorta revealed enhanced ͳ uptake of the annexinA5-micelles as compared to control-micelles, which corroborated with ex vivo ͳ NIRF images of the excised aortas. Confocal laser scanning microscopy demonstrated that the 99m Tc-annexinA5 was also shown in patients with carotid-artery ͳͺ targeted agent was associated with macrophages and apoptotic cells, whereas the non-specific ͳͻ control agent showed no clear uptake by such cells. ͳͲ ͳͳ Neovascularization ͳʹ Neovascularization is also considered a vulnerability component as it can promote intraplaque ͳ͵ haemorrhage and cholesterol deposition (113, 201). Dynamic contrast enhanced MRI using ͳͶ extravascular non-specific gadolinium contrast agents e.g., Gd-DTPA (14, 75, 76) and intravascular ͳͷ agents (B-22956/1, gadofosveset) (26, 95, 97) was shown to correlate with plaque neovascularization. ͳ In addition to VCAM-1, described above, endothelial cells of neovessels express integrin Įvȕ3 (63). ͳ Imaging of plaque neovessels has been achieved with gadolinium-coated perfluorocarbon ͳͺ nanoparticles conjugated with an arginine-glycine-aspartic acid (RGD) peptidometic molecule. In vivo ͳͻ MRI experiments performed in cholesterol-fed rabbits with intimal hyperplasia, showed signal ͳͺͲ enhancement after administration of the Įvȕ3-targeting particles that colocalized with Įvȕ3 endothelial ͳͺͳ cells lining the vasa vasorum. The same particles have been used as vehicles for antiangiogenic drug ͳͺʹ delivery in rabbit aortas (211, 212). A low-molecular weight peptidomimetic of Arg-Gly-Asp (mimRGD) ͳͺ͵ grafted to gadolinium diethylenetriaminepentaacetate (Gd-DTPA-g-mimRGD) has also been used to ͳͺͶ image neovascularization in ApoE-/- mice (Figure 1) (12). Additionally, Įvȕ3 imaging in cancer and MI ͳͺͷ was also feasible using ultrasound (36), PET (54), SPECT (106), NIRF (90), and MRI (161) agents. ͳͺ ͳͺ Extracellular matrix and vascular remodeling ͳͺͺ The balance between the production and degradation of extracellular matrix proteins (collagen, ͳͺͻ elastin, proteoglycans) is essential for atheroma expansion and stability. Multi-contrast in vivo MRI ͳͻͲ has been used to evaluate the thickness and integrity of the fibrous cap in human carotid disease (53, ͳͻͳ 109, 217). The recent development of a small molecular weight gadolinium based elastin-targeting ͳͻʹ contrast agent, enabled in vivo MR imaging of atherosclerosis progression in the brachiocephalic ͳͻ͵ artery of ApoE-/- mice (Figure 1) (101) and visualization of vascular remodeling after stent-induced ͳͻͶ coronary injury in a swine model (202). Furthermore, CNA-35 functionalized nanoparticles have been ͳͻͷ used to image aortic aneurysm progression (84) and atherosclerosis (31, 195). Ex vivo application of ͳͻ magnetization transfer (MT) was shown to discriminate the collagenous fibrous cap and the media ͳͻ from the lipid core and adventitia in human endarterectomy samples (Figure 1) (133, 142). ͳͻͺ The direction of vascular remodeling (expansive versus constrictive) and its association with ͳͻͻ plaque vulnerability has recently been explored. Traditionally, positive remodeling defined as the ʹͲͲ increase of the outer vessel wall area was considered advantageous as it prevents luminal obstruction ʹͲͳ (48). However, additional evidence showed that it is also associated with plaque vulnerability (137) ʹͲʹ and may lead to clinical sequelae including myocardial infarction (MI) and stroke. In vivo assessment ʹͲ͵ of vascular remodeling in humans has been primarily achieved with intravascular ultrasound (IVUS) ʹͲͶ and CT [66-68]. Importantly, recent prospective studies using IVUS and/or CT have identified plaque ʹͲͷ burden and positive arterial remodelling as a good surrogate marker for high-risk plaques (15, 115, ʹͲ 174). Non-invasive imaging of vascular remodeling by MRI has also been feasible in pre-clinical ʹͲ models of atherosclerosis (141, 173), patients with coronary (81, 107) and carotid artery disease (5, ʹͲͺ 194). ʹͲͻ ʹͳͲ Intraplaque hemorrhage and thrombus ʹͳͳ Intraplaque hemorrhage is a major contributor to plaque vulnerability, and mural thrombosis is the ʹͳʹ end-point of plaque rupture that may initiate myocardial injury due to acute vessel occlusion. Non- ʹͳ͵ contrast enhanced MR imaging of red-blood cell rich thrombus or hemorrhage relies on the changes ʹͳͶ of T1 and T2 relaxation times of different oxygenation states of hemoglobin in erythrocytes. This ʹͳͷ approach has been used to visualize and estimate the age of hematoma (24, 49), venous thrombosis ʹͳ (112, 145), intraplaque hemorrhage (111), arterial thrombus (27, 200), and intracoronary thrombus ʹͳ (Figure 1) (71). Detection of thrombus size and protein content has also been achieved by ʹͳͺ magnetization transfer and diffusion weighted MRI applied ex vivo and in vivo (80, 140, 199, 200). ʹͳͻ Moreover, the development of targeted contrast agents for fibrin (Figure 1) (8, 9, 38, 72, 162, 168- ʹʹͲ 171, 175, 210), platelets (72, 85, 155), and Į2-Įntiplasmin (108) significantly improved the detection ʹʹͳ and age-characterization of thrombus. Activated platelets have additionally been targeted via their ͺ ʹʹʹ gpIIb/IIIa receptor for non-invasive molecular imaging of intravascular thrombosis (4, 203, 204). These ʹʹ͵ contrasts agents should ideally help to better visualize thrombus, and also differentiate between acute ʹʹͶ and chronic thrombus, and therefore guide further medical interventions. ʹʹͷ ʹʹ PART B: Imaging of Myocardial Infarction ʹʹ Acute myocardial infarction (AMI) is still one of the main causes of morbidity in Western countries ʹʹͺ (208). Myocardial ischemia progresses with the duration of coronary occlusion, and the delay in time ʹʹͻ to reperfusion determines the extent of irreversible necrosis extending from the sub-endocardial ʹ͵Ͳ layers towards the epicardium. MRI is an extremely powerful modality for the assessment of function, ʹ͵ͳ perfusion, and tissue characterization in AMI in a single examination. In particular, it can detect the ʹ͵ʹ location and extent of necrosis (147), infarct size, myocardial edema (myocardium at risk), ʹ͵͵ microvascular obstruction leading to intramyocardial hemorrhage (44), and assess ventricular ʹ͵Ͷ volumes and function for the evaluation of post-infarction remodeling (51). In this section we will focus ʹ͵ͷ on the use of MRI in the detection of the area at risk, infarct size, and salvaged myocardium. ʹ͵ ʹ͵ Detection of myocardial ischemia (area at risk, infarct size, salvaged myocardium) ʹ͵ͺ The area at risk is defined as the myocardial area related to an occluded coronary artery with ʹ͵ͻ complete absence of blood flow whereas the infarct size represents the sub-region within the area at ʹͶͲ risk that undergoes irreversible damage and progresses to complete tissue necrosis. Subsequently, ʹͶͳ the salvaged myocardium corresponds to the region of the area at risk that experiences reversible ʹͶʹ damage. Studies have shown that the duration of ischemia is the major factor determining the fraction ʹͶ͵ of the area at risk that progresses to become irreversibly damaged infarcted region (147, 148). ʹͶͶ Traditionally, the myocardium at risk has been measured by SPECT, using the injection of a ʹͶͷ technetium-based tracer (160), and by contrast echocardiography (68). Over the last years, both ʹͶ preclinical and clinical studies have shown that T2W MRI sequences, which are sensitive to the ʹͶ concentration of water-bound protons can be used to visualize and quantify the area at risk. The high ʹͶͺ signal intensity on the T2W images is indicative of higher tissue water content and may reflect ͻ ʹͶͻ myocardial inflammation and tissue edema (Figure 2) (42). In an early experimental study in dogs the ʹͷͲ mean T2 relaxation time for one-day old infarcted regions was significantly higher from that of the ʹͷͳ remote myocardium. Concomitantly, the percent water content of the infarcted area was significantly ʹͷʹ greater than that of normal regions. Such changes resulted in a linear correlation between the T2 ʹͷ͵ relaxation time and percent water content (59). Later studies in animal models verified the correlation ʹͷͶ of the area at risk measured by T2W MRI images with corresponding histological sections in swine ʹͷͷ (46) and canine (2) models of MI. The latter study also demonstrated that the T2 hyperintense area ʹͷ more closely resembled the hypokinetic zone identified on displacement encoding with stimulated ʹͷ echoes (DENSE) systolic strain maps. Interestingly, some of these hypokinetic areas showed a partial ʹͷͺ recovery of function on follow up studies of chronic MI. Moreover, quantitative T2 mapping reliably ʹͷͻ identified myocardial edema without the limitations encountered by T2W short tau inversion recovery ʹͲ imaging (T2-STIR), and may therefore be clinically more robust in showing acute ischemic injury ʹͳ (198). ʹʹ For diagnostic purposes it is essential to accurately identify not only the area at risk but also ʹ͵ the actual infarct size and salvaged myocardium in order to differentiate between irreversible (infarct) ʹͶ and reversible (edema, ischemia) areas of myocardial damage. Longer durations of ischemia ʹͷ generally produce more transmural infarcts as opposed to infarcts with increasing circumferential ʹ extent. Thus, the transmural extent of the infarction is inversely related to the extent of salvaged ʹ myocardium. The extent of the salvaged area at risk contains prognostic information and may serve ʹͺ as a therapeutic target. A better differentiation between the areas of reversible and irreversible ʹͻ damage can be achieved using delayed enhancement imaging with non-specific gadolinium contrast ʹͲ agents (e.g., Gd-DTPA). Contrast-enhanced images can be acquired early or late after contrast ʹͳ administration. ʹʹ ʹ͵ Early gadolinium enhancement (EGE) for measuring area at risk ʹͶ The hyperenhanced region on EGE, taken about 2 minutes after contrast administration, was shown ʹͷ to correlate with the area at risk derived from T2W images in patients with successfully reperfused ͳͲ ʹ AMI who underwent an MRI examination within 4 days after the event (102). The hyperenhanced ʹ region on EGE extended transmurally and was consistently larger than that on late gadolinium ʹͺ enhancement MRI. The relative peri-infarct zone was calculated as the difference in hyperenhanced ʹͻ regions between EGE and LGE, and normalized to the individual infarct size. The relative peri-infarct ʹͺͲ zone was inversely correlated with the transmurality of infarction and the time from symptom to ʹͺͳ reperfusion. Furthermore, a pre-clinical study in rats (132) showed that the enhanced region ʹͺʹ overestimated infarct size immediately after the injection of Gd-DTPA (5-7 minutes), although 40 ʹͺ͵ minutes post injection the area of enhancement decreased and matched the infarct size. ʹͺͶ ʹͺͷ Late gadolinium enhancement (LGE) for measuring infarct size and salvaged myocardium ʹͺ Preclinical studies in dogs demonstrated that LGE distinguishes between reversible and irreversible ʹͺ ischemic injury independent of wall motion and infarct age (37, 78). Non-viable infarcted tissue is ʹͺͺ usually seen as an area of “hyperenhancement” after contrast injection. This work was further ʹͺͻ validated when higher gadolinium concentrations were measured in the infarcted area by regional ʹͻͲ electrolyte concentrations using electron probe x-ray microanalysis (146). Contrast uptake in acute MI ʹͻͳ occurs because of the expansion of the extracellular space due to edema and inflammation, and ʹͻʹ cellular breakdown that allow the contrast agent to enter the intracellular space. The clinical value of ʹͻ͵ LGE is that: (i) the transmural extent of the infarct on day 3 was shown to be a better predictor of ʹͻͶ improvement in contractile function than the actual occlusion time in animal models (61), and (ii) the ʹͻͷ transmurality of the infarct was also shown to predict myocardial viability and recovery of contractile ʹͻ function after revascularization in humans (Figure 2) (22, 79, 157). ʹͻ Finally, a combination of T2W, LGE, and perfusion MRI imaging has been used. A pig model ʹͻͺ of reperfused MI showed that first pass perfusion MRI most accurately reflected the infarct area, and ʹͻͻ that the high signal intensity on T2W images reflects both irreversibly and reversibly injured, but ͵ͲͲ essentially viable, peri-infarct zone (23). An imaging approach combining LGE and T2W MRI in ͵Ͳͳ patients with acute MI and successful reperfusion 3 +/- 3 days after the event showed that the high ͵Ͳʹ signal intensity on T2W MRI reflected reversible myocardial damage and LGE reflected irreversibly ͳͳ ͵Ͳ͵ injured myocardium (42). Combination of T2W MRI and LGE was also used to accurately differentiate ͵ͲͶ acute from chronic MI (1). Although chronic infarcts are relatively acellular they also enhance with ͵Ͳͷ gadolinium agents because of increased extracellular space due to fibrosis and decrease in the ͵Ͳ washout kinetics of the contrast agent due to the collagenous nature of the remodeled myocardium. ͵Ͳ ͵Ͳͺ MRI versus SPECT imaging of myocardial infarction ͵Ͳͻ The main advantage of MRI LGE is its spatial resolution of 1–2 mm (in plane) contrary to about 10 ͵ͳͲ mm with SPECT scans (205). The superior spatial resolution makes LGE MRI more suitable for the ͵ͳͳ detection of sub-endocardial infarcts when perfusion by SPECT appears unaltered or when the ͵ͳʹ infarcts themselves were undetected by SPECT (67, 82, 205). Furthermore, comparisons between ͵ͳ͵ P7F WHWURIRVPLQ perfusion ͵ͳͶ patients with ST-segment elevation myocardial infarction provided the most direct validation that T2 ͵ͳͷ abnormalities represent the area at risk (18). SPECT imaging and T2W short tau inversion recovery (T2-STIR) MRI in ͵ͳ ͵ͳ MRI versus PET imaging of myocardial infarction ͵ͳͺ The main advantage of MRI LGE is its spatial resolution of 1-2 mm (in plane) contrary to about 2-4 ͵ͳͻ mm with PET scans. Similarly to SPECT, PET images are also less sensitive in identifying sub- ͵ʹͲ endocardial infarcts compared to LGE MRI (83, 89). ͵ʹͳ ͵ʹʹ Targeted molecular imaging of myocardial infarction ͵ʹ͵ Although anatomic, functional, perfusion, and infarct size imaging has been validated and the ͵ʹͶ prognostic value of these measurements is widely accepted, the application of molecular imaging ͵ʹͷ using targeted contrast agents may enable the identification of pathologically altered biological ͵ʹ processes that would allow early intervention before the disease progresses to the symptomatic ͵ʹ stage. In the next section we will focus on the biological processes involved in myocardial infarction ͵ʹͺ and post infarct remodeling and discuss the availability of molecular targets allowing their ͳʹ ͵ʹͻ visualization. Representative imaging examples of these biological processes are summarized in ͵͵Ͳ Figure 2. ͵͵ͳ ͵͵ʹ Apoptosis and necrosis in MI ͵͵͵ Hours after the onset of ischemia, cardiomyocyte death occurs via two distinct pathways; apoptosis ͵͵Ͷ and necrosis. Although LGE MRI, described above, provides an accurate measure of infarct size, it ͵͵ͷ does not differentiate between these biological processes. It is evident that cells that show early ͵͵ features of an apoptotic program may have the potential to be salvaged if they could be detected ͵͵ early. Similarly to atherosclerosis, imaging of apoptosis in MI is mainly based on targeting either ͵͵ͺ annexinA5 or exposed DNA fragments. Imaging of annexinA5 and/or differentiation of apoptosis from ͵͵ͻ necrosis has been achieved with 99Tc-SPECT (40, 62, 153) fluorescence imaging (34), and MRI (165, ͵ͶͲ 166). The spatial and temporal presence of macrophages in the infarcted region has been imaged ͵Ͷͳ with different modalities. Magnetofluorescent cross-linked iron-oxide nanoparticles (CLIO-Cy5.5) ͵Ͷʹ injected intravenously two days after experimental MI were detected two days later in the infarcted ͵Ͷ͵ region of the heart using T2*W MRI (Figure 2) (165). Recently, a DNA-binding Gd chelate for the ͵ͶͶ detection of cell death by MRI has also been developed (45). ͵Ͷͷ ͵Ͷ Inflammation and wound healing in MI ͵Ͷ Activation of the vascular endothelium is crucial for leucocyte recruitment. PET/CT imaging of ͵Ͷͺ vascular adhesion molecule-1 (VCAM-1) expressed on endothelial cells has been achieved using a ͵Ͷͻ tetrameric peptide ͵ͷͲ PET image, delayed hyperenhancement after iodine injection in the CT image, and a high signal on ͵ͷͳ autoradiography. Monocytes recruited to the injured myocardium (tissue monocytes/macrophages) ͵ͷʹ from the spleen and bone marrow reservoirs play a central role in infarct healing (123). In a mouse ͵ͷ͵ model of MI, it has been shown that the recruitment involves a biphasic process in which Ly6-Chigh ͵ͷͶ monocytes dominate the first 4 days after the event to remove cellular debris whereas Ly6-Clow F-4V (Figure 2) (122). 7KH infarcted myocardium showed a strong signal in the 18 ͳ͵ ͵ͷͷ appear between days 5-10 days to promote tissue repair and resolution of inflammation (126). ͵ͷ Insufficient or excessive recruitment of monocytes into the infarcted area has been shown to impair ͵ͷ wound healing in preclinical (135) and clinical studies (192). ͵ͷͺ dependent infiltration of injected biochemically inert nanoemulsions of perfluorocarbons (PFCs) into ͵ͷͻ the border zone of infarcted areas in murine injury models, and histology demonstrated a co- ͵Ͳ localization of PFCs with cells of the monocyte/macrophage system (Figure 2) (39). Myocardial ͵ͳ inflammation was also visualized with ͵ʹ signal showed significantly increased uptake in the infarcts of mice on day 5 after coronary ligation ͵͵ (standardized uptake value 2.7 r 0.1) when compared with myocardium in control mice (1.3 r 0.2; p ͵Ͷ < 0.01). On day 14, the ͵ͷ Interestingly, there were differences between the activity in non-infarcted remote myocardium on day ͵ 5 after MI and control hearts (percent injected dose/gram of tissue, remote 8.9 r 0.5; control 5.1 r ͵ 1.0; p < 0.05). The MRI component of hybrid datasets enabled the precise definition of the infarct area ͵ͺ and analysis of anatomic and functional parameters (93). In addition to imaging resident macrophages ͵ͻ using iron-particels by T2*W MRI (Figure 2), other studies showed the feasibility of tracking the ͵Ͳ distribution of iron-labeled macrophages by injecting the contrast agent prior to MI and then imaging ͵ͳ the animals post-MI (110, 216). These studies demonstrated that pre-loaded macrophages infiltrate in ͵ʹ the infarcted myocardium up to day 4 post-MI, consistent with histological studies validating the ͵͵ presence of CD68 macrophages. However, MPIOs showed persistent localization in the infarct even ͵Ͷ 14 days post-MI whereas histological studies showed a progressive decrease of macrophage content ͵ͷ 4 days post-MI (215). A combination of fluorescence molecular tomography (FMT-CT) and physiologic ͵ MRI imaging was used to specifically image Ly6-Chigh monocytes and their role in infarct healing ͵ (135). 18 18 FDG-PET 18 FDG signal approached control values (MI 1.6 r 0.1; remote 1.4 r 0.1). Enzymatic activity in MI H/(19)F MRI at 9.4 T revealed a time- FDG-PET (Figure 2) (6, 93). The time course of ͵ͺ ͵ͻ (1) ͳͶ ͵ͺͲ Monocytes/macrophages are active cells secreting a variety of enzymes and cytokines. ͵ͺͳ Myeloperoxidase (MPO) is an inflammatory enzyme abundantly expressed in neutrophils that induces ͵ͺʹ production of hypochlorous acid (HOCl) which is cytotoxic. MPO is released post-MI (126) and ͵ͺ͵ although it does not significantly affect tissue necrosis it has a profound adverse effect on LV ͵ͺͶ remodeling and function (197). MPO in MI has been imaged using an activable MPO-Gd contrast ͵ͺͷ agent (Figure 2) (21, 124) that is first radicalized by MPO and then either spontaneously oligomerizes ͵ͺ or binds to matrix proteins, all leading to enhanced r1 relaxivity and delayed washout kinetics. In a ͵ͺ serial imaging study, MPO activity in the myocardium peaked 2 days after coronary ligation in mice. ͵ͺͺ Finally, a fluorogenic sensor for monitoring peroxynitrite (ONOO(-)) and myeloperoxidase-mediated ͵ͺͻ hypochlorous acid (HOCl/OCl(-)) production has been developed and utilized for ex vivo imaging of ͵ͻͲ reactive oxygen/nitrogen species in myocardial ischemia (134). Another enzyme family actively ͵ͻͳ involved in myocardial healing is matrix metalloproteinases that are capable of degrading all types of ͵ͻʹ extracellular matrix proteins. In myocardial ischemia increased MMP activity may lead to infarct ͵ͻ͵ expansion that contributes to ventricular rupture and dilation. Imaging of MMPs and cathepsin activity ͵ͻͶ (ProSense) has been achieved with SPECT using a ͵ͻͷ and fluorescent modalities (Figure 2) (19, 93, 125). 99m Tc-labeled radiotracer (99mTc-RP805) (176) ͵ͻ ͵ͻ Neovascularization in MI ͵ͻͺ Angiogenesis occurs naturally after MI to restore perfusion with oxygen and nutrients to the ischemic ͵ͻͻ myocardium. Several imaging modalities have been developed to image angiogenesis mainly by ͶͲͲ targeting the Įvȕ3 integrin, expressed on the cell surface of proliferating endothelial cells and the ͶͲͳ vascular endothelial growth factor (VEGF). Serial in vivo dual-isotope SPECT imaging with an ͶͲʹ labeled Įvȕ3-targeted agent demonstrated focal radiotracer uptake in hypoperfused regions of canine ͶͲ͵ myocardium where angiogenesis was stimulated. There was a 4-fold increase in myocardial ͶͲͶ radiotracer uptake in the infarcted region associated with histological evidence of angiogenesis and ͶͲͷ increased expression of the Įvȕ3 integrin (106). A novel compound called Regioselectivity ͶͲ Addressable Functionalized Template-RGD (RAFT-RGD) is composed of four cyclo(RGDfK) ͳͷ 111 In- ͶͲ sequences tethered on a cyclodecapeptide that specifically binds to the Įvȕ3 integrin and is co- ͶͲͺ internalized with the receptor, suggesting increased affinity of the peptide scaffold for the Įvȕ3 integrin. ͶͲͻ Tthe infarcted area was readily visible in vivo in a rat model of reperfused MI by SPECT with the ͶͳͲ 99m Ͷͳͳ Moreover, a PET (18F-Galakto-RGD) agent, carrying the cyclic Arg-Gly-Asp (cRGD) peptidic Ͷͳʹ sequence that specifically binds to the Įvȕ3-targeting agent was used to assess the time course of Ͷͳ͵ post-MI angiogenesis in rats (60). In this model, focal accumulation in the infarcted area started at ͶͳͶ day 3, peaked between 1 and 3 weeks, and decreased to baseline at 6 months after reperfusion (60). Ͷͳͷ The feasibility for translating the preclinical work in the clinical setting was demonstrated when the Ͷͳ same agent was later used in a patient two weeks after MI and PCI (99). Another PET tracer (64Cu- Ͷͳ DOTA-VEGF121) showed minimal baseline myocardial uptake that increased significantly at day 3 Ͷͳͺ after MI and remained elevated for 2 weeks post-MI, after which it returned to baseline levels (Figure Ͷͳͻ 2) (149). Finally, cyclic Asn-Gly-Arg (cNGR)–labeled paramagnetic quantum dots (pQDs) have been ͶʹͲ developed for MRI imaging of angiogenesis (131). The tripeptide cNGR homes specifically to CD13, Ͷʹͳ an aminopeptidase that is strongly upregulated during myocardial angiogenesis. Injection of cNGR- Ͷʹʹ pQDs resulted in a strong negative contrast that was located mainly in the infarcted myocardium of Ͷʹ͵ mice 7 days after surgery and up to 2 hours after intravenous contrast agent administration. This ͶʹͶ negative contrast was significantly less in MI mice injected with unlabeled pQDs and in sham- Ͷʹͷ operated mice injected with cNGR-pQDs. Validation with ex vivo 2-photon laser scanning microscopy Ͷʹ revealed a strong colocalization of cNGR-pQDs with vascular endothelial cells. Tc-RAFT-RGD compound but not with the negative control 99m Tc-RAFT-RAD (Figure 2) (32). Ͷʹ Ͷʹͺ Extracellular matrix in MI Ͷʹͻ The extracellular matrix plays a fundamental and increasingly more appreciated role in acute MI and Ͷ͵Ͳ infarct healing (33). During the inflammatory phase (rodents: 1h-48h, larger animals: 1h-4d), cytokines Ͷ͵ͳ and adhesion molecules become upregulated leading to leukocyte recruitment to the infarct zone. Ͷ͵ʹ Simultaneously, protease activation increases resulting in degradation of matrix proteins and Ͷ͵͵ generation of low molecular weight fragments that exert potent pro-inflammatory effects. Later on, as ͳ Ͷ͵Ͷ the acute inflammatory response subsides, mesenchymal cells infiltrate the infarct marking the Ͷ͵ͷ transition to the proliferative phase (rodents: 48h-5d, larger animals: 4d-14d) when myofibroblasts Ͷ͵ secret extracellular matrix and angiogenesis occurs. During the maturation phase (rodents: 5d-28d, Ͷ͵ larger animals: 14d-2months) the cellularity of the infarct decreases and lysyl-oxidase becomes Ͷ͵ͺ upregulated inducing matrix cross-linking and formation of a dense collagen-based scar. Formation of Ͷ͵ͻ a stable cross-linked extracellular matrix may shield the myofibroblasts from mechanical tension ͶͶͲ promoting quiescence. Conversely, overabundant collagen is also harmful because it hinders diastolic ͶͶͳ function and predisposes to arrhythmia. A type I collagen-specific peptide was identified using phage ͶͶʹ display and subsequently modified to improve affinity for collagen (17). The peptide conjugated to ͶͶ͵ gadolinium (EP-3533) enabled in vivo molecular MR imaging of fibrosis in a murine model of healed ͶͶͶ post infarction myocardial scarring (Figure 2) (56) and perfusion in a swine model (172). In the murine ͶͶͷ MI model, dynamic T1W MRI revealed that the washout time for EP-3533 was significantly longer ͶͶ (195 minutes) than those for Gd-DTPA (25 minutes) in regions of scarring. The area of enhancement ͶͶ correlated with the histological presence of collagen. The gadolinium concentration in scar was ͶͶͺ twofold higher compared to that of remote myocardium fifty minutes after EP-3533 injection. Another ͶͶͻ collagen specific peptide (collagelin) has been identified and used for SPECT imaging in a rat model ͶͷͲ of healed MI. Scintigraphic imaging following injection of Ͷͷͳ of the probe occurred in rats with MI, but not in controls (118). 99m Tc-labelled-collagelin showed that uptake Ͷͷʹ Newly synthesized collagen fibers in the ischemic myocardium become cross-linked into Ͷͷ͵ interconnected matrix. In addition to lysyl-oxidase, tissue and plasma transglutaminate (FXIII) are ͶͷͶ involved in this process (120). The in vivo enzyme activity of FXIII within the infarct was assessed Ͷͷͷ using an Ͷͷ the probe as a substrate and cross-links it to extracellular matrix proteins, leading to local entrapment Ͷͷ of Ͷͷͺ was associated with increased left ventricular dilation post-MI. Conversely, FXIII-treated mice showed Ͷͷͻ increased FXII activity and a faster resolution of the neutrophil response, enhanced macrophage ͶͲ recruitment, increased collagen content and augmented angiogenesis in the healing infarct. Finally, 111 111 Indium-labelled affinity peptide (111In-DOTA-FXIII) (Figure 2) (119, 193). FXIII recognizes In-DOTA-FXIII in the healing infarct. Decreased FXIII SPECT signal enhancement in the infarct ͳ Ͷͳ an MRI elastin-specific contrast agent showed increased deposition of elastin 7 days post-MI and Ͷʹ enabled visualization of myocardial remodeling in a mouse model of coronary ligation (209). The CNR Ͷ͵ peaked at 45 minutes post injection and it was significantly higher than for Gd-DTPA at 30 minutes. ͶͶ Changes in myocardial microstructure are important components of the tissue response to Ͷͷ infarction but are difficult to resolve with current imaging techniques. A novel technique, diffusion Ͷ spectrum MRI tractography (DSI tractography), has been shown to resolve 3D myofiber architecture. Ͷ Meshlike networks of orthogonal myofibers in infarcted myocardium may resist mechanical Ͷͺ remodeling but also probably increase the risk for lethal reentrant arrhythmias (167). Ͷͻ ͶͲ Outlook Ͷͳ Extensive progress in the field of molecular imaging of atherosclerosis and myocardial infarction has Ͷʹ enabled the in vivo detection of several biological processes involved in disease progression and Ͷ͵ resolution, and monitoring of interventions both in the preclinical and clinical setting using MRI and ͶͶ other imaging modalities. Developments of novel imaging agents with improved signal detection Ͷͷ properties, sensitivity, specificity, and favourable pharmacokinetics together with improvements in Ͷ MRI acquisition and image processing protocols have elucidated disease biology and therapeutic Ͷ mechanisms and shed more light on the longitudinal processes of atherosclerotic plaque progression Ͷͺ and instability, myocardial infarct healing, regeneration and repair. Translation of these new imaging Ͷͻ methods in the clinical arena is a very challenging aspect of molecular imaging, as it requires clinical ͶͺͲ trials with histological and clinical end-points that demonstrate utility of the complimentary information Ͷͺͳ to that already clinically available. However, if successful, it may revolutionize medicine as it may Ͷͺʹ allow more accurate disease assessment and personalized care in patients with atherosclerosis or Ͷͺ͵ after myocardial infarction. ͶͺͶ Ͷͺͷ Ͷͺ Ͷͺ ͳͺ Ͷͺͺ Ͷͺͻ Figure Legends ͶͻͲ Figure 1: Examples of available imaging modalities and targets for atherosclerosis. Ͷͻͳ Endothelium, Molecular MRI imaging of increased endothelial permeability in the brachiocephalic Ͷͻʹ artery of atherosclerotic ApoE-/- mice using gadofosveset and complementary Evan’s blue staining Ͷͻ͵ (139). MRI detection of endothelial adhesion molecules (VCAM-1 and P-selectin) in the aortic root of ͶͻͶ ApoE-/- mice using dual-targeted microparticles of iron oxide (MPIO)(103). Inflammation Ͷͻͷ (macrophages), MRI of macrophage content in the brachiocephalic artery of ApoE-/- mice after Ͷͻ administration of very small iron oxide particles (VSOP) using susceptibility gradient mapping (100). Ͷͻ MRI of macrophages in the abdominal aorta of ApoE-/- mice using immunomicelles targeting the Ͷͻͺ macrophage scavenger receptor (3). Copyright (2007) National Academy of Sciences, U.S.A. Lipids, Ͷͻͻ MRI of plaque lipid using recombinant LDL-like gadolinium-based nanoparticles in the thoracic aorta ͷͲͲ of ApoE-/- mice (213) - Reproduced by permission of The Royal Society of Chemistry. MRI of plaque ͷͲͳ lipid using recombinant HDL-like gadolinium-based nanoparticles in the abdominal aorta of ApoE-/- ͷͲʹ mice (41). Ex vivo MRI detection of lipids in human endarterectomy plaque using diffusion-weighted ͷͲ͵ imaging (DWI) (143). Enzymes, MRI of myeloperoxidase activity in atherosclerotic plaque of ͷͲͶ cholesterol-fed rabbits using an enzyme-sensitive gadolinium-based contrast agent [bis-5HT- ͷͲͷ DTPA(Gd) [MPO(Gd)] (150). Apoptosis, MRI of apoptosis in the abdominal plaque of ApoE-/- mice ͷͲ using ͷͲ angiogenesis in ApoE-/- mice using a low-molecular weight peptidomimetic of Arg-Gly-Asp (mimRGD) ͷͲͺ grafted to gadolinium diethylenetriaminepentaacetate (Gd-DTPA-g-mimRGD) (12). Extracellular ͷͲͻ matrix (elastin), MRI of intraplaque elastin in the brachiocephalic artery of ApoE-/- mice using a low- ͷͳͲ molecular weight gadolinium-based contrast agent (101). Extracellular matrix (collagen), Ex vivo ͷͳͳ MRI detection of collagen-rich fibrous cap in human endarterectomy plaques using magnetization ͷͳʹ transfer (142). Thrombus, MRI direct thrombus imaging (MRDTI) due to the T1 shortening effect of ͷͳ͵ methemoglobin (71). MRI of thrombus associated with plaque rupture in a rabbit model using a fibrin- annexinA5-functionalized bimodal nanoparticles ͳͻ (196). Neovascularization, MRI of ͷͳͶ binding gadolinium-labeled peptide (EP-1873) (9). All images were reprinted and/or adopted with ͷͳͷ permission. ͷͳ ͷͳ Figure 2: Examples of available imaging modalities and targets for myocardial infarction ͷͳͺ Edema, MRI detection of edema using T2W images in a subject 3 days after reperfused MI (42). ͷͳͻ Necrosis, Gadolinium-contrast enhanced MRI using Gd-DTPA detects irreversible myocardial ͷʹͲ ischemic injury due to increased extracellular space (79). Apoptosis, MRI detection of myocyte ͷʹͳ apoptosis using T2*W MRI after injection of annexin-based iron loaded nanoparticles (165). ͷʹʹ Inflammation (VCAM-1), PET/CT imaging of vascular adhesion molecule-1 (VCAM-1) expressed on ͷʹ͵ endothelial cells using the tetrameric peptide 18F-4V (122).Inflammation (Macrophages), 1H/19F-MRI ͷʹͶ detection of macrophages in cardiac ischemia after injection of perfluorocarbon nanoemulsions. Photo ͷʹͷ courtesy of Dr. Flogel. ͷʹ myocardium 7days post-MI (6). MRI detection of macrophage infiltration in infarcted myocardium ͷʹ using T2*W MRI after injection of very small very small iron oxide particles (VSOP). Photo courtesy of ͷʹͺ Dr. Protti. Enzymatic activity (MPO), MRI of MPO activity 2 days after MI in mice (124). Enzymatic ͷʹͻ activity (MMP), Fluorescence reflectance image shows higher matrix metalloproteinase sensor ͷ͵Ͳ activation in MI (red color) compared to the remote (yellow box) 6 days after the surgery (93). ͷ͵ͳ Neovascularization, SPECT imaging of myocardial angiogenesis in rats using the Įvȕ3 integrin- ͷ͵ʹ targeted tracer ͷ͵͵ using a ͷ͵Ͷ inversion recovery MRI detection of myocardial scarring in mice using a gadolinium-based collagen- ͷ͵ͷ binding contrast agent (EP-3533) (56). Extracellular matrix (transglutaminase), SPECT imaging of ͷ͵ transglutaminase activity using an ͷ͵ images were reprinted and/or adopted with permission. 18 FDG-PET detection of metabolically active macrophages in the murine 99m Tc-RAFT-RGD (32). PET imaging of the VEGF receptor in rat myocardial infarct 64 Cu-DOTA-VEGF121 tracer (149). Extracellular matrix (collagen), Delayed enhancement 111 Indium labeled affinity peptide (111In-DOTA-FXIII) (119). 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LIPIDS (cholesteryl esters, cholesterol crystals) MPO(Gd] M MPO IHC A) DWI DWI Lipids d 24h Post Pre Post v 3) MPO (Gd) Post A-O d) MyeloAnnexinA5 (Gd-micelles) peroxidase se O3 (G te Ex vivo DWI 4. ENZYMES LD L dD DL ( 5. APOPTOSIS (G rH gr in s 6. Neovascularization v (G d-i rec eng mm ep e un to r om r ice lle s) 24h Post tra iza ns tio fer n Post CO LL AG Ma gn EN et SGM 1. ENDOTHELIUM In Magnetization transfer ility tide Gd-peptide 04) (EP 2104) T1W Direct thrombus mbus imaging ging eset) C Permeab B 48h Post SPECT/CT day 3 11 1 (tra In-DO nsg TA -F l SP utam XIII ina EC T/C s T e) Collagen CE-IR Co en llag T2W 7. EXTRACELLULAR MATRIX (Days - weeks) 1. EDEMA (Hours) H 2O n ulatio accum M IR LGE MRI (EP3533) 64Cu-DOTA- Increased Ly-6hii 2. NECROSIS extracellular (Hours) Ly-6 Ly 6loo Gd space 6. NEOVASCULARIZATION ( 2 weeks) VEGF121 (PET) 3. APOPTOSIS (Hours) 5. ENZYMATIC ACTIVITY (Days - weeks) MMP 4. INFLAMMATION (Days) MPO 18F-4V PET/CT 19 FM RI DG 18 F VSOP T2*W MRI Day 14 post MI Fused 18FDG-PET & MRI 2 days post VSOP ET MPO-Gd T1w MRI -P Activatable able cence fluorescence sensor AnxCLIOCy5.5 VC AM -1 Mac r pha oge TAF ) -R c )T D grin 9m (9 RG inte T 3 EC v ( SP MRI IR LGE MRI (Gd-DTPA) T2*W MR I
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