Multimodality Cardiovascular Molecular Imaging, Part II

Abstract

HomeCirculation: Cardiovascular ImagingVol. 2, No. 1Multimodality Cardiovascular Molecular Imaging, Part II Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBMultimodality Cardiovascular Molecular Imaging, Part II Matthias Nahrendorf, MD, PhD, David E. Sosnovik, MD, Brent A. French, PhD, Filip K. Swirski, PhD, Frank Bengel, MD, Mehran M. Sadeghi, MD, Jonathan R. Lindner, MD, Joseph C. Wu, MD, PhD, Dara L. Kraitchman, VMD, PhD, Zahi A. Fayad, PhD and Albert J. Sinusas, MD Matthias NahrendorfMatthias Nahrendorf From the Centers for Systems Biology (M.N.) and Molecular Imaging Research (M.N., D.E.S., F.K.S.), and Cardiology Division (D.E.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Department of Biomedical Engineering (B.A.F.), University of Virginia, Charlottesville, Va; Radiology and Cardiovascular Nuclear Medicine (F.B.), Johns Hopkins University School of Medicine, Baltimore, Md; Cardiovascular Molecular Imaging Laboratory (M.M.S), Section of Cardiovascular Medicine, Yale University School of Medicine, and VA Connecticut Healthcare System, New Haven, Conn; Cardiovascular Division (J.R.L.), Oregon Health and Science University, Portland, Ore; Departments of Medicine (Cardiology) and Radiology (Molecular Imaging Program at Stanford) (J.C.W.), Stanford University School of Medicine, Stanford, Calif; Russell H. Morgan Department of Radiology and Radiological Science (D.L.M.), The Johns Hopkins University School of Medicine, Baltimore, Md; Translational and Molecular Imaging Institute (Z.A.F.), Mount Sinai School of Medicine, New York, N.Y.; and Department of Medicine and Diagnostic Radiology (A.J.S.), Yale University School of Medicine, New Haven, Conn. Search for more papers by this author , David E. SosnovikDavid E. Sosnovik From the Centers for Systems Biology (M.N.) and Molecular Imaging Research (M.N., D.E.S., F.K.S.), and Cardiology Division (D.E.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Department of Biomedical Engineering (B.A.F.), University of Virginia, Charlottesville, Va; Radiology and Cardiovascular Nuclear Medicine (F.B.), Johns Hopkins University School of Medicine, Baltimore, Md; Cardiovascular Molecular Imaging Laboratory (M.M.S), Section of Cardiovascular Medicine, Yale University School of Medicine, and VA Connecticut Healthcare System, New Haven, Conn; Cardiovascular Division (J.R.L.), Oregon Health and Science University, Portland, Ore; Departments of Medicine (Cardiology) and Radiology (Molecular Imaging Program at Stanford) (J.C.W.), Stanford University School of Medicine, Stanford, Calif; Russell H. Morgan Department of Radiology and Radiological Science (D.L.M.), The Johns Hopkins University School of Medicine, Baltimore, Md; Translational and Molecular Imaging Institute (Z.A.F.), Mount Sinai School of Medicine, New York, N.Y.; and Department of Medicine and Diagnostic Radiology (A.J.S.), Yale University School of Medicine, New Haven, Conn. Search for more papers by this author , Brent A. FrenchBrent A. French From the Centers for Systems Biology (M.N.) and Molecular Imaging Research (M.N., D.E.S., F.K.S.), and Cardiology Division (D.E.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Department of Biomedical Engineering (B.A.F.), University of Virginia, Charlottesville, Va; Radiology and Cardiovascular Nuclear Medicine (F.B.), Johns Hopkins University School of Medicine, Baltimore, Md; Cardiovascular Molecular Imaging Laboratory (M.M.S), Section of Cardiovascular Medicine, Yale University School of Medicine, and VA Connecticut Healthcare System, New Haven, Conn; Cardiovascular Division (J.R.L.), Oregon Health and Science University, Portland, Ore; Departments of Medicine (Cardiology) and Radiology (Molecular Imaging Program at Stanford) (J.C.W.), Stanford University School of Medicine, Stanford, Calif; Russell H. Morgan Department of Radiology and Radiological Science (D.L.M.), The Johns Hopkins University School of Medicine, Baltimore, Md; Translational and Molecular Imaging Institute (Z.A.F.), Mount Sinai School of Medicine, New York, N.Y.; and Department of Medicine and Diagnostic Radiology (A.J.S.), Yale University School of Medicine, New Haven, Conn. Search for more papers by this author , Filip K. SwirskiFilip K. Swirski From the Centers for Systems Biology (M.N.) and Molecular Imaging Research (M.N., D.E.S., F.K.S.), and Cardiology Division (D.E.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Department of Biomedical Engineering (B.A.F.), University of Virginia, Charlottesville, Va; Radiology and Cardiovascular Nuclear Medicine (F.B.), Johns Hopkins University School of Medicine, Baltimore, Md; Cardiovascular Molecular Imaging Laboratory (M.M.S), Section of Cardiovascular Medicine, Yale University School of Medicine, and VA Connecticut Healthcare System, New Haven, Conn; Cardiovascular Division (J.R.L.), Oregon Health and Science University, Portland, Ore; Departments of Medicine (Cardiology) and Radiology (Molecular Imaging Program at Stanford) (J.C.W.), Stanford University School of Medicine, Stanford, Calif; Russell H. Morgan Department of Radiology and Radiological Science (D.L.M.), The Johns Hopkins University School of Medicine, Baltimore, Md; Translational and Molecular Imaging Institute (Z.A.F.), Mount Sinai School of Medicine, New York, N.Y.; and Department of Medicine and Diagnostic Radiology (A.J.S.), Yale University School of Medicine, New Haven, Conn. Search for more papers by this author , Frank BengelFrank Bengel From the Centers for Systems Biology (M.N.) and Molecular Imaging Research (M.N., D.E.S., F.K.S.), and Cardiology Division (D.E.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Department of Biomedical Engineering (B.A.F.), University of Virginia, Charlottesville, Va; Radiology and Cardiovascular Nuclear Medicine (F.B.), Johns Hopkins University School of Medicine, Baltimore, Md; Cardiovascular Molecular Imaging Laboratory (M.M.S), Section of Cardiovascular Medicine, Yale University School of Medicine, and VA Connecticut Healthcare System, New Haven, Conn; Cardiovascular Division (J.R.L.), Oregon Health and Science University, Portland, Ore; Departments of Medicine (Cardiology) and Radiology (Molecular Imaging Program at Stanford) (J.C.W.), Stanford University School of Medicine, Stanford, Calif; Russell H. Morgan Department of Radiology and Radiological Science (D.L.M.), The Johns Hopkins University School of Medicine, Baltimore, Md; Translational and Molecular Imaging Institute (Z.A.F.), Mount Sinai School of Medicine, New York, N.Y.; and Department of Medicine and Diagnostic Radiology (A.J.S.), Yale University School of Medicine, New Haven, Conn. Search for more papers by this author , Mehran M. SadeghiMehran M. Sadeghi From the Centers for Systems Biology (M.N.) and Molecular Imaging Research (M.N., D.E.S., F.K.S.), and Cardiology Division (D.E.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Department of Biomedical Engineering (B.A.F.), University of Virginia, Charlottesville, Va; Radiology and Cardiovascular Nuclear Medicine (F.B.), Johns Hopkins University School of Medicine, Baltimore, Md; Cardiovascular Molecular Imaging Laboratory (M.M.S), Section of Cardiovascular Medicine, Yale University School of Medicine, and VA Connecticut Healthcare System, New Haven, Conn; Cardiovascular Division (J.R.L.), Oregon Health and Science University, Portland, Ore; Departments of Medicine (Cardiology) and Radiology (Molecular Imaging Program at Stanford) (J.C.W.), Stanford University School of Medicine, Stanford, Calif; Russell H. Morgan Department of Radiology and Radiological Science (D.L.M.), The Johns Hopkins University School of Medicine, Baltimore, Md; Translational and Molecular Imaging Institute (Z.A.F.), Mount Sinai School of Medicine, New York, N.Y.; and Department of Medicine and Diagnostic Radiology (A.J.S.), Yale University School of Medicine, New Haven, Conn. Search for more papers by this author , Jonathan R. LindnerJonathan R. Lindner From the Centers for Systems Biology (M.N.) and Molecular Imaging Research (M.N., D.E.S., F.K.S.), and Cardiology Division (D.E.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Department of Biomedical Engineering (B.A.F.), University of Virginia, Charlottesville, Va; Radiology and Cardiovascular Nuclear Medicine (F.B.), Johns Hopkins University School of Medicine, Baltimore, Md; Cardiovascular Molecular Imaging Laboratory (M.M.S), Section of Cardiovascular Medicine, Yale University School of Medicine, and VA Connecticut Healthcare System, New Haven, Conn; Cardiovascular Division (J.R.L.), Oregon Health and Science University, Portland, Ore; Departments of Medicine (Cardiology) and Radiology (Molecular Imaging Program at Stanford) (J.C.W.), Stanford University School of Medicine, Stanford, Calif; Russell H. Morgan Department of Radiology and Radiological Science (D.L.M.), The Johns Hopkins University School of Medicine, Baltimore, Md; Translational and Molecular Imaging Institute (Z.A.F.), Mount Sinai School of Medicine, New York, N.Y.; and Department of Medicine and Diagnostic Radiology (A.J.S.), Yale University School of Medicine, New Haven, Conn. Search for more papers by this author , Joseph C. WuJoseph C. Wu From the Centers for Systems Biology (M.N.) and Molecular Imaging Research (M.N., D.E.S., F.K.S.), and Cardiology Division (D.E.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Department of Biomedical Engineering (B.A.F.), University of Virginia, Charlottesville, Va; Radiology and Cardiovascular Nuclear Medicine (F.B.), Johns Hopkins University School of Medicine, Baltimore, Md; Cardiovascular Molecular Imaging Laboratory (M.M.S), Section of Cardiovascular Medicine, Yale University School of Medicine, and VA Connecticut Healthcare System, New Haven, Conn; Cardiovascular Division (J.R.L.), Oregon Health and Science University, Portland, Ore; Departments of Medicine (Cardiology) and Radiology (Molecular Imaging Program at Stanford) (J.C.W.), Stanford University School of Medicine, Stanford, Calif; Russell H. Morgan Department of Radiology and Radiological Science (D.L.M.), The Johns Hopkins University School of Medicine, Baltimore, Md; Translational and Molecular Imaging Institute (Z.A.F.), Mount Sinai School of Medicine, New York, N.Y.; and Department of Medicine and Diagnostic Radiology (A.J.S.), Yale University School of Medicine, New Haven, Conn. Search for more papers by this author , Dara L. KraitchmanDara L. Kraitchman From the Centers for Systems Biology (M.N.) and Molecular Imaging Research (M.N., D.E.S., F.K.S.), and Cardiology Division (D.E.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Department of Biomedical Engineering (B.A.F.), University of Virginia, Charlottesville, Va; Radiology and Cardiovascular Nuclear Medicine (F.B.), Johns Hopkins University School of Medicine, Baltimore, Md; Cardiovascular Molecular Imaging Laboratory (M.M.S), Section of Cardiovascular Medicine, Yale University School of Medicine, and VA Connecticut Healthcare System, New Haven, Conn; Cardiovascular Division (J.R.L.), Oregon Health and Science University, Portland, Ore; Departments of Medicine (Cardiology) and Radiology (Molecular Imaging Program at Stanford) (J.C.W.), Stanford University School of Medicine, Stanford, Calif; Russell H. Morgan Department of Radiology and Radiological Science (D.L.M.), The Johns Hopkins University School of Medicine, Baltimore, Md; Translational and Molecular Imaging Institute (Z.A.F.), Mount Sinai School of Medicine, New York, N.Y.; and Department of Medicine and Diagnostic Radiology (A.J.S.), Yale University School of Medicine, New Haven, Conn. Search for more papers by this author , Zahi A. FayadZahi A. Fayad From the Centers for Systems Biology (M.N.) and Molecular Imaging Research (M.N., D.E.S., F.K.S.), and Cardiology Division (D.E.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Department of Biomedical Engineering (B.A.F.), University of Virginia, Charlottesville, Va; Radiology and Cardiovascular Nuclear Medicine (F.B.), Johns Hopkins University School of Medicine, Baltimore, Md; Cardiovascular Molecular Imaging Laboratory (M.M.S), Section of Cardiovascular Medicine, Yale University School of Medicine, and VA Connecticut Healthcare System, New Haven, Conn; Cardiovascular Division (J.R.L.), Oregon Health and Science University, Portland, Ore; Departments of Medicine (Cardiology) and Radiology (Molecular Imaging Program at Stanford) (J.C.W.), Stanford University School of Medicine, Stanford, Calif; Russell H. Morgan Department of Radiology and Radiological Science (D.L.M.), The Johns Hopkins University School of Medicine, Baltimore, Md; Translational and Molecular Imaging Institute (Z.A.F.), Mount Sinai School of Medicine, New York, N.Y.; and Department of Medicine and Diagnostic Radiology (A.J.S.), Yale University School of Medicine, New Haven, Conn. Search for more papers by this author and Albert J. SinusasAlbert J. Sinusas From the Centers for Systems Biology (M.N.) and Molecular Imaging Research (M.N., D.E.S., F.K.S.), and Cardiology Division (D.E.S.), Massachusetts General Hospital and Harvard Medical School, Boston, Mass; Department of Biomedical Engineering (B.A.F.), University of Virginia, Charlottesville, Va; Radiology and Cardiovascular Nuclear Medicine (F.B.), Johns Hopkins University School of Medicine, Baltimore, Md; Cardiovascular Molecular Imaging Laboratory (M.M.S), Section of Cardiovascular Medicine, Yale University School of Medicine, and VA Connecticut Healthcare System, New Haven, Conn; Cardiovascular Division (J.R.L.), Oregon Health and Science University, Portland, Ore; Departments of Medicine (Cardiology) and Radiology (Molecular Imaging Program at Stanford) (J.C.W.), Stanford University School of Medicine, Stanford, Calif; Russell H. Morgan Department of Radiology and Radiological Science (D.L.M.), The Johns Hopkins University School of Medicine, Baltimore, Md; Translational and Molecular Imaging Institute (Z.A.F.), Mount Sinai School of Medicine, New York, N.Y.; and Department of Medicine and Diagnostic Radiology (A.J.S.), Yale University School of Medicine, New Haven, Conn. Search for more papers by this author Originally published1 Jan 2009https://doi.org/10.1161/CIRCIMAGING.108.839092Circulation: Cardiovascular Imaging. 2009;2:56–70Molecular imaging has the potential to profoundly impact preclinical research and future clinical cardiovascular care. In Part I of this 2-part consensus article on multimodality cardiovascular molecular imaging, the imaging methodology, evolving imaging technology, and development of novel targeted molecular probes relevant to the developing field of cardiovascular molecular imaging were reviewed.1 Part II of this consensus article will review the targeted imaging probes available for the identification and evaluation of critical pathophysiological processes in the cardiovascular system. These include novel imaging strategies for the evaluation of inflammation, thrombosis, apoptosis, necrosis, vascular remodeling, and angiogenesis. The current article will also review the role of targeted imaging of a number of cardiovascular diseases, including atherosclerosis, ischemic injury, postinfarction remodeling, and heart failure, as well as the emerging fields of regenerative, genetic, and cell-based therapies. Special emphasis is placed on multimodal imaging, as these hybrid techniques promise to advance the field by combining approaches with complementary strengths and off-setting limitations.2,3Although some applications of molecular imaging are well established, other clinical applications are under development and still emerging, such as early detection of atherosclerosis or unstable plaque.4 The goals of molecular imaging are to refine risk assessment, facilitate the early diagnosis of disease before the occurrence of debilitating events, aid in the development of personalized therapeutic regimens and to monitor the efficacy of complex therapies. However, to translate the evolving targeted imaging probes, technologies, and applications into clinical care, the imaging community will need to overcome several hurdles. Therefore, the current review will also discuss the opportunities and challenges associated with the implementation and advancement of targeted molecular imaging in clinical practice, and the realization of image-directed personalized medicine.Critical Pathophysiological ProcessesIn this initial section, we will review the role of targeted molecular imaging for the evaluation of a number of critical pathophysiological processes of the cardiovascular system.InflammationThe chemical and spatiotemporal diversity of inflammatory factors and a growing appreciation of inflammation in cardiovascular disease have engendered interest in targeting the immune system for cardiovascular molecular imaging. Among the prospective targets, proteolytic enzymes and circulating leukocytes have received the most attention. The development of “smart” protease-activatable probes equipped with specific peptide sequences that can be recognized by proteases (ie, cathepsins, matrix metalloproteinases [MMPs]) and that, on enzyme recognition and cleavage, dequench their fluorochromes and fluoresce,5 has given rise to optical imaging of proteolysis in a number of cardiovascular conditions.6–8Studies investigating the accumulation of leukocytes to tissue reflect directly how inflammation can be targeted for molecular imaging of the inflammatory cascade. A number of ex vivo and in vivo approaches in both atherosclerosis and heart failure have reported sensitive and quantitative imaging of monocyte accumulation to inflammatory sites (Figure 1).9–11 Naturally phagocytic, these myeloid cells can be labeled easily with optical, nuclear, and superparamagnetic agents for multiscopic, multimodality imaging. Cell trackers such as VT680, a near-infrared reagent that allows for in vivo multiscopic imaging, readily labels leukocytes ex vivo.12111In-oxine, an FDA-approved isotope cell-tracker can report on monocyte accumulation in atherosclerosis and heart failure by autoradiography and single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging.10,11 For studies in which longer tracking times are needed, stably-transfected fluorescent proteins under control of specific promoters can be used. For example, mice that express green fluorescent protein under the CX3CR1 promoter have yielded valuable insights into monocyte biology.13 Collectively, these studies have begun to illuminate the kinetics of cellular infiltration in living animals and thus have provided novel biological insight as well as the possibility for clinical translation. Among the challenges that remain are the high cell turnover rates that dilute signal and prevent long-term imaging, possible activation and cell loss due to ex vivo labeling, the need to discriminate between various myeloid subsets, and the need to target selectively nonphagocytic leukocytes. As more mechanistic insights of immune mechanisms that govern cardiovascular disease become available through classical and imaging approaches, imaging targets will be identified with the hope to, eventually, image the inflammatory cascade comprehensively at its various stages. Download figureDownload PowerPointFigure 1. Inflammation. A, Cytospin of cell-sorted monocytes, adapted from Swirski et al.11 B, SPECT-CT image after injection of 111In-labeled monocytes that migrated to inflamed atherosclerotic lesions in the aortic root of an apoE−/− mouse (arrow), adapted from Kircher et al.9 C, Autoradiography of excized aorta after adoptive tranfer of radioactively labeled monocytes shows accumulation in the plaque-rich aortic root.11 D–F, Adoptive transfer of radioactively labeled Ly6Chi monocytes on day 2 after myocardial infarction.10 The SPECT/CT image, ex vivo autoradiography, and concomitant 2–3-5-triphenyl tetrazolium chloride staining show accumulation of labeled monocytes in the infarct (M.N. and F.S., unpublished data).ThrombosisThrombosis plays a central role in myocardial infarction, stroke, atrial fibrillation and venous thrombo-embolism. The potential of molecular imaging in these conditions is 2-fold: (1) to physically detect and diagnose thrombi and (2) to characterize their nature and propensity to respond to anticoagulation and thrombolysis. Strategies to image the central events in thrombus formation including platelet activation,14 the generation of fibrin,15 and the cross-linking of fibrin strands by FXIII,16 have been developed.Ligands to the glycoprotein IIbIIIa receptor have been conjugated to technetium,14 and iron-oxide microparticles17 for SPECT and MRI, respectively. A peptide specific for activated FXIII has been used to image venous thrombosis using fluorescence imaging techniques in vivo.16 However, the most extensive experience to date in the imaging of thrombosis in vivo has been with EP2104R (Epix Pharmaceuticals, Lexington, Mass) a small gadolinium chelate targeted to fibrin.18 Studies with EP2104R in rabbits and swine documented the ability of the agent to detect acute and chronic arterial and venous thrombi.19,20 On the basis of this extensive preclinical experience, 52 patients with suspected thrombosis have now been imaged with this agent.21 The initial clinical experience with EP2104R shows that the agent is able to successfully detect arterial, venous and intracardiac thombosis in humans (Figure 2). This important experience demonstrates both the feasibility and potential value of targeted cardiovascular molecular MRI in patients. Download figureDownload PowerPointFigure 2. Thrombosis. A and B, molecular MRI of coronary thrombosis in a swine model using EP-2104R, a fibrin-specific contrast agent. SSFP sequence (A) and IR sequence (B) 2 hours after EP2104R, adapted with permission.145 C–E, Molecular MRI in patients, adapted with permission.21 C, Aortic thrombus of an 82-year-old female patient. D and E, Aortic thrombus in the descending thoracic aorta of a 65-year-old male patient using inversion recovery black-blood gradient-echo imaging.ApoptosisApoptosis plays an important role in diseases of both the myocardium and the vasculature. During ischemia-reperfusion up to 30% of cardiomyocytes (CMs) in the injured myocardium become apoptotic.22 The level of CM apoptosis in heart failure is significantly lower (<1%) but persists over many months resulting in the net loss of a large number of CMs.23 The inhibition of apoptosis with caspase-inhibitors in animal models of both ischemia-reperfusion and heart failure is highly cardioprotective.24–26 Modulation of CM apoptosis thus provides an attractive target for both molecular imaging and therapy of cardiovascular disease.The hallmark of apoptosis is the activation of the cytoplasmic protease caspase-3. Small molecules, such as isatins, have been labeled with positron-emission tomography (PET) tracers and used to target caspase-3,27 but the experience with these agents in still very preliminary. A more extensively used approach has been to target the presence of phosphatidylserine on the outer cell membrane of apoptotic cells.28 Phosphatidylserine is a membrane phospholipid, normally found only on the inner cell membrane, which becomes translocated to the outer cell membrane soon after the activation of caspase-3. Phosphatidylserine on the apoptotic cell membrane has been targeted with Annexin V25 and the C2 domain of synaptotagmin.29 Pioneering work with technetium-labeled annexin in humans has shown that cell death in the myocardium can be imaged with this agent in the acute coronary syndromes,30 heart failure,31 and transplant rejection.32More recently, approaches to image CM apoptosis with molecular MRI have been developed.33 Annexin V was conjugated to the magnetofluorescent nanoparticle, CLIO-Cy5.5, to yield the magnetofluorescent annexin, AnxCLIO-Cy5.5.33,34 This construct has a level of biological activity similar to that of unmodified annexin, and has been shown to colocalize strongly with Annexin-fluorescein isothiocyanate.33,34 AnxCLIO-Cy5.5 has been used to image CM apoptosis by MRI in vivo in a mouse model of ischemia reperfusion (Figure 3).33 Annexin has also been conjugated to a small gadolinium loaded liposome and used to image CM apoptosis in an isolated perfused heart model.35 The ability of this construct to be used in vivo, however, will require further study. Download figureDownload PowerPointFigure 3. Apoptosis. A–C, Molecular MRI of CM apoptosis in vivo in a mouse model of ischemia-reperfusion, adapted with permission.33 A, The apoptosis sensing magnetofluorescent nanoparticle, AnxCLIO-Cy5.5, accumulates in injured myocardium producing signal hypointensity (arrow) and a reduction in T2*. B and C, In vivo T2* maps created in regions of myocardium with equivalent degrees of hypokinesis in a mouse injected with AnxCLIO-Cy5.5 (B) and a mouse injected with the control probe (C). D and E, Imaging of cell death with techenetium-labeled annexin in a patient with an acute coronary syndrome, adapted with permission.30 D, Perfusion defect (arrow) in the patient 6 to 8 weeks after the acute coronary syndrome. E, Uptake of 99mTc annexin-V (arrow) at the time of the event correlates well with the perfusion defect. L, liver. F, Uptake of 99mTc annexin-V in a patient before carotid endarterectomy. A strong correlation was seen in this study between uptake of the probe and macrophage content of the plaque, adapted with permission.36The role of apoptosis in plaque rupture is being increasingly appreciated. Apoptosis of plaque macrophages, in particular, has been associated with plaque destabilization and rupture. Moreover, the uptake of technetium-labeled annexin in plaques with high macrophage content has been documented in both animal models and humans (Figure 3).36,37 Molecular imaging of apoptosis may thus play an important future role in facilitating the development of novel therapies for diseases of both the myocardium and vulnerable atherosclerotic plaque. Techniques to image cellular necrosis are highly complementary and synergistic with those to image apoptosis, and are discussed in more length in the section on ischemia below.Fibrosis and ScarringIn ischemic heart disease and heart failure, 2 distinct forms of fibrosis are of interest: the fibrosis that characterizes the healed myocardial infarct and the fibrosis that may occur in the remote myocardium not subject to previous ischemic injury. Delayed-enhancement cardiac magnetic resonance has proven highly valuable in detecting both acute and chronic forms of myocardial injury. However, the gadolinium chelates commonly used in delayed-enhancement cardiac magnetic resonance studies are not targeted agents, with the time-dependent enhancement depending on both myocardial blood flow and volume of distribution.38 Thus when delayed-enhancement cardiac magnetic resonance provides for the direct visualization of necrotic and scarred tissue, conventional contrast agents are unable to distinguish between the 2. Recently, however, a collagen-targeted MRI contrast agent was developed for the molecular imaging of fibrosis39 that was subsequently used to characterize postinfarction myocardial scarring in a murine model.40Figure 4 shows a short-axis CMR image acquired before and after the injection of the collagen-targeted contrast agent (EP-3533), and a corresponding tissue slice in which collagen was stained with Picrosirius red. Download figureDownload PowerPointFigure 4. Molecular imaging of postinfarct collagen deposition. A, CMR image shows a short-axis slice acquired before contrast. B, After the injection of the collagen-targeted contrast agent (EP-3533). C, Corresponding tissue slice at right shows collagen in red after Picrosirius staining, adapted with permission.40Vascular RemodelingVascular remodeling is a key pathological attribute in atherosclerosis, aneurysm formation, postangioplasty restenosis, and graft arteriosclerosis. Vascular remodeling involves changes in the vessel diameter or structure. Neointima formation secondary to vascular smooth muscle cell (VSMC) proliferation and migration, extracellular matrix reorganization and concurrent inflammation are important players in the remodeling process.Targeting VSMC proliferation is a promising approach for early detection of vessel wall hyperplasia. Z2D3, an antibody to a membrane lipid antigen present on proliferating VSMCs, localized to the neointima of injured aorta of high-lipid fed rabbits,41 and its uptake correlated with VSMC proliferation rate.42 The feasibility of imaging vascular remodeling in coronary arteries was originally demonstrated by 111In-Z2D3 F(ab′)2 planar imaging in a swine model of intimal proliferation after coronary stenting.43Integrins, a family of heterodimeric cell surface glycoprotein adhesion molecules, mediate cell-extracellular matrix and cell-cell interactions, and are involved in cell adhesion, proliferation, migration, differentiation, and serve as potential targets for imaging of vascular remodeling. The αvβ3 integrin is expressed by endothelial cells (ECs), VSMCs,44 platelets, growth factor-stimulated monocytes and T lymphocytes,45,46 is upregulated early in response to vascular injury, and appears to be a suitable target for imaging of cell proliferation. An 111In-labeled peptidomimetic tracer (RP748, Lantheus) with high affinity for the active conf