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Molecular imaging will replace perfusion imaging: The impossible dream
CONTROVERSIES IN NUCLEAR CARDIOLOGY: ANTAGONIST Molecular imaging will replace perfusion imaging: The impossible dream E. Gordon DePuey, MD THE PROLOGUE Who selected me for this unenviable task of arguing against the future of molecular imaging in nuclear cardiology, anyway? Who could possibly want to embrace such a retrogressive/obstructionist point of view, potentially alienating friends and colleagues? After all, is it not our pursuit as academic “knights-errant” to lead our field forward, adventurously, undaunted—Don Quixote in the quest of the beautiful, elusive Dulcinea del Toboso (Figure 1)? So, reluctantly, in this article I argue that radionuclide molecular imaging will not replace perfusion imaging. CONVENTIONAL NUCLEAR IMAGING: ALDONZA LORENZO, THE FAMILIAR HOMETOWN PEASANT GIRL WITH A TAINTED REPUTATION AND LOW SELF-ESTEEM Actually, if we define molecular imaging as a “noninvasive examination of the integrative functions of molecules, genes, and cells in intact whole-body systems,”1 it is particularly difficult to argue against the future of radionuclide molecular imaging because molecular, or “targeted,” imaging is already an important, integral part of nuclear medicine and nuclear cardiology. The first well-established, clinically relevant nuclear technique was the radioiodine uptake and scan, which evaluates the incorporation of iodine into the thyroid cell by means of transport, organification, and coupling. Liver scanning is dependent on Kupffer’s cells trapping sulfur colloid, and bone scanning, the most commonly performed general nuclear medicine examination, track the activity of osteoblasts in the bone cell envelope as they incorporate radiolabeled phosphonate compounds. In nuclear cardiology technetium 99m pyrophosphate infarctFrom the Departments of Radiology and Nuclear Medicine, St Luke’sRoosevelt Hospital Center, New York, NY. Reprint requests: E. Gordon DePuey, MD, Division of Nuclear Medicine, Department of Radiology, St Luke’s-Roosevelt Hospital Center, Amsterdam Avenue at 114th Street, New York, NY 10025. J Nucl Cardiol 2008;15:435-41. 1071-3581/$34.00 Copyright © 2008 by the American Society of Nuclear Cardiology. doi:10.1016/j.nuclcard.2008.04.003
avid imaging capitalizes on the leakage of calcium salts through irreversibly damaged myocardial cell membranes to identify infarcted tissue. Cardiac positron emission tomography (PET) utilizes rubidium 82 and nitrogen 13 ammonia to evaluate myocardial perfusion and fluorine 18 fluorodeoxyglucose (FDG) to track the shift of myocardial substrate metabolism from fatty acids to glucose in ischemic but viable myocardial cells. So in a sense, we are already molecular imaging specialists! Through these mainstays of “targeted” nuclear imaging, we have realized our potential to monitor molecular processes, but we have similarly learned the shortcomings of our methodology. For example, the accuracy of thyroid radioiodine uptake measurements is confounded by a host of factors including medications, iodinated contrast agents, and even multivitamins and dietary supplements. Today, after nearly 4 decades of scintillation camera development, single photon emission computed tomography (SPECT) imaging of the thyroid is not routinely performed because of low target count density and the inability of general-purpose scintillation detectors to approximate the neck. Given its limited spatial resolution, particularly the difficulty in identifying a small “cold” defect within a large traceravid object, liver scintigraphy has essentially been replaced by techniques with far superior resolution such as sonography, computed tomography (CT), and magnetic resonance imaging (MRI). The bone scan, though highly sensitive in detecting osteoblastic metastases, unfortunately lacks specificity in differentiating metastatic disease from degenerative, post-traumatic, inflammatory, or hypertrophic changes. Tc-99m pyrophosphate infarctavid scintigraphy is seldom performed nowadays. Because tracer localization is dependent on not only the volume of cell necrosis but also residual blood flow to deliver the tracer to the target cells, infarct quantification may be inaccurate. Sensitivity in detecting subendocardial infarcts is suboptimal as a result of the geometry of the target and low tracer avidity. Moreover, infarct tracer avidity is time dependent, peaking 24 to 72 hours after infarction. In addition, because patient management decisions are much more dependent on the functional consequences of the infarct (ie, left ventricular volume and ejection fraction and the presence of an aneurysm or 435
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blood pool clearance. Antifibrin’s utilization was further limited by concerns regarding insensitivity, antigenicity, and difficulty in differentiating the 3 deep veins of the calf. Doppler venography, despite its inability to differentiate acute from chronic thrombosis, quickly supplanted antifibrin scintigraphy because of its ready accessibility even at the patient’s bedside, low cost, lack of ionizing radiation, and ability to anatomically localize the thrombosis. Thus, although nuclear imaging remains a crucial diagnostic tool, we have learned the limitations of our techniques, which in many cases have been supplanted by superior methods. These limitations may be grouped as follows:
Figure 1. Don Quixote and Sancho Panza, Honoré Daumier, 1808-1879. (This image [or other media file] is in the public domain because its copyright has expired. This applies to the United States, Canada, the European Union, and those countries with a copyright term of life of the author plus 70 years.)
pseudoaneurysm), functional/anatomic evaluation with echocardiography, which may be performed immediately after myocardial infarction at the patient’s bedside, has become a procedure routinely performed in patients following myocardial infarction. With attenuation correction and higher photon energy, Rb-82 PET and N-13 ammonia PET are touted to provide improved image quality compared with SPECT with Tc-99m perfusion agents. Nevertheless, as a result of physiologic cardiac motion and inherent instrumentation limitations, even PET still lacks resolution sufficient to identify subendocardial ischemia and/or scar and could possibly, one day, be replaced by higher-resolution MRI or CT contrast techniques. Like commercially available Tc-99m agents, Rb-82 uptake is not linearly related to coronary blood flow, so measurements of absolute myocardial blood flow are inaccurate. F-18 FDG PET to assess myocardial viability is so dependent on the underlying metabolic milieu (ie, serum glucose and insulin levels) that in busy clinical laboratories, FDG viability scans are impractical in most diabetic patients or even those with fasting hyperglycemia. Other “targeted” approaches using radiolabeled antibodies, such as indium 111 antimyosin and Tc-99m antifibrin, have been developed and even commercialized, but they have never found an important role in patient management. Antimyosin’s clinical applicability was limited by the same physiologic factors as those cited previously for Tc-99m pyrophosphate, and the utility of infarct-avid radiotracer was also hampered by its cost and the necessity for delayed images to allow for
1. Resolution A. Limited instrumentation spatial resolution B. Inaccessibility of the target organ, because of organ depth and/or patient anatomy C. Physiologic target motion 2. Suboptimal target-to-background ratio A. Low target tracer avidity B. Nonspecificity of the pathophysiologic mechanism of tracer localization C. Factors in the cellular environment influencing radiotracer uptake D. Slow blood pool clearance necessitating delayed imaging E. Time dependence of tracer avidity 3. Inaccuracy of quantitative techniques A. Nonlinearity of target tracer uptake 4. Tracer antigenicity 5. Clinical practicality A. Accessibility/convenience compared with other methodologies B. Delay in patient management 6. Clinical relevance A. Functional, not pathophysiologic, factors often determine patient management 7. Cost Nonetheless, advancements in cardiac molecular imaging with radionuclides have raised our level of excitement and hope for the future of our field. Will it be possible to scintigraphically identify a sequence of cellular events as they occur and monitor the effect of interventions that alter these processes? Let us review just a few of these potential applications of cardiac radionuclide molecular imaging, with consideration of the drawbacks and limitations cited previously for exist-
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ing nuclear techniques as well as the potential of competing methodologies. MOLECULAR IMAGING: DULCINEA DEL TOBOSO, THE IMAGINARY, IMPOSSIBLY BEAUTIFUL OBJECT OF OUR QUEST Identification of Vulnerable Plaque and Processes Associated with Arterial Wall Damage Atherosclerosis is a dynamic, multifactorial, pathophysiologic process for which there are numerous potential targets available for radionuclide imaging. Arterial wall damage is associated with inflammation, lipid deposition, oxidative stress, macrophage infiltration, extracellular matrix digestion, cell apoptosis, and thrombosis. Indeed, all of these processes have been evaluated as potential advancements of radionuclide molecular imaging whereby information regarding plaque formation and vulnerability rather than only relatively advanced arterial anatomic narrowing and the associated hemodynamic consequences can be evaluated. Excellent overviews of radionuclide techniques for cardiac molecular imaging and biologic targeting of atherosclerotic plaque have been published previously.2-4 Initial attempts to image atherosclerotic plaque used radiolabeled compounds known to accumulate in atherosclerotic plaque such as iodine-125 autologous human low-density lipoprotein (LDL), Tc-99m LDL, I-125 LDL, or tracers that could potentially track the immune response to vascular injury such as In-111 immunoglobulin G Fab fragments and I-125 monocyte chemoattractant.5-11 However, attempts to image atherosclerotic plaque with such methods met with very limited success because of high blood pool activity and the suboptimal target-to-background ratios that could be achieved with these macromolecular compounds. Moreover, the size of atherosclerotic lesions was generally beyond the resolution capabilities of human nuclear imaging systems. Other techniques have targeted more specific markers of vascular injury. As a response to endovascular damage, vascular remodeling and proliferation occur. Radiolabeled antagonists to integrin, such as the In-111– labeled ␣v3 integrin–specific molecule, have been shown to track progressive cell proliferative processes after carotid artery injury in mice.12 In addition, matrix metalloproteinases (MMPs) are a family of proteolytic enzymes associated with degradation of myocardial extracellular matrix and with the process of vascular remodeling. As cell membrane integrity is lost with plaque rupture, there is a local release of macrophages that have phagocytized toxic material, particularly free cholesterol. With macrophage cell death, MMPs increase locally in the lesion. Iodine 123–labeled MMP inhibitor
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also has been shown to allow in vivo imaging of vascular damage in mice after ligation of the carotid artery.13,14 In addition to these reparative processes, apoptosis of cells and macrophages and smooth muscle proliferation occur in response to vascular injury.15,16 Tc-99m annexin targets phosphatidylserine, a molecule expressed on the cell membrane of macrophages and smooth muscle cells after apoptotic cell death. A radiolabeled, negatively charged, modified antibody, Z2D3, has been used to identify smooth muscle proliferation.15 Whereas these novel techniques to identify reparative processes in response to endovascular damage are indeed exciting, the practicality of these approaches is doubtful. One questions if the animal models presently used to evaluate such new, potential radiopharmaceuticals are clinically relevant. Is the physiologic response to carotid ligation analogous to the chronic, multifactorial causative factors resulting in coronary artery disease? Vascular injury associated with atherosclerosis may be localized, and tracer-avid lesions may be of insufficient mass or volume to be detectable by human in vivo imaging methods. Localization of some radiotracers such as annexin, as noted previously, is relatively nonspecific. Moreover, the ultimate practicality of such an approach in living human subjects is questionable. Imaging mouse carotid arteries is sufficiently challenging, requiring specialized small animal imaging systems. However, in humans, if our goal is to detect coronary disease, the target lies deep within the body, moves with respiration and cardiac contraction, and lies adjacent to the cardiac blood pool. Perhaps only with specially designed endovascular scintillation probes will it be possible to detect such processes. However, with such probes, correlative imaging with contrast enhancement of the coronary arteries (ie, CT or MRI coronary angiography) will be necessary for purposes of anatomic reference. Though potentially valuable as a research tool, it is unlikely that such a technique would ever be clinically applicable. In a cost-conscious health care environment, would patients at risk for coronary disease ever be screened by use of such an invasive (and presumably very costly) approach? A widely available modality in nuclear cardiology that has been shown to visualize atherosclerotic plaque in the abdominal aorta and carotid arteries is F-18 FDG PET.17-20 FDG uptake is related to macrophage density, but as we well know from extensive experience in oncologic imaging, radiotracer accumulation may be associated with nonspecific inflammatory processes.21 For identification of coronary atherosclerotic plaque, F-18 FDG PET may be confounded not only by the size and depth of the target, nonspecific uptake associated with vasculitis, and brown fat in the interatrial septum, but also—most importantly— by marked tracer avidity of the adjacent myocardium.
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As nuclear cardiologists, we must also seriously and fairly consider the potential of other modalities for imaging atherosclerosis. Coronary calcium scoring, which is widely available (though not always reimbursed), is a fast and simple method to identify coronary calcification. Although coronary calcification is not closely related to either the degree of atherosclerotic narrowing or the hemodynamic significance of coronary lesions, calcification is essentially always associated with atherosclerosis and has now also been shown to be related to the long-term risk of cardiac events. One might question whether the much more sophisticated and substantially more costly, labor-intensive, and time-consuming nuclear molecular imaging techniques described previously will provide diagnostic and prognostic information that is more valuable than that from the “lowly,” often maligned, coronary calcium score. Beyond calcium scoring and the definition of coronary luminal morphology, multislice CT demonstrates promise in identifying the composition of atherosclerotic plaque and thus vulnerability.22,23 MRI can identify changes in tissue composition within the vascular wall, including remodeling, and probe the composition of plaques, including the accumulation of iron in macrophages.24-27 Antibodies for Molecular Imaging of the Cardiovascular System The technical limitations of antimyosin and antifibrin monoclonal antibodies for human imaging have been discussed previously. In addition, antimyosin accumulation may be nonspecific, associated with either “oncotic” or “apoptotic” cell death.28-30 Positively charged protein antibodies may be attracted nonspecifically to negatively charged molecules. To limit persistent blood pool concentration and, consequently, the delay in target imaging, antibody fragments have been investigated. An immunoglobulin M monoclonal antibody, Z2D3, that targets a lipid complex antigen associated with smooth muscle cell proliferation has been developed.15 Visualization of atherosclerotic lesions in rabbit aortas was possible 48 hours after injection of In-111– labeled negatively charged polymerized Z2D3 F(ab’)2. However, as with other antibody imaging methods, blood clearance was slow (half-time, 920 minutes), and nontarget radiotracer concentrations in the liver, bones, and kidneys were undesirably high even with this antibody fragment.31 Moreover, vulnerable arterial plaque may not necessarily be related to smooth muscle proliferation. Thus, despite many years of investigation, it seems unlikely that monoclonal antibodies or even highly customized antibody fragments will ever be clinically useful to identify subclinical atherosclerotic lesions.
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Issues of target nonspecificity, high blood pool concentration and slow clearance, inconvenience, and prohibitive cost most likely will prevent this methodology from gaining widespread clinical applicability. Moreover, as discussed previously for other nuclear molecular imaging methods under investigation to target vulnerable plaque, imaging techniques with spatial resolution far superior to scintigraphy will most likely be more sensitive, more specific, more time-efficient, and less costly than targeted radiolabeled antibodies. Molecular Imaging of Cardiovascular Gene Products Certainly one of the most exciting emerging facets of clinical cardiology is the prospect of gene therapy for a variety of applications, including treatment of coronary artery disease by modifying angiogenic factors such as vascular endothelial growth factor and fibroblast growth factor, reduction of restenosis after angioplasty by inhibiting smooth muscle cell proliferation, improvement of congestive heart failure by gene transfer of calcium adenosine triphosphate (ATP) pump, inhibition of atherosclerosis by overexpression of a high-density lipoprotein receptor, and reduction of hypoxia-induced apoptosis of cardiac myocytes.1 Multiple factors that influence the success of gene therapy could potentially be evaluated with molecular imaging probes, answering several clinically relevant questions: Has the vector delivered to the heart indeed reached its target site? What is the time course of gene expression? Do other nontarget sites demonstrate gene expression? Is the level of genetic expression sufficient to result in a therapeutic effect? And do the kinetics of gene expression correlate with anatomic repair and/or functional improvement? One approach to track these genetic processes is to directly probe a target—that is, the receptor, an enzyme, messenger ribonucleic acid, or other molecules—with a radiolabeled probe. However, investigations using such a direct approach have met with limited success because of a low concentration or density of target molecules, limited tracer penetration across the cell membrane, slow blood clearance of unbound probes, and a poor targetto-background ratio, all common problems generally encountered with macromolecular imaging. An alternate, indirect approach to track these genetic processes has entailed reporter gene imaging in experimental animals. Once a reporter gene is first introduced into the target tissue, transcription of the reporter gene and translation of the messenger ribonucleic acid produce protein products that can be targeted with reporter molecular probes. A reporter probe can be altered by a process such as phosphorylation to be trapped intracellularly. If the probe is also radiolabeled, its tissue distribution can be tracked by
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scintigraphy, potentially providing noninvasive, quantitative, and repetitive imaging of genetic processes in a living organism. This technique also holds promise in monitoring stem cell therapy in treating ischemic heart disease.32 Cell labeling with In-111 oxyquinoline and Tc-99m hexamethyl propylene has been deployed in endothelial progenitor cells, hematopoietic stem cells, and mesenchymal stem cells.33,34 Although receptor gene imaging is perhaps the most innovative and promising of the radionuclide molecular imaging techniques, many of the familiar limitations seen with other target imaging radionuclide methods nevertheless stand before us as substantial obstacles: the host response may alter the function and biologic halflife of the reporter gene; the reporter probe itself may alter physiologic processes of cell metabolism; the radioactive label may alter the integrity of the reporter gene; the radiotracer may be transferred to nontargeted cells; the limited physical half-life of the radiotracer may impair our ability to track ongoing cellular processes; and frequently repeated imaging may be prohibitive with regard to radiation dosimetry. Furthermore, in common with many other proposed nuclear molecular imaging techniques, sensitivity may be significantly limited by high background activity and small targets beyond the resolution of SPECT and PET systems designed for human imaging. In addition, like the majority of potential radionuclide molecular imaging techniques discussed previously, it is questionable whether techniques used in experimental animals obtained with microSPECT or microPET systems can ever be adapted to human imaging systems. With these daunting potential limitations, we must again consider more rapid imaging techniques with superior spatial resolution and the additional possibility of repetitive evaluation, such as MRI by use of superparamagnetic probes or immunofluorescence imaging, to hold greater potential.32,35,36 A REASONABLE APPROACH: SANCHO PANZA’S WISDOM AND CONSOLATION ON THE TRIP BACK HOME Are Not Functional Consequences More Important Than Disease Identification in Patient Management? The exciting experimental molecular imaging techniques described previously all evaluate, albeit with limitations, pathophysiologic processes that ultimately affect myocardial perfusion and global and regional cardiac function.37,38 Myocardial perfusion imaging assesses the consequences of flow-limiting coronary artery disease produced by vulnerable plaque. However, our methodology is significantly limited by radiopharmaceuticals whose uptake is not linearly related to coronary
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Figure 2. Don Quixote, Honoré Daumier, 1808-1879. (The work of art depicted in this image and the reproduction thereof are in the public domain worldwide. The reproduction is part of a collection of reproductions compiled by The Yorck Project. The compiliation copyright is held by Zenodot Verlagsgesellschaft mbH and licensed under the GNU Free Documentation License.)
blood flow, resulting in relative insensitivity in detecting flow-limiting coronary stenoses. Quantification of myocardial perfusion with PET remains elusive and not routinely performed, and efforts to quantify perfusion with attenuation-corrected SPECT seem to have gained minimal attention in recent years. Efforts to significantly improve the spatial resolution of gated perfusion SPECT and PET with improved detector characteristics, cardiac and respiratory gating, and CT coregistration are under way but have not been afforded a high profile or priority in journals and at national and international meetings. Likewise, evaluation of cardiac function, not only of the left ventricle but of all the cardiac chambers, is now possible with gated blood pool SPECT, a technique that is grossly underused perhaps because it has not yet been optimized. Thus there is much work yet to be done to optimize our functional assessment of new therapeutic techniques.
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Although nuclear molecular imaging will undoubtedly serve as a very valuable research tool, particularly in small experimental animals imaged with highly specialized instrumentation, I believe that primarily as a result of their technical superiority and potentially superior cost-effectiveness, competing imaging modalities may make nuclear molecular imaging on a wide-scale clinical basis less attractive. We should instead direct our sincerest efforts to improving our existing techniques in order to make them relevant to accurately assess the physiologic consequences of new pharmacologic, antibody, and gene therapies.
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THE EPILOGUE In summary, considering the inherent limitations of nuclear imaging, our quest to position radionuclide techniques at the forefront of molecular imaging unfortunately seems a bit “quixotic,” defined by Webster’s Third New International Dictionary as “idealistic and utterly impractical; marked by rash, lofty ideas or chivalrous action doomed to fail.”39 With the current limitations of nuclear imaging techniques, probing molecular targets indeed seems a bit like jousting at windmills. However, in consolation, as nuclear cardiologists, we must not lose sight of the fact that we already have at hand excellent tools in widespread clinical use to assess myocardial perfusion and global and regional function. Like for Don Quixote, these familiar, functional tools— our Aldonza—with some care and encouragement can become our Dulcinea in the era of cardiovascular molecular imaging and new therapeutic strategies. But unlike this errant knight, our story will not end in disillusionment and melancholy (Figure 2). Nuclear cardiology is here to stay! Acknowledgment
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The author has indicated he has no financial conflicts of interest. 19.
References 1. Wu JC, Tseng JR, Gambhir SS. Molecular imaging of cardiovascular gene products. J Nucl Cardiol 2004;11:491-505. 2. Bengel FM. Atherosclerosis imaging on the molecular level. J Nucl Cardiol 2006;13:111-8. 3. Strauss HW, Grewal RK, Pandit-Taskar N. Molecular imaging in nuclear cardiology. Semin Nucl Med 2004;34:47-55. 4. Dobrucki LW, Sinusas AJ. Cardiovascular molecular imaging. Semin Nucl Med 2005;35:73-81. 5. Lees RS, Lees AM, Strauss HW. External imaging of human atherosclerosis. J Nucl Med 1983;24:154-6. 6. Lees RS, Garabedian HD, Lees AM, Schumacher DJ, Miller A, Isaacsohn JL, et al. Technetium-99m low density lipoproteins: Preparation and biodistribution. J Nucl Med 1985;26:1056-62. 7. Leitha T, Staudenherz A, Gmeiner B, Hermann M, Hüttinger M, Dudczak R. Technetium-99m labelled LDL as a tracer for quanti-
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tative LDL scintigraphy. II. In vivo validation, LDL receptor-dependent and unspecific hepatic uptake and scintigraphic results. Eur J Nucl Med 1993;20:674-9. Lees AM, Lees RS, Schoen FJ, Isaacsohn JL, Fischman AJ, McKusick KA, et al. Imaging human atherosclerosis with 99mTclabeled low density lipoproteins. Arteriosclerosis 1988;8:461-70. Fischman AJ, Rubin RH, Khaw BA, Kramer PB, Wilkinson R, Ahmad M, et al. Radionuclide imaging of experimental atherosclerosis with nonspecific polyclonal immunoglobulin G. J Nucl Med 1989;30:1095-100. Tsimikas S, Palinski W, Halpern SE, Yeung DW, Curtiss LK, Witztum JL. Radiolabeled MDA2, an oxidation-specific, monoclonal antibody, identifies native atherosclerotic lesions in vivo. J Nucl Cardiol 1999;6(Pt 1):41-53. Ohtsuki K, Hayase M, Akashi K, Kopiwoda S, Strauss HW. Detection of monocyte chemoattractant protein-1 receptor expression in experimental atherosclerotic lesions: An autoradiographic study. Circulation 2001;104:203-8. Sadeghi MM, Krassilnikova S, Zhang J, Gharaei AA, Fassaei HR, Esmailzadeh L, et al. Detection of injury-induced vascular remodeling by targeting activated (alpha)v(beta)3 integrin in vivo. Circulation 2004;110:84-90. Kopka K, Breyholz HJ, Wagner S, Law MP, Riemann B, Schröer S, et al. Synthesis and preliminary biological evaluation of new radioiodinated MMP inhibitors for imaging MMP activity in vivo. Nucl Med Biol 2004;31:257-67. Schäfers M, Riemann B, Kopka K, Breyholz HJ, Wagner S, Schäfers KP, et al. Scintigraphic imaging of matrix metalloproteinase activity in the arterial wall in vivo. Circulation 2004;109:2554-9. Narula J, Petrov A, Ditlow C, Pak KY, Chen FW, Khaw BA. Maximizing radiotracer delivery to experimental atherosclerotic lesions with high-dose, negative charge-modified Z2D3 antibody for immunoscintigraphic targeting. J Nucl Cardiol 1997;4:226-33. Kolodgie F, Petrov A, Virmani R, Narula N, Verjans JW, Weber DK, et al. Targeting of apoptotic macrophages and experimental atheroma with radiolabeled annexin V: A technique with potential for noninvasive imaging of vulnerable plaque. Circulation 2003; 108:3134-9. Ogawa M, Ishino S, Mukai T, Asano D, Teramoto N, Watabe H, et al. (18)F-FDG accumulation in atherosclerotic plaques: Immunohistochemical and PET imaging study. J Nucl Med 2004;45:1245-50. Tawakol A, Migrino RQ, Hoffman U, Abbara S, Houser S, Gerwirtz H, et al. Noninvasive in vivo measurement of vascular inflammation with F-18 fluorodeoxyglucose positron emission tomography. J Nucl Cardiol 2005;12:294-301. Rudd JH, Warburton EA, Fryer TD, Jones HA, Clark JC, Antoun N, et al. Imaging atherosclerotic plaque inflammation with [18F]fluorodeoxyglucose positron emission tomography. Circulation 2002;105:2708-11. Tahara N, Kai H, Yamagishi S, Mizoguchi M, Nakaura H, Ishibashi M, et al. Vascular inflammation evaluated by [18F]fluorodeoxyglucose positron emission tomography is associated with the metabolic syndrome. Am J Cardiol 2007;49:1533-9. Davies JR, Rudd JHF, Weissberg PL, Narula J. Radionuclide imaging for the detection of inflammation in vulnerable plaques. J Am Coll Cardiol 2006;47(Suppl):C57-68. Becker CR, Nikolaou K, Muders M, Babaryka G, Crispin A, Schoepf UJ, et al. Ex vivo coronary atherosclerotic plaque characterization with multi-detector-row CT. Eur Radiol 2003;13:2094-8. Leber AW, Knez A, White CW, Becker A, von Ziegler F, Muehling O, et al. Composition of coronary atherosclerotic plaques in patients with acute myocardial infarction and stable angina pectoris determined by contrast-enhanced multislice computed tomography. Am J Cardiol 2003;91:714-8.
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24. Botnar RM, Stuber M, Kissinger KV, Kim WY, Spuentrup E, Manning WJ. Noninvasive coronary vessel wall and plaque imaging with magnetic resonance imaging. Circulation 2000;102: 2582-7. 25. Sirol M, Itskovich VV, Mani V, Aguinaldo JG, Fallon JT, Misselwitz B, et al. Lipid-rich atherosclerotic plaques detected by gadofluorine-enhanced in vivo magnetic resonance imaging. Circulation 2004;109:2890-6. 26. Takaya N, Yuan C, Chu B, Saam T, Polissar NL, Jarvik GP, et al. Presence of intraplaque hemorrhage stimulates progression of carotid atherosclerotic plaques: A high-resolution magnetic resonance imaging study. Circulation 2005;111:2768-75. 27. Ruehm SG, Carot C, Vogt P, Kolb S, Debatin JF. Magnetic resonance imaging of atherosclerotic plaque with ultrasmall superparamagnetic particles of iron oxide in hyperlipidemic rabbits. Circulation 2001;103:415-22. 28. Khaw B. Antibodies for molecular imaging in the cardiovascular system. J Nucl Cardiol 2005;12:591-604. 29. Kerr JFR, Wyllie AH, Currie AR. Apoptosis: A basic biological phenomenon with ranging implications in tissue kinetics. Br J Cancer 1972;26:239-57. 30. Shirai T. Commentary: oncosis and apoptosis: Two faces of necrosis in a new proposal to clear up the confusion regarding cell death. Toxicol Pathol 1999;27:495-6. 31. Carrió I, Pieri PL, Narula J, Prat L, Riva P, Pedrini L, et al. Noninvasive localization of human atherosclerotic lesions with
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In-111-labeled monoclonal Z2D3 antibody specific for proliferating smooth muscle cells. J Nucl Cardiol 1998;5:551-7. Zhang SJ, Wu JC. Comparison of imaging techniques for tracking cardiac stem cell therapy. J Nucl Med 2007;48:1916-9. Van Westreenen HL, Cobben DC, Jager PL, van Dullemen HM, Wesseling J, Elsinga PH, et al. Comparison of 18F-FLT PET and 8F-FDG PET in esophageal cancer. J Nucl Med 2005;46: 400-4. Wieder HA, Geinitz H, Rosenberg R, Lordick F, Becker K, Stahl A, et al. PET imaging with [(18)F]3’-fluorothymidine for prediction of response to neoadjuvant treatment in patients with rectal cancer. Eur J Nucl Med Mol Imaging 2007;34:878-83. Weissleder R, Moore A, Mahmood U, Bhorade R, Benveniste H, Chiocca EA, et al. In vivo magnetic resonance imaging of transgene expression. Nat Med 2000;6:351-5. Ichikawa T, Högemann D, Saeki Y, Tyminski E, Terada K, Weissleder R, et al. MRI of transgene expression: Correlation to therapeutic gene expression. Neoplasia 2002;4:523-30. Beeres SL, Bengel FM, Bartunek J, Atsma DE, Hill JM, Vanderheyden M, et al. Role of imaging in cardiac stem cell therapy. Am J Cardiol 2007;49:1137-48. Cresci S, Gropler RJ. Image-guided cardiovascular functional genomics: Finding the needle in the haystack. J Nucl Cardiol 2007;14:275-6. Webster’s Third New International Dictionary. Springfield (MA): Merriam-Webster; 1986.
avid imaging capitalizes on the leakage of calcium salts through irreversibly damaged myocardial cell membranes to identify infarcted tissue. Cardiac positron emission tomography (PET) utilizes rubidium 82 and nitrogen 13 ammonia to evaluate myocardial perfusion and fluorine 18 fluorodeoxyglucose (FDG) to track the shift of myocardial substrate metabolism from fatty acids to glucose in ischemic but viable myocardial cells. So in a sense, we are already molecular imaging specialists! Through these mainstays of “targeted” nuclear imaging, we have realized our potential to monitor molecular processes, but we have similarly learned the shortcomings of our methodology. For example, the accuracy of thyroid radioiodine uptake measurements is confounded by a host of factors including medications, iodinated contrast agents, and even multivitamins and dietary supplements. Today, after nearly 4 decades of scintillation camera development, single photon emission computed tomography (SPECT) imaging of the thyroid is not routinely performed because of low target count density and the inability of general-purpose scintillation detectors to approximate the neck. Given its limited spatial resolution, particularly the difficulty in identifying a small “cold” defect within a large traceravid object, liver scintigraphy has essentially been replaced by techniques with far superior resolution such as sonography, computed tomography (CT), and magnetic resonance imaging (MRI). The bone scan, though highly sensitive in detecting osteoblastic metastases, unfortunately lacks specificity in differentiating metastatic disease from degenerative, post-traumatic, inflammatory, or hypertrophic changes. Tc-99m pyrophosphate infarctavid scintigraphy is seldom performed nowadays. Because tracer localization is dependent on not only the volume of cell necrosis but also residual blood flow to deliver the tracer to the target cells, infarct quantification may be inaccurate. Sensitivity in detecting subendocardial infarcts is suboptimal as a result of the geometry of the target and low tracer avidity. Moreover, infarct tracer avidity is time dependent, peaking 24 to 72 hours after infarction. In addition, because patient management decisions are much more dependent on the functional consequences of the infarct (ie, left ventricular volume and ejection fraction and the presence of an aneurysm or 435
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blood pool clearance. Antifibrin’s utilization was further limited by concerns regarding insensitivity, antigenicity, and difficulty in differentiating the 3 deep veins of the calf. Doppler venography, despite its inability to differentiate acute from chronic thrombosis, quickly supplanted antifibrin scintigraphy because of its ready accessibility even at the patient’s bedside, low cost, lack of ionizing radiation, and ability to anatomically localize the thrombosis. Thus, although nuclear imaging remains a crucial diagnostic tool, we have learned the limitations of our techniques, which in many cases have been supplanted by superior methods. These limitations may be grouped as follows:
Figure 1. Don Quixote and Sancho Panza, Honoré Daumier, 1808-1879. (This image [or other media file] is in the public domain because its copyright has expired. This applies to the United States, Canada, the European Union, and those countries with a copyright term of life of the author plus 70 years.)
pseudoaneurysm), functional/anatomic evaluation with echocardiography, which may be performed immediately after myocardial infarction at the patient’s bedside, has become a procedure routinely performed in patients following myocardial infarction. With attenuation correction and higher photon energy, Rb-82 PET and N-13 ammonia PET are touted to provide improved image quality compared with SPECT with Tc-99m perfusion agents. Nevertheless, as a result of physiologic cardiac motion and inherent instrumentation limitations, even PET still lacks resolution sufficient to identify subendocardial ischemia and/or scar and could possibly, one day, be replaced by higher-resolution MRI or CT contrast techniques. Like commercially available Tc-99m agents, Rb-82 uptake is not linearly related to coronary blood flow, so measurements of absolute myocardial blood flow are inaccurate. F-18 FDG PET to assess myocardial viability is so dependent on the underlying metabolic milieu (ie, serum glucose and insulin levels) that in busy clinical laboratories, FDG viability scans are impractical in most diabetic patients or even those with fasting hyperglycemia. Other “targeted” approaches using radiolabeled antibodies, such as indium 111 antimyosin and Tc-99m antifibrin, have been developed and even commercialized, but they have never found an important role in patient management. Antimyosin’s clinical applicability was limited by the same physiologic factors as those cited previously for Tc-99m pyrophosphate, and the utility of infarct-avid radiotracer was also hampered by its cost and the necessity for delayed images to allow for
1. Resolution A. Limited instrumentation spatial resolution B. Inaccessibility of the target organ, because of organ depth and/or patient anatomy C. Physiologic target motion 2. Suboptimal target-to-background ratio A. Low target tracer avidity B. Nonspecificity of the pathophysiologic mechanism of tracer localization C. Factors in the cellular environment influencing radiotracer uptake D. Slow blood pool clearance necessitating delayed imaging E. Time dependence of tracer avidity 3. Inaccuracy of quantitative techniques A. Nonlinearity of target tracer uptake 4. Tracer antigenicity 5. Clinical practicality A. Accessibility/convenience compared with other methodologies B. Delay in patient management 6. Clinical relevance A. Functional, not pathophysiologic, factors often determine patient management 7. Cost Nonetheless, advancements in cardiac molecular imaging with radionuclides have raised our level of excitement and hope for the future of our field. Will it be possible to scintigraphically identify a sequence of cellular events as they occur and monitor the effect of interventions that alter these processes? Let us review just a few of these potential applications of cardiac radionuclide molecular imaging, with consideration of the drawbacks and limitations cited previously for exist-
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ing nuclear techniques as well as the potential of competing methodologies. MOLECULAR IMAGING: DULCINEA DEL TOBOSO, THE IMAGINARY, IMPOSSIBLY BEAUTIFUL OBJECT OF OUR QUEST Identification of Vulnerable Plaque and Processes Associated with Arterial Wall Damage Atherosclerosis is a dynamic, multifactorial, pathophysiologic process for which there are numerous potential targets available for radionuclide imaging. Arterial wall damage is associated with inflammation, lipid deposition, oxidative stress, macrophage infiltration, extracellular matrix digestion, cell apoptosis, and thrombosis. Indeed, all of these processes have been evaluated as potential advancements of radionuclide molecular imaging whereby information regarding plaque formation and vulnerability rather than only relatively advanced arterial anatomic narrowing and the associated hemodynamic consequences can be evaluated. Excellent overviews of radionuclide techniques for cardiac molecular imaging and biologic targeting of atherosclerotic plaque have been published previously.2-4 Initial attempts to image atherosclerotic plaque used radiolabeled compounds known to accumulate in atherosclerotic plaque such as iodine-125 autologous human low-density lipoprotein (LDL), Tc-99m LDL, I-125 LDL, or tracers that could potentially track the immune response to vascular injury such as In-111 immunoglobulin G Fab fragments and I-125 monocyte chemoattractant.5-11 However, attempts to image atherosclerotic plaque with such methods met with very limited success because of high blood pool activity and the suboptimal target-to-background ratios that could be achieved with these macromolecular compounds. Moreover, the size of atherosclerotic lesions was generally beyond the resolution capabilities of human nuclear imaging systems. Other techniques have targeted more specific markers of vascular injury. As a response to endovascular damage, vascular remodeling and proliferation occur. Radiolabeled antagonists to integrin, such as the In-111– labeled ␣v3 integrin–specific molecule, have been shown to track progressive cell proliferative processes after carotid artery injury in mice.12 In addition, matrix metalloproteinases (MMPs) are a family of proteolytic enzymes associated with degradation of myocardial extracellular matrix and with the process of vascular remodeling. As cell membrane integrity is lost with plaque rupture, there is a local release of macrophages that have phagocytized toxic material, particularly free cholesterol. With macrophage cell death, MMPs increase locally in the lesion. Iodine 123–labeled MMP inhibitor
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also has been shown to allow in vivo imaging of vascular damage in mice after ligation of the carotid artery.13,14 In addition to these reparative processes, apoptosis of cells and macrophages and smooth muscle proliferation occur in response to vascular injury.15,16 Tc-99m annexin targets phosphatidylserine, a molecule expressed on the cell membrane of macrophages and smooth muscle cells after apoptotic cell death. A radiolabeled, negatively charged, modified antibody, Z2D3, has been used to identify smooth muscle proliferation.15 Whereas these novel techniques to identify reparative processes in response to endovascular damage are indeed exciting, the practicality of these approaches is doubtful. One questions if the animal models presently used to evaluate such new, potential radiopharmaceuticals are clinically relevant. Is the physiologic response to carotid ligation analogous to the chronic, multifactorial causative factors resulting in coronary artery disease? Vascular injury associated with atherosclerosis may be localized, and tracer-avid lesions may be of insufficient mass or volume to be detectable by human in vivo imaging methods. Localization of some radiotracers such as annexin, as noted previously, is relatively nonspecific. Moreover, the ultimate practicality of such an approach in living human subjects is questionable. Imaging mouse carotid arteries is sufficiently challenging, requiring specialized small animal imaging systems. However, in humans, if our goal is to detect coronary disease, the target lies deep within the body, moves with respiration and cardiac contraction, and lies adjacent to the cardiac blood pool. Perhaps only with specially designed endovascular scintillation probes will it be possible to detect such processes. However, with such probes, correlative imaging with contrast enhancement of the coronary arteries (ie, CT or MRI coronary angiography) will be necessary for purposes of anatomic reference. Though potentially valuable as a research tool, it is unlikely that such a technique would ever be clinically applicable. In a cost-conscious health care environment, would patients at risk for coronary disease ever be screened by use of such an invasive (and presumably very costly) approach? A widely available modality in nuclear cardiology that has been shown to visualize atherosclerotic plaque in the abdominal aorta and carotid arteries is F-18 FDG PET.17-20 FDG uptake is related to macrophage density, but as we well know from extensive experience in oncologic imaging, radiotracer accumulation may be associated with nonspecific inflammatory processes.21 For identification of coronary atherosclerotic plaque, F-18 FDG PET may be confounded not only by the size and depth of the target, nonspecific uptake associated with vasculitis, and brown fat in the interatrial septum, but also—most importantly— by marked tracer avidity of the adjacent myocardium.
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As nuclear cardiologists, we must also seriously and fairly consider the potential of other modalities for imaging atherosclerosis. Coronary calcium scoring, which is widely available (though not always reimbursed), is a fast and simple method to identify coronary calcification. Although coronary calcification is not closely related to either the degree of atherosclerotic narrowing or the hemodynamic significance of coronary lesions, calcification is essentially always associated with atherosclerosis and has now also been shown to be related to the long-term risk of cardiac events. One might question whether the much more sophisticated and substantially more costly, labor-intensive, and time-consuming nuclear molecular imaging techniques described previously will provide diagnostic and prognostic information that is more valuable than that from the “lowly,” often maligned, coronary calcium score. Beyond calcium scoring and the definition of coronary luminal morphology, multislice CT demonstrates promise in identifying the composition of atherosclerotic plaque and thus vulnerability.22,23 MRI can identify changes in tissue composition within the vascular wall, including remodeling, and probe the composition of plaques, including the accumulation of iron in macrophages.24-27 Antibodies for Molecular Imaging of the Cardiovascular System The technical limitations of antimyosin and antifibrin monoclonal antibodies for human imaging have been discussed previously. In addition, antimyosin accumulation may be nonspecific, associated with either “oncotic” or “apoptotic” cell death.28-30 Positively charged protein antibodies may be attracted nonspecifically to negatively charged molecules. To limit persistent blood pool concentration and, consequently, the delay in target imaging, antibody fragments have been investigated. An immunoglobulin M monoclonal antibody, Z2D3, that targets a lipid complex antigen associated with smooth muscle cell proliferation has been developed.15 Visualization of atherosclerotic lesions in rabbit aortas was possible 48 hours after injection of In-111– labeled negatively charged polymerized Z2D3 F(ab’)2. However, as with other antibody imaging methods, blood clearance was slow (half-time, 920 minutes), and nontarget radiotracer concentrations in the liver, bones, and kidneys were undesirably high even with this antibody fragment.31 Moreover, vulnerable arterial plaque may not necessarily be related to smooth muscle proliferation. Thus, despite many years of investigation, it seems unlikely that monoclonal antibodies or even highly customized antibody fragments will ever be clinically useful to identify subclinical atherosclerotic lesions.
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Issues of target nonspecificity, high blood pool concentration and slow clearance, inconvenience, and prohibitive cost most likely will prevent this methodology from gaining widespread clinical applicability. Moreover, as discussed previously for other nuclear molecular imaging methods under investigation to target vulnerable plaque, imaging techniques with spatial resolution far superior to scintigraphy will most likely be more sensitive, more specific, more time-efficient, and less costly than targeted radiolabeled antibodies. Molecular Imaging of Cardiovascular Gene Products Certainly one of the most exciting emerging facets of clinical cardiology is the prospect of gene therapy for a variety of applications, including treatment of coronary artery disease by modifying angiogenic factors such as vascular endothelial growth factor and fibroblast growth factor, reduction of restenosis after angioplasty by inhibiting smooth muscle cell proliferation, improvement of congestive heart failure by gene transfer of calcium adenosine triphosphate (ATP) pump, inhibition of atherosclerosis by overexpression of a high-density lipoprotein receptor, and reduction of hypoxia-induced apoptosis of cardiac myocytes.1 Multiple factors that influence the success of gene therapy could potentially be evaluated with molecular imaging probes, answering several clinically relevant questions: Has the vector delivered to the heart indeed reached its target site? What is the time course of gene expression? Do other nontarget sites demonstrate gene expression? Is the level of genetic expression sufficient to result in a therapeutic effect? And do the kinetics of gene expression correlate with anatomic repair and/or functional improvement? One approach to track these genetic processes is to directly probe a target—that is, the receptor, an enzyme, messenger ribonucleic acid, or other molecules—with a radiolabeled probe. However, investigations using such a direct approach have met with limited success because of a low concentration or density of target molecules, limited tracer penetration across the cell membrane, slow blood clearance of unbound probes, and a poor targetto-background ratio, all common problems generally encountered with macromolecular imaging. An alternate, indirect approach to track these genetic processes has entailed reporter gene imaging in experimental animals. Once a reporter gene is first introduced into the target tissue, transcription of the reporter gene and translation of the messenger ribonucleic acid produce protein products that can be targeted with reporter molecular probes. A reporter probe can be altered by a process such as phosphorylation to be trapped intracellularly. If the probe is also radiolabeled, its tissue distribution can be tracked by
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scintigraphy, potentially providing noninvasive, quantitative, and repetitive imaging of genetic processes in a living organism. This technique also holds promise in monitoring stem cell therapy in treating ischemic heart disease.32 Cell labeling with In-111 oxyquinoline and Tc-99m hexamethyl propylene has been deployed in endothelial progenitor cells, hematopoietic stem cells, and mesenchymal stem cells.33,34 Although receptor gene imaging is perhaps the most innovative and promising of the radionuclide molecular imaging techniques, many of the familiar limitations seen with other target imaging radionuclide methods nevertheless stand before us as substantial obstacles: the host response may alter the function and biologic halflife of the reporter gene; the reporter probe itself may alter physiologic processes of cell metabolism; the radioactive label may alter the integrity of the reporter gene; the radiotracer may be transferred to nontargeted cells; the limited physical half-life of the radiotracer may impair our ability to track ongoing cellular processes; and frequently repeated imaging may be prohibitive with regard to radiation dosimetry. Furthermore, in common with many other proposed nuclear molecular imaging techniques, sensitivity may be significantly limited by high background activity and small targets beyond the resolution of SPECT and PET systems designed for human imaging. In addition, like the majority of potential radionuclide molecular imaging techniques discussed previously, it is questionable whether techniques used in experimental animals obtained with microSPECT or microPET systems can ever be adapted to human imaging systems. With these daunting potential limitations, we must again consider more rapid imaging techniques with superior spatial resolution and the additional possibility of repetitive evaluation, such as MRI by use of superparamagnetic probes or immunofluorescence imaging, to hold greater potential.32,35,36 A REASONABLE APPROACH: SANCHO PANZA’S WISDOM AND CONSOLATION ON THE TRIP BACK HOME Are Not Functional Consequences More Important Than Disease Identification in Patient Management? The exciting experimental molecular imaging techniques described previously all evaluate, albeit with limitations, pathophysiologic processes that ultimately affect myocardial perfusion and global and regional cardiac function.37,38 Myocardial perfusion imaging assesses the consequences of flow-limiting coronary artery disease produced by vulnerable plaque. However, our methodology is significantly limited by radiopharmaceuticals whose uptake is not linearly related to coronary
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Figure 2. Don Quixote, Honoré Daumier, 1808-1879. (The work of art depicted in this image and the reproduction thereof are in the public domain worldwide. The reproduction is part of a collection of reproductions compiled by The Yorck Project. The compiliation copyright is held by Zenodot Verlagsgesellschaft mbH and licensed under the GNU Free Documentation License.)
blood flow, resulting in relative insensitivity in detecting flow-limiting coronary stenoses. Quantification of myocardial perfusion with PET remains elusive and not routinely performed, and efforts to quantify perfusion with attenuation-corrected SPECT seem to have gained minimal attention in recent years. Efforts to significantly improve the spatial resolution of gated perfusion SPECT and PET with improved detector characteristics, cardiac and respiratory gating, and CT coregistration are under way but have not been afforded a high profile or priority in journals and at national and international meetings. Likewise, evaluation of cardiac function, not only of the left ventricle but of all the cardiac chambers, is now possible with gated blood pool SPECT, a technique that is grossly underused perhaps because it has not yet been optimized. Thus there is much work yet to be done to optimize our functional assessment of new therapeutic techniques.
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Although nuclear molecular imaging will undoubtedly serve as a very valuable research tool, particularly in small experimental animals imaged with highly specialized instrumentation, I believe that primarily as a result of their technical superiority and potentially superior cost-effectiveness, competing imaging modalities may make nuclear molecular imaging on a wide-scale clinical basis less attractive. We should instead direct our sincerest efforts to improving our existing techniques in order to make them relevant to accurately assess the physiologic consequences of new pharmacologic, antibody, and gene therapies.
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8.
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THE EPILOGUE In summary, considering the inherent limitations of nuclear imaging, our quest to position radionuclide techniques at the forefront of molecular imaging unfortunately seems a bit “quixotic,” defined by Webster’s Third New International Dictionary as “idealistic and utterly impractical; marked by rash, lofty ideas or chivalrous action doomed to fail.”39 With the current limitations of nuclear imaging techniques, probing molecular targets indeed seems a bit like jousting at windmills. However, in consolation, as nuclear cardiologists, we must not lose sight of the fact that we already have at hand excellent tools in widespread clinical use to assess myocardial perfusion and global and regional function. Like for Don Quixote, these familiar, functional tools— our Aldonza—with some care and encouragement can become our Dulcinea in the era of cardiovascular molecular imaging and new therapeutic strategies. But unlike this errant knight, our story will not end in disillusionment and melancholy (Figure 2). Nuclear cardiology is here to stay! Acknowledgment
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The author has indicated he has no financial conflicts of interest. 19.
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