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Cardiovascular Molecular Imaging¹

¹ From the Department of Medicine, Division of Cardiology (J.C.W.), Department of Radiology, Molecular Imaging Program at Stanford (J.C.W., S.S.G.), and Bio-X Program (S.S.G.), Stanford University, 300 Pasteur Dr, Edwards Bldg R354, Stanford, CA 94305-5344; and Department of Nuclear Medicine, Johns Hopkins University, Baltimore, Md (F.M.B.). Received January 25, 2006; revision requested March 24; revision received April 7; final version accepted June 1. Address correspondence to J.C.W. (e-mail: joewu{at}stanford.edu).

View larger version (21K): [in this window] [in a new window] [Download PPT slide]   Figure 1a: From atherosclerotic plaque biology toward molecular plaque imaging. (a) Atherosclerosis and vascular structure. Image shows development of expansive vascular remodeling, which may result in substantially increased vulnerability without luminal narrowing. Ultimately, changes lead to acute plaque rupture or to chronic stenosis with luminal narrowing (right). (b) Criteria of plaque vulnerability as targets for imaging. Image depicts morphologic and biologic features of vulnerable plaques, which are suitable targets for imaging approaches. (c) Future perspective in regard to multimodality imaging of plaque morphology and biology. Image highlights the potential of hybrid imaging technologies, which may allow noninvasive fusion of morphology from angiography with biology from nuclear imaging of plaque-targeted molecular probes (nuclear and fusion images are simulated).

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 1b: From atherosclerotic plaque biology toward molecular plaque imaging. (a) Atherosclerosis and vascular structure. Image shows development of expansive vascular remodeling, which may result in substantially increased vulnerability without luminal narrowing. Ultimately, changes lead to acute plaque rupture or to chronic stenosis with luminal narrowing (right). (b) Criteria of plaque vulnerability as targets for imaging. Image depicts morphologic and biologic features of vulnerable plaques, which are suitable targets for imaging approaches. (c) Future perspective in regard to multimodality imaging of plaque morphology and biology. Image highlights the potential of hybrid imaging technologies, which may allow noninvasive fusion of morphology from angiography with biology from nuclear imaging of plaque-targeted molecular probes (nuclear and fusion images are simulated).

View larger version (44K): [in this window] [in a new window] [Download PPT slide]   Figure 1c: From atherosclerotic plaque biology toward molecular plaque imaging. (a) Atherosclerosis and vascular structure. Image shows development of expansive vascular remodeling, which may result in substantially increased vulnerability without luminal narrowing. Ultimately, changes lead to acute plaque rupture or to chronic stenosis with luminal narrowing (right). (b) Criteria of plaque vulnerability as targets for imaging. Image depicts morphologic and biologic features of vulnerable plaques, which are suitable targets for imaging approaches. (c) Future perspective in regard to multimodality imaging of plaque morphology and biology. Image highlights the potential of hybrid imaging technologies, which may allow noninvasive fusion of morphology from angiography with biology from nuclear imaging of plaque-targeted molecular probes (nuclear and fusion images are simulated).

View larger version (29K): [in this window] [in a new window] [Download PPT slide]   Figure 2a: Imaging in myocardial ischemia. (a) Imaging markers in CAD. (b) Examples of morphologic, functional, and molecular images. LAD = left anterior descending artery, LCA = left coronary artery, LCX = left circumflex artery, RCA = right coronary artery.

View larger version (27K): [in this window] [in a new window] [Download PPT slide]   Figure 2b: Imaging in myocardial ischemia. (a) Imaging markers in CAD. (b) Examples of morphologic, functional, and molecular images. LAD = left anterior descending artery, LCA = left coronary artery, LCX = left circumflex artery, RCA = right coronary artery.

View larger version (51K): [in this window] [in a new window] [Download PPT slide]   Figure 3: Examples of patterns of myocardial viability from perfusion-metabolism PET imaging. Representative left ventricular (LV) short- and long-axis sections from two patients with severe ventricular dysfunction are depicted in "hot metal" color scale (brighter color indicates higher radioactivity concentration). In top two rows, an anteroseptal perfusion defect is present in [13N]–NH3 perfusion images, with concomitant matched reduction of uptake of the metabolic tracer FDG. This pattern indicates the presence of scar tissue, which will not benefit from revascularization. In bottom two rows, a perfusion defect is shown in the anterior and apical wall. Enhanced FDG uptake is found in the metabolic study, indicating the presence of ischemically compromised hibernating myoardium, which will benefit from revascularization. Note that relatively reduced uptake of FDG in normally perfused inferior wall is consistent with use of fatty acids as substrate in this area of normally perfused myocardium. LA = left atrium, RA = right atrium, RV = right ventricle.

View larger version (72K): [in this window] [in a new window] [Download PPT slide]   Figure 4: Multimodality imaging of myocardial viability. Short-axis MR images show late enhancement of gadopentetate dimeglumine (in gray scale) and PET images show glucose metabolism (using FDG) and perfusion (using [13N]–NH3[NH3]). PET images are displayed in a hot metal color scale where brighter color indicates higher radioactivity concentration. Nontransmural late enhancement, indicating subendocardial scar tissue, is shown on MR images. PET scans show reduced perfusion in the same area (bottom middle), but FDG uptake is less reduced and higher compared with perfusion (top middle). This perfusion-metabolism mismatch indicates residual viability in the subepicardial portion of the area with subendocardial scar. IR TrueFISP +Gd = inversion-recovery true fast imaging with steady-state precession and gadolinium-based contrast agent.

View larger version (39K): [in this window] [in a new window] [Download PPT slide]   Figure 5a: 123I-MIBG imaging in patients with HF. (a) Schematic shows most commonly used radioligands for assessment of cardiac pre- and postsynaptic processes. (b) SPECT MIBG study in healthy volunteer. Short-axis tomograms and reconstructed polar maps show normal MIBG distribution and washout. (c) SPECT MIBG study in patient with dilated cardiomyopathy. Short-axis tomograms and reconstructed polar maps show decreased and heterogeneous myocardial MIBG activity. ATP = adenosine triphosphate, DOPA = dihydroxyphenylalanine, cAMP = cyclic adenosine monophosphate, NE = norepinephrine. (Reprinted, with permission, from reference 91.)

View larger version (63K): [in this window] [in a new window] [Download PPT slide]   Figure 5b: 123I-MIBG imaging in patients with HF. (a) Schematic shows most commonly used radioligands for assessment of cardiac pre- and postsynaptic processes. (b) SPECT MIBG study in healthy volunteer. Short-axis tomograms and reconstructed polar maps show normal MIBG distribution and washout. (c) SPECT MIBG study in patient with dilated cardiomyopathy. Short-axis tomograms and reconstructed polar maps show decreased and heterogeneous myocardial MIBG activity. ATP = adenosine triphosphate, DOPA = dihydroxyphenylalanine, cAMP = cyclic adenosine monophosphate, NE = norepinephrine. (Reprinted, with permission, from reference 91.)

View larger version (56K): [in this window] [in a new window] [Download PPT slide]   Figure 5c: 123I-MIBG imaging in patients with HF. (a) Schematic shows most commonly used radioligands for assessment of cardiac pre- and postsynaptic processes. (b) SPECT MIBG study in healthy volunteer. Short-axis tomograms and reconstructed polar maps show normal MIBG distribution and washout. (c) SPECT MIBG study in patient with dilated cardiomyopathy. Short-axis tomograms and reconstructed polar maps show decreased and heterogeneous myocardial MIBG activity. ATP = adenosine triphosphate, DOPA = dihydroxyphenylalanine, cAMP = cyclic adenosine monophosphate, NE = norepinephrine. (Reprinted, with permission, from reference 91.)

View larger version (69K): [in this window] [in a new window] [Download PPT slide]   Figure 6: Four strategies of imaging reporter gene and reporter probe. A, Enzyme-based bioluminescence imaging. Expression of the firefly luciferase reporter gene leads to the firefly luciferase reporter enzyme, which catalyzes the reporter probe (D-luciferin) that results in a photochemical reaction. This yields low levels of photons that can be detected and quantified by a charge-coupled device camera. B, Enzyme-based PET imaging. Expression of the herpes simplex virus type 1 thymidine kinase (HSV1-tk) reporter gene leads to the thymidine kinase reporter enzyme, HSV1-TK, which phosphorylates and traps the PET reporter probe 9-(4-[18F]fluoro-3-hydroxymethylbutyl)guanine (FHBG) intracellularly. Radioactive decay of 18F isotopes can be detected with PET. C, Receptor-based PET imaging. 3-(2-[18F]fluoroethyl)spiperone (18FESP) is a reporter probe that interacts with the dopamine 2 receptor (D2R) to result in probe trapping on or in cells expressing the D2R gene. D, Receptor-based MR imaging. Overexpression of engineered transferrin receptor (TfR) results in increased cell uptake of the transferrin-monocrystalline iron oxide nanoparticles. These changes result in a detectable contrast change on MR image. FPCV = 8-[18F]fluoropenciclovir, holo-Tf = holo-transferrin. (Reprinted, with permission, from reference 98.)

View larger version (52K): [in this window] [in a new window] [Download PPT slide]   Figure 7a: Molecular imaging of cardiac perfusion, metabolism, and gene expression. (a) Schematic of Ad-CMV-VEGF121-CMV-HSV1-sr39tk mediated gene expression. The translated product of VEGF121 is soluble and excreted extracellularly, whereas the translated product of HSV1-sr39tk (HSV1-sr39TK) traps FHBG intracellularly by phosphorylation. PCMV = CMV promoter. (b) At day 2, representative images showing normal perfusion ([13N]–NH3) and metabolism (FDG) in a sham rat, anterolateral infarction in a control rat, and anterolateral infarction in a study rat (Ad-CMV-VEGF121-CMV-HSV1-sr39tk) in short, vertical, and horizontal axis (gray scale). The color scale is expressed as percentage injected dose per gram (%ID/g) for FHBG uptake. Only the study rat showed robust HSV1-sr39tk reporter gene activity near the site of injection. (Reprinted, with permission, from reference 124.)

View larger version (20K): [in this window] [in a new window] [Download PPT slide]   Figure 7b: Molecular imaging of cardiac perfusion, metabolism, and gene expression. (a) Schematic of Ad-CMV-VEGF121-CMV-HSV1-sr39tk mediated gene expression. The translated product of VEGF121 is soluble and excreted extracellularly, whereas the translated product of HSV1-sr39tk (HSV1-sr39TK) traps FHBG intracellularly by phosphorylation. PCMV = CMV promoter. (b) At day 2, representative images showing normal perfusion ([13N]–NH3) and metabolism (FDG) in a sham rat, anterolateral infarction in a control rat, and anterolateral infarction in a study rat (Ad-CMV-VEGF121-CMV-HSV1-sr39tk) in short, vertical, and horizontal axis (gray scale). The color scale is expressed as percentage injected dose per gram (%ID/g) for FHBG uptake. Only the study rat showed robust HSV1-sr39tk reporter gene activity near the site of injection. (Reprinted, with permission, from reference 124.)

View larger version (57K): [in this window] [in a new window] [Download PPT slide]   Figure 8: Functional imaging studies in a patient after MI who underwent intracoronary infusion of circulating blood–derived progenitor cells. A, Left ventricular angiograms before circulating blood–derived progenitor cell therapy and, B, at 4-month follow-up. C, Pretherapeutic and, D, posttherapeutic corresponding FDG PET bull's-eye views of the left ventricle of the patient. LAD = left anterior descending artery, LCX = left circumflex artery, RCA = right coronary artery. (Reprinted, with permission, from reference 132.)

View larger version (36K): [in this window] [in a new window] [Download PPT slide]   Figure 9: Optical bioluminescence and PET imaging of cell transplantation in rat myocardium. A, Study animal transplanted with embryonic H9c2 cardiomyoblasts emits significant cardiac bioluminescence activity at days 1, 2, 4, 8, 12, and 16 (P < .05 vs control). Control rat shows background signal only. B, The location, magnitude, and duration of cell survival are determined by longitudinal imaging of FHBG activity (gray scale) within the same rat. C, Tomographic views of cardiac micro-PET images shown in short, vertical, and horizontal axes. At day 2, study animal transplanted with cardiomyoblasts expressing HSV1-sr39tk shows significant FHBG uptake (color scale) superimposed on [13N]–NH3 images (gray scale). Control animal shows homogeneous [13N]–NH3 perfusion but background FHBG uptake. D, Autoradiography in the same study animal at day 2 confirms trapping of 18F by transplanted cells at the lateral wall at finer spatial resolution (approximately 50 µm). %ID/g = percentage infective dose per gram, p/sec/cm2/sr = photons per second per square centimeter per steradian. (Reprinted, with permission, from reference 143.)