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Non-Invasive Macrophage Imaging for Detection of Vulnerable PlaqueApplications and LimitationsAmershamMorteza Naghavi, MD
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AB
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Which one is vulnerable, A or B?The one with inflammation (macrophage infiltration)
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Morphology vs. Activity ImagingInactive and non-inflamed plaqueActive and inflamed plaqueSimilar in IVUSOCTMRI w/o CMMorphologyDifferent ActivityThermography, Spectroscopy, immunoscintigraphy, MRI with targeted contrast media
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Plaque Morphology vs.
Plaque Activity We Need Both
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Imaging Inflammation- by MRI- by CTBoth are available today!
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Imaging Inflammation- by MRIPioneered in 1980sRummeny E, Weissleder R, Stark DD, Elizondo G, Ferrucci JT. Radiologe. 1988 Aug;28(8):380-6.
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Superparamagnetic and Ultra-superparamagnetic Iron OxideBlood pool Magnetic resonance (MR) imaging contrast media with a central core of iron oxide generally coated by a polysaccharide layer
Shortening MR relaxation timeEngulfed by and accumulated in cells with phagocytic activity
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Particle Core Size Particle Size Blood (nm) (nm) Half-life
Combidex 5-6 20-30 8hFeridex 4-6 35-50 2.40.2hDDM 43/34/102 6.4 20-30 6h ClariscanMION 4-6 17 variesFeruglose --- --- --- --- Examples of commercially available SPIOs
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USPIOs Enter the Atherosclerotic Plaque ThroughMacrophages that engulfed themFissured or thin cap Extensive angiogenesis vasa vasorum leakage Intra plaque hemorrhage
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In-vitro Study of Macrophage SPIO Uptake In a series of in-vitro studies we have tested
the rate of SPIO uptake by human activated monocytes in different conditions regardingincubation time and concentration of SPIO.All SPIO were labeled by a fluorescent dye(DCFA).
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FL-labeled SPIO Incubated Macrophages 24hr
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Double DAPI Staining with Fluorescence-labeled SPIO Macrophages after 24hr Incubation
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Hypothesis
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vasa vasorum
Over magnification is a major advantage of SPIO
Darkening property of SPIO in the white background of fat and water of plaque is another advantage
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SPIO and T2 EffectIn-vitro study to show the effect of macrophage SPIO uptake on their T2 relaxation time
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Macrophage Uptake of Feridex with Time and Concentration Shown by T2 ReductionConcentration mol/ml
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Histopathologic Studies of ApoE KO Mice Injected with SPIO (Abdominal Aorta)H&E stainingIron Staining
CD 68 stainingIron particles
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Histopathologic Study of Wild Type MiceInjected With SPIO (Thoracic Aorta) H&E stainingCD68 stainingIron staining
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Comparison of the Number of the Iron Particles (per HPF) in ApoE KO Mice Plaque vs. Normal Wall
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MR Image of Abdominal Aorta After SPIO Injection in ApoE and Control Mice
ApoE deficient mouse
C57B1 (control) mouse
Before Injection
After Injection (5 Days )
Dark (negatively enhanced) aortic wall, full of iron particles
Bright aortic lumen and wall without negative enhancement and no significant number of iron particles in pathology
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Injection of Cytokine Increases SPIO-Loaded Macrophage Density in Aortic Plaques (Apo E Deficient Mice)Naghavi et al Circulation 2003
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Naghavi et al Circulation 2003
Injection of Cytokine Increases SPIO-Loaded Macrophage Density in a Coronary Plaque (Apo E Deficient Mice)
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Histopathologic studies of Thoracic aorta in WatanabeHereditary Hypercholesterolemic rabbit after SPIO injectionH&E stainingIron stainingIron staining
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Histopathologic studies of Thoracic aorta in Watanabe Hereditary Hypercholesterolemic rabbit after SPIO injectionH&E stainingIron stainingIron stainingIron particles
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R=0.956Correlation between Iron positive cells in Iron staining and cell density in H&E staining in rabbitatherosclerotic aorta.
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17
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Cell Denity in H&E staining
SPIO positive cell -Iron staining
Plaque Cell Density vs SPIO
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HPFsNumber of nucleated cells per HPF(H&E staining)0.956113827
13735
270
32012
4106
52824
62617
7129
8118
9128
101810
111818
123322
1388
1430
15115
16146
171412
1853
196050
201424
211410
226540
2332
245035
2554
261010
276452
2821
574431
574431
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Cell Denity in H&E staining
SPIO positive cell -Iron staining
Plaque Cell Density vs SPIO
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MR Angiography 3D with Gadolinium-DTPA in Watanabe RabbitBefore SPIO injectionAfter SPIO injection
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MRI Identifies Plaque Inflammation by SPIO NanoparticlesWatanabe rabbitPost-SPIOWatanabe rabbitcontrolNZW rabbitcontrolNZW rabbitPost-SPIO
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Ex-vivo MR study of the thoracic aorta in Watanabe and Wild type rabbit after SPIO injection compared to control.(Gradient echo)
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Schmitz et al
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Schmitz et al
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Schmitz et al
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Ruhem et al
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Ruhem et al
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Ruhem et al
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Ruhem et al
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Ruhem et al
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Kooi et al
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Kooi et al
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Kooi et al
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Kooi et al
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Ho et al
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Ho et al
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MR signal changes after CsA treatment. A group with allotransplants was treated with CsA for either 7 days (n=5) or 4 days (n=5) after initial MRI experiments showed decrease of MR signal intensity according to degree of graft rejection. On POD 14, transplanted rats were reinjected with USPIO particles, and then MRI experiments were performed. Animals treated 7 days showed minimal changes in MR signal intensity 24 hours after reinjection (A and B), and animals treated 4 days showed MR signal intensity that was significantly decreased after USPIO injection (C and D). MR images of short-axis view of graft are shown. MR images before USPIO infusion are at A and C, and images taken 24 hours after infusion are at B and D. Ho et al
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Ho et al
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Imaging Macrophage Activity in the Brain Using Ultrasmall Particles of Iron Oxide
Jeff W.M. Bultea and Joseph A. Franka Laboratory of Diagnostic Radiology Research National Institutes of Health Bethesda, MD
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SPIO MR imagine of macrophage is feasible for clinical applications.
It will be of great interest to investigate the cost-effectiveness of this technique in comparison with alternative diagnostic approaches.
Conclusion
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Poor spatial and temporal resolution for coronary applicationsCostCumbersome (injection and delayed imaging)
Limitations
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