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Non-Invasive
Macrophage Imaging for
Detection of Vulnerable Plaque
Applications and Limitations
Amersham
Morteza Naghavi, ...
A
B
Which one is
vulnerable, A or B?
The one with
inflammation
(macrophage infiltration)
Morphology vs. Activity Imaging
Inactive and
non-inflamed
plaque
Active and
inflamed
plaque
Similar in
IVUS OCT MRI
w/o CM...
Plaque Morphology
vs.
Plaque Activity
We Need Both
Imaging Inflammation
- by MRI
- by CT
Both are available today!
Imaging Inflammation
- by MRI
Pioneered in 1980s
Rummeny E, Weissleder R, Stark DD, Elizondo G, Ferrucci JT.
Radiologe. 19...
SuperparamagneticSuperparamagnetic
andand
Ultra-superparamagneticUltra-superparamagnetic
Iron OxideIron Oxide
lBlood pool ...
Particle Core Size Particle Size Blood
(nm) (nm) Half-life
Combidex 5-6 20-30 8h
Feridex 4-6 35-50 2.4±0.2h
DDM 43/34/102 ...
USPIOs Enter the AtheroscleroticUSPIOs Enter the Atherosclerotic
Plaque ThroughPlaque Through
lMacrophages that engulfed
t...
In-vitro Study of Macrophage
SPIO Uptake
 In a series of in-vitro studies we have tested
the rate of SPIO uptake by human...
FL-labeled SPIO Incubated Macrophages 24hr
Double DAPI Staining with Fluorescence-labeled SPIO Macrophages
after 24hr Incubation
Hypothesis
vasa vasorum
Over magnification is a major advantage of SPIO
Darkening property of SPIO in the white background of fat
and...
SPIO and T2 Effect
In-vitro study to show the effect of
macrophage SPIO uptake on their
T2 relaxation time
0
10
20
30
40
50
60
70
80
90
50 250 control
20 min
60 min
6 hours
24 hours
Macrophage Uptake of Feridex with Time
and Conc...
Histopathologic Studies of ApoE KO Mice
Injected with SPIO (Abdominal Aorta)
H&E staining
Iron Staining CD 68 staining
Iro...
Histopathologic Study of Wild Type Mice
Injected With SPIO (Thoracic Aorta)
H&E staining
CD68 stainingIron staining
Comparison of the Number of the Iron Particles (per
HPF) in ApoE KO Mice Plaque vs. Normal Wall
0
5
10
15
Atherosclerotic
...
MR Image of Abdominal Aorta After SPIO
Injection in ApoE and Control Mice
ApoE
deficien
t mouse
C57B1
(control)
mouse
Befo...
Injection of Cytokine Increases SPIO-Loaded Macrophage
Density in Aortic Plaques (Apo E Deficient Mice)
Naghavi et al Circ...
Naghavi et al Circulation 2003
Injection of Cytokine Increases SPIO-Loaded Macrophage
Density in a Coronary Plaque (Apo E ...
Histopathologic studies of Thoracic aorta in Watanabe
Hereditary Hypercholesterolemic rabbit after SPIO injection
H&E stai...
Histopathologic studies of Thoracic aorta in Watanabe
Hereditary Hypercholesterolemic rabbit after SPIO injection
H&E stai...
Plaque Cell Density vs SPIO
0
10
20
30
40
50
60
0 10 20 30 40 50 60 70
Cell Denity in H&E staining
SPIOpositivecell-Iron
s...
MR Angiography 3D with Gadolinium-DTPA in
Watanabe Rabbit
Before SPIO injection After SPIO injection
MRI Identifies Plaque Inflammation by SPIO Nanoparticles
Watanabe rabbit
Post-SPIO
Watanabe rabbit
control
NZW rabbit
cont...
Ex-vivo MR study of the thoracic aorta in Watanabe and
Wild type rabbit after SPIO injection compared to control.
(Gradien...
Schmitz et al
Schmitz et al
Schmitz et al
Ruhem et al
Ruhem et al
Ruhem et al
Ruhem et al
Ruhem et al
Kooi et al
Kooi et al
Kooi et al
Kooi et al
Ho et al
Ho et al
MR signal changes after CsA treatment. A group with allotransplants was treated with CsA for either 7 days
(n=5) or 4 days...
Ho et al
• Imaging Macrophage
Activity in the Brain Using
Ultrasmall Particles of Iron
Oxide
Jeff W.M. Bultea and Joseph A. Franka ...
• SPIO MR imagine of macrophage is
feasible for clinical applications.
• It will be of great interest to
investigate the c...
• Poor spatial and temporal
resolution for coronary
applications
• Cost
• Cumbersome (injection and
delayed imaging)
Limit...
Spio mri studies by dr naghavi-presented to ge-amersham
Spio mri studies by dr naghavi-presented to ge-amersham
Spio mri studies by dr naghavi-presented to ge-amersham
Spio mri studies by dr naghavi-presented to ge-amersham
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Spio mri studies by dr naghavi-presented to ge-amersham

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Spio mri studies by dr naghavi-presented to ge-amersham

  1. 1. Non-Invasive Macrophage Imaging for Detection of Vulnerable Plaque Applications and Limitations Amersham Morteza Naghavi, MD
  2. 2. A B
  3. 3. Which one is vulnerable, A or B? The one with inflammation (macrophage infiltration)
  4. 4. Morphology vs. Activity Imaging Inactive and non-inflamed plaque Active and inflamed plaque Similar in IVUS OCT MRI w/o CM Morphology Different Activity Thermography, Spectroscopy, immunoscintigraphy, MRI with targeted contrast media…
  5. 5. Plaque Morphology vs. Plaque Activity We Need Both
  6. 6. Imaging Inflammation - by MRI - by CT Both are available today!
  7. 7. Imaging Inflammation - by MRI Pioneered in 1980s Rummeny E, Weissleder R, Stark DD, Elizondo G, Ferrucci JT. Radiologe. 1988 Aug;28(8):380-6.
  8. 8. SuperparamagneticSuperparamagnetic andand Ultra-superparamagneticUltra-superparamagnetic Iron OxideIron Oxide lBlood pool Magnetic resonance (MR) imaging contrast media with a central core of iron oxide generally coated by a polysaccharide layer Shortening MR relaxation time Engulfed by and accumulated in cells with phagocytic activity
  9. 9. Particle Core Size Particle Size Blood (nm) (nm) Half-life Combidex 5-6 20-30 8h Feridex 4-6 35-50 2.4±0.2h DDM 43/34/102 6.4 20-30 6h Clariscan MION 4-6 17 varies Feruglose --- --- --- --- Examples of commercially available SPIOs
  10. 10. USPIOs Enter the AtheroscleroticUSPIOs Enter the Atherosclerotic Plaque ThroughPlaque Through lMacrophages that engulfed them lFissured or thin cap l Extensive angiogenesis l vasa vasorum leakage l Intra plaque hemorrhage
  11. 11. 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 regarding incubation time and concentration of SPIO. All SPIO were labeled by a fluorescent dye (DCFA).
  12. 12. FL-labeled SPIO Incubated Macrophages 24hr
  13. 13. Double DAPI Staining with Fluorescence-labeled SPIO Macrophages after 24hr Incubation
  14. 14. Hypothesis
  15. 15. 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
  16. 16. SPIO and T2 Effect In-vitro study to show the effect of macrophage SPIO uptake on their T2 relaxation time
  17. 17. 0 10 20 30 40 50 60 70 80 90 50 250 control 20 min 60 min 6 hours 24 hours Macrophage Uptake of Feridex with Time and Concentration Shown by T2 Reduction Concentration µmol/ml
  18. 18. Histopathologic Studies of ApoE KO Mice Injected with SPIO (Abdominal Aorta) H&E staining Iron Staining CD 68 staining Iron particles
  19. 19. Histopathologic Study of Wild Type Mice Injected With SPIO (Thoracic Aorta) H&E staining CD68 stainingIron staining
  20. 20. Comparison of the Number of the Iron Particles (per HPF) in ApoE KO Mice Plaque vs. Normal Wall 0 5 10 15 Atherosclerotic Aorta Average number of iron particles per sample P <0.001
  21. 21. MR Image of Abdominal Aorta After SPIO Injection in ApoE and Control Mice ApoE deficien t 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
  22. 22. Injection of Cytokine Increases SPIO-Loaded Macrophage Density in Aortic Plaques (Apo E Deficient Mice) Naghavi et al Circulation 2003
  23. 23. Naghavi et al Circulation 2003 Injection of Cytokine Increases SPIO-Loaded Macrophage Density in a Coronary Plaque (Apo E Deficient Mice)
  24. 24. Histopathologic studies of Thoracic aorta in Watanabe Hereditary Hypercholesterolemic rabbit after SPIO injection H&E staining Iron staining Iron staining
  25. 25. Histopathologic studies of Thoracic aorta in Watanabe Hereditary Hypercholesterolemic rabbit after SPIO injection H&E staining Iron staining Iron staining Iron particles
  26. 26. Plaque Cell Density vs SPIO 0 10 20 30 40 50 60 0 10 20 30 40 50 60 70 Cell Denity in H&E staining SPIOpositivecell-Iron staining Series1 R=0.956 Correlation between Iron positive cells in Iron staining and cell density in H&E staining in rabbit atherosclerotic aorta.
  27. 27. MR Angiography 3D with Gadolinium-DTPA in Watanabe Rabbit Before SPIO injection After SPIO injection
  28. 28. MRI Identifies Plaque Inflammation by SPIO Nanoparticles Watanabe rabbit Post-SPIO Watanabe rabbit control NZW rabbit control NZW rabbit Post-SPIO Watanabe Rabbit Post-SPIO Watanabe Rabbit Control NZW Rabbit Post-SPIO NZW Rabbit Control
  29. 29. Ex-vivo MR study of the thoracic aorta in Watanabe and Wild type rabbit after SPIO injection compared to control. (Gradient echo) Watanabe rabbit Post-SPIO Watanabe rabbit control NZW rabbit Post-SPIO NZW rabbit control
  30. 30. Schmitz et al
  31. 31. Schmitz et al
  32. 32. Schmitz et al
  33. 33. Ruhem et al
  34. 34. Ruhem et al
  35. 35. Ruhem et al
  36. 36. Ruhem et al
  37. 37. Ruhem et al
  38. 38. Kooi et al
  39. 39. Kooi et al
  40. 40. Kooi et al
  41. 41. Kooi et al
  42. 42. Ho et al
  43. 43. Ho et al
  44. 44. 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
  45. 45. Ho et al
  46. 46. • 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
  47. 47. • 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
  48. 48. • Poor spatial and temporal resolution for coronary applications • Cost • Cumbersome (injection and delayed imaging) Limitations

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