This document discusses the use of super paramagnetic iron oxide (SPIO) as a contrast agent for MRI to visualize vulnerable atherosclerotic plaques. SPIO can accumulate in macrophages and allow detection of inflammation in plaques. The document outlines studies showing SPIO uptake in plaques of animal models, with greater uptake seen in more inflamed vulnerable plaques. It proposes that SPIO-enhanced MRI could identify active macrophages and characteristics of vulnerability like thin caps and angiogenesis in human plaque imaging studies.

1. Visualization of
Atherosclerotic Vulnerable
Plaque
Super Paramagnetic Iron Oxide As a
Contrast Media for MRI
Mitra Rajabi, MD
Mohammed Asif, MD

2. 2
Atherosclerosis
• Coronary artery disease is the leading
cause of death in the USA and the
developed countries.
• The majority of myocardial infarctions
are not caused by atherosclerotic
plaques that cause a hemodynamically
significant stenosis, but rather by
smaller plaques, which called
”vulnerable “plaque.

3. 3
Vulnerable Plaque
• Large lipid core
• Thin fibrous cap
• Inflammation

4. 4

5. 5
Ruptured Vulnerable Plaque

6. 6
Available/Suggested Techniques
for Detection of Vulnerable
Plaques
Invasive
 Angiography
 IVUS
 MRI
 OCT
 Angioscopy
 Spectroscopy
 Thermography
 Elastography
Non-Invasive
 MRA&MRI
 EBCT
 Radioisotope
Imaging

7. 7
Intra Vascular Ultra Sound

8. 8
Angioscopy
A B C

9. 9
Optical Coherence Tomography

10. 10
Spectroscopy

11. 11
Thermography

12. 12
Electron Beam Computed
Tomography

13. 13
Magnetic Resonance
Angiography(MRA)

14. 14
Magnetic Resonance Imaging

15. 15
Intravascular MRI

16. 16
Elastography Femoral artery

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Nuclear Cardiology
• Instrumentations and techniques
Planar
SPECT
PET
• Radiopharmaceuticals
Thallium201
Technetium99

18. 18
Radiotracers for imaging
Atherosclerosis
• Platelets
• Low density Lipoproteins (LDL)
• Lipoprotein(a)
• Modified LDL
• Monocytes
• Fibrinogen
• Fibronectin

19. 19
….Continue
• Porphyrins
• Human IgG
• Peptides
• Monoclonal antibodies

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A patient with 80% stenosis of the right 1 hour
after injection of 99
Te-ox-LDL.
R L
Transaxial section of neck
obtained by SPET
Anteroposterior
gamma camera image

21. 21
Gamma images
of an
experimental
atherosclerotic
rabbit injected
with negative
charge–modified
111
In-labeled
chimeric Z2D3-
73.30 F(ab')2
Immediately 24 hours
48 hours

22. 22

23. 23
SPECT Images: Focal uptake of the right carotid artery absent uptake
on the left side. Carotid angiogram showing the stenotic region
corresponding to the plaque.

24. 24
Endarterectomy specimen With Intense Radioactivity to
the Z2D3 Antibody Uptake

25. 25
Immunoperoxidase staining of the endarterectomy specimen
demonstrates antibody uptake in the region that contains smooth muscle
cells. The uptake is represented by the brown peroxide stain. The lipid-
and foam cell-rich areas are negative for color reaction

26. 26

27. 27
Cerebral angiography(A), US (B),
and platelet imaging (C ,D) in a
patient with T.I.A. obvious
ulcerated lesions in the right
internal carotid artery(Rt) (Large
arrows in A and B ) (57% stenosis
with a unilateral plaque score of
6.0); carotid bifurcation (small
arrows in B&C), pathological,
positive platelet accumulation in
the right carotid artery. Images in
C and D were obtained by means
of a dual-tracer method that used
(C) In 111-labeled platelets and
(D) Tc 99m-labeled human serum
albumin

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Other Targeted studies
Lipid-conjugated Gd-DTPA was
incorporated into the surfactant layer of
biotinylated perfluorocarbon emulsions
(Biotinylated antifibrin monoclonal
antiobodies and avidin were used to
couple the emulsion nanoparticles to
fibrin clots. (Flacke et al, ISMRM 2000)

29. 29
The need for assessment of functional
properties of plaques in particular its
macrophage activity is beyond doubt, as
these inflammatory cells are considered the
major culprit agents promoting plaque
rupture
Presence of inflammation has led to find
new diagnostic ways based on thermal and
or PH detection of vulnerable plaques, and
the idea of finding active macrohages by
using new contrast media for MR imaging
of plaques. MR spectroscopy

30. MRI Study of
Macrophages Activity
and Functional Property
of Atherosclerotic
Plaques (SPIO,USPIO)

31. 31
SPIO, USPIO
• Magnetic resonance imaging
contrast medium with a central
core of iron oxide generally
coated by a polysaccharide layer
• Shortening MR relaxation time
• Phagocyted by and accumulated
in cells with phagocytic activity

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SPIO in Macrophages

33. 33
SPIO Injection
A 4-cm
metastasis in
segment 4

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SPIO /USPIO
• MR contrast for detection of cancer and
liver diseases
• MR contrast for MR angiographies
• MR contrast for detection of
apoptosis(ISMRM)

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Our Previous Study Shows the Iron
Particles in The Plaques
No plaque, No Iron

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Comparison of the Number of Iron Particles in
ApoE &Normal Mice
0
5
10
15
Atherosclerotic
Aorta
Average
number of iron
particles per
sample
P <0.001
Normal

37. 37
Extra Magnification withSPIO

38. 38
Normal artery
Stable
Plaque

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Vulnerable Plaque

40. 40

41. 41
Stable Plaque

42. 42
Inflammation Imaging

43. 43
USPIOs Enter the Atherosclerotic
Plaque Through
• Macrophages that engulfed them
• Fissured or thin cap
• Extensive angiogenesis
• vasa vasorum leakage
• Intra plaque hemorrhage

44. 44
Hypotheses
• Active macrophages in the inflamed vulnerable
plaques can be visualized following injection of
USPIO into the systemic circulation by virtue of a
significant change in T1 and T2 relaxation time of the
plaque after injection. Also other characteristics of
vulnerability such as thin/disrupted cap shoulders,
extensive angiogenesis associated with loose vasa
vaserum which causes extravasation and leaking of
macromolecules… and intra plaque hemorrhage all of
them representing vulnerable plaque may contribute
to retaining of USPIO inside the plaque.
• These MR imaging findings correlate with
vulnerability of the plaque

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Study Design
P a t h o lo g y e v a lu a t io n
H & E , P e a r l's , I m m u n o s t a in in g
S a c r if ic e & in v it r o M R I
M R I w it h a n d w it h o u t in t r a v a s c u la r c o il
in 3 t h , 5 t h , 7 t h d a y
U S P I O in je c t io n
M R I w it h & w it h o u t in t r a v a s c u la r M R c o il
1 0 R a b b it s

46. 46
Under Study
• Magnetic resonance imaging of
carotid atherosclerotic plaques
with MRI using a dedicated
phase array coil (special
superficial coil)

47. 47
Preliminary studies in Imaging the
Aorta in Apo-E mice
• MRI of the thoracic and abdominal aorta
of Apo-E mouse with Respiratory gating
• Intravenous injection of 40µmol Fe/Kg
Feridex to Apo-E mice
• MRI in Days 1,2 ,5 and 10 after injection

48. 48
Pre injection MRI

49. 49
MRI 5 Days After Injection

50. 50
• We have seen Feridex particles are
trapped by RES mostly in liver and
spleen, some pulmonary macrophages,
and also lymphatic nodes.
• 5- We plan to redo the study with other
soon to be available contrast media
names Combidex, Clariscan, MION,
LCIO, AND our own plaque
specific USPIO in collaboration
with Dr Daniel Chan.

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