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Everybody has
atherosclerosis, the
question is who has
Vulnerable Plaque
Non-invasive Detection of
Vulnerable Plaque using
SPIO Enhanced MRI
Morteza Naghavi MD,
Mitra Rajabi MD, Maamoun AbouQamar...
Detection of
Inflammation (macrophage infiltration),
Fissured/Permeable Cap,
Leaking Angiogenesis,
and Intra-Plaque
Hemorr...
No film!
No picture!!
Not even notes!!!
PLEASE
The Online Cardiovascular Research Community
www.VulnerablePlaque.org
All slides will be available on:

What is what?
 Vulnerable Plaque ?
 MRI in atherosclerosis?
 SPIO ?
 SPIO + MRI 
Detection of
Vulnerable Plaque
?
What is
Vulnerable Plaque?
 Based on the pioneering works done by
Michael Davies, Erling Falk, Valentin
Fuster, Jim Wille...
Vulnerable Plaque is
currently called as rupture-prone plaque
that is hemo-dynamically insignificant
(not stenotic <75%).
...
Characteristics of VP
 Thin fibrous cap
(perhaps <50-100 microns)
 Large lipid core
 Dense macrophage infiltration
Plaque Erosion
 Virmani, and recently Thiene and van der Wal
have emphasized that plaque rupture is not
the underlying ca...
Therefore,
 A definition based on
clinical outcome may well
recognize eroded plaque
as vulnerable plaque,
since they both...
Also,
We think there are at least two other types
of plaque pathology that could be
included in the list of vulnerable pla...
Vulnerability
 To rupture?
Or
 To induce thrombosis?
The latter seems to be a broader and
more conclusive definition. It...
Different Types of Vulnerable Plaque
As underlying Cause of Acute Coronary Events
Normal
Rupture-prone
Fissured Eroded
Cri...
Rupture-prone inflamed plaque
Vulnerable Plaque Type 1
To be
discussed
&
approved
by the
Scientific
Advisory
Board of
VP.o...
Fissured Plaque with Old and Fresh Overlaying Thrombi
Vulnerable Plaque Type 2
Eroded Plaque with Exposed Proteoglycans Prone to Thrombosis
Vulnerable Plaque Type 3
Intra-Plaque Hemorrhage Prone to Thrombosis
Vulnerable Plaque Type 4
Vulnerable Plaque Type 5
Asymptomatic significantly stenotic plaque prone to occlusion
Emerging Diagnostic Techniques
Angioscopy
Intravascular Ultrasound (IVUS)
Intravascular Thermography
Intravascular Optical...
- Raman Spectroscopy
- Near-Infrared Diffuse Reflectance Spectroscopy
-Fibrousis and lipid measurement
-pH and lactate mea...
Emerging Diagnostic Techniques
B. Non-Invasive Techniques:
A. MRI
1- MRI without contrast media
2- MRI with contrast media...
Emerging Diagnostic Techniques
C. Endothelial function test
-Flow mediated dilatation of brachial artery
-ACh induced vaso...
We sought a
 non-invasive technique
that could be used to
characterize
vulnerability of
atherosclerotic plaque
according ...
Biochem Biophys Res Commun 1987 Dec 16;149(2):437-
42
High-resolution proton NMR spectra of human arterial plaque.
Zajicek...
Persistency goes above
pioneering
 In Early 90, as the body of
knowledge of vulnerable plaque
rapidly grew up, it was
per...
Fayad et al,
Circulation.
2000 May
30;101(21):
2503-9.
Thoracic Aorta
Carotid artery plaqueCCA
Carotid bifurcation
ICA stenosis & plaque
Courtesy of
Dr. Yuan
University of
Washington
Seattle
Fayad et al
Circulation
2000 Aug
1;102(5):506-10
Coronary Art.
Our Dream!
Structure or Morphology
vs.
Function or Physiology
of plaque
 Why do we need to go beyond
morphological assessment of
pla...
Functional vs. Structural Imaging
Inactive and
non-inflamed
plaque
Active and
inflamed plaque
Different
Similar
IVUS OCT M...
Unstable Plaque, High-Risk
Plaque, Soft Plaque
Low-Risk Plaque,
Hard Plaque
Thin fibrous cap Thick fibrous cap
Large lipid...
Small or large plaque
volume
Small or large plaque
volume
Eccentric (positive
remodeling)
Concentric (negative
remodeling)...
Less calcified ? More calcified
High strain (elasticity) Low strain (stiff)
Hemodynamically
insignificant
(< 75% stenosis)...
Active Plaques
Unstable Plaque
High-Risk Plaque
Quiescent Plaque
Low-Risk Plaque
High traffic (monocyte and T
cell recruit...
MRI Structural
Characterization of Plaque
 Obviously it provides invaluable
information about the anatomy of plaque:
cap ...
Therefore,
We need a way to
non-invasively
image
inflammation in
the plaque
MRI as a Screening Test
 If the goal is to include MRI in a package
of population based screening tests for
early detecti...
SPIO
 Super
 Paramagnetic
 Iron
 Oxide
Colloidal coated such as dextran
150-100 nanometer particle size
Shortening MR ...
USPIO
 Ultra
 Super
 Paramagnetic
 Iron
 Oxide
Smaller size which yields a longer
circulation time
Particle Core Size ParticleSize Blood
(nm) (nm) half life
Combidex 5-6 20-30 8h
Feridex 4-6 35-50 2.4±0.2h
MION 4-6 17 var...
SPIO Labeled (A, C, E) andSPIO Labeled (A, C, E) and
Unlabeled (B, D, F) T-cellUnlabeled (B, D, F) T-cell
SamplesSamples
Intravenously injected SPIO are
opsonized by plasma proteins and are then
efficiently internalized into macrophages
and ot...
Type Species Iron Uptake ± SD (ng/106
cells) Particles per Cell
Primary isolates
Peritoneal macrophages Mouse 970 ± 77 4,8...
Flash MR Image of a Rat Kidney With
Experimental Nephritic Syndrome, Before
(Right)and 24h After USPIO Injection(left)
Correlation between macrophage and MR
signal variation in the kidney cortex
Iron staining,shows particles in perivascular in
encephalitis and immunohistochemistry shows
positivity of macrophages
Enc...
Cardiac Application
 Monitoring rejection of transplanted
heart and lungs following rat
allograft and homograft
transplan...
Old literature never ceases to amaze me!
Iron particles observed
immediately under the
endothelium 5 hours after the
admin...
vasa vasorum
Over magnification is a major advantage of
SPIO
Iron staining of mouse circulating
monocyte after 15 minutes
Iron staining of mouse circulating
monocyte after 30 minutes
SPIO Accumulation in
Atherosclerotic Plaque
Atherosclerotic plaqueNormal aortic segment
Iron staining of Apo E K/O Aorta, ...
ApoE Mouse 3 Days After
Injection
H&E Pearl’s
Aorta-2
Aortic Root after 5 days
C57Black
No plaque, No Iron
Pearl’s staining
0
5
10
15
Atherosclerotic
Aorta
Average
number of iron
particles per
sample
P <0.001
Comparison of the Number of the Iron ...
TE: 12ms TR: 2500 FOV: 6x6
256x256
MR Image of Abdominal Aorta After
SPIO Injection in Mouse
Apo E
deficient
mouse
C57B1
(control)
mouse
Before Injection Aft...
Figure 4. Ex vivo imaging of contrast-filled aortic specimen of (A) hyperlipidemic rabbit 5 days
after administration of S...
Figure 3. A, Coronal MIP and (B) sagittal oblique and (C) coronal
oblique reformatted images of contrast-enhanced 3D MRA d...
Figure 5. Cross-sectional histopathological sections with Prussian blue staining of aorta of same
hyperlipidemic rabbit as...
Mri spio
Mri spio
Mri spio
Mri spio
Mri spio
Mri spio
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Mri spio

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Mri spio

  1. 1. Everybody has atherosclerosis, the question is who has Vulnerable Plaque
  2. 2. Non-invasive Detection of Vulnerable Plaque using SPIO Enhanced MRI Morteza Naghavi MD, Mitra Rajabi MD, Maamoun AbouQamar MD, Michael Quast PhD, Daniel Chan PhD, Mohammad Madjid MD, Khawar Gul MD, Ward Casscells MD, James Willerson MD Texas Heart InstituteThe University of Texas-Houston
  3. 3. Detection of Inflammation (macrophage infiltration), Fissured/Permeable Cap, Leaking Angiogenesis, and Intra-Plaque Hemorrhage Introducing a non-invasive and potentially screening technique for
  4. 4. No film! No picture!! Not even notes!!! PLEASE
  5. 5. The Online Cardiovascular Research Community www.VulnerablePlaque.org All slides will be available on: 
  6. 6. What is what?  Vulnerable Plaque ?  MRI in atherosclerosis?  SPIO ?  SPIO + MRI  Detection of Vulnerable Plaque ?
  7. 7. What is Vulnerable Plaque?  Based on the pioneering works done by Michael Davies, Erling Falk, Valentin Fuster, Jim Willerson, Peter Liby, Jim Muller, Renu Virmani, Al van der Wal, PK Shah, and many other investigators…* * For a complete list of pioneers see “Who is who” at www.VulnerablePlaque.org
  8. 8. Vulnerable Plaque is currently called as rupture-prone plaque that is hemo-dynamically insignificant (not stenotic <75%). These plaques rupture into blood and their thrombogenic content cause acute thrombosis. Plaque rupture may or may not be clinically apparent.
  9. 9. Characteristics of VP  Thin fibrous cap (perhaps <50-100 microns)  Large lipid core  Dense macrophage infiltration
  10. 10. Plaque Erosion  Virmani, and recently Thiene and van der Wal have emphasized that plaque rupture is not the underlying cause of all coronary thrombotic events.  In 30-60% of cases depending on the age and sex, sudden death due to acute coronary thrombosis is resulted from non-ruptured but superficially eroded plaques.  Eroded plaques may or may not be inflamed  They are like prone-ruptured plaques mostly hemo-dynamically insignificant (<75%)
  11. 11. Therefore,  A definition based on clinical outcome may well recognize eroded plaque as vulnerable plaque, since they both cause acute coronary thrombotic event and yet both are hemo-dynamically insignificant
  12. 12. Also, We think there are at least two other types of plaque pathology that could be included in the list of vulnerable plaques:  Plaques with fissured cap and mural thrombosis  Plaques with extensive angiogenesis and intra-plaque hemorrhage These plaque may or may not overlap with the other two categories
  13. 13. Vulnerability  To rupture? Or  To induce thrombosis? The latter seems to be a broader and more conclusive definition. It is also clinically more relevant.
  14. 14. Different Types of Vulnerable Plaque As underlying Cause of Acute Coronary Events Normal Rupture-prone Fissured Eroded Critical Stenosis Hemorrhage
  15. 15. Rupture-prone inflamed plaque Vulnerable Plaque Type 1 To be discussed & approved by the Scientific Advisory Board of VP.org
  16. 16. Fissured Plaque with Old and Fresh Overlaying Thrombi Vulnerable Plaque Type 2
  17. 17. Eroded Plaque with Exposed Proteoglycans Prone to Thrombosis Vulnerable Plaque Type 3
  18. 18. Intra-Plaque Hemorrhage Prone to Thrombosis Vulnerable Plaque Type 4
  19. 19. Vulnerable Plaque Type 5 Asymptomatic significantly stenotic plaque prone to occlusion
  20. 20. Emerging Diagnostic Techniques Angioscopy Intravascular Ultrasound (IVUS) Intravascular Thermography Intravascular Optical Coherence Tomography (OCT) Intravascular Elastography Intravascular and Transesophageal MRI Intravascular Nuclear Imaging Intravascular Electrical Impedance Imaging Intravascular Tissue Doppler Intravascular Shear Stress Imaging Intravascular (Photonic) Spectroscopy A. Invasive Techniques -Intravascular
  21. 21. - Raman Spectroscopy - Near-Infrared Diffuse Reflectance Spectroscopy -Fibrousis and lipid measurement -pH and lactate measurement - Fluorescence Emission Spectroscopy - Spectroscopy with contrast media … Invasive Techniques Intravascular (Photonic) Spectroscopy Intra-coronary assessment of endothelial function Intra-coronary measurement of MMPs and cytokines
  22. 22. Emerging Diagnostic Techniques B. Non-Invasive Techniques: A. MRI 1- MRI without contrast media 2- MRI with contrast media: Gadolinium-DPTA 2- MR Imaging of Inflammation: Super Paramagnetic Iron Oxide (SPIO and USPIO) 3- MR Imaging of Thrombosis using monoclonal Ab B. Electron Beam Computed Tomography (EBCT) C. Multi-Slice Fast Spiral / Helical CT D. Nuclear Imaging (18-FDG, MCP-1, Annexin V)
  23. 23. Emerging Diagnostic Techniques C. Endothelial function test -Flow mediated dilatation of brachial artery -ACh induced vasorectivity of coronary artery D. Blood Tests and Serum Markers - CRP - Proinflamatory cytokines - Lp-PLA2 - MMPs ? - Anti-body against endothelial cells
  24. 24. We sought a  non-invasive technique that could be used to characterize vulnerability of atherosclerotic plaque according to our proposed definitions
  25. 25. Biochem Biophys Res Commun 1987 Dec 16;149(2):437- 42 High-resolution proton NMR spectra of human arterial plaque. Zajicek J, Pearlman JD, Merickel MB, Ayers CR, Brookeman JR, Brown MF. Well-resolved proton (1H) NMR spectra of solid human arterial plaque can be acquired. Studies have been carried out of human fatty plaque obtained postmortem (ex vivo), the total lipids extracted from human atheroma, and a model mixture of cholesteryl esters whose lipid composition resembles that of human atheroma. In each case, well-resolved 1H NMR spectra were obtained at body temperature (37 degrees C), with little or no underlying broad signal. Such sharp 1H NMR spectra are typical of isotropic fluids, whereas solid and liquid-crystalline materials give rise to much broader spectral lines. The results suggest the sharp 1H NMR spectra of human atheromatous lesions at body temperature are due largely to the presence of intracellular and extracellular droplets of cholesteryl esters in the isotropic liquid phase. These findings provide a necessary basis for use of 1H NMR techniques to image quantitatively the lipid constituents of human atheroma in vivo, and to study their chemical and physical properties. Despite a series of pioneering works by Brown et al, and others
  26. 26. Persistency goes above pioneering  In Early 90, as the body of knowledge of vulnerable plaque rapidly grew up, it was persistent works led by Fuster, Touissant, Yuan, and Fayad, and later by others that brought to our attention the feasibility of non- invasive structural characterization of plaque using magnetic resonance imaging of aortic, carotid, and finally coronary wall.
  27. 27. Fayad et al, Circulation. 2000 May 30;101(21): 2503-9. Thoracic Aorta
  28. 28. Carotid artery plaqueCCA Carotid bifurcation ICA stenosis & plaque Courtesy of Dr. Yuan University of Washington Seattle
  29. 29. Fayad et al Circulation 2000 Aug 1;102(5):506-10 Coronary Art.
  30. 30. Our Dream!
  31. 31. Structure or Morphology vs. Function or Physiology of plaque  Why do we need to go beyond morphological assessment of plaques? Why do we need both?  The short answer is: because not all plaques with similar morphology would result in similar outcome. Remember Erling Falk’s landmark experiments of mice swimming Olympic !
  32. 32. Functional vs. Structural Imaging Inactive and non-inflamed plaque Active and inflamed plaque Different Similar IVUS OCT MRI w/o CM Structural: Functional: Thermography, Spectroscopy, MRI w/ CM
  33. 33. Unstable Plaque, High-Risk Plaque, Soft Plaque Low-Risk Plaque, Hard Plaque Thin fibrous cap Thick fibrous cap Large lipid pool Small or no lipid pool Low collagen content High collagen content High modified cholesterol Low modified cholesterol Extensive angiogenesis Less angiogenesis (?) Structural or Morphologic Classification Vulnerable Plaque Stable Plaque
  34. 34. Small or large plaque volume Small or large plaque volume Eccentric (positive remodeling) Concentric (negative remodeling) Disrupted / fissured cap No thrombosis Overlaying thrombosis High collagen content Endothelial denudation Intact endothelial lawyer Exposed proteoglycans (versican and hyaluronan) Not exposed but may contain as much Structural or Morphologic Classification Vulnerable Plaque Stable Plaque Cont…
  35. 35. Less calcified ? More calcified High strain (elasticity) Low strain (stiff) Hemodynamically insignificant (< 75% stenosis) … Hemodynamically significant (>75% stenosis) … Structural or Morphologic Classification Stable PlaqueVulnerable Plaque Cont…
  36. 36. Active Plaques Unstable Plaque High-Risk Plaque Quiescent Plaque Low-Risk Plaque High traffic (monocyte and T cell recruitment) Low traffic (monocyte and T cell recruitment) Hot with increased temperature heterogeneity Normal temperature with minimal heterogeneity Acidic with high pH heterogeneity Normal or high pH with minimum pH heterogeneity High oxidative stress (excessive oxygen and nitrogen free radical formation) Low oxidative stress Excessive apoptosis … Minimum apoptosis … Functional or Physiologic Classification Vulnerable Plaque Stable Plaque
  37. 37. MRI Structural Characterization of Plaque  Obviously it provides invaluable information about the anatomy of plaque: cap thickness, plaque volume, remodeling,  Using multi-spectral imaging techniques, it may also provide information of great significance for histo-chemical characterization of plaque: collagen and lipid content, calcification, hemorrhage  But it does not image inflammation nor plaque activity
  38. 38. Therefore, We need a way to non-invasively image inflammation in the plaque
  39. 39. MRI as a Screening Test  If the goal is to include MRI in a package of population based screening tests for early detection of patients at risk for acute coronary event, we need to ask MRI for all it has to offer.  MRI has many potentials that need to be explored for studying vulnerable plaque.  In our approach we simply have tried to learn from experiences learned over years in cancer and other fields
  40. 40. SPIO  Super  Paramagnetic  Iron  Oxide Colloidal coated such as dextran 150-100 nanometer particle size Shortening MR relaxation time mainly R2 Phagocyted by and accumulated in cells with phagocytic activity
  41. 41. USPIO  Ultra  Super  Paramagnetic  Iron  Oxide Smaller size which yields a longer circulation time
  42. 42. Particle Core Size ParticleSize Blood (nm) (nm) half life Combidex 5-6 20-30 8h Feridex 4-6 35-50 2.4±0.2h MION 4-6 17 varies
  43. 43. SPIO Labeled (A, C, E) andSPIO Labeled (A, C, E) and Unlabeled (B, D, F) T-cellUnlabeled (B, D, F) T-cell SamplesSamples
  44. 44. Intravenously injected SPIO are opsonized by plasma proteins and are then efficiently internalized into macrophages and other phagocytic cells Cellular uptake into macrophages is through C3 receptors. Both phagocytosis and pinocytosis are involved. It has previously demonstrated that SPIO particles extravasate into the intrstitium of some solid tumors and that these particles accumulate within tumor cells located adjacent to vessels.
  45. 45. Type Species Iron Uptake ± SD (ng/106 cells) Particles per Cell Primary isolates Peritoneal macrophages Mouse 970 ± 77 4,850,000 Lymph node lymphocytes Mouse 19.1 ± 0.3 95,500 Lymph node lymphocytes Rat 11.5 ± 4.3 57,500 Splenic lymphocytes Mouse 18.7 ± 0.1 93,500 Splenic lymphocytes Rat 19.8 ± 1.3 99,000 Blood lymphocytes Human 27.9 ± 3.6 139,500 Tumor cells SVEC4-10 endothelial cells Mouse 118 ± 25 590,000 C6 glioma Rat 25.0 ± 3.0 125,000 9L gliosarcoma Rat 17.0 ± 2.0 85,000 J774 sarcoma (macrophage-like) Rat 310 ± 28 1,550,000 LX1 small cell lung cancer Human 29.2 ± 2.2 145,000 BT 20 breast adenocarcinoma Human 38.2 ± 4.0 190,000 MCF-7 breast adenocarcinoma Human 11.9 ± 1.6 60,000 HBL100 breast adenocarcinoma Human 33.2 ± 0.1 165,000 D4.475 breast adenocarcinoma Human 21.1 ± 0.8 105,000 LS174T colon adenocarcinoma Human 60.0 ± 1.5 300,000 U87 glioma Human 18.4 ± 0.5 90,000 Note.—Uptake was measured after 1 hour incubation of 100,000 cells in the presence of 100 µg of 125 I-labeled LCDIO.
  46. 46. Flash MR Image of a Rat Kidney With Experimental Nephritic Syndrome, Before (Right)and 24h After USPIO Injection(left)
  47. 47. Correlation between macrophage and MR signal variation in the kidney cortex
  48. 48. Iron staining,shows particles in perivascular in encephalitis and immunohistochemistry shows positivity of macrophages Encephalitis
  49. 49. Cardiac Application  Monitoring rejection of transplanted heart and lungs following rat allograft and homograft transplantation, w/wo cyclosporin Hu et al
  50. 50. Old literature never ceases to amaze me! Iron particles observed immediately under the endothelium 5 hours after the administration, in artery, in a rat with 7 days hypertension 33 years ago !!!
  51. 51. vasa vasorum Over magnification is a major advantage of SPIO
  52. 52. Iron staining of mouse circulating monocyte after 15 minutes
  53. 53. Iron staining of mouse circulating monocyte after 30 minutes
  54. 54. SPIO Accumulation in Atherosclerotic Plaque Atherosclerotic plaqueNormal aortic segment Iron staining of Apo E K/O Aorta, 24 hour after SPIO injection Iron particles
  55. 55. ApoE Mouse 3 Days After Injection H&E Pearl’s Aorta-2
  56. 56. Aortic Root after 5 days
  57. 57. C57Black No plaque, No Iron Pearl’s staining
  58. 58. 0 5 10 15 Atherosclerotic Aorta Average number of iron particles per sample P <0.001 Comparison of the Number of the Iron Particles in Apo E KO Mice Plaque vs. Normal Wall Normal Vessel Wall
  59. 59. TE: 12ms TR: 2500 FOV: 6x6 256x256
  60. 60. MR Image of Abdominal Aorta After SPIO Injection in Mouse Apo E 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
  61. 61. Figure 4. Ex vivo imaging of contrast-filled aortic specimen of (A) hyperlipidemic rabbit 5 days after administration of Sinerem, (B) normal control rabbit 5 days after administration of Sinerem, and (C) hyperlipidemic rabbit that did not receive Sinerem. Marked susceptibility artifacts are present in aortic wall of hyperlipidemic rabbit that had received Sinerem (A). No such changes are visualized in other 2 rabbits (B, C). Reuhm et al, Circulation 2001
  62. 62. Figure 3. A, Coronal MIP and (B) sagittal oblique and (C) coronal oblique reformatted images of contrast-enhanced 3D MRA data sets of same hyperlipidemic rabbit as depicted in Figure 1 obtained 5 days after intravenous injection of USPIO agent Sinerem. Note susceptibility effects originating within vessel wall and representing Fe uptake in macrophages embedded in plaque. Reuhm et al, Circulation 2001
  63. 63. Figure 5. Cross-sectional histopathological sections with Prussian blue staining of aorta of same hyperlipidemic rabbit as depicted in Figures 1 and 3, killed 5 days after administration of USPIO agent Sinerem. Note thickening of intima with marked staining of Fe particles embedded in atherosclerotic plaque formations. Rheum et al, Circulation 2001

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