Successfully reported this slideshow.
We use your LinkedIn profile and activity data to personalize ads and to show you more relevant ads. You can change your ad preferences anytime.
Non-invasive Detection of
Vulnerable Plaque using
SPIO Enhanced MRI
Mitra Rajabi MD, Maamoun AbouQamar MD,
Michael Quast P...
Everybody has
atherosclerosis, the
question is who has
Vulnerable Plaque
The Online Cardiovascular Research Community
www.VulnerablePlaque.org
All slides will be available on:
Vulnerable Plaque?
Atherosclerotic plaques
that cause sudden
luminal clot formation
and lead to heart attack
and stroke.
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
Eroded Plaque with Exposed Proteoglycans Prone to Thrombosis
Vulnerable Plaque Type 2
Fissured Plaque with Old and Fresh Overlaying Thrombi
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
Further new types of Vulnerable
Plaque to be discovered in
future.
Less angiogenesis (?)Extensive angiogenesis
Low modified cholesterolHigh modified cholesterol
High collagen contentLow col...
Not exposed but may
contain as much
Exposed proteoglycans
(versican and hyaluronan)
Intact endothelial lawyerEndothelial d...
Hemodynamically
significant
(>75% stenosis)
…
Hemodynamically
insignificant
(< 75% stenosis)
…
Low strain (stiff)High stra...
Minimum apoptosis
…
Excessive apoptosis
…
Low oxidative stressHigh oxidative stress
(excessive oxygen and nitrogen free
ra...
Plaque characterization
by MRI has been
introduced by Toussaint
and others to study
structural properties of
atherosclerot...
Carotid artery plaqueCCA
Carotid bifurcation
ICA stenosis & plaque
Courtesy of
Dr. Chun Yuan
University of
Washington,
Sea...
Question!
 Lets assume that we are in our
dreamland and non-invasive MR
imaging of coronary artery with
<100 micron resol...
Plaque Morphology
vs.
Plaque Activity
 Why do we need to go beyond
morphological assessment of
plaques? Why do we need bo...
Functional vs. Structural Imaging
Inactive and
non-inflamed
plaque
Active and
inflamed plaque
Different
Similar
IVUS OCT M...
Therefore,
We need a
combined method
to image both
morphology and
activity of plaques
We need MRI with vulnerable plaque
targeted contrast media that identifies:
1- Inflammation (macrophage infiltration),
2- ...
Willerson et al:
Study of fluorescent labeled
macrophage homing into
Apo E deficient mice
Circ 1998
SPIO
 Super
 Paramagnetic
 Iron
 Oxide
Colloidal coated nano-particles of iron oxide, e.g.
dextran coated SPIO
20-100 ...
USPIO
 Ultra
 Super
 Paramagnetic
 Iron
 Oxide
Smaller particle size which yields a
longer circulation time, yet less...
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
MION 4-6 17 va...
Prior works done by
others for imaging
inflammation by MRI
and SPIO
Maamoun add Ref
Flash MR Image of a Rat Kidney With
Experimental Nephritic Syndrome, Before
(Right)and 24h After USPIO Injection(left)
Maa...
Correlation between macrophage and MR
signal reduction in the kidney cortex
Maamoun add Ref
Cardiac Application
 Monitoring rejection of transplanted
heart and lungs following rat
allograft and homograft
transplan...
Old literature!
Iron particles observed
immediately under the
endothelium 5 hours after the
administration, in artery, in ...
Our Hypothesis:
 Vulnerable atherosclerotic plaques
which have 1) active recruitment of
monocytes and T cells, 2)
extensi...
vasa vasorum
Over magnification is a major advantage of SPIO
Darkening property of SPIO in the white background of fat and...
Why negative enhancement?!!
Positive Contrast Negative ContrastV.S.
Gd-compounds SPIOs
+ -
Knowing that plaque has white b...
What we have done:
 - In vitro study of SPIO uptake by
macrophages using fluorescent
labeled home-made SPIO
 -In vitro s...
What we have done:
 - In vivo study of bio distribution of
SPIO in Apo E deficient
atherosclerotic mice vs normal wild
ty...
Invitro Study of
Macrophage SPIO Uptake
 In a series of invitro studies we
have tested the rate of SPIO
uptake by human a...
FL-labeled SPIO Incubated Macrophages 24hr
Mouse Peritoneal Macrophages Incubated with SPIO after 6hr
Double DAPI Staining with Fluorescence-labeled SPIO
Macrophages after 24hr Incubation
SPIO and T2 Effect
Invitro study to show the effect
of macrophage SPIO uptake on
their T2 relaxation time
Protocol:
 We used 8 flasks of CBM macrophages.
 After preparing the cells, Feridex was
added with the proper concentrat...
time
concentration
20
Min
1
Hour
6
Hours
24
Hours
50µl 100µl 250µl 500µl control control
Expected T2 Reduction Effect
Macrophage Uptake of Feridex After 20
Min Shown by T2 Reduction
0
10
20
30
40
50
60
70
80
90
50 100 250 500 control contro...
0
10
20
30
40
50
60
70
80
90
50 100 250 500 control control
60 min
Macrophage Uptake of Feridex After 60
Min Shown by T2 R...
0
10
20
30
40
50
60
70
80
90
50 100 250 500 control control
6 Hours
Macrophage Uptake of Feridex After 6hr
Shown by T2 Red...
0
10
20
30
40
50
60
70
80
90
50 100 250 500 control control
24 Hours
Macrophage Uptake of Feridex After 24hr
Shown by T2 R...
0
10
20
30
40
50
60
70
80
90
50 100 250 500 control control
20 min
60 min
6 hours
24 hours
Macrophage Uptake of Feridex wi...
0
10
20
30
40
50
60
70
80
90
20 Min 60 Min 6 Hours 24 Hours
50
100
250
500
control
control
Macrophage Uptake of Feridex wi...
Study of production of
Reactive Oxygen Species
by SPIO Incubated
Macrophages
Since the production of
reactive oxygen species
(ROS) in the plaque might
have unfavorable effects on
the biology of the p...
Facts
 Any event of phagocytosis is immediately followed by
a transient release of super oxide due to the
assembly of the...
Method
 · The suspension of SPIO (1.25-10 uL) was added to
macrophages (1x10*4/well in 96 well plates). Cells
were incuba...
Results
· SPIO was internalized by macrophages as
early as 15 min after addition.
· Uptake was followed by release of supe...
Dosage of SPIO: 1.25micL
0
500
1000
1500
2000
2500
3000
3500
15min 30min 45min NOSPIO
Sample1
Sample2
Sample3
ROS Producti...
Dosage at 2.5micL
0
500
1000
1500
2000
2500
3000
3500
15min 30min 45min
Sample1
Sample2
Sample3
ROS Production: Time VS SP...
Dosage at 5micL
0
500
1000
1500
2000
2500
3000
15min 30min 45min
Sample1
Sample2
Sample3
ROS Production: Time VS SPIO Conc...
Dosage at 10micL
0
200
400
600
800
1000
1200
1400
1600
1800
15min 30min 45min
Sample1
Sample2
Sample3
ROS Production: Time...
SPIO biodistribution in
ApoE mice
Iron staining of mouse circulating
monocyte after 15 minutes
Iron staining of mouse circulating
monocyte after 30 minutes
Specimens were
taken at interval
of 3mm from
arotic root to the
renal aorta
SPIO Accumulation in
Atherosclerotic Plaque
Atherosclerotic plaque
in aortic root
Normal aortic segment
Iron staining of A...
ApoE Mouse 3 Days After
Injection
H&E Pearl’s
Aorta-2
Atherosclerotic plaque in thoracic aorta
Aortic Root after 5 days
Dense infiltration of iron particles as
shown by light blue in Pearl’s staining
Aortic Plaque at Renal Level After 3 days
Control C57Black
No plaque, No Iron
Pearl’s staining
0
5
10
15
Atherosclerotic
Aorta
Average
numberofiron
particlesper
sample
P<0.001
Comparison of the Number of the Iron Part...
MRI SPIO study of
Apo E v.s. Normal Mice
TE: 12ms TR: 2500 FOV: 6x6
256x256
Only respiratory gating was done
Images of aorta from renal level
MR Image of Abdominal Aorta After
SPIO Injection in Apo E and Control Mice
Apo E
deficient
mouse
C57B1
(control)
mouse
Bef...
MRI Imaging of
Atherosclerosis using SPIO
Studies done recently by others:
 1- Schmitz SA, Coupland SE, Gust R,
Winterhal...
Group I II III IV
USPIO 0 50µmol Fe/kg 50µmol 200µmol
Time - 8 hr 24 hr 48 hr
Schmitz et al J. Inv. Radiol. 2000
Control
SPIO
Injected
Schmitz et al J. Inv. Radiol. 2000
Schmitz et al J. Inv. Radiol. 2000
Schmitz et al
J. Inv. Radiol.
2000
Schmitz et al
J. Inv. Radiol. 2000
2- Ruehm SG, Corot C, Vogt P, Kolb S,
Debatin JF.
Magnetic resonance imaging of atherosclerotic
plaque with ultrasmall sup...
A, Coronal MIP and (B) sagittal oblique and (C) coronal oblique
reformatted images of contrast-enhanced 3D MRA data set co...
A, Coronal MIP and (B) sagittal oblique and (C) coronal oblique
reformatted images of contrast-enhanced 3D MRA data sets o...
A, Intraluminal signal measured in single large ROI (9 mm2
) revealed significant
increase in SNR, with maximum reached at...
Ex vivo imaging of contrast-filled aortic specimen of (A) hyperlipidemic rabbit 5 days
after administration of Sinerem, (B...
Cross-sectional histopathological sections with Prussian blue staining of aorta of same
hyperlipidemic rabbit as depicted ...
Conclusion:
 Non-invasive MRI study of
atherosclerotic plaques using SPIO
(pre and post injection
comparison) may be a li...
SPIO Clinical Trial:
- The first human clinical trial on
detection of carotid vulnerable plaque
using SPIO in patients und...
Dr. Naghavi – The first
volunteer subject in his
Carotid MRI SPIO Study
Multi-Center Trial:
 The second site of the study is
going to be Univ. of Washington
Seattle directed by Dr. Yuan.
 The ...
The Online Cardiovascular Research Community
www.VulnerablePlaque.org
All slides will be available on:
WWW.HotPlaque.Com
Non invasive detection of vulnerable plaque 2
Non invasive detection of vulnerable plaque 2
Non invasive detection of vulnerable plaque 2
Non invasive detection of vulnerable plaque 2
Non invasive detection of vulnerable plaque 2
Non invasive detection of vulnerable plaque 2
Non invasive detection of vulnerable plaque 2
Non invasive detection of vulnerable plaque 2
Non invasive detection of vulnerable plaque 2
Non invasive detection of vulnerable plaque 2
Non invasive detection of vulnerable plaque 2
Non invasive detection of vulnerable plaque 2
Non invasive detection of vulnerable plaque 2
Non invasive detection of vulnerable plaque 2
Non invasive detection of vulnerable plaque 2
Non invasive detection of vulnerable plaque 2
Upcoming SlideShare
Loading in …5
×

Non invasive detection of vulnerable plaque 2

298 views

Published on

SHAPE Society

Published in: Health & Medicine
  • Be the first to comment

Non invasive detection of vulnerable plaque 2

  1. 1. Non-invasive Detection of Vulnerable Plaque using SPIO Enhanced MRI Mitra Rajabi MD, Maamoun AbouQamar MD, Michael Quast PhD, Jigna Wei MD, Daniel Chan PhD, Mohammad Madjid MD, Khawar Gul MD, Ponnada Narayana PhD, Ward Casscells MD, James Willerson MD, Morteza Naghavi MD Texas Heart InstituteThe University of Texas-Houston
  2. 2. Everybody has atherosclerosis, the question is who has Vulnerable Plaque
  3. 3. The Online Cardiovascular Research Community www.VulnerablePlaque.org All slides will be available on:
  4. 4. Vulnerable Plaque? Atherosclerotic plaques that cause sudden luminal clot formation and lead to heart attack and stroke.
  5. 5. Different Types of Vulnerable Plaque As underlying Cause of Acute Coronary Events Normal Rupture-prone Fissured Eroded Critical Stenosis Hemorrhage
  6. 6. Rupture-prone inflamed plaque Vulnerable Plaque Type 1
  7. 7. Eroded Plaque with Exposed Proteoglycans Prone to Thrombosis Vulnerable Plaque Type 2
  8. 8. Fissured Plaque with Old and Fresh Overlaying Thrombi Vulnerable Plaque Type 3
  9. 9. Intra-Plaque Hemorrhage Prone to Thrombosis Vulnerable Plaque Type 4
  10. 10. Vulnerable Plaque Type 5 Asymptomatic significantly stenotic plaque prone to occlusion
  11. 11. Further new types of Vulnerable Plaque to be discovered in future.
  12. 12. Less angiogenesis (?)Extensive angiogenesis Low modified cholesterolHigh modified cholesterol High collagen contentLow collagen content Small or no lipid poolLarge lipid pool Thick fibrous capThin fibrous cap Low-Risk Plaque, Hard Plaque Unstable Plaque, High-Risk Plaque, Soft Plaque Structural or Morphologic Classification Vulnerable Plaque Stable Plaque
  13. 13. Not exposed but may contain as much Exposed proteoglycans (versican and hyaluronan) Intact endothelial lawyerEndothelial denudation High collagen contentOverlaying thrombosis No thrombosisDisrupted / fissured cap Concentric (negative remodeling) Eccentric (positive remodeling) Small or large plaque volume Small or large plaque volume Structural or Morphologic Classification Vulnerable Plaque Stable Plaque Cont…
  14. 14. Hemodynamically significant (>75% stenosis) … Hemodynamically insignificant (< 75% stenosis) … Low strain (stiff)High strain (elasticity) More calcifiedLess calcified ? Structural or Morphologic Classification Stable PlaqueVulnerable Plaque Cont…
  15. 15. Minimum apoptosis … Excessive apoptosis … Low oxidative stressHigh oxidative stress (excessive oxygen and nitrogen free radical formation) Normal or high pH with minimum pH heterogeneity Acidic with high pH heterogeneity Normal temperature with minimal heterogeneity Hot with increased temperature heterogeneity Low traffic (monocyte and T cell recruitment) High traffic (monocyte and T cell recruitment) Quiescent Plaque Low-Risk Plaque Active Plaques Unstable Plaque High-Risk Plaque Functional or Physiologic Classification Vulnerable Plaque Stable Plaque
  16. 16. Plaque characterization by MRI has been introduced by Toussaint and others to study structural properties of atherosclerotic plaque. MRI and Plaque Characterization:
  17. 17. Carotid artery plaqueCCA Carotid bifurcation ICA stenosis & plaque Courtesy of Dr. Chun Yuan University of Washington, Seattle
  18. 18. Question!  Lets assume that we are in our dreamland and non-invasive MR imaging of coronary artery with <100 micron resolution is easily obtained, now the question is whether we are able to accurately detect all vulnerable plaques only by studying their structural properties or we need more?
  19. 19. Plaque Morphology vs. Plaque Activity  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.
  20. 20. 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
  21. 21. Therefore, We need a combined method to image both morphology and activity of plaques
  22. 22. We need MRI with vulnerable plaque targeted contrast media that identifies: 1- Inflammation (macrophage infiltration), 2- Fissured/Permeable Cap, 3- Leaking Angiogenesis and 4- Intra-Plaque Hemorrhage 5- …
  23. 23. Willerson et al: Study of fluorescent labeled macrophage homing into Apo E deficient mice Circ 1998
  24. 24. SPIO  Super  Paramagnetic  Iron  Oxide Colloidal coated nano-particles of iron oxide, e.g. dextran coated SPIO 20-100 nanometer particle size Phagocyted by, and accumulated in cells with phagocytic activity Shortening MR relaxation time, early T2 and late T1 effect
  25. 25. USPIO  Ultra  Super  Paramagnetic  Iron  Oxide Smaller particle size which yields a longer circulation time, yet less phagocytosis and more uptake by non- immune cells
  26. 26. 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 MION 4-6 17 varies … … … …. Examples of Commercially Available SPIO
  27. 27. Prior works done by others for imaging inflammation by MRI and SPIO
  28. 28. Maamoun add Ref
  29. 29. Flash MR Image of a Rat Kidney With Experimental Nephritic Syndrome, Before (Right)and 24h After USPIO Injection(left) Maamoun add Ref
  30. 30. Correlation between macrophage and MR signal reduction in the kidney cortex Maamoun add Ref
  31. 31. Cardiac Application  Monitoring rejection of transplanted heart and lungs following rat allograft and homograft transplantation, w/wo cyclosporin Ho et al, ISMRM 2000
  32. 32. Old literature! Iron particles observed immediately under the endothelium 5 hours after the administration, in artery, in a rat with 7 days hypertension 33 years ago !!! Gordon et al, 1968 Maamoun add Ref
  33. 33. Our Hypothesis:  Vulnerable atherosclerotic plaques which have 1) active recruitment of monocytes and T cells, 2) extensive leaking angiogenesis 3) fissured or permeable cap can be detected by excessive uptake of SPIO particles.
  34. 34. 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
  35. 35. Why negative enhancement?!! Positive Contrast Negative ContrastV.S. Gd-compounds SPIOs + - Knowing that plaque has white background due to its fat and water
  36. 36. What we have done:  - In vitro study of SPIO uptake by macrophages using fluorescent labeled home-made SPIO  -In vitro study of SPIO uptake by macrophages and its effect on T2 relaxation time  -In vitro study of effect of SPIO on macrophage biology and super oxide production
  37. 37. What we have done:  - In vivo study of bio distribution of SPIO in Apo E deficient atherosclerotic mice vs normal wild type C57 black mice  In vivo MRI study of aortic wall in Apo E deficient mice vs. wild type normal mice 4.7 T -in collaboration with Dr Quast’s lab UTMB
  38. 38. Invitro Study of Macrophage SPIO Uptake  In a series of invitro 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)
  39. 39. FL-labeled SPIO Incubated Macrophages 24hr
  40. 40. Mouse Peritoneal Macrophages Incubated with SPIO after 6hr
  41. 41. Double DAPI Staining with Fluorescence-labeled SPIO Macrophages after 24hr Incubation
  42. 42. SPIO and T2 Effect Invitro study to show the effect of macrophage SPIO uptake on their T2 relaxation time
  43. 43. Protocol:  We used 8 flasks of CBM macrophages.  After preparing the cells, Feridex was added with the proper concentration to each labeled tube.  Incubation was done at 37 C.  For each time, pellet the tubes at 1000 rpm’s for 5 min.  Washed with 1X PBS for 5 min 3 times.  Resuspended in 2% paraformaldehyde, to fix the cells.
  44. 44. time concentration 20 Min 1 Hour 6 Hours 24 Hours 50µl 100µl 250µl 500µl control control Expected T2 Reduction Effect
  45. 45. Macrophage Uptake of Feridex After 20 Min Shown by T2 Reduction 0 10 20 30 40 50 60 70 80 90 50 100 250 500 control control 20 min Concentration µl
  46. 46. 0 10 20 30 40 50 60 70 80 90 50 100 250 500 control control 60 min Macrophage Uptake of Feridex After 60 Min Shown by T2 Reduction Concentration µl
  47. 47. 0 10 20 30 40 50 60 70 80 90 50 100 250 500 control control 6 Hours Macrophage Uptake of Feridex After 6hr Shown by T2 Reduction Concentration µl
  48. 48. 0 10 20 30 40 50 60 70 80 90 50 100 250 500 control control 24 Hours Macrophage Uptake of Feridex After 24hr Shown by T2 Reduction Concentration µl
  49. 49. 0 10 20 30 40 50 60 70 80 90 50 100 250 500 control control 20 min 60 min 6 hours 24 hours Macrophage Uptake of Feridex with Time and Concentration Shown by T2 Reduction Concentration µl
  50. 50. 0 10 20 30 40 50 60 70 80 90 20 Min 60 Min 6 Hours 24 Hours 50 100 250 500 control control Macrophage Uptake of Feridex with Concentration and Time Shown by T2 Reduction µl
  51. 51. Study of production of Reactive Oxygen Species by SPIO Incubated Macrophages
  52. 52. Since the production of reactive oxygen species (ROS) in the plaque might have unfavorable effects on the biology of the plaque, we have planned to check if the SPIO would excessively produce ROS.
  53. 53. Facts  Any event of phagocytosis is immediately followed by a transient release of super oxide due to the assembly of the NADPH oxidase against the plasma membrane. Subsequently the oxidase translocates onto the phagosomes containing the SPIO to produce intracellular ROS.  Thus an early extra cellular secretion of super oxide is detectable (using luminol) soon after phagocytosis and a later event of intracellular secretion is measurable using DCFDA dye .
  54. 54. Method  · The suspension of SPIO (1.25-10 uL) was added to macrophages (1x10*4/well in 96 well plates). Cells were incubated for 1 h and washed to remove extra cellular FDIO. For each dose three wells were tested. Isoluminol substrate was added and super oxide induced luminescence measured at 15, 30 and 45 min intervals using a luminometer.
  55. 55. Results · SPIO was internalized by macrophages as early as 15 min after addition. · Uptake was followed by release of super oxide for all four doses tested. Super oxide was released by SPIO at all doses tested (1.25-10 ul)
  56. 56. Dosage of SPIO: 1.25micL 0 500 1000 1500 2000 2500 3000 3500 15min 30min 45min NOSPIO Sample1 Sample2 Sample3 ROS Production: Time VS SPIO Concentration
  57. 57. Dosage at 2.5micL 0 500 1000 1500 2000 2500 3000 3500 15min 30min 45min Sample1 Sample2 Sample3 ROS Production: Time VS SPIO Concentration
  58. 58. Dosage at 5micL 0 500 1000 1500 2000 2500 3000 15min 30min 45min Sample1 Sample2 Sample3 ROS Production: Time VS SPIO Concentration
  59. 59. Dosage at 10micL 0 200 400 600 800 1000 1200 1400 1600 1800 15min 30min 45min Sample1 Sample2 Sample3 ROS Production: Time VS SPIO Concentration
  60. 60. SPIO biodistribution in ApoE mice
  61. 61. Iron staining of mouse circulating monocyte after 15 minutes
  62. 62. Iron staining of mouse circulating monocyte after 30 minutes
  63. 63. Specimens were taken at interval of 3mm from arotic root to the renal aorta
  64. 64. SPIO Accumulation in Atherosclerotic Plaque Atherosclerotic plaque in aortic root Normal aortic segment Iron staining of Apo E K/O Aorta, 24 hour after SPIO injection Iron particles
  65. 65. ApoE Mouse 3 Days After Injection H&E Pearl’s Aorta-2 Atherosclerotic plaque in thoracic aorta
  66. 66. Aortic Root after 5 days Dense infiltration of iron particles as shown by light blue in Pearl’s staining
  67. 67. Aortic Plaque at Renal Level After 3 days
  68. 68. Control C57Black No plaque, No Iron Pearl’s staining
  69. 69. 0 5 10 15 Atherosclerotic Aorta Average numberofiron particlesper sample P<0.001 Comparison of the Number of the Iron Particles in Apo E KO Mice Plaque vs. Normal Wall Normal-Looking Vessel Wall of Same Apo E Mice
  70. 70. MRI SPIO study of Apo E v.s. Normal Mice
  71. 71. TE: 12ms TR: 2500 FOV: 6x6 256x256 Only respiratory gating was done
  72. 72. Images of aorta from renal level
  73. 73. MR Image of Abdominal Aorta After SPIO Injection in Apo E and Control Mice 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 in pathology
  74. 74. MRI Imaging of Atherosclerosis using SPIO Studies done recently by others:  1- Schmitz SA, Coupland SE, Gust R, Winterhalter S, Wagner S, Kresse M, Semmler W, Wolf KJ Superparamagnetic iron oxide-enhanced MRI of atherosclerotic plaques in Watanabe hereditable hyperlipidemic rabbits. Invest Radiol. 2000 Aug;35(8):460-71.
  75. 75. Group I II III IV USPIO 0 50µmol Fe/kg 50µmol 200µmol Time - 8 hr 24 hr 48 hr Schmitz et al J. Inv. Radiol. 2000
  76. 76. Control SPIO Injected Schmitz et al J. Inv. Radiol. 2000
  77. 77. Schmitz et al J. Inv. Radiol. 2000
  78. 78. Schmitz et al J. Inv. Radiol. 2000
  79. 79. Schmitz et al J. Inv. Radiol. 2000
  80. 80. 2- Ruehm SG, Corot C, Vogt P, Kolb S, Debatin JF. Magnetic resonance imaging of atherosclerotic plaque with ultrasmall superparamagnetic particles of iron oxide in hyperlipidemic rabbits. Circulation. 2001 Jan 23;103(3):415-22. Studies done recently by others: MRI Imaging of Atherosclerosis using SPIO
  81. 81. A, Coronal MIP and (B) sagittal oblique and (C) coronal oblique reformatted images of contrast-enhanced 3D MRA data set collected after intravenous administration of Gd-DOTA displaying aorta of 7- month-old hyperlipidemic rabbit. Aortic wall is smooth, without evidence of luminal narrowing. Reuhm et al, Circulation 2001
  82. 82. 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
  83. 83. A, Intraluminal signal measured in single large ROI (9 mm2 ) revealed significant increase in SNR, with maximum reached at day 5 after contrast administration. These changes reflect T2* effects, which decreased over time. B, SNR values based on 3 ROI measurements in aortic wall of each animal failed to reveal statistical difference between precontrast and 5 days post-Sinerem image sets in normal control rabbits. In hyperlipidemic animals, conversely, significant decrease in SNR corresponding to select USPIO uptake in plaque formations containing MPS cells was evident. Reuhm et al, Circulation 2001
  84. 84. 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
  85. 85. 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
  86. 86. Conclusion:  Non-invasive MRI study of atherosclerotic plaques using SPIO (pre and post injection comparison) may be a likely method for detection of vulnerable plaques  Further studies particularly human clinical trials are warranted
  87. 87. SPIO Clinical Trial: - The first human clinical trial on detection of carotid vulnerable plaque using SPIO in patients undergoing carotid endartherectomy Baseline SPIO Injection 1hr post- injection 5days Scan Surgery
  88. 88. Dr. Naghavi – The first volunteer subject in his Carotid MRI SPIO Study
  89. 89. Multi-Center Trial:  The second site of the study is going to be Univ. of Washington Seattle directed by Dr. Yuan.  The interim report of the trial will be presented at AHA 2001 in Anaheim
  90. 90. The Online Cardiovascular Research Community www.VulnerablePlaque.org All slides will be available on:
  91. 91. WWW.HotPlaque.Com

×