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Everybody Has Atherosclerosis
The Question Is Who Has
Vulnerable Plaque
Paradigm Shift in Cardiology
“Magnetic Resonance I...
Sudden Cardiac Death
Acute MI
Vulnerable
Plaque(s)
Stop Vulnerable Plaque, Prevent Heart Attack!
 On the basis of his studies of the
triggers of MI, James E. Muller et al
described “coronary occlusive
thrombi occurs wh...
Vulnerable Plaque, the youngest creature in the land of cardiology
has just turned in 8 y!
VPiologists call him VP!!
Carl von Rokitansky (1804-1878)
Rokitansky gaveearly
detailed descriptionsof
arterial disease. Heis
alleged to haveperform...
First studies on inflammation of vessels, particularly phlebitis, Started at
a time when Cruveilhier2had just stated: La p...
Olcott 1931 “plaque rupture”
Leary 1934 “rupture of atheromatous abscess”
Wartman 1938 “rupture-induced occlusion”
Horn 19...
Published in 1967
The Abscess
“Grutzbalg” Hypothesis
N Engl J Med 1999
“Atherosclerosis; an
inflammatory disease”
Ross R.
Russell Ross
Atherosclerosis; arterial “Response to I...
Erling Falk Michael Davies
Autopsy Series
Thin Fibrous Cap + Large Lipid Core + Dense Macrophage
A culprit ruptured plaque...
Seymour Glagov
Compensatory Enlargement
of Human Atherosclerotic Coronary
Arteries N Engl J Med 1987 May
28;316(22):1371-5...
Angiographic progression of coronary
artery disease and the development of
myocardial infarction.
Ambrose JA, Tannenbaum M...
Falk E., Shak P.K., Fuster V. Circulation 1995
Non-stenotic (<75%) plaques cause about 80% of deadly MI
Macrophage-
driven MMPs
soften plaquecap
and prompt it to
rupture
P.K. Shah
Peter Libby
Thefateof atherosclerosisand
itsth...
•Eroded Plaque
Rupture-prone
plaques are not the
only type of
vulnerable plaque
•Calcium Nodule
van der Wal - Netherlands
...
Dangerous forms of
atherosclerotic
plaques prone to
thrombosis
Vulnerable Plaque?
Ruptured Plaques (~70%)
1. Stenotic (~20%)
2. Non-stenotic (~50%)
Non-ruptured Plaques (~
30%)
1. Erosion (~20%)
2. Calcif...
 Culprit Plaque; a retrospective terminology
 Vulnerable Plaque; a prospective terminology
 Vulnerable Plaque = Future ...
Natural History of
Vulnerable Plaques
Illustrated:
~70%
Percent of stenosis
Frequency of plaques
“Risk” per each plaque
Culprit Risk per
each type of
Vulnerable Plaque
(Log)...
Rupture-Prone Plaque
Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001
Macrophage
Necrotic lipid
core
Thin fibrouscap
Eroded Plaque
Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001
Endothelial
denudation
Proteoglycans
Fissured / Healed Plaque
Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001
Mural thrombi
Wounded
plaque
Plaque with a Intimal Calcified Nodule
Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001
Calcified nodule
Intra-Plaque Hemorrhage with Intact Cap
Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001
Leaking
angiogenesisor
ruptureof...
Critically Stenotic but Asymptomatic Plaque
Naghavi et al, Cur Ath Rep 2001Vulnerable Plaque
>75% lumina
narrowing
Different Types of Vulnerable Plaques
Major Underlying Cause of Acute Coronary Events
Normal
Rupture-prone
Fissured Eroded...
Emerging
Techniques for
Detection of
Vulnerable Plaque
Emerging Diagnostic Techniques
A. Invasive Techniques
Angioscopy
IntravascularUltrasound (IVUS)
IntravascularThermography
...
- 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. Blood Tests / Serum Markers
- CRP
- ICAM-1, VCAM, p-Selectin, sCD40-L
- Proinflamatory c...
Angioscopy
Advantages:
Intuitive (anatomic)
Simple (easy to understand)
Disadvantages:
Visualizes only the surface of t...
Intravascular Ultrasound (IVUS):
Advantage:
Reveals the morphology
of the plaque
Differs between soft
(hypo-echoic) and ...
Optical Coherence Tomography (OCT)
Advantage:
Very high-resolution
Disadvantages:
Needs continuous saline wash / proxima...
Intravascular Thermography
Advantages:
Simplicity in theory; hot plaque
Gives information about plaque
inflammation
Disa...
Casscells W, et al.
Thermal detection of cellular infiltrates in living atherosclerotic
plaques: possible implications for...
Photonic Spectroscopy
Advantage:
 Chemical compounds
Disadvantage:
Based on statistical analysis and
calibration is alw...
Intravascular Elastography
Advantages:
Provides novel information, showing stiffness
Small added cost to IVUS
Disadvanta...
Intravascular Nuclear Imaging
Immuno-scintigraphy
Advantage:
One may use radio-labeled antibodies to detect
specific anti...
Magnetic Resonance Imaging
Plaque Characterization and Angiography
Advantages:
Lack of ionizing radiation
Non-invasive
...
Human Carotid Plaque
Courtesy of
Dr. Chun Yuan
University of Washington
Fuster and Fayad and colleagues reinforced earlier MRI investigation of plaque for invivo
non-invasive detection of vulner...
Noninvasive Coronary Vessel Wall and Plaque Imaging With
Magnetic Resonance Imaging
René M. Botnar; Matthias Stuber; Kraig...
Intravascular MRI
Advantages:
Lack of ionizing
radiation
High resolution
Potential for NMR spectroscopy
Disadvantages:
...
Coronary Calcium Imaging
EBT and MSCT
Advantages:
Quick and easy
Provide information about total
burden of atheroscleros...
Race for Non-Invasive Coronary
Angiography
• Multi-Slice Fast Computed
Tomography (MSCT)
• Magnetic Resonance
Angiography
...
Two Major Players in Massive
Clinical VP Screening
•MRI
•CT
•A new competitor is
warming up!
Plaque Morphology
vs.
Plaque Activity
Why do we need both?
Morphology vs. Activity Imaging
Inactive and
non-inflamed
plaque
Active and
inflamed
plaque
May Appear Similar
in
IVUS OCT...
Which one is
vulnerable plaque?
High Level of Sensitivity and Specificity Needed
• Knowing the high prevalence of
atherosclerosis in apparently healthy
po...
Major Criteria of Vulnerable Plaque
• Cap Thickness
• Lipid Core
• Plaque inflammation (macrophage density)
For clinical s...
I would chouse
Inflammation
Good News!
•MRI can give us more
than one choice, indeed it
can provide all of them.
• CT is promising too, but there is m...
Plaque Activity = Plaque Inflammation
Plaque Inflammation =
Plaque Macrophage Density =
Plaque Monocyte Recruitment
Rate
N...
Vulnerable plaque targeted contrast media
needed to identify the following:
1- Inflammation (macrophage infiltration),
2- ...
SSuperuper PParamagneticaramagnetic IIronron OOxide andxide and
Ultra-small Super Paramagnetic IronUltra-small Super Param...
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 ...
Reported Applications of SPIO in MR Imaging:
-Detection of Hepatic Lesions
(primary and metastatic cancers)
-Experimental ...
HypothesisHypothesis
Active macrophages residing inside
the plaque and recruitment of
monocytes into an inflamed
vulnerabl...
Our proposed solution: SPIO MR Imaging
MR contrast media for imaging inflammation and other characteristics of vulnerable ...
USPIOs Enter the AtheroscleroticUSPIOs Enter the Atherosclerotic
Plaque ThroughPlaque Through
Monocyte containing
engulfed...
In-vitro Study of Macrophage
SPIO Uptake
 In a series of in-vitro studies we have tested
the rate of SPIO uptake by human...
Fluorescent-labeled SPIO incubated with macrophages 24 hr
Macrophages avidly take up SPIO nano-particles
SPIO and T2 Effect
In-vitro relaxation study shows the effect
of SPIO dose and incubation time on
intra-macrophage SPIO ne...
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...
In-vivo distribution of SPIO in ApoE
deficient and wild type mice:
•For the initial study, we use the mouse model of
ather...
Pre and Post-SPIO Enhanced Magnetic
Resonance Imaging of ApoE K/O and Wild
Type Mice:
We used 4.7 tesla MRI unit in our st...
Apo E deficient mice MRI SPIO experiment
SPIO Accumulation in
Atherosclerotic Plaque
Atherosclerotic plaque
in aortic root
Normal aortic segment
Iron staining of A...
Histopathologic study of the Mouse injected
With SPIO (Thoracic Aorta)
ApoE KO mouse, Movat staining,
proximal aorta
Coron...
Histopathologic study of ApoE KO Mouse injected
With SPIO (Thoracic Aorta)
CD68 staining
(aortic plaque)
Iron Staining (ao...
Histopathologic study of ApoE KO Mouse
injected With SPIO (Abdominal Aorta)
H&E staining
Iron Staining CD 68 staining
Iron...
Histopathologic study of wild type Mouse
injected With SPIO (Thoracic Aorta)
H&E staining
CD68 stainingIron staining
MR Image of Abdominal Aorta
After SPIO Injection in Mouse
Apo E
deficient
mouse
C57B1
(control)
mouse
Before Injection Aft...
Rabbit Aorta, x10 magnification
Iron Staining H&E Staining
Rabbit Aorta, x40 magnified
Iron Staining H&E Staining
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
Ex-vivo MR study of the thoracic aorta in Watanabe and
Wild type rabbit after SPIO injection compared to control.
3D MR An...
Ex-vivo MR study of the thoracic aorta in Watanabe and
Wild type rabbit after SPIO injection compared to control.
(Gradien...
No cytokine injected
Apo E SPIO Injected
Iron Staining
H&E Staining
No cytokines
Apo E SPIO Injected
Iron Staining
H&E Staining
No cytokines SPIO Injected Apo E
Only plaque with SPIO C3Ex40
No Cytokines SPIO Injected Apo E
C3E
SPIO Found in Circulating Monocytes
Iron Staining
H&E Staining
T2Fx10
TNFα/IL-1ß SPIO Injected Apo E
Iron Staining H&E Staining
TNFα/IL-1ß SPIO Injected Apo E
H&E StainingH&E Staining
Increased Superficial Macrophage Density
TNFα/IL-1ß
Iron Staining Iron Staining
TNFα/IL-1ß
Iron Staining H&E Staining
TNFα/IL-1ß
Iron Staining Macrophage Staining
TNFα/IL-1ß
Iron Staining H&E Staining
TNFα/IL-1ß
Iron Staining H&E Staining
TNFα/IL-1ß
Iron Staining H&E Staining
New SPIO Development
Towards Plaque Targeted SPIO
Six mice were injected IP with mineral oil, and 24
hours later same amou...
New SPIO Development
Towards Plaque Targeted SPIO
Bare
SPIO
New SPIO Development
Towards Plaque Targeted SPIO
Dextran
Coated
New SPIO Development
Towards Plaque Targeted SPIO
Lipid
Coated
New SPIO Development
Towards Plaque Targeted SPIO
Receptor
Targeted
SPIO
Imaging of inflammation in
rabbit model of atherosclerosis
using USPIO
Ruehm et al. Circulation 2001
Gadolinium VS. SPIO
1- Non-Specific (improved by Gd-Lutetium still lipid
targeted rather than inflammation)
2- White on wh...
SPIO Clinical Trial:
• The first human clinical trial on
detection of carotid vulnerable plaque
using SPIO in patients und...
0.05 mg/kg
SPIO Score vs. Calcium Score
The aim of the project is to develop a novel SPIO
Score for quantitative monitoring of plaque...
SPIO Clinical Trial:
• The first human clinical trial on
detection of carotid vulnerable plaque
using SPIO in patients und...
… the question is not
only vulnerable plaque
Stay Tuned!
HotPlaque.com 2000!
Texas Heart Institute University of Texas-Houston
Center for Vulnerable Plaque Research
Denton A. Cooley Building (floor 1...
Association for Eradication of Heart Attack
www.VP.org
Everybody has atherosclerosis
Everybody has atherosclerosis
Everybody has atherosclerosis
Everybody has atherosclerosis
Everybody has atherosclerosis
Everybody has atherosclerosis
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Everybody has atherosclerosis

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Everybody has atherosclerosis

  1. 1. Everybody Has Atherosclerosis The Question Is Who Has Vulnerable Plaque Paradigm Shift in Cardiology “Magnetic Resonance Imaging of Plaque Inflammation” CIMIT Vulnerable Plaque Program February 11th, 2002 Morteza Naghavi, MD University of Texas Houston and Texas Heart Institute
  2. 2. Sudden Cardiac Death Acute MI Vulnerable Plaque(s) Stop Vulnerable Plaque, Prevent Heart Attack!
  3. 3.  On the basis of his studies of the triggers of MI, James E. Muller et al described “coronary occlusive thrombi occurs when atherosclerotic plaques become vulnerable to rupture … during vulnerable periods…" 5 years later in 1994 he coined the term of History of Atherosclerosis from www.VP.org Who Brought the Name of “Vulnerable Plaque” to Medical Literature? Muller JE, Abela GS, Nesto RW, Tofler GH. Triggers, acute risk factors and vulnerable plaques: the lexicon of a new frontier. J Am Coll Cardiol. 1994 Mar 1;23(3):809-13. Review. Vulnerable Plaque.
  4. 4. Vulnerable Plaque, the youngest creature in the land of cardiology has just turned in 8 y! VPiologists call him VP!!
  5. 5. Carl von Rokitansky (1804-1878) Rokitansky gaveearly detailed descriptionsof arterial disease. Heis alleged to haveperformed 30,000 autopsies. Rokitansky in 1841 championed theThrombogenic Theory. Heproposed that the depositsobserved in theinner layer of thearterial wall derived primarily from fibrin and other blood elementsrather than being theresult of apurulent process. Subsequently, theatheroma resulted from thedegeneration of thefibrin and other blood proteinsasaresult of apreexisting crasisof theblood, and finally thesedepositsweremodified toward apulpy masscontaining cholesterol crystalsand fatty globules. Thistheory cameunder attack by Virchow
  6. 6. First studies on inflammation of vessels, particularly phlebitis, Started at a time when Cruveilhier2had just stated: La phlebite domine toute la pathologie.3 First a great number of preparatory studies on fibrin, leukocytes, meta-morphosis of blood, published separately. … Rudolf Virchow 1821-1902 The Father of Cellular Pathology Virchow appreciates prior works. Virchow presented hisinflammatory theory. Heutilized thenameof "endarteritisdeformans." By thishe meant that theatheromawasaproduct of an inflammatory processwithin theintimawith thefibrous thickening evolved asaconsequenceof areactivefibrosisinduced by proliferating connectivetissuecells within theintima.
  7. 7. Olcott 1931 “plaque rupture” Leary 1934 “rupture of atheromatous abscess” Wartman 1938 “rupture-induced occlusion” Horn 1940 “plaque fissure” Helpern 1957 “plaque erosion” Crawford 1961 “plaque thrombosis” Gore 1963 “plaque ulceration” Friedman 1964 “macrophage accumulation” Byers 1964 “thrombogenic gruel” Chapman 1966 “plaque rupture” Plaque Fissure in Human Coronary Thrombosis (Abstract) Fed. Proc. 1964, 23, 443 Paris Constantinidis “Thedestruction of thehyalinized wall separating lumen from theatheromawas almost alwaysobserved to bepreceded by or associated with itsinvasion by lipid containing macrophages.” Friedman and van den Bovenkamp 1965 Unheralded Pioneers
  8. 8. Published in 1967
  9. 9. The Abscess “Grutzbalg” Hypothesis
  10. 10. N Engl J Med 1999 “Atherosclerosis; an inflammatory disease” Ross R. Russell Ross Atherosclerosis; arterial “Response to Injury” N Engl J Med 1976 Aug 12;295(7):369-77 The pathogenesis of atherosclerosis (first of two parts). Ross R, Glomset JA.
  11. 11. Erling Falk Michael Davies Autopsy Series Thin Fibrous Cap + Large Lipid Core + Dense Macrophage A culprit ruptured plaque 1981-1990
  12. 12. Seymour Glagov Compensatory Enlargement of Human Atherosclerotic Coronary Arteries N Engl J Med 1987 May 28;316(22):1371-5 <50% stenosis Luminal area is not endangered until more than 40% of internal elastic lamina is destructed and occupied by plaque Coronary artery disease is a disease of arterial wall not lumen. Positive Remodeling <80% stenosis
  13. 13. Angiographic progression of coronary artery disease and the development of myocardial infarction. Ambrose JA, Tannenbaum MA, Alexopoulos D, Hjemdahl-Monsen CE, Leavy J, Weiss M, Borrico S, Gorlin R, Fuster V. Department of Medicine, New York Cardiac Center, Mount Sinai Medical Center, New York 10029. Simultaneously, Little et al, Haft et al reported that majority of culprit lesions are found on previously non-critical stenosis plaques. Conclusion: “Myocardial infarction frequently develops from non-severe lesions.” J Am Coll Cardiol 1988 Jul;12(1):56-62 Ambrose, Fuster, and colleagues X-Ray Angiographically Invisible Plaques
  14. 14. Falk E., Shak P.K., Fuster V. Circulation 1995 Non-stenotic (<75%) plaques cause about 80% of deadly MI
  15. 15. Macrophage- driven MMPs soften plaquecap and prompt it to rupture P.K. Shah Peter Libby Thefateof atherosclerosisand itsthrombotic complication are governed by immunesystem. Goran Hansson Allard van der Wal and others
  16. 16. •Eroded Plaque Rupture-prone plaques are not the only type of vulnerable plaque •Calcium Nodule van der Wal - Netherlands Renu Virmani -USA Thiene - Italy Kolodgie F., Burk A.P., Farb A., and Virmani R.
  17. 17. Dangerous forms of atherosclerotic plaques prone to thrombosis Vulnerable Plaque?
  18. 18. Ruptured Plaques (~70%) 1. Stenotic (~20%) 2. Non-stenotic (~50%) Non-ruptured Plaques (~ 30%) 1. Erosion (~20%) 2. Calcified Nodule (~5%) Plaque Pathology Responsible for Coronary Thrombotic Death In summary:
  19. 19.  Culprit Plaque; a retrospective terminology  Vulnerable Plaque; a prospective terminology  Vulnerable Plaque = Future Culprit Plaque Terminologies
  20. 20. Natural History of Vulnerable Plaques Illustrated:
  21. 21. ~70% Percent of stenosis Frequency of plaques “Risk” per each plaque Culprit Risk per each type of Vulnerable Plaque (Log) Culprit lesions found in autopsy series of acute MI Different Types of Plaque Vulnerable to Thrombosis All Male Female ~10% <5% ~20% 50% Angiography ~80% <5% ~20% ~55% ~20% <5% <5% ~20% Rupture Prone Eroded Calcified NoduleHemorrhage Positive Remodeling Fissured /Healed Natural History of Vulnerable Atherosclerotic Plaques
  22. 22. Rupture-Prone Plaque Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001 Macrophage Necrotic lipid core Thin fibrouscap
  23. 23. Eroded Plaque Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001 Endothelial denudation Proteoglycans
  24. 24. Fissured / Healed Plaque Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001 Mural thrombi Wounded plaque
  25. 25. Plaque with a Intimal Calcified Nodule Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001 Calcified nodule
  26. 26. Intra-Plaque Hemorrhage with Intact Cap Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001 Leaking angiogenesisor ruptureof vasa vaserum
  27. 27. Critically Stenotic but Asymptomatic Plaque Naghavi et al, Cur Ath Rep 2001Vulnerable Plaque >75% lumina narrowing
  28. 28. Different Types of Vulnerable Plaques Major Underlying Cause of Acute Coronary Events Normal Rupture-prone Fissured Eroded Critical Stenosis Hemorrhage Naghavi et al, Cur Ath Rep 2001
  29. 29. Emerging Techniques for Detection of Vulnerable Plaque
  30. 30. Emerging Diagnostic Techniques A. Invasive Techniques Angioscopy IntravascularUltrasound (IVUS) IntravascularThermography IntravascularOptical Coherence Tomography (OCT) IntravascularElastography Intravascularand Transesophageal MRI IntravascularNuclearImaging IntravascularElectrical Impedance Imaging IntravascularTissue Doppler IntravascularShearStress Imaging Intravascular(Photonic) Spectroscopy
  31. 31. - 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
  32. 32. 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 Tomography (EBT) C. Multi-Slice Fast Spiral / Helical Computed Tomography D. Nuclear Imaging (18-FDG, MCP-1, Annexin V, CD40)
  33. 33. Emerging Diagnostic Techniques C. Blood Tests / Serum Markers - CRP - ICAM-1, VCAM, p-Selectin, sCD40-L - Proinflamatory cytokines - Lp-PLA2 - Ox-LDL Ab - PAPP-A D. Endothelial Function Test -Intra coronary acethylcholine test -Noninvasive flow mediated dilatation of brachial artery - Anti-body against endothelial cells
  34. 34. Angioscopy Advantages: Intuitive (anatomic) Simple (easy to understand) Disadvantages: Visualizes only the surface of the plaque Requires a proximal occluding balloon The spatial resolution is limited Glistening yellow plaque Uchida et al, Japan
  35. 35. Intravascular Ultrasound (IVUS): Advantage: Reveals the morphology of the plaque Differs between soft (hypo-echoic) and Hard (hyper-echoic) plaques Disadvantages: Doesn’t give information about plaque inflammation Low spatial resolution (~ 200 µm) Nissen, Yock, and Fitzgerald
  36. 36. Optical Coherence Tomography (OCT) Advantage: Very high-resolution Disadvantages: Needs continuous saline wash / proximal occlusion Limited penetration Does not give information about plaque inflammation Light Lab Inc.Mark Brezinski, James Fujimoto, Eric Swanson
  37. 37. Intravascular Thermography Advantages: Simplicity in theory; hot plaque Gives information about plaque inflammation Disadvantages: Plaque temperature is affected by blood flow Volcano Therapeutics Inc.
  38. 38. Casscells W, et al. Thermal detection of cellular infiltrates in living atherosclerotic plaques: possible implications for plaque rupture and thrombosis. Lancet. 1996 May 25;347(9013):1447-51. Vulnerable plaques are hot and acidic! Ward Casscells and James Willerson showed ex-vivo that human carotid atherosclerotic plaques have temperature heterogeneity and plaques with thinner cap and higher macrophage infiltration give off more heat. Two years later Morteza Naghavi invented Thermosensor Basket catheter and showed invivo temperature heterogeneity in Hypercholestrolemic Dogs and Watanabe Rabbits. Coincidentally Stefanadis et al in 1999 confirmed significant temperature heterogeneity invivo in patients with unstable angina and acute MI. Stefanadis C, et al. Thermal heterogeneity within human atherosclerotic coronary arteries detected in vivo: A new method of detection by application of a special thermography catheter. Circulation. 1999 Apr 20;99(15):1965-71.
  39. 39. Photonic Spectroscopy Advantage:  Chemical compounds Disadvantage: Based on statistical analysis and calibration is always an issue S/N is a serious problem Still not proven to be able to distinguish vulnerable plaques from stable ones Near Infrared Reflectance Spectroscopy InfraReDx Inc. NIR Spectroscopy Robert Lodder, James Muller, and Pedro Moreno
  40. 40. Intravascular Elastography Advantages: Provides novel information, showing stiffness Small added cost to IVUS Disadvantage: Does not give any chemical – compositional data, nor shows inflammation de Korte et al. Thorax Center, Erasmus University Rotterdam
  41. 41. Intravascular Nuclear Imaging Immuno-scintigraphy Advantage: One may use radio-labeled antibodies to detect specific antigens in plaque like MCP-1 Disadvantages: Radiation and safety problems Poor resolution and flow artifacts Lack of specificity ImetrX Inc.William Strauss and Vartan Ghazarossian
  42. 42. Magnetic Resonance Imaging Plaque Characterization and Angiography Advantages: Lack of ionizing radiation Non-invasive Provides enormous information about flow as well as plaque Enhancement by contrast agents and NMR spectroscopy Disadvantages: Ineligibility of patients with metal prostheses High cost Longer time for adoption by cardiologists
  43. 43. Human Carotid Plaque Courtesy of Dr. Chun Yuan University of Washington
  44. 44. Fuster and Fayad and colleagues reinforced earlier MRI investigation of plaque for invivo non-invasive detection of vulnerable plaque with large lipid pool and thin fibrous caps.
  45. 45. Noninvasive Coronary Vessel Wall and Plaque Imaging With Magnetic Resonance Imaging René M. Botnar; Matthias Stuber; Kraig V. Kissinger; Won Y. Kim; Elmar Spuentrup; Warren J. Manning. Circulation. 2000;102:2582
  46. 46. Intravascular MRI Advantages: Lack of ionizing radiation High resolution Potential for NMR spectroscopy Disadvantages: Invasive and slower than fluoroscopy Needs open/short bore high field magnet Longer time for adoption by cardiologists Surgi-Vision Inc.Ergin Atalar IVUS
  47. 47. Coronary Calcium Imaging EBT and MSCT Advantages: Quick and easy Provide information about total burden of atherosclerosis Disadvantages: Cannot distinguish vulnerable from stable plaque (poor plaque characterization) Inadequate specificity, may not accurately predict near future event May not be suitable for monitoring treatment Calcium Score Imatron Inc.Rumberger, Aard, Raggi, and others
  48. 48. Race for Non-Invasive Coronary Angiography • Multi-Slice Fast Computed Tomography (MSCT) • Magnetic Resonance Angiography (MRA) • Electron Beam Tomography (EBT)
  49. 49. Two Major Players in Massive Clinical VP Screening •MRI •CT •A new competitor is warming up!
  50. 50. Plaque Morphology vs. Plaque Activity Why do we need both?
  51. 51. Morphology vs. Activity Imaging Inactive and non-inflamed plaque Active and inflamed plaque May Appear Similar in IVUS OCT MRI w/o CM Morphology Show Different Activity Thermography, Spectroscopy, immunoscientigraphy, MRI with targeted contrast media…
  52. 52. Which one is vulnerable plaque?
  53. 53. High Level of Sensitivity and Specificity Needed • Knowing the high prevalence of atherosclerosis in apparently healthy population, in order to accurately detect vulnerable plaques and vulnerable patients, it is imperative to obtain information about both structure and activity of plaque assuring minimum false positive and false negative results. NO MORE TREADMILL TEST!
  54. 54. Major Criteria of Vulnerable Plaque • Cap Thickness • Lipid Core • Plaque inflammation (macrophage density) For clinical screening of vulnerable plaques, if you were to have only ONE shot, which one would you aim at?
  55. 55. I would chouse Inflammation
  56. 56. Good News! •MRI can give us more than one choice, indeed it can provide all of them. • CT is promising too, but there is more homework for CT fans.
  57. 57. Plaque Activity = Plaque Inflammation Plaque Inflammation = Plaque Macrophage Density = Plaque Monocyte Recruitment Rate Note: leaking angiogenesis follows inflammation but is not specific enough.
  58. 58. Vulnerable plaque targeted contrast media needed to identify the following: 1- Inflammation (macrophage infiltration), 2- Fissured/Permeable Cap, 3- Leaking Angiogenesis and 4- Intra-Plaque Hemorrhage 5- Denuded Endothelium
  59. 59. SSuperuper PParamagneticaramagnetic IIronron OOxide andxide and Ultra-small Super Paramagnetic IronUltra-small Super Paramagnetic Iron OxideOxide ((SPIOSPIO – USPIO)– USPIO) Blood 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
  60. 60. 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 Available SPIOs
  61. 61. Reported Applications of SPIO in MR Imaging: -Detection of Hepatic Lesions (primary and metastatic cancers) -Experimental nephritic syndrome in laboratory animals -Monitoring rejection of transplanted heart or kidney in the animal model of allograft transplantation. -Experimental detection of CNS lesions in laboratory animals. MR Imaging of Inflammation is not New
  62. 62. HypothesisHypothesis Active macrophages residing inside the plaque and recruitment of monocytes into an inflamed vulnerable plaques can be visualized by SPIO contrast enhanced MRI. Decrease in MR signal intensity (negative enhancement) is correlated with the density of active macrophages residing inside plaque.
  63. 63. Our proposed solution: SPIO MR Imaging MR contrast media for imaging inflammation and other characteristics of vulnerable plaque
  64. 64. USPIOs Enter the AtheroscleroticUSPIOs Enter the Atherosclerotic Plaque ThroughPlaque Through Monocyte containing engulfed SPIO particles Fissured or thin cap  Extensive angiogenesis l and leaking vasa vasorum  Intra plaque hemorrhage
  65. 65. 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).
  66. 66. Fluorescent-labeled SPIO incubated with macrophages 24 hr Macrophages avidly take up SPIO nano-particles
  67. 67. SPIO and T2 Effect In-vitro relaxation study shows the effect of SPIO dose and incubation time on intra-macrophage SPIO negative enhancement
  68. 68. 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
  69. 69. In-vivo distribution of SPIO in ApoE deficient and wild type mice: •For the initial study, we use the mouse model of atherosclerosis. • •ApoE deficient mouse has similar atherosclerotic lesions to human and the lesions are more common in the aortic arch and thoracic aorta. • We used ApoE deficient mice and normal variant (C57BL mice) as control. •The SPIO that we used was Feridex (Berlex) injectable solution. •Animals were sacrificed on day 3 and 5 after injection.
  70. 70. Pre and Post-SPIO Enhanced Magnetic Resonance Imaging of ApoE K/O and Wild Type Mice: We used 4.7 tesla MRI unit in our study. After baseline MR imaging with respiratory gating, we injected 1mMolFe/kg super paramagnetic iron oxide to six ApoE deficient and two C57bl mice through the tail vein. Post-contrast MR imaging were performed in day 5 with the same parameters (TR=2.5 sec, TE=0.012 sec, FOV=6.6 cm, slice thickness=2.0mm, flip angle (orient)=trans, and matrices=256x256). We selected the aorta at the level of kidney for comparison of the baseline and post-contrast images.
  71. 71. Apo E deficient mice MRI SPIO experiment
  72. 72. 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
  73. 73. Histopathologic study of the Mouse injected With SPIO (Thoracic Aorta) ApoE KO mouse, Movat staining, proximal aorta Coronary Cross section Atherosclerosis plaque
  74. 74. Histopathologic study of ApoE KO Mouse injected With SPIO (Thoracic Aorta) CD68 staining (aortic plaque) Iron Staining (aortic plaque) Iron Staining (coronary section) Iron particles Iron particles
  75. 75. Histopathologic study of ApoE KO Mouse injected With SPIO (Abdominal Aorta) H&E staining Iron Staining CD 68 staining Iron particles
  76. 76. Histopathologic study of wild type Mouse injected With SPIO (Thoracic Aorta) H&E staining CD68 stainingIron staining
  77. 77. 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
  78. 78. Rabbit Aorta, x10 magnification Iron Staining H&E Staining
  79. 79. Rabbit Aorta, x40 magnified Iron Staining H&E Staining
  80. 80. Histopathologic studies of Thoracic aorta in Watanabe Hereditary Hypercholesterolemic rabbit after SPIO injection H&E staining Iron staining Macrophage staining
  81. 81. Histopathologic studies of Thoracic aorta in Watanabe Hereditary Hypercholesterolemic rabbit after SPIO injection H&E staining Iron staining Iron staining Iron particles
  82. 82. 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.
  83. 83. MR Angiography 3D with Gadolinium-DTPA in Watanabe Rabbit Before SPIO injection After SPIO injection
  84. 84. Ex-vivo MR study of the thoracic aorta in Watanabe and Wild type rabbit after SPIO injection compared to control. 3D MR Angiography with Gadolinium-DTPA Watanabe rabbit post-SPIO Watanabe rabbit control NZW rabbit control NZW rabbit post-SPIO
  85. 85. 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
  86. 86. No cytokine injected Apo E SPIO Injected Iron Staining H&E Staining
  87. 87. No cytokines Apo E SPIO Injected Iron Staining H&E Staining
  88. 88. No cytokines SPIO Injected Apo E Only plaque with SPIO C3Ex40
  89. 89. No Cytokines SPIO Injected Apo E C3E SPIO Found in Circulating Monocytes Iron Staining H&E Staining
  90. 90. T2Fx10 TNFα/IL-1ß SPIO Injected Apo E Iron Staining H&E Staining
  91. 91. TNFα/IL-1ß SPIO Injected Apo E H&E StainingH&E Staining Increased Superficial Macrophage Density
  92. 92. TNFα/IL-1ß Iron Staining Iron Staining
  93. 93. TNFα/IL-1ß Iron Staining H&E Staining
  94. 94. TNFα/IL-1ß Iron Staining Macrophage Staining
  95. 95. TNFα/IL-1ß Iron Staining H&E Staining
  96. 96. TNFα/IL-1ß Iron Staining H&E Staining
  97. 97. TNFα/IL-1ß Iron Staining H&E Staining
  98. 98. New SPIO Development Towards Plaque Targeted SPIO Six mice were injected IP with mineral oil, and 24 hours later same amount of above SPIOs were injected IP, 24 hours later, macrophages were isolated from the mice, 24 hours later, the following pictures were taken .
  99. 99. New SPIO Development Towards Plaque Targeted SPIO Bare SPIO
  100. 100. New SPIO Development Towards Plaque Targeted SPIO Dextran Coated
  101. 101. New SPIO Development Towards Plaque Targeted SPIO Lipid Coated
  102. 102. New SPIO Development Towards Plaque Targeted SPIO Receptor Targeted SPIO
  103. 103. Imaging of inflammation in rabbit model of atherosclerosis using USPIO Ruehm et al. Circulation 2001
  104. 104. Gadolinium VS. SPIO 1- Non-Specific (improved by Gd-Lutetium still lipid targeted rather than inflammation) 2- White on white background 3- Only represent plaque angiogenesis 4- No over-magnification …
  105. 105. SPIO Clinical Trial: • The first human clinical trial on detection of carotid vulnerable plaque using SPIO in patients undergoing carotid endartherectomy Baseline Scan SPIO Injection 1hr post- injection 5days Scan Surgery days 5-7
  106. 106. 0.05 mg/kg
  107. 107. SPIO Score vs. Calcium Score The aim of the project is to develop a novel SPIO Score for quantitative monitoring of plaque inflammation based on negative enhancement.
  108. 108. SPIO Clinical Trial: • The first human clinical trial on detection of carotid vulnerable plaque using SPIO in patients undergoing carotid endartherectomy Baseline Scan SPIO Injection 1hr post- injection 5days Scan Surgery days 5-7
  109. 109. … the question is not only vulnerable plaque Stay Tuned!
  110. 110. HotPlaque.com 2000!
  111. 111. Texas Heart Institute University of Texas-Houston Center for Vulnerable Plaque Research Denton A. Cooley Building (floor 10th ) www.CVPR.org 2002
  112. 112. Association for Eradication of Heart Attack www.VP.org

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