8. What Do We Know About
Vulnerable Plaque?
Morteza Naghavi, MD
Center for Vulnerable Plaque Research
University of Texas at Houston
Texas Heart Institute
October 2001
Mohammad Madjid, MD Silvio Litovsky, MD Alireza Zarrabi, MD
MaziarAzadpour, MD Parsa Mirhaji, MD Cornelius Nwora, MD
Ward Casscells, MD JamesWillerson, MD
10. 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
11. 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.
12. 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
13. 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.
14. James T. Willerson 1981
N Engl J Med 1981 Mar 19;304(12):685-91
Plaque Thrombosis
15. Erling Falk Michael Davies
Autopsy Series
Thin Fibrous Cap + Large Lipid Core + Dense Macrophage
A culprit ruptured plaque
1981-1990
16.
17. 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 IEL is
destructed and occupied by plaque
Coronary artery disease is a disease of arterial wall
disease not lumen.
18. 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
Angiographically Invisible Plaques
19. Falk E., Shak P.K., Fuster V. Circulation 1995
Non-stenotic (<75%) plaques cause about 80% of deadly MI
20. Macrophage-
driven MMPs
soften plaquecap
and prompt it to
rupture
P.K. Shah
Peter Libby
Atherosclerosis and its
thrombotic complication is
governed by immunecells.
Goran Hansson
…
Allard van derWal
21. 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
James E. Muller 1994
Muller coined the term of “Vulnerable” Plaque
Muller likened Vulnerable Plaques to American nuclear missiles stored underground in
Nevada desert where they could be vulnerable to Russians’ long-range missile attack!
22. •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.
23. “Who is Who”
on
www.VP.org
Thefield of vulnerableplaqueisbest owed to
many known and unknown scientistswho have
worked hard to shed light on our way to prevent
and eradicateheart attacksin thefuture.
To seeamorecompletelist pleasevisit:
25. ~65%
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
~70% <5% ~20%
~55% ~20%
<5%
<5% ~20%
Rupture Prone Eroded Calcified NoduleHemorrhage
Positive Remodeling
Fissured /Healed
Natural History
of Vulnerable
Atherosclerotic
Plaques
26. 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:
27. Culprit Plaque; a retrospective terminology
Vulnerable Plaque; a prospective terminology
Vulnerable Plaque = Future Culprit Plaque
Clarification of Terminologies
33. Critically Stenotic but Asymptomatic Plaque
Naghavi et al, Cur Ath Rep 2001Vulnerable Plaque
34. 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
37. - 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
38. 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)
39. Emerging Diagnostic Techniques
C. Blood Tests / Serum Markers
- CRP
- ICAM-1, VCAM, p-Selectin
- 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
40. 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
41. 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
43. 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 possibly 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.
44. 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
45. 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
46. 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
47. 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
48. 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
51. 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.
52. 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
53. 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
54. 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.John Rumberger, Paolo Raggi, and others
55. Race for Non-Invasive Coronary
Angiography
• Multi-Slice Fast Computed
Tomography (MSCT)
• Magnetic Resonance
Angiography
(MRA)
• Electron Beam Tomography
(EBT)
57. 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
58. High Level of Sensitivity and Specificity
Needed
• Knowing the extensive prevalence of
atherosclerosis, in order to accurately
detect vulnerable plaques, it is
imperative to obtain information about
both structure and activity of plaque
assuring minimum false positive and
negative results.
NO MORE TREADMILL TEST!
61. The Question seems to be
MORE THAN ONE:
2.Who hasvulnerableblood?
3.Who hasvulnerableheart?
4.Who isvulnerablepatient?
1.Who hasvulnerableplaque?√
62. Who Has Vulnerable Blood?
• In which patient the blood tends to create
an occlusive thrombus on a vulnerable
plaque, thereby resulting in an acute
clinical syndrome?
• In other words:
Who has hyper-coagulable or “vulnerable blood”?
63. Who Has Vulnerable Heart?
• Whose heart is more sensitive to an acute
ischemic episode due to sub-occlusive or
occlusive thrombi, thereby resulting in
fatal arrhythmia and sudden out-of-
hospital cardiac arrest?
• In other words:
Who has “vulnerable heart”?
73. In vivo intravascular study showing a significantly higher
temperature as well as temperature heterogeneity in
femoral artery of 5 Labrador atherosclerotic dogs
76. Stefanadis et al, 1999
First in vivo human intra-coronary
thermometry study
77.
78.
79.
80.
81. of Atherosclerotic Plaques and its Correlation with
•Morteza Naghavi MD,
•Reji John MD, Said Siadaty MD,
•Sameh Naguib MD, Roxana Grasu MD,
•KC Kurian MD, Mohammad Madjid MD,
•James T. Willerson MD, Ward
Casscells MD,
The University of Texas-HoustonTexas Heart
pH HeterogeneitypH Heterogeneity
Temperature HeterogeneityTemperature Heterogeneity
88. Correlation of pH and Temperature in Human Carotid Plaques Varied by
the Areas
We see a marked inverse correlation between temperature
and pH of plaques that varies by macroscopic characteristics
of plaques.
p < 0.01
97. SPIO Accumulation in
Atherosclerotic Plaque
Atherosclerotic plaqueNormal aortic segment
Iron staining of Apo E K/O Aorta, 24 hour after SPIO injection
Iron
particles
100. 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
101. Association of Influenza
Vaccination and Reduced Risk of
Recurrent Myocardial Infarction
Morteza Naghavi, MD., Zeba Barlas, MD.,
Said Siadaty, MD., Sameh Naquib, MD.,
Mohammad Madjid, MD., Silvio Litovsky,
MD, S. Ward Casscells, MD.
