SHAPE Society

1. The Holy Grail of Cardiology
Vulnerable PlaquesVulnerable Plaques

2. From Vulnerable Plaques toFrom Vulnerable Plaques to
Vulnerable PatientsVulnerable Patients
The 1The 1stst
Guideline ofGuideline of Association forAssociation for
Eradication of Heart Attack (AEHA)Eradication of Heart Attack (AEHA)
for Definition of Vulnerable Plaque andfor Definition of Vulnerable Plaque and
Vulnerable PatientVulnerable Patient
(VP.org)(VP.org)
Morteza Naghavi, Erling Falk, Mohammad Madjid,
Silvio Litovsky, Ward Casscells, Renu Virmani,
James T. Willerson

3. Underlying Cause of All (fatal and non-fatal) Heart Attacks
(Sudden Cardiac Death + Acute Coronary Syndrome)
With Occlusive Thrombi
With Rupture
>70% Stenosis
With Significant Atherosclerotic or
Ischemic Heart
<70% Stenosis
Without Significant Atherosclerosis or
Atherosclerosis-Derived Myocardial Damage
Without Occlusive Thrombi
Without Rupture With
Old Myocardial Damage
Without
Old Myocardial Damage
Only Myocardial-Derived Factors
(primary conductive disorders, …)
Erosion Calcified Nodule Others
With Critical Stenosis Without Critical Stenosis
With Expansive
Remodeling
Without Expansive
Remodeling
~1.5 millions in the US

4. Blood Myocardium
Plaque
Victim /
Patient

5. Underlying pathologies ofUnderlying pathologies of
“culprit” coronary lesions“culprit” coronary lesions
1.1. Ruptured Plaques (~70%)Ruptured Plaques (~70%)
 Stenotic (~20%)Stenotic (~20%)
 Non-stenotic (~50%)Non-stenotic (~50%)
2.2. Non-Ruptured Plaques (~ 30%)Non-Ruptured Plaques (~ 30%)
 ErosionErosion
 Calcified NoduleCalcified Nodule
 Others / UnknownOthers / Unknown
MJ Davies, Circ. 1990; Falk et al. Circ. 1995; Virmani et al. ATVB 2000

6. Terminology:Terminology:
Culprit Plaque:Culprit Plaque:
aa RetrospectiveRetrospective TerminologyTerminology
Vulnerable PlaqueVulnerable Plaque::
aa ProspectiveProspective TerminologyTerminology

7. Vulnerable Plaque:Vulnerable Plaque:
Plaques with highPlaques with high
likelihood oflikelihood of
thrombosis or rapidthrombosis or rapid
progressprogress

8. Interchangeable TerminologiesInterchangeable Terminologies
YESYES NONO
Vulnerable Plaque =Vulnerable Plaque = Vulnerable Plaque=Vulnerable Plaque=
High-Risk PlaqueHigh-Risk Plaque Soft-PlaqueSoft-Plaque
Dangerous PlaqueDangerous Plaque Non-Calcified PlaqueNon-Calcified Plaque
AHA Type IV PlaqueAHA Type IV Plaque
Non-Stenotic PlaqueNon-Stenotic Plaque

9. Vulnerable
Blood
Vulnerable
Myocardium
Vulnerable
Plaque
Vulnerable
Patient

10. Proposed Histopathological andProposed Histopathological and
Clinical Criteria for Definition ofClinical Criteria for Definition of
Vulnerable PlaqueVulnerable Plaque
•• MajorMajor Criteria:Criteria:
1.1. Active Inflammation (monocyte/Active Inflammation (monocyte/
macrophage infiltration)macrophage infiltration)
2.2. Thin Cap with Large Lipid CoreThin Cap with Large Lipid Core
3.3. Endothelial Denudation with SuperficialEndothelial Denudation with Superficial
Platelet AggregationPlatelet Aggregation
4.4. Fissured / Wounded PlaqueFissured / Wounded Plaque

11. Proposed Histopathological andProposed Histopathological and
Clinical Criteria for Definition ofClinical Criteria for Definition of
Vulnerable PlaqueVulnerable Plaque
•• MinorMinor Criteria:Criteria:
1.1. Superficial Calcified noduleSuperficial Calcified nodule
2.2. Glistening YellowGlistening Yellow
3.3. Intraplaque HemorrhageIntraplaque Hemorrhage
4.4. Critical StenosisCritical Stenosis
5.5. Positive Remodeling?Positive Remodeling?

12. Ideal method forIdeal method for
screening vulnerablescreening vulnerable
plaque/patientplaque/patient
 Non-invasiveNon-invasive
 InexpensiveInexpensive
 AccurateAccurate
 Widely ReproducibleWidely Reproducible

13. Proposed Histopathological andProposed Histopathological and
Clinical Criteria for Definition ofClinical Criteria for Definition of
Vulnerable PlaqueVulnerable Plaque
•• MajorMajor Criteria:Criteria:
1.1. Active Inflammation (monocyte/Active Inflammation (monocyte/
macrophage infiltration)macrophage infiltration)
2.2. Thin Cap with Large Lipid CoreThin Cap with Large Lipid Core
3.3. Endothelial Denudation with SuperficialEndothelial Denudation with Superficial
Platelet AggregationPlatelet Aggregation
4.4. Fissured / Wounded PlaqueFissured / Wounded Plaque

14. Thermography: a NovelThermography: a Novel
Approach for Identification ofApproach for Identification of
Vulnerable PlaquesVulnerable Plaques
Mohammad Madjid, MD,Mohammad Madjid, MD,
Ward Casscells, MD,Ward Casscells, MD,
James T. Willerson, MD,James T. Willerson, MD,
Morteza Naghavi, MDMorteza Naghavi, MD

15. Cardinal Signs of InflammationCardinal Signs of Inflammation
PainPain
RednessRedness
HEATHEAT
SwellingSwelling
InflammationInflammation

16. HypothesisHypothesis
Vascular inflammation and plaqueVascular inflammation and plaque
vulnerability can be identified byvulnerability can be identified by
the heat released from activatedthe heat released from activated
macrophages in the plaque.macrophages in the plaque.

17. Temperature heterogeneity over the surfaceTemperature heterogeneity over the surface
of an endartherectomized carotid plaqueof an endartherectomized carotid plaque
Casscells W et al. Lancet. 1996;347:1447-51

18. While macrophage/monocytes (with high metabolic rate) density wasWhile macrophage/monocytes (with high metabolic rate) density was
related to higher temperature, such a relation wasn’t seen with smoothrelated to higher temperature, such a relation wasn’t seen with smooth
muscle cell density (with less metabolic activity)muscle cell density (with less metabolic activity)

19. Inverse relation between temperatureInverse relation between temperature
difference and cap thicknessdifference and cap thickness

20. Infrared experiments showInfrared experiments show
temperature heterogeneitytemperature heterogeneity
Our dog model of atherosclerosis develops
marked lesions in its coronary arteries (left panel).
We observed significant temperature
heterogeneity along the coronary arteries of these
dogs using an infrared camera (right panel).
An infrared camera image shows
marked temperature
heterogeneity over the surface of
an atherosclerotic carotid plaque

21. Inverse correlation of pH and temperature (ºC) inInverse correlation of pH and temperature (ºC) in
endartherectomized human carotid artery plaquesendartherectomized human carotid artery plaques
Naghavi et al. Atherosclerosis, 2002, in press

22. In vivo StudiesIn vivo Studies

23. Thermosensor Basket CatheterThermosensor Basket Catheter

25. Dog Model of AtherosclerosisDog Model of Atherosclerosis
Femoral Artery
Atherosclerotic
With Temperature Heterogeneity
Carotid Artery
Non-Atherosclerotic
Without Temperature Heterogeneity

26. Higher absolute temperature as well as temperature heterogeneity in femoral
arteries of atherosclerotic dogs compared to their carotid arteries which are
free of disease.
P<0.05

27. Temperature heterogeneity inTemperature heterogeneity in
atherosclerotic lesions of Watabae rabbitsatherosclerotic lesions of Watabae rabbits
Temperature heterogeneity
In aortae of atherosclerotic mice
No temperature heterogeneity
In aortae of normal mice

28. Infrared angio-thermographyInfrared angio-thermography
cathetercatheter

29. Human StudiesHuman Studies
Our findings have been confirmedOur findings have been confirmed
in clinical settings by the Hellenicin clinical settings by the Hellenic
group of Stefandis andgroup of Stefandis and
colleagues, and also in Belgiumcolleagues, and also in Belgium
and the Netherlands.and the Netherlands.

30. In vivoIn vivo thermal heterogeneity within humanthermal heterogeneity within human
atherosclerotic coronary arteriesatherosclerotic coronary arteries
Stefanadis et al. Circulation. 1999;99:1965-71

31. The risk of an adverse cardiac event in patients with highThe risk of an adverse cardiac event in patients with high
temperature difference is significantly higher than that intemperature difference is significantly higher than that in
ACS patients with low temperature differenceACS patients with low temperature difference
Stefanadis et al. J Am Coll Cardiol. 2001;37:1277-83Stefanadis et al. J Am Coll Cardiol. 2001;37:1277-83

32. Stefanadis et al. J Mol Cell Cardiol. 2000;32:43-52
Strong correlation between C-reactive protein (CRP) (and serum
amyloid A (SAA) ) and the temperature differences

33. Administration of atorvastatin in patients with coronary arteryAdministration of atorvastatin in patients with coronary artery
disease results in less heat production from the culprit lesion anddisease results in less heat production from the culprit lesion and
less temperature difference.less temperature difference.
Stefanadis et al. Eur Heart J (in press)
StatinsNo statin
Temperaturedifference
2.5
2.0
1.5
1.0
.5
0.0
-.5
P<0,001

34.  Toutozas et al reported correlation betweenToutozas et al reported correlation between
temperature and expansive remodeling andtemperature and expansive remodeling and
MMP-9 concentrationMMP-9 concentration
 Verheye et al showed significant temperatureVerheye et al showed significant temperature
heterogeneity in cholesterol fed rabbits whichheterogeneity in cholesterol fed rabbits which
was reduced after changing from high to low-was reduced after changing from high to low-
cholesterol diet in rabbits.cholesterol diet in rabbits.
Toutouzas et al. Circulation. 2000;102:II-707;
Toutouzas et al. J Am Coll Cardiol. 2001;37:356A
Verheye et al. Circulation Supple Oct. 2001;

35. Disclosure:Disclosure:
Volcano Therapeutics, Inc.Volcano Therapeutics, Inc.

36. ThermaStar® Catheter
Not cleared by
the FDA and not
available for
commercial sale.

37. Center for Vulnerable Plaque ResearchCenter for Vulnerable Plaque Research
Houston, TexasHouston, Texas
Khawar Gul, MDKhawar Gul, MD
Said Siadaty, MDSaid Siadaty, MD
Sameh Naguib, MDSameh Naguib, MD
Bujin Gu, PhDBujin Gu, PhD
Reji John, MDReji John, MD
Basit Malik, MDBasit Malik, MD
KC Courian, MDKC Courian, MD
Roxana Grausu, MDRoxana Grausu, MD
Mohammad Madjid, MD, Ward Casscells, MD, James T. Willerson, MD, Morteza Naghavi, MDMohammad Madjid, MD, Ward Casscells, MD, James T. Willerson, MD, Morteza Naghavi, MD