This document discusses animal models for studying vulnerable plaque and atherosclerosis. It describes how the chicken, pig, mouse, and rabbit models each have advantages and disadvantages for replicating different aspects of human disease. The mouse has been genetically modified to better model plaque development. No single animal model fully captures the human condition, but they provide insights into disease mechanisms. The document also notes that no current animal model replicates the plaque rupture seen in human heart attacks.

1. HOSSEIN EFTEKHARI,MD
 VULNERABLE PLAQUE
 ANIMAL MODELS
 PERCUTANEOUS CORONARY
INTERVENTION

2. AT THE BEGINNING OF
20thCENTRY,CVD ACCOUNTED FOR
LESS THAN 10 PERCENT OF ALL
DEATHS WORLD WIDE.AT IT’S
END,CVD ACCOUNTED FOR NEARLY
HALF OF ALL DEATH IN DEVELOPED
COUNTRIES.BY 2020,CVD WILL CLAIM
25 MILLION DEATHS ANNUALLY AND
WILL SURPASS INFECTIOUS DISEASE
AS THE WORLD’S NUMBER ONE
CAUSE OF DEATH AND DISABILITES.

3. THREE COMPLEMENTARY
STRATEGIES TO REDUCE
MORBIDITY AND MORTALITY
FROM CVD:
 Lowering overall burden of CVD risk factors in
the entire population through population-wide
public health measures (national campaign).
 Identifying and targeting high-risk subgroup of
population who may benefit from preventive
intervention.
 Resources can be allocated to acute and
chronic treatment and secondary prevention.

4. VULNERABLE P’s
 Vulnerable population
 Vulnerable patient
 Vulnerable plaque

5. Vulnerable plaques, vulnerable myocardium, andVulnerable plaques, vulnerable myocardium, and
hypercoagulablehypercoagulable state of the blood lead tostate of the blood lead to
sudden cardiac death and acute myocardial infarction.sudden cardiac death and acute myocardial infarction.
Vulnerable
Blood
Vulnerable
Myocardium
Vulnerable
Plaque
Vulnerable
Patient

7. What causes heart attack?

8. Mostly it is secondary to acute
thrombosis over an underlying
vulnerable plaque.

9. lipid-rich core
thrombus
cap
cap

10. The vast majority of plaque of
disruptions are self-contained
and clinically silent.So plaque
disruption leading to ACS is not a
rule but an exception in a
-symptomatic patients with non-
obstructing atherosclerosis but
contributes to plaque progression
and luminal narrowing.

11.  Culprit Plaque; a retrospective terminology
 Vulnerable Plaque; a prospective terminology
VulnerablePlaque= FutureC ulprit Plaque
Clarification of Terminologies

12. Vulnerable
Plaque
The short answer is:

13. What are
vulnerableplaques?

14. Dangerous forms of
atherosclerotic plaques
that can rupture or
induce thrombosis and
lead to critical disruption
of blood flow.
The short answer is:

15. Proposed Histopathological and ClinicalProposed Histopathological and Clinical
Criteria for Definition of VulnerableCriteria for Definition of Vulnerable
PlaquePlaque
•• MajorMajor Criteria:Criteria:
1.1. Active Inflammation (Active Inflammation (monocytemonocyte//
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

16. Proposed Histopathological and ClinicalProposed Histopathological and Clinical
Criteria for Definition of VulnerableCriteria for Definition of Vulnerable
PlaquePlaque
•• MinorMinor Criteria:Criteria:
1.1. Superficial Calcified noduleSuperficial Calcified nodule
2.2. Glistening YellowGlistening Yellow
3.3. IntraplaqueIntraplaque HemorrhageHemorrhage
4.4. Critical StenosisCritical Stenosis
5.5. Positive Remodeling?Positive Remodeling?

17. Plaque Rupture: Definition
Structural failure of the fibrocellular cap11 that
separates an atheromatous core22 from the lumen
of an atherosclerotic artery (ie, lumen ↔ core).
11
cap defectcap defect//gapgap rupture, fissure, break, tear
not just missingnot just missing endotheliumendothelium
22
lipidlipid--richrich Greek athere, gruel (soft)
Propensity to rupture
 lipidlipid--richrich corecore + → +++
no coreno core →→ no capno cap -

18. Plaque Rupture

19. Ruptured Plaques (~70%)
1. Stenotic (~20%)
2. Non-stenotic (~50%)
Non-ruptured Plaques (~ 30%)
1. Erosion (~20%)
2. Calcified Nodule (~5%)
3. Others / Unknown (~5%)
Plaque Pathology Responsible for Coronary Thrombotic Death
In summary:

20. Vulnerable Plaque and Vulnerable
Patient, The Challenge of
Cardiovascular Medicine in 21st
Century
An introductory tutorial from
VP.org
In conjunction with
The Center for Vulnerable Plaque Research
University of Texas Houston and
Texas Heart Institute

21. Ideal method for screeningIdeal method for screening
vulnerable plaque/patientvulnerable plaque/patient
 NonNon--invasiveinvasive
 InexpensiveInexpensive
 AccurateAccurate
 Widely ReproducibleWidely Reproducible

22. Emerging
Techniques for
Detection of
Vulnerable Plaque

23. Emerging Diagnostic Techniques
A. Invasive Techniques
Angioscopy
Intravascular Ultrasound (IVUS)
Intravascular T hermography
Intravascular Optical CoherenceT omography (OC T )
Intravascular E lastography
Intravascular and T ransesophageal MRI
Intravascular Nuclear Imaging
Intravascular E lectrical ImpedanceImaging
Intravascular T issueDoppler
Intravascular Shear Stress Imaging
Intravascular (Photonic)Spectroscopy

24. - 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

25. 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)

26. 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

27. CONCLUSION
It is well established that
composition and size of lipid
core,composition and thickness of
fibrous cap, inflammatory
process,and the quantity of SMC’s
within a plaque are predictors of
plaque rupture.

28. ANIMAL MODELS FOR
EXPERIMENTAL STUDIES

29. THE IMPORTANCE OF
ANIMAL MODEL
Animal models are important to
research directed toward better
understanding of human
atherosclerosis.For this reason
much effort has been expended
to identify and characterize
species suitable as animal model.

30. Criteria needed for choosing
animal model
Susceptibility under standard system
of husbandry
Ready availability at reasonable cost
Ready trainability and size adequate
for all project lab procedure
Recognition that behavior responses
to experimental situations may
determine result

31. The ideal animal model of
human atherosclrosis:
*Should be easy to acquire and
maintain at reasonable cost
*Easy to handle
*Proper in size
*Should be reproducible in lab
*Should have well-defined genetic
characteristics
*Should share with human the
most important aspect of disease

32. THE CHICKEN AS A MODEL
*The chicken is good animal model for
atherosclerosis study because it is:
 Omnivorous
 Small and suitable for prolonged lab
investigation
 Able to develop spontaneous atherosclerosis
 Capable of producing atherosclerosis after
cholesterol feeding
 Plasma level of cholesterol and triglyceride
are similar to those in human
 Lipid composition of LDL , HDL and
chylomicron resemble those in human
 There is no essential difference between
vascular lesion in chicken on high cholesterol

33. DISADVANTAGES OF CHICKEN
Nonmammals
Lesion site inconsistent
Complication uncommon
Intramyocardial coronary
involvement
Chicken herpes virus can be the
sources of variability

34. THE PIG AS A MODEL
* Some similarities between man and pig in
atherosclerosis:
 Atherosclerosis in man and pigs develops most
frequently in aorta,coronary and intracranial arteries
 The age at which lesion originate and the rate of
progression in any lesion is independent of other
 The origin and distribution of coronary artery in man
and pig corresponds closely
 The histological change of growth and aging that
leads to atherosclerosis of aorta and coronary
artery are closely similar
 According to the mean age of death and its relation
to morphological character and size of lesion,the
sequel of atherosclerosis in man and pig also
correspond closely

35. MOUSE AS A MODEL
*As a species the mouse is highly resistant
to atherosclerosis.But through induced
mutation lines of mice have been
developed to be susceptible to
atherosclerosis,such as:
 Mice that are deficient in apoE
 Mice that are deficient in LDL receptor
 Transgenic mice that express human apoE
 Transgenic mice with transdominant mutant
form of apoE

36. pathology Comparison of atherosclerosispathology Comparison of atherosclerosis
ApoE-deficient
mouse
Human
Fatty streak with
MAC and Tcells
yes yes
Fibrous plaque with
SMC
yes yes
Lesion calcification yes yes
Oxidized apitopes
present
yes yes
Lesions at branches
and sites with
disturbed flow
yes yes
Diet responsiveness yes yes
Aneurysms observed yes yes
Plaque rupture no yes

37. NO PLAQUE RUPTURE IN
ANIMAL MODEL
Atherosclerosis plaque rupture is the
main cause of coronary thrombosis
and MI but currently,there is no animal
model of plaque disruption ?

38. THE POTENTIAL CAUSE OF LACK
OF PLAQUE RUPTURE IN MICE
May be due to small diameter of
mice aorta (<1mm) which
increase surface tension
preventing plaque rupture

39. RABBIT AS AN ANIMAL MODEL
Advantages:
Lesion well characterized
Lesion inducible with dietary
cholesterol
Reproduce rapidly
Relatively inexpensive

40. RABBIT AS AN ANIMAL MODEL
Disadvantages:
Whole body cholesterol is different from human
Lesions don’t duplicate many important features
of human
Lesions usually occur in aortic arch and thoracic
aorta
Distribution of coronary artery lesion is different
from human(proximal portions aren't involved)
Only proximal portion of carotid artery usually
involved and cerebral vessels spare

41. AN EXPERIMENTAL MODEL OF
PLAQUE RUPTURE
 In rabbit model embedding inflatable
balloon in to the atherosclerotic plaque
and measuring the pressure needed to
inflate the plaque-covered balloon may
be an index of plaque mechanical
strength