HOSSEIN EFTEKHARI,MDVULNERABLE PLAQUEANIMAL MODELSPERCUTANEOUS CORONARY

INTERVENTION

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.

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.

VULNERABLE P’s

Vulnerable populationVulnerable patientVulnerable plaque

Vulnerable plaques, vulnerable myocardium, and Vulnerable plaques, vulnerable myocardium, and hypercoagulablehypercoagulablestate of the blood lead to state 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

What causes heart attack?

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

lipid-rich corethrombus

cap

cap

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.

Culprit Plaque; a retrospective terminology

Vulnerable Plaque; a prospective terminology

Vulnerable Plaque =Future Culprit Plaque

Clarification of Terminologies

Vulnerable Plaque

The short answer is:

What are vulnerable plaques?

Dangerous forms of atherosclerotic plaques

that can rupture or induce thrombosis and

lead to critical disruption of blood flow.

The short answer is:

Proposed Histopathological and Clinical Proposed Histopathological and Clinical Criteria for Definition of Vulnerable Criteria for Definition of Vulnerable

PlaquePlaque MajorMajorCriteria:Criteria:1.1. Active Inflammation (Active Inflammation (monocytemonocyte/ /

macrophage infiltration) macrophage infiltration) 2.2. Thin Cap with Large Lipid Core Thin Cap with Large Lipid Core 3.3. Endothelial Denudation with Superficial Endothelial Denudation with Superficial

Platelet Aggregation Platelet Aggregation 4.4. Fissured / Wounded Plaque Fissured / Wounded Plaque

Proposed Histopathological and Clinical Proposed Histopathological and Clinical Criteria for Definition of Vulnerable Criteria for Definition of Vulnerable

PlaquePlaque MinorMinorCriteria:Criteria:1.1. Superficial Calcified nodule Superficial Calcified nodule 2.2. Glistening Yellow Glistening Yellow 3.3. IntraplaqueIntraplaqueHemorrhage Hemorrhage 4.4. Critical StenosisCritical Stenosis5.5. Positive Remodeling? Positive Remodeling?

Plaque Rupture: Definition

Structural failure of the fibrocellular cap11 that separates an atheromatous core22 from the lumen of an atherosclerotic artery (ie, lumen core).1 1 cap defectcap defect//gapgap rupture, fissure, break, tear

not just missing not just missing endotheliumendothelium2 2 lipidlipid--richrich Greek athere, gruel (soft)

Propensity to rupture lipidlipid--richrich corecore + +++no coreno core no capno cap -

Plaque Rupture

Ruptured Plaques (~70%)1. Stenotic (~20%)2. Non-stenotic (~50%)

Non-ruptured Plaques (~ 30%)1. Erosion (~20%)2. Calc ified Nodule (~5%)3. Others / Unknown (~5%)

Plaque Pathology Responsible for Coronary Thrombotic Death

In summary:

Vulnerable Plaque and Vulnerable Patient, The Challenge of

Cardiovascular Medicine in 21st Century

An introductory tutorial from

VP.orgIn conjunction with

The Center for Vulnerable Plaque ResearchUniversity of Texas Houston and

Texas Heart Institute

Ideal method for screening Ideal method for screening vulnerable plaque/ patientvulnerable plaque/ patient

NonNon--invasiveinvasive InexpensiveInexpensive AccurateAccurate Widely Reproducible Widely Reproducible

Emerging Techniques for

Detection of Vulnerable Plaque

Emerging Diagnostic Techniques A. Invasive TechniquesAngioscopy

Intravascular Ultrasound (IVUS)Intravascular ThermographyIntravascular Optical Coherence Tomography (OCT)

Intravascular ElastographyIntravascular and Transesophageal MRIIntravascular Nuclear ImagingIntravascular Electrical Impedance Imaging

Intravascular Tissue DopplerIntravascular Shear Stress ImagingIntravascular (Photonic) Spectroscopy

- 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

Emerging Diagnostic TechniquesB. 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)

Emerging Diagnostic TechniquesC. 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

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.

ANIMAL MODELS FOR EXPERIMENTAL STUDIES

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.

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 procedureRecognition that behavior responses to experimental situations may determine result

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 process

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 diet and that of human

DISADVANTAGES OF CHICKEN

NonmammalsLesion site inconsistentComplication uncommonIntramyocardial coronary involvementChicken herpes virus can be the sources of variability

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

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

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 yesAneurysms observed yes yesPlaque rupture observed

nono yes

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 ?

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

RABBIT AS AN ANIMAL MODEL

Advantages:Lesion well characterizedLesion inducible with dietary cholesterol Reproduce rapidlyRelatively inexpensive

RABBIT AS AN ANIMAL MODEL

Disadvantages:Whole body cholesterol is different from humanLesions don’t duplicate many important features of humanLesions usually occur in aortic arch and thoracic aortaDistribution 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

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