First Meeting of UT-THI and Rice Coalition

A Nano-Mega Initiative!

Friday, June 07, 2002Denton A. Cooley Building

Texas Medical CenterHouston, Texas

How the World Dies Today?

Atherosclerotic Diseases Are Not Diseases of Affluence!

• Only 2.7 millions of 6.3 million of who died by IHD were in the developed country.

• Cerebrovascular disease (stroke) killed 4.4 million people, of whom only 1.4 million were in the developed world.

Leading cause of death in the United States since the beginning

of the 20th century?

Except for one year (1924)!

Fatal Heart Attack!

What causes heart attack?

Vulnerable Plaque

The short answer is:

What isvulnerable plaque?

Dangerous forms of fat buildup (atherosclerotic

plaques) in the arterial wall that can rupture or induce

thrombosis and lead to critical disruption of blood

flow.

The short answer is:

Vulnerable Plaque Ruptured Plaque

Everybody has atherosclerosis, the question is who has vulnerable plaque

Sudden Cardiac DeathAcute MI

VulnerablePlaque(s)

Vulnerable Plaque and Vulnerable Patient, The Challenge of

Cardiovascular Medicine in 21st Century

An introductory tutorial from

The Center for Vulnerable Plaque Research

University of Texas Houston and Texas Heart Institute

What Do We Know About Vulnerable Plaque?

Center for Vulnerable Plaque ResearchUniversity of Texas at Houston

Texas Heart InstituteOctober 2001

Morteza Naghavi, MDMohammad Madjid, MD Silvio Litovsky, MD Alireza Zarrabi, MDMaziar Azadpour, MD Parsa Mirhaji, MD Cornelius Nwora, MD

Ward Casscells, MD James Willerson, MD

Salute to Pioneers

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 his inflammatory theory. He utilized the name of "endarteritis deformans." By this he meant that the atheroma was a product of an inflammatory process within the intima with the fibrous thickening evolved as a consequence of a reactive fibrosis induced by proliferating connective tissue cells within the intima.

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

“The destruction of the hyalinized wall separating lumen from the atheroma was almost always observed to be preceded by or associated with its invasion by lipid containing macrophages.”

Friedman and van den Bovenkamp 1965

Unheralded Pioneers

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.

James T. Willerson 1981N Engl J Med 1981 Mar 19;304(12):685-91

Plaque Thrombosis

Erling Falk Michael Davies

Autopsy Series

Thin Fibrous Cap + Large Lipid Core + Dense Macrophage

A culprit ruptured plaque

1981-1990

Plaque Eruption (Volcano!)

Seymour GlagovCompensatory 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 disease not lumen.

Positive Remodeling<80%

stenosis

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

Falk E., Shak P.K., Fuster V. Circulation 1995

Non-stenotic (<75%) plaques cause about 80% of deadly MI

Macrophage- driven MMPs soften plaque cap and prompt it to rupture

P.K. Shah

Peter LibbyThe fate of

atherosclerosis and its thrombotic complication are governed by immune

system.

Goran Hanssonand others

Allard van der Wal

and others

•Eroded Plaque

Rupture-prone plaques are not the only type of vulnerable plaque

•Calcium Nodulevan der Wal - Netherlands

Renu Virmani -USA

Thiene - Italy

Kolodgie F., Burk A.P., Farb A., and Virmani R.

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!

“Who is Who” on

www.VP.org

The field of vulnerable plaque is best owed to many known and unknown

scientists who have worked hard to shed light on our way to prevent and

eradicate heart attacks in the future. To see a more complete list please visit:

Natural History ofVulnerable Plaques

Illustrated:

~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

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:

Rupture-Prone Plaque

Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001

Macrophage

Necrotic lipid core

Thin fibrous cap

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

Intra-Plaque Hemorrhage with Intact Cap

Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001

Leaking angiogenesis or rupture of

vasa vaserum

Different Types of Vulnerable Plaques Major Underlying Cause of

Acute Coronary Events

NormalRupture-prone

Fissured ErodedCritical Stenosis Hemorrhage

Naghavi et al, Cur Ath Rep 2001

Emerging Techniques for Detection of

Vulnerable Plaque

Emerging Diagnostic Techniques A. Invasive Techniques

AngioscopyIntravascular Ultrasound (IVUS)Intravascular Thermography

Intravascular Optical Coherence Tomography (OCT)Intravascular Elastography

Intravascular and Transesophageal MRIIntravascular Nuclear Imaging

Intravascular Electrical Impedance ImagingIntravascular 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

Angioscopy

Advantages:Intuitive (anatomic) Simple (easy to understand)

Disadvantages:Visualizes only the surface of the plaqueRequires a proximal occluding balloonThe spatial resolution is limited

Glistening yellow plaque

Uchida et al, Japan

Intravascular Ultrasound (IVUS):

Advantage:Reveals the morphology of the plaqueDiffers between soft (hypo-echoic) and Hard (hyper-echoic) plaques

Disadvantages:Doesn’t give information about plaque inflammationLow spatial resolution (~ 200 m)

Nissen, Yock, and Fitzgerald

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

Intravascular Thermography

Advantages:Simplicity in theory; hot plaque Gives information about plaque inflammation

Disadvantages:Plaque temperature is affected by blood flow

Volcano Therapeutics Inc.

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.

Photonic Spectroscopy

Advantage: Chemical compounds

Disadvantage:Based on statistical analysis and calibration is always an issueS/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

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

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

Magnetic Resonance ImagingPlaque Characterization and Angiography

Advantages:Lack of ionizing radiation Non-invasive Provides enormous information about flow as well as plaqueEnhancement by contrast agents and NMR spectroscopy

Disadvantages:Ineligibility of patients with metal prosthesesHigh costLonger time for adoption by cardiologists

Human Carotid Plaque

CCA

Carotid bifurcation

ICA stenosis & plaque

Courtesy of

Dr. Chun Yuan University of Washington Seattle

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 vulnerable plaque with large lipid pool and thin fibrous caps.   

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

Intravascular MRI

Advantages:Lack of ionizing radiation High resolution Potential for NMR spectroscopy

Disadvantages:Invasive and slower than fluoroscopyNeeds open/short bore high field magnetLonger time for adoption by cardiologists

Surgi-Vision Inc.Ergin Atalar

IVUS

Coronary Calcium ImagingEBT 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 eventMay not be suitable for monitoring treatment

Calcium Score

Imatron Inc.Rumberger, Aard, Raggi, and others

Race for Non-Invasive Coronary Angiography

• Multi-Slice Fast Computed Tomography (MSCT)

• Magnetic Resonance Angiography (MRA)

Plaque Morphology vs.

Plaque Activity

Why do we need both?

Morphology vs. Activity Imaging

Inactive and non-inflamed plaque

Active and inflamed

plaque Appear Similar in

IVUS OCT MRI w/o CM

Morphology

Show Different

Activity

Thermography, Spectroscopy, immunoscientigraphy, MRI with

targeted contrast media…

2001 2050

Genomic

Proteomic

2010 2020 2030 2040

VP Treatment

Home-based VP Screening Test

Heart Attack

Eradicated

Annual Death of MI

<10,000

Cloning Heart

VP Rx as OTC or Vaccine?

Eradication of Heart Attack

VP Detection

Mission:

Center for Vulnerable Plaque Research Ongoing Projects

Non-invasive Invasive

Diagnostic • MRI SPIO• CT Detection of Inflammation• NanoScan

• MR Guide Wire & Catheter• Intravascular Magnetometer

Therapy • Coronary Dialysis

• Vaccine

Association for Eradication of Heart Attack

www.VP.org