#1 killer of human beings in the 21st century

#1 killer of human

beings in the 21st century?

Fatal Heart Attack!

What causes heart attack?

Vulnerable Plaque

The short answer is:

What is vulnerable plaque?

Dangerous forms of atherosclerotic plaques

that can rupture or induce thrombosis and

lead to critical disruption of blood flow.

The short answer is:

Everybody has atherosclerosis, the question is who has vulnerable plaque

Sudden Cardiac DeathAcute MI

What Do We Know About Vulnerable Plaque?

Morteza Naghavi, MD

Center for Vulnerable Plaque ResearchUniversity of Texas at Houston

Texas Heart InstituteOctober 2001

Mohammad 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

Carl von Rokitansky (1804-1878)

Rokitansky gave early detailed descriptions of arterial disease. He

is alleged to have performed 30,000

autopsies.

Rokitansky in 1841 championed the Thrombogenic Theory. He proposed that the deposits observed in the inner layer of the arterial wall

derived primarily from fibrin and other blood elements rather than being the result of a purulent process. Subsequently, the atheroma resulted from the

degeneration of the fibrin and other blood proteins as a result of a preexisting crasis of the blood, and finally these deposits were modified toward a pulpy

mass containing cholesterol crystals and fatty globules. This theory came under attack by Virchow

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

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 IEL is destructed and occupied by plaque

Coronary artery disease is a disease of arterial wall disease not lumen.

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 LibbyAtherosclerosis and its thrombotic complication is governed by immune

cells.

Goran Hansson…

Allard van der Wal

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!

•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.

“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:

~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

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:

Culprit Plaque; a retrospective terminology 

Vulnerable Plaque; a prospective terminology

Vulnerable Plaque = Future Culprit Plaque

Clarification of Terminologies

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

Fissured / Healed Plaque

Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001

Plaque with a Subluminal Calcified Nodule

Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001

Intra-Plaque Hemorrhage with Intact Cap

Vulnerable Plaque Naghavi et al, Cur Ath Rep 2001

Critically Stenotic but Asymptomatic Plaque

Naghavi et al, Cur Ath Rep 2001Vulnerable Plaque

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

AngioscopyIntravascular Ultrasound (IVUS)Intravascular ThermographyIntravascular Optical Coherence Tomography (OCT)Intravascular ElastographyIntravascular and Transesophageal MRIIntravascular Nuclear ImagingIntravascular Electrical Impedance ImagingIntravascular Tissue DopplerIntravascular Shear Stress ImagingIntravascular (Photonic) Spectroscopy

A. Invasive Techniques

- 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

- 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

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 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.

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

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.John Rumberger, Paolo Raggi, and others

Race for Non-Invasive Coronary Angiography

• Multi-Slice Fast Computed Tomography (MSCT)

• Magnetic Resonance Angiography (MRA)

• Electron Beam Tomography (EBT)

Plaque Morphology vs.

Plaque Activity

Why do we need both?

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

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!

Potential Intravascular Solutions:

• IVUS + Thermography• OCT + Thermography• OCT + NIR Spectroscopy• IVUS + Raman Spectroscopy• …

… the question is who has vulnerable plaque

The Question seems to be MORE THAN ONE:

2.Who has vulnerable blood?

3. Who has vulnerable heart?

4. Who is vulnerable patient?

1.Who has vulnerable plaque?√

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”?

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”?

Who is Vulnerable Patient?

Whoever has more vulnerable plaque, vulnerable blood, and vulnerable heart.

The Beat Goes On…

r = -0.63

p = 0.0001

Basket CatheterBasket Catheter

Wires with built-in Thermocouples

0.0014” Flexible Guide wire

Flexible guide wire

Collapsed basket

Shaft

A penny!

0.014” Diameter

In vivo intravascular study showing a significantly higher temperature as well as temperature heterogeneity in femoral artery of 5 Labrador atherosclerotic dogs

Marked temperature variations

Relatively quite homogenous

Stefanadis et al, 1999First in vivo human intra-coronary thermometry study

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-Houston Texas Heart Institute

pH HeterogeneitypH Heterogeneity

Temperature HeterogeneityTemperature Heterogeneity

pH

9.008.88

8.758.63

8.508.38

8.258.13

8.007.88

7.757.63

7.507.38

7.257.13

7.006.88

6.756.63

No

of p

oint

s w

ith th

e sa

me

ph

140

120

100

80

60

40

20

0

pH Distribution in 48 Human Carotid Plaques

This histogram demonstrates distribution of pH measured in 858 points in 48 carotid plaques of 48 patients. A marked

variation ranging from 6.5 to 8.9 is seen.

2220231717191026252428N =

11 human umbilical artery

pH

9.59.39.18.98.78.58.38.17.97.77.57.37.16.96.76.56.36.15.95.75.5

pH Heterogeneity in 11 Human Umbilical Arteries

pH

9.008.88

8.758.63

8.508.38

8.258.13

8.007.88

7.757.63

7.507.38

7.257.13

7.006.88

6.756.63

No

of p

oint

s w

ith th

e sa

me

ph

140

120

100

80

60

40

20

0

pH Distribution in 48 Human Carotid Plaques

This histogram demonstrates distribution of pH measured in 858 points in 48 carotid plaques of 48 patients. A marked

variation ranging from 6.5 to 8.9 is seen.

Watanabe Rabbit Aorta

pH

9.5

9.0

8.5

8.0

7.5

7.0

6.5

6.0

5.5

pH Heterogeneity in 9 Watanabe Rabbit Aortas

2220231717191026252428N =

11 human umbilical artery

pH

9.59.39.18.98.78.58.38.17.97.77.57.37.16.96.76.56.36.15.95.75.5

pH Heterogeneity in 11 Human Umbilical Arteries

calcified&thrombosedLipid Rich

pH

9.0

8.5

8.0

7.5

7.0

6.5

pH in Lipid Rich Yellow Areas vs. Calcified areas

Areas with large lipid core exhibit higher temperature and lower pH

p < 0.01

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

Fluorescence Single-Emission Imaging Microscopy of a Predominantly Lipid Rich Plaque Shows Significant Microscopic pH

Heterogeneity Mostly Acidic

Catheter Tipped with a Side Looking Silvered Conical 0.5 mm Mirror

cm0.5mm

6.60

6.80

7.00

7.20

7.40

7.60

6.60 6.80 7.00 7.20 7.40 7.60

electrode pH

NIR

pH

R2 = 0.63RMSD = 0.14 pH units

Non-invasive Magnetic Resonance

Imaging of Vulnerable Plaque

Using SPIO Nano-Particles

SPIO Accumulation in Atherosclerotic Plaque

Atherosclerotic plaqueNormal aortic segment

Iron staining of Apo E K/O Aorta, 24 hour after SPIO injection

Iron

particles

0

5

10

15

AtheroscleroticAorta

Averagenumber of ironparticles persample

P <0.001

Comparison of the Number of the Iron Particles in Apo E Mice Plaque vs. Normal Wall

Normal

Vessel Wall

Hypothesis:

Because Macrophages Phagocytose Hemoglobin and Store Hemosiderin, Injection of Superparamagnetic Iron

Oxide Particles Will Permit MR Imaging of Organizing Hemorrhage, Thrombosis,

and Inflammation

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

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.

Fibrin-rich luminal thrombus

Prevention of unpredicted acute coronary events by early detection and treatment

of vulnerable plaques/patients.

The GOAL:

2001 2050

Genomic

Proteomic

2010 2020 2030 2040

Cellomic?!

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:

Association for Eradication of Heart Attack

www.VP.org

Mohammad Madjid, MD   

Reza Mohammadi, MD

Parsa Mirhaji, M.D.

Mohammed Reza Khan, MD

Khawar Gul, M.D.

Business @ the Speed of Thought

William H. GatesChairman and Chief Software

ArchitectMicrosoft Corporation

Research @ the Speed of Internet

Mort Gates!!!