#1 killer of human beings in the 21st century
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Transcript of #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!!!