Arterial remodeling paul sch

Arterial Remodeling In Stable VersusArterial Remodeling In Stable Versus
Unstable Coronary Syndromes:Unstable Coronary Syndromes:
An Intravascular Ultrasound StudyAn Intravascular Ultrasound Study
Arterial Remodeling In Stable VersusArterial Remodeling In Stable Versus
Unstable Coronary Syndromes:Unstable Coronary Syndromes:
An Intravascular Ultrasound StudyAn Intravascular Ultrasound Study
Paul Schoenhagen, MD,FAHAPaul Schoenhagen, MD,FAHA
Steven E Nissen, MD,FACCSteven E Nissen, MD,FACC
E Murat Tuzcu, MD,FACCE Murat Tuzcu, MD,FACC
The Cleveland Clinic FoundationThe Cleveland Clinic Foundation
Paul Schoenhagen, MD,FAHAPaul Schoenhagen, MD,FAHA
Steven E Nissen, MD,FACCSteven E Nissen, MD,FACC
E Murat Tuzcu, MD,FACCE Murat Tuzcu, MD,FACC
The Cleveland Clinic FoundationThe Cleveland Clinic Foundation

BackgroundBackground
• Originally, Glagov described arterial remodeling as anOriginally, Glagov described arterial remodeling as an
increase in external elastic membrane area withinincrease in external elastic membrane area within
atherosclerotic lesions.atherosclerotic lesions.
• In early CAD, remodeling maintains lumen area despiteIn early CAD, remodeling maintains lumen area despite
increasing plaque burden.increasing plaque burden.
• Although first observed in necropsyAlthough first observed in necropsy studiesstudies, remodeling, remodeling
has been confirmedhas been confirmed in vivoin vivo by intravascular ultrasound.by intravascular ultrasound.
• The relationship between remodeling and various clinicalThe relationship between remodeling and various clinical
ischemic syndromes remains uncertain.ischemic syndromes remains uncertain.

Intravascular UltrasoundIntravascular Ultrasound
vessel wall/ plaquelumen
IVUS Catheter

Objectives and Study DesignObjectives and Study Design
•• Retrospectively analyze intravascular ultrasoundRetrospectively analyze intravascular ultrasound
images in a series of patients with either stable anginaimages in a series of patients with either stable angina
or recent onset of unstable symptomatology.or recent onset of unstable symptomatology.
•• Examine the relationship between clinical presentationExamine the relationship between clinical presentation
and plaque features at the culprit lesion, including:and plaque features at the culprit lesion, including:
• Presence, direction and extent of arterial remodelingPresence, direction and extent of arterial remodeling
• Plaque morphology (echogenicity)Plaque morphology (echogenicity)
• Plaque eccentricityPlaque eccentricity

Methods: PatientsMethods: Patients
Patients with pre-interventionalPatients with pre-interventional
ultrasound of native coronary arteriesultrasound of native coronary arteries
(n=216)(n=216)
Excluded (n=85)
Study Patients (n=131)Study Patients (n=131)
Stable (n=46)Stable (n=46)
Stable Angina (n=37)Stable Angina (n=37)
(+) ETT (n=9)(+) ETT (n=9)
Unstable (n=85)Unstable (n=85)
Unstable Angina (n=76)Unstable Angina (n=76)
Acute MI (n=9)Acute MI (n=9)
Ostial or bifurcation lesions,Ostial or bifurcation lesions,
heavy calcium, image qualityheavy calcium, image quality

Methods: Image AnalysisMethods: Image Analysis
• Intravascular ultrasound images obtained from aIntravascular ultrasound images obtained from a
proximal reference site and culprit lesion site.proximal reference site and culprit lesion site.
• Quantitative variables:Quantitative variables:
– EEM area, lumen area, and plaque areaEEM area, lumen area, and plaque area
• Plaque morphology:Plaque morphology:
– Echolucent, echodense, mixed, calcifiedEcholucent, echodense, mixed, calcified
• Eccentricity Index:Eccentricity Index:
MaximumMaximum -- Minimum Plaque ThicknessMinimum Plaque Thickness
Maximum Plaque ThicknessMaximum Plaque Thickness
xx 100100

Positive
Remodeling
Culprit Lesion
EEM Contour
Proximal
Reference
Proximal
Reference
Direction of Arterial RemodelingDirection of Arterial Remodeling
Schoenhagen et al. Circulation 2000; 101:598-603
Negative
Remodelin
g
Culprit Lesion
EEM Contour
Remodeling Ratio (RR) = EEM area lesion / EEM area proximal reference
Negative
Remodeling
RR < 0.95
Positive
Remodeling
RR > 1.05

Example: Positive RemodelingExample: Positive Remodeling
RemodelingRemodelingIndexIndex ==
18.918.9 mmmm22
14.914.9 mmmm22
== 1.271.27
Proximal Reference Lesion
EEM = 14.9 mm2
EEM = 18.9 mm2

Example: Negative RemodelingExample: Negative Remodeling
Proximal ReferenceProximal Reference LesionLesion
EEMEEM = 16.0 mm= 16.0 mm22
EEMEEM = 11.5 mm= 11.5 mm22
RemodelingRemodelingIndexIndex ==
11.511.5 mmmm22
16.016.0 mmmm22
== 0.720.72

Clinical and Demographic FeaturesClinical and Demographic Features
Stable (n = 46)Stable (n = 46) Unstable (n = 85)Unstable (n = 85)
p = NS for all characteristics
AgeAge 62.6 years62.6 years 59.5 Years59.5 Years
MaleMale 71.7 %71.7 % 64.7 %64.7 %
FemaleFemale 28.3%28.3% 35.3 %35.3 %
LADLAD 56.6%56.6% 51.8%51.8%
LCxLCx 21.7%21.7% 17.6%17.6%
RCARCA 21.7%21.7% 30.6%30.6%

Clinical and Demographic CharacteristicsClinical and Demographic Characteristics
SSttaabblle (e (nn=4=466)) UUnsnsttaabblle (e (nn==885)5)
DiDiaabbeteteess 226.6.11%% 119.9.77%%
HHypypeerrtteennsisioonn 447.7.88%% 663.3.22%%
HHypypeerrlilippidideemimiaa 446.6.77%% 550.0.00%%
SSmomokikinngg 552.2.22%% 660.0.55%%
CCAAD FaD Fammililyy HHisisttoorryy 226.6.11%% 228.8.99%%
Risk Factors for Coronary Artery Disease
p = NS for all characteristics

Reference and Lesion MeasurementsReference and Lesion Measurements
Stable Unstable p value
Proximal Reference
Plaque Area 6.20 mm2
6.10 mm2
NS
EEM Area 14.1 mm2
15.2 mm2
NS
% Area Reduction 42.3 40.3 NS
Target Lesion
Plaque Area 11.1±4.8 mm2
13.9±5.5 mm2
0.005
EEM Area 13.0±4.8 mm2
16.1±6.2 mm2
.04
% Area Reduction 83.1±6.7 85.0+6.4 NS
Remodeling Index 0.94 1.06 0.008

Results: Extent of RemodelingResults: Extent of Remodeling
00
2020
4040
6060
Percent
of
Cohort
Positive
Remodeling
Absence of
Remodeling
Negative
Remodeling
Unstable
Stable
*p=0.0003 *p=0.3 *p=0.006

Results: Plaque MorphologyResults: Plaque Morphology
0
10
20
30
40
Percent
of
Cohort
Echolucent Echodense Mixed Calcified
Unstable
Stable
p=0.02 p=0.4 p=1.0 p=0.3

Stable Presentation and Negative RemodelingStable Presentation and Negative Remodeling
Proximal ReferenceProximal Reference LesionLesion
EEMEEM = 10.5 mm= 10.5 mm22
EEMEEM = 7.5 mm= 7.5 mm22
Mixed Morphology with Remodeling Index = 0.71

Unstable Presentation: Positive RemodelingUnstable Presentation: Positive Remodeling
Echolucent Plaque with Remodeling Index = 1.42
Proximal ReferenceProximal Reference
EEMEEM = 14.3 mm= 14.3 mm22
EEMEEM = 20.3 mm= 20.3 mm22
Culprit LesionCulprit Lesion

LimitationsLimitations
• Selection bias:Selection bias:
– The cohort included only relatively severe lesionsThe cohort included only relatively severe lesions
selected for pre-interventional ultrasound imaging.selected for pre-interventional ultrasound imaging.
• Presence of ultrasound catheter within severePresence of ultrasound catheter within severe
lesions may alter vessel geometry.lesions may alter vessel geometry.
• Classification of plaque morphology based uponClassification of plaque morphology based upon
subjective visual criteria.subjective visual criteria.

ConclusionConclusion
• Significant differences in ultrasound characteristicsSignificant differences in ultrasound characteristics
between unstable and stable lesions:between unstable and stable lesions:
– Greater plaque burden despite similar luminal narrowingGreater plaque burden despite similar luminal narrowing
– Greater extent of positive remodelingGreater extent of positive remodeling
• A prospective study of the relationship between clinicalA prospective study of the relationship between clinical
presentation and plaque morphology is warranted:presentation and plaque morphology is warranted:
– Hypothesis: Bulky remodeled plaques may be moreHypothesis: Bulky remodeled plaques may be more
vulnerable to mechanical forces, thus leading to plaquevulnerable to mechanical forces, thus leading to plaque
rupture and acute coronary syndromes.rupture and acute coronary syndromes.

Remodeling and Clinical PresentationRemodeling and Clinical Presentation
Stable and Unstable
Syndromes and
Remodeling:
IVUS
Pathology
Smits et al.
Schoenhagen et al.
Nakamura et al.
Filardo et al.
Nishioka et al.
Alibelli-Chemarin et al.
Burke et al.
Varnava et al.
Cardiovas. Res.’99;41:458-464
Circulation ‘00;101:598-603
J Am Coll Cardiol ‘01;37:63-9
Am J Cardiol ‘00;85:760-762
JACC ‘97;29:125A, abstract
JACC ‘98;31:276A, abstract
Circulation ’02;105:297-303
Circulation ’02;105:939-943

Coronary RemodelingCoronary Remodeling
ProgressioProgressio
nn
EEM shrinkageEEM shrinkage
NormalNormal
vesselvessel
MinimalMinimal
CADCAD
EEM expansionEEM expansion Lumen shrinkageLumen shrinkage
SevereSevere
CADCAD
ModerateModerate
CADCAD
SevereSevere
CADCAD
Period of Instability?Period of Instability?
Regression?Regression?
Schoenhagen et al. JACC 2001;38:297-306

The prevalence of inflammatory cells in
non ruptured atherosclerotic plaques
G. Pasterkamp
Experimental Cardiology, UMC and Interuniversity
cardiology Institute of the Netherlands, Utrecht, The
Netherlands
Published in part in :
Arterioscl Thromb and Vasc Biol 1999;19:54-58.

Background
Plaque rupture and subsequent plaque
thrombosis is found to be associated with the
presence of inflammatory cells.
Davies et al. Br Heart J 1985;53:363-373
Van der Wal et al. Circulation 1994;89:36-44
Moreno et al. Circulation 1994;90:775-778

Question
Is the presence of inflammatory cells
A- specific for plaque rupture or
B- a commonly observed phenomenon in
atherosclerotic lesions?
What is the prevalence of moderate/heavy local
inflammation in non ruptured atherosclerotic
lesions?

Post mortem study:
• Atherosclerotic femoral (n=50) and coronary
arteries (n=74) from patients that did not die of
cardiovascular disease.
• In each artery, 4-6 non ruptured cross-sections
revealing atherosclerosis were studied for the
presence of macrophages (CD 68) and T-
lymphocytes (CD45RO).

Femoral artery
45% of all cross-sections revealed moderate
or heavy staining for macrophages in the cap
or shoulder of non ruptured plaques.

Question
If one would randomly stain 5-6 cross-sections
obtained from an atherosclerotic artery for
inflammatory cells, how often would at least
one cross-section reveal moderate to heavy
staining for inflammatory cells?

Femoral arteries
In 84% of all femoral arteries at least one
cross-section revealed moderate or haevy
staining for macrophages or T-lymphocytes in
cap or shoulder of the non ruptured
athertosclerotic plaque.

Question
If one would find many cross-sections with
inflammation in one coronary artery: would that be
predictive for the occurrence of plaque inflammation
in another coronary artery?
Right and left coronary arteries were compared within
the individual (next slide)

-= no staining, + = moderate staining, ++ = heavy staining,
No relation was observed between the degree of staining for
inflammatory cells between the left and right coronary artery.
Left coronary artery
Right coronary artery - + ++
- 3 4 0
+ 2 11 2
++ 0 3 0

Conclusion
• The presence of inflammatory cells is a
common phenomenon in non ruptured
atherosclerotic lesions.
• The degree of local inflammation is locally
determined and has no/low predictive value
for the presence of inflammation in other
arteries.
(Pasterkamp et al. ATVB 1999, Vink et al JACC 2001)

Discussion
• Considering these results: what is the
predictive value of local inflammation for the
occurrence of plaque rupture?
• Visualization of the vulnerable plaque when
inflammation is used as marker:
– Specificity for local plaque rupture or predictive
value for plaque rupture may be disappointing.

Definitions of arterial remodeling in post
mortem and Intravascular ultrasound
research
G. Pasterkamp
Experimental Cardiology, UMC and Interuniversity
cardiology Institute of the Netherlands, Utrecht, The
Netherlands

Arterial remodeling
Gradual Luminal narrowing
Expansive
remodeling
Constrictive
remodeling
Glagov et al. New Engl J Med 1987;316:1371-1375
Pasterkamp et al. Circulation 1995;91:1444-1449

Background
In international literature, the modes of
arterial geometrical remodeling are
differentially defined resulting in different
prevalence numbers.
The current presentation will show and
discuss the most widely used definitions

L = Lesion
R1 = most proximal site
R2 = proximal reference with normal lumen and least amount
of plaque
R3 = distal reference with normal lumen and least amount of
plaque
lumen
plaque
LR2 R3R1

Definition 1
Remodeling Index (RI)= VA L / ( (VA R2 + VA R3)/2)
lumen
plaque
LR2 R3R1
Expansive remodeling when RI >1.05
Intermediate remodeling when RI >0.95 or < 1.05
Constrictive remodeling when RI <0.95
Smits et al. Heart 1999;82:461-464
von Birgelen et al. J Am Coll Cardiol 2001;37:1864-1870.
Schoenhagen et al. Circulation 1999;101:598-603

Definition 2
RI= VA L / ( (VA R2 + VA R3)/2)
lumen
plaque
LR2 R3R1
Dangas et al. Circulation 1999;99:3149-3154.
Nakamura et al. J Am Coll Cardiol. 2001 Jan;37(1):63-9
Okura et al. J Am Coll Cardiol 2001;37:1031-1035.

Definition 3
lumen
plaque
LR2 R3R1
Expansive remodeling when VA L > VA R2 and VA L > VA R3
Constrictive remodeling when VA L < VA R2 and VA L < VA R3
Other values: intermediate remodeling
Nishioka et al. J Am Coll Cardiol 1996;27:1571-1576
Wexberg et al. J Am Coll Cardiol 2000;36:1860-1869.

Definition 4
lumen
plaque
Expansive/no remodeling when VA L / VA R2 > 0.78
Constrictive remodeling when VA L / VA R2 < 0. 78
Mintz et al Circulation 1997;95:1791-1798.
Upper limit of normal tapering over 10 mm never exceeds
21% of vessel area reference limit at 0.78
LR2 R3R1

Definition 5
RI= VA L / ( VA R1)
lumen
plaque
LR2 R3R1
Taylor et al. J Am Coll Cardiol 1999 Sep;34(3):760-7

Definition 6
RI = VA L / VA R2 (site with least
amount of plaque
lumen
plaque
LR2 R3R1
Expansive remodeling when RI > 1.05
Constrictive remodeling when RI < 0.95
Other values: intermediate remodeling
Pasterkamp et al. J Am Coll Cardiol 1995;26:422-428.
(Only applied peripheral arteries)

Remodeling definitions lead to large variations in
prevalence numbers.
expansive
remodeling
intermediate
remodeling
constrictive
remodeling
definition
remodeling
Mintz et al 512 (85%) 91 (15%) 4
Nishioka et al 19 (53%) 7 (20%) 9 (27%) 3
Smits et al 24 (35%) 16 (23%) 29 (42%) 1
Wexberg et al 70 (29%) 110 (45%) 64 (26%) 3
Dangas et al. 269 (42%) 377 (58%) 2
Nakamura et al. 68 (54%) 57 (46%) 2
Okura et al. 59 (55%) 49 (45%) 2
Von Birgelen et al. 38 (48%) 22 (28%) 19 (24%) 1
Pasterkamp et al. 226 (37%) 383 (63%) 2
Schoenhagen et al. 70 (53%) 26 (20%) 35 (27%) 1

Which definition is best?
All studies are cross-sectional
The reference is not free of atherosclerotic disease
The reference may have been remodeled in either direction
We do not know which definition gives us the best estimate of
the prevalence of the different remodeling modes.

Which definitions make sense?
• Definitions 1-4 share the same receipt, only the
tresholds differ.
• Definition 5 may be used in casuistic studies, but in
larger studies on prevalence this definition should
not be used (it will, by definition, approximate the 50% for each
remodeling mode)
• Definition 6 can only be used in non tapering
vessels.

Conclusion
• The prevalence of constrictive and expansive
remodeling differs widely in literature due to the
application of different definitions.
• Without serial studies, there is no gold standard for
the reference site.
• The definition of the remodeling modes merit
careful consideration when prevalences are
mentioned.

Plaque Thermography:Plaque Thermography:
Some Like it Hot.Some Like it Hot.
Hippokration Hospital, Dept. of Cardiology, Athens Medical School

Thermography CatheterThermography Catheter

Thermography CatheterThermography Catheter
One thermistor
Sizes: 3 – 4.5 F
Limitations
-‘Flail’ phenomenon in large vessels or stenoses < 50%
- One thermistor

New Thermography Catheters
Balloon-Occluded Thermography Catheter
Low pressure balloon Thermistor

New Thermography Catheters
Balloon-Occluded Multisensor Thermography Catheter
Low pressure balloon Thermistors

Thermal Heterogeneity – Clinical SyndromeThermal Heterogeneity – Clinical Syndrome
Stefanadis et al, Circulation April 1999

Statins and TemperatureStatins and Temperature
Stefanadis et al. Eur Heart J (in press)
StatinsNo statins
Temperaturedifference
2.5
2.0
1.5
1.0
.5
0.0
-.5
P<0,001

Statins and TemperatureStatins and Temperature
Stefanadis et al. Eur Heart J (in press)
StatinsNo statins
Temperaturedifferences(o
C)
2.5
2.0
1.5
1.0
.5
0.0
-.5
SYNDROME
SA
UA
AMI
P<0,001

ΔΤ - Percutanenous Coronary InterventionsΔΤ - Percutanenous Coronary Interventions
FV
EventNo Event
2.0
1.5
1.0
0.5
0
-0.5
P < 0.01
Stefanadis C et al, J Am Col Cardiol 2001 April

AMIUAEA
2.0
1.5
1.0
0.5
0
-0.5
P < 0.10
P < 0.01
P < 0.001

Coronary Thermography
• Thermal heterogeneity exists in vivo in
atherosclerotic plaque
• Statins decrease thermal heterogeneity possibly
by anti-inflammatory mechanism
• Thermal heterogeneity in the culprit lesion is a
prognostic factor for adverse cardiac events after
percutaneous interventions
• Is thermal heterogeneity a sensitive marker for
future cardiac events?

Primary end point: Death, MI, TLR in 12 months
Secondary end points:
-Procedural complications
-Cost effectiveness over 12 months
Stenting of culprit lesion only Stenting of culprit + non-culprit lesions
Randomization
Non-culprit lesion(s) with > 0.10O
C ∆T
Patients with ACS and multivessel disease
THERMO ACS:
Culprit or Multivessel Revascularization based on
Thermography in patients with ACS

…… Thermography Beyond Coronary ArteriesThermography Beyond Coronary Arteries

Aortic Thermography CatheterAortic Thermography Catheter
Thermistor
Dept. of Cardiology, Athens Medical School 2001

Study PopulationStudy Population
•18 patients with angiographically documented CAD
•12 patients angiographically normal coronary
arteries

Aortic Thermography Ongoing ProtocolsAortic Thermography Ongoing Protocols
Dept. of Cardiology, Athens Medical School 2001
• Measurement of atherosclerotic lesions in the aorta
• Measurement of the stenotic aortic valves

Vulnerable Lesion or Vulnerable
Patient?

Coronary Sinus ThermographyCoronary Sinus Thermography
Increased Coronary Sinus Temperature inIncreased Coronary Sinus Temperature in
Patients With Coronary Artery Disease asPatients With Coronary Artery Disease as
Determined by Coronary SinusDetermined by Coronary Sinus
ThermographyThermography

To investigate whether there is temperature difference of
blood between the coronary sinus and the right atrium in
patients with significant lesions in left coronary artery vs
patients without lesions evaluated by angiography by a
new coronary sinus thermography catheter.
PurposePurpose

Temperature MeasurementsTemperature Measurements

Thermography SystemThermography System

CS
Th
In Vivo Coronary Sinus ThermographyIn Vivo Coronary Sinus Thermography

37,8
37,85
37,9
37,95
38
38,05
38,1
38,15
38,2
38,25
0 100 200 300 400 500 600 700 800
Coronary Sinus
Right Atrium
Coronary Sinus
Right Atrium
DΤ(o
C) In Vivo Coronary Sinus ThermographyIn Vivo Coronary Sinus Thermography

ResultsResults
CADControl
Temperaturedifference(o
C)
.4
.3
.2
.1
0.0
P=0.02

Ongoing ProtocolsOngoing Protocols
Temperature MeasurementTemperature Measurement
Tachycardia
Arrhythmias (Atrial Fibrillation)
Medication
Heart Failure
Transplantation
Organ Function
Brain
Liver
Kidneys

ConclusionsConclusions
• New catheters for coronary thermography are being
developed to increase the sensitivity of the current
systems.
• Thermography is currently being used in the whole
cardiovascular system (peripheral arteries, valves)
• Coronary sinus temperature measurements may provide in
the future important information for the patient; not only
for the plaque

Revisiting the Basics, Culprit vs. Non-Culprit: Luminal
Narrowing, Plaque Volume, Cap thickness and plaque
inflammation
It is now widely accepted that the main determinant(s) of acute clinical events in coronary
heart disease is the composition of the atherosclerotic lesion. In this review, we will
discuss several plaque characteristics that are considered to be factors in the plaque
vulnerability.
Abstract

Abstract (con’t)
Luminal narrowing.
In a classic paper, Ambrose et al, reported that acute myocardial infarctions
frequently developed in lesions that were not considered stenotic a few months
before the ischemic event. Shortly afterwards, Little et al confirmed these
findings. Moreover, in their series, 19 out of 29 patients had an occluded vessel
responsible for their new myocardial infarction that was less than 50% stenotic
in their previous angiogram, and 28 out of 29 patients had less than 70%
narrowing in their culprit vessel on the first angiogram. In some biomechanical
models, increase of stenosis leads to decrease of peak stress in the plaque,
especially in lipid-rich plaques. It should be remembered, however, that plaque
burden is a strong predictor of vascular events as demonstrated by a high EBCT
score. The plaque burden, however, is predictive of the patient’s prognosis, not
of a particular lesion progression. Also, a prospective five-year angiographic
follow-up of factors associated with progression of coronary artery disease in
the Coronary Artery Surgery Study showed that initial lesion severity was
predictive of late segment occlusion.

Plaques containing a highly thrombogenic lipid-rich core are more at risk for rupture if the
size of the lipid core is large. In studies on aortae of individuals who died suddenly of
coronary artery disease, Davis et al estimated that when lipid accounted for >40% of the
plaques, there is high risk for plaque rupture. It is also possible that the chemical components
of the atheroma are major determinants of plaque consistency and therefore, of plaque
vulnerability. Specifically, liquid cholesterol esters are softer than crystalline cholesterol.
Likewise, higher core temperature induces core softness, making it less likely for the fibrous
cap to bear the circumferential stress and predisposing it for rupture.
.
Abstract (con’t)
Plaque volume and composition

Abstract (con’t)
Fibrous cap thickness.
• Extracellular collagen-rich matrix produced by smooth muscle cells underlie the
cap thickness and strength. The peak circumferential stress is inversely related
to the cap thickness. An important determinant of cap thickness and composition
is the presence or absence of inflammatory cells, mainly macrophages.

Abstract (con’t)
Plaque inflammation (mainly cap
and vicinity).
Disruption of the fibrous cap is usually associated with heavy infiltration by
macrophages and not uncommonly, T-lymphocytes as well. Macrophages
especially may release several matrix-degrading proteases (MMPs): MMP-1
(collagenases), MMP-2 and 9 (gelatinases) and MMP-3 (stromelysin). Their
main role is to degrade the fibrillar collagen that underlies the skeleton of the
fibrous cap. A word of caution is well advised since Pasterkamp et al showed
significant inflammation of the caps and shoulders of plaques in the femoral
and coronary arteries. Clearly, inflammation is only one of many parameters,
many yet to be reported, that determine plaque vulnerability.

Abstract (con’t)
Summary
In summary, size and composition of the lipid core, thickness and
composition of the fibrous cap, and inflammation within or in the
vicinity of the fibrous cap are well-established predictors of plaque
rupture. Predictors of other forms of lesions underlying luminal
thrombosis (e.g. erosion) are not yet well characterized.

Myocardial infarction frequently develops from
previously non-severe lesions
• Initial percent stenosis of infarct-related artery at restudy of 23 patients
with myocardial infarction (Group I), or new occlusions in 18 patients
without myocardial infarctions (Group II). The degree of stenosis was
lower in the infarct group. From Ambrose et al, JACC 1988;12:56-62

Relation between severity of the stenosis at the
future infarct site and time from initial angiography
• There is no relation between severity of the stenosis at the future infarct site and
the time from initial angiography until the development of the acute myocardial
infarction. In addition, severe stenoses were infrequent in the infarct-related
artery on the initial angiogram. From Little at al. Circulation 1988;78:1157-66

Review of studies that examined the severity of
coronary stenosis lesions before the myocardial
infarction
• From Fishbein & Siegel. Circulation 1996;94:2662-6

Is the size of the lipid core related to the degree of
vessel stenosis?
The size of the lipid core has no correlation with the severity of the arterial
stenosis. From Davies MJ et al. Br Heart J 1993;69:377-81

Plaque lipid content is a marker of vulnerability
Unstable plaques have a higher lipid content than stable plaques. From
Davies MJ et al. Basic Res Cardiol 1994;89:I:33-9

Lipid contents in stable (group A), combined stable
and unstable plaques (B) and unstable plaques (C).
Although there was considerable overlap between the groups the mean values
were very different. Only one plaque in group A had a value over 40% while
41 of the 45 plaques in group C exceeded the value of 40%. From Davies MJ
et al. Br Heart J 1993;69:377-81

Macrophage and smooth muscle cell contents of the
fibrous cap in stable and unstable plaques
Lipid-filled macrophages occupy a larger portion of the cap tissue in unstable plaques.
Conversely, the volume of cap tissue occupied by smooth muscle cells is much
smaller in unstable plaques. From Davies MJ et al. Basic Res Cardiol 1994;89:I;33-
9

Is cap thickness inversely related to the maximum
circumferential stress?
In arterial models, decreasing cap thickness dramatically increases the maximum
circumferential stress, thus predisposing to plaque rupture. From Loree et al. Circ
Res 1992;71:850-8

Is stenosis inversely related to the maximum
circumferential stress?
When a lipid core is present, increasing stenosis severity markedly decreases the
maximum circumferential stress. In the absence of lipid core, this relationship is
not as steep. From Loree et al. Circ Res 1992;71:850-8

Why is peak circumferential stress important?
The peak circumferential stress was compared in 12 ruptured and 12
stable coronary lesions. Peak stresses are significantly increased in
ruptured plaques and are considered an important factor in the genesis
of the rupture. From Cheng et al. Circulation 1993;87:1179-87

Is the plaque rupture site related to the stress
concentration?
There is a very good correlation between the rupture site and the regions
of peak stress concentration. From Cheng et al. Circulation
1993;87:1179-87

Ratio of smooth muscle cells and macrophages in
cap tissue in different plaques settings
Stable plaques are characterized by an excess of smooth muscle cells. In
unstable plaques the ratio reaches unity or less. From Davies MJ et al.
Basic Res Cardiol 1994;89:I-33-9

Fibrous cap extracellular matrix and cellularity in
vulnerable plaques
Arterial segment with atheromatous core with heavy staining of picro Sirius red within the cap
confirmed with polarized light microscopy (A and C), and absent staining for CD68 in the cap
and moderate CD68 staining in the shoulder and heavy CD68 staining at the base of the
plaque (E) (asterick). Arterial segment with atheromatous core and thin/local absent picro
Sirius red staining of the cap confirmed by polarized light microscopy (B and D). CD68
staining was heavily positive for cap and shoulder (F).

Thermal heterogeneity in the coronary
atherosclerotic plaque
Based on earlier studies by Casscells et al showing termal heterogeneity in ex-vivo
atherosclerotic plaques, Stefanadis et al showed that temperature heterogeneity
increases progressively from stable angina to acute myocardial infarction patients.
From Stefanadis et al. Circulation 1999;99:1965-71

CONCLUSIONS
• Size and composition of lipid core, thickness and
composition of fibrous cap, and inflammation within or
in the vicinity of the fibrous cap are well-established
predictors of plaque rupture.
• Predictors of other forms of lesions underlying luminal
thrombosis (e.g. erosion) are not as well characterized.

Out of Hospital Sudden CardiacOut of Hospital Sudden Cardiac
Death (SCD): Declining orDeath (SCD): Declining or
Escalating?Escalating?
Alireza Zarrabi, M.D.Alireza Zarrabi, M.D.
Center for Vulnerable Plaque ResearchCenter for Vulnerable Plaque Research
The University of Texas Health Science Center at HoustonThe University of Texas Health Science Center at Houston
and, Texas Heart Institute, U.S.A.and, Texas Heart Institute, U.S.A.
March 2002March 2002

 Every 29 seconds, one American suffers from anEvery 29 seconds, one American suffers from an
unexpected heart attack. Sadly, one will dieunexpected heart attack. Sadly, one will die
nearly every minute.nearly every minute.
 Every year 225,000 people die of heart attackEvery year 225,000 people die of heart attack
before reaching the hospital.before reaching the hospital.

 The single most important cause of death in the adultThe single most important cause of death in the adult
population of the industialized world is sudden cardiacpopulation of the industialized world is sudden cardiac
death (SCD) due to coronary disease.death (SCD) due to coronary disease. 11
 SCD is defined as follows: " Natural death due to cardiacSCD is defined as follows: " Natural death due to cardiac
causes, heralded by abrupt loss of consciousness withincauses, heralded by abrupt loss of consciousness within
one hour of the onset of acute symptoms; preexistingone hour of the onset of acute symptoms; preexisting
heart disease may have been known to be present, butheart disease may have been known to be present, but
the time and mode of death are unexpected.the time and mode of death are unexpected. 22

 50% of victims of sudden out-of-hospital cardiac50% of victims of sudden out-of-hospital cardiac
death have no prior diagnosis of heart diseasedeath have no prior diagnosis of heart disease
(asymptomatic).(asymptomatic). 33
 More than 60% of cardiac death continues toMore than 60% of cardiac death continues to
remain sudden. In 1998, there were 719 456remain sudden. In 1998, there were 719 456
cardiac disease deaths among US residentscardiac disease deaths among US residents
aged >=35 years, of which 456,076 (63.3%)aged >=35 years, of which 456,076 (63.3%)
were defined as SCD.were defined as SCD. 44

 The number of adolescents and young adultsThe number of adolescents and young adults
dying each year from sudden cardiac arrest rosedying each year from sudden cardiac arrest rose
by about 10% between 1989 and 1996, the firstby about 10% between 1989 and 1996, the first
study of nationwide trends in the United Statesstudy of nationwide trends in the United States
has shown.has shown. 77
 The number of sudden cardiac deaths in the 15-The number of sudden cardiac deaths in the 15-
34 age group went up from 2,724 in 1989 to34 age group went up from 2,724 in 1989 to
3,000 in 1996, an increase of 10%. Of all the3,000 in 1996, an increase of 10%. Of all the
young people who died over the eight yearyoung people who died over the eight year
period, 71% were men and 29% women.period, 71% were men and 29% women. 77

Age-adjusted death rates (per 100 000 US
population) for sudden cardiac death
among men aged 35 years and older by
race in the US from 1989 to 1990.
Adapted from:Adapted from: Zhi-Jie Zheng, George A. Mensah, et al.; Sudden Cardiac Death in the United States, 1989Zhi-Jie Zheng, George A. Mensah, et al.; Sudden Cardiac Death in the United States, 1989
to 1998 .Circulation. 2001;104:2158to 1998 .Circulation. 2001;104:2158

Age-adjusted death rates (per 100 000 US
population) for sudden cardiac death among
women aged 35 years and older by race in
the US from 1989 to 1990.
Adapted from:Adapted from: Zhi-Jie Zheng, George A. Mensah, et al.; Sudden Cardiac Death in the United States, 1989Zhi-Jie Zheng, George A. Mensah, et al.; Sudden Cardiac Death in the United States, 1989
to 1998 .Circulation. 2001;104:2158to 1998 .Circulation. 2001;104:2158

 400,000 to 450,000 SCD per year from 1989400,000 to 450,000 SCD per year from 1989
to 1998 occurred out of hospital, in theto 1998 occurred out of hospital, in the
emergency room, or as "dead on arrival."emergency room, or as "dead on arrival." 66
 The automated external defibrillators (AEDs)The automated external defibrillators (AEDs)
represents an efficient method of deliveringrepresents an efficient method of delivering
defibrillation to persons experiencing out-of-defibrillation to persons experiencing out-of-
hospital cardiac arrest and its use appears to behospital cardiac arrest and its use appears to be
safe and effective.safe and effective. 88

Survival to 1 month relative to delay time from cardiac arrest to firstSurvival to 1 month relative to delay time from cardiac arrest to first
defibrillation for bystander-witnessed patients with ventriculardefibrillation for bystander-witnessed patients with ventricular
tachycardia/ventricular fibrillation on first electrocardiogram (n =tachycardia/ventricular fibrillation on first electrocardiogram (n =
2,748).2,748). ArrowArrow indicates median delay time (13 minutes).indicates median delay time (13 minutes).
Adapted from: Holmberg M, Holmberg S, Herlitz J.; The problem of out-of-hospital cardiac-arrest prevalence of
sudden death in Europe today. Am J Cardiol. 1999 Mar 11;83(5B):88D-90D.
(Minutes)

 There is evidence of a slight decline in averageThere is evidence of a slight decline in average
delay times in patients hospitalized in 1997 (5.5delay times in patients hospitalized in 1997 (5.5
hours) compared with those hospitalized in 1994hours) compared with those hospitalized in 1994
(5.7 hours).(5.7 hours).
 Approximately 20% of patients presented to theApproximately 20% of patients presented to the
hospital within 1 hour of acute symptom onset,hospital within 1 hour of acute symptom onset,
and slightly more than two thirds presentedand slightly more than two thirds presented
within 4 hours.within 4 hours.

 Delay times are shorter in patients withDelay times are shorter in patients with
cardiogenic shock than less severely ill patients.cardiogenic shock than less severely ill patients.
 Patients with previous acute MI or those withPatients with previous acute MI or those with
history of coronary angioplasty presented tohistory of coronary angioplasty presented to
hospital with shorter delay times.hospital with shorter delay times.

 Poor knowledge of warning symptoms of heartPoor knowledge of warning symptoms of heart
attack and lack of a convenient method for out-attack and lack of a convenient method for out-
of-hospital screening of patients with chestof-hospital screening of patients with chest
discomfort are among major factors contributingdiscomfort are among major factors contributing
to the overwhelming burden of out-of-hospitalto the overwhelming burden of out-of-hospital
SCD.SCD.

“Epidemiology”“Epidemiology”
I.I. Women increasingly die with SCD out-of-Women increasingly die with SCD out-of-
hospital.hospital.
II.II. The increased death rates for SCD amongThe increased death rates for SCD among
younger women warrants additionalyounger women warrants additional
investigation of their potential risk factors.investigation of their potential risk factors.

“Pathology”“Pathology”
I.I. Coronary thrombosisCoronary thrombosis (a product of vulnerable(a product of vulnerable
plaque and vulnerable blood)plaque and vulnerable blood) does not exist indoes not exist in
43-51% of SCD cases. In other words, about43-51% of SCD cases. In other words, about
half of SCDs are not caused by plaque rupturehalf of SCDs are not caused by plaque rupture
or coronary thrombosis.or coronary thrombosis.
II.II. This reiterates the fact that SCD is a productThis reiterates the fact that SCD is a product
ofof vulnerable plaque + vulnerable blood +vulnerable plaque + vulnerable blood +
vulnerable myocardiumvulnerable myocardium..

“Public Health”“Public Health”
I.I. Pre-hospital delay in the US has not declinedPre-hospital delay in the US has not declined
in the past few decades and holds as a majorin the past few decades and holds as a major
bottle neck in our challenge against SCD.bottle neck in our challenge against SCD.

“Public Health”“Public Health”
II.II. The encouraging declines in the proportion ofThe encouraging declines in the proportion of
cardiac deaths occurring in the hospital or thecardiac deaths occurring in the hospital or the
emergency room may reflect the improvements inemergency room may reflect the improvements in
emergency services and more timely andemergency services and more timely and
appropriate treatment in hospital.appropriate treatment in hospital.
However, the increased trend in SCD outside ofHowever, the increased trend in SCD outside of
the hospital reiterates the need for public healththe hospital reiterates the need for public health
initiatives to improve the early recognition of heartinitiatives to improve the early recognition of heart
attack symptoms and signs with rapidattack symptoms and signs with rapid
intervention.intervention.

 For saving more lives from SCD which one ofFor saving more lives from SCD which one of
the following should be our first impression:the following should be our first impression:
A.A. Detection and treatment of vulnerableDetection and treatment of vulnerable
plaque?plaque?
B. Detection and treatment of vulnerable heart?B. Detection and treatment of vulnerable heart?
C. Rapid out-of-hospital screening, detection,C. Rapid out-of-hospital screening, detection,
and treatment of patients with cardiac chestand treatment of patients with cardiac chest
discomfort?discomfort?

ReferencesReferences
1- Priori SG, Wellens JJ, Zipes DP, et al.; Task Force on Sudden Cardiac Death of the1- Priori SG, Wellens JJ, Zipes DP, et al.; Task Force on Sudden Cardiac Death of the
European Society of Cardiology. Eur Heart J. 2001 Aug;22(16):1374-450.European Society of Cardiology. Eur Heart J. 2001 Aug;22(16):1374-450.
2- Braunwald E, Heart disease: a tetbook of cardiovascular medicine. WB Saunders2- Braunwald E, Heart disease: a tetbook of cardiovascular medicine. WB Saunders
Publishing Co., 1997:742-79.Publishing Co., 1997:742-79.
3- Wellens JJ; JACC 1997; 30:1500.3- Wellens JJ; JACC 1997; 30:1500.
4- Zhi-Jie Zheng, George A. Mensah, et al.; Sudden Cardiac Death in the United States,4- Zhi-Jie Zheng, George A. Mensah, et al.; Sudden Cardiac Death in the United States,
1989 to 1998 .Circulation. 2001;104:2158.1989 to 1998 .Circulation. 2001;104:2158.
5- Farb A, Virmani R, et al. Sudden coronary death.frequency of active coronary lesions,5- Farb A, Virmani R, et al. Sudden coronary death.frequency of active coronary lesions,
and MI. Circulation 1995; 92:1701.and MI. Circulation 1995; 92:1701.
6- Goff DC Jr, Sellers DE, McGovern PG, et al. Knowledge of heart attack symptoms in a6- Goff DC Jr, Sellers DE, McGovern PG, et al. Knowledge of heart attack symptoms in a
population survey in the United States: the REACT Trial. Rapid Early Action forpopulation survey in the United States: the REACT Trial. Rapid Early Action for
Coronary Treatment. Arch Intern Med. 1998; 158: 2329–2338.Coronary Treatment. Arch Intern Med. 1998; 158: 2329–2338.
7-7- 2002 Heart and Stroke Statistical Update; American Heart Association.
8- Marenco JP, Wang PJ, Link MS, Homoud MK, Estes NA 3rd. ; Improving survival from
sudden cardiac arrest: the role of the automated external defibrillator. JAMA. 2001
Mar 7;285(9):1193-200.
9- Goldberg RJ, Gurwitz JH, Gore JM.; Duration of, and temporal trends (1994-1997) in,
prehospital delay in patients with acute myocardial infarction: the second National
Registry of Myocardial Infarction. Arch Intern Med 1999 Oct 11;159(18):2141-7.

Abstract
Macrophage apoptosis: a double edge
sword?
Apoptosis, a form of genetically programmed cell death, plays an essential role in different physiologic
and pathologic processes including atherosclerosis, in which it affects all cell types including
endothelial cells, vascular smooth muscle cells (VSMCs), and macrophages. Over the course of the
plaque progression, pro- and anti-apoptotic signals abound. In other organ systems, apoptosis limits the
number of a particular cell type that accumulates in the lesion. The issue in atherosclerosis, however, is
clearly more complex. The loss of VSMCs can be detrimental for plaque stability since most of the
fibrous cap collagen required for the tensile strength of the cap is produced by VSMCs. Apoptosis of
macrophages, on the other hand, could be beneficial for plaque stability if apoptotic bodies were
removed. Several investigators have reported, however, that apoptotic bodies in the advanced
atherosclerotic plaque are often not scavenged, can activate the coagulation cascade, potentially leading
to plaque rupture and luminal thrombosis. Many of the apoptotic bodies are of macrophage origin.
Moreover, interventions like statin therapy have shown that beneficial effects on the plaque, namely
shrinkage of the lipid core, decrease of the inflammatory burden and thickening of the fibrous cap, are
accompanied by a decrease in apoptotic activity. It is therefore not surprising that most investigators
believe that apoptosis is detrimental to plaque stability.

Abstract (con’t)
sword?
Our group has long been interested in the thermal heterogeneity of the atherosclerotic plaque
and on the effect of plaque heating on the processes of inflammation and apoptosis. In a
recent study by Dr. Birendra Lal in Dr. Yong-Jian Geng’s laboratory at the University of
Texas Houston, eleven freshly living human carotid endarterectomy specimens were heated
in DMEM medium at 42°C for 15 minutes followed by incubation at 37°C for 6 hours. In
unheated controls, 4% of the VSMCs and 8% of macrophages were TUNEL positive. In the
specimens with the short term heating, 46% of the macrophages and 10% of the SMCs were
TUNEL positive. Immunostaining for tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-
6) demonstrated lower levels of both cytokines in the heated group. Moreover, thermal
stimulation also inactivated NF-κB (a transcription factor involved in cytokine expression,
cell proliferation, etc) in macrophages derived from THP-1 cells by phorbol esters as
demonstrated by gel shift assays.

Abstract (con’t)
sword?
In another set of experiments performed by Dr. Mitra Rajabi in Dr. Yong-Jian Geng’s
laboratory at the University of Texas Houston, mouse VSMCs were divided in two groups,
half heated at 42°C for 15 minutes before returning to 37°C. Two hours after heating, both
heated and non-heated dishes were divided in 3 groups: a) TNF-α 10ng/ml, b) TNF-α
10ng/ml and IFN-γ 10ng/ml, and c) no cytokines. After 12, 36 and 48 hours, the nitrite
production, a marker of iNOS expression, was statistically significant lower in the heated as
compared to the non-heated groups.

Abstract (con’t)
sword?
We therefore believe that specific therapies like local gentle heating have a potential
therapeutic effect by decreasing markers of inflammation coupled to their pro-apoptotic
effects on macrophages. In addition, the operator in the catheterization laboratory could
add adjuvant therapy like balloon dilation, stenting and anticoagulation, thereby
preventing the potential complications of plaque rupture and thrombosis from happening
in vivo.
In summary, although large body of evidence considers apoptosis in the plaque to be risky
and detrimental, we believe that under certain controlled conditions, gentle heating could
decrease the plaque vulnerability.

APOPTOSIS & ATHEROSCLEROSIS
∀• While apoptosis is a key negative regulator of the cell density in oncogenesis, organ
development, and immune response, the role of apoptosis in atherosclerosis is more complex.
• Variation in the rate of apoptosis of different cell types promotes differences in growth
rates, structure and stability of the plaques.
• Several cytokines known to be pro-apoptotic, such as tumor necrosis-α (TNF-α),
interleukin-1β, and interferon γ (IFN- γ) and products of genes involved in the cell cycle
regulation (Fas/Fas ligand, caspase, p53 and c-Myc) have been found in vascular cells and
atherosclerotic plaques.
• Apoptotic rate is higher in advanced plaques

APOPTOSIS OF DIFFERENT CELL
TYPES IN PLAQUE TISSUE
ENDOTHELIAL CELLS
∀ • Lesion-prone regions show increased endothelial cell (EC) turnover ratio.
∀ • ECs undergo apoptosis when coming in contact with circulating or local factors like
angiotensin II, oxidized LDL, reactive oxygen species (ROS) and inflammatory cytokines.
• Apoptotic ECs assume pro-coagulant characteristics due to increased exposure to
phosphatidylserine and loss of normal anticoagulant membrane properties.
• Apoptotic ECs increase migration of monocytes and T-lymphocytes.

VASCULAR SMOOTH MUSCLE CELLS
 Apoptosis of vascular smooth muscle cells (VSMC) reduces the rate of plaque
growth. At the same time, since VSMCs are the source of interstitial collagen fibers type
I, plaque stability might be affected.
 Migration of macrophages to areas of VSMC apoptosis has been described.
 Overall effects of VSMCs apoptosis are complex and difficult to predict but generally
felt to be deleterious for plaque stability.

MACROPHAGES
•• Macrophages may activate several matrix metalloproteinases which degrade interstitial
collagen, thus weakening the fibrous cap.
• Macrophages produce cytokines that may induce VSMCs apoptosis.
• Loss of macrophages results in decreased scavenging products of cell degradation, leading to
accumulation of necrotic debris and coagulation activation.
• Therefore, apoptosis of macrophages, may have both pro- and anti-destabilizing effects.

T-LYMPHOCYTES
∀• Lymphocytes produce molecules with important regulatory functions on the
plaque cell death (cytokines, perforin, Fas).
∀• Apoptosis of lymphocytes is not well understood in the context of
atherosclerosis.

Effect of heat on apoptosis of
macrophages and smooth muscle cells
At 37 °C, the proportion of apoptotic SMC and macrophage were 4% and 8%
respectively. At 42 °C, these proportions increased to 10% and 46% respectively.

Effect of heat on macrophage apoptosis
∀
TUNEL and HAM-56 double staining. There is significant increase
in the number of TUNEL positive macrophages after heating (8% to 46%)

Effect of heat on SMC apoptosis
∀
TUNEL and α actin double staining. There is insignificant increase in the number of
TUNEL positive SMCs after heating (4% to 10%).

Effect of heat on macrophage
ultrastructure
∀
Human carotid atherectomy specimen. A: Normal macrophage in unheated plaque. B: Two
apoptotic macrophages inheated plaque condensed chromatin is same in both cells.

Effect of heat on macrophage
ultrastructure (con’t)
∀
C: Enlarged view of B. D: Foam cell at the end stage of apoptotic process. Extra cellular
debris is also present.

Effect of heat on TNF -α
immunoreactivity
∀
TNF- α immunoreactivity decreases markedly with heating

Conclusion
∀
 Gentle short-term thermal treatment induces apoptosis in human atherosclerotic
lesions, reduces expression of pro-inflammatory cytokines TNFα and IL-6, and
inactivates NFκB (as demonstrated by electrophoretic mobility shift assay, data not
shown).
 These data suggest that thermal treatment may have potential for treating
advanced atherosclerotic lesions by reducing inflammation and triggering apoptosis in
macrophages.

Contrast Enhanced MRI of the
Vulnerable Plaque, Black or
White?
Maziar Azadpour, MD
Morteza Naghavi, MD
Center for Vulnerable Plaque Research

One can divide intravascular MRI contrast media into
three different phases:
• Arterial
• Blood pool
• Extracellular

Arterial Phase is the most suitable one for
angiography and needs rapid sequences with
minimum TR to optimize the enhancement.
Blood Pool Phase is significant for highly
vascular organs such as liver, which benefits the
most from enhancement in this phase.
Extracellular Phase in which certain tissues such
as fibrous tissue and inflammatory processes
could be detected.
Different MRI contrasts agents have their own
unique property to affect each of the above
mentioned phases.

Yuan et al. demonstrated that multi-spectral MRI
Without contrast media can produce high- resolution
Images of carotid plaques and can discriminate
between clinically relevant structural components
Of atherosclerotic vessel wall.

Weiss, Cannon et al used positive enhancement
Contrast media, Gadolinium-DTPA (Whitening)
to Obtain double inversion recovery, fast spin
echo images of the common carotid arteries
and infrarenal aorta at 1.5 T both before and
after injection in 52 subjects which 17 of whom
had no risk factors for atherosclerosis and thus
served as controls.

They hypothesized that arterial inflammation
would cause increases in wall thickness, T2-
weighted signal intensity, and/or arterial Wall
gadolinium contrast enhancement Because Of
enhanced endothelial permeability with
Increased tissue water, cellular infiltration and
Vasa vasorum dilation or neovascularization.

Levels of serum markers of inflammation in subjects with abnormal
MRI compared to groups with normal MRI
Bar graphs show levels of serum markers of inflammation in 22
Subjects With abnormal MRI compared with 30 subjects with normal
MRI vascular studies.
Weiss CR, Arai AE, Bui MN, Agyeman KO, Waclawiw MA, Balaban RS, Cannon RO 3rd. Arterial wall MRI
characteristics are associated with elevated serum markers of inflammation in humans. : J Magn Reson Imaging
2001 Dec

Levels of serum markers of inflammation in subjects with increased
Wall thickness, normal wall thickness but increased postcontrast
Signal intensity and/or T2-weighted and with normal MRI studies.
Weiss CR, Arai AE, Bui MN, Agyeman KO, Waclawiw MA, Balaban RS, Cannon RO 3rd. Arterial wall
MRI characteristics are associated with elevated serum markers of inflammation in humans.
: J Magn Reson Imaging 2001 Dec
Bar graphs show levels of serum markers of inflammation in 14 subjects
With increased wall thickness but increased postcontrast signal intensity
And/or T2-weighted (Gd/T2), and 30 subjects with normal MRI studies.

• Weiss and colleagues suggested that MRI
with gadolinium may permit the identification
Of inflammation, even in the absence of increased
Wall thickness.
• They determined that T2-weighted and
gadolinium contrast-enhanced properties Of MRI
may identify arterial inflammation at an earlier
Stage than is manifested by increased thickness
of the arterial wall.

• Also confirming the findings of Weiss et al,
Wasserman and Colleagues recently presented
That gadolinium enhancement of carotid arteries
By MRI was associated with fibrocellular tissue
In atherosclerotic plaque during subsequent
Microscopic analysis following endarterectomy.
• Preliminary work indicates gadolinium accumulates
In the arterial wall of patients with elevated serum
Markers of inflammation and in more advanced
Atheroma. Wasserman et al. determined that contrast
Administration (gadolinium) increased the MRI signal
of atherosclerotic plaques in rabbits.

Recently Yuan et al also showed that the use of
gadolinium improve the ability of MRI to detect
Neovascularization in the carotid atherosclerotic
Plaque and improve the differentiation of necrotic
Core from fibrous tissue in the plaque.
: Yuan C, Kerwin WS, Ferguson MS, Polissar N, Zhang S, Cai J, Hatsukami TS
Contrast-enhanced high resolution MRI for atherosclerotic carotid artery tissue
characterization. Magn Reson Imaging. 2002 Jan

Ruehm,Schmitz and Naghavi
independently reported a new method for MR
imaging of inflammation in atherosclerotic
Plaque using SPIO (super paramagnetic iron
Oxide). SPIO nanoparticles are FDA approved
Negative (blackening) contrast media for cancer
detection and lymphography. They are avidly taken
up by circulating monocytes and tissue macrophages
Thereby creating irregular dark spot on the inflamed
Atherosclerotic plaques.

Schmitz et al J. Inv. Radiol. 2000
Control
SPIO
Injected

Schmitz et al J. Inv. Radiol. 2000

Conclusion:
1. Gadolinium accumulates in the inflamed region
of arterial wall because of enhanced endothelial
Permeability with increased tissue water, cellular
Infiltration and vasa vasorum dilatation or
Neovascularization.
2. This technique may provide additional
Information related to activity of plaque,
besides structural imaging.

Conclusion:
3. SPIO has shown promising pre-clinical results
As an MRI contrast medium for the detection of
Atherosclerotic plaques, by providing negative
Enhancement (darkening) of the affected area.
4. Further clinical studies for both group of agents
Are required in order to confirm the hypothesis
And apply this methods in the clinical settings.

References:
1. Lauenstein T, Holtmann G, Schoenfelder D, Bosk S, Ruehm SG, Debatin JF
MR colonography without colonic cleansing: a new strategy
to improve patient acceptance.AJR Am J Roentgenol. 2001 Oct;177(4):823-7.
2. Schmitz SA, Taupitz M, Wagner S, Wolf KJ, Beyersdorff D, Hamm B.
Magnetic resonance imaging of atherosclerotic plaques using
superparamagnetic iron oxide particles.J Magn Reson Imaging. 2001 Oct;
3. Morteza Naghavi, Mitra Rajabi, Mohammad Asif, Michael Quast, Jingna Wei,
Daniel Chan, Mohammad Madjid, Khawar Gul, Samuel Ward Casscells III, James T.
Willerson. Detection of Macrophage infiltration and intraplaque hemorrhage in
Vulnerable atherosclerotic plaque using Magnetic Resonance Imaging contrast
media, Super paramagnetic iron oxide (SPIO). Proc Intl Soc. Mag Reson Med
9 (2001) 640.
4. Yuan C, Hatsukami TS, Obrien KD
High-Resolution magnetic resonance imaging of normal and atherosclerotic
human coronary arteries ex vivo: discrimination of plaque tissue components.
J Investig Med. 2001 Nov

References:
5.
Yuan C, Mitsumori LM, Ferguson MS, Polissar NL, Echelard D, Ortiz G, Small R, Davies JW, Kerwi
In vivo accuracy of multispectral magnetic resonance imaging for identifying lipid-
rich necrotic cores and intraplaque hemorrhage in advanced human carotid
plaques, Circulation. 2001 Oct 23
6.
Weiss CR, Arai AE, Bui MN, Agyeman KO, Waclawiw MA, Balaban RS, Cannon RO 3rd.
Arterial wall MRI characteristics are associated with elevated serum markers of
inflammation in humans.
J Magn Reson Imaging. 2001 Dec
7. Wasserman BA, Haacke EM, Li D.
Carotid plaque formation and its evaluation with angiography, ultrasound, and
MR angiography.J Magn Reson Imaging. 1994 Jul-Aug

Atherosclerosis, an Autoimmune Disease?
What could be the culprit antigen(s)? A brief appraisal of the role of heat
shock proteins.
Mohammad Madjid, MD
Center for Vulnerable Plaque Research
University of Texas-Houston Health Science Center and
Texas Heart Institute

 In1856 Virchow described atherosclerosis as “endarteritis”. A
century later Russel Ross named atherosclerosis “an
inflammatory disease”. Ross likened atherosclerosis to other
chronic inflammatory diseases such as rheumatoid arthritis and
glomerulonephritis. 1
 The central role of immune system in atherosclerosis and its
clinical complications is now widely accepted. Many
investigators are searching to find out what antigens attract
immune cells into the arterial wall and possibly later on into
atherosclerotic plaques. 2,3,4
 Autoantibodies against oxidized low-density lipoprotein
(oxLDL), cardiolipin, beta2-glycoprotein-I and heat-shock
protein 60/65 have been suggested. 2

 Georg Wick, Qingbo Xu, and colleagues have
hypothesized that an autoimmune reaction against
heat shock protein 60s, expressed by endothelial cells
in areas that are subject to increased hemodynamic
stress, is the initiating event in atherogenesis. 5,6
 The hypothesis indicates that because a high degree
of antigenic homology exists between microbial
(bacterial and parasitic) and human HSP60, the 'cost'
of immunity to microbes might be the danger of cross-
reactivity with human HSP60 expressed by the
endothelial cells of stressed arteries subjected to
classical risk factors.7

 Two major families of HSPs (60s and 70s) have been
related to atherosclerosis. Unlike HSP60s, HSP70s are
not reported as strong triggers of autoimmune reactions,
however, Bond, Johnson and colleagues have suggested
certain role for HSP70s in atherosclerosis. 8,9
 Chen et al described autologous hsp60 as a danger signal
to the innate immune system.10
 Xu et al. showed induction of arteriosclerosis in
normocholesterolemic rabbits by immunization with heat
shock protein 65. 5
 George, Afek, and colleagues reported induction of
arteriosclerosis in normocholesterolemic rabbits by
immunization with heat shock protein 65. 11,12

 A number of other experimental and observational studies
have shown a significant relationship between heat shock
proteins and atherosclerosis. 9,11,13,14
 In humans, expression of HSP60 is correlated positively with
atherosclerotic severity, with the highest levels of expression
seen in the shoulder regions and around the necrotic core of
atherosclerotic plaques. 15

 In addition to its antigenic properties, bacterial HSP60 product
may stimulate macrophages by production of cytokines such
as TNF-α and also MMPs. It may as well interfere with innate
immunity by binding to CD14 and activating monocytes and/or
macrophages and endothelial cells. 8, 21, 22
 Bocharov et al reported that HSP60 is a high-affinity high-
density lipoprotein binding protein suggesting a potential
mechanism to explain the known association between
immunity developed against HSP60 and the development of
atherosclerosis. 16

 Comparing the similarities between atherosclerosis and
other autoimmune disorders such as rheumatoid arthritis
(as indicated by Ross in the following slide) can also give
some hints about the potential role of autoimmune
mechanisms in atherosclerosis and it’s complications. 1
 Interestingly, recent studies have uncovered an important
role for heat shock proteins in pathogenesis of rheumatoid
arthritis. 17,18
 Like in rheumatoid arthritis, the suggested role of HSPs in
atherosclerosis may also in part explain the missing link
between infectious agents and atherosclerosis where a
high degree of antigenic homology between human and
microbial HSPs can cause cross-reaction. 17,7

DiseaseDisease Monocytes &Monocytes &
MacrophageMacrophage
LymphocyteLymphocyte GranulocyteGranulocyte Connective-Connective-
Tissue CellsTissue Cells
ExtracellularExtracellular
MatrixMatrix
Pathogenetic MechanismsPathogenetic Mechanisms
AtherosclerosisAtherosclerosis
++ ++ -- SMCsSMCs Collagen type I,Collagen type I,
III, IV, elastin,III, IV, elastin,
fibronectin,fibronectin,
proteoglycanproteoglycan
Endothelial-cell injury andEndothelial-cell injury and
dysfunction; fibrous cap; newdysfunction; fibrous cap; new
matrix formation &matrix formation &
degeneration; necrotic coredegeneration; necrotic core
CirrhosisCirrhosis
++ ++ -- FibroblastsFibroblasts Collagen type I,Collagen type I,
IIIIII
Parenchymal cell injury, newParenchymal cell injury, new
matrix and scarring replacingmatrix and scarring replacing
necrotic parenchymanecrotic parenchyma
RheumatoidRheumatoid
arthritisarthritis ++ ++ +/-+/- SynovialSynovial
fibroblastsfibroblasts
Collagen type I,Collagen type I,
III, fibronectin,III, fibronectin,
Synovial-cell injury; erosion ofSynovial-cell injury; erosion of
cartilage; new matrix scarringcartilage; new matrix scarring
(pannus)(pannus)
Glomeruloscle-Glomeruloscle-
rosisrosis ++ ++ -- Mesangial cellsMesangial cells Collagen type I,Collagen type I,
IV, fibronectinIV, fibronectin
Epithelial- and endothelial-cellEpithelial- and endothelial-cell
injury and dysfunction; decreaseinjury and dysfunction; decrease
in glomerular filtration; newin glomerular filtration; new
matrix formation;matrix formation;
Pulmonary fibrosisPulmonary fibrosis
++ ++ +/-+/- SMCs,SMCs,
FibroblastsFibroblasts
Collagen typeCollagen type
III, IV,III, IV,
fibronectinfibronectin
Inflammatory exudate in alveoliInflammatory exudate in alveoli
& bronchi; organized by& bronchi; organized by
extensive matrix deposition andextensive matrix deposition and
scarringscarring
ChronicChronic
pancreatitispancreatitis ++ ++ -- FibroblastsFibroblasts Collagen,Collagen,
fibronectin,fibronectin,
Epithelial injury; periductalEpithelial injury; periductal
inflammation; interstitial fatinflammation; interstitial fat
necrosis; new matrix formationnecrosis; new matrix formation
Ross R. Atherosclerosis--an inflammatory disease. N Engl J Med. 1999 Jan 14;340(2):115-26

 Kanwar, Krissansen, et al. found that expression of
HSP60 and HSP70 was strongly upregulated very
early at lesion-prone sites in the aortas of young
apoE-/- knockout mice and then dramatically down-
regulated in the chronic lesions of aged mice. 20
 They showed that HSP60 and HSP70 were detectable
in the aortas of 3-week-old apoE-/- mice and were
highly expressed in the aortas of 8-week-old mice. 20

 Kanwar et al. indicated that in 8-week-old apoE-/-
mice, HSP60 and 70 were strongly expressed at valve
commissures of the aortic sinus, extending to the free
aortic wall and including expression by endothelial and
intimal cells. 20
 They concluded that HSP60 and HSP70 were
heterogeneously expressed in lesions of 20-week-old
mice. HSP60 and HSP70 were strongly expressed in
advanced plaques of the abdominal aorta of 20-week-
old mice, whereas medial layers lack expression. 20

 In 69-week-old mice, there was complete loss of
HSP60 and HSP70 in advanced complicated
collagen-rich plaques of the aortic sinus. (down-
regulated in aged mice) 20
 As a result of this study, lesion-prone sites
displayed strong endothelial HSP60 expression,
whereas non–lesion-prone sites of the distal
abdominal aorta lacked hsp expression. 20
 Monocytes/macrophages expressing HSP70 and
hsp60 (data not shown) were the most prominent
cell type in lesions. 20

Summary:Summary:
1- Autoimmune reactions (cellular and humoral) against HSPs
particularly HSP60s may play an important role in early stage
development of atherosclerosis.
2- HSP60s and HSP70s released from necrotic cells in the core
area of advanced plaques may stimulate the innate immune
response to promote inflammation and attract new
inflammatory cells thereby may link to complications of plaque
such as rupture and or thrombosis.
3- Humoral and cellular reactions against HSP60 work in
conjunction with classical proven CVD risk factors.

Debates:Debates:
I. According to our current body of knowledge, the
development of atherosclerosis seems to have two major
preceding components, metabolic disorder (lipid abnormality
etc.) and inflammatory disorder (enhanced immune or
autoimmune response). The question is which one comes
first?
II. Since the complication of atherosclerosis (vulnerable
plaque) is more important than it’s development (stable
plaque), the question is which one of the two (1-metabolic, 2-
Immune) components of atherosclerosis plays a more
important role?

Debates:Debates:
III. How feasible is the idea of vaccination against HSPs or
oxidized-LDL or other suggested antigens? Can we induce
tolerance against HSPs without damaging the innate
immune system?
IV. Which one is more feasible? Eradication of atherosclerosis
by vaccination against triggers of plaque development, or,
eradication of vulnerable plaque by vaccination against
triggers of plaque vulnerability?

1. Ross R. Atherosclerosis--an inflammatory disease.
N Engl J Med. 1999 Jan 14;340(2):115-26. Review
2. Shoenfeld Y, Sherer Y, George J, Harats D. ;Autoantibodies associated with atherosclerosis.
Ann Med. 2000 Dec;32 Suppl 1:37-40. Review.
3. Hansson, G.; Immunological markers of atherosclerosis.
Lancet. 1993 Jan 30;341(8840):278.
4. Witztum JL, Palinski W. ; Are immunological mechanisms relevant for the development of
atherosclerosis? Clin Immunol. 1999 Feb;90(2):153-6. Review.
5. Xu Q, Dietrich H, Steiner HJ, Gown AM, Schoel B, Mikuz G, Kaufmann SH, Wick G. ;
Induction of arteriosclerosis in normocholesterolemic rabbits by immunization with heat
shock protein 65. Arterioscler Thromb. 1992 Jul;12(7):789-99.
6. Wick G, Schett G, Amberger A, Kleindienst R, Xu Q.; Is atherosclerosis an immunologically
mediated disease?; Immunol Today. 1995 Jan;16(1):27-33. Review.
References

7. Wick G, Perschinka H, Millonig G. ; Atherosclerosis as an autoimmune disease: an update.;
Trends Immunol. 2001 Dec 1;22(12):665-669.
8. Johnson AD, Berberian PA, Tytell M, Bond MG. ; Differential distribution of 70-kD heat
shock protein in atherosclerosis. Its potential role in arterial SMC survival.; Arterioscler
Thromb Vasc Biol. 1995 Jan;15(1):27-36.
9. Berberian PA, Myers W, Tytell M, Challa V, Bond MG.; Immunohistochemical localization of
heat shock protein-70 in normal-appearing and atherosclerotic specimens of human
arteries.; Am J Pathol. 1990 Jan;136(1):71-80.
10. Chen W, Syldath U, Bellmann K, Burkart V, Kolb H.; Human 60-kDa heat-shock protein: a
danger signal to the innate immune system.; J Immunol. 1999 Mar 15;162(6):3212-9.
11. George J, Shoenfeld Y, Afek A, Gilburd B, Keren P, Shaish A, Kopolovic J, Wick G, Harats
D.; Enhanced fatty streak formation in C57BL/6J mice by immunization with heat shock
protein-65. Arterioscler Thromb Vasc Biol. 1999 Mar;19(3):505-10.
References

12. Afek A, George J, Gilburd B, Rauova L, Goldberg I, Kopolovic J, Harats D, Shoenfeld Y.;
Immunization of low-density lipoprotein receptor deficient (LDL-RD) mice with heat shock
protein 65 (HSP-65) promotes early atherosclerosis.; J Autoimmun. 2000 Mar;14(2):115-21.
13. Hansen PR, Chew M, Zhou J, Daugherty A, Heegaard N, Jensen P, Mouritsen S, Falk E.;
Freunds adjuvant alone is antiatherogenic in apoE-deficient mice and specific immunization
against TNFalpha confers no additional benefit.
Atherosclerosis. 2001 Sep;158(1):87-94.
14. George J, Afek A, Gilburd B, Shoenfeld Y, Harats D.; Cellular and humoral immune
responses to heat shock protein 65 are both involved in promoting fatty-streak formation in
LDL-receptor deficient mice.
J Am Coll Cardiol. 2001 Sep;38(3):900-5.
15. Kleindienst R, Xu Q, Willeit J, Waldenberger FR, Weimann S, Wick G.
Immunology of atherosclerosis. Demonstration of heat shock protein 60 expression and T
lymphocytes bearing alpha/beta or gamma/delta receptor in human atherosclerotic lesions.;
Am J Pathol. 1993 Jun;142(6):1927-37.
References

16. Bocharov AV, Vishnyakova TG, Baranova IN, Remaley AT, Patterson AP, Eggerman TL.;
Heat shock protein 60 is a high-affinity high-density lipoprotein binding protein.; Biochem
Biophys Res Commun. 2000 Oct 14;277(1):228-35.
17. Gaston, JS.; Heat shock proteins and arthritis--new readers start here.
Autoimmunity. 1997;26(1):33-42. Review.
18. Schett G, Tohidast-Akrad M, Steiner G, Smolen J.; The stressed synovium.; Arthritis Res.
2001;3(2):80-6. Review.
19. Gaston, JS. ; Heat shock proteins and arthritis--new readers start here.; Autoimmunity.
1997;26(1):33-42. Review.
20. Rupinder K. Kanwar, Jagat R. Kanwar, Dongmao Wang, Douglas J. Ormrod,
and Geoffrey W. Krissansen Temporal Expression of Heat Shock Proteins 60
and 70 at Lesion-Prone Sites During Atherogenesis in ApoE-Deficient Mice
Arterioscler Thromb Vasc Biol 2001 21: 1991-1997.
References

21.21. Kol A, Sukhova GK, Lichtman AH, Libby P.Kol A, Sukhova GK, Lichtman AH, Libby P. Chlamydial heat shock protein 60 localizes inChlamydial heat shock protein 60 localizes in
human atheroma and regulates macrophage tumor necrosis factor-alpha and matrixhuman atheroma and regulates macrophage tumor necrosis factor-alpha and matrix
metalloproteinase expression. Circulation. 1998 Jul 28;98(4):300-7.metalloproteinase expression. Circulation. 1998 Jul 28;98(4):300-7.
22.22. Kol A, Lichtman AH, Finberg RW, Libby P, Kurt-Jones EA.Kol A, Lichtman AH, Finberg RW, Libby P, Kurt-Jones EA. Cutting edge: heat shock proteinCutting edge: heat shock protein
(HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60(HSP) 60 activates the innate immune response: CD14 is an essential receptor for HSP60
activation of mononuclear cells. J Immunol. 2000 Jan 1;164(1):13-7.activation of mononuclear cells. J Immunol. 2000 Jan 1;164(1):13-7.
References

Embolic Protection DevicesEmbolic Protection Devices
Jay S. Yadav
M.D.
Director, Vascular
Intervention
Department of
Cardiovascular
Medicine
The Cleveland
Clinic Foundation

Everyone Embolizes
ejt 048–114
Pettelot, et al. Circ 97:1522, 1998Pettelot, et al. Circ 97:1522, 1998

Embolization
Common and under recognized
CABG 6% stroke
CEA 3-10%
SVG PTCA 4-18% NQMI
Coronary Intervention 9%?
Arterial Thrombolysis 6-20% foot ischemia
Venous Thrombolysis 5-20% pulm embol
Mitral Valvuloplasty 1-28%
AAA stent grafting 5-11% foot ischemia

Acute Coronary Syndromes
ejt 029–144
The “Hot” VesselThe “Hot” Vessel
MicrovascularMicrovascular
ObstructionObstruction
1000x1000x
5x5x

BasalBasal PeakPeak
00
55
1010
1515
2020
2525
Heparin Alone, N=98
Abciximab, N=102
² * Coronary Flow Velocity (cm/s)² * Coronary Flow Velocity (cm/s)
IIb/IIIa ↓ in Acute
MI
ejt 106– 2110
↑↑ Microvascular PerfusionMicrovascular Perfusion
p = 0.15
* From baseline to day 14* From baseline to day 14
p = 0.024
Neumann, et al. Circ 98:2695–2701, 1998Neumann, et al. Circ 98:2695–2701, 1998

Transcranial Doppler (TCD)
MIDDLE
CEREBRAL
ARTERY
VELOCITY
CM/SEC
EMBOLI
BALLOON INFLATED DEFLATED

Ex-Vivo Carotid Plaque Embolization
Model - Ohki

Embolic Particles were generated from each plaque
Ex-Vivo Carotid Plaque Embolization Model
Ohki T et al. J Vasc Surg 1998; 27:463-71
YADAV

Ex-Vivo Carotid Plaque Embolization Model
Ohki T et al. J Vasc Surg 1998; 27:463-71
Number of emboli and lesion characteristics
Echolucent
0
25
50
75
100
125
Echogenic
Numberofparticles
p=0.012
Numberofparticles
0
25
50
75
100
125
50 60 70 80 90 100
% Stenosis

Why Are There Not More
Strokes With Carotid Stenting?
Rapp et al J Vasc Surgery 2000;32:68-76
Ex vivo carotid plaque PTA
Particles injected into Rat ICA
Grp A: <200 u 100 particles
Grp B: 200 to 500 u 100 particles
50 atheroemboli / gram of brain
Human brain 1300 g, rat brain 2 g

Rapp et al J Vasc Surgery 2000;32:68-76
Most particles released during
PTA/Stenting
<200 u 200-500 u
Day 1 & 3 nl neuronal
isch
Day 7 neuronal ischemia

Anti-Embolization Devices
Occlusive:
– Distal Flow Arrest
» Theron - Balloon Occlusion Catheter
» PercuSurge - Balloon Occlusion Guidewire
– Proximal Flow Arrest
» Arteria- Balloon Occlusion Guide
Catheter

Anti-Embolization Devices
Non-Occlusive:
– Supported Filters:
» AngioGuard - Guidewire Filter
» MedNova - Guidewire Filter
» Trap- Nitinol Filter
– Unsupported Filters:
» EPI- Guidewire Filter
» Etrap - Guidewire Filter

Arteria Proximal Flow Arrest - Parodi

External to internal carotid
flow during common carotid
Occlusion:
Baseline External Occlusion: 1 pt
ICA to ECA flow: 10 pts / 7.3 %
ECA to ICA flow: 62 pts / 84.9 %
Results:

1st Generation 3.9F sheath - 0.014” Wire
Capture Efficiency
Particle Retention
Trackability & Flexibility
One to One Torquability
Radiopacity
Withdraws into 0.035” angioplasty balloon
Universal Application
Uninterrupted blood flow
( 80µm pores )
EPI

DeviceWire
• Offered in 2.5, 3.0, 3.5, 4.0, 5.0, 6.0, and 7.0 mm basket diameters*.
7.0mm
4.0mm
2.5mm
*Sizes Nominal
Microvena Trap

PercuSurge Guard Wire
SAFER trial
SVG’s randomized to regular wires vs
Percusurge
750 pts
60 centers

Age 68
DM 35%
Class III/IV angina 75%
Lesion length 15 mm
Thrombus 38%

PS No PS
TIMI III 98 % 94 %
No Reflow 3.4 % 8 %
Q MI 1.1 % 2.2 %
NQ MI 7.3 % 14.4 %
MACE 8.4 % 17.3 % p=.001

Acute MI
Belli, AJC,2000, TCT abstracts
20 pts AMI
Percusurge
17 primary PTCA, 3 rescue
All received Abciximab
Procedural success: 18/20
TIMI III: 14/20

Renal Artery Intervention
Henry, AJC, Oct 2000, TCT abstracts
30 renal arteries - 27 ostial
Percusurge
Technical Success: 30/30
Renal art occl time: 418 secs (149 - 797)
No renal fx deterioration at 6 months

Reduced Delivery Profile
New 4 mm @ 3.2 F profile
Current 4 mm @ 4.6 F profile
Crossing Profiles
4 mm 3.2 F
5 mm 3.3 F
6 mm 3.5 F
7 mm 3.7 F
8 mm 3.9 F
Lubricious coating on delivery sheath

German Experience
Eberhard Grube, Siegburg, GR
21 patients :
–9 native coronary
–4 carotid bifurcation
–6 SVG

Cordis AngioGuard Clinical Data
Vessel diam 3.3 + 0.35 mm (2.8-5.8)
Stenosis 89% + 8.5% (70% - 95%)
Procedural Success 100%

Cordis AngioGuard Pathologic Data
U of Minnesota
Particles recovered from all patients
Number 147 + 111 (20 - 361)
Size (Area) 0.10 mm2
+ 0.5 mm2
(0.015-20)
Embolic Burden per pt:
37 mm2
+ 36 mm2
(0.6 mm2
- 110 mm2
)

Filter Surface Coverage
31 32
36
0
5
10
15
20
25
30
35
40
% Filter Surface Coverage
SVG Carotid Native Coronary
Average % of filter surface covered with embolic particles
Range 0-80Range 0-60Range 5-50

Embolic Particle Size
0
100000
200000
300000
400000
X-sectionalareaum^2
Largest
Maximum particle size recovered

Embolic Particle Size
0
10000
20000
30000
40000
X-sectionalareaum^2
Average
Average particle size recovered

Coronary SVG
Carotid
E. Grube
Siegburg, GR

Material Recovered during PTCA

SAPPHIRE RCT + Registry
– 30 Centers
– 600 - 900 RCT
– 400 Registry
– 30 patients per center

SAPPHIRE
– Asymptomatic >80%
– Symptomatic >70%
– RCT
– High risk

SAPPHIRE: Profile of high risk
patients in trial
CHF class III/IV and / or LVEF <30%
Open heart surgery W/I 6 weeks
Recent MI (>24hrs <4weeks)
Unstable angina (CCS class III/IV)
Synchronous severe CAD and carotid
disease
Severe pulmonary disease (FEV<1.0)

SAPPHIRE: Profile of high risk
patients in trial
Contralateral carotid occlusion
Contra. laryn palsy; post-rad Rx, prev. CEA
CCA lesions below clavicle
High cervicl ICA
Severe tandem lesions

Sapphire
Status of Patient Entry
Total enrollment
– 715 pts -
Randomized
– 312 pts
Stent registry
– 400 pts (closed)
Surgical registry
– 3

CREST - RCT
Symptomatic Patients (NASCET)
Enrolling 2500
– CEA vs. CS
– 60 Centers
– Enrollment - 40+ pts/center - 3 yrs

REGISTRIES
– ARCHER 300 pts
– EndoTex 300 pts
– Shelter 630 pts
– CARESS 2000 pts
– Maverick 400 pts

Guidant ACCUNET™ Embolic Protection System
Filter Basket Specifications
Polyurethane filter
over Nitinol basket
Diameters: 4-8 mm
Filter pore size ≤
120 microns
Designed to maintain
perfusion
Caution: Investigational device. Limited by Federal (U.S.) Law to investigational use.

CAROTID Trials
Trials Device D.P.D.
Sapphire 5F Precise Angioguard-ex
Crest 6F Acculink Accunet
Shelter 5.5 F Wallstent Percusurge
Caress 5.5 F Wallstent Percusurge
EndoTex 5F Nexstent TBA
Archer 6F Acculink Accunet
Maverick Medtronic-AVE Percusurge
Bard 7F Memotherm Trial Stopped
EPI

Conclusions
Definite Role for Emboli Prevention
Devices in Coronary and Peripheral
Intervention
Selective and Data Driven
Most Compelling for Carotids, SVGs, MI,
Renals

GPIIb/IIIa Inhibition and EmboliGPIIb/IIIa Inhibition and Emboli
Prevention Devices?Prevention Devices?

Editorial Slides
VP Watch, January 16, 2002, Volume 2, Issue 2
Part II - Animal Models of Heart Attack?A Review

Part - I
 Cell culture is a convenient way to ask mechanistic
questions, but it lacks complexity of a real disease thus
limiting the scope of testable hypotheses. Human
observations provide rich soil for making hypotheses, but
for obvious ethical reasons our ability to test these
hypotheses in men is very limited. Animal models are
essential for testing mechanistic hypotheses in a
controlled manner.1
 Ideal animal model is situated in the middle of this range.
1

1- Japanese
quail
2- Pigeon
3- Chicken
Reported Animal Models for
Atherosclerosis
4- Dog
5- Monkey
6- Pig
7- Rat
8- Rabbit
9- Mouse

 Quail:
- Studies on Japanese quail have shown that the RES
birds were resistant to the disease and developed little
atherosclerosis on a diet containing 1% cholesterol. The
SUS birds were sensitive and developed severe
atherosclerosis in 8-9 wks on a diet containing only 0.5%
cholesterol. 14,15,16

 Pigeon:
- Tesar and Kottke showed that two distinct types of fatty
streaks can be identified in white Carneau pigeon and
their biologic features can be defined and related to their
propensity for atherogenesis.6

 Chicken:
- Wong discussed that chicken is a good animal model for
the study of atherosclerosis research because it is able to
develop spontaneous atherosclerosis and capable of
producing atherosclerosis after cholesterol feeding with
elevated hypercholesterolemia. There is no essential
difference between vascular lesions seen in chickens as
a result of cholesterol diet and that of atherosclerosis
observed in man.2,3

 Dog:
- Reducing platelet accumulation at sites of balloon
angioplasty may attenuate restenosis. Willerson, et al.
tested this hypothesis by inducing repetitive platelet
aggregation at coronary angioplasty sites in cholesterol
sensitive dogs and measured subsequent neointima
formation. 4,5

 Monkey:
- Blaton and Peeters discussed that the chimpanzee
lipoproteins are useful models for understanding the
relationship between function and structure of the plasma
lipoproteins in health and disease. Baboon and rhesus
monkeys show similar results, but more differences to the
human lipoproteins in health and disease were
observed.8,9

 Swine:
- Massmann, and others showed relations between
spontaneous and induced arterial lesions in swine and
arteriosclerosis in humans. 7,21

 Rat:
- Bennani-Kabchi et al. showed the potential of the sand rat
to develop atherosclerotic lesions at different stages
which opens the field to therapeutic tests of new anti-
atherogenic agents.
- More recently Herrera et al. demonstrated that cholesteryl
ester transfer protein can be proatherogenic. The
interaction of polygenic hypertension and hyperlipidemia
in the pathogenesis of atherosclerosis in Tg [hCETP] DS
rats substantiates epidemiological observations in
humans.10,11

 Rabbit:
- Hereditary Watanabe rabbit - Clubb et al.
evaluated temporal distribution of leukocytes,
macrophages, foam cells, vascular smooth muscle cells,
and subendothelial lipid in Watanabe heritable
hyperlipedimic (WHHL) rabbit aortas.19
- Cholesterol fed New Zealand rabbit -
Atherosclerotic plaques were produced in New Zealand
White rabbits by intermittent cholesterol feeding.20

 Rekhter, et al. have developed a rabbit model
in which an atherosclerotic plaque can be
ruptured at will after an inflatable balloon
becomes embedded into the plaque. This
model as well can be used for induction of
thrombi associated with plaque rupture. 17

 Mouse:
- The apoE-deficient mouse contains the entire spectrum of
lesions observed during atherogenesis and is the first
mouse model to develop lesions similar to those in
humans. 12,13

Part - II
 The process of atherosclerotic plaque disruption has been
difficult to monitor because of the lack of an animal model of
plaque rupture. 23
 More than 30 years ago, Constantinides and Chakravarti
triggered plaque rupture and thrombosis in aorta of
chlolesterol fed rabbits by intraperitoneal injection of
Russell's viper venom (RVV, a potent procoagulant and
endothelial toxin) followed by the intravenous injection of
histamine, a vasopressor. 25
 The aortas of the rabbits were then accordingly found to
have disrupted atherosclerotic plaques with overlying
platelet-rich thrombi. 25

 The advantage of Constantinides model is use of a
biological intervention for triggering localized plaque
thrombosis. However the non-physiological use of a toxic
and potent thrombogenic substance (snake toxin) to
induce plaque thrombosis can be considered a major
drawback. 24
 Other disadvantages of the Constantinides model are the
low yield of triggering (only about one third of the rabbits
developed thrombosis) and the long (8-month)
preparatory period. 24

 Abela, Muller and colleagues challenged the limitations of
Constantinides model by having the rabbits undergo aortic
balloon injury followed by 8 weeks of 1% cholesterol diet. 24
 In addition, they wanted to determine whether mechanical
injury to the aorta early in the preparatory phase could
enhance the development of vulnerable plaques, thereby
increasing the yield of disrupted plaques and shortening the
preparatory period. the rate of plaque disruption after
pharmacological triggering increased to 71%. 24
 They found that the rate of plaque disruption after
pharmacological triggering increased up to 71%.24

 Johnstone, Manning, and colleagues used the modified
Constantinides model and documented plaque disruption by
MRI that resemble those found in human coronary arteries. 23
 A major advantage of the use of a rabbit over other animals
is that the rabbit’s aorta is approximately the same anatomic
size as the human coronary artery. 23

 As highlighted in this week of VP Watch, Braun,
Krieger, et al. showed that mice with homozygous null
mutations in the genes for both the LDL and apoE
receptors (SR-BI/apoE double knockout mice) exhibit
morphological and functional defects with similarities
to those seen in human coronary heart disease.22
 The SR-BI/apoE dKO mice are distinct
because they have extensive coronary artery
lesions with fibrin deposition and
spontaneously develop extensive MIs on a
standard chow diet at a very young age (5
weeks).22

 The authors indicated that severe occlusive,
fibrin-containing coronary arterial lesions,
probable ischemia, multiple MIs, enlarged
hearts, and cardiac dysfunction in very young
('5 weeks old), low-fat/ low-cholesterol fed
SR-BI/apoE dKO mice provide a novel model
of CHD.22
 Fibrin deposits were found in the core regions
of 8 of 10 lesions in 3 of 3 dKO mice.22
 However, clear evidence for plaque rupture was not
found in these animals neither was thin fibrous
cap.22

Arterial remodeling paul sch

Arterial remodeling paul sch

Recommended

Recommended

More Related Content

What's hot

What's hot (20)

Viewers also liked

Viewers also liked (17)

Similar to Arterial remodeling paul sch

Similar to Arterial remodeling paul sch (20)

More from Society for Heart Attack Prevention and Eradication

More from Society for Heart Attack Prevention and Eradication (20)

Recently uploaded

Recently uploaded (20)

Arterial remodeling paul sch

Editor's Notes