Existing intravascular imaging technology for plaque characterization

The Ultimate Existing IntravascularThe Ultimate Existing Intravascular
Imaging Technology for PlaqueImaging Technology for Plaque
CharacterizationCharacterization
Patrick W. Serruys, MD, PhDPatrick W. Serruys, MD, PhD
Professor of Interventional CardiologyProfessor of Interventional Cardiology
Thoraxcenter, Erasmus MC, RotterdamThoraxcenter, Erasmus MC, Rotterdam
1212stst
Nov 2005, 14:30-14:45,Nov 2005, 14:30-14:45,
Hyatt Regency HotelHyatt Regency Hotel
AEHA VP summit
Luminology, Virtual Histology, Palpography, Shear Stress
Mapping and Vasa vasorum Imaging
All in One!

C h e s t- P a in
a tta c k
N o n - In v a s iv e
Im a g in g
B io m a r k e r s
E n tr ie s in t h e D ia g n o s tic p r o c e s s
µ
The “new diagnostic world“
of the vulnerable plaque
Chest pain MSCT Biomarkers
QCA
<50%DS
QIVUS
>50% EEM
obstruction
VH
Necrotic core
rich lesion
Palpography
High-Strain
iv MRI OCT
Thin cap
Invasive assessment
of non-flow limiting lesion
Chest pain
High Risk
Vasa
vasorum
Necrotic core

Mean PB (%)
Mean MLD (mm)
Proximal Distal
0
10
20
30
40
50
60
0
1
2
3
4
5
6
90 patients
121 vessels
4840 CSAs
Percentage
mm
Sub-segments 1 2 3 4
Luminology
Conclusions At the startof the stenosis, ICUS demonstrated
a mean 50±11% totalvessel area stenosis, with a
characteristic loss of disease-free arcs of arterial wall
Escaned J and Serruys PW. Circulation. 1996 Sep
1;94(5):966-72.

Intravascular Imaging Modalities
IVUS (gray scale)
(plaque size)
(echogenicity)
(Vasa vasorum)
IVUS Palpography
(mechanical properties)
Optical Coherence Tomography
Intravascular MRI
Virtual Histology
(plaque composition)
Acquired
with single
pull back
IVUS
catheter

A B D
a b c d Distal
TOMTEC Surgical view®
ECG gated acquisition
C
remodeling Non-ECG gated acquisition
First step
identify regions
with 40 - 50 % EEM Obstruction

Nair A et al. Circulation. 2002;106:2200-2206
FIBROUS
FIBROFATT
Y
CALCIUM
LIPID CORE
MEDIA
VH Legend
Virtual Histology or… How to convert an
ex Vivo IVUS image into a color coded
histological cross section… by correlating
backscattered radiofrequency signals with
human ex vivo coronary histology

Incidence of IVUS-Derived Thin-Cap Fibroatheroma (IDTCFA)
Global characterization of coronary plaque rupture phenotype
using 3-vessel intravascular ultrasound radiofrequency data
analysis
Coronary artery remodeling and plaque composition
Plaque Composition and Shear Stress
Change in plaque composition along coronary artery
Rodriguez-Granillo GA,Serruys P W. In vivo intravascular derided thin-cap fibroatheroma detection
using ultrasound radiofrequency data analysis. J Am Coll Cardiol. In press.
GA Rodriguez-Granillo et al and Serruys. Submitted
Rodriguez Granillo GA, Serruys PW, García-García HM, et al. Heart. Jun 17; [Epub ahead ofRodriguez Granillo GA, Serruys PW, García-García HM, et al. Heart. Jun 17; [Epub ahead of
print].print].Coronary plaque composition of non-culprit lesions by in vivo intravascular ultrasound radiofrequency dataCoronary plaque composition of non-culprit lesions by in vivo intravascular ultrasound radiofrequency data
analysis is related to clinical presentation.analysis is related to clinical presentation.
Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al. Am Heart Journal.Am Heart Journal. In pressIn press
Plaque Composition and its Relationship with Acknowledged Shear Stress Patterns in Coronary Arteries.Plaque Composition and its Relationship with Acknowledged Shear Stress Patterns in Coronary Arteries.
Rodriguez Granillo GA, Serruys PW et al. JACC. In press Rodriguez Granillo GA, Serruys PW et al. JACC. In press
Distance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo AnDistance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo An
Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans.Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans.
Valgimigli M, Serruys PW, et al. Eur Heart J.Valgimigli M, Serruys PW, et al. Eur Heart J. Revision.Revision.
In-vivo relationship between compositional and mechanica
imaging of coronary arteries
In vivo relationship between compositional and mechanical imaging of coronary arteries: insightsIn vivo relationship between compositional and mechanical imaging of coronary arteries: insights
from intravascular ultrasound radiofrequency data analysis.from intravascular ultrasound radiofrequency data analysis.
Rodriguez Granillo GA, Serruys PW et al. Am Heart J. In press.Rodriguez Granillo GA, Serruys PW et al. Am Heart J. In press.
#1
#2
#3
#4
#5
#6

Definition of IVUS-Derived Thin-Cap
Fibroatheroma (IDTCFA)
1. Focal (adjacent to non-TCFA)
2. Lipid core ≥10%
3. In direct contact with the lumen
4. Percent area obstruction ≥40%
CALCIFIED PLAQUE
MACROPHAGE FOAM CELLS
NECROTIC CORE
COLLAGEN
FIBROUS
FIBROFATT
Y
CALCIUM
LIPID CORE
MEDIA
VH Legend
Histology legend
•Per 3 consecutive frames with all characteristics
Rodriguez-Granillo GA,Serruys P W. In vivo intravascular derided thin-cap fibroatheroma detection using
ultrasound radiofrequency data analysis. J Am Coll Cardiol. In press.

IDTCFAIDTCFA IDTCFA/cmIDTCFA/cm
Stable (N=Stable (N= 3232))
ACSACS (N=(N=2323))
p valuep value
1.0 (0.0,2.8)1.0 (0.0,2.8) 0.2 (0.0,0.7)0.2 (0.0,0.7)
3.0 (0.0, 5.0)3.0 (0.0, 5.0) 0.7 (0.0,1.3)0.7 (0.0,1.3)
0.0310.0310.0180.018
Incidence of IDTCFA lesions in non-culprit
coronary vessels (n= 55)
Continuous variables are presented as medians (25th
, 75th
percentile) or means ±
SD when indicated.
Rodriguez-Granillo GA et al. J Am Coll Cardiol. In
press.
#1

Baseline characteristics (n: 40)
20 patients with one or more plaque ruptures
20 patients without plaque rupture
n (%)
Age (years±SD) 55.7±11.0
Male sex 29 (72.0)
Diabetes 4 (10.0)
Hypertension 17 (42.5)
Current smoking 15 (37.5)
Previous smoking 6 (15.0)
Hypercholesterolemia 20 (50.0)
Family history of coronary disease 19 (47.5)
Body mass index (kg/m2 ±SD) 27.1±3.4
LDL (mmol/L±SD) 2.70±0.7
HDL (mmol/L±SD) 1.20±0.5
Clinical Presentation
Stable angina 13 (32.5)
Unstable angina 12 (30.0)
Acute myocardial infarction 15 (37.5)
#1

Three-vessel imaging using
IVUS-VH in a 57 year-old
male presenting with
unstable angina.
Plaque rupture in the ostial
LAD (LAD a).
The underlying substrate of
the cavity is rich in necrotic-
core (red) and calcium
(white), whereas the
thrombus has migrated
distally (LAD c, *).
Patient 051229
#2

Differences between the coronaries (n= 101)
LAD (n= 37) LCx (n= 32) RCA (n=32) p value

Analyzed length (mm±SD) 42.37±17.7 48.85±20.9 51.76±16.6 0.06
Geometrical parameters
Lumen CSA (mm2
) 8.53±2.6 9.26±3.2 11.07±4.6 0.01
Vessel CSA (mm2
) 14.94±4.6 14.18±5.6 16.81±6.8 0.17
Plaque CSA (mm2
) 6.43±2.8 4.92±3.3 5.74±3.0 0.13
Plaque max. thickness (mm) 1.05±0.3 0.84±0.3 0.85±0.3 0.002
Plaque burden (%) 42.2±9.9 33.17±9.2 33.96±10.3 <0.001

Compositional parameters
Calcium (%) 3.81±3.2 2.94±2.9 1.78±1.7 0.01
Fibrous (%) 59.52±13.1 53.44±14.3 57.39±14.9 0.20
Fibrolipidic (%) 18.46±8.3 17.07±7.7 19.45±9.8 0.54
Necrotic core (%) 11.48±6.8 8.88±6.1 8.78±5.2 0.12
Values are expressed in means ±SD. ANOVA was used to compare groups except from * where Kruskal-Wallis was applied. LAD,
LCx and RCA refer to left anterior descending, left circumflex and right coronary arteries, respectively. CSA refers to cross-sectional
area.
#2
< <
>
>
>
>
The LAD presented more severe plaques, more calcified
plaques and showed a trend towards larger necrotic core
content of plaques compared to the LCx and the RCA
respectively

Focal characteristics of ruptured plaques (20)
and minimal lumen area (MLA) controls (n= 28)

Rupture site MLA site p value

Lumen CSA (mm2
) 9.47±6.3 6.76±4.2 <0.001
Vessel CSA (mm2
) 19.09±9.3 19.15±9.8 0.95
Plaque CSA (mm2
) 9.63±4.2 12.38±6.9 0.01
Plaque max. thickness (mm) 1.38±0.3 1.71±0.5 0.002
Plaque burden (%) 51.32±10.6 64.06±10.1 <0.001

Calcium (%) 6.07±6.3 4.60±4.6 0.10
Fibrous (%) 59.46±11.8 60.22±9.6 0.60
Fibrolipidic (%) 16.99±9.4 22.08±9.8 0.01
Necrotic core (%) 17.48±10.8 13.10±6.5 0.03
Values are expressed in means ±SD. CSA refers to cross-sectional area.
#2
Plaque rupture sites showed a higher relative
content of necrotic core compared to MLA sites
(17.48±10.8 % vs. 13.10±6.5 %, p= 0.03) and a
trend towards higher calcified component.
<
>
<
<
>

IVUS-derived of patients with and without
the presence of plaque rupture

Rupture (n=20) No rupture (n=20) p value

Lumen CSA (mm2
) 9.6±3.3 9.2±2.3 0.60
Vessel CSA (mm2
) 16.5±6.0 13.8±2.7 0.08
Plaque CSA (mm2
) 6.9±3.3 4.6±1.4 0.01
Plaque burden (%) 40.7±7.6 33.7±8.4 0.01

Calcium CSA (mm2
) 0.15±0.16 0.07±0.08 0.05
Fibrous CSA (mm2
) 2.48±1.7 1.24±0.7 0.01
Fibrolipidic CSA (mm2
) 0.82±0.8 0.44±0.3 0.06
Necrotic core CSA (mm2
) 0.44±0.3 0.22±0.2 0.01
#2
Conclusions: In this study, patients with at least one
PR in their coronary tree had in average more
severe IVUS-derived characteristics compared to
patients without evidence of PR.
>
>
>
>
>
>
>

Positive remodeled sections have been associated with:
1. Worse clinical presentation
2. Higher macrophage counts
3. Larger lipid cores
4. Pronounced medial thinning
Vulnerable plaque
phenotype
Smits PC, et al. Heart. 1999;82:461-4.
Schoenhagen P, et al. Circulation.
2000;101:598-603.
Nakamura M, et al. J Am Coll Cardiol.
2001;37:63-9.
Vascular
remodeling
Burke AP, et al. Circulation. 2002;105:297-303.
Varnava AM, et al. Circulation. 2002;105:939-43.
Schaar JA, et al. Eur Heart J. 2004;25:1077-82.
Positive
remodeling
Negative
remodeling
RI = EEM CSA (MLA site) /
EEM CSA (reference site)
= RI= RI ≥ 1.05≥ 1.05
= RI ≤ 0.95= RI ≤ 0.95
Remodeling index
(RI)
#3

y: 47,197x - 32,165
r: 0,83 p: <0,0001
0
5
10
15
20
25
30
35
0,5 0,6 0,7 0,8 0,9 1 1,1 1,2 1,3 1,4
Remodeling index
Lipidcore%CSA
Coronary Artery Remodeling is related to
plaque composition determined by IVUS-
VH
n= 41
r:0.83, p<0.0001
#3
0.95 1.05
Remodeling
LipidScore%CSA
Positive
remodeling
Negative
remodeling

Geometrical and compositional data
at the site of the minimal lumen area
Remodeling index:
≤0.95 0.96-1.04 ≥1.05
n= 29 (70.7)3 (7.3) 9 (22)
EEM area obstruction (MLA) 63.1±7.5 69.1±8.6 59.9±9.9
Calcium CSA (%) 1.38±2.7 2.07±3.2 1.67±1.6
Fibrous CSA (%) 68.6±13.7 62.9±9.5 58.1±12.9
Fibrolipidic CSA (%) 23.5±9.9 19.9±6.9 18.1±12.6
Lipid core CSA (%) 6.66.6±6.9±6.9 15.1±7.6 22.1±6.3*15.1±7.6 22.1±6.3*
* p<0.0001
#3

Plaque Composition and its Relationship with
Acknowledged Shear Stress Patterns in Coronary
Arteries
Atherosclerosis has a tendency to arise more frequently in low-oscillatory shear stress
(LOSS) regions such as in inner curvature of non-branching segments and opposite to the
flow-divider (FD) at bifurcations.
Jeremias et al. Atherosclerosis 2000;152:209-15.
Kimura et al. J Am Coll Cardiol 1996;27:825-31
Kornet L et al. Arterioscler Thromb Vasc Biol 1999;19:2933-9.
In-vivo data regarding tissue composition of the flow divider remains unknown.
Furthermore, to date, no study has explored the characteristics of plaques located in the
proximal LAD compared to the left main coronary artery (LMCA).
In the present study, we sought to explore the morphological and compositional
characteristics of plaque located at an acknowledged LOSS area (outer wall of the ostial
LAD, OLAD) and compare them to the characteristics of plaque located at an average
shear stress region (distal LMCA, DLMCA).
Rodriguez-Granillo GA, García-García HM, Wentzel J et al.
J Am Coll Cardiol. In press.
#4

Shear stress in a bifurcation
Steinman et al. 1999
# 4

The carina was identified as
the frame immediately distal
to the take-off of the
circumflex.
The maximal plaque
thickness (MPT) was
calculated at this level
and spatially located
according to a
circumference ranging
from 0 to 360º, being the
inner and opposite part
of the carina at 0 and
180º respectively.
hemisphere of the
carina.
LCx (0º) Mean angle
MPT (171º)
Carina
Distal left main
METHODS
Rodriguez-Granillo GA, García-García HM, Wentzel J et al.
#4

OLAD DLMCA p value
Plaque burden (%) 45±10.2 36.4±10.8 <0.0001
Plaque eccentricity 14.5±11.6 10.4±7.6 0.05
Max. plaque thickness (mm) 1.24±0.4 1.04±0.3 0.002
Necrotic core (%) 12.4±9.2 7.9±8.6 <0.0001
Calcium (%) 4.1±5.1 1.3±2.0 <0.0001
Fibrous (%) 64.5±13.6 64.9±13.3 0.82
Fibrolipidic (%) 18.4±11.8 24.9±12.8 0.005
Geometrical and compositional comparative results between the
ostial left anterior descending coronary artery (OLAD) and the distal
left main coronary artery (DLMCA) (n= 44).
Rodriguez-Granillo GA, García-García HM, Wentzel J et al. J Am Coll Cardiol. In press.
RESULTS
Values are presented as means ± standard deviation. Plaque eccentricity was defined as the ratio of maximal
to minimal plaque thickness. Plaque burden was defined as {[(EEMarea
-Lumenarea
)/EEMarea
] X 100}
<
>
>
>
>
>
Atherosclerosis has a tendency to arise more frequently in
low-oscillatory shear stress (LOSS) regions such as in
segments opposite to the flow-divider (FD) at bifurcations.
#4

Necrotic core content distribution
along left coronary artery
0
10
20
30
40
50
*
*
LMCA Carina 1° 2° 3° 4° 5° 6°
Long LMCA ( n= 2 4 )Short LMCA ( n= 2 4 )NecroticCore(%)
Length of LMCA was stratified according
to median value (6 mm)
*: p<0.05 vs. short LMCA
Distance from the Ostium as an Independent
Determinant of Coronary Plaque Composition In Vivo
#4

analysis
Distance from the Ostium as an Independent Determinant of Coronary Plaque Composition In VivoDistance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo
An Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans.An Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans.
In-vivo relationship between compositional and mechanica
imaging of coronary arteries
#1
#2
#3
#4
#5
#6

IVUS-VH cross sectional areas
along a coronary vessel
#5

0 -10mm 11 -20 mm 21 -30 mm 31-40 mm
Lipidcore%
SA group (n=28) UA group (n=15)
Whole population (n=43)
10
20
30
40
0
Per-segment distribution of relative lipid
content in the study population
#5

0
5
10
15
20
25
30
35
40
0-10 11-20 21-30 ≥31
IDTCFA
Distance from the ostium (mm)
Percent
Total lesions = 99
p=0.008
35.4 %
31.3 %
19.2 %
14.1 %
Clustering of IDTCFA along the coronaries
(In-Vivo data)
Rodriguez-Granillo GA et al. J Am Coll Cardiol. In press.
#5

Kolodgie F, Virmani R. Curr Op in Cardiol. 2001;16:285-
Clustering of vulnerable plaque
(Ex-vivo data)
#5

Palpography… How to convert an ex vivo IVUS image into a
color coded high strain/low strain tomogram… by correlating
backscattered radiofrequency signals with human ex vivo
coronary histology
Sensitivity (88%) and Specificity(89%) to detect vulnerable plaque
defined as :
Fibrous cap ≤250 um, moderate to heavy macrophage infiltration, and ≥ 40% atheroma
Schaar JA, et al.Serruys Circulation 2003; 108: 2636

ROtterdam Classification (ROC)
0-0.60-0.6II
0.6-0.90.6-0.9IIII
0.9-1.20.9-1.2IIIIII
>1.2>1.2IVIV
Strain (%)Strain (%)Grades (ROC)Grades (ROC)

Palpography at follow-up, paired data
(n=51)
BLBL FUPFUP P-valueP-value
Stable/silent (N=23)Stable/silent (N=23)
ROC III/IV per cmROC III/IV per cm
Unstable (N=16)Unstable (N=16)
STEMI (N=12)STEMI (N=12)
IBIS StudyIBIS Study
0.290.29
1.211.21 1.171.17 0.560.56
1.781.78 1.411.41
2.302.30 1.151.15 0.0030.003
0.02
C . Van Mieghem et al,Serruys JACC, in press
In contrast to conventional imaging modalities that frequently
reveal static luminal and plaque dimensions, novel IVUS-based
plaque -palpography -can detect significant alterations in
coronary plaque characteristics over a relatively short time
interval. This study highlights the dynamic changes in the strain
of coronary plaques that are remote from the culprit lesions in
patients with myocardial infarction. Whether the persistence of a
high-strain pattern is a harbinger of cardiovascular events
remains to be determined in future much larger studies.

analysis
Distance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo AnDistance from the Ostium as an Independent Determinant of Coronary Plaque Composition In Vivo An
Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans.Intravascular Ultrasound Study Based Radiofrequency Data Analysis In Humans.
In-vivo relationship between compositional and
mechanical imaging of coronary arteries
#1
#2
#3
#4
#5
#6

LCx
LCx
LMCA Distal LAD
* *
040471
What is the agreement between strain
(palpography) and compositional (IVUS-VH)
imaging?
# 6

Insights From Intravascular Ultrasound Radiofrequency Data Analysis
123 palpography previously analyzed spots (27 patients) were randomly
selected by an independent observer
ROC III-IV, n= 60
(high strain, labelled red and yellow
respectively)
ROC I-II, n= 63
(low strain, labelled blue)
Co-localization of the same spots in the IVUS-VH
software with side-by-side view
Two IVUS pullbacks:
PalpographyPalpography: 20 MHz Avanar
IVUS-VHIVUS-VH: 30 MHz Ultracross
# 6

What is the agreement between strain
imaging?
After adjusting for all IVUS-VH derided variablesAfter adjusting for all IVUS-VH derided variables (calcified(calcified
content, fibrous content, fibrolipidic content, necrotic corecontent, fibrous content, fibrolipidic content, necrotic core
content, eccentricity index, percent atheroma volume andcontent, eccentricity index, percent atheroma volume and
contact of necrotic core with the lumen)contact of necrotic core with the lumen) ,,
the only independent predictor of high strain was thethe only independent predictor of high strain was the
contact of NC with the lumen [OR 5.0 (CI 95% 1.7-contact of NC with the lumen [OR 5.0 (CI 95% 1.7-
14.1), p= 0.003].14.1), p= 0.003].
# 6

7 # Distribution of necrotic core in human7 # Distribution of necrotic core in human
coronary plaques is related to the bloodcoronary plaques is related to the blood
flow direction: An in vivo assessmentflow direction: An in vivo assessment
using intravascular ultrasoundusing intravascular ultrasound
radiofrequency data analysisradiofrequency data analysis
8 # Shear stress imaging and palpography8 # Shear stress imaging and palpography
Frank Gijsen et al and Serruys, work in progress
Garcia Garcia et al and Serruys, work in progress

Biological observations
related to flow direction
Dirksen et al., Circ. 1998
Flow
High density Low density High densityLow density
Tricot et al., Circ. 2000
Macrophages Flow Smooth muscle cells
Hemodynamics Laboratory
Thoraxcenter Rotterdam

Most diseased part
Sub-segment 2
Sub-segment 1
Sub-segment 3
Sub-segment 2
UPSTREAM DOWNSTREAM
Flow direction

Total no. of CSA
with NC >10%
Mean PB (%)
Mean MLD (mm)
p=0.014
Proximal Distal
0
100
200
300
400
500
600
0
10
20
30
40
50
60
0
1
2
3
4
5
6
90 patients
121 vessels
4840 CSAs
NumberofCSA
Percentage
mm
MLA

# Distribution of necrotic core in human# Distribution of necrotic core in human
coronary plaques is related to the bloodcoronary plaques is related to the blood
flow direction: An in vivo assessmentflow direction: An in vivo assessment
using intravascular ultrasoundusing intravascular ultrasound
radiofrequency data analysisradiofrequency data analysis
# Shear stress imaging and palpography# Shear stress imaging and palpography
Frank Gijsen et al and Serruys, work in progress
Garcia Garcia et al and Serruys, work in progress

MethodsMethods
Shear stress:
3D lumen and wall info from ANGUS (biplane
ANGiography and IVUS) combined with
Computational Fluid Dynamics.
Strain data:
IVUS based data palpography data render
radial strain map at lumen wall.
Challenge:
match ANGUS (CVIS) with palpography data
(Volcano) using anatomical landmarks.
Wentzel JJ, Serruys PW et al. Circ 2003;Jul 8;108(1):17-23.
Slager CJ, Serruys PW et al. Circ 2000; Aug 1;102(5):511-6.

Shear stress distribution
over advanced plaque
High shear stress
Cap
Blood
flow
Lipid core
Low shear stress
Patient
population:
10 patients
21 segments
22 plaques

midcap
upstream
shoulder
shoulder
downstream
flow
Scoring system for shear
stress and strain:
1: high
0: average
-1: low
Patient population:
10 patients
21 segments
22 plaques
MethodsMethods

Results: shear stressResults: shear stress
1 0 -1
downstream
15
1 0 -1
shoulders
14
8
1 0 -1
midcap
11
5
1
1 0 -1
upstream
1
87
u s m d
0.38
0.64 0.59
-1.00

Results:Results: strainstrain
0.31
0.55
0.12
-0.47
u s m d
1 0 -1
downstream
9
42
1 0 -1
shoulders
12
10
1 0 -1
upstream
8
5
3
1 0 -1
midcap
4
11
2

ResultsResults
u s m d
meanstrain
p < 0.01
p < 0.01
meanshearstress
0.38
0.64 0.59
-1.00
p = 0.07
0.31
0.55
0.12
-0.47

Slager et al, Serruys. Nature Clinical Practice, Nature 2005; 2:401-7

When non-flow limiting lesion < 50% stenosis
When TCFA focal (3 slices), proximal < 30mm
When ROC 3/4
When positive remodeling index > 1.05
When EEM obstruction>40%
When large lipid core (> 10%)
in direct contact with lumen
Thin Cap Fibro Atheroma ? Vulnerable Plaque?

Prone to erosion
No necrotic lipid pool
No thin fibrous cap
No inflammation
Calcified Nodule (eruptive)
lesion with fibrous cap disruption
Intra-plaque Hemorrhage
Leaking from vasa vasorum or
extensive angiogenesis
Micro CT imagingMicro CT imaging
No specific diagnostic tool ?No specific diagnostic tool ?
Micro CT imagingMicro CT imaging
High cholesterol diet (12 weeks)
Imaging techniques targeting Vulnerable
Plaque other than TCFA

 Main design specifications
efficient at transmit (fc = 20 MHz)
sensitive at receive (fc = 40 MHz)
small size (< 1 mm)
by Rik Vos, Erik Droog and Gerrit van Dijk
TU Delft & TNO-TPD
New IVUS catheter for detection of vasa vasorum

In vivo Experiments: Example 1
20 MHz Fundamental 40 MHz Harmonic
- Bolus Injection of Dec. Sonovue
- Rabbit 6 wks atherosclerosis
Scale = 10 mm across

Conclusions
•The development of an accurate diagnostic tool with the
capability of simultaneously assessing more than one of the
different acknowledged features of “high-risk” plaques could
potentially enhance the prognostic value of the invasive
detection of vulnerable plaque.
•A high prevalence of “high-risk” lesions has been found
throughout the coronary tree by means of palpography and IVUS-
VH.
•The distribution of the high risk plaques along the coronaries is
clearly clustered from the ostium, compromising mainly the
proximal segment.
•Prospective studies are needed in order to evaluate the
prognostic value and natural history of the allegedly high-risk
lesions.
•The multifocal aspect of the instability process added to the
unpredictability of the natural history of these lesions and the
uncertainty about whether vulnerable plaque characteristics might
subsequently lead to fatal or non-fatal ischemic events –are
suggesting that potential local preventive strategies could not be
cost-effective.

Conclusions
•A high prevalence of “high-risk” lesions has been found throughout
the coronary tree by means of palpography and IVUS-VH.
•The multifocal aspect of the instability process added to the
unpredictability of the natural history of these lesions and the
uncertainty about whether vulnerable plaque characteristics might
subsequently lead to fatal or non-fatal ischemic events –are
suggesting that potential local preventive strategies could not be
cost-effective.

When non-flow limiting lesion < 50% stenosis
When TCFA focal (3 slices), proximal < 30mm
When positive remodeling index > 1.05
When EEM obstruction>40%
When large lipid core (> 10%)
Vulnerable Plaque?

Virtual histology
RF Signal
Post Processing SignalsInvestigational Use Only Nair A, et al. Circulation; 106: 2200

5
2
6
1 3 4
Frequency (MHz)
dB
Spectral Parameters
Database of Parameters
Classification Tree
Minimum,maximum power ,slope,frequency band etc…
Nair A, et al. Circulation; 106: 2200

ROI 111 roof
ROI 54
mid-band
fit >-11.4
ROI 57ROI 57
mid-bandmid-band
fit <-11.4fit <-11.4
ROI 22
minimum power
>-8.6 type= C
ROI 32ROI 32
minimumminimum
power <-8.6power <-8.6
ROI 23ROI 23
slope>-0.05slope>-0.05
ROI 12 slopeROI 12 slope
>.0305>.0305
ROI 45 slopeROI 45 slope
<.0305<.0305
ROI 9
slope<-0.05
type=
F
ROI 5
maximum
power >-12.65
type=FL
ROI 7
maximum
power <-12.65
type=FL
ROI 17 mid-ROI 17 mid-
band fit >-16band fit >-16
ROI 28 mid-ROI 28 mid-
band fit <-16band fit <-16
ROI 17ROI 17
frequency atfrequency at
maxmax
power>23.34power>23.34
ROI 6ROI 6
maxmax
power<23.34power<23.34
type = Ctype = C
ROI 7ROI 7
slope>0.23slope>0.23
type=type=
CNCN
ROI 10ROI 10
slope<0.23slope<0.23
ROI 5
slope>0.08
type=
CN
ROI 5
slope<0.08
type=
F
ROI 12ROI 12
max power>29.9max power>29.9
type = Ftype = F
ROI 5ROI 5
max power<29.9max power<29.9
type = Ftype = F
ROI 17 Y-int>-26.8ROI 17 Y-int>-26.8
ROI 11 Y-int<-26.8
type= F
ROI 11ROI 11
minimumminimum
power >-24.8power >-24.8
ROI 6
minimum
power <-24.8
type=FL
ROI 5ROI 5
maximummaximum
power >-13.3power >-13.3
type=FLtype=FL
ROI 6ROI 6
maximummaximum
power <-13.3power <-13.3
type=Ftype=F
Statistical
classification
+ calcium
- calcium
+ fibrous
- fibrous
+ lipid
-lipid
+ NECROTIC
-NECROTIC

FIBROUS
FIBROFATTY
CALCIUM
LIPID CORE
MEDIA
VH LegendClassification
Tree
Ma xP < -25.05
Type: Colla gen
#of RO Is : 5
Ma xP > -25.05
Type: Colla gen
# of RO Is : 26
Int < -28.65
# of RO Is : 3 1
Int < -14.8
Type: Colla ge n
#of RO Is: 5
Int > -14.8
Type: Colla ge n
#of RO Is: 5
F at MaxP < 21 .045
#of RO Is: 10
F at MaxP > 21 .045
Typ e: Collage n
#of RO Is: 17
MB F < -65.0 9
#of RO Is : 27
Int < -4.195
Type: Calcium
# of RO Is : 6
Int > -4.195
Typ e: Collage n
# of RO Is : 5
MB F > -65.0 9
#of RO Is : 11
F at Ma xP < 30.03
# of RO Is : 38
MaxP < -16.09 5
Type: Colla gen
#of RO Is : 6
F at MaxP < 34.275
Typ e: N ecr otic
#of RO Is : 6
MB F < -6 6.66
Typ e: Fib roLipidic
# of RO Is : 5
MB F > -6 6.65
Type: Collagen
# of RO Is : 5
Ma xP < -1 2.145
#of RO Is : 10
Ma xP > -1 2.145
Typ e: Fibro-Lipidic
# of RO Is : 5
F at MaxP > 34.275
# of RO Is : 15
MaxP < -9.915
#of RO Is : 21
F at Ma xP < 35.5
Type: Colla ge n
#of RO Is : 8
F at Ma xP > 35.5
Type: Colla ge n
#of RO Is : 9
MaxP > -9.915
#of RO Is : 17
MaxP > -16.09 5
#of RO Is : 38
F at Ma xP > 30.03
#of RO Is : 44
Int > -28.65
# of RO Is : 8 2
MBF < -55.6 95
#of RO Is : 1 13
MinP <-17 .9 15
Typ e: Collagen
#of RO Is : 5
MB F < -53.15
Type: Calcium
#of RO Is : 8
MB F > -53.15
Type: Calcium
# of RO Is : 20
MinP > -17.9 15
# of RO Is : 2 8
MB F >-5 5.695
#of RO Is : 33
146
# of RO Is :


TREE
ROOT













IVUS virtual histology

efinition of
rget segment
IVUS
OCT
Off-Line Data Synchronization

Interm
* distalproximal
LCX D1 D2
Palpography 4-D IVUS
Interm
Second step
identify regions
with 40 - 50 % EEM Obstruction
which contains at least
one high strain spot ROC III /IV

• Large necrotic lipid core
• Thin fibrous cap
• Paucity of SMCs
• Dense Macrophage infiltration
(metalloproteinases)
• Progressive matrix degeneration
•Angiographically non-significant
• Positive remodelling
Rupture Prone Plaque
Specific diagnostic tool ?Specific diagnostic tool ?

Imaging techniques targeting the TCFA
Modality Resolution Penetration Fibrous cap Lipid core
Angioscopy NA Poor + ++
OCT 10 um Poor ++++++ ++
Thermography NA Poor - -
Spectroscopy NA Poor + ++
IVMRI 160 um Good + ++++++
IVUSIVUS 100 um Good + ++
PalpographyPalpography NA NA ++ +
VHVH 100 um Good ++ ++++++
Modality Inflammation Calcium Thrombus
Remodeling
Angioscopy - - ++++++ -
OCTOCT ++ ++++++ + -
Thermography ++++++ - - -
Spectroscopy ++ ++ - -
IVMRI - + - -
IVUSIVUS - ++++++ + ++++++
PalpographyPalpography ++ - + -
VHVH - ++++++ - ++++++
NC

Intravascular Imaging Modalities
IVUS (gray scale)
(plaque size)
(echogenicity)
IVUS Palpography
(mechanical properties)
Optical Coherence Tomography
Intravascular MRI
Virtual Histology
(plaque composition)
Acquired
with single
pull back
IVUS
catheter

Should we pursue a combined
approach using different catheter-
based techniques to potentially
enhance the prognostic value for
the detection of vulnerable plaque?
While exciting and promising,
there is still no gold-standard and
all current techniques have
different pitfalls…

ynchronization
IVUS
OCT

IVUS
OCT

OCT
ROC III
Dense calcium 10%
Fibrous 67%
Fibro-fatty 8%
Necrotic core 15%
Lumen: 8.00 mm2
Vessel: 15.92 mm2
Plaque burden: 50%
Synchronized IVUS
and OCT PB 2

IVUS
OCT
2 %
0 %ROC III
Dense calcium 10%
Fibrous 67%
Fibro-fatty 8%
Necrotic core 15%
direct lumen contact
Lumen: 8.00 mm2
Vessel: 15.92 mm2
Plaque burden: 50%
Vulnerable Plaque ?
Thin fibrous cap
0.12mm
Synchronized IVUS and OCT PB 2

MSCT Left coronary artery
LAD
LCx1st
Marginal
Left main
LAD
Ca++
3D rendered

P
MSCT Left main IVUS VH
HU MSCT
Mean HU:
588
Distal

P
HU MSCT
Mean HU:
231
Mid

P
HU MSCT
Mean HU:
76
Proximal

Low Shear Stress
Slager et al, Serruys. Nature Clinical Practice, in press.

Spatially restricted
endothelial
anti-inflammatory signaling
Slager et al and Serruys, Nat Clin Pract Card 2005

Mean PB (%)
Mean MLD (mm)
p=0.014
Proximal Distal
0
10
20
30
40
50
60
0
1
2
3
4
5
6
90 patients
121 vessels
4840 CSAs
Percentage
mm
Luminology

Intravascular ultrasound findings at the site proximal to the stenosis (A), at the start of the
stenosis as defined by automated stenosis analysis (B), and at the site of maximal luminal
obstruction (C), defined also by automated stenosis analysis. Note the marked change in
distribution of atheroma around the lumen (center of the crosshair) at the three levels.

Downstream Upstream
ROI
Vessel
Lumen
Geometrical analysis
Composition analysis
MDP

Non-invasive
assessment
µ
QCA
<50%DS
QIVUS
>50% EEM
obstruction
VH
Necrotic core
rich lesion
Palpography
High-Strain
iv MRI OCT
Thin cap
Vasa
vasorum
Necrotic core

Restricted
diffusion →
slow decay of
MR signal →
Low ADC
Restricted
diffusion →
slow decay of
MR signal →
Low ADC
Non-
restricted
diffusion →
Fast decay of
MR signal →
High
apparent
diffusion
coefficient
(ADC)
Non-
restricted
diffusion →
Fast decay of
MR signal →
High
apparent
diffusion
coefficient
(ADC)
Diffusion Weighted MR – Concept

Intravascular MRI CatheterIntravascular MRI Catheter
NC
NCMagnet
Coil
Luminal Zone
Mural Zone
Schneiderman J. J Am Coll Cardiol. 2005;45(12):1961-

Ex-Vivo AortasEx-Vivo Aortas (single sector; n=16(single sector; n=16((
Fibrous cap atheroma Ulcerated plaque
Healthy tissue Vulnerable plaque
250µ
100µ
100µ
100µ
100µ
Schneiderman J. J Am Coll Cardiol. 2005;45(12):1961-

29 Lesions
Device Success28
6 Guide wire artifact
3 Extensive calcium/Extensive calcium/
Incomplete appositionIncomplete apposition
to vessel wallto vessel wallImaging Success19
Top Image I Coronary Study Results

IVMRI Lipid Fraction in Ex-vivo
Coronaries and In-vivo FIM Patients
#11

P
Aorta
Left main
LAD
IVUS VH Left main
Prox > distal

P
Distal cross-section
Mid cross-section
Prox cross-section
LAD
LCx
DMP
P
M
D
MSCT Left main

Number of patients
Proof of concept
registries
Cross correlation studies
Natural history trials
Randomized therapy studies
Diagnosis*Diagnosis*
** 1. Biomarkers1. Biomarkers
2. Plaque physiology2. Plaque physiology
3. Plaque morphology3. Plaque morphology
5-105-10
yearsyears
TherapyTherapy
Clinical Trial ParadigmClinical Trial Paradigm

Case 605 LCx
IVUS probe position MRI probe position
IVUS IVUS - VH MRI
IV-MRI – Rotterdam patients

Conclusions
•In this in vivo study, IVUS-VH identified IVUS-derived thin-cap
fibroatheroma as a more prevalent finding in ACS than in stable angina
patients.
•The significantly higher prevalence of IDTCFA in non-culprit coronaries
of patients presenting with an ACS supports the theory that holds ACS
as multifocal processes.
•The distribution of the IDTCFA in the coronaries was in line with
previous ex vivo and clinical studies, with a clear clustering pattern from
the ostium, thus supporting the non-uniform distribution of vulnerable
plaques along the coronary tree.
•We found no significant correlation between the presence of
conventional risk factors and the occurrence of IDTCFA .
•Prospective studies are needed in order to evaluate the prognostic
value and natural history of such finding.

A high prevalence of “high-risk” lesions has been found throughout the
coronary tree by means of angiography 33
, angioscopy 11
, IVUS 32
and
palpography 15
. Furthermore, the unpredictability of the natural history of
such lesions and the uncertainty about if vulnerable plaque
characteristics might subsequently lead to fatal or non-fatal ischemic
events suggests that potential local preventive strategies could not be
cost-effective.
Nevertheless, the development of an accurate diagnostic tool with the
capability of simultaneously assessing more than one of the different
acknowledged features of “high-risk” plaques could potentially enhance
the prognostic value of the invasive detection of vulnerable plaque.
Since IVUS-VH and palpography utilize the same source data
(radiofrequency data analysis), information regarding both techniques
might be obtained using the same pullback; potentially increasing the
prognostic value of certain seemingly pejorative plaque characteristics
assessed in prospective natural history studies.

Co-localization
1) Localize selected palpo
frame in colour blinded view
2) Localize matching frame in IVUS VH using:
Longitudinal and cross-sectional views
Landmarks (side-branches, veins,
pericardium)
Calcified spots and morpholohy of the plaque
3) Reconstruct the IVUS-VH image4) Contruct IVUS-VH database with all IVUS-
VH variables of the matched frame (Calcium
%, fibrous %, fibrolipidic %, necrotic core %,
vessel area obtruction %, eccentricity index,
necrotic core contact with the lumen)
5) Unblind (Process the Palpography results
and match them with the IVUS-VH’s)

TCFA detection
“We clearly can’t apply all these techniques
due to practical issues, therefore we should
focus on a single state-of-the-art tool”
IVUS + VH + Palpography?
(1 pullback provides information about lipid core,
inflammation, remodeling and cap thickness)

Accordingly, the combined
based techniques might potentially
the detection of vulnerable plaque
all techniques have different
pitfalls…

 What is the prognostic value of allWhat is the prognostic value of all
these diagnostic tools?these diagnostic tools?
 The prognostic value needs to beThe prognostic value needs to be
established in longitudinal follow-upestablished in longitudinal follow-up
studies!studies!

C h e s t- P a in
a tta c k
Im a g in g
B io m a r k e r s
Q C A
< 5 0 % D S
Q IV U S
> 5 0 % E E M
r e d u c tio n
V H
L ip id - n e c r o tic
le s io n
P a lp o g r a p h y
H ig h - S tra in
T h e r m o g r a p h y
> 0 .0 8 C e lc iu s
O C T
< 1 6 0
In v a s iv e a s s e s s m e n t
o f n o n - flo w lim itin g le s io n
µ
The “new diagnostic world “ of the vulnerable
plaque
Chest pain MSCT Biomarkers
Vulnerable plaque triage
Identify high risk patients (Framingham score)
Cholesterol levels + CRP
Non-invasive imaging + novel biomarkers
In case of invasive assessment
If non-flow limiting lesion < 50% stenosis
If TCFA focal (3 slices), proximal < 30mm
DES
If ROC 3/4
If positive remodeling index > 1.05
Cost
Benefit???
If EEM obstruction>40%
Systemi
c
therapy
If large lipid core (> 10%)

RCA
51
9372
70
55
25
LCA
55
90
42
51
71
48
48
30
53
16
MSCT Coronary Plaque Burden
Distribution (%)
(41 patients: stable / unstable 59.5 ± 10 yrs)

Necrotic core relation with the lumen
No contact Contact p value
Calcium (%) 0.25± 0.7 1.6± 2.5 0.001 +
Fibrous (%) 76± 13.7 64± 12 <0.001 -
Fibrolipidic (%) 21± 14 19± 9 0.21 =
Necrotic core (%) 3± 4 16± 11 <0.001 +
PAV (%) 49± 9 51± 11 0.38 =
Eccentricity
index 0.15± 0.1 0.23± 0.1 0.01 +
Percent atheroma volume (PAV) was defined as EEMarea
-Lumenarea
/EEMarea
X
100, where EEM refers to external elastic membrane. EI refers to plaque
eccentricity index, defined as minimum plaque thickness divided by
maximum plaque thickness.
Plaque composition and conventional intravascular
ultrasound output in cross-sections with and without
necrotic core contact with the lumen

38%
62%
P(-) P(+) Noncalc MX Calc
32%
43%
25%
53%
> 50%<50%
Plaque Extent Plaque Type Plaque Size
47%
MSCT Coronary Plaque Burden
41 patients (473 segments)

Clinical presentation
Acute coronary syndrome
Younger < 60 yrs
Diabetes
Troponin positive
Biological marker
hsCRP
Non-invasive MSCT
Calcific plaque
Non-calcific plaque
Total coronary plaque burden
Invasive techniques
ICUS
Palpography
Thermography
OCT
High-risk patient
Presence of plaque
High-risk plaque
Algorithm to detect
high-risk plaque in
a high-risk patient

Disrupted Coronary Plaque
Unstable patient with ST-segment depression

Major criteria
Yes? Lipid core size
No Thin Cap
No Inflammation
MSCT Vulnerable Plaque: Limitations
Naghavi Circulation 2003;108:1664
Lipid plaque Thrombotic plaque
35 HU 10 HU
Yes Coronary stenosis
No Fissured plaque
No Endoth. denudation

64-MSCT coronary plaque imaging
Mixed plaqueNon-calcific
plaque
Calcific plaque

Major criteria
Yes? Lipid core size
No Thin Cap
No Inflammation
Yes Coronary stenosis
No Fissured plaque
No Endoth. denudation
MSCT Vulnerable Plaque: Limitations
Minor criteria
Yes Remodeling
No Endothelial dysf.
No Intraplaque hemorrh.
No Glistening yellow
No Superf. Calc. nodule
Naghavi Circulation 2003;108:1664
Lipid plaque Thrombotic
plaque
35 HU 10 HU

Trophy Images or Reality ?Trophy Images or Reality ?
Sens.: 77% (38 – 94)
Spec. :71% (42 – 97)
Budoff JACC 2003;42:1867
Third generation
Bornert et al. Magn. Reson. Med 2001;46:789-794

16 slice MSCT Ruptured Plaque
“ Indirect evidence “

OCT 10 um Poor +++ ++
IVMRI 160 um Good + +++
VHVH 100 um Good ++ +++
Remodeling
Angioscopy - - +++ -
OCT ++ +++ + -
Thermography +++ - - -
IVMRI - + - -
IVUSIVUS - +++ + +++
VHVH - +++ - +++
NC

• Male, 56 years, stable angina,Male, 56 years, stable angina,
history of non-Q-wave MIhistory of non-Q-wave MI
• Risk factors: Smoking,Risk factors: Smoking,
NIDDM, hypertension,NIDDM, hypertension,
hypercholesterolemia, familyhypercholesterolemia, family
historyhistory
• Proximal LAD 36% stenosisProximal LAD 36% stenosis
Fibrous Lesion
Lipid-Rich LesionLipid-Rich Lesion
• Male, 77 years, unstable anginaMale, 77 years, unstable angina
• Risk factors: HypertensionRisk factors: Hypertension
• Proximal LAD 21% stenosisProximal LAD 21% stenosis
Coronary Study
Typical Cases

How to
integrate information from
different intravascular tools?

IVUS probe position MRI probe position
IVUS IVUS - VH MRI
Matching by Angiography

2.9F
20 MHz
Solid state transducer
(64 elements)
 Gray scale
 VH IVUS
 Palpography
Simultaneous Data Acquisition
Volcano Eagle Eye Catheter

LADLAD
IVUS and OCT EvaluationIVUS and OCT Evaluation
IVUS PB OCT PB

• High incidence of yellow non-disrupted plaques in by angioscopy (3.4±1.8, n=21).
• Yellow plaques were equally prevalent in the infarct-related and non–infarct-related
coronary arteries
ACS as a multifocal instability
process
Asakura M. J Am Coll Cardiol. 2001 Apr;37(5):1284-8
Culprit lesion

Multiple plaque rupture: 3-vessel IVUS assessment
in 24 first ACS patients
0
10
20
30
40
50
60
70
80
90
100
Patients(%)
In
culprit
lesion
Outside
culprit
lesion
In other
vessel
In both
other
vessels
Rioufol G et al. Circulation.2002;106:804

One-year outcome of single vs multiple
complex coronary plaques after MI
0
5
10
15
20
25
30
35Patients(%)
Recurrent AC
S
Repeat PTCA
PTCA
non-culprit
CA
BG
Single
Multiple
Goldstein JA. NEJM. 2000;343:527-8
p≤ 0.001 p≤ 0.001 p≤ 0.001 p≤ 0.001

Editorial:
“The coronary tree may veritably
teem with plaques at high risk of
rupture and thrombosis”
“For every culprit lesion, other
potentially troublesome plques
may lurk undetected”
Libby P. J Am Coll Cardiol 2005; 45(10):1585-1594.
“Clearly, early invasive management, including local intervention on the
culprit lesion in conjunction with contemporary pharmacologic “adjuvants,”
can improve outcomes of many with acute coronary syndromes. Still,
recurrent cardiovascular events in this population remain unacceptably
high. We must think not only locally, fixed by our traditional focus on the
culprit lesion, but also consider globally the other vulnerable plaques in the
coronary and other arteries of patients with acute coronary syndromes.”

Angiographically complex lesions
were present in 40% of patients
with ACS

“Because the vulnerable plaques
are not abundant and are often
located proximally in major
arteries, an effort to detect
vulnerable plaques is justified”.
Narula J, Finn AV and DeMaria AN. J Am
Coll Cardiol. 2005;45(12):1970-1973

OCT 10 um Poor +++ ++
IVMRI 160 um Good + +++
VHVH 100 um Good ++ +++
Remodeling
Angioscopy - - +++ -
OCT ++ +++ + -
Thermography +++ - - -
IVMRI - + - -
IVUSIVUS - +++ + +++
VHVH - +++ - +++

In Vitro Predictive Accuracy of IVUS based
Tissue Characterization from Results,
61LADs, 104 sections
Tissue Type
Predictive Accuracies
Train – 75% Test – 25%
Fibrous
(n = 115)
90 80
Fibro-Lipid
(n = 63)
93 81
Lipid-Core
(n = 88)
89 85
Calcium
(n = 56)
91 93

In Vitro Experience
91
88
93
87
85
83
Calcified, lipid
necrotic core
Fibrotic cap
about 400 µm

Should we pursue a combined
based techniques to potentially
the detection of vulnerable plaque?
all techniques have different
pitfalls…

Insights From Intravascular Ultrasound Radiofrequency Data Analysis
Objective:
To explore in vivo the hypothesis that high strain regions
have necrotic core-rich plaques as sub-intimal substrate.
Definition of high strain
A region was defined as a high-strain spot when it had high strain [>1.2% at
4 mm Hg pressure difference (ROC III-IV)] that spanned an arc of at least
12° at the surface of a plaque (identified on the IVUS recording) adjacent to
low-strain regions (<0.5% at 4 mm Hg pressure difference). The highest
value of strain was taken as the strain level of the spot. Such characteristics
should be present for at least 1 whole cardiac cycle.

123 palpography previously analyzed spots (27 patients)
were randomly selected by an independent observer
ROC III-IV, n= 60
(high strain, labelled red and
yellow respectively)
ROC I-II, n= 63
(low strain, labelled blue)
Co-localization of the same spots in the
IVUS-VH software with side-by-side view
Two IVUS pullbacks:
Palpography: 20 MHz Avanar
IVUS-VH: 30 MHz Ultracross

LCx
LCx
LMCA Distal LAD
* *
040471

What is the relation between strain
imaging?
After adjusting for all IVUS-VH derided variablesAfter adjusting for all IVUS-VH derided variables (calcified(calcified
content, fibrous content, fibrolipidic content, necrotic corecontent, fibrous content, fibrolipidic content, necrotic core
content, eccentricity index, percent atheroma volume andcontent, eccentricity index, percent atheroma volume and
contact of necrotic core with the lumen)contact of necrotic core with the lumen) ,,
the only independent predictor of high strain was thethe only independent predictor of high strain was the
contact of NC with the lumen [OR 5.0 (CI 95% 1.7-contact of NC with the lumen [OR 5.0 (CI 95% 1.7-
14.1), p= 0.003].14.1), p= 0.003].

““The coronary tree may veritably teem with plaques atThe coronary tree may veritably teem with plaques at
high risk of rupture and thrombosis”high risk of rupture and thrombosis”
““For every culprit lesion, other potentially troublesomeFor every culprit lesion, other potentially troublesome
plaques may lurk undetected”plaques may lurk undetected”
Libby P. J Am Coll Cardiol 2005; 45(10):1585-1594.
Editorial comment:
““Because the vulnerable plaques are not abundant andBecause the vulnerable plaques are not abundant and
are often located proximally in major arteries, an effort toare often located proximally in major arteries, an effort to
detect vulnerable plaques is justified”.detect vulnerable plaques is justified”.
Narula J, Finn AV and DeMaria AN. J Am Coll Cardiol. 2005;45(12):1970-1973

One-year outcome of single vs multiple
complex coronary plaques after MI
0
5
10
15
20
25
30
35
Patients(%)
Recurrent ACS
Repeat PTCA
PTCA
non-culprit
CABG
Single
Multiple
p≤ 0.001p≤ 0.001 p≤ 0.001 p≤ 0.001
Angiographically complex lesions were
present in 40% of patients with ACS

Non-invasive assessment (MSCT)

16 – slice MSCT ( prototype Straton 370ms )
Selected patients (61) with atypical
chest pain or stable angina
HR < 70 bpm (spontaneous / drugs)
No or mild presence of calcium
Coronary tree (> 2 mm)
Sensitivity 95 %
Specificity 98 %
Mollet JACC 2005;45:128

-200
-100
0
100
200
300
400
500
600
700
Sal Low Mid High
CM Pla Ca Surr
Impact of lumen attenuation on plaque measurementsImpact of lumen attenuation on plaque measurements
HU
Calcium andCalcium and
peri-vascularperi-vascular
fat are notfat are not
influenced byinfluenced by
intra-luminalintra-luminal
attenuation.attenuation.
PlaquePlaque
attenuationattenuation
increases asincreases as
the intra-the intra-
vascularvascular
attenuationattenuation
increases.increases.

Method
• High quality digital imagesHigh quality digital images
of histology were printed.of histology were printed.
• Transparent film was tapedTransparent film was taped
over page.over page.
• Borders drawn with blackBorders drawn with black
permanent markerpermanent marker
• Dr Virmani asked to reviewDr Virmani asked to review
corresponding slide andcorresponding slide and
draw her version of VH ondraw her version of VH on
the transparent film usingthe transparent film using
coloured markers.coloured markers.
• Green – fibrous; LimeGreen – fibrous; Lime
green – fibrofatty; Red –green – fibrofatty; Red –
necrotic core; purple –necrotic core; purple –
calciumcalcium
• Dr Virmani was not shownDr Virmani was not shown
the Grayscale or VHthe Grayscale or VH

CCF 04106 B2
Color Scheme – Same as VH
Except, Calcium = Purple
• Notes:Notes:
 FibroatheromaFibroatheroma
 Blue = vesselsBlue = vessels
 Necrotic core with speckledNecrotic core with speckled
microcalficationmicrocalfication
Grey-Scale VH Virmani-VH

Intracoronary OCT Calcified Nodule
Thickness of fibrous cap: 0.17mm
Calcified nodule: 0.43mm2
Plaque With a disruptive calcified nodule

Why do we need to detect
the TCFA?
In a series of 200 sudden death
cases, 60% of acute thrombi
resulted from disruption of
TCFA
Virmani R. Arterioscler Thromb Vasc Biol. 2000;5:1262-75

64-slice MSCT : Higher resolution, faster !
Assessment of entire coronary tree
Isotropic imaging: 0.4 x 0.4 x 0.4mm
tube rotation time: 330 msec
Scan time: ∼12 seconds
51 patients; 61 yrs
Sensitivity :95%
Specificity :96%
Mollet ACC 2005, abst.

Definition of IVUS-Derived Thin-Cap
Fibroatheroma (IDTCFA)
1. Focal (adjacent to non-TCFA)
2. Lipid core ≥10%
3. In direct contact with the lumen
4. Vessel area obstruction ≥40%
FIBROU
S
FIBROFAT
Y
CALCIU
M
LIPID
CORE
MEDIA
VH Legend
•Per 3 consecutive frames with all characteristics
Rodriguez-Granillo GA, García-
García HM, McFadden E et al.

Does spatialDoes spatial
heterogeneity ofheterogeneity of
(experimental) plaques(experimental) plaques
contain informationcontain information

• Plaque rupture occurs predominantelyPlaque rupture occurs predominantely
upstream of plaques in carotid arteryupstream of plaques in carotid artery
• Vulnerable plaque occurs at first 30 cmVulnerable plaque occurs at first 30 cm
of coronary arteriesof coronary arteries
• This heterogeneity may help to identifyThis heterogeneity may help to identify
us with regional mechanismus with regional mechanism
independent of classical risk factorsindependent of classical risk factors
Introduction

• Introduce a new 3D histology techniqueIntroduce a new 3D histology technique
• Provide evidence for the mechanismProvide evidence for the mechanism
that local accumulation of lipidsthat local accumulation of lipids
activates inflammatory cells to produceactivates inflammatory cells to produce
plaque weakoning factorsplaque weakoning factors
Introduction

50403020100
x106
Distance from Renal Artery (mm)
0
1
2
3
PlaqueArea(µm2
)
Plaque Area
5
1
0
1
5
0
50403020100
Density(%)
Macrophages
60
50403020100
40
20
Density(%)
Lipids
0
60
50
40
30
20
10
0
50403
0
2
0
100
Density(%)
Smooth Muscle Cells

0
5
10
15
20
25
50403020100
VI-index
Plaque area
VI-index
VI=
SMC
MO + Lipids

oxLDL distibutionMMP activity
smcsmc
mac
mac
MMP-activity Ox-LDL accumulation
unknown
unknown

Plaque rupture proximal of
minimal lumen
• Coronary arteryCoronary artery
Fujii, et al. Circulation 2003Fujii, et al. Circulation 2003
• Carotid arteryCarotid artery
Lovett and Rothwell,Lovett and Rothwell,
Cerebrovasc Dis 2003Cerebrovasc Dis 2003
Dirksen et al., CirculationDirksen et al., Circulation
19981998
Masawa, PathologyMasawa, Pathology
International 1994International 1994
 Reason(s)?
 Direct mechanical effect of shear stress Gertz and Roberts, Editorial Am J
Card, 1990
 Biological effect of shear stress on cap stability Hemodynamics Laboratory
Slager et al., Nat Clin Pract Card 2005

Cap weakening due to High
Shear Stress

0
100
200
300
400
500
600
No. of CSA
with NC >10%
Mean PB * 10
Mean MLD *100
p=0.014
Proxima
l
Distal

-4 -2 0 2 4
Log Calcium
-4
-2
0
2
4
LogNecroticCore
Pearson Correlation Coefficient 0,74**, p=0.000
**Correlation is significant at the 0.01 level (2-tailed).

1 2
3
4
NC>20%
NC>15%
NC>10%
NC>5%
0
100
200
300
400
500
600
700
800
900
Distribution of the number of CSAs according to the
mean percentage of necrotic core along the
atherosclerotic plaque

1
2
3
4
NC>20%
NC>15%
NC>10%
NC>5%
0
100
200
300
400
500
600
700
800
900

Directed Flush Catheter (Lightlab
OPTICAL COHERENCE TOMOGRAPHY
(OCT)
140140
1–151–15
Thin fibrous cap
Resolution
Probe Size
(μm)
(μm)

 Detection of lipid-rich plaque Yabushita, Circulation 2002.
 Spectroscopy: chemical composition Schmitt, IEEE, 2002.
 Vizualization of thin fibrous cap Jang, 4th VP Symposium, Chicago 2002
 Detection of macrophages
OCT – Potential for VP DetectionOCT – Potential for VP Detection
MacNeill, JACC 2004
I. K. Jang, presented in Chicago 2002

dist prox
Plaque rupture?
Thrombus
OCT Imaging: Culprit lesion

dist prox
a
a
a b
b
b
TCFA
OCT Imaging: Culprit lesion

Can OCT help us in predicting intraplaque
hemorrage?
Intracoronary OCT
Side Branch or Vasa Vasorum?

020854
LAD
62 year, male, CCS III
hypertension,
smoking,
hypercholesterolemia
Intracoronary OCT
Thick Fibrous Cap Atheroma
Plaque Prone to Erosion
Lipid Necrotic Core
Lipid

calcium
thrombus
E. Regar, P.W. Serruys
Plaque With a disruptive calcified nodule

MSCT
Pim de Feyter
Carlos van Mieghem
Nico Mollet
Thoraxcenter’s “vulnerable plaque
detection”group:
IVUS-VH
Gastón Rodriguez-Granillo
Héctor M. García-García
Marco Valgimigli
Palpography
Anton van der Steen
Johannes Schaar
OCT / IVMRI
Evelyn Regar

METHODOLOGY
Geometrical validation of intravascular ultrasound radiofrequency data analysisGeometrical validation of intravascular ultrasound radiofrequency data analysis
(Virtual Histology(Virtual HistologyTMTM
) acquired with a 30 MHz Boston Scientific Corporation imaging) acquired with a 30 MHz Boston Scientific Corporation imaging
catheter.catheter.
Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al. Catheter Cardiovasc Interv.Catheter Cardiovasc Interv. In press.In press.
Reproducibility of Intravascular Ultrasound Radiofrequency Data Analysis:Reproducibility of Intravascular Ultrasound Radiofrequency Data Analysis:
Implications for the Design and Conduction of Longitudinal Studies. RodriguezImplications for the Design and Conduction of Longitudinal Studies. Rodriguez
Granillo GA, Serruys PW et al. In process.Granillo GA, Serruys PW et al. In process.
Methodological Considerations and Approach to Cross-Technique Comparisons usingMethodological Considerations and Approach to Cross-Technique Comparisons using
In Vivo Coronary Plaque Characterization Based on Intravascular UltrasoundIn Vivo Coronary Plaque Characterization Based on Intravascular Ultrasound
Radiofrequency Data Analysis: Insights From the Integrated Biomarker and ImagingRadiofrequency Data Analysis: Insights From the Integrated Biomarker and Imaging
Study (IBIS).Study (IBIS).
Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al. International Journal of CardiovascularInternational Journal of Cardiovascular
Interventions.Interventions. 2005;7(1):52-8.2005;7(1):52-8.
Rationale and methods of the integrated biomarker and imaging study (IBIS):Rationale and methods of the integrated biomarker and imaging study (IBIS):
combining invasive and non-invasive imaging with biomarkers to detectcombining invasive and non-invasive imaging with biomarkers to detect
subclinical atherosclerosis and assess coronary lesion biologysubclinical atherosclerosis and assess coronary lesion biology
Van Mieghem CAG,Van Mieghem CAG, Serruys PW et al.Serruys PW et al. Int J Cardiovasc Imaging. 2005 Aug;21(4):425-Int J Cardiovasc Imaging. 2005 Aug;21(4):425-
41.41.

PLAQUE COMPOSITION OF
NON-CULPRIT ARTERIES
Coronary plaque composition of non-culprit lesions by in vivoCoronary plaque composition of non-culprit lesions by in vivo
intravascular ultrasound radiofrequency data analysis is related tointravascular ultrasound radiofrequency data analysis is related to
clinical presentation.clinical presentation.
Global characterization of coronary plaque rupture phenotype using 3-Global characterization of coronary plaque rupture phenotype using 3-
vessel intravascular ultrasound radiofrequency data analysis.vessel intravascular ultrasound radiofrequency data analysis.
Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al.

HISTOLOGICAL
SURROGATES
In vivo intravascular ultrasound derived thin-cap fibroatheromaIn vivo intravascular ultrasound derived thin-cap fibroatheroma
detection using utrasound radiofrequency data analysis.detection using utrasound radiofrequency data analysis.
Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al. J Am Coll Cardiol.J Am Coll Cardiol. InIn
presspress

CORONARY REMODELLING
Coronary artery remodelling is related to plaqueCoronary artery remodelling is related to plaque
composition.composition.
Rodriguez Granillo GA, Serruys PW, García-Rodriguez Granillo GA, Serruys PW, García-
García HM, et al. Heart. Jun 17; [Epub aheadGarcía HM, et al. Heart. Jun 17; [Epub ahead
of print].of print].

NON-UNIFORM DISTRIBUTION OF
PLAQUE COMPOSITION ALONG
CORONARY VESSELS
Distance from the Ostium as an Independent Determinant ofDistance from the Ostium as an Independent Determinant of
Coronary Plaque Composition In Vivo An IntravascularCoronary Plaque Composition In Vivo An Intravascular
Ultrasound Study Based Radiofrequency Data Analysis InUltrasound Study Based Radiofrequency Data Analysis In
Humans.Humans.
Valgimigli M, Serruys PW, et al. Eur Heart J.Valgimigli M, Serruys PW, et al. Eur Heart J. Submitted.Submitted.
Plaque composition in the left main Stem mimics the distal butPlaque composition in the left main Stem mimics the distal but
not the proximal tract of left coronary artery. Influence ofnot the proximal tract of left coronary artery. Influence of
clinical presentation, length of the left main trunk, lipid profileclinical presentation, length of the left main trunk, lipid profile
and systemic inflammatory status.and systemic inflammatory status. SubmitedSubmited
Valgimigli M, Serruys PW et al.Valgimigli M, Serruys PW et al.

COMBINED IMAGING
APPROACH
Detection of a lipid-rich, highly deformable plaque in an angiographically non-diseasedDetection of a lipid-rich, highly deformable plaque in an angiographically non-diseased
proximal LAD.proximal LAD.
Rodriguez Granillo GA, Serruys PW et al. Eurointervention. In press.Rodriguez Granillo GA, Serruys PW et al. Eurointervention. In press.
In vivo relationship between compositional and mechanical imaging of coronaryIn vivo relationship between compositional and mechanical imaging of coronary
arteries: insights from intravascular ultrasound radiofrequency data analysis.arteries: insights from intravascular ultrasound radiofrequency data analysis.
Rodriguez Granillo GA, Serruys PW et al. Am Heart J. Submitted.Rodriguez Granillo GA, Serruys PW et al. Am Heart J. Submitted.
In vivo, cardiac-cycle related intimal displacement of coronary plaques assessed by 3-In vivo, cardiac-cycle related intimal displacement of coronary plaques assessed by 3-
D ECG-gated intravascular ultrasound: exploring its correlate with tissueD ECG-gated intravascular ultrasound: exploring its correlate with tissue
deformability identified by palpography.deformability identified by palpography.
Rodriguez Granillo GA, Serruys PW et al. International Journal of CardiovascularRodriguez Granillo GA, Serruys PW et al. International Journal of Cardiovascular
Imaging. In press.Imaging. In press.
Non-invasive Detection of Subclinical Coronary Atherosclerosis Coupled WithNon-invasive Detection of Subclinical Coronary Atherosclerosis Coupled With
Assessment, Using Novel Invasive Imaging Modalities, of Changes in PlaqueAssessment, Using Novel Invasive Imaging Modalities, of Changes in Plaque
Characteristics: The IBIS Study (Characteristics: The IBIS Study (IIntegratedntegrated BBiomarker andiomarker and IImagingmaging SStudy).tudy).
Van Mieghem, Serruys PW et al. J Am Cardiol C. In press.Van Mieghem, Serruys PW et al. J Am Cardiol C. In press.

PLAQUE PROGRESSION
In vivo variability in quantitative coronary ultrasound and tissueIn vivo variability in quantitative coronary ultrasound and tissue
characterization with mechanical and phased-array catheters.characterization with mechanical and phased-array catheters.
Rodriguez Granillo GA, Serruys PW et al. International Journal ofRodriguez Granillo GA, Serruys PW et al. International Journal of
Cardiovascular Imaging. In press.Cardiovascular Imaging. In press.
Statin therapy promotes plaque regression: a meta-analysis of theStatin therapy promotes plaque regression: a meta-analysis of the
studies assessing temporal changes in coronary plaque volumestudies assessing temporal changes in coronary plaque volume
using intravascular ultrasound.using intravascular ultrasound.
Rodriguez Granillo GA, Serruys PW et al. Submitted.Rodriguez Granillo GA, Serruys PW et al. Submitted.

Shear Stress
• Plaque Composition and its Relationship withPlaque Composition and its Relationship with
Acknowledged Shear Stress Patterns inAcknowledged Shear Stress Patterns in
Coronary Arteries.Coronary Arteries.
• Rodriguez Granillo GA, Serruys PW et al.Rodriguez Granillo GA, Serruys PW et al.
JACC. In pressJACC. In press

C h e s t- P a in
a tta c k
Im a g in g
B io m a r k e r s
Chest pain
MSCT Biomarkers
High Risk

Focal characteristics of ruptured plaques (20)
and minimal lumen area (MLA) controls (n= 28)

Rupture site MLA site p value

Lumen CSA (mm2
) 9.47±6.3 6.76±4.2 <0.001
Vessel CSA (mm2
) 19.09±9.3 19.15±9.8 0.95
Plaque CSA (mm2
) 9.63±4.2 12.38±6.9 0.01
Plaque burden (%) 51.32±10.6 64.06±10.1 <0.001

Calcium CSA (mm2
) 0.33±0.3 0.35±0.3 0.62
Calcium (%) 6.07±6.3 4.60±4.6 0.10
Fibrous CSA (mm2
) 3.76±2.2 5.48±3.8 0.01
Fibrous (%) 59.46±11.8 60.22±9.6 0.60
Fibrolipidic CSA (mm2
) 1.27±1.3 2.19±2.0 0.02
Fibrolipidic (%) 16.99±9.4 22.08±9.8 0.01
Necrotic core CSA (mm2
) 0.98±0.7 1.10±0.7 0.34
Necrotic core (%) 17.48±10.8 13.10±6.5 0.03
#1

GA Rodriguez-Granillo, HM Garcia-Garcia, M Valgimigli, et
al.
Submitted
Department of Cardiology, Thoraxcenter, Erasmus Medical Center, Rotterdam
Global characterization of coronary plaque
rupture phenotype using 3-vessel intravascular
ultrasound radiofrequency data analysis
Disclosure: GA Rodriguez-Granillo has received
a research grant from Volcano Therapeutics.
#1

1 2 3 4
Subsegments
0
10
20
30
40
50
60
70
%
CALCIFIED
LIPIDCORE
FIBROLIPID
FIBROUS
Upstream Downstream

37
37
36
36
35
35
34
34
34
33
33
32
32
31
31
30
30
29
29
28
28
28
27
27
26
26
25
Frames
0
20
40
60
80
100Relativecomposition
CALCIFIED
LIPIDCORE
FIBROLIPID
FIBROUS
pat 40122
MDP DownstreamUpstream

Existing intravascular imaging technology for plaque characterization

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Editor's Notes