SHAPE Society

1. FROM THE VULNERABLE PLAQUE TO THE BURDEN OF DISEASE
EVOLVING UNDERSTANDING OF THE VULNERABLE PATIENT
Valentin Fuster MD,PhD
AHA, New Orleans, November 6, 2004

3. CT AND MR IMAGING OF MAIN COMPONENTS
OF ATHEROTHROMBOTIC PLAQUE
Modality CT MR
Unit HU SI*
Sequence 200† T1W PDW T2W TOF
Thrombus 20 +/- +/- +/- +
Lipid 50 + + - +/-
Fibrous 100 +/- + +/- +/-
Calcium > 300 - - - -
Z.A. Fayad, V.Fuster., Circ Res 2001;89:305
ZA Fayad, V Fuster, K Nikolaou, C Becker. Circ 2002;106:2026
RP Choudhury, V Fuster, JJ Badimon et al., ATVB 2002; 22:1065
† Vessel contrast enhancement - * Signal intensity (SI) relative to adjacent muscle
+ = hyperintense; +/- = isointense; - = hypointense

4. HIGH RISK PLAQUES (HRP)
HIGH RISK BLOOD (HRB)
BURDEN OF ATHEROTHROMBOSIS DISEASE (BAD)
1. HRP / HRB / BAD - SYSTEMIC
2. HRP - ABUNDANT
3. HRP AND HRB - REGIONALLY DIFFERENT
4. BAD - MRI / CT : DIAGNOSTIC VS PATHOGENETIC
Maseri A, Fuster V, Circulation 2003; 107: 2068
Fuster V, Kim RJ, Circulation 2004 (In Press)

5. 0
10
20
30
40
50
60
70
80
76%
24%
61%
28%
Percent
Thrombus in
culprit lesions
Thrombus in
non-isch vessels
ACS
Stable
P<0.01
P<0.05
ACUTE CORONARY SYNDROME:
A PAN-CORONARY PROCESS?
ANGIOSCOPY of culprit ischemic lesions and non-ischemic related vessels
in 33 ACS pts and 29 stable angina pts
ANGIOSC.T Ohba et al JACC 2001;(Supl):349A–M Asakura et al JACC 2001;37:1284 Yellow
ANGIOG. J A Goldstein et al NEJM 2000; 343: 915 AUTOPSY E Falk BHJ 1983;50:127- BIOK (WBC)
A.Buffon et al NEJM 2002;347:5 - IVUS C Rioufol Circ 2002;106:804, MK Hong et al Circ 2004;110:928
M Madjid et al. “Finding Vulnerables Plaques, It is worth the effort?” ATVB 2004;24:1775

6. TF
MMPs
CAMs
Macrophages
Pro-Adhesion/Migration
TXA2
PAI-1
Prothrombotic
Platelet
Aggregation
Fibrinolysis
Flow Reversal
Mechanical & Biohumoral
Risk Factors
LDL
ET
Extracellular Matrix
Fibroblasts
Vasa Vasorum
SMC contraction
migration
proliferation
PDGF
V Fuster et al 2004 (Subm)

7. Macrophages and Neovessels in Human
Atherosclerotic Plaques – Predominant in Diabetes
Moreno PR., Purushothaman KR., Fuster V., et al Circ. 2004;110:2032
Moreno PR., Fuster V., JACC Dec 2004 (In Press)
CD-68 (Red) and CD-34 (Blue)
Diabetes No
Diabetes

8. PLAQUE WITH INFLAMMATION & RUPTURED IEL
Moreno PR, Purushothaman K-R, O’Connor WN, Fuster V, Circ. 2002;105:2504
Moreno PR, Purushothaman KR, Fuster V, et al. Circ 2004;110:2032

9. Independent Predictors of Plaque Rupture
Multivariate Analysis P value OddsRatio
Lower Upper
Cap Thickness< 60 microns <0.001 23.5 9.3 58.9
Rupture of Internal Elastic Lamina <0.001 13.7 4.02 46.9
Cap Inflammation Score 0.002 3.12 1.51 6.45
Plaque Base Neovessel Density 0.003 1.47 1.14 1.9
Lipid Area 0.037 1.15 1.01 1.32
95%Confidence Intervals
Moreno PR, Purushothaman KR, Fuster V et al Circ 2004;110:2032

10. 1)-CT Evaluation
Fuster V, Kim RJ, Circ 2004 (In Press)

11. BAA 62 HU
DC
Despite the increasedDespite the increased spatial resolutionspatial resolution of the new generation ofof the new generation of
MDCTMDCT scanners,scanners, MRIMRI is better foris better for plaqueplaque characterization (Rabbitcharacterization (Rabbit
model)model)
s JF, Poon M, Sanz J, Rius T, Fuster V, Badimon JJ.s JF, Poon M, Sanz J, Rius T, Fuster V, Badimon JJ. Circ.Circ. 20042004 (In Pre(In Pre

12. 2) - In vivo MR evaluation of aortic
Atherosclerosis, risk factors and CAD at angiography
MRI slices of aorta and
plaque scores
Taniguchi, H et. al. Am Heart J 2004;148:137 (Japan).
BAD-MAPI – (Fayad ZA et al) 2004-2005

13. 1 2 3 4
0
5
10
15
1 2 3 4
0
5
10
15
LDL-cholesterol quartiles
Thoracic Aorta Abdominal Aorta
Plaque Extent Score
P=NS
P<0.02
(by Kruskal/Wallis test)
1 2 3 4
0
10
20
30
P<0.001
(by Kruskal/Wallis test)
Total Plaque Extent Score
1 2 3 4
0
10
20
30
P<0.002
Thoracic Aorta Score Predicts CAD
H Taniguchi et al., AHJ 2004; 148:137
2A) MRI AORTA ATHEROSCLEROSIS SCORE
Fibrinogen quartiles CRP quartiles
Plaque Extent also related to Age & Systolic BP (T & A Aorta) and degree of Smoking (A Aorta)

14. Mid heart Aorta- 12 slices Longitudinal View
Ca++
68 year old patient with CAD showing aortic plaque
MRI Plaque Imaging
BAD-MAPI (Fayad ZA et al.) 2004-2005

15. CHD RISK IN WOMEN - FRAMINGHAM SCORING (FRS) - 10 y
Age, y HDL cholesterol
< 35 -9 ≥ 60 -3
35-39 -4 50-59 0
40-44 0 45-49 1
45-49 3 35-44 2
50-54 6 < 35 5
55-59 7 Syst BP
60-64 8 < 120 -3
65-69 8 120-129 0
70-74 8 130-139 1
Cholesterol 140-149 2
< 160 -2 > 160 3
169-199 0 Diabetes
200-239 1 No 0
240-279 2 Yes 4
≥ 280 3 Smoking
No 0
Yes 2
Points
0
1
2
3
4
5
6
7
8
9
10
11
12
13
>14
Total CHD
(%)
2
3
4
5
7
8
10
13
16
20
25
31
37
45
> 53
Hard CHD
(%)
2
2
3
4
5
6
7
9
13
16
20
25
30
35
> 45
Grundy SM, Pasternak R, Greenland P, Smith S, Fuster V, Circ 1999; 100:1481
ATP III - Aggressive Rx: Framingham, Diabetes, Metab. Synd: obese, BP, HDL, TC, Gluc
- Physical inactivity JAMA 2001; 285:2475

16. Descriptive
StatisticsParameter No Mean St dev Min Max Range
Age 99 54.3 20.55 9 87 78
Framingham
Score
44 7.27 3.99 1 20 19
10-Year Risk 42 0.118 0.069 0.03 0.31 0.28
Total Chol 84 199.9 57.3 105 366 261
LDL 83 120.7 54.5 46 303 257
HDL 84 53.2 16.8 20 100 80
TGC 83 139.3 122.9 32 891 859
HbA1C 20 6.75 1.57 4.7 10.9 6.2
BMI 82 25.98 5.2 15.1 42.5 27.3
BSA (m2
) 80 1.89 0.30 1.13 2.85 1.72
BAD-MAPI (Fayad ZA et al.) 2004-2005

17. Correlation of Age & Wall Area of Carotid (mm2) using MRI
0
20
40
60
80
0 10 20 30 40 50 60 70 80 90 100
Age vs WACAR
Age
WACAR
r = 0.522
BAD-MAPI (Fayad ZA et al.) 2004-200

18. MRI - MAXIMAL THORACIC WALL THICKNESS
INTEROBSERVER VARIATION
MESA (AE Li et al.) AJR 2004; 182:593
2 3 4 5 6 7 8 9 10
2
3
4
5
6
7
8
9
Observer 2
Observer1

19. Comparing Framingham Risk Factor Score and
Coronary Artery Disease (CAD)
0
2
4
6
8
10
12
14
NO YES
CAD
FraminghamScore
p = 0.447
BAD-MAPI (Fayad ZA et al.) 2004-2000

20. Comparing Wall Area (mm2
) and
Coronary Artery Disease (CAD)
Wall Area Aorta - CAD
100
150
200
250
300
NO YES
CAD
WADA
p < 0.001 *
BAD-MAPI (Fayad ZA et al.) 2004-2000

21. Wyttenbach R……..Corti R. Circ 2004;110:1156
EFFECTs OF PTA & EVBT ON VASCULAR REMODELING
HUMAN FEMOROPOPLITEAL ARTERY - MRI

22. T1W PDW T2W
RGB
Fibrous cap
Lipid Core
Clustered
2B) Lipid Rich Plaque
Itskovich VV, Samber D, Mani V, et al Magn Reson Med 2004; 52: 515

23. 2C) Targeted Contrast Agent -
Approaches
Choudhury RP; Fuster V; Fayad ZA Nature Drug Disc. 2004;3:1

24. Cell & Molecular MRI Targets
In Atherothrombotic Plaques
Lipinski MJ, Fuster V, Fisher EA, Fayad ZA, Nature Cardiov. Med. 2004;1:1

25. Lipid-Rich Atherosclerotic Plaques Detected by
Gadofluorine-Enhanced In Vivo Magnetic Resonance Imaging
Sirol, M et. al. Circulation 2004; 109: 2890.
In vivo T1W MR image of the rabbit abdominal aorta
24-hours post-gadofluorine injection

26. Lipid Rich Atherosclerotic Rabbit 24h
Post Gadofluorine
n=10 NZW
Atherosclerotic rabbits
No Enhancement in
Controls (n=6)
Pre Contrast
24 H Post
Gadofluorine
Sirol, M et. al. Circulation 2004; 109: 2890 – AHA 2004 -

27. In Vivo Aortic Atherosclerotic Plaque in ApoE-KO Mice
Gd Immunomicelles
Macrophages scavenger receptor I&II Murine (CD204)
9.4T
TR=500 ms; TE= 8.6 ms
101 µm in plane spatial resolution
500 µm slice thickness
Injected -
13.7µmol/kg
Lipinski M; Fayad ZA, Fuster V et al. ISMRM 2004
A. DAPI cell nuclei (blue)
B. Gd Immunomicelle-CD204-NDB (green)
C. Ab CD 68 (Mφ)
D. Merge (orange) - localization in Mφ
Merge
PRE-CONTRAST 24 hours POST-CONTRAST

28. Pre-contrast 48 hours post-contrast1 hr post-contrast 24 hr post-contrast
20x
lumen
wall
40x
Frias JC, Fayad ZA, Fuster V et al. ISMRM 2004
rHDL-Gd-DTPA-DMPE-NBD conjugate (green)
rHDL-Gd-DTPA-DMPE
apoE-KO mice, 4.36 mmol/kg, 9.4T MRM

29. 4x
Acute Thrombus
4x
1-week-old Thrombus
10x
8-week-old Thrombus
4x
6-week-old Thrombus
Fibrin Gradually Replaced by Collagen in Older Thrombi

30. Detection of Occlusive thrombus in the Rabbit
Using Fibrin-Targeted MR Contrast Agent
Pre Contrast Post Contrast
T1-Weighted
sequence
2D BB FSE
Sirol M. et al. Circ 2004 (In Press) - AHA 2004

31. Chronic Thrombus Detection
Age Characterization Using Fibrin-Targeted MR Contrast
Agent
N=14 NZW Rabbits
Acute 1 Week 2 Weeks 4 Weeks 6 Weeks 8 WeeksNormal
Artery
Pre
Post contrast
Sirol M. et al. Circ 2004 (In Press) - AHA 2004

32. HIGH RISK PLAQUES (HRP)
HIGH RISK BLOOD (HRB)
BURDEN OF ATHEROTHROMBOSIS DISEASE (BAD)
VULNERABLE PATIENT’S MYOCARDIUM (VPM) 1
1. HRP / HRB / BAD - SYSTEMIC
2. HRP - ABUNDANT
3. HRP AND HRB - REGIONALLY DIFFERENT
4. BAD - CT / MRI: PATHOGENETIC VS DIAGNOSTIC
5. VMP
Maseri A, Fuster V, Circulation 2003; 107: 2068
Fuster V, Kim RJ, Circulation 2004 (In Press)

33. ROLE OF IMAGING TECHNOLOGY (MRI)
Ischemia at Stress (epicard. vs microv.)
- Decreased Perfusion (Dipyrid., Adenosine)
- Decreased Contractility (Dobutamine)
Non Viability (i.e., scarring), Myoc.Dysfunction
- Contrast Hyperenhancement
- No Increased Contractility (Dobutamine)
Viability (hibernation, stunning), Myoc.Dysfunct
- No Contrast Hyperenhancement
- Increase Contractility Dobutamine)

34. Molecular Genetic Advances in Cardiovascular Medicine
Focus on the Myocyte
Anversa, P et. al. Circulation 2004;109:2832.
Process of differentiation of adult stem cells in cell lineages of
the organ of origin
24

35. AUTOLOGOUS CARDIAC STEM CELL THERAPY FOR ISCHEMIC MYOCARDIAL DISEASE
Principal Investigator: Valentin Fuster, MD, PhD
Co-Principal Investigator: Bernardo Nadal-Ginard, MD, PhD
T=0 min Pig preparation
T=12 min Short-axis cine sequences : Ventricular Function and Site of Injection.
T=19 min T2-weighted dark-blood imaging to detect Myocardial Edema.
T=29 min Start Adenosine Infusion.
T=33 min Gadolinium injection and Stress Perfusion imaging
T=36 min Long asix views of the Left Venricle (4-chamber, two-chamber)
T=48 min Rest Perfusion.
T=58 min Delayed Enhancement imaging to assess extent of infarction
T=65 min Repeated Delayed Enhancement (contrast washout kinetics)
T=± 90 min End of study.
S Rajagopalan: MRI-Project Leader),

36. T=0 min Patient preparation
T=12 min Short-axis cine sequences for Ventricular Function and Site of Injection.
T=20 min Start Adenosine Infusion.
T=-24 min Gadolinium injection and Stress Perfusion.
T=36 min Long-axis cine views of the Left Ventricle (4-chamber, 3-chamber, 2
chamber). T=40 min Rest Perfusion.
T=50 min Delayed Enhancement imaging to assess extent of infarction.
T=60 min End of study.
S Rajagopalan: MRI-Project Leader
AUTOLOGOUS CARDIAC STEM CELL THERAPY FOR ISCHEMIC MYOCARDIAL DISEASE
Principal Investigator: Valentin Fuster, MD, PhD
Co-Principal Investigator: Bernardo Nadal-Ginard, MD, PhD

37. FROM THE VULNERABLE PLAQUE TO THE BURDEN OF DISEASE
EVOLVING UNDERSTANDING OF THE VULNERABLE PATIENT
Valentin Fuster MD,PhD
AHA, New Orleans, November 6, 2004