SHAPE Society

1. I-III IV-Va
Asymptomatic
Modified from V Fuster et al., NEJM 1992; 326: 242 and NEJM 2002 (Subm)
VI
Angina
Vb-Vc
Ca++
Phase 3 - 4Phase 1 Phase 2 Phase 5
Stabilization
Vb-Vc
ATHEROTHROMBOSIS
ACS

2. 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 NEJM 2002 (Subm)

4. G. Helft, S. Worthley, V. Fuster, J.J. Badimon et al. Circ 2002;105:993]
Progression and Regression of Atherosclerotic Lesions
Monitoring With Serial Noninvasive Magnetic Resonance
Imaging

5. CORONARY REMODELING IN NON OBSRTUCTIVE CAD
W.Y.Kim et al Circ 2002;106:296 (Multicenter)

6. A.M. Varnava Circ 2002;105;939 (London)
Plaque Vulnerability, Remodeling, Adventitia Thickness

7. TYPE VI PLAQUE WITH RUPTURED IEL
P.R. Moreno, K-R Purushothaman, V.Fuster et al.,
Circulation 2002;105:2504

8. TYPE VI PLAQUE WITH IMFLAMMATION & RUPTURED IEL
P.R.Moreno, K-R Purushothaman, V. Fuster et al
Circulation. 2002;105:2504

9. Early Plaques Advanced, Non-Disrupted Disrupted
Rupture of IEL Medial Inflammation
Medial Fibrosis Medial Atrophy
P=0.0001
P=0.0001 P=0.0001
P=0.008
598 Human Aortic Plaques By AHA Classification
Moreno PR, et al. Circulation 2002;105:2504

10. Diabetic Atherosclerotic Microangiopathy
Moreno PR, Purushothaman KR, O’Connor WN, Fuster V. 2002 (Subm)
Diabetic
Non- Diabetic
P=0.02
420
440
460
480
500
520
540
No Diabetes Diabetes
Total Neovessels
200
220
240
260
280
300
320
340
360
No Diabetes Diabetes
Media Neovessels
P=0.02
P=0.002

11. Sprouting Angiogenesis in Human Atherosclerosis
Moreno PR, Purushothaman KR, Echeverri D, Fuster V, 2002 (Subm)
CD-34 (Purple)
Double Immunohistochemestry
α-actin (Brown)

12. 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 NEJM 2002 (Subm)

13. I-III IV-Va
No Sx
Modified from V Fuster et al., NEJM 1992; 326: 242 and NEJM 2002 (Subm)
VI
Angina
Vb-Vc
Ca++
Phase 3 - 4Phase 1 Phase 2 Phase 5
Stabilization
Vb-Vc
ATHEROTHROMBOSIS
ACS

14. Independent Predictors for Plaque Disruption P Value
Number of Vasa Vasorum at Plaque Base 0.0001
Rupture of Internal Elastic Lamina (%) 0.01
Fibrous Cap Thickness (microns) 0.02
Percent Lipid Area (%) 0.025
Total Intimal Plaque Area (mm2) 0.031
Multiple Regression Analysis

15. LIPID CORE PROGRESSION / REGRESSION AND
NEOVASCULARIZATION
Progression Regression
High-Risk1
Disrupted2
Fibro-Calcific3
P
(n=89) (n=55) (n=18) Value
Lipid Area (mm2
) 3.5 ± 3.5 6.6 ± 3.5 2.03 ± 1.7 0.0001
Plaque Neovessels 41 ± 23 66 ± 19 22 ± 11 0.0001
Media Neovessels 284 ± 87 412 ± 133 201 ± 99 0.0001
Adventitia
Neovessels 118 ± 69 194 ± 83 100 ± 42 0.0001
Total Neovessels 444 ± 134 671 ± 188 324 ± 140 0.0001
1
Type IV-Va 2
Type VI 3
Type Vb-Vc
P Moreno, K-R Puroshothaman, V Fuster et al., Circ 2002 (In Press)

16. M.Shinnar, J.A.Fallon, J.J.Badimon, V.Fuster, ATVB 1999;19:2756 – Sensitivity & Specificity

18. Baseline 6 months
Aortic Atherosclerotic Plaque Evaluated by MR
Image Matching over Time
Pulmonary veins
LAD
Corti R, Fuster V, Fayad ZA, Badimon JJ, et al.Circ 2002;106:2884
Ascending
Aorta
Descending
Aorta

19. Effects of Lipid Lowering on Human
Aortic and Carotid Plaques
Study Design
Hypercholesterolemic patients
Carotid Plaques ≥ 2mm
and/or
Thoracic Aortic Plaque ≥ 4mm
+
LDL-Cholesterol ≥ 130 mg/dl
or HDL < 45 mg/dl
Simvastatin 20 Simvastatin 80
MRI Follow-up
6, 12, 18, 24 mo.
MRI & RANDOMIZATION
Corti R, Fayad ZA, Fuster V, et al. Circ. 2001;104:249-252

20. -6 0 6 12 18 24 30 36 42 48 54
0
50
100
150
200
250
300
350
Follow-up (Weeks)
Plasmalipidlevels(mg/dl)
HDL: increase - 5%
LDL: decrease - 30-35%
N=21 patients
Total Cholesterol
LDL Cholesterol
HDL Cholesterol
LIPID-LOWERING ON HUMAN ATHEROSCLEROSIS
COURSE OF PLASMA LIPID LEVELS
R Corti, V Fuster, ZA Fayad, JJ Badimon et al., Circ 2002; 106:2884

21. MRI-LIPID LOWERING (SIMVASTATIN)
AND REGRESSION OF ATHEROSCLEROSIS
AORTA
(n=44 plaques)
CAROTID ARTERY
(n=32 plaques)
LUMEN
AREA(mm2)
ANOVA p<0.001
0
100
600
500
300
200
400
BL 6 12 18 24
R Corti, V Fuster, ZA Fayad et al., Circ 2002; 106:2884
ANOVA p<0.001
0
10
30
20
40
BL 6 12 18 24
0
50
350
250
150
100
200
300
BL 6 12 18 24
VESSELWALL
AREA(mm2)
ANOVA p<0.001 ANOVA p<0.001
0
10
60
50
30
20
40
BL 6 12 18 24

22. LIPID-LOWERING ON HUMAN ATHEROSCLEROSIS
CHANGES IN VESSEL WALL DIMENSIONS (CONTROLS)
R Corti, V Fuster, ZA Fayad, JJ Badimon et al Circ 2002;106:2884
-6
-4
-2
0
2
4
6
Dimension(mm)
Baseline
12 Mo.
24 Mo.
Baseline vs. 24
Mo.

23. Baseline 24 months follow up
R Corti, J J Wentzel, Z A Fayad, J J Badimon, V Fuster 2002 (Subm)

24. LIPID CORE PROGRESSION / REGRESSION AND
NEOVASCULARIZATION
Progression Regression
High-Risk1
Disrupted2
Fibro-Calcific3
P
(n=89) (n=55) (n=18) Value
Lipid Area (mm2
) 3.5 ± 3.5 6.6 ± 3.5 2.03 ± 1.7 0.0001
Plaque Neovessels 41 ± 23 66 ± 19 22 ± 11 0.0001
Media Neovessels 284 ± 87 412 ± 133 201 ± 99 0.0001
Adventitia
Neovessels 118 ± 69 194 ± 83 100 ± 42 0.0001
Total Neovessels 444 ± 134 671 ± 188 324 ± 140 0.0001
1
Type IV-Va 2
Type VI 3
Type Vb-Vc
P Moreno, K-R Puroshothaman, V Fuster et al., Circ 2002 (In Press)

25. HIGH CHOLESTEROL, SIMVASTATIN
VASA VASORUM
S. H. Wilson, et al. Circ 2002:105:415

26. 5 mm2
(5%)
46 mm2
(84%)
6 mm2
(10%)
0.7 mm2
(1%)
49 mm2
(77%)
2 mm2
(3%)
3 mm2
(3%)
10.7 mm2
(17%)
Treated (n=8)
Total plaque area = 58 mm2
Untreated (n=8)
Total plaque area = 64 mm2
IN VIVO CAROTID PLAQUES AT MRI - INTENSIVE LIPID LOWERING1
Fibrous tissue area, mm2 (% of total plaque)
Lipid plus calcium area, mm2 (% of total plaque)
Lipid deposits area, mm2 (% of total plaque)
Calcium cluster area, mm2 (% of total plaque)
1
Three Drugs X-Q Zhao et al., ATVB 2001;21:1623

27. I-III IV-Va
Asymptomatic
Modified from V Fuster et al., NEJM 1992; 326: 242 and NEJM 2002 (Subm)
VI
Angina
Vb-Vc
Ca++
Phase 3 - 4Phase 1 Phase 2 Phase 5
Stabilization
Vb-Vc
ATHEROTHROMBOSIS
ACS

29. A. Tedgui et al. Thromb Haemost 2001;86;422
EXPRESSION OF CASPASE 3 IN MACROPHAGES (LIPID CORE ,
HUMAN CAROTID PLAQUE)

30. Co-localization of Caspase-3 and Tissue Factor AntigenCo-localization of Caspase-3 and Tissue Factor Antigen
in Lipid-Rich Area of Human Carotid Atheromain Lipid-Rich Area of Human Carotid Atheroma
R. HutterR. Hutter et al., Circ 2002 (Subm)et al., Circ 2002 (Subm)

31. Apoptosis and Tissue Factor Expression inApoptosis and Tissue Factor Expression in
Macrophages of Human Coronary Atheroma (n=5)Macrophages of Human Coronary Atheroma (n=5)
R Hutter et al Circ 2002 (Subm) – Apo-E -/-

32. 20
40
60
80
20 40 60
TissueFactorExpressionTissueFactorExpression
Caspase-3 ExpressionCaspase-3 Expression
R = 0.72R = 0.72
PP < .01< .01
%%
%%
Correlation Between Intimal Apoptosis and Tissue FactorCorrelation Between Intimal Apoptosis and Tissue Factor
In Lipid-Rich Areas of Coronary and Carotid AtheromaIn Lipid-Rich Areas of Coronary and Carotid Atheroma
R. HutterR. Hutter et al., Circ 2002 (Subm)et al., Circ 2002 (Subm)

33. Co-Expression of Tissue-Factor and Active Caspase-3Co-Expression of Tissue-Factor and Active Caspase-3
In Neointimal Foam Cells of ApoE-/- MouseIn Neointimal Foam Cells of ApoE-/- Mouse
ApoE-/-ApoE-/-

34. 20
40
60
20 40 60
TissueFactorExpressionTissueFactorExpression
Caspase-3 ExpressionCaspase-3 Expression
R = 0.81R = 0.81
PP < .01< .01
%
Correlation Between Apoptosis and Tissue FactorCorrelation Between Apoptosis and Tissue Factor
Expression in Neointima of Apo-E -/- MiceExpression in Neointima of Apo-E -/- Mice
Randolph Hutter et al 2002
%

35. CELLULAR CHOLESTEROL ACCUMULATIONS AND
CELL DEATH
I. Tabas JCI 2002;110:905

36. Ultrastructural Detection of Apoptosis and NecrosisUltrastructural Detection of Apoptosis and Necrosis
in Human Atheromain Human Atheroma

37. Enhanced
Reverse Cholesterol Transp.
HDL
Anti-Atherothrombotic
Effect
Anti-inflammatory
Anti-thrombotic
Pro-fibrinolytic
Anti-oxidant
HDL AS ANTI-ATHEROTHROMBOTIC
PK Shah et al., Circ 2001; 104:2376

39. J.X. Rong et al. Circ 2001;104:2447-2452
ELEVATING HDL IN APO-E DEFICIENT MICE
Macrophage Content

40. J.X. Rong et al. Circ 2001;104:2447-2452
ELEVATING HDL IN APO-E DEFICIENT MICE
Smooth Muscle α-Actin Content

41. Background
Peroxisome proliferator-activated receptors (PPARs) are a
subfamilly of nuclear receptors which control a variety of cellular
functions. PPAR-γ agonist have potential pleiotropic effects required to
induce plaque regression and stabilization.
 Reverse Cholesterol
Transport
Free cholesterol
 scavegenreceptor CLA-1
HDL
Vessel Wall
Liver
 ET-1, PAI-1
 Thrombosis
Blood
HDL
Hepatic cell Apo A-1
 ABC-1 receptor
 MCP-1, VCAM, chemokines
 ET-1
 Recruitment, adherence and
homingof macrophages
 Vasoconstriction
 MMPs
 SMCMigration
Roberto Corti JACC 2002;248A

42. EFFECT OF SIMVASTATIN AND PPARγ AGONIST ON
RABBIT ATHEROSCLEROTIC LESIONS: BIOLOGICAL
CHANGES
Infrarenal Aorta
Immunohistochemistry
Plaque size (correlation to MRI)
Frozen + Formalin-fixed section
Aortic Arch
MMP1&3-activ. / Caspase-activ. / TF
Fresh-frozen section

43. Rabbit Aorta plaque size
-25
-20
-15
-10
-5
0
5
10
15
20
*
*
*
*p=0.045
p=0.012
PPARγ
regression diet
progression
simvastatin
simvastatin+ PPARγ
p<0.01 vs. progression
*
Changes in Vessel Wall Area vs. AT-Baseline (%)Changes in Vessel Wall Area vs. AT-Baseline (%)
Comparison of the treatmentsComparison of the treatments
R Corti et al JACC 2002;248A

44. Rabbit Aorta plaque composition
0
10
20
30
40
50
60
70
80
90
****
plaque area (%) RAM-11 +plaque area (%) RAM-11 +
0
10
20
30
40
50
60
0
10
20
30
40
50
60
70
vessel wall area (%)vessel wall area (%) αα-actin +-actin +
vessel wall area (%)vessel wall area (%) αα-actin/collagen +-actin/collagen +
regression diet
progression
control
simvastatin+PPARγ
simvastatin
PPARγ
p<0.05 vs. control
*
*
*
* *
*
*
R Corti et al JACC 2002;248A

45. Results: MMP-activity
0
5
10
15
20
25
30
35
40
45
50
* *
*
regression diet
progression
control
simvastatin+PPARγ
simvastatin
PPARγ
p<0.05 vs. progression
*
Optical Density (arbitrary units)Optical Density (arbitrary units)
72kDa -- MMP-2
Roberto Corti et al JACC 2002;248A

46. Active
6-week
wash-
out
period
Patient
Identification
Consent Form
Screening and
Enrollment Qualifying baseline labs
baseline MRI & UFCT
Patient Randomization
low-dose Statin low-dose Statin
+ Fibrate
high-dose Statin
1 year-post MRI & UFCT
2 year-post MRI & UFCT
3 year-post MRI & UFCT
ACTIVE
TREATMENT
ACTIVE
TREATMENT
3 YEARS
FOLLOW-UP
DATA ANALYSIS
MRI - DIABETES ATHEROSCLEROSIS LIPID ALTERING STUDY

47. S. Achenbach et al 2002
MSCT – SENSATION 16

50. Dynamic Contrast Enhanced MRA
Global Evaluation of the Arterial and Venous Systems
M.Poon, Z.A.Fayad, V.Fuster 2002

51. LAD Wall
Fayad ZA; Fuster V et al. Circ. 2000;102;506-510
RCA Wall
LAD Wall
Black-Blood Coronary Plaque MR
Eccentric (“lipid-rich”) Concentric (“fibrotic”) Ectatic (“remodeled”)

52. Fayad ZA, Fuster V, Nikolaou K, Becker C. Circ. 2002 ( In Press)
Carotid Aortic Arch Desc. Aorta
Complex Plaques – Systemic Disease

53. I-III IV-Va
Asymptomatic
Modified from V Fuster et al., NEJM 1992; 326: 242 and NEJM 2002 (Subm)
VI
Angina
Vb-Vc
Ca++
Phase 3 - 4Phase 1 Phase 2 Phase 5
Stabilization
Vb-Vc
ATHEROTHROMBOSIS
ACS

54. CVMR-ISL
Zahi Fayad, PhD
Gilbert Aguinaldo, MD
Vitalii Itskovich, PhD
Gabor Mizsei, MS
Dan Samber, MS
Frank Macalusso, RT
Karen Metroka
Paul Wisdom, RT
Cardiology
Valentin Fuster, MD, PhD
Juan Badimon, PhD
Michael Poon, MD
Stella Palentia, RN
Don Smith, MD
Meir Shinnar, MD, PhD
Pedro R Moreno MD
Pathology
John Fallon, MD, PhD
Molecular Biology
Yale Nemerson, MD
Mark Taubman, MD
Edward Fisher, MD, PhD
Ernane Reis, MD
Robin Choudhury, MD
Funding
NIH-HL 94013
NIH-HL 61801
NIH-HL 07208
BMS Inv. award
Merck
Cardiology Fellows
Ursula Rauch MD
Roberto Corti, MD
Julio Osende, MD
Antonia Sambola, MD
Stephen Worthley, MD
Gerard Helft, MD
Randolph Hutter MD
The Mount Sinai Medical Center
The Cardiovascular Institute
Radiology
Burton Drayer, MD
Jeff Goldman, MD
Neurology
Jessey Weinberger, MD

60. ATHEROTHROMBOSIS: APPROACH IN
2002
Aggressive
Intervention1
Effective
Prevention 3
Coronary Atherothrombosis
Atherothrombosis
Subclinical
Atherothrombosis
Low
Risk
Modified from V Fuster, Circulation 1999; 99:1132
Multiple Risk F.
Acute Coronary Syndromes
Early
Detection 2
1
Secondary Prevention , 2,3
Primary Prevention

61. Reproducibility of Vessel Wall Measurement
3.51.52CAROTID ARTERY
(N = 4 plaques)
2.64.56AORTA
(N = 5 plaques)
Percent
error
(%)
Mean of 5
contiguous slices
Error (mm2)
Slice Specific
Error (mm2)N=6 patients
14
Analysis Courtesy
of Leslie Shaw
Corti R, Fuster V, Fayad ZA, Badimon JJ et al. Circ 2002; 106:2884

62. CHD RISK IN WOMEN ACCORDING TO FRAMINGHAM SCORING - 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 (obes, BP, HDL, TC, Gluc)
JAMA 2001; 285:2475

63. HDL AND CRP AS RISK FACTORS FOR CAD
P. Libby, PM Ridker, A. Maseri Circ 2002;105:1135

64. Effect of Lipid-lowering by Simvastatin onEffect of Lipid-lowering by Simvastatin on
Human Atherosclerotic Aortic LesionsHuman Atherosclerotic Aortic Lesions
Corti R, Fuster V, ZA Fayad, Badimon JJ et al., Circulation 2002;106:2284Corti R, Fuster V, ZA Fayad, Badimon JJ et al., Circulation 2002;106:2284

65. 5 cm
A B C
D E F

66. Co-localization of Caspase-3 and Tissue-Factor AntigenCo-localization of Caspase-3 and Tissue-Factor Antigen
in Cultured Monocytes Treated with oxLDLin Cultured Monocytes Treated with oxLDL
Hutter R. et al 2002 (Subm)