Acc 2005-1, v pl-vp

THE EPIDEMIC OF CVD – NEED FOR NEW APPROACHES
Epidemiology and Change in Emphasis
- From the High Risk Plaque to the High Risk Symptomatic Patient
- From the High Risk Asymptomati to the Intermediate and Low Risk Patient
HRSP - Therapeutic Polypill & Single Pill
HRAP - BAD, Diagnostic MR Imaging
- BAD, Diagnostic & Rx - MR Plaque Composition
- BAD, Diagnostic Molecular MR Contrast Enhanced,
IRAP - Diagnostic CACS & CRP Biomarkers
LRAP - Government, Polymeal, Children
SHAPE & AEHA.
Orlando, March 05, 2005

0
5
10
15
20
25
30
1990 2020
MillionsofDeaths
fromCardiovascularCauses
Western countries
Non-Western (developing)
countries
5
9
6
19
DEATHS FROM CARDIOVASCULAR CAUSES,
WORLDWIDE, IN 1990 AND ESTIMATED FOR 2020
KS Reddy. NEJM 2004; 350:2438

Prevalence of Obesity & Diabetes in the U.S.
1990/19911990/1991 20002000
ejt 0901–120
Mokdad et al., JAMA 286:1195–1200, 2001Mokdad et al., JAMA 286:1195–1200, 2001
No DataNo Data < 4%< 4% 4%-6%4%-6% > 6%> 6%
No DataNo Data < 10%< 10% 10%-14%10%-14% 15%-19%15%-19% ≥≥ 20%20%
ObesityObesity
DiabetesDiabetes

0
10
20
30
40
50
Hypertri-
glycerinemia
Low
HDL
Hyper-
glycemia
Central
Obesity
Male
Female
Prevalence(%)
Hyper-
tension
METABOLIC ABNORMALITIES
AMERICAN ADOLESCENTS (12-19 Y)1
1
NHANES III - n=1960
S.D.de Ferranti et al., Circ 2004; 110:2494

SHAPE & AEHA. Within This Context

ATHEROTHROMBOSIS: APPROACH IN 2005
Aggressive
Intervention3
Effective
Prevention1
2.Chronic Atherothrombosis
2. CAD Equivalents
HRAP- Subclinical
MRI / CT
Low
Risk
Modified from V Fuster, Circulation 1999; 99:1132
IRAP – Risk Frs
CACS / CRP
1.Acute Coronary Syndromes
Early
Detection 2
HRAP: High Risk Asymptomatic Patient - >2% y - >20% 10y
IRAP: Intermediate Risk Asymptomatic Patient – 0.5-2% y - 5-20% 10y
LOW RISK: FRS - < 0.5%y - < 5% 10 y

METHODS TO ASSESS PLAQUE VULNERABILITY
Intravascular ultrasound
Three-dimensional reconstruction
Ultrasound elastography
Intravascular ultrasound flow measurements
Virtual histology
Angiography
Direct visualization
Optical coherence tomography
RAMAN (near infrared) spectroscopy
Thermography
Computed tomography
Contrast
Ultrafast
Magnetic Resonance
Phase Contrast
Nuclear
Intravascular
B Meier. Heart 2004; 90:1395

HIGH RISK PLAQUES - HRP
HIGH RISK BLOOD - HRB
BURDEN OF ATHEROTHROMBOSIS DISEASE - BAD
a) HRP / HRB / BAD - Systemic
b) HRP – Abundant
c) HRP AND HRB – Regionally Different
Maseri A, Fuster V, Circulation 2003; 107: 2068
Fuster V, Kim RJ, Circulation 2005 (In Press)

ACS (N=198) & SYSTEMIC ENDOTHELIAL DYSFUNCTION (FBF) – 5 DAYS 1
ADJUSTED RISK FACTORS, CV EVENTS (DEATH, MI, STROKE)- Av 4 YRS
Fichtlscherer et al., Circ 2004; 110:1926 (Frankfurt)
70
80
90
100
0 365 730 1095 1460 1825
days of follow up
Proportionofpatients
withouCVevents(%)
Logrank test p<0.03
Acetylcholine - dose - response
70
80
90
100
0 365 730 1095 1460 1825
days of follow up
Proportionofpatients
withouCVevents(%)
Logrank test p<0.08
Sodium nitroprusside - dose - response
≥ 35.0 (1. quartile)
< 34.9 (2. quartile)
≥ 31.6 (1. quartile)
1
Improved response at 8 weeks adds to the prediction (ACH)

CAD (ACS 54%) - CULPRIT VESSEL / LESION – N=843
NON-STENOTIC YELLOW PLAQUES / THROMBUS – N=1253
0
20
40
60
80
100
1 2 3
Color Grade of Plaque
PrevalenceofThrombosis
*
† ‡
(%)
*P=.0003 vs grade 1. †P<.0001 vs grade 1. ‡P<.0001 vs grade 2
Y Ueda et al., AHJ 2004; 148:842 (Osaka)

CAROTID ACTIVE PLAQUES (ENDARTERECTOMY)
CAP RUPTURE AND CAP EROSION BY STUDY GROUP
ICTB (LG Spagnoli et al.) JAMA 2004; 292:1895 (Rome, Mineapolis, Mayo)
C Yuan et al Circ 2002;105:181 (Seattle) – MRI – Several Plaques
No. of Plaques (%) P Val
Ipsilat. Stroke With TIA Asymptom. Stroke vs Stroke vs TIA vs
(n=96) (n=91) (n=82) TIA Asympt. Asympt.
Thromb. active % 74.0 35.2 14.6 <.001 <.001 .002
Cap rupture 66.7 23.1 13.4 <.001 <.001 .004
Cap erosion 7.3 12.1 1.2 .51 .09 .03

- From the High Risk Asymptomatic to the Intermediate and Low Risk Patient
SHAPE & AEHA.

Aggressive
Intervention3
Effective
Prevention1
Chronic Atherothrombosis
CHD Equivalents
HRAP- Subclinical
CT / MRI
Low
Risk
IRAP – Risk Frs
CACS / CRP
Acute Coronary Syndromes
Early
Detection 2
LOW RISK: FRS - < 0.5%y - < 5% 10 y

x
Patient Transport In-hospital Reperfusion
2004
2014
0 1 2 3
A B C D
Hours
Methods of Speeding Time to Reperfusion:
A B C D
Media Campaign 911 Expansion Regionalization PCI-Eluted Stents
Patient Education Pre-hosp. Rx MI protocol New devices / demand
1. MI - TIME TO REPERFUSION – 2005, 2015
X New antithrombotics, Myoc-Imaging., AICD, RF modification
x
X

1. ACS – A PRE-HOSPITAL POLYPILL
V Fuster 2005
Definite ACS with
Possible ACS Definite ACS High risk/intervention
Tx R Bl. Tx R Bl. Tx R Bl
+ +
Clopidogrel - Like Clopidogrel - Like
+ +
Oral Fr Xa Inhib Oral Fr Xa Inhib
+ +
Statin Statin
+
Oral Antithrombin

2. CAD EQUIVALENTS, CHRONIC ATHEROTHROMBOSIS
AND A POLYPILL
• ASA
• CLOPIDOGREL
• STATINS / LDL- C (HDL- C)
• ACE INHIBITORS
• BEHAVIOR MODIFICATION
• INTERVENTION (PCI VS CABG): LIFE QUALITY VS QUANTITY
CHALLENGES: COMPLIANCE, COSTS

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

Longitudinal View
Ca++
BAD (Fayad ZA, Mani V, Fuster V et al.) 2005
Multi Slice Black Blood Imaging
Rapid Extended Coverage (REX) Turbo Spin Echo Technique
Mid heart Aorta- 12 slices

Descriptive
StatisticsParameter No Mean St dev Min Max Range
Age 100 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

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

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
*

CAD (N=167) – STATIN vs NIACIN / STATIN
CIMT
-0.01
0
0.01
0.07
0.02
0.03
0.04
0.05
0.06
Placebo PlaceboER Niacin ER Niacin
No DM / MS DM / MS Present
ChangeinCIMT(mm±SEM)
ARBITER 2 (AJ Taylor et al.) Circ 2004; 110:3510

THE FREEDOM TRIAL
FUTURE REVASCULARIZATION EVALUATION
IN PATIENTS WITH DIABETES MELLITUS:
OPTIMAL MANAGEMENT OF MULTIVESSEL DISEASE
Risk Factor modification and Rx are critical.
1) BAD-MRI: Diabetics vs Non Diabetics
NHLBI 2005 (PI V Fuster)

0
10
20
30
40
50
60
70
80
90
100
MRI (1st) Histology
Percent
66.3 64
23.7
5.1 5
20.3
6.3 9.4
CAROTID PLAQUE COMPOSITION
(AS PERCENTAGE OF THE WALL)
Fibrous Tissue
Lipid Necrotic Core
Loose Matrix
Calcification
T Saam et al., ATVB 2005; 25:234 – In Vivo (Seattle, Wash)
M Shinnar et al., ATVB 1999; 19:2756 - Ex Vivo (New York)

MRI (no fat sat)
MRI (fat sat)
LAD
Lumen
LV
RV
RVOT
LAD WallX-ray angiogram
LAD
~6 mm max wall thickness
Fayad ZA et al.
Circ. 2000;102;506-510
Eccentric (“lipid-rich”)
MRI - Plaque Composition

Baseline 24 months follow up
R Corti, J J Wentzel, Z A Fayad, J J Badimon, V Fuster 2005 (Subm)
A ) MRI-LIPID LOWERING (SIMVASTATIN 20 or 80 mg/d)
AND REGRESSION OF ATHEROSCLEROSIS
R Corti, ZA Fayad, V Fuster, et al. Circ. 2001;104:249-252
R Corti, V Fuster, ZA Fayad, JJ Badimon et al. Circ 2002;106:2884

Independent of dose, LDL-C < 100 mg/dl had more regresion
Corti, J J Wentzel, Z A Fayad, J J Badimon, V Fuster 2005 (Subm)

R Corti, J J Wentzel, Z A Fayad, J J Badimon, V Fuster 2005 (Subm) PROVE IT
- TIMI 22 (C Cannon et al.), NEJM 2004; 350:15 - Clinical

Abdominal
Aorta
Thoracic
Aorta Baseline MRI Repeat MRI
after 12 months
treatment
3 contiguous slice
(no interslice gap
Lower corner
of Th9
Upper corner
of L4
Total vascular area
Lumen area
Maximal
vessel wall thickness
Minimal
vessel wall thickness
Yonemura A; Momiyama Y; Fayad ZA et al. JACC 2005;45:733-42
MRI - ATHEROSCLEROSIS AORTA – ATORVASTATIN (12mo,N=40)

-60
-
40
-20
0
20
40
60
80
ΔVWA
Thoracic Aorta Abdominal Aorta(%)
-60 -50 -40 -30 -20 -10 0
ΔLDL-C (%)
r=0.64
P<0.001
-60 -50 -40 -30 -20 -10 0
ΔLDL-C (%)
-60
-
40
-20
0
20
40
60
80
ΔVWA
(%)
r=0.34
P<0.005
5-mg dose
20-mg dose
MRI - ATHEROSCLEROSIS AORTA – ATORVASTATIN (12mo,N=40)

Baseline 12 months
A)
B)
LDL-C(mg/dl) VWA(mm
C)
D)
316
↓
195
-38%
161
↓
107
-34%
110
↓
79
-28%
224
↓
202
-10%
20 mg/day
5 mg/day
230
↓
180
-20%
212
↓
130
-39%
95
↓
109
+15%
119
↓
129
+9%
20 mg/day
5 mg/day

B) MRI - HDL-Cholesterol
Rabbit / IV HDL, Apo E / HDL, Rabbit / PPAR-y /
Fenofibrate
1
10
J.X. Rong et al. Circ 2001;104:2447
High-chol. Diet
Simv. + PPAR-y
Badimon JJ, Badimon L, Fuster V, JCI 1990; 85:1234, 1990
Rong JX et al Circ 2001;104:2447

PPARs in Atherosclerosis:
Castrillo A et. al. J Clin Invest. 2004;114:1538.
A C Li et al. J Clin Invest 2004;114:1564
PPAR signaling pathways influence
macrophage gene expression and
foam cell formation

T2WPDWT1W
ClusterRGB
l
nc
iph
fc
lf
df
pvf
l
nc
iph
fc
lf
df
pvf
l-lumen
nc-necrotic core
iph-intra plaque
hemorrhage
fc-fibrocellular
tissue
df-dense fibrous
tissue
lf=loose fibrous
tissue
pvf-perivascular
fat
Itskovich VV, Samber D, Mani V, et al Magn Reson Med 2004; 52: 515
In-Vivo Cluster Analysis for Plaque Characterization

THE FREEDOM TRIAL
IN PATIENTS WITH DIABETES MELLITUS:OPTIMAL
MANAGEMENT OF MULTIVESSEL DISEASE
2) MRI-Diabetics: Reversibility, Statins-PPAR

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

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

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 -

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

In Vivo Detection of Macrophages
in Human Carotid Atheroma
Use of Post-Ultrasmall Superparamagnetic Particles of Iron (USPIO) MRI
Pre-USPIO
Post-USPIO
24h
Post-USPIO
36h
Areas of USPIO accumulation (Pearls staining, b)
colocalizing with
areas of high macrophage content (MAC 387 stain, c)
in the fibrous cap region
Trivedi AR et al. Stroke 2004; 35: 1631

Pre Contrast
Post Contrast
3 day old thrombus
Crush injured left
carotid artery
30 minutes
P.I.
60 minutes P.I.
Molecular Imaging of Fibrin with MR
Chronic Rabbit Model
Thrombus
in Left CCA
fibrin MRA
Fayad ZA
Imaging Science Laboratories
Control
H&E
Sirol M. et al. Circulation 2005 (In Press)

Diabetes and PAD - Proposed Sequence for an
Integrated Plaque (IP)-MRI Diagnostic Protocol
Combination of multi-weighted, post-Gadolinium and post-USPIO imaging
Dellegrottaglie S, Mani V, Fayad Z, Moreno P, Fuster V, Rajagopalan S. 2005
PDW MRI of the
Superficial femoral
artery

THE FREEDOM TRIAL
IN PATIENTS WITH DIABETES MELLITUS:
OPTIMAL MANAGEMENT OF MULTIVESSEL DISEASE
3) MRI - Contrast Enhanced PAD

Aggressive
Intervention3
Effective
Prevention1
Chronic Atherothrombosis
CHD Equivalents
HRAP- Subclinical
CT / MRI
Low
Risk
IRAP- Risk Frs
CACS / CRP
Early
Detection 2
LOW RISK: FRS - < 0.5%y - < 5% 10 y

0 5 10 20 30 40
10
20
30
40
Initial Probability (%)
Posterior
Probability(%)
40% 25%35%
Identity Line
TRADITIONAL RISK PROBABILITY – IRAP & HRAP (FRS)
AND POSTERIOR NON-INVASIVE PROBABILITY
PWF Wilson et al., JACC 2003; 41:1898
NAHNES III (TA Jacobson et al.) Arch Int Med 2000; 160:1361
5

1) PREDICTED 7-YEAR EVENT RATES FOR CHD DEATH OR
NONFATAL MI FOR CATEGORIES OF FRS OR CACS
P Greenland et al., JAMA 2004; 291:210
0-9 10-15 16-20 ≥ 21
Framingham Risk Score, %
CoronaryDeathor
NonfatalMI,%
0
4
8
12
16
20
CACS
0
1-100
101-300
≥ 301

0.0
5.0
10.0
15.0
20.0
25.0
Framingham 10-Year CAD Risk (%)
0-1 2-4 5-9 >10
MultivariableRelativeRisk
<1.0 1.0-3.0 >3.0
High-Sensitivity C-Reactive Protein (mg/L)
2) RELATIVE RISK OF CV EVENT – FRS & CRP
WHS (PM Ridker et al.) NEJM 2002; 347:1557

Aggressive
Intervention3
Effective
Prevention1
Coronary Atherothrombosis
CHD Equivalents
HRAP- Subclinical
CT / MRI
Low
Risk
IRAP - Risk Frs.
CACS / CRP
Early
Detection 2
LOW RISK: FRS - < 0.5%y - < 5% 10 y

1) RISK FACTORS FOR WHICH INTERVENTION
IS PROVEN TO LOWER RISK –
GOVERNMENT ?
Cessation1
↓ 10%2
DP ↓ 6 mmHg3
↓
Cigarette Smoking1
50% ↓ CHD ------ ------
Cholesterol2
------ 30% ↓ CHD ------
Hypertension3
------ ------ 16% ↓ CHD
42% ↓ Stroke
CH Hennekens, Circ 1998; 97:1095

2) EFFECT OF INGREDIENTS OF POLYMEAL
IN REDUCING RISK OF CVD
% Reduction (95% CI)
Ingredients in Risk of CVD Source
Wine (150 ml/d) 32 (23 to 41) DiCastelnuovo, 2002 (MA)
Fish (114 g x 4 w) 14 (8 to 19) Whelton, 2004 (MA)
Dark Chocolate (100 g/d) 21 (14 to 27) Taubert, 2003 (RCT)
Fruit/Vegetables (400 g/d) 21 (14 to 27) John, 2002 (RCT)
Garlic (2.7 g/d) 25 (21 to 27) Ackerman, 2001 (MA)
Almonds (68 g/d) 12.5 (10.5 to 13.5) Jenkins, Sabate. 2002,03 (RCT)
Combined Effect 76 (63 to 84)
MA = meta-analysis; RCT = randomized controlled trial
OH Franco et al., BMJ 2004; 329:1447
Polypill - NJ Wald et al., BMJ 2003; 326:1419
Statin, ASA, Folic Acid, BP (ACE-I, β-blocker, Thiazide) - % Reduction 85%

3) NIH Launches Study of 100,000 U.S. Kids 2.7 Billion
Kaiser, J Science 2004;306:1883.
Random sampling across the US to follow the health of children from birth to age 21.

LRAP - Preventive - Government, Polymeal, Children
SHAPE & AEHA. Innovative, Feasible (RF)?, Simple?, Preventive?, Polyauthor?

2) C-Reactive Protein
Structure Affects Function
Dissociation from pentameric to monomeric form of CRP to exert
proatherosclerotic effects
Verma, S et. al. Circulation 2004;109:1914.

AngiographyCTA-MIP
1) CT- Calcified and Obstructive lesion LAD

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

1) ROLE FOR GOVERNMENTS ON PREVENTION
TA Pearson et al., Circ 2003; 107:645
Diet
Sedentary
Lifestyle
Tobacco
Hyperlipidemia
Hypertension
Earlyrecognition
ofSymptomatic
Disease
Risk Factor/Risk Behavior
Community
Setting
Essential Public
Health Services
Policy/Legislation
Assuring Personal Health Services
Religious
Organizations
Organizational Partnerships
Education/media
Surveillance
Whole
communities
Schools
Worksites
Healthcare
Facilities

Descriptive Statistics: Image Parameters
Parameter Count Mean Stdev Min Max Range
Average Wall
AreaCarotids
(mm2
)
100 29.28 11.45 13.14 60.81 47.67
Normalized
Plaque Index
Carotid
100 4.98 1.89 2.19 14.56 12.37
Average Wall
Area Aorta
(mm2
)
100 144.78 62.41 36.43 309.91 273.47
Normalized
Plaque Index
Aorta
100 7.20 2.21 3.60 13.18 9.58
Max Wall
Thickness
Carotid (mm)
100 5.82 2.63 1.41 16.27 14.86
Max Wall
Thickness
Aorta (mm)
100 5.97 3.18 2.83 18.44 15.61

Contrast-Enhanced MRI for
Atherosclerotic Plaque Tissue Characterization
Yuan C, Kerwin S, Ferguson MS, et al.
Journal of Magnetic Resonance Imaging 2002; 15: 62

T1W PDW T2W
RGB
Fibrous cap
Lipid Core
Clustered
Itskovich VV, Samber D, Mani V, et al Magn Reson Med 2004; 52: 515
In-Vivo Cluster Analysis for Plaque Characterization

X
x
Patient Transport In-hospital Reperfusion
2004
2014
0 1 2 3 4
A B C D
Hours
Methods of Speeding Time to Reperfusion:
A B C D
Media Campaign 911 Expansion Regionalization PCI-Eluted Stents
Patient Education Pre-hosp. Rx MI protocol New devices / demand
3a) MI - TIME TO REPERFUSION – 2005, 2014

CORONARY CALCIUM AND CORONARY DISEASE EVENTS
Calcium Score Threshold
> 0 ≥ 100 ≥ 200 ≥ 600
Subjects above threshold (%) 64 19 12 4
Sensitivity (%) 91 71 54 26
Specificity (%) 36 82 89 96
Positive predictive value (%) 3.2 8.6 10.5 14.1
Negative predictive value (%) 99.5 99.2 98.8 98.2
Relative risk 5.9 10.7 8.9 8.0
(95% CI) (3.0-11.6) (7.1-16.3) (6.1-12.9) (5.3-12.1)
St. Francis Study (AD Guerci et al.) 2005 (Submitted)

Actin
Actin
Macrophages
Macrophages
MMP-1
MMP-1
Endothelin-1
Endothelin-1
Apoptosis
Apoptosis
TPinhibitorControl
The Selective TP Receptor Antagonist S18886 has
Anti-atherosclerotic and Plaque Stabilizing Effects
S18886 transforms lesions towards a more stable phenotype
Viles-Gonzalez JF, Fuster V, Corti R, Badimon JJ.Viles-Gonzalez JF, Fuster V, Corti R, Badimon JJ. EHJEHJ,, 20052005 (In Press(In Press

R Corti, J J Wentzel, Z A Fayad, J J Badimon, V Fuster 2005 (Subm)

18
FDG-PET CT PET/CT
Fluorodeoxygluose 18 PET / CT
Monocytes / Thrombus
Rudd JHF et al. Circ 2002;105:2708-2711
ICA

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

COMPARISON OF SOFT, INTERMEDIATE, AND CALCIFIED PLAQUES
BY MDCT (PLAQUE MAP) AND IVUS
S Komatsu et al., Circ J 2005; 69:72
IVUS
Soft Intermediate Calcified
MDCT-positive 144 134 84
MDCT-negative 12 19 10
Sensitivity (%) 92 87 89

0 5 10 15 20
0
1
0.1
0.8
0.4
0.6
Years
Survival
ST Depression
0 5 10 15 20
0
1
0.1
0.8
0.4
0.6
Years
Failure THR
0 5 10 15 20
0
1
0.1
0.8
0.4
0.6
Years
Low METs
Absent Present
SURVIVAL FREE OF CHD IN HIGH-RISK MEN
CJ Balady et al., Circ 2004; 110:1920 (Framingham)

CVMR-ISL
Zahi Fayad, PhD
Gilbert Aguinaldo, MD
Robin P Choudhury, MD
Vitalii Itskovich, PhD
Michael J Lipinski
Teresa Rius, MD
Frank Macalusso, RT
Karen Metroka, RT
Javier Sanz, MD
M.Sirol,MD
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
KR Purushothaman,MD
Molecular Biology
Yale Nemerson, MD
Mark Taubman, MD
Edward Fisher, MD, PhD
Ernane Reis, MD
K-R Purushothaman
Funding
NIH-HL 94013
NIH-HL 61801
NIH-HL 07208
BMS Inv. Award
Merck, GSK,
Schering AG
CV Research Fellows
Ursula Rauch MD
Roberto Corti, MD
Julio Osende, MD
Antonia Sambola, MD
Stephen Worthley, MD
Juan F Viles MD
Randolph Hutter MD
The Mount Sinai Medical Center
The Cardiovascular Institute
Radiology
Burton Drayer, MD
Jeff Goldman, MD
Neurology
Jessey Weinberger, MD

15
16
17
18
19
20
21
22
23
Baseline End of Follow-up
TREATMENT
CONTROL
Total Vessel Area (mm2
) Vessel Wall Area (mm2
)
S18886 induces regression of advanced atherosclerotic plaques
Viles-Gonzalez JF, Fuster V, Corti R, Badimon JJ.Viles-Gonzalez JF, Fuster V, Corti R, Badimon JJ. European Heart JournalEuropean Heart Journal, 2005, 2005

Viles-Gonzalez JF, Fuster V, Corti R, Badimon JJ.Viles-Gonzalez JF, Fuster V, Corti R, Badimon JJ. European Heart JournalEuropean Heart Journal, 2005, 2005

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

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

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

0
1
2
3
4
5
6
Baseline 6 months
PlaqueVolume(cm3
)
0
0.5
1
1.5
2
2.5
Baseline 6 months
PlaqueArea(cm2
)
0
2
4
6
8
10
12
Baseline 6 months
LumenVolume(cm3
)
0
1
2
3
4
5
6
Baseline 6 months
LumenArea(cm2
)
14
16
7
8
SIMVASTATIN –TE MRI
AORTIC PLAQUE VOLUME AORTIC LUMEN VOLUME
JAC Lima et al., Circ 2004; 110:2336

PREVENTING CARDIOVASCULAR DISEASE,
DIABETES AND CANCER
AHA, ADA, ACS – Circulation 2004;109:3244
Eat right - Mediterranean, serving size
Get active - >30min, >3days/week
Do not smoke - Advocacy, programs …

GENERAL PREVENTION GUIDELINES FOR CANCER, CVD AND
DIABETES IN ADULTS
20 30 40 50+AGETEST
BMI
Blood Pressure
Lipid Profile
Blood Glucose test
Clinical Breast Exam (CBE)
and Mammography
Pap test
Colorectal Screening
Prostate specific antigen
test and/digital rectal exam
Each regular health care visit
Each regular health care visit (or at least
once every 2 years if BP < 120/80 mm Hg)
Every 5 years
Every 3 years
CBE every 3 yrs
Yearly CBE and
Mammography
Yearly
Every 1-3 years; depends on
type of test and past results.
Frequency depends
on test preferred
Offer yearly, assist
informed decisions
ACS/ADA/AHA - Circ 2004; 109:3244

3) CARDIOVASCULAR HEALTH IN CHILDHOOD
CHALLENGES 20021
1
Multidisciplinary - Schools
2
Above 10 years and less demanding levels than in adults
AHA Statement (CL Williams et al.) Circ 2002; 106:143
1. Physical Activity Promotion methods
2. Obesity (< IR Type II Diabetes) Prevention methods
Nutrition
3. Hypertension Identification
4. Cholesterol Identification
Nutrition
Statins2
LDL > 190
LDL > 160 + FU
5. Cigarette Smoking Prevention methods

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

-1 0 1 2 3 4 5Years
Cardiovascular disease
Perinatal disease
Injuries
Cancer
Chronic obstructive
pulmonary disease
HIV infection or AIDS
Other causes
Coronary heart
disease
Stroke
Other heart
disease
U.S. LIFE EXPECTANCY 1970 & 2000 – SUCCESS OF RESEARCH ON THERAPIES
C Lenfant et al., NEJM 2003; 349:9
NCHS and AHA 2002 - Leading cause of death -

Ischemic stroke
Transient ischemic attack
Myocardial infarction
Angina pectoris (stable, unstable)
Sudden death
Critical limb ischemia, gangrene,
Systemic – Clinical Regions 2, 25-30%; 3, 5-10%
Atherothrombotic Disease (CAPRI & TASC)
Viles-Gonzalez J, Fuster V, Badimon JJ. EHJViles-Gonzalez J, Fuster V, Badimon JJ. EHJ 20042004; 25:1; 25:1

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)
Viles JF, Poon M, Sanz J, Rius T, Fuster V, Badimon JJ.Viles JF, Poon M, Sanz J, Rius T, Fuster V, Badimon JJ. Circ.Circ. 20042004
(In Press)(In Press)

CT Evaluation
Fuster V, Kim RJ, Circ 2005 (In Press)

C ) Selective TP Receptor Antagonist S18886 has
Baseline End of Treatment
Follow-up With Serial High Resolution Magnetic Resonance
Viles-Gonzalez JF, Fuster V, Corti R, Badimon JJ.Viles-Gonzalez JF, Fuster V, Corti R, Badimon JJ. EHJEHJ,, 20052005 (In(In

FROM GENES TO HEALTH AND HEALTH TO GENES 1,2
TRAINING / MENTORS
Imaging: Non Inv. Molec.
Clinical Proteinomics
Inform. / Science / Techn.
Behav. Instrum./ Technol.
Clinical Trials Infrastr.
TRANSLATIONAL
GENES ⇔ CELL ⇔ TISSUE ⇔ PHYSIOL. ⇔ PHENOTYPE ⇔ POPUL. ⇔HEALTH
ENVIROMENT
Regenerative Biol./ Replac.Therapy.
.
Embryogenesis / Development
Immunobiol./ Inflammation / Thromb.
Public Health / Genom.Protein.
Health Promotion
1
NHLBI SPARK I 1998-2002
Circ 1999; 99:1132 & 2064 - Defined
Circ 2002;106:162 - Update
2
1
42
ClinicalTrials
ENABLING APPROACHES3
SPECIFIC AIMS

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