Dr fuster's slides part i

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

- From the High Risk Asymptomati to the Intermediate and Low Risk Patient
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
Acute Coronary Syndromes
Early
Detection 2
LOW RISK: FRS - < 0.5%y - < 5% 10 y

Dr fuster's slides part i

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Dr fuster's slides part i

Notes de l'éditeur