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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.
San
Orlando, March 05, 2005
0
5
10
15
20
25
30
1990 2020
Mill
ions
of D
eath
sfr
om C
ardi
ovas
cula
r Cau
ses
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 0901–120Mokdad et al., JAMA 286:1195–1200, 2001Mokdad et al., JAMA 286:1195–1200, 2001No 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
LowHDL
Hyper-glycemia
CentralObesity
MaleFemale
Prev
alen
ce (%
)
Hyper-tension
METABOLIC ABNORMALITIESAMERICAN ADOLESCENTS (12-19 Y)1
1NHANES III - n=1960
S.D.de Ferranti et al., Circ 2004; 110:2494
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. Within This Context
San
Orlando, March 05, 2005
ATHEROTHROMBOSIS: APPROACH IN 2005
AggressiveIntervention3
EffectivePrevention1
2.Chronic Atherothrombosis 2. CAD Equivalents
HRAP- SubclinicalMRI / CT
LowRisk
Modified from V Fuster, Circulation 1999; 99:1132
IRAP – Risk FrsCACS / 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% 10yLOW RISK: FRS - < 0.5%y - < 5% 10 y
METHODS TO ASSESS PLAQUE VULNERABILITY
Intravascular ultrasoundThree-dimensional reconstructionUltrasound elastographyIntravascular ultrasound flow measurementsVirtual histology
AngiographyDirect visualizationOptical coherence tomographyRAMAN (near infrared) spectroscopy
ThermographyComputed tomography
ContrastUltrafast
Magnetic ResonancePhase ContrastNuclearIntravascular
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)
Viles-Gonzalez J, Fuster V, Badimon JJ. Eur. Heart J 2004; 25:1
Moreno P, Fuster V, JACC 2004; 44:2099
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
Prop
ortio
n of
pat
ient
sw
ithou
CV
even
ts (%
)
Logrank test p<0.03
Acetylcholine - dose - response
70
80
90
100
0 365 730 1095 1460 1825
days of follow up
Prop
ortio
n of
pat
ient
sw
ithou
CV
even
ts (%
)
Logrank test p<0.08
Sodium nitroprusside - dose - response
35.0 (1. quartile)
< 34.9 (2. quartile)
< 24.3 (3. quartile)
< 15.6 (4. quartile)
31.6 (1. quartile)
< 31.5 (2. quartile)
< 18.7 (4. quartile)
< 24.1 (3. quartile)
1Improved response at 8 weeks adds to the prediction (ACH)
CAD (ACS 54%) - CULPRIT VESSEL / LESION – N=843NON-STENOTIC YELLOW PLAQUES / THROMBUS – N=1253
0
20
40
60
80
100
1 2 3Color Grade of Plaque
Prev
alen
ce o
f Thr
ombo
sis
*
† ‡
(%)
*P=.0003 vs grade 1. †P<.0001 vs grade 1. ‡P<.0001 vs grade 2Y 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
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 Asymptomatic 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.
San
Orlando, March 05, 2005
ATHEROTHROMBOSIS: APPROACH IN 2005
AggressiveIntervention3
EffectivePrevention1
Chronic Atherothrombosis CHD Equivalents
HRAP- SubclinicalCT / MRI
LowRisk
Modified from V Fuster, Circulation 1999; 99:1132
IRAP – Risk Frs CACS / CRP
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% 10yLOW RISK: FRS - < 0.5%y - < 5% 10 y
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.
San
Orlando, March 05, 2005
ATHEROTHROMBOSIS: APPROACH IN 2005
AggressiveIntervention3
EffectivePrevention1
2.Chronic Atherothrombosis 2. CAD Equivalents
HRAP- SubclinicalMRI / CT
LowRisk
Modified from V Fuster, Circulation 1999; 99:1132
IRAP – Risk FrsCACS / 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% 10yLOW RISK: FRS - < 0.5%y - < 5% 10 y
x
Patient Transport In-hospital Reperfusion
2004
20140 1 2 3
A B C D
Hours
Methods of Speeding Time to Reperfusion:
A B C DMedia Campaign 911 Expansion Regionalization PCI-Eluted StentsPatient 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 withPossible 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
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.
San
Orlando, March 05, 2005
ATHEROTHROMBOSIS: APPROACH IN 2005
AggressiveIntervention3
EffectivePrevention1
Chronic Atherothrombosis CHD Equivalents
HRAP- SubclinicalCT / MRI
LowRisk
Modified from V Fuster, Circulation 1999; 99:1132
IRAP – Risk Frs CACS / CRP
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% 10yLOW RISK: FRS - < 0.5%y - < 5% 10 y
CHD RISK IN WOMEN - FRAMINGHAM SCORING (FRS) - 10 y
Age, y HDL cholesterol < 35 -9 60 -335-39 -4 50-59 040-44 0 45-49 145-49 3 35-44 250-54 6 < 35 555-59 7 Syst BP60-64 8 < 120 -365-69 8 120-129 070-74 8 130-139 1
Cholesterol 140-149 2< 160 -2 > 160 3169-199 0 Diabetes200-239 1 No 0240-279 2 Yes 4 280 3 Smoking
No 0Yes 2
Points
012345678910111213
>14
Total CHD(%)
2345781013162025313745
> 53
Hard CHD(%)
22345679131620253035
> 45
Grundy SM, Pasternak R, Greenland P, Smith S, Fuster V, Circ 1999; 100:1481ATP 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 78Framingham
Score44 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 261LDL 83 120.7 54.5 46 303 257HDL 84 53.2 16.8 20 100 80TGC 83 139.3 122.9 32 891 859
HbA1C 20 6.75 1.57 4.7 10.9 6.2BMI 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 (Fayad ZA, Mani V, Fuster V et al.) 2005
Comparing Framingham Risk Factor Score and Coronary Artery Disease (CAD)
0
2
4
6
8
10
12
14
NO YES
CAD
Fram
ingh
am S
core
p = 0.447
BAD (Fayad ZA, Mani V, Fuster V et al.) 2005
Comparing Wall Area (mm2) and
Coronary Artery Disease (CAD)
Wall Area Aorta - CAD
100
150
200
250
300
NO YES
CAD
WA
DA p <
0.001*
BAD (Fayad ZA, Mani V, Fuster V et al.) 2005
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 NiacinNo DM / MS DM / MS Present
Cha
nge
in C
IMT
(mm
± S
EM)
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)
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.
San
Orlando, March 05, 2005
0102030405060708090
100
MRI (1st) Histology
Perc
ent
66.3 64
23.7
5.1 520.3
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
LVRV
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)
Lima JAC et al., Circ 2004; 110:2336 - TE-MRI (Hopkins)
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
REVERSAL (SE Nissen et al), JAMA 2004;291:1071 – IVUS (655)
A
bdom
inal
A
orta
Tho
raci
c A
orta
Baseline MRI Repeat MRI after 12 months of
treatment
3 contiguous slices(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
ΔVW
A
Thoracic Aorta Abdominal Aorta(%)
-60 -50 -40 -30 -20 -10 0ΔLDL-C (%)
r=0.64P<0.001
-60 -50 -40 -30 -20 -10 0ΔLDL-C (%)-60
-40
-20
0
20
40
60
80
ΔVW
A
(%)
r=0.34P<0.005
5-mg dose20-mg dose
Yonemura A; Momiyama Y; Fayad ZA et al. JACC 2005;45:733-42
MRI - ATHEROSCLEROSIS AORTA – ATORVASTATIN (12mo,N=40)
Baseline 12 monthsA)
B)
LDL-C (mg/dl) VWA (mm2)
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
Yonemura A; Momiyama Y; Fayad ZA et al. JACC 2005;45:733-42
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, 1990Rong JX et al Circ 2001;104:2447Corti R. et al JACC. 2004;43:464 – Corti R et al ,Circ. 2004 (Subm)
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
nciph
fc
lf
df
pvf
l
nc
iphfc
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
FUTURE REVASCULARIZATION EVALUATION
IN PATIENTS WITH DIABETES MELLITUS:OPTIMAL
MANAGEMENT OF MULTIVESSEL DISEASE
2) MRI-Diabetics: Reversibility, Statins-PPAR NHLBI 2005 (PI V Fuster)
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.
San
Orlando, March 05, 2005
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 Contrast24 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
20xlumen
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-USPIO24h
Post-USPIO36h
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 thrombusCrush injured left carotid
artery
30 minutes P.I.
60 minutes P.I.
Molecular Imaging of Fibrin with MRChronic 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
FUTURE REVASCULARIZATION EVALUATION
IN PATIENTS WITH DIABETES MELLITUS:
OPTIMAL MANAGEMENT OF MULTIVESSEL DISEASE
3) MRI - Contrast Enhanced PAD
NHLBI 2005 (PI V Fuster)
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.
San
Orlando, March 05, 2005
ATHEROTHROMBOSIS: APPROACH IN 2005
AggressiveIntervention3
EffectivePrevention1
Chronic Atherothrombosis
CHD Equivalents
HRAP- Subclinical CT / MRI
LowRisk
Modified from V Fuster, Circulation 1999; 99:1132
IRAP- Risk Frs CACS / CRP
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% 10yLOW RISK: FRS - < 0.5%y - < 5% 10 y
CHD RISK IN WOMEN - FRAMINGHAM SCORING (FRS) - 10 y
Age, y HDL cholesterol < 35 -9 60 -335-39 -4 50-59 040-44 0 45-49 145-49 3 35-44 250-54 6 < 35 555-59 7 Syst BP60-64 8 < 120 -365-69 8 120-129 070-74 8 130-139 1
Cholesterol 140-149 2< 160 -2 > 160 3169-199 0 Diabetes200-239 1 No 0240-279 2 Yes 4 280 3 Smoking
No 0Yes 2
Points
012345678910111213
>14
Total CHD(%)
2345781013162025313745
> 53
Hard CHD(%)
22345679131620253035
> 45
Grundy SM, Pasternak R, Greenland P, Smith S, Fuster V, Circ 1999; 100:1481ATP III - Aggressive Rx: Framingham, Diabetes, Metab. Synd: obese, BP, HDL, TC, Gluc- Physical inactivity JAMA 2001; 285:2475
0 5 10 20 30 40
10
20
30
40
Initial Probability (%)
Post
erio
rPr
obab
ility
(%)
40% 25%35%
Identity Line
TRADITIONAL RISK PROBABILITY – IRAP & HRAP (FRS) AND POSTERIOR NON-INVASIVE PROBABILITY
PWF Wilson et al., JACC 2003; 41:1898NAHNES III (TA Jacobson et al.) Arch Int Med 2000; 160:1361
5
1) PREDICTED 7-YEAR EVENT RATES FOR CHD DEATH ORNONFATAL MI FOR CATEGORIES OF FRS OR CACS
P Greenland et al., JAMA 2004; 291:210
0-9 10-15 16-20 21Framingham Risk Score, %
Cor
onar
y D
eath
or
Non
fata
l MI,
%
0
4
8
12
16
20 CACS01-100101-300 301
0.0
5.0
10.0
15.0
20.0
25.0
Framingham 10-Year CAD Risk (%)0-1 2-4 5-9 >10
Mul
tivar
iabl
e R
elat
ive
Ris
k
<1.0 1.0-3.0 >3.0High-Sensitivity C-Reactive Protein (mg/L)
2) RELATIVE RISK OF CV EVENT – FRS & CRP
WHS (PM Ridker et al.) NEJM 2002; 347:1557
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.
San
Orlando, March 05, 2005
ATHEROTHROMBOSIS: APPROACH IN 2005
AggressiveIntervention3
EffectivePrevention1
Coronary Atherothrombosis CHD Equivalents
HRAP- SubclinicalCT / MRI
LowRisk
Modified from V Fuster, Circulation 1999; 99:1132
IRAP - Risk Frs.CACS / CRP
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% 10yLOW RISK: FRS - < 0.5%y - < 5% 10 y
1) RISK FACTORS FOR WHICH INTERVENTIONIS PROVEN TO LOWER RISK –
GOVERNMENT ?
Cessation1 10%2 DP 6 mmHg3
Cigarette Smoking1 50% CHD ------ ------
Cholesterol2 ------ 30% CHD ------
Hypertension3 ------ ------ 16% CHD42% Stroke
CH Hennekens, Circ 1998; 97:1095
2) EFFECT OF INGREDIENTS OF POLYMEALIN 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 trialOH Franco et al., BMJ 2004; 329:1447Polypill - NJ Wald et al., BMJ 2003; 326:1419Statin, ASA, Folic Acid, BP (ACE-I, -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.
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 - Preventive - Government, Polymeal, Children SHAPE & AEHA. Innovative, Feasible (RF)?, Simple?, Preventive?, Polyauthor? ?
San
Orlando, March 05, 2005
2) C-Reactive ProteinStructure 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
Die
t
Sede
ntar
yLi
fest
yle
Toba
cco
Hyp
erlip
idem
iaH
yper
tens
ion
Early
reco
gniti
onof
Sym
ptom
atic
Dis
ease
Risk Factor/Risk Behavior
CommunitySetting
Essential PublicHealth Services
Policy/LegislationAssuring Personal Health Services
ReligiousOrganizations
Organizational PartnershipsEducation/media
SurveillanceWhole
communities
Schools
Worksites
HealthcareFacilities
Descriptive Statistics: Image ParametersParameter 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
BAD (Fayad ZA, Mani V, Fuster V et al.) 2005
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
20140 1 2 3 4
A B C D
Hours
Methods of Speeding Time to Reperfusion:
A B C DMedia Campaign 911 Expansion Regionalization PCI-Eluted StentsPatient 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
TP in
hibi
tor
Con
trol
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)
18FDG-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 COMPONENTSOF 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;106:2026RP 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 PLAQUESBY 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 15 200
1
0.1
0.8
0.40.6
Years
Surv
ival
ST Depression
0 5 10 15 200
1
0.1
0.8
0.40.6
Years
Failure THR
0 5 10 15 200
1
0.1
0.8
0.40.6
Years
Low METs
Absent Present
SURVIVAL FREE OF CHD IN HIGH-RISK MEN
CJ Balady et al., Circ 2004; 110:1920 (Framingham)
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 NiacinNo DM / MS DM / MS Present
Cha
nge
in C
IMT
(mm
± S
EM)
ARBITER 2 (AJ Taylor et al.) Circ 2004; 110:3510
CVMR-ISLZahi Fayad, PhD
Gilbert Aguinaldo, MDRobin P Choudhury, MD
Vitalii Itskovich, PhDMichael J LipinskiTeresa Rius, MD
Frank Macalusso, RTKaren Metroka, RT
Javier Sanz, MDM.Sirol,MD
CardiologyValentin Fuster, MD, PhD
Juan Badimon, PhD Michael Poon, MDStella Palentia, RN
Don Smith, MDMeir Shinnar, MD, PhD
Pedro R Moreno MD
Pathology John Fallon, MD, PhD KR Purushothaman,MD
Molecular BiologyYale Nemerson, MDMark Taubman, MD
Edward Fisher, MD, PhDErnane Reis, MD
K-R PurushothamanFunding
NIH-HL 94013NIH-HL 61801NIH-HL 07208
BMS Inv. AwardMerck, GSK, Schering AG
CV Research FellowsUrsula Rauch MD
Roberto Corti, MDJulio Osende, MD
Antonia Sambola, MDStephen Worthley, MD
Juan F Viles MDRandolph Hutter MD
The Mount Sinai Medical CenterThe Cardiovascular Institute
RadiologyBurton Drayer, MDJeff Goldman, MD
Neurology Jessey Weinberger, MD
15
16
17
18
19
20
21
22
23
Baseline End of Follow-up
TREATMENTCONTROL
Total Vessel Area (mm2) Vessel Wall Area (mm2)
The Selective TP Receptor Antagonist S18886 has Anti-atherosclerotic and Plaque Stabilizing Effects
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
The Selective TP Receptor Antagonist S18886 has Anti-atherosclerotic and Plaque Stabilizing Effects
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 RabbitUsing 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 DetectionAge Characterization Using Fibrin-Targeted MR Contrast
Agent
N=14 NZW RabbitsAcute 1 Week 2 Weeks 4 Weeks 6 Weeks 8 WeeksNormal
Artery
Pre
Post contrast
Sirol M. et al. Circ 2004 (In Press) - AHA 2004
Descriptive Statistics: Image ParametersParameter 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
BAD (Fayad ZA, Mani V, Fuster V et al.) 2005
In vivo MR evaluation of aorticAtherosclerosis, risk factors and CAD at angiography
MRI slices of aorta andplaque scores
Taniguchi H, ZA Fayad et. al. Am Heart J 2004;148:137 (Japan).BAD (Fayad ZA, Mani V, Fuster V et al.) 2005
0
1
2
3
4
5
6
Baseline 6 months
Plaq
ue V
olum
e (c
m3 )
0
0.5
1
1.5
2
2.5
Baseline 6 months
Plaq
ue A
rea
(cm
2 )
0
24
68
1012
Baseline 6 months
Lum
en V
olum
e (c
m3 )
0123456
Baseline 6 months
Lum
en A
rea
(cm
2 )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 …
See your doctor – Road map by decade, >20y
GENERAL PREVENTION GUIDELINES FOR CANCER, CVD ANDDIABETES 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 leastonce every 2 years if BP < 120/80 mm Hg)
Every 5 years
Every 3 years
CBE every 3 yrs Yearly CBE andMammography
Yearly Every 1-3 years; depends ontype of test and past results.
Frequency dependson test preferred
Offer yearly, assistinformed decisions
ACS/ADA/AHA - Circ 2004; 109:3244
3) CARDIOVASCULAR HEALTH IN CHILDHOODCHALLENGES 20021
1Multidisciplinary - Schools2Above 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 methodsNutrition
3. Hypertension Identification
4. Cholesterol IdentificationNutritionStatins2 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 obstructivepulmonary disease
HIV infection or AIDS
Other causes
Coronary heartdisease
Stroke
Other heartdisease
U.S. LIFE EXPECTANCY 1970 & 2000 – SUCCESS OF RESEARCH ON THERAPIES
C Lenfant et al., NEJM 2003; 349:9NCHS and AHA 2002 - Leading cause of death -
Ischemic strokeTransient ischemic attackMyocardial infarctionAngina pectoris (stable, unstable)Sudden death
Intermittent claudication
Critical limb ischemia, gangrene, necrosis
Systemic – Clinical Regions 2, 25-30%; 3, 5-10%Atherothrombotic Disease (CAPRI & TASC)
Viles-Gonzalez J, Fuster V, Badimon JJ. EHJ Viles-Gonzalez J, Fuster V, Badimon JJ. EHJ 20042004; 25:1; 25:1
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)
Viles-Gonzalez J, Fuster V, Badimon JJ. Eur. Heart J 2004; 25:1
Moreno P, Fuster V, JACC 2004; 44:2099
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)
Viles-Gonzalez J, Fuster V, Badimon JJ. Eur. Heart J 2004; 25:1
Moreno P, Fuster V, JACC 2004; 44:2099
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 NiacinNo DM / MS DM / MS Present
Cha
nge
in C
IMT
(mm
± S
EM)
ARBITER 2 (AJ Taylor et al.) Circ 2004; 110:3510
BAA 62 HU
DC
Despite the increased Despite the increased spatial resolutionspatial resolution of the new generation of of the new generation of MDCT MDCT scanners, scanners, MRI MRI is better for is better for plaqueplaque characterization (Rabbit model) characterization (Rabbit 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)S Komatsu et al., Circ J S Komatsu et al., Circ J 2005 2005; 69:72 – ; 69:72 – MDCT “Plaque Map” in CAD is GoodMDCT “Plaque Map” in CAD is Good
CT Evaluation
Fuster V, Kim RJ, Circ 2005 (In Press)
Poon M, Rius T, J, Sanz J, Nikolaou K, Fuster V 2005 (Subm)
C ) Selective TP Receptor Antagonist S18886 has Anti-atherosclerotic and Plaque Stabilizing Effects
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 Press) (In Press)
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. Within This Context
San
Orlando, March 05, 2005
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.
TRANSLATIONALGENES CELL TISSUE PHYSIOL. PHENOTYPE POPUL. HEALTH ENVIROMENT
Regenerative Biol./ Replac.Therapy..
Embryogenesis / Development
Immunobiol./ Inflammation / Thromb. Public Health / Genom.Protein.
Health Promotion
1NHLBI SPARK I 1998-2002 Circ 1999; 99:1132 & 2064 - Defined Circ 2002;106:162 - Update2NHLBI SPARK II 2003-2007 - Prospective (Jan 20, 2003)
1
4
2
Clin
ical
Tri
als
ENABLING APPROACHES3
SPECIFIC AIMS