THE EPIDEMIC OF CVD NEED FOR NEW APPROACHES

1
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
2
DEATHS FROM CARDIOVASCULAR CAUSES, WORLDWIDE, IN
1990 AND ESTIMATED FOR 2020
Western countries Non-Western (developing)
countries
30
25
6
20
19
Millions of Deaths from Cardiovascular Causes
15
5
10
9
5
0
1990
2020
KS Reddy. NEJM 2004 3502438
3
Prevalence of Obesity Diabetes in the U.S.
1990/1991
2000
Obesity
No Data
lt 10
10-14
15-19
³ 20
Diabetes
No Data
lt 4
4-6
gt 6
ejt 0901120
Mokdad et al., JAMA 28611951200, 2001
4
METABOLIC ABNORMALITIES AMERICAN ADOLESCENTS
(12-19 Y)1
Male Female
50
40
30
Prevalence ()
20
10
0
Hypertri- glycerinemia
Low HDL
Hyper- glycemia
Central Obesity
Hyper- tension
1NHANES III - n1960
S.D.de Ferranti et al., Circ 2004 1102494
5
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
• 
  

Orlando, March 05, 2005
6
(No Transcript)
7
ATHEROTHROMBOSIS APPROACH IN 2005
1.Acute Coronary Syndromes
Aggressive Intervention3
2.Chronic Atherothrombosis
2. CAD Equivalents
HRAP- Subclinical MRI / CT
Early Detection 2
IRAP Risk Frs CACS / CRP
Effective Prevention1
Low Risk
HRAP High Risk Asymptomatic Patient - gt2 y -
gt20 10y IRAP Intermediate Risk Asymptomatic
Patient 0.5-2 y - 5-20 10y LOW RISK FRS - lt
0.5y - lt 5 10 y
Modified from V Fuster, Circulation 1999 991132
8
METHODS TO ASSESS PLAQUE VULNERABILITY
Intravascular ultrasound Three-dimensional
reconstruction Ultrasound elastography Intravasc
ular ultrasound flow measurements Virtual
histology Angiography Direct visualization Optic
al coherence tomography RAMAN (near infrared)
spectroscopy Thermography Computed
tomography Contrast Ultrafast Magnetic
Resonance Phase Contrast Nuclear Intravascular
B Meier. Heart 2004 901395
9
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 251 Moreno P, Fuster V, JACC
2004 442099


10
ACS (N198) SYSTEMIC ENDOTHELIAL DYSFUNCTION
(FBF) 5 DAYS 1 ADJUSTED RISK FACTORS, CV
EVENTS (DEATH, MI, STROKE)- Av 4 YRS
Acetylcholine - dose - response
Sodium nitroprusside - dose - response
100
100
? 35.0 (1. quartile)
? 31.6 (1. quartile)
90
90
lt 34.9 (2. quartile)
Proportion of patients withou CV events ()
Proportion of patients withou CV events ()
lt 31.5 (2. quartile)
lt 24.3 (3. quartile)
lt 18.7 (4. quartile)
80
80
lt 24.1 (3. quartile)
lt 15.6 (4. quartile)
Logrank test plt0.03
Logrank test plt0.08
70
70
0
365
730
1095
1460
1825
0
365
730
1095
1460
1825
days of follow up
days of follow up
1Improved response at 8 weeks adds to the
prediction (ACH)
Fichtlscherer et al., Circ 2004 1101926
(Frankfurt)
11
CAD (ACS 54) - CULPRIT VESSEL / LESION
N843 NON-STENOTIC YELLOW PLAQUES / THROMBUS
N1253
()
100
80
60

Prevalence of Thrombosis
40

20
0
1
2
3
Color Grade of Plaque
P.0003 vs grade 1. Plt.0001 vs grade 1.
Plt.0001 vs grade 2 Y Ueda et al., AHJ 2004
148842 (Osaka)
12
CAROTID ACTIVE PLAQUES (ENDARTERECTOMY) CAP
RUPTURE AND CAP EROSION BY STUDY GROUP
No. of Plaques () P Val Ipsilat.
Stroke With TIA Asymptom. Stroke vs Stroke vs TIA
vs (n96) (n91) (n82) TIA Asympt. Asympt.
Thromb. active 74.0 35.2 14.6 lt.001 lt.001 .002
Cap rupture 66.7 23.1 13.4 lt.001 lt.001 .004
Cap erosion 7.3 12.1 1.2 .51 .09 .0
3
ICTB (LG Spagnoli et al.) JAMA 2004 2921895
(Rome, Mineapolis, Mayo) C Yuan et al Circ
2002105181 (Seattle) MRI Several Plaques
13
(No Transcript)
14
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.
• 
  

Orlando, March 05, 2005
15
ATHEROTHROMBOSIS APPROACH IN 2005
Acute Coronary Syndromes
Aggressive Intervention3
Chronic Atherothrombosis
CHD Equivalents
HRAP- Subclinical CT / MRI
Early Detection 2
IRAP Risk Frs CACS / CRP
Effective Prevention1
Low Risk
HRAP High Risk Asymptomatic Patient - gt2 y -
gt20 10y IRAP Intermediate Risk Asymptomatic
Patient 0.5-2 y - 5-20 10y LOW RISK FRS - lt
0.5y - lt 5 10 y
Modified from V Fuster, Circulation 1999 991132
16
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
17
ATHEROTHROMBOSIS APPROACH IN 2005
1.Acute Coronary Syndromes
Aggressive Intervention3
2.Chronic Atherothrombosis
2. CAD Equivalents
HRAP- Subclinical MRI / CT
Early Detection 2
IRAP Risk Frs CACS / CRP
Effective Prevention1
Low Risk
HRAP High Risk Asymptomatic Patient - gt2 y -
gt20 10y IRAP Intermediate Risk Asymptomatic
Patient 0.5-2 y - 5-20 10y LOW RISK FRS - lt
0.5y - lt 5 10 y
Modified from V Fuster, Circulation 1999 991132
18
1. MI - TIME TO REPERFUSION 2005, 2015
Patient Transport In-hospital
Reperfusion
x


2004


A
B
C
D
x

2014
X
0
1
2
3
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
X New antithrombotics, Myoc-Imaging., AICD, RF
modification
19
1. ACS A PRE-HOSPITAL POLYPILL
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

V Fuster 2005
20
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

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 - Government, Polymeal, Children
  
• 
  
• 
  SHAPE AEHA.
• 
  

Orlando, March 05, 2005
22
ATHEROTHROMBOSIS APPROACH IN 2005
Acute Coronary Syndromes
Aggressive Intervention3
Chronic Atherothrombosis
CHD Equivalents
HRAP- Subclinical CT / MRI
Early Detection 2
IRAP Risk Frs CACS / CRP
Effective Prevention1
Low Risk
HRAP High Risk Asymptomatic Patient - gt2 y -
gt20 10y IRAP Intermediate Risk Asymptomatic
Patient 0.5-2 y - 5-20 10y LOW RISK FRS - lt
0.5y - lt 5 10 y
Modified from V Fuster, Circulation 1999 991132
23
CHD RISK IN WOMEN - FRAMINGHAM SCORING (FRS) -
10 y
Age, y HDL cholesterol lt 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 lt 35 5 55-59 7 Syst
BP 60-64 8 lt 120 -3 65-69 8 120-129 0 70-74 8
130-139 1 Cholesterol 140-149 2 lt 160 -2 gt
160 3 169-199 0 Diabetes 200-239 1 No 0 240-27
9 2 Yes 4 ? 280 3 Smoking No 0 Yes 2
Total CHD () 2 3 4 5 7 8 10 13 16 20 25 31 37 45
gt 53
Hard CHD () 2 2 3 4 5 6 7 9 13 16 20 25 30 35 gt
45
Points 0 1 2 3 4 5 6 7 8 9 10 11 12 13 gt14
Grundy SM, Pasternak R, Greenland P, Smith S,
Fuster V, Circ 1999 1001481 ATP III -
Aggressive Rx Framingham, Diabetes, Metab. Synd
obese, BP, HDL, TC, Gluc - Physical inactivity
JAMA 2001 2852475
24
Multi Slice Black Blood Imaging Rapid Extended
Coverage (REX) Turbo Spin Echo Technique
Ca
Longitudinal View
Mid heart Aorta- 12 slices
BAD (Fayad ZA, Mani V, Fuster V et al.) 2005
25
Descriptive Statistics
BAD (Fayad ZA, Mani V, Fuster V et
al.) 2005
26
Comparing Framingham Risk Factor Score and
Coronary Artery Disease (CAD)
p 0.447

BAD (Fayad ZA, Mani V, Fuster V et al.) 2005
27
Comparing Wall Area (mm2)
and Coronary Artery Disease
(CAD)
p lt 0.001

BAD (Fayad ZA, Mani V, Fuster V et al.) 2005

28
CAD (N167) STATIN vs NIACIN / STATIN CIMT
0.07
0.06
0.05
0.04
Change in CIMT (mm SEM)
0.03
0.02
0.01
0
-0.01
Placebo
Placebo
ER Niacin
ER Niacin
No DM / MS
DM / MS Present
ARBITER 2 (AJ Taylor et al.) Circ 2004 1103510
29
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)
30
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
31
CAROTID PLAQUE COMPOSITION (AS PERCENTAGE OF
THE WALL)
100
90
Fibrous Tissue Lipid Necrotic Core Loose
Matrix Calcification
80
66.3
64
70
60
Percent
50
40
23.7
30
20.3
20
9.4
5.1
5
6.3
10
0
MRI (1st)
Histology
T Saam et al., ATVB 2005 25234 In Vivo
(Seattle, Wash) M Shinnar et al., ATVB 1999
192756 - Ex Vivo (New York)
32
MRI - Plaque Composition
X-ray angiogram
LAD Wall
LAD
LAD Lumen
RVOT
Eccentric (lipid-rich)
LV
6 mm max wall thickness
RV
MRI (fat sat)
Fayad ZA et al. Circ. 2000102506-510
MRI (no fat sat)
33
A ) MRI-LIPID LOWERING (SIMVASTATIN 20 or
80 mg/d) AND REGRESSION OF
ATHEROSCLEROSIS
Baseline
24 months follow up
R Corti, ZA Fayad, V Fuster, et al. Circ.
2001104249-252 R Corti, V Fuster, ZA Fayad, JJ
Badimon et al. Circ 20021062884
R Corti, J J Wentzel, Z A Fayad, J J Badimon, V
Fuster 2005 (Subm)
34
Independent of dose, LDL-C lt 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 1102336 - TE-MRI (Hopkins)
35
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 35015 -
Clinical REVERSAL (SE Nissen et al), JAMA
20042911071 IVUS (655)
36
MRI - ATHEROSCLEROSIS AORTA ATORVASTATIN
(12mo,N40)
Yonemura A Momiyama Y Fayad ZA et al. JACC
200545733-42
37
MRI -
ATHEROSCLEROSIS AORTA ATORVASTATIN (12mo,N40)
Yonemura A Momiyama Y Fayad ZA et al. JACC
200545733-42
38
Yonemura A Momiyama Y Fayad ZA et al. JACC
200545733-42
39
B) MRI - HDL-Cholesterol Rabbit / IV HDL, Apo
E / HDL, Rabbit / PPAR-y / Fenofibrate
High-chol. Diet
1
10
Simv. PPAR-y
J.X. Rong et al. Circ 20011042447
Badimon JJ, Badimon L, Fuster V, JCI 1990
851234, 1990 Rong JX et al Circ
20011042447 Corti R. et al JACC. 200443464
Corti R et al ,Circ. 2004 (Subm)
40
PPARs in Atherosclerosis
PPAR signaling pathways influence macrophage
gene expression and foam cell formation
Castrillo A et. al. J Clin Invest.
20041141538. A C Li et al. J Clin Invest
20041141564
41
In-Vivo Cluster Analysis for Plaque
Characterization
T2W
PDW
T1W
l-lumen nc-necrotic core iph-intra plaque
hemorrhage fc-fibrocellular tissue df-dense
fibrous tissue lfloose fibrous
tissue pvf-perivascular fat
Itskovich VV, Samber D, Mani V, et al Magn
Reson Med 2004 52 515
42
THE FREEDOM TRIAL
FUTURE REVASCULARIZATION EVALUATION IN PATIENTS
WITH DIABETES MELLITUSOPTIMAL MANAGEMENT OF
MULTIVESSEL DISEASE 2) MRI-Diabetics
Reversibility, Statins-PPAR
NHLBI 2005 (PI V Fuster)
43
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
44
Cell Molecular MRI Targets In
Atherothrombotic Plaques
Lipinski MJ, Fuster V, Fisher EA, Fayad ZA,
Nature Cardiov. Med. 200411
45
Targeted Contrast Agent - Approaches
Choudhury RP Fuster V Fayad ZA Nature Drug
Disc. 200431
46
Lipid Rich Atherosclerotic Rabbit 24h Post
Gadofluorine
n10 NZW Atherosclerotic rabbits No Enhancement
in Controls (n6)
24 H Post Gadofluorine
Pre Contrast
Sirol, M et. al. Circulation 2004 109 2890
AHA 2004 -
47

1 hr post-contrast
Pre-contrast
24 hr post-contrast
48 hours post-contrast
rHDL-Gd-DTPA-DMPE
rHDL-Gd-DTPA-DMPE-NBD conjugate (green)
apoE-KO mice, 4.36 mmol/kg, 9.4T MRM
Frias JC, Fayad ZA, Fuster V et al. ISMRM 2004
48
In Vivo Detection of Macrophages in Human
Carotid Atheroma Use of Post-Ultrasmall
Superparamagnetic Particles of Iron (USPIO) MRI
Pre-USPIO
Post-USPIO 24h
Areas of USPIO accumulation (Pearls staining, b)
colocalizing with areas of high macrophage
content (MAC 387 stain, c) in the fibrous cap
region
Post-USPIO 36h
Trivedi AR et al. Stroke 2004 35 1631
49
Molecular Imaging of Fibrin with MR Chronic
Rabbit Model
Pre Contrast
Crush injured left carotid artery
3 day old thrombus
Post Contrast
Control
30 minutes P.I.
60 minutes P.I.
fibrin
MRA
HE
Fayad ZA Imaging Science Laboratories
Sirol M. et al. Circulation 2005 (In Press)
50
Diabetes and PAD - Proposed Sequence for an
Integrated Plaque (IP)-MRI Diagnostic
Protocol Combination of multi-weighted,
post-Gadolinium and post-USPIO imaging
PDW MRI of the Superficial femoral artery
Dellegrottaglie S, Mani V, Fayad Z,
Moreno P, Fuster V, Rajagopalan S. 2005
51
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)
52
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
53
ATHEROTHROMBOSIS APPROACH IN 2005
Acute Coronary Syndromes
Aggressive Intervention3
Chronic Atherothrombosis
CHD Equivalents
HRAP- Subclinical CT / MRI
Early Detection 2
IRAP- Risk Frs CACS / CRP
Effective Prevention1
Low Risk
HRAP High Risk Asymptomatic Patient - gt2 y -
gt20 10y IRAP Intermediate Risk Asymptomatic
Patient 0.5-2 y - 5-20 10y LOW RISK FRS - lt
0.5y - lt 5 10 y
Modified from V Fuster, Circulation 1999 991132
54
CHD RISK IN WOMEN - FRAMINGHAM SCORING (FRS) -
10 y
Age, y HDL cholesterol lt 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 lt 35 5 55-59 7 Syst
BP 60-64 8 lt 120 -3 65-69 8 120-129 0 70-74 8
130-139 1 Cholesterol 140-149 2 lt 160 -2 gt
160 3 169-199 0 Diabetes 200-239 1 No 0 240-27
9 2 Yes 4 ? 280 3 Smoking No 0 Yes 2
Total CHD () 2 3 4 5 7 8 10 13 16 20 25 31 37 45
gt 53
Hard CHD () 2 2 3 4 5 6 7 9 13 16 20 25 30 35 gt
45
Points 0 1 2 3 4 5 6 7 8 9 10 11 12 13 gt14
Grundy SM, Pasternak R, Greenland P, Smith S,
Fuster V, Circ 1999 1001481 ATP III -
Aggressive Rx Framingham, Diabetes, Metab. Synd
obese, BP, HDL, TC, Gluc - Physical inactivity
JAMA 2001 2852475