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.

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


LRAP - Government, Polymeal, Children SHAPE & AEHA. Within This Context

San


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)



31.6 (1. 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


San





Chronic Atherothrombosis CHD Equivalents

HRAP- SubclinicalCT / MRI

LowRisk


IRAP – Risk Frs CACS / CRP

Acute Coronary Syndromes

Early Detection 2




San





2.Chronic Atherothrombosis 2. CAD Equivalents

HRAP- SubclinicalMRI / CT

LowRisk


IRAP – Risk FrsCACS / CRP

1.Acute Coronary Syndromes

Early Detection 2


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



San





Chronic Atherothrombosis CHD Equivalents


LowRisk


IRAP – Risk Frs CACS / CRP


Early Detection 2


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


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


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*


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)



San


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


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


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


IN PATIENTS WITH DIABETES MELLITUS:OPTIMAL

MANAGEMENT OF MULTIVESSEL DISEASE

2) MRI-Diabetics: Reversibility, Statins-PPAR NHLBI 2005 (PI V Fuster)



San


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


IN PATIENTS WITH DIABETES MELLITUS:

OPTIMAL MANAGEMENT OF MULTIVESSEL DISEASE

3) MRI - Contrast Enhanced PAD

NHLBI 2005 (PI V Fuster)



San





Chronic Atherothrombosis

CHD Equivalents

HRAP- Subclinical CT / MRI

LowRisk


IRAP- Risk Frs CACS / CRP


Early Detection 2


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



San





Coronary Atherothrombosis CHD Equivalents


LowRisk


IRAP - Risk Frs.CACS / CRP


Early Detection 2


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.


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

San


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


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

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)


-0.01

0

0.01

0.07

0.02

0.03

0.04

0.05

0.06


Cha

nge

in C

IMT

(mm

± S

EM)


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)


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 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


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


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


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


-0.01

0

0.01

0.07

0.02

0.03

0.04

0.05

0.06


Cha

nge

in C

IMT

(mm

± S

EM)


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)


LRAP - Government, Polymeal, Children SHAPE & AEHA. Within This Context

San


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

Acc 2005-1, v pl-vp

Health & Medicine

Transcript of Acc 2005-1, v pl-vp