Fuster aha-2005-dallas-biomarkers,

J Sanz, V Fuster, JF Viles-Gonzalez, P Moreno 2005 (In Press)
Atherothrombotic disease
Cardiovascular events
Major risk factors
Genetic & Progenitor Cell
Markers
Serum
Markers
Early Detection
Imaging Markers
BIOCHEMICAL AND BIOIMAGING MARKERS
*
*

PREVALENCE OF MAJOR RISK FACTORS
IN THE UNITED STATES
37.7
34.4
18.8
7.3
1.6 0.2
0
1
2
3
4
5
Number of
Risk Factors
Major risk factors: Advancing age, elevated BP, diabetes mellitus, cigarette
smoking, elevated total (and LDL) cholesterol, decreased HDL cholesterol,
obesity (particularly abdominal), physical inactivity, family history of premature
CHD. KJ et al., Arch Intern Med 2004:164:181

CONVENTIONAL RISK FACTORS WILL ACCOUNT FOR MORE THAN
90% OF HARD CV EVENTS IN THE NEXT DECADE
0
20
40
60
80
100
Events,%
Men Women
All Ages 35-44y 45-54y 65-74y55-64y All Ages 35-44y 45-54y 65-74y55-64y
40.3
43.4 38.7
32.2
47.3 41.4
37.7 47.2
33.1 45.6
26.5 25.7
26.9 26.2 27.1 29.1
34.3 33.4 28.8
25.8
8.6 12.5 8.1 8.8 6.5 8 11.3 8 9.7 6.3
Vasan RS et al., Ann Int Med 2005; 142:393
Risk
Factors
3
2
1
Marginal

CLINICAL EPIDEMIOLOGY OF NOVEL BIOCHEMICAL MARKERS
IN THE PREDICTION OF FUTURE CARDIOVASCULAR EVENTS
Prospective Standardized Additive to Additive to
Studies Commercial Lipid Framingham
Biomarker Convincing? Assay Available? Screening? Risk Score?
Inflammation
hsCRP ++++ +++ +++ ++
sICAM-1 ++ +/- + -
SAA ++ - + -
Interleukin-6 ++ - + -
Interleukin-18 ++ - + -
Myeloperoxidase + - +/- -
sCD40 ligand + - - -
Altered Thrombosis
tPA/PAI-1 ++ +/- - -
Fibrinogen +++ +/- ++ -
Homocysteine +++ +++ +/- -
D-dimer ++ + - -
Oxidative Stress
Oxidized LDL +/- - - -
Altered lipids
Lipoprotein(a) +++ +/- +/- -
LDL particles size ++ +/- +/- -
PM Ridker et al., Circ 2004; 109:IV-6

1- PREVALENCE OF HIGH C-REACTIVE PROTEIN LEVELS IN MEN AND
WOMEN BASED ON CORONARY HEART DISEASE RISK FACTORS (N=15341)
0
5
40
10
35
15
30
20
25
MenMen Women
Prevalence,%
Normal Borderline High
High CRP - Any high or borderline risk factors: 73% Men; 65% Women
NHANES III (M Miller et al) Arch Int Med 2005; 165:2063

2- ODDS RATIOS FOR CORONARY HEART DISEASE AMONG 2459
PATIENTS WITH CORONARY HEART DISEASE AND 3969 CONTROLS
1 2 4
Odds Ratio for Coronary Heart Disease
Risk Factor
Total cholesterol
Current cigarett smoking
(vs nonsmoking)
Systolic blood pressure
C-reactive protein
Erythrocyte sed rate
von Willebrand factor
Area under the ROC
Curve (95% CI)
0.61 (0.59-0.62)
0.63 (0.62-0.64)
0.64 (0.63-0.65)
0.65 (0.64-0.67)
0.65 (0.64-0.67)
0.66 (0.64-0.67)
Similar data with updated meta-analysis (n=7068)
Reykjavik Study (J Danesh et al.) N Engl J Med 2005; 350:1387 (UK)

3- BIOMARKERS - KAPLAN-MEIER CURVES OF UNADJUSTED
CUMULATIVE SURVIVAL ACCORDING TO BASELINE (N=764)
C Kistorp et al., JAMA 2005; 293:1109 (Copenhagen)
0 1 2 3 4 5 6
0
1.0
0.1
0.9
0.2
0.8
0.3
0.7
0.4
0.6
0.5
Follow-up, y
CumulativeSurvival
NT-proBNP
Tertile 1
Tertile 2
Tertile 3
0 1 2 3 4 5 6
0
1.0
0.1
0.9
0.2
0.8
0.3
0.7
0.4
0.6
0.5
Follow-up, y
Urinary Albumin/
Creatinine Ratio
0 1 2 3 4 5 6
0
1.0
0.1
0.9
0.2
0.8
0.3
0.7
0.4
0.6
0.5
Follow-up, y
C-Reactive Protein

1- Race and Gender Differences in C-Reactive
Protein Levels
Dallas Heart Study (A Khera et al.) JACC 2005; 46:464
2- C-Reactive Protein as a Screening Test for
Cardiovascular Risk in a Multiethnic Population
“CRP varies substantially between people of different ethnic
origin and is influenced by their differences in metabolic
factors.”
SS Anand et al., ATVB 2004; 24:1509 (Canada)

3-THE MONICA OPTIMAL HEMOSTATIC STUDY
“While there is increasing evidence from prospective studies (and
meta-analyses) that several thrombotic factors are associated
with increased risk of CHD, there are few previous studies
relating these factors to international differences in CHD risk. We
suggest that thrombotic factors such as fibrinogen, vWF and
fibrin D-dimer (which have been adjusted for age, smoking habit,
and body mass index in each population ) appear more strongly
associated with the population risk of CHD in this study than total
cholesterol or smoking habit. Our study results are consistent
with those recently reported from the PRIME study, in which
fibrinogen alone accounted for 30% of the excess risk of CHD in
Belfast compared with France, while all the classical risk factors
together explained only 25%.”
MONICA (J Yarnell et al.) EHJ 2005; 26:332

INDICATIONS FOR THE MEASUREMENT OF hsCRP
• Class I: None
• Class IIa: As an independent, but integrated marker of risk in
those judged as intermediate risk by global risk assessment (5%
to 20% risk of CHD in 10 years).
• Class IIb: As an independent marker for recurrent ischemic events
(death, MI, and restenosis after percutaneous coronary
intervention) in patients with chronic stable angina or acute
coronary syndromes.
• Class III: The adult population should not be screened for hsCRP.
Relative Risk of hsCRP - low < 1 mg/l; av 1.0 to 3.0 mg/l; > 3.0 mg/l. high
CDC / AHA (TA Pearson et al) Circ 2003;107:499

Major risk factors
Markers
Serum
Markers
Early Detection
Imaging Markers
* *
*
*

THE IDEAL CARDIOVASCULAR
BIOMARKER
1. Method-Related Features
• High Sensitivity and Specificity
• Reproducibility and Low Coefficient of Variation
• Easy to Perform and Analyze
• Applicable across gender, ethnicity and age spectrum
• Cost-Effective
• Reasonable to understand origin and mechanism
2. Clinical-Related Features
• For Research in Pathophysiology, as per Mechanismes of Disease
• For Research in Therapy, as per Clinical Management Guidance
• For Clinical Diagnosis, as per not very Sensitive or Specific clues
• For Clinical Prognosis and Risk Stratification, as per Triage
V Fuster, Nature Cardiovascular 2006 (in Press)

I-III IV-Va VI
Fatty Streak
Pre-atheroma
Atheroma
Fibro-atheroma
Rapid Progression
Rupture -Erosion
Stabilization
Regression
AP
ACS
Phase 3Phase 1 Phase 2 Phase 4
Vb-Vc
Ca++
421 5 63

TF
MMPs
CAMs
Macrophages
Pro-Adhesion/Migration
TXA2
PAI-1
Prothrombotic
Platelet
Aggregation
Fibrinolysis
Flow Reversal
Mechanical & Biohumoral
Risk Factors
LDL
ET
Extracellular Matrix
Fibroblasts
Vasa Vasorum
SMC contraction
migration
proliferation
PDGF
Fuster V et. al.

CLINICAL APPLICABILITY OF POTENTIAL SURROGATE FUNCTIONAL
AND STRUCTURAL MARKERS FOR CARDIOVASCULAR DISEASE
Methodology Sensitivity/ Identifies Tracks With
Available/ Methodology Specificity for Severity of Treatment of
Convenient Standardized Disease Disease Disease
Endothelial dysfunc. + + ++ ++ +
Blood pressure +++ ++ + ++ +++
Arterial stiffness ++ + ++ ++ +
Albuminuria ++ ++ ++ ++ ++
Ankle-brachial Index+++ +++ + ++ ?
Serum collagen + + ? ? ?
Marker
Carotid intimal ++ ++ ++ ++ +
medial thickness
LV hypertrophy ++ ++ ++ ++ ++
EBCT (Calc. Score) + +++ + + ?
Retinal photography + + ++ (?) ? ?
CBJ Nanani et al.Circ 2004;109:IV-22 - JN Cohn et al.Circ 2004;109:IV-31

SURROGATE INDICES OF ENDOTHELIAL FUNCTION
Serum markers
ET-1, vWF, t-PA, PAI-1, ICAMs, VCAMs
E-selectin, P-selectin
ADMA
Nitric oxide production assays
Urine NO3-, Urine cGMP
Functional tests
Invasive provocative testing
With forearm plethysmography
With coronary angiography
Positron emission tomography and MRI
Flow mediated dilation
With forearm plethysmography
With brachial artery ultrasonography
MD Faulx et al., AHJ 2003; 145:443 (Cleveland)

1) THE PARADOX OF CAD (N= 519 Stable) - CIRCULATING CD34+
KDR+ ENDOTHELIALPROGENITOR CELLS
0
1.00
0.98
0.90
0.96
0.92
0.94
0 100 200 300
P=0.01
Days
Event-freeSurvival
Group 3 (highest)
Group 3 (lowest)
Group 2
365
N Werner et al. NEJM 2005;10:999 ( Germany)

.00
.02
.04
.06
.08
.10
.12
.14
20 9030 8040 7050 60
Age
R = -0.256, p=0.008
CD34+
KDR+
/PMNC(in%)
43
CD34+
KDR+
/PMNC(in%)
N=
.00
.02
.04
.06
.08
.10
.12
.14
44 17 16
control
Stable CAD
unstable CAD
(Trop-T-neg)
unstable CAD
(Trop-T-pos)
P=0.012
P=0.001
P=0.006
2) REDUCED EPC NUMBER (CD34+
KDR+
/PMNC) PREDICT
AGE AND CARDIOVASCULAR EVENTS
Surrogate Marker of Endothelial damage / repair?
C Schmidt-Luche et al. Circ 2005; 111:2981 (Frankfurt)

3) Smoking Cessation Rapidly Increases Circulating
Progenitor Cells in Peripheral Blood in Chronic
Smokers
“The recovery of EPC levels was greater in light
smokers than in heavy smokers. The decreased
number of circulating EPCs would make smokers
susceptible to cardiovascular disease, and even
short-time cessation of smoking may be an
effective means to reduce cardiovascular risk.”
T Kondo, et al., ATVB 2004; 24:1442 (Nagoya, Japan)

VEGF Regulates Reendothelialization and Neointima Formation
in a Mouse Model of Arterial Injury
Hutter R et. al. Circulation 2004;110:2430.
Detection of luminal endothelial cells in injured mouse femoral artery by
vWF immunostaining.

Rosiglitazone or PPAR-γ Agonist Attenuate SMC response (mice)
PPAR-γ Agonist modulate BM derived APC
to promote endothelial lineage
Hung Wang, C et. al. Circulation 2004;109:1392.
Kong D et al. Circ 2004;110:2039 – G-CSF

1) Unstable Angina, MI - JA Ambrose……V Fuster JACC 1986;7:472
3) MRI-Media Advent. - G Helft, et al. Circ 2002;105:993 – Hyperch. Rabbit
- SG Worthley et al. Circ 2000;101:586 –WHHL Rabbit
2)

Frantz, S et. al. Circ Res. 2005; 96: 15.
Beutler, B Mol Immunol. 2004; 40: 845.
Role of the Toll-like receptor (TLR)
In Innate Immunity and Angiogenesis.

Direct Angiogenic Effect of TLR-4 Independent From Hypoxia
Inflammatory Cytokines
IL-1β,TNF-α
PDGF
Angiopoeitin-4
Flt-1
Angiopoeitin-2
PIGF
VEGF
HIF-1α
Growth Factors
IGF-1/2, EGF, TGFβ1, FGF-2
A
N
G
I
O
G
E
N
E
S
I
S
A
N
G
I
O
G
E
N
E
S
I
S
Gene transcription
Toll-Like Receptor 4
Hellwig-Burgel T et al J Interferon Cytokine Res 2005;25:297

PARADOX IN CAD - TLR4 - EVENTS - STATINS (N=655)
TLR4 ASP299GLY POLYMORPHISM –HYPORESPONSE
REGRESS (SM Boekholdt et al.) Circ 2003; 107:2416 (Netherlands)
K Edfeldt et al., EHJ 2004; 75:1447 - MI
(MI Survivors 1213, Controls 1561) (Karolinska Inst)
0 200 400 600 800
100
90
80
70
Carriers - Prevention
Non-carriers - Prevention
Non-carriers - Placebo
Carriers - Placebo
Percent

THE PARADOX OF POST-MI
RECURRENT CORONARY EVENTS BY NUMBER OF CARRIED RISK
GENOTYPES (N=1008 - 42 GENETIC VARIANTS)
Years
0.00
0.05
0.10
0.15
0.20
0.25
0.30
0.35
0.40
0.0 0.5 1.0 1.5 2.0
CoronaryEventRate
≤ 1
≥ 5
2–4
Gene-Environment interaction? Fit Test Selection?
Post Mi changes in risks? Risk heterogeneity?
TFCES (A Moss et al.,) AJC 2005; 46:177 (Rochester, NY)

PUBLISHED STUDIES OF ASSOCIATION BETWEEN
Glu298Asp POLYMORPHISM AND IHD
.1 .5 1 5 10
Decreased risk Increased risk
Asp/Asp (Glu/Asp+Glu/Glu)
Case Control Odds Ratio Weight Odds ratio
Study Asp/Asp/Total Asp/Asp/Total (95% CI) % (95% CI)
Jeter Cob / Khan, N10/134 258/225 6.2 0.63 (0.33, 1.21)
Wang, CL 2/218 3/218 0.9 0.66 (0.11,4.01)
Col, H 8/95 37/478 3.5 0.80 (0.33, 1.98)
Col, H 78/605 22/158 9.5 0.81 (0.46,1.35)
Poirier, O Fren 49/368 54/421 13.4 1.04 (0.68,1.58)
Grenath, B 63/571 88/823 17.3 1.06 (0.73,1.51)
Pulkrinen, A 59/559 11/110 5.1 1.06 (0.54,2.09)
Gardemann, A 234/2085 50/533 21.8 1.22 (0.89,1.68)
Poirier, O - Belf 32/163 25/155 8.3 1.27 (0.71,2.26)
Aras, O 29/205 9/117 3.0 1.98 (0.90,4.34)
Shimasala, Y 1/285 1/807 0.2 2.13 (0.13,3.24)
Mangorani, AD 45/249 16/183 4.7 2.30 (1.26,4.22)
Colombo, M 32/201 7/114 2.3 2.85 (1.23,6.79)
Morgorani, AD 107/288 14/138 3.8 4.96 (2.72, 9.05)
Total (95% CI) 739/6036 571/6106 100.0 1.31 (1.13,1.51)
Test for overall effect p=0.0003
JP Casas et al., Circ 2004; 109:1359 (London, Bethesda)

Lack of MEF2A Mutations in Coronary Artery
Disease
“We identified the 21-bp MEF2A coding sequence deletion in 1 of
300 elderly control subjects without CAD. 1500 additional
individuals without CAD revealed 2 more subjects with the
MEF2A 21-bp deletion. Genotyping of 19 family members of the
3 probands with the 21-bp deletion in MEF2A revealed that the
mutation did not cosegregate with early CAD. These studies
support that MEF2A mutations are not a common cause of CAD
in white people and argue strongly against a role for the MEF2A
21-bp deletion in autosomal dominant CAD.”
L Weng et al., JCI 2005; 115:1016
L Weng, C Fan, SE Topol, et al., Science 2003; 302:1578

MICROVESSEL SPROUTING, INCREASED RED BLOOD CELL EXTRAVASATION,
AND PERIVASCULAR INFLAMMATION IN DIABETES MELLITUS
Microvessel
Sprouting
Peri-vascular
Inflammation
Moreno PR, Purushothaman KR, Fuster V et al Circ 2004;110:2032
Moreno PR, Purushothaman KR, O’Connor WN, Fuster V. AHA 2005
Red Blood Cell
Extravasation

MACROPHAGE ERYTHROPHAGOCYTOSIS IS INCREASED IN DIABETES MELLITUS
Moreno PR, Purushothaman KR, Fuster V. AHA 2005
NO DIABETES DIABETESMACROPHAGE
ERYTHROPHAGOCYTOSIS
P < 0.0001

Angiogenesis Hemorrhage
Hb Macrophage
CD-163
Hb-Hp-1
Hp-1
Anti-Inflammatory
(IL-10)
Plaque
Stabilization
Hp-1 Genotype
Hb-Hp-2
Hp-2
ROS
Plaque
Destabilization
Pro-Inflammatory
(NF-κB)
Hp-2 Genotype Moreno PR, Levy AA, Fuster V. 2005

OxLDL VALUES - CAD, STENTS
MAJOR ADVERSE CARDIAC EVENTS1
(N=687)
0
20
40
60
80
100
0 1 2 3 4 5 6 7 8 9 10 11 12
Months
Event-freeSurvival
Low OxLDL group
High OxLDL group
P=0.59
1
Death, MI, Revascularization
S Braun et al AHJ 2005;150:550
C Meinsinger et al Circ 2005;112:651 – Healthy Popul, Predictive of ACS

PLAQUE WITH INFLAMMATION & RUPTURED IEL
Moreno PR, Purushothaman K-R, O’Connor WN, Fuster V, Circ. 2002;105:2504
Moreno PR, Purushothaman KR, Fuster V, et al. Circ 2004;110:2032

Inflammatory Markers at the Site of Ruptured Plaque in
Acute Myocardial Infarction
Maier W et. al. Circulation 2005;111:1355 (Zurich).
Collection of Blood and
Plaque

Inflammatory Markers at the Site of Ruptured
Plaque in Acute Myocardial Infarction
Locally Increased Interleukin-6 and Serum Amyloid A but
Decreased C-Reactive Protein
“Coronary levels of IL-6 and SAA at the site of
plaque rupture were increased relative to the
systemic circulation, indicating local production
of biologically active inflammatory mediators. In
contrast, CRP was locally decreased, at least in
part by uptake by the phagocyting cells,
suggesting a systemic origin of the protein.”
W Maier et al., Circ 2005; 111:1355

Baseline 24 months follow up
R Corti, V Fuster, Z A Fayad, et al. JACC 2005;46:106
JJ Wentzel, Corti R, Fayad ZA et al. JACC 2005; 45:846
1) 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;106:288

Longitudinal View
Ca++
Yonemura A, Momiyama Y, Fayad ZA et al. JACC 2005; 45: 733
BAD (Fayad ZA, Mani V, Fuster V et al.) 2005 – Predicts CAD
2- Multi Slice Black Blood Imaging
Rapid Extended Coverage (REX) Turbo Spin Echo Technique
Mid heart Aorta- 12 slices

-60
-
40
-20
0
20
40
60
80
ΔVWA
Thoracic Aorta Abdominal Aorta(%)
-60 -50 -40 -30 -20 -10 0(%)
r=0.64
P<0.001
-60 -50 -40 -30 -20 -10 0(%)
-60
-
40
-20
0
20
40
60
80
ΔVWA
(%)
r=0.34
P<0.005
5-mg dose
20-mg dose
Yonemura A; Momiyama Y; Fayad ZA et al. JACC 2005;45:733-42
Momiyama Y et al AHA 2005 – BEZAFIBRATE (N=32): TGC, HDL-C
2) MRI - ATHEROSCLEROSIS AORTA – ATORVASTATIN (12mo,N=40)
ΔLDL-CΔLDL-C

Comparing Framingham - IRFS and MRI - VWA
Coronary Artery Disease
0
2
4
6
8
10
12
14
NO YES
CAD
FraminghamScore
p = 0.447
BAD (Fayad ZA, Mani V, Fuster V et al.) Subm 2005
Wall Area Aorta - CAD
100
150
200
250
300
NO YES
CAD
WADA
p < 0.001
FRAMINGHAM - IRFS & CAD MRI – VWA & CAD

2) 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

Risk Factors Integrated
with Chemical & Imaging Biomarkers
Cardiovascular Event Recurrence
“We analyzed the relation of established risk factors and
markers of atherosclerosis with the risk of recurrent
CVD in 766 participants. After adjustment for
established risk factors, creatinine, albumin, and
carotid IMT in the highest quartile (vs lowest quartile)
and carotid plaque with acoustic shadowing (vs no
plaque) were independently associated with recurrent
CVD events.”
ARIC (K Wattanakit et al.,) Am Heart J 2005; 149:606V
Mani et al. Circ 2005;112 (Suppl II) II 363 – MRI-IMT

ANKLE-BRACHIAL INDEX - POPULATION-BASED STUDIES
(META-ANALYSIS)
Sensitivity of Specificity of Positive
Low ABI Low ABI Likelihood
Outcome (95% CI) (95% CI) Ratio (95% CI)
CHD 16.5 (12.8-20.2) 92.7 (92.1-93.3) 2.53 (1.45-4.40)
Stroke 16.0 (12.9-19.1) 92.2 (91.9-92.5) 2.45 (1.76-3.41)
All-cause mortality 37.2 (27.8-34.6) 88.9 (88.2-59.6) 3.97 (3.17-4.96)
Cardiovascular mortality 41.0 (33.8-48.2) 87.9 (87.2-88.6) 5.61 (3.45-9.13)
<0.60-0.90 - ≥ 50% Stenosis - 90% Sensitivity, 96% Specificity
AV Dooby, SS Anand. ATVB 2005; 25:1463 (Mc Master Univ)

High-Density Lipoproteins: A New Potential Therapeutic Target
for the Prevention of Cardiovascular Disease
Bryan Brewer, H Arterioscler Thromb Vasc Biol 2004;24:387.
3 major pathways by which HDL may mediate cholesterol
efflux from the cholesterol-loaded macrophages and
3 major family molecules being involved - PPAR, HDL, CETP

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

Pre-contrast 48 hours post-contrast1 hr post-contrast 24 hr post-contrast
20x
lumen
wall
40x
Frias JC, Fayad ZA, Amirbekian V, Fuster V et al. ISMRM 2004
Lipinski M, Fayad ZA, Fuster V, Nature CPCM. 2004;1:1 Macr.Scav. Rec
Trivedi AR et al. Stroke 2004; 35: 1631 - Particles of Iron (USPIO) MRI
rHDL- Gd-DTPA-DMPE-NBD conjugate (green)
rHDL-Gd-DTPA-DMPE
apoE-KO mice, 4.36 mmol/kg, 9.4T MRM

Macrophage Infiltration and Thrombus Formation in Coronary
Specimens from Patients with Unstable Angina
95 patients
0
5
10
15
20
25
Diabetes (n=47) No Diabetes (n=48)
p=0.003
PercentMacrophageArea
Thrombus 62% 40% (p=0.03)
Diabetes
No Diabetes
Moreno PR.,Fuster V. Circ 1994; 90: 775 – Infiltration
Circ 1996;94: 3090 – Thrombosis /TF
Circ 2000;102:2180 – Diabetes (Intima)

Macrophage ApoptosisMacrophage Apoptosis andand Tissue-FactorTissue-Factor Expression inExpression in
Human Coronary and CarotidHuman Coronary and Carotid AtheromaAtheroma
Hutter R et al.Hutter R et al. CirculationCirculation 20042004; 109: 2001; 109: 2001

STEMI - THROMBUS AGE AFTER THROMBO-SUCTION:
PROPORTIONS OF TREATET PATIENTS (N=199)
Fresh thrombus (< 1 day)
Lytic thrombus (1-5 days)
Organized thrombus (> 5 days)
Fresh and organized thrombus
98/199 (49%)
70/199 (35%)
17/199 ( 9%)
14/199 (7%)
SZH Rittersma et al., Circ 2005; 111:1160 (Amsterdam)

THROMBUS “AGING” AND MRI
Rabbit Aorta Corti R.et al. Circ. 2001;103:2420 – Pig Carotid. JACC 2002;39:1366
TF Act in Humans J.D.Marmur et al Circ. 1996;943:1226
2 weeks 8 weeks
2.5 mm
A
Baseline
2.5 mm
B
2.5 mm
C

Pre Contrast
Post Contrast
3 day old thrombus
Crush injured left
carotid artery
30 minutes
P.I.
60 minutes P.I.
Thrombus
in Left CCA
fibrin MRA
Control
H&E
Sirol M, Fuster V, Fayad Z et. al. Circulation 2005 (In Press)
MRI images of a rabbit carotid artery thrombus after
EP-2104R injection (Fibrin Specific)

M Sirol, V Fuster, JJ Badimon et al., Circ 2005 (In Press)
0
2
4
6
8
10
12
Thrombus age
NormalizedCNR
Pre 8 wks6 wks4 wks3 wks2 wks1 wk48 hr≤ 6 hr
CAROTID THROMBUS (ACUTE, SUBAC,CHRONIC) IN NZW RABBITS (N=18)
MRI IMAGE BEFORE AND AFTER EP2104R (FIBRIN TARGET CONTRAST)

MRI - HDL-Cholesterol
abbit / IV HDL, Apo E / HDL, Rabbit / PPAR-y / Fenofibrat
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 - Apo A1 in Rabbits
Rong JX et al Circ 2001;104:2447
Corti R. et al JACC. 2004;43:464 - Corti R et al ,Circ . 2005 (Subm)

0
5
30
10
25
15
20
Chow PravaD-4F D-4F + Prava
%AorticSurface
WithLesion
79%
p<0.0001
ORAL 4F (Apo 1 Peptide) & STATINS INHIBIT
ATHEROSCLEROSIS
IN APO E LDL-RECEPTOR DEFICIENT MICE
M Navab et al., Circ 2004; 109:3215
M Navab et al., Circ 2002; 105:290
M Navab et al., ATVB 2005; 25:1426

Jun STAT1 STAT3Fosp66 p50
PPAR agonists
(fatty acids, fibrates, glitazones)
Trans-repression
Anti-inflammatory properties
Trans-activation
Lipid and glucose homeostasis
PPAR
PPAR
PPAR
RXR
RXR
GGGGACTTTCCC TGAGTCA CTGGGA AGGTCA (N) AGGTCA
NF-κB-RE TRE ISGF-RE PPRE Target gene
PPAR AGONISTS – ACTIV. NUCLEAR RECEPTORS - GENE EXPRES.
N Marx et al., Circ Res 2004; 94:1168
AI Shulman, DJ Mangelsdorf. NEJM 2005; 353:605

Rapamycin & Its Application to Stent Restenosis
SO Marx &A Marks Circ. 2001;104:852 – M Poon, JJ Badimon, V Fuster Circ. 2002;359:619s

THE BADIMON PERFUSION CHAMBERTHE BADIMON PERFUSION CHAMBER
LDL-C. Rauch et al., Ather 2000; 153:181-G Dangas et al. Thr Haem 2000; 83:685
Diabetes. Osende J et al JACC 2001;38:1307 - Sambola A et al Circ 2003;107:973

Risk Factors and Blood TF-AcT
0
100
200
300
400
500
600
Hyperlipidemic Smoker Diabetic Control
FXa,pM/min
p=0.01
A. Sambola et al. Circ 2003;107:973
p=0.0001
Smoker
After 2hs
p< 0.05

The P-selectin, Tissue factor, Leukocytosis triad
Polgar J et. al. J Thromb Haemost 2005;3:1590. (Boston)
U Rauch,Ann Int Med 2001;134:225 - P-Selectin (Platelet)-CD 15(Monocyte)
BS Coller, ATVB 2005; 25:658 - Leukocytosis

RELATIONSHIP OR RISK FACTORS AND ARTERIAL
THROMBOTIC EVENTS (Cont.)
Prothrombin G20210A mutation Possibly
Protein C deficiency Not established
Protein S deficiency Not established
Antithrombin III deficiency Not established
Platelet Gp IIb/IIIa C1565T polym Not established
Platelet Gp Ib-IX-V C3550T Not established
Platelet Gp Ia/Iia C807T and G873A Not established
Arterial Thrombotic Risk Factor Associated With Disease
D Feinbloom, KA Bauer ATVB 2005;25:2043 (Harvard)
FSC - JAMA 2005; 294:1799 – Meta-Analysis, Fibrinogen in CAD & Stroke

WBC-MONOCYTES
s
CRP AND ATEHRO-THROMBOSIS
Modified from R. S. Munford et al. NEJM 2001; 344; 2017
TF and CRP Inhibition – V. Fuster et al 2005 (Subm)

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)
1) RELATIVE RISK OF CV EVENT – FRS & CRP
WHS (PM Ridker et al.) NEJM 2002; 347:1557

CRP IN INTERMEDIATE RISK FACTOR POPULATION
100 Intermediate
Risk Patients
(FRS 6-20)
n=41 - 41%
0.55 ± 0.26 (mg/L)
n=34 - 34%
1.64 ± 0.54 (mg/L)
n=25 - 25%
7.73 ± 4.59 (mg/L)
hsCRP<1.0 mg.L-1
hsCRP>3.0 mg.L-1
hsCRP 1.0-3.0 mg.L-1
High
Intermediate
Low
RL Bard et el AJC 2005;95:1378 (Ann Arbor, Mi)

Statins Reduce Interleukin-6-Induced C-Reactive
Protein in Human Hepatocytes
New Evidence for Direct Antiinflammatory Effects of Statins
C Arnaud et al., ATVB 2005; 25:1231 (Geneva)

PRIMARY PREVENTION, STATINS, NORMAL LDL-C, HIGH CRP
No History of CAD
Men > 55, Women > 65
LDL-C < 130 mg/dl
CRP ≥ 2 mg/l
Lipids
hs-CRP
Family History
Lipids
hs-CRP
LFTs
Lipids
hs-CRP
LFTs
HbA1C
Lipids
hs-CRP
HbA1C
Rosuvastatin 20 mg (n=7500)
Placebo (n=7500)
MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA
Screening
Visit
Randomization
Visit
Safety
Visit
Biannual Follow-up
Visits
End-of-Study
Visit
4-week
Run-in
JUPITER (PM Ridker et al.) Circ 2003; 108:2292

N-Terminal-Pro-B–Type Natriuretic Peptide
Universal Marker of Cardiovascular Risk?
AM Richards. Circ 2005; 112:9 (Christchurch, New Zealand)

Mechanism of cardiac secretion of natriuretic peptides
to maintain intravascular volume homeostasis
Rodeheffer RJ J Am Coll Cardiol 2004;44:740.

Major risk factors
Markers
Serum
Markers
Early Detection
Imaging Markers
Tp,CRP,BNP

ATHEROTHROMBOSIS: APPROACH IN 2005
Aggressive
Intervention3
Effective
Prevention1
Chronic Atherothrombosis
Chronic CAD Equivalents
HRAP- Subclinical
MRI / CT
Low
Risk
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% 10y
LOW RISK: FRS - < 0.5%y - < 5% 10 y

x
Patient Transport In-hospital Reperfusion
2005
2010
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
1. MI - TIME TO REPERFUSION – 2005, 2010

BNP AND THE RISKS OF DEATH AND HEART FAILURE1
(FRAMINGHAM - N=3346 Asx - FU 5-2Y)
0 1 2 3 4 5 6
Years
CumulativeIncidenceofDeath
0.00
0.02
0.04
0.06
0.08
Highest third
(≤ 4 pg/mL)
Lowest third
(4.1-12.7 pg/mL)
Middle third
(≥12.7 pg/mL)
0 1 2 3 4 5 6
Years
CumulativeIncidenceofDeath
0.00
0.01
0.02
0.03
0.04
Highest third
(≤ 4 pg/mL)
Lowest third
(4.1-12.7 pg/mL)
Middle third
(≥12.7 pg/mL)
1
Also AF, Stroke, 1st CV Event
TJ Wang et al., NEJM 2004; 250:7

BNP LEVELS IN DIASTOLIC DYSFUNCTION
SYSTOLIC DYSFUNCTION (EF < 50% - N=50)
0
100
200
300
400
500
Preserved LV
diastolic function
LV diastolic
dysfunction
BNP(pg/ml)
P=0.012
T Goto et al., AJC 2005; 95:1383 (Naguya, Japan)
YM Law et al., AJC 2005; 95:474 (Portland & Pittsburgh - Pediatric, Adolesc.

0
16
2
14
4
12
6
10
8
Death,myocardialinfarction(%)
> 250 ng/L
≤ 250 ng/L
< 0.01 µg/L
0.01-0.1 µg/L
> 0.1 µg/L
NT-proBNP Troponin T
7.1
5.6
1.3
ACS (NON-ST ELEVATION)
PREDICTIVE VALUE OF BASELINE NT-proBNP and TnT (n=1791)
PRISM (C Heeschen et al.) Circ 2004; 110:3206 (Frankfurt)

0 10 20 30
Follow-up (days)
0
3
6
9
12
15
18
Mortality(%)
Quartile 4 (n=439)
Quartile 3 (n=439)
Quartile 2 (n=437)
Quartile 1 (n=441)
Log rank = 64.7: p=0.00001
ACS - CUMULATIVE INCIDENCE OF DEATH AT 30 DAYS,
ACCORDING TO QUARTILE OF NT-proBNP
ANMCO (M. Galucci et al.) Circ 2004; 110:128
Also independent predictor of heart failure

NT-pro-BNP (MEDIAN VALUES) IN CONTROLS AND CAD PATIENTS
(1-, 2-, OR 3-VESSELS) - RELATION TO EF
0
100
200
300
400
500
600
Controls
n=195
1-vessel
n=159
2-vessels
n=190
3-vessels
n=335
NT-pro-BNPConcentration(pg/ml)
P=0.005
0
200
400
600
800
1000
1200
P<0.001
Controls
n=195
Stable
Angina
n=385
Unstable
Angina
n=108
Myocardial
Infarction
n=191
G Ndrepepa et al., AJC 2005; 95:553 (Munich)

SUMMARY OF RECOMMENDATIONS OF BNP/NT-pro-BNP
Class I - It is advisable to perform a BNP/NT-pro-BNP assay in order to
rule out the diagnosis of CHF in patients with a suspicious diagnosis
Class I - BNP and NT-pro-BNP plasma levels may provide valuable
information in the clinical assessment of patients with CHF when risk
stratification for death is required.
Class I - BNP/NT-pro-BNP measurement is useful to establish the death
risk profile in the short and long term in patients with ACS.
Class IIa - It is advisable to perform a BNP/NT-pro-BNP assay in order to
confirm the diagnosis of heart failure in patients with a suspicious
diagnosis.
Class IIa - The BNP or NT-pro-BNP measurement should be performed at
admission in all patients with documented ACS.
ITALIAN CONSENSUS (M Emdin et al.) Ital Heart J 2005; 6:430

Aggressive
Intervention3
Effective
Prevention1
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

ROAD MAP FOR THE NONINVASIVE EVALUATION OF
ATHEROTHROMBOTIC DISEASE 2005-20101-
Non-Coronary Coronary
Whole Body MRA1
Stenosis CTA
Quantification MRA2
Whole Body FB-MRI3
Burden of Molecular MRI
Disease (LDL only)4
Multi-Contrast FB-MRI5
Plaque Molecular MRI6
Characterization
Vertical Direction? CT/MR or MR alone?
Fuster V, Kim RJ. Circ 2005; 112:135 - SanzJ, Fuster V. 2005 (In Press)
1. Fencholm M et al., J MRI 2005; 21:596 - 2. Jabake C et al., EHJ 2005 (accessed July 10)
3. Taniginch H et al., AHJ 2004; 148:139 - 4. Sirol M et al., Circ 2004; 109:2023
5. Itskovich VV et al., J MRI 2004; 19:459 - 6. Lipinsky et al., 2005

CT Evaluation
Fuster V, Kim RJ, Circ 2005;112:135
Poon M, Rius T, J, Sanz J, Nikolaou K, Fuster V 2005 (Subm)

Longitudinal View
Ca++
Yonemura A, Momiyama Y, Fayad ZA et al. JACC 2005; 45: 733
BAD (Fayad ZA, Mani V, Fuster V et al.) 2005 – Predicts CAD
Multi Slice Black Blood Imaging
Rapid Extended Coverage (REX) Turbo Spin Echo Technique
Mid heart Aorta- 12 slices

RATES PER 1000 PERSON-YEARS OF FIRST MI OR CHD DEATH
BY BASELINE CRP, STRATIFIED BY SEX AND PRESENCE OF
SUBCLINICAL ATHEROSCLEROSIS (N=3971 >75y)
Men
Yes YesNo No
CRP
(mg/L)
Subclinical Disease
Women
0
10
20
30
40
<1
1-3
>3
IncidenceRateper
1000PersonYears
Beyond Risk Assessment, especially in Intermediate Framingham Risk
CHS (N Cushman et al.) Circ 2005; 112:25

Risk Factors Integrated
with Chemical & Imaging Biomarkers
Cardiovascular Event Recurrence
“We analyzed the relation of established risk factors and
markers of atherosclerosis with the risk of recurrent
CVD in 766 participants. After adjustment for
established risk factors, creatinine, albumin, and
carotid IMT in the highest quartile (vs lowest quartile)
and carotid plaque with acoustic shadowing (vs no
plaque) were independently associated with recurrent
CVD events.”
ARIC (K Wattanakit et al.,) Am Heart J 2005; 149:606

-1.0
-.5
0
0.5
1.0
1.5
2.0
Baseline Follow-up
6-9 mo
Change
baseline to
follow-up
Time Interval
Hs-CRP(mg/dL)
p<0.001 p<0.001 p=0.040
-10
0
10
20
30
40
50
Baseline Follow-up
Change
baseline to
follow-up
SAA(mg/dL) Time Interval
p<0.001 p<0.001 p=0.012
ASx CAROTID DISEASE PROGRESSION - CRP AND SAA (N=1268)
Patients without progression
Patients with progression
ICARAS (M Schillinger et al.) - Circ 2005; 111:2203

THE EFFECT OF MULTIPLE RISK FACTORS ON IMT
FEMORAL ARTERIES IN YOUNG ADULTS (N=1030 - AGE 24-43)
0 1 or 2 3 4+
Number of risk factors
MeanIMT(mm)
0.56
0.81
0.61
0.66
0.71
0.76
p for trend = 0.003
Bogalusa Heart Study (TK Paul et al.) AJC 2005; 95:469 (Tulane)

PREVALENCE OF CORONARY ARTERY DISEASE, AORTIC VALVE
CALCIUM AND MITRAL ANNULAR CALCIUM, IN PATIENTS WITH
AND WITHOUT A DECREASED ANKLE-BRACHIAL INDEX (ABI)
ABI
Abnormal Normal
(n = 118) (n = 118)
Variable (%) (%) p Value
Coronary artery disease 89 (75) 34 (29) <0.001
Aortic valve calcium 65 (55) 35 (30) <0.001
Mitral annular calcium 56 (47) 22 (19) <0.001
Aortic valve calcium or mitral 81 (69) 43 (36) <0.001
annular calcium
H Park et al., Am J Cardiol 2005; 95:1005

Aggressive
Intervention3
Effective
Prevention1
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

Virtual CT Angioscopy “Fly Through”
Calcified lesions in the LAD
Rius T, Sanz J, Fuster V, Poon M, 2005 (Subm)

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

Hong KongMyanmar
India
World Heart Day 2004

World Heart Day 2005, Sunday 25th
September
“Healthy Shape Healthy Weight” theme

Major risk factors
Markers
Serum
Markers
Early Detection
Imaging Markers

THE IDEAL CARDIOVASCULAR BIOMARKER
1. Method-Related Features
• High Sensitivity and Specificity
• Reproducibility and Low Coefficient of Variation
• Easy to Perform and Analyze
• Applicable across gender, ethnicity and age spectrum
• Cost-Effective
2. Clinical-Related Features
• For Research in Pathophysiology, as per Mechanismes of Disease
• For Research in Therapy, as per Clinical Guidance
• For Clinical Diagnosis, as per not very Sensitive or Specific clues
• For Clinical Prognosis and Risk Stratification, as per Triage
V Fuster, Nature Cardiovascular 2006 (in Press)

BIOMARKERS IN DIAGNOSIS AND RISK STRATIFICATION
IN ACUTE CORONARY SYNDROMES
Biomarker
CK-MB cTnI/T hs-CRP BNP/NT- IMA MPO CD40L
proBNP
Diagnosis Yes Yes No No Yes Result No
unclear
Outcomes Death Death/MI/RI Death/MI/RI CHF No Death/MI Death/MI
Short term Yes Yes Yes Yes ---- Yes Yes
Long term Yes Yes Yes Yes ---- Yes Yes
Independent Yes Yes Yes Yes ---- Yes Yes
FDA approval Yes Yes Yes Yes Yes No No
Guidelines Class I Class I Class IIa Yes No No No
IMA = Ischemia-modified albumin; MPO = myelopyroxidase; RI = recurrent infarction
AS Maisel, V Bhella, E Braunwald, Nature Cardiov 2005 (In Press)

Study Dose, mg Pts, n Net Change in CRP level
Studies That Reported Studies That Reported
Absolute Change, mg/L Percentage Change, %
Atorvastatin
Ballantyne et al. 2003 80 57
van de Ree et al. 80 64
Chan et al. 2003 40 13
van de Ree et al. 2003 10 67
Lovastatin
Ridker et al. 2001 20-40 2885
-2 -1 0 -100% -75% -50% -25% 0%
EFFECT OF STATINS ON C-REACTIVE PROTEIN (CRP) LEVEL:
INDIVIDUAL STUDIES AND SUMMARY ESTIMATES
EM Balk et al., Ann Int Med 2003; 139:670

HRs FOR 1-YEAR MORTALITY AFTER AMI ACCORDING TO
CRP LEVEL AND STATINS (N=4545)
OACIS (K Kinja et al.) AJC 2005; 91:117 (Osaka)
PROVE IT - TIMI 22 (Ridker P et al.) N Engl J Med 2005; 352:20
0
1
2
3
4
5
6
7
8 P-trend = 0.001
CRP < 2.9
Statin
CRP < 2.9
No Statin
CRP ≥ 2.9
No Statin
CRP ≥ 2.9
Statin
HazardRatio

THE FREEDOM TRIAL NHLBI 2005 (PI V Fuster)
FUTURE REVASCULARIZATION EVALUATION
IN PATIENTS WITH DIABETES MELLITUS:OPTIMAL MANAGEMENT OF
MULTIVESSEL DISEASE
1)EPC: Trial Diabetics vs Non Diabetics
2)BAD-MRI: Trial Diabetics vs Non Diabetics
(SH Aguiar et al AHA 2005 – N=35 vs 38)
3) BAD-MRI: Trial Diabetics vs Registered Diabetics
(SH Aguiar et al AHA 2005 – HbA1c)

0 1 2 3 4 5 6 7 8 9 10 11
Time (years)
1.01
0.85
0.87
0.89
0.91
0.93
0.95
0.97
0.99Survival(%)
Never-smokers
Ex-smokers
Current-smokers (not E4+)
Current-smokers (E4+)
MPHS II (SE Humphries et al., Lancet 2001; 358:115)
SURVIVAL CURVES OF CAD BY SMOKING AND APO-E GENOTYPE
(N=3052 MEN)

0 2 4 6 8 10 12
0.5
0.6
0.7
0.8
0.9
1
Years of follow-up
Propmenevent-free
genotype x smoking
interaction p=0.003
N9 N-Smoke
D9 N-Smoke
D9 Smoke
N9 Smoke
SMOKING AND LPL GENE MUTATIONS
CAD - EVENTS (N=2700 - FU=6Y)
NPHS II (P Talmud et al.) Atherosclerosis 2000; 149:75

C-Reactive Protein
Pepys, MB et. al. J Clin Invest. 2003; 111: 1805.
Negative Electr. Microgr. Crystal Structure Space-filling model

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.

Atorvastatin Affects Leukocyte Gene Expression
in Dyslipidemia Patients: In Vivo Regulation of
Hemostasis, Inflammation and Apoptosis
V Wibaut-Berlaimont et al., J Thromb Haemost 2005; 3:677 (London)
Hutter R, et al 2005 (Subm) - Prevented by Caspase Inhibitor & TFPI

RELATIONSHIP OR RISK FACTORS AND ARTERIAL
THROMBOTIC EVENTS
Arterial Thrombotic Risk Factor Associated With Disease
Elevated homocysteine Established
Elevated CRP Established
Presence of LA Likely, data limited
Elevated levels of aCL Possibly elevated IgG
Elevated titers of β2-GPI antibodies Possibly β2-GPI antibody– dependent LA
Elevated fibrinogen Established
Elevated FVII Not established
Elevated PAI-1 Not established
Factor V Leiden G1691A mutation Possibly
D Feinbloom, KA Bauer ATVB 2005;25:2043 (Harvard)

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