Vulnerable or High Risk Plaque Multimodality Plaque Imaging
1. Plaque Progression - Nomenclature, 1990 -1995
2. Plaque Imaging - Invasive / Non-Invasive 1995 -2010
3. HRP Bioimage Study - Disease Burden 2010 -2012
4. The Two Extreme Paradox 2012 -2020
J-F Toussaint, V Fuster et. al. ATVB.1995;15:1533V Fuster et al., NEJM 1992; 326:242 –326:310V Fuster, Circ 1994; 90:2126 - AHA Report Circ 1995; 92:1355 E Falk, PK Shah, V Fuster Circ 1995;92:657-
Mechanisms Leading to Myocardial Infarction: InsightsFrom Studies of MRI (Autpsy) & Vascular Biology
PHASE 4
I-III
PHASE 1 PHASE 2
PHASE 3
PHASE 5Acute SyndromesMyocardial infarctionUnstable anginaIschemic sudden death
No Symptoms
IV-Va
VI
VI
Vb-Vc
V Fuster et al., NEJM 1992; 326:242 –326:310 - Vulnerable Plaque (JM) - HRP (VF)V Fuster, Circ 1994; 90:2126 - AHA Report Circ 1995; 92:1355 (modified)E Falk, PK Shah, V Fuster Circ 1995;92:657- J-F Toussaint, V Fuster et. al. ATVB.1995;15:1533
Anginapectoris
PHASE 4VI
Plaques, Autopsy / Imaging 1990 -1995
Vulnerable or High Risk Plaque Multimodality Plaque Imaging
1. Plaque Progression - Nomenclature, 1990 -1995
2. Plaque Imaging - Invasive / Non-Invasive 1995 -2010
3. HRP Bioimage Study - Disease Burden 2010 -2012
4. The Two Extreme Paradox 2012 -2020
1995-2005 Expedition, 2005-2010 Consolidation
R Corti, V Fuster EHJ. 2011 (April 19)
CONFIDENTIAL – Oct 9, 2007
Morphological Imaging,1995-2010
MM Sadeghi, ZA Fayad et. al. J Nucl Med 2010; 51:51S
Vulnerable or High Risk Plaque Multimodality Plaque Imaging
1. Plaque Progression - Nomenclature, 1990 -1995
2. Plaque Imaging - Invasive / Non-Invasive 1995 -2010
3. HRP Bioimage Study - Disease Burden 2010 -2012
4. The Two Extreme Paradox 2012 -2020
1b). PESA & AWHS 1a). HRP > 55y,40-54y, n= 8,000 , FU 0,3,6 y N=7000 FU 3y
Omics (Copenhagen, Duke, HRP, Framingham)Telomere (S.blot, qPCR, Fresh)
Predictive ?Economics ?
Life Style & Imaging ?
CARDIOVSCULAR RISK FACTORS (7) & LIFE STYLE
>2 Risk Factors
1. MI & 2. Stroke
25% in 10 Yrs
75% in 30 Yrs
3. DBD & 4. AD Quality
Framingham (2010) 5, Interheart (2004)2:Obesity, Sedentary(Diet)
c
c
HRP - Bioimage Initiative 2008 - 2012
– Largest industry funded biomarker initiative ever
– Unique structure of collective funding, design, oversight, and interpretation, while study execution is done by a third-party
– HRP Initiative extended through • Copenhagen Heart Studies (CCHS and
CGPS)• Framingham Heart Study under
NIH/NHLBI CRADA
PI: V. Fuster, Co-PI: E. Falk, P. Muntendam - AHJ 2010;160:49
HRP - Bioimage Iniciative - Steering Committee
Valentin Fuster, MD, PhD (Chair) Carol McCall, FSA, MAAAErling Falk, MD, PhD (Co-Chair) Pedro R. Moreno, MDJuan José Badimon, PhD B.G. Nordestgaard, MD, PhDMat Daemen, MD, PhD James H.F. Rudd, MD, PhDZahi A. Fayad, PhD Prediman K. Shah, MDMario Garcia, MD Henrik Sillesen, MDGeoffrey S. Ginsburg, MD Anton van der Steen, PhDStanley L. Hazen, MD, PhD Prof. Sir Magdi M. YacoubSpencer B. King, III, MD Chun Yuan, PhD
BG Medicine (Peter Muntendam) & Humana (Carol McCall)
HRP - BioImage Study - 63% > 2 Risk Factors
PI: Valentin Fuster, Co-PI: Earling Falk, Peter Muntendam - AHJ 2010;160:49
H Sillesen, V Fuster et. al. JACC Cardiovasc Img 2012 (In Press).
HRP-Bioimage: Overlap Of Imaging Modalities
First Mobile 3T at WorkHRP - BioImage Study – Mobile Units
PI: Valentin Fuster, Co-PI: Erling Falk, Peter Muntendam - AHJ 2010;160:49
Carotid Plaque Burden, cm2
3D US Manual (Sweep 2D) vs 3D Transducer
Focal structure into the arterial lumen of at least 0.5 mm or 50% of surrounding IMT value. 37% missed at Clasical 2D
CardioSCORE - R7 - ApoA1, Apo B, B2M, CEA, CRP, Lp(a),Transferrin
H Sillesen, V Fuster et. al JACC Imag 2012 (In Press).
PHASE 1 - PLAQUE BURDEN - 3D US SWEEP PRIMARY EVENTS - N=186, 18 MONTHS
Variables OR (95% CI) P value Chi-square
Burden, > 4.20 cm2 3.63 (2.26-5.82) <0.0001 28.5
Burden, 2.58-4.20 cm2 1.83 (1.09-3.05) 0.022 5.3
Burden, 0.01-2.57 cm2 1.15 (0.65-2.00) 0.64 0.2
H Sillesen, E Falk, P Muntendam, V Fuster, JACC Img 2012 (Subm)
(n = 1456) (n = 1456) (n = 1457) (n = 1454)
PHASE 1 - COMPARATIVE PREVALENCE BETWEEN DEGREE OF CACAND DEGREE OF CAROTID PLAQUE BURDEN BY 3D SWEEP
IMT vs CAC: +Ilio-Femoral: +++
U Baber, R Mehran, P Muntendam, M Garcia, H Sillesen, E Falk, V Fuster, 2012
PHASE 2 - BIOLMAGE (3D-US & CAC) & CardioSCORE-R7 Events By December 2011
Acute MI 17%
IschemicStroke18%Coronary
Revasc. 16%
Death 27%
P Muntendam, E Falk, V Fuster 2012
PHASE 2 – BioImage (CACD-3DUS) & CardioScore Significant Risk Prediction For 1ary Events
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0 100 200 300 400 500 600 700 800
Time (days)
Cum
ulat
ive In
ciden
ce
> 400 101-400 1-100 0
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0 100 200 300 400 500 600 700 800
Time (days)
Cum
ulat
ive In
ciden
ce> 230 mm3 70-230 mm3< 70 mm3none detected
0
0.01
0.02
0.03
0.04
0.05
0.06
0.07
0.08
0.09
0.1
0 100 200 300 400 500 600 700 800
> 5.8 4.7-5.7 3.6-4.6< 3.5
Time (days)
Cum
ulat
ive In
ciden
ce
CACS 3D carotid ultrasound CardioSCORE blood test
N=3557 for all plots that have 3D carotid US
Cumulative Event Rate by Category
P Muntendam, E Falk, V Fuster 2012 How Much Risk Prediction Is Added To The Frs ?
PHASE 2 – BioImage (3D-US & CAC) Significant Added Risk Prediction For 1ary Events
P Muntendam, E Falk, V Fuster 2012 How Much Risk Prediction Is Added To The Frs ?
PHASE 2 – CardioScore Significant Added Prediction to FRS at 1ary Events
26 48 56
The Sensitivity of Detection Increases From 26% for FRS alone to 56% with the combination
1b). PESA & AWHS 1a). HRP > 55y,40-54y, n= 8,000 , FU 0,3,6 y N=7000 FU 3y
Omics (Copenhagen, Duke, HRP, Framingham)Telomere (S.blot, qPCR, Fresh)
Predictive ?Economics ?
Life Style & Imaging ?
Vulnerable or High Risk Plaque Multimodality Plaque Imaging
1. Plaque Progression - Nomenclature, 1990 -1995
2. Plaque Imaging - Invasive / Non-Invasive 1995 -2010
3. HRP Bioimage Study - Disease Burden 2010 -2012
4. The Two Extreme Paradox 2012 -2020
TRIAL MVD DM INTERV. MT. EP.
SYNTAX + - ++ - ++
BARI - + + + +
FREEDOM + + ++ + +
1. COMPLEX CHRONIC CORONARY DISEASE
DataRevascul. <CABG
Sx Sc. (Reg ) <CABG
Ischemic Score
Intervent. = MT SxSc <CABG, Xov.42%
Intervent. = MT Ischemic Score
FREEDOM Score (3)Risk Frs 80% - PolypillNon Invasive Imaging
FAME - - + - +
COURAGE - - + + +
Conclusions Methods-Interests Concerns: Risk Frs.-Rx
1. MEETING TARGETS FOR RISK FACTOR CONTROL?Risk Factors - Proportion of Participants at Goal % – 1 yearTrials LDL SBP DBP Hb A1C
Meet Goals
Base FUBARI-
2D 75 56 70 5214 20
COURAGE 51 55 55 5912 19
FREEDOM 55 63 53 5512 20
Freedom, Bari-2D, Courage Investigators, 2012 (Subm.)PURE (S Yusuf et al.) Lancet 2011; Aug 28 - Poor Countries,7% !!!NHANES, AHA, NHLBI-JNC-7, NHLBI-NCEP P Muntner, V Fuster et al., AHJ 2011; 161: 719 – 49 seconds !!!!
FOOD INTERACTION
PHARMACOKINETIC INTERACTION WITH
ASPIRIN
PHARMACOKINETIC INTERACTION WITH
SYMVASTATIN
PHARMACOKINETIC INTERACTION WITH
RAMIPRIL
PHARMACODYNAMIC INTERACTION WITH ASPIRIN
PHARMACODYNAMIC INTERACTION WITH
SYMVASTATIN
PHARMACODINAMIC INTERACTION WITH
RAMIPRIL
BIO-EQUIVALENCE
FOCUS 1General
Adherence
FOCUS 2Polypill
Adherence
ArgentinaBrazilParaguay
ItalySpain
ASA, Statin, ACE-Inhibitor
1. POLYPILL CNIC-FERRER: ADHERENCE – ECONOMICS
G Sanz, V Fuster Am. H J 2011;162:811 – Semin. Thor. Cardiov 2011;23:24
Molecular Imaging – PEN – 2011-2015NIH Program of Excellence in Nanotechnology
HHSN2682010000045C$16,447,515 – 5 years
Zahi Fayad, MSSM Valentin Fuster, MSSM Roger Hajjar, MSSM Martin Schwarz, MSSMRobert Langer, MITOmid Farokhzad, BrighamEdward A. Fisher, NYUIra Tabas, Columbia
1 Genetics (SIRCA) / Stem Cell Rx. 2010 (Subm), Fibrosis3. Radiology 2010; 256:774 - Feo-MRI, Gold-Micro CT, MPI 2. Molecular Pharmaceutics 2010, Oct 28 – Corticoid Rx
Sj Nicholis et al JACC 2006;47:992 M Lobatto, V Fuster, ZA Fayad, W Mulder. Molec Pharmac 2010;7:20.Liposome encapsulated Prednisolone M Lobatto, V Fuster, ZA Fayad, W Mulder. Nat Rev Drug Discov 2011;10:963.rHDL Nanoparticles Statin Loaded
Biological Imaging & Local Treatment
Rx
Vulnerable or High Risk Plaque Multimodality Plaque Imaging
1. Plaque Progression - Nomenclature, 1990 -1995
2. Plaque Imaging - Invasive / Non-Invasive 1995 -2010
3. HRP Bioimage Study - Disease Burden 2010 -2012
4. The Two Extreme Paradox 2012 -2020