Leadership Team Effort - VHIR...1960-2010, coronary & vascular disease Sir H Sheehan 1960 – V...
Transcript of Leadership Team Effort - VHIR...1960-2010, coronary & vascular disease Sir H Sheehan 1960 – V...
A Two Way Translational Approaches Strategies for Satisfaction – The Circle
Leadership Team Effort
Barcelona , January 10, 2014
A Two Way Translational Approach
1. Basic Research
Patient
2. Clinical Research
3. Global Research
European Advisory Committee on Health – July 2013
1. A Transition From Disease to Health 2. Heart – Brain Integration 3. Imaging / Omics / Regeneration / Life Style
Complex (4) – CAD To VD
Subclinical (3) -- Arterial To DBD-Aging
Health (3) -- Global To Focal
1960 1990 2000 2010 2015
1990 2000 2010 2015 2020
A Transition From Disease to Health Heart – Brain Integration Imaging / Omics / Regeneration / Life Style
Complex (1/4) – CAD To VD
Subclinical (3) -- Arterial To DBD-Aging
Health (3) -- Global To Focal
1960 1990 2000 2010 2015
1990 2000 2010 2015 2020
1960-2010, CORONARY & VASCULAR DISEASE
Sir H Sheehan 1960 – V Fuster, PhD Thesis 1970 A Arbab-Zadeh, M Nakano, R Virmani, V Fuster, et. al. Circ. 2012;125:1147
1a). 1960-1970, Platelets as Biomarker of Myoc. Inf.
1b).1970-1980, Platelet Studies “In Vivo”
1). 1975, VWD Pigs
2).1976, CABG Dogs
V Fuster et. al. J. Clin. Invest 1978;61:722 - Circ. Res. 1982; 51:587
V Fuster et. al. Circ.1979;60:1508
1c). 1980 -1990 - Benefit Of Periop. Asa + Dipyrid. On Early Postop. SVBG Patency
Patients
20
10
60 80 100 120
20
30
40
Distal Anastom.
Placebo
Treated
Placebo
Treated
Cu
mu
lati
ve o
cclu
sio
n r
ate
s (
%)
20
10
60 80 100 120
20
30
40
JH Chesebro, V Fuster et al., N. Engl. J. Med. 1982; 307:73 JH Chesebro, V Fuster et al., N. Engl. J. Med. 1984; 310:209 V Fuster, JH Chesebro et al., Circ 1986; 73:227
Days
A Transition From Disease to Health Heart – Brain Integration Imaging / Omics / Regeneration / Life Style
Complex (2/4) – CAD To VD
Subclinical (3) -- Arterial To DBD - Aging
Health (3) -- Global To Focal
1960 1990 2000 2010 2015
1990 2000 2010 2015 2020
2a). 1990 –1995, The High Risk Plaque - Autopsy
Plaque Erosion With
Nonocclusive Thrombi- ++++
Plaque Erosion With
Occlusive Thrombus – 25%
Plaque Rupture With
Occlusive Thrombus - 75%
JA Ambrose, V Fuster 1987-1990. Plaque Rupture – Small at Angiography
V Fuster, JJ Badimon et al., N.Engl.J.Med. 1992; 326:242 - HRP V Fuster, JJ Badimon et al., N.Engl.J.Med. 1992; –326:310 - HRP A Arbab-Zadeh, M Nakano, R Virmani, V Fuster, et. al. Circ. 2012;125:1147
J-F Toussaint, V Fuster et. al. ATVB.1995;15:1533 - Diffuse V Fuster,JJ Badimon,L Badimon NEJM.1992;326:242 &310 - Diffuse V Fuster, Circ 1994; 90:2126 - AHA Report Circ 1995; 92:1355 E Falk, PK Shah, V Fuster Circ 1995;92:657-
2a). 1990 -1995, Plaques MRI – Non Invasive Burden of Disease
Modified from G Niccoli et. al. JACC Cardiovasc Img. 2013;6:1108
GW Stone, J Narula JACC: Cardiov. Imag. 2013:6;1124
A Arbab-Zadeh, M Nakano, R Virmani, V Fuster, et. al. Circ. 2012;125:1147
2a). 1990 -1995, High Risk Plaque Mild at Angiography, Significant at IVUS & Pathology
STABLE PLAQUE
Angiogr., IVUS
UNSTABLE PLAQUE
Angiogr., IVUS, Pathology
RUPTURED PLAQUE
Pathology
PHASE 4
I-III
PHASE 1 PHASE 2
PHASE 3
PHASE 5 Acute Syndromes Myocardial infarction Unstable angina Ischemic sudden death
No Symptoms
IV-Va
VI
VI
Vb-Vc
V Fuster et al., N.Engl.J. Med 1992; 326:242 –326:310 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
Angina pectoris
PHASE 4 VI
2a). 1990 -1995, Plaques, Autopsy / Imaging
2b).1995–2000, Restenosis & Sirolimus DES
Gallo R, Fuster V, Badimon JJ et al. Circ 1999; 99; 2164 Worthley SG, Badimon JJ, Fuster V. Circ 2000; 101: 2956 SO Marx &A Marks Circ. 2001;104:852 M Poon, JJ Badimon, V Fuster. Lancet 2002;359:619.
2b). 2000, RANDOMIZED TRIALS WITH DRUG-ELUTED STENTS RESTENOSIS RATE AT 6 MONTHS
Drug-coated stent
Control
P<0.001 P<0.001
P<0.01
P<0.01
4
27
0
26
37
6.4
11
0 0
10
20
30
40
50
Trial: N: Drug: Funding:
ASPECT 177
Paclitaxel
Cook Inc.
RAVEL 238
Sirolimus Cordis, J&J
SCORE 106
QP-2 (Taxol) Quanam
TAXUS-1 61
Paclitaxel Boston Sc.
Perc
en
t
RAVEL (MC Morice, JE Sousa et al.) ESC- Sept 2001
A Transition From Disease to Health Heart – Brain Integration Imaging / Omics / Regeneration / Life Style
Complex (3/4) – CAD To VD
Subclinical (3) -- Arterial To DBD - Aging
Health (3) -- Global To Focal
1960 1990 2000 2010 2015
1990 2000 2010 2015 2020
3a) 2000–2005, CAD & Diabetes – Autopsy, Ex Vivo
95 patients with Unstable Angina
0
5
10
15
20
25
Diabetes (n=47) No Diabetes (n=48)
p=0.003
Perc
en
t M
acro
ph
ag
e A
rea
TF-Thrombus 62% 40% (p=0.03)
Diabetes
No Diabetes
V Fuster et al., NEJM 1992; 326:242 - 326:310 – Autopsy: Diffuse Moreno PR.,Fuster V, et al. Circ 2000;102:2180 – Inflammatory
K-P Purushothaman, V Fuster, PR Moreno, et al., JACC 2012; 60:112
3a). Oxidative Stress Macrophage Dependant
in Diabetic Plaques
3a) Basic Mechanisms of Diabetic Vascular Disease
JM Castellano, J Kovacic, V Fuster - End. Clin. of North Am 2014 (In Press)
3a). 2000-2005, High Risk Carotid Disease - PET/MRI
RR Moustafa, J Rudd et. al. Circ Cardiov. Imag. 2010;3:536
R Corti & V Fuster EHJ 2011 (April 19) JD Spence. Circ. 2013;127:739
Diffuse, Inflammatory, Lipid Deposition
MV-Stenting With Drug-eluting
Eligibility: DM patients with MV-CAD eligible for stent or surgery Exclude: Patients with acute ACS, LM Disease, Severe CHF
CABG With or Without CPB
Randomized 1:1
Primary Outcome: Composite of earliest occurring of: All cause mortality, Non-fatal MI, and Non-fatal Stroke
3b). 2005-2010, FREEDOM Design
New Engl J Med 2012;367:2375
30
20
10
0
Death
/Str
oke/M
I, %
PCI/DES
Logrank P=0.005
CABG PCI/DES
CABG
5-Year Event Rates: 26.6% vs. 18.7%
0 1 2 3 4 5 6
Years post-randomization
3b). 2005–2010, 1ary OUTCOME – DEATH / STROKE / MI
New Engl. J. Med 2012; 367: 2375
3b). 2005-2010, TARGETING RISK FACTOR CONTROL
Risk Factors - Proportion of Participants at Goal % – 1 year
Trials LDL SBP DBP Hb A1C Meet Goals
Base FU
BARI-2D 75 56 70 52 14 20
COURAGE 51 55 55 59 12 19
FREEDOM 55 63 53 55 12 20
Freedom, Bari-2D, Courage Investigators, JACC 2013;61:1607 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 !!!!
3b). POLYPILL FOR SECONDARY PREVENTION.
G Sanz, V Fuster Am. H J 2011;162:811 – Semin. Thor. Cardiov 2011;23:24
JC Kovacic, EG Nabel, V Fuster Circ 2011; 123: 1900
JC Kovacic, EG Nabel, V Fuster – Circ. 2011;123:1650
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
ASA, Statin, ACE-Inhibitor
Argentina
Brazil
Paraguay
Italy
Spain
FOCUS 1 & 2
A Transition From Disease to Health Heart – Brain Integration Imaging / Omics / Regeneration / Life Style
Complex (4/4) – CAD To VD
Subclinical (3) -- Arterial To DBD - Aging
Health (3) -- Global To Focal
1960 1990 2000 2010 2015
1990 2000 2010 2015 2020
4). 2010-2015, MYOCARDIUM
B Ibanez, V Fuster, J Sanz, JJ Badimon et al Circ 2007;115:2909
B Ibanez, G Cimmino, V Fuster, JJ Badimon et.al.Int J Card 2011;147:428
4a). Slowing Infarction on Time Metoprolol Administration (Pig)–CNIC (Humans)
T2W T1 T2W / T1
4a) STEMI -Early Metoprolol On Infarct Size In Ant.MI Patients Undergoing 1ary PCI (N=220)
METOCARD CNIC (B Ibanez, V Fuster et. al.) 2013 (In Press).
3 Na+
Ca2+
Ca2+
PLB SERCA
Ca2+
3 Na+
2 K+
Ca2+
H+ RyR
RyR
Na-
HX
Na+
H+
Na-K
ATPase Ca
ATPase
Na-
CaX
Na-
CaX
DHPR
DHPR
DHPR
SR
T-t
ub
ule
CUPID (M Jessup, RJ Hajjar et. al.) Circulation 2011;124:304.
4b). LV FAILURE – METABOLIC - GENE THERAPY
4b). Calcium Up-Regulation by Percutaneous
Gene Therapy In Cardiac Disease (CUPID Trial)
AAV1.SERCA2a in Class III/IV Heart Failure
Phase 1: Open-Label, Sequential Dose Escalation - N=12
Phase 2: Randomized, Double-Blind, Placebo Control - N=39
RJ Hajjar. J Clin Invest. 2013;123:53
R Hajjar et al 2014 (In Press)
4c). MI -Stem Cell Fr. Gene Transfer
Promotes Repair Via c-kit+ Cells (Rat)
E Yaniz-Galende, V Fuster, RJ Hajjar et.al. Circ Res. 2012;111:1434
A Transition From Disease to Health Heart – Brain Integration Imaging / Omics / Regeneration / Life Style
Complex (4) – CAD To VD
Subclinical (1/3) -- Arterial To DBD - Aging
Health (3) -- Global To Focal
1960 1990 2000 2010 2015
1990 2000 2010 2015 2020
3
3
1). 2010-2015, HRP - Bioimage Initiative – 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
The Lancet NCD Action (G Alleyne et. al.) Lancet. 2013;381:566
PESA & AWHS HRP > 55y,
40-54y, n= 8,000 , FU 0,3,6 y N=6000 FU 8y
Omics (Framingham)
Telomeres (S.blot, qPCR, Fresh)
1a). Predictive ? . Economics ?
1b). Life Style & Imaging Pesa Systemic Score
1a). 2010 2015
1a). 2010-2015, Carotid Plaque Burden, mm3 3D US - Manual Sweep 2D vs Transducer
Focal structure into the arterial lumen of at least 0.5 mm
or 50% of surrounding IMT value. 37% missed at Classical 2D CardioSCORE-R7-ApoA1, Apo B, B2M, CEA, CRP, Lp(a),Transferrin
H Sillesen, P Muntendam, E Falk, V Fuster et.al JACC Imag. 2012;7:681.
1a). 2010-2015, Coronary Calcification (CAC)
1a) 2010-2015, Cross Interaction Between Carotid Plaque Area & CAC
(n = 1480) (n = 1477) (n = 1479) (n = 1478)
Carotid Plaque Area Quartiles
IMT vs Focal: + Ilio-Femoral: +++
V Fuster, U Baber, R Mehran, E Falk, et al, 2014 (Subm)
1a) 2010-2015, 3D-US + CAC
Impact on Events
V Fuster, U Baber, R Mehran, E Falk, et al, 2014 (Subm)
PESA & AWHS HRP > 55y,
40-54y, n= 8,000 , FU 0,3,6 y N=6000 FU 8y
Omics (Framingham)
Telomeres (S.blot, qPCR, Fresh)
1a). Predictive ? . Economics ?
1b). Life Style & Imaging Pesa Systemic Score
1b). 2010 2015
1b) 2010-2015, PESA Systemic Score With Age And Gender (N=2578, Age 40-54yo, 35% Women)
LJ Jimenez Borregueva, AI Fernandez Ortiz, V Fuster et. al. 2013
A Transition From Disease to Health Heart – Brain Integration Imaging / Omics / Regeneration / Life Style
Complex (4) – CAD To VD
Subclinical (2/3) -- Arterial To DBD - Aging
Health (3) -- Global To Focal
1960 1990 2000 2010 2015
1990 2000 2010 2015 2020
2). 2010-2015 - Cortical Atrophy (Alzheimer’s), White Matter Abnormalities & Lacunar Stroke (?)
JC Kovacic, V Fuster et. al. Circulation. 2011;123:1900
MA Lim et. al. Clin Geriatr Med. 2009;25:191.
Promoting Cardiovascular and
Cerebrovascular Health V Fuster, S Bansilal. Stroke 2010; 41:1079
Highlight Dementia Risk to Reduce CVD
BM Mearns, V Fuster. Nature Rev Card 2010; 7:237
Cellular Senescence, Aging & Vascular Disease ( Part 2 of a 2-Part Review )
JC Kovacic, EG Nabel, V Fuster Circ 2011; 123: 1900 Complex Coronary Disease, Cerebrovascular Disease and Degenerative Brain Disease JC Kovacic, JM Castellano,V Fuster Ann. NY. Acad. Sc 2012;
2). 2010-2015, DBD / Alzheimer’s White Matter Abnormalities & Lacunar Stroke (?)
2). 2010-2015, DBD / AD - MRI – Perfusion
CV RFs, Lesion Volume, Cognitive Decline
1.V Novak, I Hajjar. Nat. Rev. Cardiol. 2010;7:686(HMS) 2. HW Querfurth, FM LaFerla. NEJM 2010; 362:329 3. WB White et al.Circ 2011;124:2312 (Farmington,Yale) 4. AHA/ASA, Stroke 2011; 42:2672 5. WHO - Dementia report 2012 6. JB Toledo et al. Brain July 10, 2013 7. C Russo, RL Sacco et.al. Circ. 2013;128:1105 8. JR Kizer Circ 2013;128:1045
Ischemia affects 60 to 90% of patients with Alzheimer’s
A Transition From Disease to Health Heart – Brain Integration Imaging / Omics / Regeneration / Life Style
Complex (4) – CAD To VD
Subclinical (3/3) -- Arterial To DBD - Aging
Health (3) -- Global To Focal
1960 1990 2000 2010 2015
1990 2000 2010 2015 2020
4a). 2010-2015, The Emerging Paradigm of
Network Medicine in the Study of Omics
Human Disease
SY Chan et. al. Circ Res. 2012;111:359
1 2 3 4
4b). 2010-2015, Genetic Variation
Determinants of Phenotype
SNPs = Single Nucleotide Polymorphisms - 5 mill. – 0.1% NBPs = Nucleotide Base Pairs - 5 billion AJ Marian et. al. Circ Res. 2011;108:1252
1
2
4
3
Telomere & Telomerase
B Niemann et. al. JACC 2011; 57: 577.
R Madonna, R De Caterina et. al EHJ 2011;32:1190 (Houston &Chieti, Italy)
JC Kovacic, EG Nabel, V Fuster – Circ. 2011;123:1650
1
3
Telomere Attrition & Shortening
F Fyhrquist et al. Nat. Rev. Cardiol. 2013;10:274
A Transition From Disease to Health Heart – Brain Integration Imaging / Omics / Regeneration / Life Style
Complex (4) – CAD To VD
Subclinical (3) -- Arterial To DBD - Aging
Health (3) -- Global To Focal
1960 1990 2000 2010 2015
1990 2000 2010 2015 2020
2011 2012 2012
2010-2015, Promoting CV Health
Circ. 2011;123:1671 a. Behavior Risk, b. Lack of Policy NCD,
12 RECOMMENDATIONS: c. No Intersectorial, d. Mixt Health Delivery
Scientific American 2013
1a,b
Research / Health
Science, Health, Education (SHE) Powered by / for Three Ages
2 . 3a,b
DBD / Aging
2a,b
LICs / HICs
“Extended healthy lives” in part due to medical research
generates dramatic returns - Albert & Mary Lasker Found.- 2002
Public CV Research Institution of The Spanish
Government & Pro CNIC (13 Private Companies)
28,144 m2 For Research. Equipped With The Most
Advanced Facilities &Technology
1a). CNIC - Academics of the Future
“Funding the Future”
1 2 3 4 5 6 7 8 9
10 11 12 13 14
15
1.- César Alierta Telefónica 2.- Ignacio Polanco Grupo Prisa 3.- Emilio Botín Fundación Marcelino Botín 4.- José Manuel Entrecanales Acciona, 5.- Valentín Fuster CNIC , President 6.- Isidro Fainé La Caixa 7.- Francisco González BBVA 8.- Luis Suárez de Lezo Repsol YPF 9.- Ignacio Garralda F. I. Médica Mutua
Madrileña 10.- Carlos Martínez Echevarría Fundación Ramón Areces 11.- Salvador Gabarró Gas Natural 12.- Luis de Carlos Uría Menéndez 13.- Rodolfo Martín Villa Fundación Endesa 14.- Miquel Roca Fundación Abertis 15.- Pablo Isla Inditex
Research: Intra & Extramural Education: Intra & Extramural (15) Facilities: Imaging, Experimental
SCIENCE July 8, 2005 & Sept 1, 2006
THE LANCET Aug 19,2006, CIRC April 2007
REV. ESP. CARD. 2012;65:511
EUROPEAN HEART J 2010;31:2067, 2012 (Press)
2008, 2009, 2010, 2011, 2012
“CNIC–Joven” Training Plan
“The Evolving” - SAB
1b) Childhood Obesity & Oportunity
1. Childhood obesity increases BP & risk for stroke “substantially” in adulthood.
2. It predicts obesity in adulthood
The Finish Study (S Mayor. BMJ) 2012;344:e3065
SESAME PROJECT KNOWLEDGE (70), ATTITUDES (20) & HABITS (10)
90
85
80
75
70
65
60
Sco
re (
mean
)
Baseline 6 months 18 months
(p<0.0001)
(p=0.0064)
(p<0.0001)
(p<0.0001)
(p=0.1197) ‡
(p=0.7417)
Teachers Parents Children Control
Céspedes J, Briceño G, Farkouh ME, Vedanthan R, Baxter J, Leal M,
Boffetta P, Woodward M, Hunn M, Dennis R, Fuster V.
The American Journal of Medicine 2013; 126, 27-35
Colombia – 25,000 Children, Spain 64 Schools – 20,000, US……
Intervention
period
36m-change in children’s KAH mean scores*
Results
40,0
50,0
60,0
70,0
80,0
90,0
100,0
0 18 36
Sco
re (
me
an)
Knowledge Attitudes Habits (physical activity)
p< 0.001 p< 0.001
p< 0.001
p< 0.001
p< 0.001
*0 – 100 scale Adjusted by sex and age of children, group, socioeconomic status, age of parents, age and
educational level of teachers . The Amer J of Med 2013;126:27
2013 Top 10 Advances in Heart Disease and Stroke Science
American Heart Association/American Stroke Association
AHA
newsroom.heart.org. Jan 2, 2014
Dr V Ruster
1a,b
Research / Health
Science, Health, Education (SHE) Powered by / for Three Ages
2 . 3a,b
DBD / Aging
2a,b
LICs / HICs
“Extended healthy lives” in part due to medical research
generates dramatic returns - Albert & Mary Lasker Found.- 2002
2a). AMPATH Centers In Kenya
BP Control / Non MD / High Technology
R Vedanthan, V Fuster, et al NHLBI / Kenia Project, 2012-2015
2b). CARDONA INTEGRAL – “FIFTY-FIFTY” – ONE YEAR
SMOKING 0 11 2 -- -- 2
OVERWEIGHT 0 12 2 -- -- 2
SEDENTARISM 0 13 2 -- -- 2
HYPERTENSION 0 14 2† -- -- 2
TOTAL HABIT SCORE 8
95% of the people have improved in one or more of the habits or RF.
SIX MONTHS
1a,b
Research / Health
Science, Health, Education (SHE) Powered by / for Three Ages
2 . 3a,b
DBD / Aging
2a,b
LICs / HICs
“Extended healthy lives” in part due to medical research
generates dramatic returns - Albert & Mary Lasker Found.- 2002
A Transition From Disease to Health Heart – Brain Integration Imaging / Omics / Regeneration / Life Style
Complex (4) – CAD To CVD
Subclinical (3) -- Arterial To DBD - Aging
Health (3) -- Global To Focal
1960 1990 2000 2010 2015
1990 2000 2010 2015 2020
.
4 T’s – Mental - Time, Talent, Transmit, Tutoring
4 A’s - Society - Attitude, Accept, Authenticity, Altruism
Frustration Motivation
Satisfaction Passivation
The Circle of Motivation
A Personal CVR Historical Journey
A Two Way Translational Approach
A Two Way Translational Approaches Strategies for Satisfaction – The Circle
Leadership Team Effort
Barcelona , January 10, 2014
A Personal CVR Historical Journey
A Two Way Translational Approach
1). 2010-2015, Population Ageing, Prevention, And The Cost Of NCD
The Lancet NCD Action (G Alleyne et. al.) Lancet. 2013;381:566