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