Presenter Disclosure Information Valentin Fuster, M.D., Ph.D.

Presenter Disclosure Information Valentin Fuster, M.D., Ph.D.

Transition From CV Disease To Health
Motivation
PCNA, Atlanta, April 10, 2014
No Disclosures
Two Pathways of Translational Medicine
1. Basic Research
Patient
2. Clinical Trials
3. Global / Guidelines
European Advisory Committee on Health – July 2013
A Transition From Disease to Health
Heart – Brain Integration
Imaging / Omics / Regeneration / Life Style
Complex
(4) –
Subclinical
Health
1970
1990
To
CP-VD
(3) -- Arterial
To
DBD-Aging
(3)
To
Focal
1990
2000
CAD
-- Global
2000
2010
2010
2015
2015
2020
1960 “YOU MUST STUDY MEDICINE AND BE A CARDIOLOGIST,
NOT A TENNIS PLAYER, NOR STUDY AGRICULTURE “
1960-1970, Platelets as Biomarker of Myoc. Inf.
Sir H Sheehan 1960 – V Fuster, PhD Thesis 1970
A Arbab-Zadeh, M Nakano, R Virmani, V Fuster, et. al. Circ. 2012;125:1147
A Transition From Disease to Health
Heart – Brain Integration
Imaging / Omics / Regeneration / Life Style
(1/4) –
Complex
CAD
To
CP-VD
Subclinical
(3) -- Arterial
To
DBD-Aging
Health
(3)
To
Focal
1970
1990
1990
2000
-- Global
2000
2010
2010
2015
2015
2020
1a).1970-1990, 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
1b). 1970 -1990 - Benefit Of Periop. Asa + Dipyrid.
On Early Postop. SVBG Patency
Cumulative occlusion rates (%)
30
Distal Anastom.
Patients
30
Placebo
20
20
Placebo
10
Days
Treated
10
Treated
20
40
60
80
100
120
20
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
60
80
100
120
A Transition From Disease to Health
Heart – Brain Integration
Imaging / Omics / Regeneration / Life Style
Complex
(2/4) –
Subclinical
(3) -- Arterial
To
Health
(3)
To
1970
1990
1990
2000
CAD
-- Global
2000
2010
To
CP-VD
DBD-Aging
Focal
2010
2015
2015
2020
2a). 1990 -2000, MRI – Non Invasive
Native CAD – Re-Stenosis
V Fuster, Circ 1994; 90:2126 - AHA Report Circ 1995; 92:1355 - HRP
E Falk, PK Shah, V Fuster Circ 1995;92:657 - HRP
J-F Toussaint, V Fuster et. al. ATVB.1995;15:1533 - Diffuse
V Fuster, JJ Badimon,L Badimon NEJM.1992;326:242 &310 – Diffuse
M Poon, JJ Badimon, V Fuster. Lancet 2002;359:619. Rapamycin
2b). 1990 -2000, Native CAD, Re-Stenosis
VI
PHASE 1
I-III
PHASE 2
PHASE 4
Acute Syndromes
Myocardial infarction
Unstable angina
Ischemic sudden death
IV-Va
VI
PHASE 4
PHASE 5
Vb-Vc
PHASE 3
VI
No Symptoms
Angina
pectoris
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)
RAVEL (MC Morice, JE Sousa et al.) ESC- Sept 2001 –Stent Restenosis
A Transition From Disease to Health
Heart – Brain Integration
Imaging / Omics / Regeneration / Life Style
(3/4) –
Complex
CAD
To
CP-VD
DBD-Aging
Subclinical
(3) -- Arterial
To
Health
(3)
To
1970
1990
1990
2000
-- Global
2000
2010
Focal
2010
2015
2015
2020
3a). 2000-2010, 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
3b). 2000–2010,
PCI/DES
CABG
Logrank P=0.005
30
Death/Stroke/MI, %
FREEDOM– DEATH / STROKE / MI
PCI/DES
20
CABG
10
5-Year Event Rates: 26.6% vs. 18.7%
0
0
1
2
3
4
5
Years post-randomization
New Engl. J. Med 2012; 367: 2375
6
A Transition From Disease to Health
Heart – Brain Integration
Imaging / Omics / Regeneration / Life Style
(4/4) –
Complex
CAD
To
CP-VD
DBD-Aging
Subclinical
(3) -- Arterial
To
Health
(3)
To
1970
1990
1990
2000
-- Global
2000
2010
Focal
2010
2015
2015
2020
4a). Slowing Infarction on Time
Metoprolol Administration (Pig)–CNIC (Humans)
T2W
T1
T2W / T1
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
4b) STEMI -Early Metoprolol On Infarct Size
In Ant.MI Patients Undergoing 1ary PCI (N=220)
METOCARD CNIC (B Ibanez, V Fuster et. al.) Circ 2013 .
4c). LV FAILURE – METABOLIC - GENE THERAPY
Na+
2 K+
NaCaX
Ca
ATPase
Ca2+
NaCaX
3
Na+
Ca2+
Ca2+
Na-K
ATPase
3 Na+
NaHX
H+
DHPR
RyR
T-tubule
SR
DHPR
PLB SERCA
RyR
Ca2+
H+
DHPR
CUPID (M Jessup, RJ Hajjar et. al.) Circulation 2011;124:304.
4d) Calcium Up-Regulation by Percutaneous Administration
of Gene Therapy In Cardiac Disease (CUPID Trial)
Phase 1 & 2 Trial of Intracoronary Administration of
AAV1.SERCA2a in Class III/IV Heart Failure
Phase 1: Open-Label, Sequential Dose Escalation
1.4x1011, 6x1011, 3x1012, 1x1013 drp N=12 (3:3:3:3)
Phase 2: Randomized, Double-Blind, Placebo Controlled.
6x1011, 3x1012, 1x1013 drp, & saline N=39 (8:8:9:14)
RJ Hajjar. J Clin Invest. 2013;123:53
R Hajjar et al 2013 (In Press)
4f). 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
(4) –
Complex
CAD
Subclinical (1/3) -- Arterial
Health
1970
1990
(3)
1990
2000
-- Global
2000
2010
To
To
To
CP-VD
DBD-Aging
Focal
2010
2015
2015
2020
2010
2015
PESA & AWHS
40-54y, n= 8,000 , FU 0,3,6 y
Life Style & Imaging?
Omics (Framingham)
Telomeres (S.blot, qPCR, Fresh)
HRP > 55y,
N=6000 FU 8y
Predictive ?
Economics ?
1a). 2010-2015, Plaque Burden,
Carotid 3D-US, Coronary Calcification
H Sillesen, P Muntendam, E Falk, V Fuster et.al JACC Imag. 2012;7:681.
1b) 2010-2015, Cross Interaction
Between Carotid Plaque Area & CAC
IMT vs Focal: +
Ilio-Femoral: +++
(n = 1480)
(n = 1477)
(n = 1479)
(n = 1478)
Carotid Plaque Area Quartiles
V Fuster, U Baber, R Mehran, E Falk, et al, 2014 (Subm)
1b) 2010-2015, 3D-US + CAC
Impact on Events
V Fuster, U Baber, R Mehran, E Falk, et al, 2014 (Subm)
2010
2015
PESA & AWHS
40-54y, n= 8,000 , FU 0,3,6 y
Life Style & Imaging
Omics (Framingham)
Telomeres (S.blot, qPCR, Fresh)
HRP > 55y,
N=6000 FU 8y
Predictive ?
Economics ?
A Transition From Disease to Health
Heart – Brain Integration
Imaging / Omics / Regeneration / Life Style
(4) –
Complex
CAD
Subclinical (2/3) -- Arterial
Health
1960
1990
(3) -1990
2000
Global
2000
2010
To
VD
To
DBD - Aging
To
2010
2015
Focal
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.
2). 2010-2015, DBD / Alzheimer’s
White Matter Abnormalities & Lacunar Stroke (?)
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 / 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
Subclinical (3/3) -- Arterial
Health
1960
1990
(3) -1990
2000
Global
2000
2010
To
To
VD
DBD - Aging
To
Focal
2010
2015
2015
2020
3). 2010-2015, Aging: Frailty
Non-specific
Extreme fatigue, unexplained weight loss, frequent infections.
Falls
So-called hot fall is related to a minor illness that reduces postural
balance below a crucial threshold necessary to maintain gait
integrity. Spontaneous falls occur in more severe frailty.
Delirium
Rapid onset of fluctuating confusion and impaired awareness.
Delirium is related to reduced integrity of brain function and is
independently associated with adverse outcomes.
Fluctuating disability
Fluctuating disability is day-to-day instability.
A Clegg et al., Lancet 2013; 381:752
3). 2010-2015, Aging / Senescence
Cellular Stress (Oxidative Stress) on Telomere
2
3
1
4
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
Aging / Senescence
Cellular Stress (Oxidative Stress) on Telomere
2
1
3
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
Molecular Pathways Implicated In Aging
CB Newgard et. al. J Clin Invest. 2013;123:946
ENVIRONMENTAL OXIDATIVE STRESS
Telomere Attrition & Shortening
•Smoking
•Obesity
•Sedentary lifestyle
•Mental stress
•Alcohol abuse
Inhibition Of Telomere Shortening
•Healthy lifestyle
F Fyhrquist et al., Nat Rev Cardiol 2013; 10:274
Promoting Health and Improving Survival Into
Very Old Age
The identification of strategies that can promote
health and productivity into old age is one of the
most important challenges facing public health.
The current study’s findings, which suggest that
modifiable social and behavioral factors increase
survival among older people, but only when
achieved early in life, preferably in childhood
MM Glymour, TL Osypuk. BMJ 2012; 345:e6452
A Transition From Disease to Health
Heart – Brain Integration
Imaging / Omics / Regeneration / Life Style
Complex
(4) –
Subclinical
Health
1970
1990
To
CP-VD
(3) -- Arterial
To
DBD-Aging
(3)
To
1990
2000
CAD
-- Global
2000
2010
Focal
2010
2015
2015
2020
1a)2015-2020, Promoting CV Health Worldwide
x
35
35
2011
June 2014
Circ. 2011;123:1671 a. Behavior Risk,
b. Lack of Policy NCD,
12 RECOMMENDATIONS:
c. No Intersectorial, d. Mixt Health Delivery
1) 2015-2020, Science, Health, Education
Powered by / for Three Ages
1
Research / Health
2 .
2
3
LICs / HICs
DBD / Polypill
“Extended healthy lives” in part due to medical research
generates dramatic returns - Albert & Mary Lasker Found.- 2002
1a). CNIC - Academics of the Future
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). For-Profit
Private Corporations
15
14
10
1
11
2
12
3
4
13
5
6
7
8
Education: Intra & Extramural (15)
Facilities: Imaging, Experimental
SCIENCE July 8, 2005 & Sept 1, 2006
THE LANCET Aug 19,2006, CIRC April 2007
EUROPEAN HEART J 2010;31:2067,
EUROPEAN HEART J 2013;34:1014,
9
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
16.-Antonio Huertas
Fundación Mapfre
1a).“CNIC–Joven” Training Plan
2009,
2010,
2011,
2012,
2013
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
1ba). Non-Profit Private Foundations
JM Santo Domingo
1ba). COLOMBIA – CHILDREN’S PROGRAM
HOW YOUR BODY
& HEART WORK
HEALTHY FOOD
HABITS
PHYSICAL
ACTIVITY
EMOTIONAL
HABITS TO AVOID
ADDICTIONS
EDUCATIVE GOAL: HEALTHY HABITS FOR CHILDREN BETWEEN 3 & 5 YRS
CHILDREN
GENERAL
PUBLIC
3-5
6-8
9-14
SESAME PROJECT
KNOWLEDGE (70), ATTITUDES (20) & HABITS (10)
Score (mean)
90
(p<0.0001)
85
(p=0.1197) ‡
(p<0.0001)
80
(p=0.0064)
(p=0.7417)
75
(p<0.0001)
p< 0.001
70
65
Intervention
period
60
Baseline
Teachers
Parents
6 months
Children
18 months
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
36m-change In Children’s KAH Mean Scores*
100.0
Score (mean)
90.0
p< 0.001
80.0
70.0
60.0
p< 0.001
50.0
40.0
0
Knowledge
18
Attitudes
36
Habits (physical activity)
The Amer J of Med 2013;126:27
Colombia – 25,000 Children, Spain 64 Schools – 20,000, US……
1bb). Non-Profit Private Foundations
1bb). SPAIN - CHILDREN’S PROGRAM
Cardona July, 2011
Madrid, October 2011-
Cardona, July 2013
Madrid, October 2013
2013 Top 10 Advances in Heart Disease and Stroke Science
American Heart Association/American Stroke Association
AHA
1ba.COLOMBIA
1bb). SPAIN
Dr V Ruster
newsroom.heart.org. Jan 2, 2014
1bc)USA
P = Pilot 1st Year; I = Intervention
IP = Peers; II = Individual; O = No Intervention
KAH-BEA = Knowledge, Attitude, Habit – BMI, Exercise, Alimentation; S = Sustained
BEWAT = BP, Exercise, Weight, Alimentation, Tobacco; PPPI = Peer-to-Peer Program Intervention
IIIP = Intensive Individual Intervention Program
HEALHY COMMUNUTIES - CARDONA
2) 2015-2020, Science, Health, Education
Powered by / for Three Ages
1
Research / Health
2 .
2
3
LICs / HICs
DBD / Polypill
“Extended healthy lives” in part due to medical research
generates dramatic returns - Albert & Mary Lasker Found.- 2002
2a). 2015-2020 AMPATH Centers In Kenya
BP Control / Non MD / High Technology
R Vedanthan, V Fuster, et al NHLBI / Kenia Project, 2012-2015
2b). 2015-2020 - CARDONA INTEGRAL – “FIFTY-FIFTY”
SMOKING
0
11
2
--
--
2
OVERWEIGHT
0
12
2
--
--
2
SEDENTARISM
0
13
2
--
--
2
HYPERTENSION
0
14
2†
--
--
2
8
TOTAL HABIT SCORE
SIX MONTHS
95% of the people have improved
in one or more of the habits or RF.
3) 2015-2020, Science, Health, Education
Powered by / for Three Ages
1
Research / Health
2 .
2
3
LICs / HICs
DBD / Polypill
“Extended healthy lives” in part due to medical research
generates dramatic returns - Albert & Mary Lasker Found.- 2002
3b) 2015-2020, CNIC-FERRER POLYPILL, 2ary PREVENTION.
FOOD INTERACTION
FOCUS 1 & 2
Argentina
Brazil
Paraguay
Italy
Spain
PHARMACOKINETIC
INTERACTION WITH ASPIRIN
BIO-EQUIVALENCE
ASA, Statin, ACE-Inhibitor
PHARMACOKINETIC
INTERACTION WITH
SYMVASTATIN
PHARMACODINAMIC
INTERACTION WITH RAMIPRIL
FREEDOM
AETNA
EU 2020
Am. H J 2011;162:811
Semin.Thor.Cardiov.Surg 2011;23:24
Nature Rev Cardiology, 2014-In Press
PHARMACODYNAMIC
INTERACTION WITH
SYMVASTATIN
PHARMACOKINETIC
INTERACTION WITH RAMIPRIL
PHARMACODYNAMIC
INTERACTION WITH ASPIRIN
-
Approval in 7
UMPIRE: High Risk, Two Polypills as FOCUS +Hctz or Atenolol vs Usual Care
86% Adherence vs 65%, Lower BP and LDL-C - Events NS --- JAMA 2013;310:918
Transition From CV Disease To Health
The Circle - Manhattan
Motivation
PCNA, Atlanta, April 10, 2014
No Disclosures
The Circle of Motivation
.
Satisfaction
Motivation
Passivation
Frustration
4 T’s – Mental - Time,
Talent, Transmit,
Tutoring
4 A’s - Society - Attitude, Accept, Authenticity, Altruism