Basic - From Atheroma to Prevent Aging (3)

Subclinical Atherosclerosis
Challenges 2010–2020
Basic - From Atheroma to Prevent Aging
(3)
Clinical – From MVD / Stroke to DBD
(3)
Population – From Risk to Health
(3)
Subclinical Atherosclerosis: 2010–2020 - Basic
EC - TRANSLATIONAL RESEARCH MODEL
A TEAM EFFORT
Basic Research
Proof of Concept
Clinical Research
Population Research
Workshop, European Commission, Brussels, Oct 2008
Cardiovasc Res 2009; 83: 425
Subclinical Atherosclerosis
Challenges 2010–2020
Basic - From Atheroma to Prevent Aging
(3)
Clinical – From MVD / Stroke to DBD
(3)
Population – From Risk to Health
(3)
Imaging the Atherothrombotic Process
Choudhury R, Fuster V, Fayad ZA Nature Rev. Drug Disc 2004;3:913.
Jaffer FA et al., Circ 2007; 116:1052 - Sanz J et al., Nature 2008; 451:953.
Mulder WJM , Fayad ZAet al. et. al. Nat CP Cardiov. Med. 2008;5:s103. CM
Matter, M Nahrendorf et. al. Eur Heart J. 2009;30:2566
HIGH RISK PLAQUE - < ACTIVE INFL.
Ph.3
HDL
LDL
Ph.1
PGC
CAMs
TF
MMPs
Ph.2
VASA V.
Moreno P, Sanz J, Fuster V,
J Am Coll Cardiol 2009;53:2315
Extracellular Matrix
Fibroblasts
Vasa Vasorum
PDGF
ET
SMC contraction
migration
proliferation
Magnetic Targeting EPG Following Carotid
Angioplasty (Rat)
PG Kyrtatos et. al. J Am Coll Cardiol Intv. 2009;2:794.
Some Mice Models Have Questioned the Concept
Senescence-Associated Changes
RT Calado et. al. N Engl J Med. 2009;361:2353.
S. Anderson et.al. J Am Soc Nephrol 2009;20:1199
M Mimeault et.al. Ageing Res Rev. 2009;8:94Age Related Disorders, Cancer, Exercise
HIGH RISK PLAQUE - > ACTIVE INFL.
Ph.3
HDL
LDL
Ph.1
PGC
CAMs
TF
MMPs
Ph.2
VAS. V.
Moreno P, Sanz J, Fuster V,
J Am Coll Cardiol 2009;53:2315
Extracellular Matrix
Fibroblasts
Vasa Vasorum
PDGF
ET
SMC contraction
migration
proliferation
2) Adventitial Neovascularization in Plaque Regression ?
Antiangiogenic Therapy?, NO ?
Doyle B. et. al. J Am Coll Cardiol. 2007;49:2073.
2) EM - Intraplaque Microvessels ,
Aberrant Junctions, RBC & Leukocyte Infiltration
JC Sluimer, R Virmani, MJAP Daemen et, al. JACC 2009;53:1517
2) Volume-rendered micro-CT imaging of
Coronary Plaques and Vasa Vasorum
M Gössl, A Lerman et. al. J Am Coll Cardiol Img 2010;3:32.
2) Dynamic Contrast Enhanced (DCE) MRI (Gd)
Pre-contrast
Post-contrast 2 min
Post-contrast 8 min
T1W
Pre-contrast
Post-contrast
FC
LC
Kerwin et al. MRM 59; 507, 2008
LC = lipid rich/necrotic core
FC = Fibrous cap
2) In Vivo Evidence of the Effects of IPH
Baseline
36 mo FU
HR Underhill, V Fuster ZA Fayad et. al. Nature. Rev. Card. 2010 (in press).
RCA
Plaque
Coronary FDG Uptake
Stent
CT
Angiogram
LV
RCA
Plaque
Fused
PET and CTA
Images
Stent
LV
JH Rudd, V Fuster, ZA Fayad et al. JACC 2010 (In Press) – PET, Ao-Ca-Cor
Change in the Lipid Rich Necrotic Core (LRNC)
in Response to Statin Therapy
LRNC
2 yrs FU
ECM
CALCIUM
HR Underhill, V Fuster, ZA Fayad et.al. Nat Rev. Card. 2010 (In Press) - MRI
K Hayashi, V Fuster, Za Fayad et al. J Card.Magn.Res. 2010 (In Press) –Ao.Ca
JH Rudd, V Fuster, ZA Fayad et al. JACC 2010 (In Press) – PET, Ao-Ca-Cor
Neovascularization of the Intima Contributes to Progression ?
Hypoxic Component with Monocyte HIF-1 Inhibitors? YES ?
HIGH RISK PLAQUE - APOPTOSIS
Ph.3
HDL
LDL
Ph.1
PGC
CAMs
THROMBUS
TF
MMPs
Ph.2
VAS. V.
Moreno P, Sanz J, Fuster V,
J Am Coll Cardiol 2009;53:2315
Extracellular Matrix
Fibroblasts
Vasa Vasorum
PDGF
ET
SMC contraction
migration
proliferation
3) MRI - Atherosclerotic Plaque Regression & TF
in Rabbits Recombinant ApoA-IMilano
3) Reduction in gene & Protein Tissue Factor Expression
Ibanez B, Badimon JJ, Fuster V, JACC 2008;51:1104. Apo A1 M Rabbits
1) Badimon JJ, Badimon L, Fuster V, JCI 1990; 85:1234 . HDL Rabbits
2) Nissen SE JAMA 2003; 290:2292 – Apo A1 M in Humans - IVUS
Imaging Atherosclerotic Burden – HRP (n=7000), FU 3y
ABI
3D US
PVD
•Carotids
•AAA
MRI
• Non coronaries
• Plaque Composition
MDCT
• Coronary Ca+
• Plaque composition
• Coronaries
FDG-PET
FDG-PET/CT
CT
Fused PET/CT
• Metabolic activity
• Coronaries?
PI: Valentin Fuster, Co-PI: Erling Falk, Peter Muntendam - AHJ 2010 (In Press)
Phase 1 MI
Decreased Myocyte Apoptosis
Metoprolol Administration (Pig)–CNIC 4,5 (Humans)
T2W
T1
T2W / T1
B Ibanez, S Prat, WS Spedl, V Fuster, J Sanz, JJ Badimon Circ 2007;115:2909
Phase 2 MI
Microvasculature / Fibrosis / Hypertrophy
Peptidomimetic Micelles to Alphavbeta3-Integrins
JW Verjans, J Narula, L Hofstra, et al., Circ 2007; 116:II-740
Hyafil, F et. al J Cardiov. Magn Reson 2007;9:278 - Rabbits
Phase 3 MI
PMO or No Reflow Zone
in Antero-apical infarction
S Rajagopalan, V Fuster Nature CPC 2006 - EM & Pers. Microv. Obstr.
HW Kim, A Farzaneh-Far, RJ Kim. JACC 2010; 55:1 – MRI: Dg, Progn, Rx
Radiolabeled CRIP Uptake After Captopril &
Losartan Treatment in Post-MI Animals (Mice)
SWM van den Borne, J Narula et. al. JACC 2008;52:2017.
EPHESUS (W Iraqi, B Pitt, et al.) Circ 2009; 119:2471 - Eplerenone
Interactions Among Cardiac Fibroblasts, PSC, Myocytes
and Extracellular Matrix in the Developing & Adult Heart
R Kakkar, RT Lee et. al. Circ Res. 2010;106:47.
Subclinical Atherosclerosis
Challenges 2010–2020
Basic - From Atheroma to Prevent Aging
(3)
Clinical – From MVD / Stroke to DBD
(3)
Population – From Risk to Health
(3)
CARDIOVASCULAR DISEASE
HEART
MI
1) BRAIN STROKE
Thrombi
1) Emboli
2
2)Thrombi
3)Hemorrh
Subclinical Atherosclerosis: 2010–2020 - Clinical
148
13
146
12
144
11
142
10
140
9
138
8
Mean systolic
Blood pressure
(mmHg)
136
7
Short portable
MMSE
134
60-64
65-69
70-74
75-79
Age Group (yrs)
TO Obisecon. Clin Geriatr Med 2009; 25:259 (NIH)
80-84
>84
6
SHP-MMSE
Mean systolic blood pressure (mmHg)
2) ADVANCED AGE, HYPERTENSION AND DEMENTIA
SBP AND SHORT PORTABLE MMSE SCORE BY INCREASING
AGE GROUPS
2) BLOOD PRESSURE,RISK DEMENTIA – LOGITUDINAL STUDIES
Late-Life Hypertension
Ueda et al. (1992)
Kuusisto et al. (1997)
Cuo et al. (1996)
Pettiti et al. (2002)
Morris et al. (2000)
Kokmen et al. (1991)
Rockwuud et al. (1996)
Mid-Life Hypertension
Launer et al. (2000)
Kivipelto et al. (2001b)
Wu et al. (2003)
Yamada et al. (2003)
Whitmer et al. (2005)
Late-Life Hypertension
Qiu et al. (2003a)
Skoog et al. (1996)
Li et al. (2007)
Yoshitake et al. (1995)
Brayne et al. (1998)
Tyas et al. (2001)
Posner et al. (2002)
Lindsay et al. (2002)
Kuller et al. (2003)
Borenstein et al. (2005)
Petitti et al. (2005)
Hypotension
Ruitenberg et al. (2001)
Morris et al. (2001)
Verghese et al. (2003)
Nilsson et al. (2007)
SP Kennelly, BA Lawlor, RA Kenny. Ageing Research Reviews 2009; 8:61
TO Obisecon. Clin Geriatr Med 2009; 25:259 (NIH) – Age, BP, Cognitive Function
3) PIB Scan of and DBD & Alzheimer’s Patients
G Miller. Science 2009;326:386.
3) Aging, HTN & Amyloid Are Alterations That in Concert
with Vascular Mechanisms Induce Neuronal Dysfunction
C. Iadecola et. al. Stroke 2009;40[suppl 1]:S40.
Y Feng, et al., Circ Res 2010; 106:373 – ACE 2
3) Mechanisms of Disease: Alzheimer’s Disease
More than 35 million people worldwide – 5.5 million in the United
States – have Alzheimer’s disease, a deterioration of memory and
other cognitive domains that leads to death within 3 to 9 years
after diagnosis. Alzheimer’s is the most common form of
dementia, accounting for 50 to 56% of cases at autopsy and in
clinical series. Combined with intracerebral vascular disease
accounts for another 13 to 17% of cases. The principal risk factor
for Alzheimer’s disease is age. Ischemic disease affects 60 to 90%
of patients with Alzheimer’s disease. The odds of receiving the
diagnosis of Alzheimer’s disease after 85 years of age exceed one
in three. As the aging population increases, the prevalence will
approach 13.2 to 16.0 million cases in the United States by midcentury. An accumulation of misfolded proteins in the aging brain
results in oxidative and inflammatory damage, which in turn leads
to energy failure and synaptic dysfunction.
HW Querfurth, FM LaFerla. NEJM 2010; 362:329
3) Role of Vascular Risk Factors and Vascular
Dysfunction in Alzheimer’s Disease
D L. Dickstein, PhD, J Walsh, BA, H Brautigam, BSc,
S D. Stockton Jr, BSc, S Ganday, MD, PhD, PR. Hof, MD
RISK FACTORS
Apolipoprotein E Genotype
Hypertension
Hypotension
Cholesterol
Diabetes Mellitus
Smoking
Mount Sinai Journal of Medicine 2010; 77:82-102
3) SURVIVAL FOR INCIDENT ALZHEIMER’S DISEASE AND INCIDENT
DEMENTIA IN STUDY COHORS (N=819491 MALES ≥ 65 Y – US VA)
Dementia
Survival probability
Survival probability
Alzheimer’s disease
1.00
0.99
0.98
1.00
0.98
0.96
0.94
0
6
12
18
24
30
36
Angiotensin recept. blockers
Lisinopril
Cardiovascular comparator
42
48
0.92
0
6
12
18
24
30
Follow-up (months)
N-C Li et al., BMJ 2010; 340:b5465 – Nursing Home Admision
36
42
48
Subclinical Atherosclerosis
Challenges 2010–2020
Basic - From Atheroma to Prevent Aging
(3)
Clinical – From MVD / Stroke to DBD
(3)
Population – From Risk to Health
(3)
1) 10 vs 30-Ys RISK OF HARD CVD FOR 45-Y.-OLD (5 RF)
30-y risk
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Abn Lipids ‒
Hypert.
‒
Smoking ‒
Diabetes ‒
10-y risk
Men
Estimated % risk of hard CVD
Estimated % risk of hard CVD
10-y risk
+
‒
‒
‒
+
+
‒
‒
+
+
+
‒
+
+
+
+
30-y risk
0.8
Women
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Abn Lipids ‒
Hypert.
‒
Smoking ‒
Diabetes ‒
+
‒
‒
‒
Framingham (MJ Pencina et al.) Circ 2009; 119:3078
+
+
‒
‒
+
+
+
‒
+
+
+
+
2b. CNIC-SANTANDER
40-55y, n= 5000, FU 6y
2a. HRP > 55y,n=7000
FU 3y
“Omics – Copenhagen Heart Study, Framingham, Duke
Imaging
First 2a)
Mobile
3T at Work Atherosclerotic
Burden – HRP (n=7000)
PI: Valentin Fuster, Co-PI: Erling Falk, Peter Muntendam - AHJ 2010 (In Press)
Imaging Atherosclerotic Burden – HRP (n=7000), FU 3y
ABI
3D US
PVD
•Carotids
•AAA
MRI
• Non coronaries
• Plaque Composition
MDCT
• Coronary Ca+
• Plaque composition
• Coronaries
FDG-PET
FDG-PET/CT
CT
Fused PET/CT
• Metabolic activity
• Coronaries?
PI: Valentin Fuster, Co-PI: Erling Falk, Peter Muntendam - AHJ 2010 (In Press)
HSillesen, V Fuster, E Falk, P Muntendam 2009
Locally Extensive - Effects of Simvastatin
Uptake of [18F]-FDG - Aortic Arch & Carotids in Humans
43 pts Tx 5-20 mg simvastatin and diet for 3 months compared to diet alone
N Tahara et. al. J Am Coll Cardiol 2006;48:1825
J HF Rudd , ZA Fayad . Nat Clin Pract Cardiovasc Med. 2008;5:s11
.
ISCHEMIC STROKE
HSillesen, V Fuster, E Falk, P Muntendam 2009
Also Other Non-Cerebral Events
Systemic Carotid Disease – Calcium Score
M Garcia, V Fuster, E Falk, P Muntendam 2009
2b) CNIC - SANTANDER – Imaging & “Omics” 2010
40-55 y, n= 5000, Fu 6 y
1st Whole Body PET/MR scanner
December 2010 – MSSM, MADRID
V Fuster, ZA Fayad 2010
3) COMMITTEE ON PREVENTING THE GLOBAL
EPIDEMIC OF CARDIOVASCULAR DISEASE
VALENTÍN FUSTER (Chair),
ARUN CHOCKALINGAM
CIRO A. DE QUADROS,
JOHN W. FARQUHAR,
ROBERT C. HORNIK,
FRANK B. HU,
PETER R. LAMPTEY,
JEAN CLAUDE MBANYA,
ANNE MILLS,
JAGAT NARULA,
Medicine
JOHN W. PEABODY,
K. SRINATH REDDY,
SYLVIE STACHENKO
DEREK YACH,
Mount Sinai Heart
Simon Fraser University
Albert B. Sabin Vaccine Institute
Stanford University School of Medicine
University of Pennsylvania
Harvard School of Public Health
Family Health International, Ghana
University of Yaoundé
London School of Hygiene &Tropical Medicine
University of California, Irvine School of
University of California, San Francisco
Public Health Foundation of India
University of Alberta
Vice-President PepsiCo
3a) US-NHLBI–IOM: Global CVD Prevention (Chair)
Promoting CV Health 2010 – 2020 (Education)
KNOWLEDGE
EPIDEMIOLOGY
ECONOMICS.
RESPONSABILITY
INTERSECTORIAL
COMMUNITY
INCENTIVE
YOUTH
NEVER TOO LATE
Washington DC , 2010
HML). Projected Deaths by Cause, 2004, 2015, 2030
R. Beaglehole et. al. Lancet 2008;372:1988.
Prevalence of CVD is increasing
Treatment (Live Longer) and Technology ($)
Rx, H-I
Rx, L-I
Rx, H-I
$368 Bill, X3 10y
MI, Pocket 80%
$ 95% - Prev $ 5%
V Fuster et. al. Nat Rev. Cardiol. 2009;6:669.
3b) US-NHLBI–IOM: Global CVD Prevention (Chair)
Promoting CV Health 2010 – 2020 (Education)
KNOWLEDGE
EPIDEMIOLOGY
ECONOMICS.
RESPONSABILITY
INTERSECTORIAL
COMMUNITY
INCENTIVE
YOUTH
NEVER TOO LATE
Washington DC, 2010
LMH) Global Demonstration Projects
1) Children (3-8yrs) – Sesame Street Colombia
2) Adults Cultural Groups – Grenada Heart Project
3) Adults Regulations & Law – NY Tobacco, Food, BP
4) The Millenium Project – Infrastructure
5) The Polypill – Adherence & Economy
3c) US-NHLBI–IOM: Global CVD Prevention (Chair)
Promoting CV Health 2010 – 2020 (Education)
KNOWLEDGE
EPIDEMIOLOGY
RESPONSABILITY
INTERSECTORIAL COMMUNITY
INCENTIVE
YOUTH
Washington DC, 2010
ECONOMICS.
NEVER TOO LATE
CNIC (Spain) - Discovering / Tutoring
July 2009
It is Never too Late for Well Being
Promotion of Physical & Mental Health
AGE
Tobacco, Exercise,
Blood Pressure, BMI - Diet
20
30
40
50+
Each regular health care visit
Each regular health care visit (or at least
once every 2 years if BP < 120/80 mm Hg)
Lipid Profile
Every 5 years
Blood Glucose test
Every 3 years
Clinical Breast Exam (CBE)
and Mammography
CBE q 3 yrs
Pap test
Yearly
Colorectal Screening
Prostate specific antigen
test and/digital rectal exam
ACS/ADA/AHA - Circ 2004; 109:3244
Yearly CBE and
Mammography
Every 1-3 years; depends on
type of test and past results.
Frequency depends
on test preferred
Offer yearly, assist
informed decisions
Subclinical Atherosclerosis
Challenges 2010–2020
Basic - From Atheroma to Prevent Aging
(3)
Clinical – From MVD / Stroke to DBD
(3)
Population – From Risk to Health
(3)
It is Never too Late for Well Being
Promotion of Physical & Mental Health
AGE
Tobacco, Exercise,
Blood Pressure, BMI - Diet
20
30
40
50+
Each regular health care visit
Each regular health care visit (or at least
once every 2 years if BP < 120/80 mm Hg)
Lipid Profile
Every 5 years
Blood Glucose test
Every 3 years
Clinical Breast Exam (CBE)
and Mammography
CBE q 3 yrs
Pap test
Yearly
Colorectal Screening
Prostate specific antigen
test and/digital rectal exam
ACS/ADA/AHA - Circ 2004; 109:3244
Yearly CBE and
Mammography
Every 1-3 years; depends on
type of test and past results.
Frequency depends
on test preferred
Offer yearly, assist
informed decisions
CNIC (Spain) - Discovering / Tutoring
July 2007
CNIC (Spain) - Discovering / Tutoring
July 2008
Myocyte apoptosis at reperfusion can be
diminished by different therapies.
Swine infarct model
caspase-3+ / Troponin T+
cells in border zone 24h after
myocardial infarction
B Ibanez, V Fuster, R Hutter,
JJ Badimon. Circ 2007;115:2909
Focus on saving what is not
already dead at reperfusion
(but at risk of).
CMRI - Neovessels In Atherosclerotic Plaques Of
Hypercholesterolemic Rabbits
Peptidomimetic Micelles Targeted to Alphavbeta3-Integrins
Hyafil, F et. al J Cardiov. Magn Reson 2007;9:278
Winter, PM, et al. . Circulation. 2003;108:2270-4.- Mice
1) Complex Coronary Artery Disease
Evidence Base Management
TRIAL
SYNTAX
BARI
MVD DM INTERV. HP.Rev Rx
+
-
-
+
++
+
++
-
+- +
Data
HP-Rev <CABG – HP =
¾Sx Sc. (Reg)<CABG
DM – Int.SxSc. CABG ?
HP = INTERV. vs RX
<CABG, SxSc
Revasc . Rx 42%
Largest DB DM
HP-Int. SxSc?
Rx Approach?
FREEDOM
Cost, QoL ?
D Capodanno et. al. AHJ. 2010;159:103 (Catania, Italy.) - EuroSCORE Refines
+
+
++
+- +-
1) Coronary Function Versus Anatomy with
Diffuse CAD and Remodeling
K Lance Gould JACC: Cardiov.Imaging 2009;2:1009.
1)2Coronary
Function
(Flow) vs Stenosis (Anatomy)
Year Survival Free
of Death/MI
Clinical Outcomes (Death + MI or MI)
FFR-Guided
Angio-Guided
730 days
4.3%
“Functionally Complete Revascularization”
Intervention of Significant Ischemic lesions and
Medical Treatment of Non-Ischemic Ones
FAME 2 - TCT 2009 – San Francisco
1)Coronary Function and Anatomic Stenosis Severity
Lance Gould JACC: Cardiov.Img 2009;2:1009
TF Christian et al., JACC Img 2009; 2:1103: MR (3.0T)- MBF (Pig)
2) Post Stroke or TIA
Carotid Plaque Stabilization & Progression
Ulcerated plaque
from a patient
with stroke
65-75%
Fibrin admixed
with fewCD68+
macrophages
Plaque rupture
with small
luminal
thrombus
Progression?
Disrupted fibrous
cap infiltrated by
CD68+macrophages
et.al. Arterioscler Thromb Vasc Biol. 2009;1:3
W. Peeters, G Pasterkamp et. al. . ATVB. 2009;29:128.
R Virmani
Year,
CI)
2) META-ANALYSIS COMPARING SAFETY
STENTING WITH ENDARTERECTOMY
IN THE RECENT CAROTID STENTING TRIALS
Carotid
Carotid
Stenting
Endarterectomy OR (95%
Events
No. of
Events
patients
EVA-35 2008
26
265
No. of
patients
11
262
2.48
SPACE 2008
42
573
32
563
1.31
ICSS
61
878
33
821
190
Total
2010
129
1666
76
1646
0.01
100
0.1
1.73
Stenting
1
10
Favors Endart.
International Carotid Stenting Study Investigators. Lancet 2010; Feb 26
WM Clark-AHA Stroke - Febr 2010 US, Canada - n= 2502 - Fu 4y- Stroke, MI, Death
CS: >Stroke (Complex Anatomy), CE >MI (Comorbidities)
It is Never too Late for Well Being
Promotion of Physical & Mental Health
• T ime to Reflect
Calmer
(Stress)
Fulfilled
(Neurosis)
• T ransmit Positive
Freedom-Happy
(Hostage)
• T utoring the Young
Responsible
(Future)
•
T alent to Discover