Basic - From Atheroma to Prevent Aging (3) Clinical – From...

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 ResearchPopulation Research

Workshop, European Commission, Brussels, Oct 2008Cardiovasc Res 2009; 83: 425





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

TFMMPsCAMs

LDL

ET

Extracellular MatrixFibroblastsVasa Vasorum

SMC contractionmigration

proliferation

PDGF

Moreno P, Sanz J, Fuster V, J Am Coll Cardiol 2009;53:2315

Ph.1 PGC

HIGH RISK PLAQUE - < ACTIVE INFL.

Ph.2VASA V.

Ph.3HDL

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

RT Calado et. al. N Engl J Med. 2009;361:2353.S. Anderson et.al. J Am Soc Nephrol 2009;20:1199M Mimeault et.al. Ageing Res Rev. 2009;8:94-

Age Related Disorders, Cancer, Exercise

Senescence-Associated Changes

TFMMPsCAMs

LDL

ET



proliferation

PDGF


Ph.1 PGC

HIGH RISK PLAQUE - > ACTIVE INFL.

Ph.2VAS. V.

Ph.3HDL

2) Adventitial Neovascularization in Plaque Regression ?

Doyle B. et. al. J Am Coll Cardiol. 2007;49:2073.

Antiangiogenic Therapy?, NO ?

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

Post-contrast

T1W

FC

Pre-contrast

LC

LC = lipid rich/necrotic coreFC = Fibrous capKerwin et al. MRM 59; 507, 2008

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).

CTAngiogram

FusedPET and CTA

Images

Plaque

Stent

LV

LV

RCA

RCA

Plaque

Stent

Coronary FDG

Uptake

JH Rudd, V Fuster, ZA Fayad et al. JACC 2010

(In Press) –

PET, Ao-Ca-Cor

HR Underhill, V Fuster, ZA Fayad et.al. Nat Rev. Card. 2010

(In Press) -

MRIK Hayashi, V Fuster, Za Fayad et al. J Card.Magn.Res. 2010 (In Press) –Ao.CaJH 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 FUECM

CALCIUM

Neovascularization of the Intima Contributes to Progression ? Hypoxic Component with Monocyte HIF-1 Inhibitors? YES ?

TFMMPsCAMs

LDL

ET



proliferation

PDGF


THROMBUS

Ph.1 PGC

HIGH RISK PLAQUE - APOPTOSIS

Ph.2 VAS. V.

Ph.3 HDL

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 Rabbits1) Badimon JJ, Badimon L, Fuster V, JCI 1990; 85:1234 . HDL Rabbits2) Nissen SE JAMA 2003; 290:2292 – Apo A1 M in Humans - IVUS

MDCT• Coronary Ca+• Plaque composition• Coronaries

• Non coronaries• Plaque CompositionMRI FDG-PET/CT

CTFDG-PET Fused PET/CT• Metabolic activity

• Coronaries?

3D US•Carotids

•AAA

Imaging Atherosclerotic Burden –

HRP (n=7000), FU 3y

ABIPVD

PI: Valentin Fuster, Co-PI: Erling Falk, Peter Muntendam - AHJ 2010 (In Press)

B Ibanez, S Prat, WS Spedl, V Fuster, J Sanz, JJ Badimon Circ 2007;115:2909

Phase 1 MI Decreased Myocyte Apoptosis Metoprolol Administration (Pig)–CNIC 4,5 (Humans)

T2W T1 T2W / T1

Phase 2 MI Microvasculature / Fibrosis / Hypertrophy Peptidomimetic Micelles to Alphavbeta3-Integrins

JW Verjans, J Narula, L Hofstra, et al., Circ 2007; 116:II-740Hyafil, F et. al J Cardiov. Magn Reson 2007;9:278 - Rabbits

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

Phase 3 MI

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.





2

HEARTMI 1) Emboli

2)Thrombi

3)Hemorrh

1) BRAIN - STROKE

Thrombi

CARDIOVASCULAR DISEASE

Subclinical Atherosclerosis: 2010–2020 - Clinical

2) ADVANCED AGE, HYPERTENSION AND DEMENTIASBP AND SHORT PORTABLE MMSE SCORE BY INCREASING

AGE GROUPS148

146

144

142

140

138

136

134

13

12

11

10

9

8

7

6

SHP-

MM

SE

Mea

n sy

stol

ic b

lood

pre

ssur

e (m

mH

g)

60-64 65-69 75-7970-74 80-84 >84Age Group (yrs)

Mean systolicBlood pressure(mmHg)Short portableMMSE

TO Obisecon. Clin Geriatr Med 2009; 25:259 (NIH)

2) BLOOD PRESSURE,RISK DEMENTIA –

LOGITUDINAL STUDIES

Late-Life Hypertension Late-Life Hypertension HypotensionUeda et al. (1992) Qiu et al. (2003a) Ruitenberg et al. (2001)Kuusisto et al. (1997) Skoog et al. (1996) Morris et al. (2001)Cuo et al. (1996) Li et al. (2007) Verghese et al. (2003)Pettiti et al. (2002) Yoshitake et al. (1995) Nilsson et al. (2007)Morris et al. (2000) Brayne et al. (1998)Kokmen et al. (1991) Tyas et al. (2001)Rockwuud et al. (1996) Posner et al. (2002)

Lindsay et al. (2002)Mid-Life Hypertension Kuller et al. (2003)Launer et al. (2000) Borenstein et al. (2005)Kivipelto et al. (2001b) Petitti et al. (2005)Wu et al. (2003)Yamada et al. (2003)Whitmer et al. (2005)

SP Kennelly, BA Lawlor, RA Kenny. Ageing Research Reviews 2009; 8:61TO 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 mid- century. 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 GenotypeHypertensionHypotensionCholesterolDiabetes MellitusSmoking

Mount Sinai Journal of Medicine 2010; 77:82-102

1.00

0.98

0.96

0.94

0.920 6 12 18 24 30 36 42 48

1.00

0.98

0.99

Surv

ival

pro

babi

lity

Surv

ival

pro

babi

lity

Angiotensin recept. blockersLisinoprilCardiovascular comparator

0 6 12 18 24 30 36 42 48

Follow-up (months)

Alzheimer’s disease Dementia

3) SURVIVAL FOR INCIDENT ALZHEIMER’S DISEASE AND INCIDENT DEMENTIA IN STUDY COHORS (N=819491 MALES ≥

65 Y –

US VA)

N-C Li et al., BMJ 2010; 340:b5465 – Nursing Home Admision





1) 10 vs 30-Ys RISK OF HARD CVD FOR 45-Y.-OLD (5 RF)

Framingham (MJ Pencina et al.) Circ 2009; 119:3078

0.90.80.70.60.50.40.30.20.1

0

10-y risk 30-y riskMen

Est

imat

ed %

risk

of h

ard

CV

D

Abn Lipids‒ + + + +Hypert. ‒ ‒ + + +Smoking ‒ ‒ ‒ + +Diabetes ‒ ‒ ‒ ‒ +

0.8

0.70.60.50.40.30.20.1

0

10-y risk 30-y riskWomen

Est

imat

ed %

risk

of h

ard

CV

D

Abn Lipids‒ + + + +Hypert. ‒ ‒ + + +Smoking ‒ ‒ ‒ + +Diabetes ‒ ‒ ‒ ‒ +

2b. CNIC2b. CNIC--SANTANDER SANTANDER 2a. HRP > 55y,n=7000 HRP > 55y,n=7000 4040--55y, n= 5000, FU 6y FU 3y55y, n= 5000, FU 6y FU 3y

“Omics –

Copenhagen Heart Study, Framingham, Duke

First Mobile 3T at Work2a) Imaging Atherosclerotic Burden – HRP (n=7000)


MDCT• Coronary Ca+• Plaque composition• Coronaries

• Non coronaries• Plaque CompositionMRI FDG-PET/CT

CTFDG-PET Fused PET/CT• Metabolic activity

• Coronaries?

3D US•Carotids

•AAA

Imaging Atherosclerotic Burden –

HRP (n=7000), FU 3y

ABIPVD


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 aloneN Tahara et. al. J Am Coll Cardiol 2006;48:1825.J HF Rudd , ZA Fayad . Nat Clin Pract Cardiovasc Med. 2008;5:s11

HSillesen, V Fuster, E Falk, P Muntendam 2009Also Other Non-Cerebral Events

ISCHEMIC STROKE

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 scannerDecember 2010 – MSSM, MADRID

V Fuster, ZA Fayad 2010

3) COMMITTEE ON PREVENTING THE GLOBAL EPIDEMIC OF CARDIOVASCULAR DISEASE

VALENTÍN FUSTER (Chair), Mount Sinai HeartARUN CHOCKALINGAM Simon Fraser UniversityCIRO A. DE QUADROS, Albert B. Sabin Vaccine InstituteJOHN W. FARQUHAR, Stanford University School of MedicineROBERT C. HORNIK, University of PennsylvaniaFRANK B. HU, Harvard School of Public HealthPETER R. LAMPTEY, Family Health International, GhanaJEAN CLAUDE MBANYA, University of YaoundéANNE MILLS, London School of Hygiene &Tropical MedicineJAGAT NARULA, University of California, Irvine School of MedicineJOHN W. PEABODY, University of California, San FranciscoK. SRINATH REDDY, Public Health Foundation of IndiaSYLVIE STACHENKO University of AlbertaDEREK YACH, Vice-President PepsiCo

KNOWLEDGE EPIDEMIOLOGY ECONOMICS. KNOWLEDGE EPIDEMIOLOGY ECONOMICS.

RESPONSABILITY INTERSECTORIAL COMMUNITYRESPONSABILITY INTERSECTORIAL COMMUNITY

INCENTIVE YOUTH NEVER TOOINCENTIVE YOUTH NEVER TOO LATE LATE

3a) US-NHLBI–IOM: Global CVD Prevention (Chair) Promoting CV Health 2010 – 2020 (Education)

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 ($)

V Fuster et. al. Nat Rev. Cardiol. 2009;6:669.

Rx, H-I $368 Bill, X3 10y Rx, L-I MI, Pocket 80% Rx, H-I $ 95% - Prev $ 5%



INCENTIVE YOUTH NEVER TOOINCENTIVE YOUTH NEVER TOO LATE LATE

3b) US-NHLBI–IOM: Global CVD Prevention (Chair) Promoting CV Health 2010 – 2020 (Education)

Washington DC, 2010

LMH) Global Demonstration Projects

1) Children (31) Children (3--8yrs) 8yrs) –– Sesame Street ColombiaSesame Street Colombia

2) Adults Cultural Groups 2) Adults Cultural Groups –– Grenada Heart Project Grenada Heart Project

3) Adults Regulations & Law 3) Adults Regulations & Law –– NY Tobacco, Food, BPNY Tobacco, Food, BP

4) The Millenium Project 4) The Millenium Project –– InfrastructureInfrastructure

5) The Polypill 5) The Polypill –– Adherence & EconomyAdherence & Economy



INCENTIVE YOUTH INCENTIVE YOUTH NEVER TOO LATE NEVER TOO LATE

3c) US-NHLBI–IOM: Global CVD Prevention (Chair) Promoting CV Health 2010 – 2020 (Education)

Washington DC, 2010

July 2009

CNIC (Spain) - Discovering / Tutoring

It is Never too Late for Well Being

Promotion of Physical

& Mental Health20 30 40 50+AGE

Tobacco, Exercise,

Blood Pressure, BMI - Diet

Lipid Profile

Blood Glucose test

Clinical Breast Exam (CBE)and Mammography

Pap test

Colorectal Screening

Prostate specific antigentest and/digital rectal exam

Each regular health care visit

Each regular health care visit (or at leastonce every 2 years if BP < 120/80 mm Hg)

Every 5 years

Every 3 years

CBE q 3 yrs Yearly CBE andMammography

Yearly Every 1-3 years; depends ontype of test and past results.

Frequency dependson test preferredOffer yearly, assistinformed decisions

ACS/ADA/AHA - Circ 2004; 109:3244





It is Never too Late for Well Being

Promotion of Physical

& Mental Health20 30 40 50+AGE

Tobacco, Exercise,

Blood Pressure, BMI - Diet

Lipid Profile

Blood Glucose test

Clinical Breast Exam (CBE)and Mammography

Pap test

Colorectal Screening

Prostate specific antigentest and/digital rectal exam

Each regular health care visit

Each regular health care visit (or at leastonce every 2 years if BP < 120/80 mm Hg)

Every 5 years

Every 3 years

CBE q 3 yrs Yearly CBE andMammography

Yearly Every 1-3 years; depends ontype of test and past results.

Frequency dependson test preferredOffer yearly, assistinformed decisions

ACS/ADA/AHA - Circ 2004; 109:3244

July 2007


July 2008


Swine infarct model caspase-3+ / Troponin T+

cells in border zone 24h after myocardial infarction

Myocyte apoptosis at reperfusion can be diminished by different therapies.

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).

Hyafil, F et. al J Cardiov. Magn Reson 2007;9:278 Winter, PM, et al. . Circulation. 2003;108:2270-4.- Mice

CMRI -

Neovessels

In Atherosclerotic Plaques OfHypercholesterolemic Rabbits

Peptidomimetic Micelles Targeted to Alphavbeta3-Integrins

TRIAL MVD DM INTERV. HP.Rev Rx TRIAL MVD DM INTERV. HP.Rev Rx

SYNTAX SYNTAX ++

--

++ ++ ++ ++ --

BARI BARI --

+ + ++ + +--

++

FREEDOM FREEDOM + + ++ ++ + ++ +--

++--

1) Complex Coronary Artery Disease

Evidence Base Management

Data

HP-Rev <CABG –

HP = Sx Sc. (Reg)<CABG

DM –

Int.SxSc. CABG ?

HP = INTERV. vs RX<CABG, SxSc

Revasc . Rx 42%

Largest DB DMHP-Int. SxSc?Rx Approach?Cost, QoL ?

D Capodanno et. al. AHJ. 2010;159:103 (Catania, Italy.) -

EuroSCORE Refines

K Lance Gould JACC: Cardiov.Imaging 2009;2:1009.

1) Coronary Function Versus Anatomy withDiffuse CAD and Remodeling

2 Year Survival Free of Death/MI

FFRFFR--GuidedGuided

AngioAngio--GuidedGuided730 days730 days

4.3%4.3%

1) Coronary Function (Flow) vs Stenosis (Anatomy)Clinical Outcomes (Death + MI or MI)

FAME 2 -

TCT

2009 –

San Francisco

““Functionally Complete RevascularizationFunctionally Complete Revascularization””Intervention of Significant Ischemic lesions and Intervention of Significant Ischemic lesions and

Medical Treatment of NonMedical Treatment of Non--Ischemic OnesIschemic Ones

Lance Gould JACC: Cardiov.Img 2009;2:1009TF Christian et al., JACC Img

2009; 2:1103: MR (3.0T)- MBF (Pig)

1)Coronary Function and Anatomic Stenosis Severity

Ulcerated plaque from a patient with stroke65-75%

Plaque rupture with small luminal thrombusProgression?

Fibrin admixed with fewCD68+ macrophages

Disrupted fibrouscap infiltrated by CD68+macrophages

2) Post Stroke or TIA Carotid Plaque Stabilization & Progression

R Virmani et.al. Arterioscler Thromb Vasc Biol. 2009;1:3W. Peeters, G Pasterkamp et. al. . ATVB. 2009;29:128.

2)

META-ANALYSIS COMPARING SAFETY STENTING WITH ENDARTERECTOMY

IN THE RECENT CAROTID STENTING TRIALSCarotid Carotid

Year, Stenting Endarterectomy OR (95% CI)

Events No. of Events No. ofpatients patients

EVA-35 2008 26 265 11 262 2.48SPACE 2008 42 573 32 563 1.31

ICSS 2010 61 878 33 821 190

Total 129 1666 76 1646 1.730.01 0.1 1

10

100

Stenting Favors Endart.

International Carotid Stenting Study Investigators. Lancet 2010; Feb 26WM 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)

• T alent to Discover Fulfilled (Neurosis)

• T ransmit Positive Freedom-Happy (Hostage)

• T utoring the Young Responsible (Future)

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Basic - From Atheroma to Prevent Aging (3) Clinical – From...

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