Mortality in Patients with Severe

Peripheral Arterial Disease (PAD)

Relative 5-Year Mortality

1. Criqui MH. Vasc Med 2001; 6(suppl 1): 3–7. 2. McKenna M et al.

Atherosclerosis 1991; 87: 119–28. 3. Ries LAG et al. (eds). SEER Cancer

Statistics Review, 1973–1997. US: National Cancer Institute; 2000.

Pa

tie

nts

(%

)

0

5

10

15

20

25

30

35

40

45

50

Colon/rectal

cancer1

Breast

cancer1

Severe

PAD2

Non-Hodgkin’s

lymphoma3

15

3844

48

1. Adult Treatment Panel II. Circulation 1994; 89:1333–63. 2. Kannel WB. J Cardiovasc Risk 1994; 1: 333–9.

3. Wilterdink JI, Easton JD. Arch Neurol1992; 49: 857–63. 4. Criqui MH et al. N Engl J Med 1992; 326: 381–6.

*Sudden death defined as death documented within 1 hour and attributed to coronary heart disease (CHD)†Includes only fatal MI and other CHD death; does not include non-fatal MI

Increased risk vs general population (%)

Original event Myocardial infarction Stroke

Myocardial infarction

Stroke

Peripheral arterial disease

5–7 x greater risk1

(includes death)3–4 x greater risk2

(includes TIA)

2–3 x greater risk2

(includes angina and

sudden death*)

9 x greater risk3

4 x greater risk4

(includes only fatal MI and

other CHD death†)

2–3 x greater risk3

(includes TIA)

Risk of a Second Vascular Event

Peripheral Arterial Disease (PAD) and

All-Cause Mortality

Normal Subjects

Asymptomatic LV-PAD†

Symptomatic LV-PAD†

Severe Symptomatic LV-PAD†

1.00

0.75

0.50

0.25

0.00

0 2 4 6 8 10 12

Su

rviv

al

Year

1. Criqui MH. Vasc Med 2001; 6(suppl 1): 3–7.

*Kaplan-Meier survival curves based on mortality from all-causes†Large-vessel PAD

Dimensiunea problemei ( EU )

European cardiovascular disease statistics 2008

peste 2 000 000 decese/an /EU : 48% din total

Epidemiologia Aterotrombozei in Europa

Incidenta la 100 000 locuitori pe an

•Tari Mediteranene

•Tari Nordice

35-64 ani > 75 ani

B / F B / F

Infarct miocardic

AVC ischemic

•Tari Mediteranene

•Tari Nordice

163 / 26

290 / 86

991 / 811

1666 /1327

145 / 51

101 / 60

1486/ 1264

1317 /1401

Sursa : Circulation, 1998,98,1421

Epidemiology of Atherothrombotic

Manifestations in the US

1. American Heart Association. 2002 Heart and Stroke Facts: Statistical Update.

2. Ouriel K et al. Lancet 2001; 358: 1257–64. 3. Weitz JI et al. Circulation 1996; 94: 3026–49.

Myocardial

infarction0.65 million*1

Incidence

7.5 million1

Prevalence

Stroke 0.5 million*1 4.6 million1

Peripheral

arterial

disease

10.5 million†3Variable depending

on population 2

*First attack only

†PAD patients in North America (USA and Canada): symptomatic (37.5%) and asymptomatic (62.5%)

Hospitalizations in the US

due to ACS

1. Cairns J et al. Can J Cardiol 1996; 12: 1279–92.

Acute coronary syndromes

1.5 million hospital admissions per year

Unstable angina (UA) Myocardial infarction

(Q-wave and non-Q-wave)

750,000 admissions 750,000 admissions

Epidemiology and Long-term Outcome

of Cerebrovascular Disease

• Incident cases/year (per 1 million inhabitants)

– 500 transient ischemic attacks

– 2,400 strokes (75%: first ever strokes)

• in 3 months: 480 (20%) deaths

• in 1 year: 700 (29%) deaths

600 (25%) dependent survivors

1,100 (46%) independent survivors

1. Hankey GJ, Warlow C. Lancet 1999; 354: 1457–63.

Long-term Outcome of Peripheral Arterial

Disease (PAD)

1. Ouriel K. Lancet 2001; 358: 1257–64.

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

Time (years)

Pa

tien

ts (

%)

Survival

Myocardial

infarction

Intervention

Amputation

Causes of death:

• 55% coronary artery disease

• 10% cerebrovascular disease

• 25% non-vascular

• < 10% other vascular

Increasing Worldwide* Prevalence of

Atherothrombotic Manifestations

*Projected populations of people aged over 50 years, and estimated prevalence of myocardial infarction

and ischemic stroke cumulated in 14 countries: Belgium, Canada, Denmark, Finland, France, Germany,

Italy, Netherlands, Norway, Spain, Sweden, Switzerland, UK, USA

1. Guillot F, Moulard O. Circulation 1998; 98(abstr suppl 1): 1421.

Populations aged

> 50 year old

205.0 million

(5.1% since 1997)

222.2 million

(13.9% since 1997)

Myocardial infarction

Ischemic stroke

Prevalence* 2000 2005

9.1 million

(12.8% since 1997)10.7 million

(32.7% since 1997)

7.1 million

(11.8% since 1997)

8.4 million

(31.6% since 1997)

Coronary mortality

Romania / EU

Peste media EU

Mai bine decat in

spatiul ex-sovietic

Evolutii in timp ( 1972 – 2000 )

Usoara tendinta la scadere

dupa 1996

BCI

Evolutii in timp ( 1972 – 2000 )

AVC

ATS – o pandemie in crestere!

• Cresterea factorilor de risc in unele zone

• Imbatranirea populatiei globale

• Accesul mai facil la serviciile medicale

• Ameliorarea metodelor diagnostice

Acute Coronary Syndrome: Average Cost in

Different European Countries (at 6 Months)

1. Brown RE et al. Eur Heart J 2002; 23: 50–8.

*Initial hospital stay accounts for > 80% of the costs

0

2,000

4,000

6,000

8,000

10,000

12,000

Cost

per

pat

ien

t (E

uro

s)

Myocardial Infarction, Ischemic Stroke,and

Event-Free PAD: Cost over 2 Years

1. Hunink MG et al. J Vasc Surg 1994; 19: 632–41.

0

5,000

10,000

15,000

20,000

25,000

30,000

35,000

MI Stroke Event-free PAD

Cost

over

2 y

ears

fro

m t

ime

of

pre

sen

tati

on

(U

S$)† angioplasty or surgery

Follow-up and rehabilitation

treatment phase

Acute

*

*Including concomitant medication.

†Cost estimates based on Medicare reimbursement rates (US, 1997) and reference 1.

Estimated cost for

Economic Impact of Coronary Heart

Disease (CHD) and Stroke

Direct versus Indirect Costs (US$)

1. American Heart Association. 2002 Heart and Stroke Facts, Statistical Update.

0

10

20

30

40

50

60

70

CHD Stroke

Cost

s (

bil

lion

US

$)

Indirect costs:

• Loss of productivity due to

morbidity or mortality

Direct costs:

• Hospital/nursing home

• Physicians/other professionals

• Drugs

• Home health care

Burden of Atherothrombosis

Summary

• Atherothrombosis is a prevalent and deadly disease

• Manifestations of atherothrombosis (including acute cardiovascular disease, ischemic heart disease and stroke) constitute the leading cause of death in developed countries, causing over half of all deaths annually in North America and Europe

• The economic burden of MI, stroke and PAD is considerable.

1. The World Health Report 2001. Geneva: WHO; 2001. 2. Criqui MH. Vasc Med 2001; 6(suppl 1): 3–7. 3.

American Heart Association. 2002 Heart and Stroke Facts, Statistical Update.

Arterial wall:

structure and function

Intima

A.Membrana bazala

C. ( cu varsta ) : CMN , colagen I si III

B.Celula endoteliala

Embriogeneza• Origine identica : angioblasti din “insulele sangvine “

• Dezvoltare diferentiata fct. de teritoriu

Anatomia • Monostrat ( inhibitie de contact )

Fiziologia• Permeabilitate selectiva

Celula endoteliala (1)

• Echilibru fluido-coagulant

Heparan sulfat proteoglicani

(cofactor AT III )

Trombomodulina

( activator prot. S si C )

Activatori ai plasminogenului

( tisular/urok. )

Factor von Willebrand

Celula endoteliala (2)

• Vasomotricitate

Endotelina 1 NO

TXA2 PGI 2

Factor activator plachetar (PAF) EDHF CO ADP-aza

Media

Artere elastice

Artere musculare

Lamina elastica interna

Media propriuzisa

Celule Musculare Netede

origine :

somite mezodermice ( 1/2 inf. )

organ proepicardic (coronare )

neuroectoderm ( 1/2 sup. )

fenotip contractil/secretor

Matrice (> elastina )

Lamina elastica externa

Adventicea

•Fibre de colagen

•Vasa vasorum

•Terminatii nervoase

•Rare celule ;Fibroblasti

Mastocite

Braunwald, 1997

DA la un copil de 2 ani.

Tromboza DA

Anatomo-patologia

Ultrasonografie (1)

Ecografie vascularaA. Carotidiana

raport intima –medie

B. Ecografie aortica

placi ATS/ tromboze

anevrisme

EcocardiografieTT : calcificari

placi aortice

TE : TCS

Ultrasonografie ( 2 )

TOPOL E, 2002

COMPARISON OF NORMAL (A) VS.

ATHEROSCLEROTIC CORONARY MORPHOLOGY (B).

Ultrasonografie ( 3 )

MOLECULAR IVUS OF ATHEROMA

COMPONENTS

Echogenic immunoliposome (ELIP)

Source: JACC 2004 ; 453-60

Angiografie

CS

CD

• Invaziva

• Iradianta

• Anatomie ,

nu functie !

+ terapie interventionala

Ultrasonografie (4)

US intravasculara ( IVUS )

Magnetic resonance images of the abdominal aorta

showing progression in the high cholesterol diet

group (upper panels) and regression in the normal

chol diet (lower panels).

ATS

Afectare a arterelor mari si mijlocii

cu acumulare intra si extracelulara de lipide ,

proliferare de celule musculare netede (CMN ) ,

depunere variabila de tesut conjunctiv si calciu

si tromboze secundare in faza finala

Endothelial dysfunction

Proteoglycan - binded LDL more prone to oxidation

LDL adhesion

Permeability

Vasoconstriction

Endothelial dysfunction ( 2 )

A. Leukocyte Adhesion Mol.--Immunoglobulins:

VCAM -1

ICAM -1

--Selectins (P, E )

B.Chemokines -- MCP-1 (ox.LDL> synthesis )

-- Interleukine-8

-- fraktalkine

-- IP-10, I-TAC , MIG

(lymphocyte selective )

C. Mitogens : Macrophage –Colony Stimulating Factor , GM-CSF ,IL-3

Leucocyte Recruitement ( Monocytes , T lymphocytes )

The activated macrophage

I. Production of :

• Inflammatory cytokines

IL-6, COX-2 ,TNF

• Metalloprotease

elastase,colagenase

• Coagulation factors

TF

II. Attempt to “solve the lipid disorder

Lipid core / Fatty steak

Foam cells Oxidized LDL internalized

by Scavenger receptors :

• A- family

• CD36

• Macrosialine

Normal LDL receptors not involved !

Extracellular lipids

SMC activation

Migration PDGF

Proliferationthrombin !

1% , but nonlinear !

Apoptosis

soluble and T cell cytokines ;involved in plaque disruption

Embryonic Phenotype Dominant embr. myosin isoform

< contractile fibres , >RER : > secretion of CF

Mecanismele initiale ale dezvoltarii placii

DislipidemieToxic

(nicotina)

ENDOTELIUEndocrine(diabet)

Mecanic(HTA)

Combinare de factori

Genetichomocisterina

Creste influxul de LDL

Initierea inflamatiei

Influx monocite

Raspuns inadecvat- Proliferare celule musculare- Depozite

Aterom

Tromboza

Different stages of atherosclerotic plaque

development

Fibrous cap stability :

Resistance mainly due to collagen fibers (CF) , IFN g

Fibrous cap instability :

1. Abnormal CF

-- impaired CF synthesis (SMC)

-- increased matrix destruction:

matrix metalloproteinases (macrophages)

elastolithic cathepsines

2. Increased intra/extraluminal pressure /stress

(lipids) (HT)

Plaque stability : normal fibrous cap

Thrombosis:

- Ruptured fibrous cap (2/3)

- Superficial erosion

WHERE will it crack :site

WHAT happens: Plaque disruption

(plaque cracking, fissuring , rupture –

thrombosis start point)

Placa vulnerabila

1. Marimea si consistenta miezului lipidic.

2. Grosimea/stabilitatea capsulei fibroase

3. Evolutia procesului inflamator si de reparatie

- Scaderea sintezei de colagen

- Cresterea catabolismului matricei extracelulare

-Reducerea numarului de celule musculare-apoptoza

- Acumulare de macrofage

E.A 2003

Characteristics of an unstable plaque

Plaque vulnerability factors

Intrinsic factors

Fibrous cap stability :

Resistance mainly due to collagen fibers

Matrix metabolism Low CF synthesis

Increased apoptosisdetermined by soluble/T-cell associated inflammatory mediators

Plaque vulnerability

Key role of macrophages

Key role of the macrophage in the

degradation of the fibrous cap

Parietal vascular inflammation

NFkB action in the inflammation process

Vulnerable plaque

Macrophage in vascular wall inflammation

Reducing the risk of plaque rupture

Thrombus formation

Macrophages release coagulation factors

Tissue factor:

the initiator of coagulation

Extrinsic vulnerability factors

HTN , hemodynamic factor and atheroclerosis

Plaque rupture : main releasing factors

Progresia leziunilor

A=adeventicia

C= calcifiere

MP = proliferarea miofibroblastica

FC =capsula fibroasa

F = fisura

Reducing the risk of thrombosis

Main risk factors for coronary heart disease

Diabet

• Atherogenicity

PHYSIOLOGY OF LIPIDS

AND LIPOPROTEINS

Digestion and metabolism of dietary fat

CHD risk according to LDL-C and TG

Atherogenicity of small dense LDL

Oxidized LDL and thrombogenesis

HDL - colesterol - structura

- - densa (1063 – 1210 )

- mici dimensiuni (6 - 10 m)

- origine tisulara mixta (intestin, ficat)

- componenta proteica mare (40-55%)

- aspect discoid initial

HDL:

an anti-atherogenic lipoprotein

Mecanismele protectiei

I. Transportul invers al colesterolului

Rolul - Apo AI (si AII?)

- guverneaza interactiunea cu alte LP si receptori

- Apo CIII - inhibitori LPL < degradarea VLDL

substrat PL scazut pentru HDL

- ( LPL - afinitate < pentru receptor)

- Proteina SR - B1 (si ABC1)

- receptor specific pentru preluarea C liber din intima

transport spre HDL in formare

HDL metabolism and reverse cholesterol

transport

HDL metabolism:

5 key genes

HDL:

apo AI-rich particles

Cholesterol efflux and reverse chol. transport is

modulated by two receptors

Apo A-I protects against atherosclerosis

Apo A-II protects against atherosclerosis

The human apo A-II transgenic mouse

Triglyceride-rich lipoproteins:

size, structure and composition

Diabet zaharat

Size and apolipoprotein composition are the main

factors determining atherogenicity of

triglyceride-rich particles

Size and apolipoprotein composition are the main

factors determining atherogenicity of

triglyceride-rich particles

Apo C-III modulates VLDL

Apo C-III in apo B particles is atherogenic

Relationship between apo C-III in apo B

containing lipoproteins and atherogenicity

PROCAM Study

MI-Incidence according to LDL-cholesterol and

triglycerides

Fibrinogen is an independent risk factor

for atherosclerosis