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Mortality in Patients with Severe

Peripheral Arterial Disease (PAD)


Relative 5-Year Mortality
48
44

Patients (%)

50
45
40

38

35
30
25
20
15
10

15

5
0

Breast
cancer1

Colon/rectal
cancer1

Severe
PAD2

Non-Hodgkins
lymphoma3

1. Criqui MH. Vasc Med 2001; 6(suppl 1): 37. 2. McKenna M et al.
Atherosclerosis 1991; 87: 11928. 3. Ries LAG et al. (eds). SEER Cancer
Statistics Review, 19731997. US: National Cancer Institute; 2000.

Risk of a Second Vascular Event


Increased risk vs general population (%)
Original event

Myocardial infarction

Stroke

Myocardial infarction

57 x greater risk1

34 x greater risk2

(includes death)

(includes TIA)

23 x greater risk2

9 x greater risk3

Stroke

(includes angina and


sudden death*)
Peripheral arterial disease

4 x greater risk4

23 x greater risk3

(includes only fatal MI and


other CHD death)

(includes TIA)

*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
1. Adult Treatment Panel II. Circulation 1994; 89:133363. 2. Kannel WB. J Cardiovasc Risk 1994; 1: 3339.
3. Wilterdink JI, Easton JD. Arch Neurol1992; 49: 85763. 4. Criqui MH et al. N Engl J Med 1992; 326: 3816.

Peripheral Arterial Disease (PAD) and


All-Cause Mortality
1.00
Normal Subjects

Survival

0.75
Asymptomatic LV-PAD

0.50

Symptomatic LV-PAD
0.25

Severe Symptomatic LV-PAD

0.00
0

Year

*Kaplan-Meier survival curves based on mortality from all-causes


Large-vessel PAD

1. Criqui MH. Vasc Med 2001; 6(suppl 1): 37.

10

12

Dimensiunea problemei ( EU )
peste 2 000 000 decese/an /EU : 48% din total

European cardiovascular disease statistics 2008

Epidemiologia Aterotrombozei in Europa


Incidenta la 100 000 locuitori pe an
Infarct miocardic

Tari Mediteranene
Tari Nordice

35-64 ani

> 75 ani

B / F

B / F

163 / 26

991 / 811

290 / 86

1666 /1327

145 / 51

1486/ 1264

101 / 60

1317 /1401

AVC ischemic
Tari Mediteranene
Tari Nordice

Sursa : Circulation, 1998,98,1421

Epidemiology of Atherothrombotic
Manifestations in the US
Incidence

Prevalence

Myocardial
infarction

0.65 million*1

7.5 million1

Stroke

0.5 million*1

4.6 million1

Peripheral
arterial
disease

Variable depending
on population 2

10.5 million3

*First attack only


PAD patients in North America (USA and Canada): symptomatic (37.5%) and asymptomatic (62.5%)
1. American Heart Association. 2002 Heart and Stroke Facts: Statistical Update.
2. Ouriel K et al. Lancet 2001; 358: 125764. 3. Weitz JI et al. Circulation 1996; 94: 302649.

Hospitalizations in the US
due to ACS
Acute coronary syndromes

1.5 million hospital admissions per year

Unstable angina (UA)

750,000 admissions
1. Cairns J et al. Can J Cardiol 1996; 12: 127992.

Myocardial infarction
(Q-wave and non-Q-wave)
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: 145763.

Long-term Outcome of Peripheral Arterial


Disease (PAD)
Causes of death:
55% coronary artery disease
10% cerebrovascular disease
25% non-vascular
< 10% other vascular

100

80

Patients (%)

Survival
60

Myocardial
infarction

40

Intervention
20

Amputation
0
0

Time (years)

1. Ouriel K. Lancet 2001; 358: 125764.

10

Increasing Worldwide* Prevalence of


Atherothrombotic Manifestations
Prevalence*

2000

2005

Populations aged
> 50 year old

205.0 million
(5.1% since 1997)

222.2 million
(13.9% since 1997)

Myocardial infarction

9.1 million
(12.8% since 1997)

10.7 million
(32.7% since 1997)

Ischemic stroke

7.1 million
(11.8% since 1997)

8.4 million
(31.6% since 1997)

*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.

Coronary mortality

Romania / EU
Peste media EU

Mai bine decat in


spatiul ex-sovietic

Evolutii in timp ( 1972 2000 )


BCI

Usoara tendinta la scadere


dupa 1996

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)
12,000

Cost per patient (Euros)

10,000
8,000
6,000
4,000
2,000
0

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


1. Brown RE et al. Eur Heart J 2002; 23: 508.

Myocardial Infarction, Ischemic Stroke,and


Event-Free PAD: Cost over 2 Years
*

Cost over 2 years from time of


presentation (US$)

35,000
30,000

Estimated cost for


angioplasty or surgery

25,000

Follow-up and rehabilitation


treatment phase

20,000
15,000

Acute

10,000
5,000
0

MI

Stroke

Event-free PAD

*Including concomitant medication.


Cost

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

1. Hunink MG et al. J Vasc Surg 1994; 19: 63241.

Economic Impact of Coronary Heart


Disease (CHD) and Stroke
Direct versus Indirect Costs (US$)
70

Costs (billion US$)

60

Direct costs:
Hospital/nursing home
Physicians/other professionals
Drugs
Home health care

50

40

30

Indirect costs:
Loss of productivity due to
morbidity or mortality

20

10

CHD

Stroke

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

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): 37. 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
TXA2
Factor activator plachetar (PAF)

NO
PGI 2
EDHF CO ADP-aza

Media
Lamina elastica interna

Media propriuzisa
Celule Musculare Netede
origine :
somite mezodermice ( 1/2 inf. )
organ proepicardic (coronare )
neuroectoderm ( 1/2 sup. )

Artere elastice

fenotip contractil/secretor
Matrice (> elastina )

Lamina elastica externa

Artere musculare

Adventicea
Fibre de colagen
Vasa vasorum
Terminatii nervoase
Rare celule ;
Fibroblasti
Mastocite

Anatomo-patologia
Tromboza DA

DA la un copil de 2 ani.

Braunwald, 1997

Ultrasonografie (1)
Ecografie vasculara
A. Carotidiana
raport intima medie
B. Ecografie aortica
placi ATS/ tromboze
anevrisme

Ecocardiografie
TT : calcificari
placi aortice
TE : TCS

Ultrasonografie ( 2 )

Ultrasonografie ( 3 )
COMPARISON OF NORMAL (A) VS.
ATHEROSCLEROTIC CORONARY MORPHOLOGY (B).

TOPOL E, 2002

MOLECULAR IVUS OF ATHEROMA


COMPONENTS
Echogenic immunoliposome (ELIP)

Source: JACC 2004 ; 453-60

Angiografie
CS

+ terapie interventionala

CD

Invaziva
Iradianta
Anatomie ,
nu functie !

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

LDL adhesion
Permeability
Vasoconstriction

Proteoglycan - binded LDL more prone to oxidation

Endothelial dysfunction ( 2 )
Leucocyte Recruitement

( Monocytes , T lymphocytes )

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

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

Proliferation
thrombin !
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


Dislipidemie
Toxic
(nicotina)
Endocrine
(diabet)

ENDOTELIU

Mecanic
(HTA)
Genetic
homocisterina

Creste influxul de LDL


Initierea inflamatiei

Combinare
de factori

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 apoptosis
determined 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

PHYSIOLOGY OF LIPIDS
AND LIPOPROTEINS
Atherogenicity

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