Mortality in Patients with Severe Peripheral Arterial Disease (PAD)

Relative 5-Year Mortality

48
50 45 40 35 30 25 20 15 10 5 0

44

38

Patients (%)

15

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
(includes death)

34 x greater risk2
(includes TIA)

Stroke

23 x greater risk2
(includes angina and sudden death*)

9 x greater risk3

Peripheral arterial disease

4 x greater risk4
(includes only fatal MI and other CHD death)

23 x greater risk3
(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
0.75 Survival Asymptomatic LV-PAD Symptomatic LV-PAD 0.25 0.00 0 2 4 6 Year 8 10 12 Severe Symptomatic LV-PAD

0.50

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

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

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 AVC ischemic

35-64 ani
B / F

> 75 ani
B / F

163 / 26
290 / 86

991 / 811
1666 /1327

Tari Mediteranene Tari Nordice

145 / 51 101 / 60

1486/ 1264 1317 /1401

Sursa : Circulation, 1998,98,1421

Epidemiology of Atherothrombotic Manifestations in the US

Incidence Myocardial infarction Stroke 0.65 million*1 0.5 million*1 Prevalence 7.5 million1 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)

Myocardial infarction (Q-wave and non-Q-wave) 750,000 admissions

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

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
Survival
Patients (%)
60

100

80

40

Myocardial infarction Intervention

20

Amputation
0 0 1 2 3 4 5 6 7 8 9 10

Time (years)

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

Increasing Worldwide* Prevalence of Atherothrombotic Manifestations

Prevalence* 2000 2005

Populations aged > 50 year old Myocardial infarction

205.0 million (5.1% since 1997) 9.1 million (12.8% since 1997) 7.1 million (11.8% since 1997)

222.2 million (13.9% since 1997) 10.7 million (32.7% since 1997) 8.4 million (31.6% since 1997)

Ischemic stroke

*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

10,000
Cost per patient (Euros)

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

35,000 30,000 25,000 20,000

*
Estimated cost for angioplasty or surgery Follow-up and rehabilitation treatment phase Acute

Cost over 2 years from time of presentation (US$)

15,000
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

60

Costs (billion US$)

50

40

Direct costs: Hospital/nursing home Physicians/other professionals Drugs Home health care Indirect costs: Loss of productivity due to morbidity or mortality

30

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 )

Artere musculare

Lamina elastica externa

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
Invaziva Iradianta Anatomie , nu functie !

CD

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
A. Leukocyte Adhesion Mol.
--Immunoglobulins: VCAM -1 ICAM -1 --Selectins (P, E ) ( Monocytes , T lymphocytes )

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

Toxic (nicotina) Endocrine (diabet)

Dislipidemie

Mecanic (HTA)

ENDOTELIU
Creste influxul de LDL

Genetic homocisterina
Combinare de factori

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 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