Mortality in Patients with Severe

Peripheral Arterial Disease (PAD)

Relative 5-Year Mortality

48
5 44
0
4 38
5
4
Patients (%)

0
3
5
3
0
2
5
2
15
0
1
5
1
05
0

Breast Colon/rectal Severe Non-Hodgkin’s

cancer1 cancer1 PAD2 lymphoma3

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.
 Risk of a Second Vascular Event
Increased risk vs general population (%)

Original event Myocardial infarction Stroke

Myocardial infarction 5–7 x greater risk1 3–4 x greater risk2

(includes death) (includes TIA)

Stroke 2–3 x greater risk2 9 x greater risk3

(includes angina and
sudden death*)
Peripheral arterial disease 4 x greater risk4 2–3 x greater risk3
(includes only fatal MI and (includes TIA)
other CHD death†)

*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; 89:1333–63. 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.
 Peripheral Arterial Disease (PAD) and
All-Cause Mortality
1.00

Normal Subjects
0.75
Survival

Asymptomatic LV-PAD†
0.50
Symptomatic LV-PAD†

0.25 Severe Symptomatic LV-PAD†

0.00
0 2 4 6 8 10 12
Year

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

†
Large-vessel PAD

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

Long-term Outcome of Peripheral Arterial
Disease (PAD)
Causes of death:
• 55% coronary artery disease
• 10% cerebrovascular disease
100 • 25% non-vascular
• < 10% other vascular
80

Survival
60
Patients

Myocardial
infarction
(%)

40
Intervention
20
Amputation

0
0 1 2 3 4 5 6 7 8 9 10
Time (years)

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

 ATS Epidemiology Europe
Incidence at 100 000 inhab/year

Infarct miocardic 35-64 ani > 75 ani

B / F B / F

•Tari Mediteranene 163 / 26 991 / 811

•Tari Nordice 290 / 86 1666 /1327

AVC ischemic
•Tari Mediteranene 145 / 51 1486/ 1264
•Tari Nordice 101 / 60 1317 /1401
Sursa : Circulation, 1998,98,1421
 Epidemiology of Atherothrombotic
Manifestations in the US
Incidence Prevalence

Myocardial 0.65 million*1 7.5 million1

infarction

Stroke 0.5 million*1 4.6 million1

Peripheral Variable depending 10.5 million†3

arterial on population 2
disease

*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: 1257–64. 3. Weitz JI et al. Circulation 1996; 94: 3026–49.
Coronary mortality
Years of life lived with disability attributable to ischemic heart disease
in 2010, in 21 Global Burden of Disease Study regions. YLD indicates
years lived with disability.
Andrew E. Moran. Circulation. The Global Burden of Ischemic Heart
Disease in 1990 and 2010, Volume: 129, Issue: 14, Pages:
1493-1501, DOI: (10.1161/CIRCULATIONAHA.113.004046) © 2014 American Heart Association, Inc.
Romania / EU
 Evolution ( 1972 – 2000 )

IHD

Descending trend after 1996

 Evolution ( 1972 – 2000 )

Stroke
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
Germany

Spain

Italy

UK
France

Netherlands

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

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

Myocardial Infarction, Ischemic Stroke,and
Event-Free PAD: Cost over 2 Years
35,000 *
30,000
Cost over 2 years from time of

Estimated cost for

25,000 angioplasty or surgery
presentation (US$)†

20,000
Follow-up and rehabilitation
treatment phase
15,000
Acute
10,000

5,000

0
M Stroke Event-free PAD
I

*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: 632–41.

 Economic Impact of Coronary Heart
Disease (CHD) and Stroke
Direct versus Indirect Costs (US$)

70

60

Direct costs:
50 • Hospital/nursing home
• Physicians/other professionals
Costs (billion

40 • Drugs
• Home health care
30
US$)

Indirect costs:
• Loss of productivity due to
20 morbidity or mortality

10

CH Stroke
D

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): 3–7. 3.
American Heart Association. 2002 Heart and Stroke Facts, Statistical Update.
 ATS –growing evidence
of a growing pandemia !

• More efficient national medical systems

• More performant diagnostic tools

• Increasing risk factors in some areas

• Globally aging population

Huge economic burden of MI, chronic IHD , stroke and PAD

 Arterial wall:
structure and function
 Intima
A. Basal membrane
C. ( with aging ) : SMC , colagen I si III
B. Endotelial cell

Embriogenesis
• Identic origin: angioblasti din “ blood islets “
• Different development in diff. areas

Anatomy
• Monostratified ( contact –inhibition )

Physiology
• Selective permeability
 Endotelial cell (1)
• Pro/antithrombotic balance

Heparan sulfat proteoglicans

(cofactor AT III )

Trombomoduline
( activator of S and C prot.)

Plasminogen activators
( tisular/urok. )

Factor von Willebrand

 Endotelial cell (2)
• Vasomotricitate
Endotelina 1 NO
TXA2 PGI 2
Factor activator plachetar (PAF) EDHF CO ADP-aza
 Media
Lamina elastica interna

Media
Smooth muscle cells
origin :
mesodermic somites ( lower half ) Arteria elastica
proepicardic organ (coronary )
neuroectoderm ( upper half )
Contractil phenotype

Matrix (> elastine )

Arteria muscularis
Lamina elastica externa
 Adventix

•Collagen fibers

•Vasa vasorum

•Nerve terminations

•Rare cells ;
Fibroblasts
Mastocites
 Pathology

AD Thrombosis

AD : 2 years old child.

Braunwald, 1997
Ultrasonography (1)
Vascular wall

A. Carotids
Intima-media thickness (IMT)

B. Thoracic & abdom. aorta

ATS plaques/ thrombosis
aneurisms

C. Heart and coronaries

TTE : calcifications
aortic/mitral annulus
TEE : LM stenosis/calcif
Ultrasonography ( 2 )
 Ultrasonography ( 3 )
COMPARISON OF NORMAL (A) VS.
ATHEROSCLEROTIC CORONARY MORPHOLOGY (B).

IVUS

TOPOL E, 2002
 Ultrasonography (4)
IVUS advantages
MOLECULAR IVUS OF ATHEROMA
COMPONENTS
Echogenic immunoliposome (ELIP)

Source: JACC 2004 ; 453-60

 Angiography
• Invasive
CS • Irradiating
• Anatomy ,
not function !

CD
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
( large and middle sized arteries )

intra and extracellular lipid accumulation ,

SMS proliferation ,

conjunctive tissue si calcium deposition

and secondary thrombosis in final fase

 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 Mecanic
Toxic (HTA)
(nicotina)
Endocrine ENDOTELIU Genetic
(diabet) homocisterina
Creste influxul de LDL
Combinare
Initierea inflamatiei 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)
Main factors of vulnerable plaque
1. Proportion and consistency of lipidic core

2. Thickness and stability of the fibrous cap

3. Evolution of inflammation si de repair

- Decreased synthesis of collagen

- Incresased catabolism of extracellular matrix

-Reduced number of SMC- increased apoptosis

- Accumulation of macrophages

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
NFκB 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
Reducing the risk of thrombosis
Extrinsic vulnerability factors
HTN , hemodynamic factor and atheroclerosis
Plaque rupture : main releasing factors
 Progresia leziunilor

A=adeventicia
C= calcification
MP = miofibroblastic proliferation
FC = fibrous cap
F = fissure