2. ATHEROSCLEROSIS
A condition characterized by :
Hardening of arteries with loss of elasticity
Characterized by intimal lesions called
atheroma that protrude into the vessel lumen
3. ARTERIOSCLEROSIS
Hardening of arteries with loss of elasticity
3 types:
1. Monckeberg medial calcific sclerosis
2. Atherosclerosis
3. Arteriolosclerosis
4. MONCKEBERG MEDIAL CALCIFIC SCLEROSIS
Most benign
Medium sized arteries – radial, ulnar
Calcification in MEDIA, usually age related,
60-70yrs
Calcification does not encroach into intima,
hence no dangerous complications
Usually involves U/L arteries
5.
6. ATHEROSCLEROSIS
No 1 killer in western world
Disease of INTIMA
Formation of fibro fatty plaques
Involves:
Elastic arteries - aorta, carotid, iliac
Medium sized muscular arteries – coronary,
popliteal, circle of willis
In smaller vessles they cause occlusion and
in larger ones medial weakening -
aneurysms
7.
8. ARTERIOLOSCLEROSIS
1. Hyaline arteriolosclerosis
Deposition of amorphous hyaline in media
Seen in – senile changes, Essential HTN, DM
2. Hyperplastic arteriolosclerosis
Arterioles become narrow
Media has concentric layers of smooth muscle
hypertrophy – onion skin
Seen in Malignant hypertension
11. PATHOGENESIS OF ATHEROSCLEROSIS
Hypothesis:
1. Intimal cellular proliferation
2. Repetitive formation and organization of
thrombi
3. Response - to – injury
A process of chronic inflammation in response
to a chronic or acute injury
Key players:
1. Modified lipoproteins
2. Monocyte derived macrophage
3. T lymphocytes
4. Smooth muscles from media
12. Atherogenesis: developmental process of
atheromatous plaque
Characterized by remodeling of arteries
leading to sub endothelial accumulation of
fatty substances called plaques
A slow process, developed over many years,
1st lesion being fatty dots
13. I. ENDOTHELIAL INJURY
It leads to:
Increased vascular permeability
Leukocyte adhesion
Thrombus formation
What causes injury??
a) Haemodynamic stress: plaques tend to occur
in areas of disturbed blood flow
1. Branch points
2. Ostia of vessels
3. Post wall of abd aorta
14. Laminar flow of blood is protective.
It suppresses expression of leukocyte adhesion
molecules
Augments production of NO by endothelial cells
which not only cause vasodilatation but also acts
as local anti-inflmmatory autacoid - limiting
adhesion molecule expression
Laminar flow stimulates production of
superoxide dismutase from endothelial cells –
anti oxidant
15.
16. b) Lipid Abnormalities
Inc LDL
Inc lipoprotein a
Dec HDL
How these lipid abnormalities are bad?
Inc LDL means more cholesterol goes to
peripheries
They damage endothelial cells
1. Make them more permeable – more lips go
inside
2. NO released from endothelial cells do not allow
platelets to stick. But excess lipids – formation
of free radicals which neutralize NO – platelets
17. 3. LDL in intima gets oxidized and plays role in
atheroma formation
Other risk factors causing endothelial injury:
c) Smoking
d) Toxins
e) Microbes – CMV, chlamydia Pneumoniae
f) Homocystine
g) Inflammatory cytokines
18. INITIATION OF LESION:
Initial lesions are fatty dots and streaks
Accumulation of lipoprotein particles may not
result form increased permeability or
‘leakiness’
Lipoprotein may accumulate as they bind to
some GAG in the extracellular matrix
19. II. ACCUMULATION OF LIPOPROTEINS IN VESSEL
WALL
Usually ldl
It gets oxidized
20. III. MONOCYTE ADHESION TO ENDOTHELIUM
Healthy endothelium does not express
adhesion molecules for WBC
VCAM-1 (vascular endothelial cell adhesion
molecule expressed in response to injury
Monocytes convert to macrophages and bind
to these VCAM-1 and enter the sub
endothelial space
21. They release cytokines that stimulates
lymphocytes. These lymphocytes also
produce chemical mediators that stimulate
macrophages.
Macrophages release:
1. IL 1
2. TNF
3. MCP 1 (monocyte chemotactic protein 1)
Lymphocytes release:
1. Gamma IF
22.
23. IV. SMOOTH MUSCLE CELL PROLIFERATION
AND EXTRA CELLULAR MATRIX
PRODUCTION
The next major player coming rushing to the
site is Smooth Muscle cells from the MEDIA
Due to the environment with theses
chemicals, the SMCs change their behavior.
Their contractile protein dissolves and they
behave primitively – only proliferation.
SMC also release ECM and collagen
24. FOAM CELLS
Derived from macrophages and smooth
muscle cells that have taken up a lot of
cholesterol
Macrophages release ros that oxidises LDL
Oxidized LDL is more delicious so taken up
more my macrophages and SMC – foam
cells
25.
26. Some of the foam cells overladen with lipid
will burst and become necrotic. Their
contents leak out, so a lipid core is formed.
The SMCs which are multiplying are present
both above and below this lipid core
encircling it
SMCs near the endothelial surface multiply
more due the proximity to Growth Factors.
They secrete GAG and collagen
extracellularly –FIBRIN CAP
27. Fibrin cap is composed of:
Smooth muscle cells
Collagen, GAG
Some lymphocytes
Some macrophages
28.
29.
30.
31. Below the fibrous cap lies the core
Growth factors go to the shoulder of the
lesion and stimulate vasa vasorum. So new
vessels grow in from the sides. (play imp role
in plaque Hg)
32.
33. RISK FACTORS FOR ATHEROSCLEROSIS
Fixed risk factors:
1. Age
2. Sex: M>>F (women protected until menopause
– estrogen)
3. Genetics : htn, dm, hypercholesterlemia have a
genetic component
34. Modifiable risk factors:
1. Hyperlipidemia:
Omega 3 fatty acid in fish oil is good
Baked products with PUFA bad
2. Hypertension : responsible for both initiation
and progression
3. Tobacco smoking
4. DM
5. Homocystinuria : some people develop this due
to folate & B6 def
6. Chronic inflammation
7. Obesity
8. Type A personality
35. AMERICAN HEART ASSOCIATION
CLASSIFICATION OF ATHEROSCLEROSIS
1. Type 1/ initial lesion/ fatty dots:
1mm yellow dots
Starts appearing in early life, even at 1yr in
aorta
Almost all children have such lesion by 10yrs
Contain just few scattered macrophages
36.
37. 2. Type 2 lesions/ fatty streaks:
Linear kesons formed by fusion of dots
Upto 1cm
Develops at early age ~10yrs
They are precursors of mature plaques
But their location are not similar to location of
plaques (thus every fatty streak is not going to
grow into a plaque)
Consists of more macrophages, more foam
cells and some T cells
38.
39. 3. Type 3 lesion/ intermediate lesions:
Lipids are present not only in macrophages but
also extracellularly. Hence different from II.
4. Type 4/ atheromatous plaque:
Presence of core of lipid surrounded by foam
cells
5. Type 5/ fibroatheromatous lesion:
Neovascularization at shoulder
Fibrin cap
Central core of lipid + necrotic debri
40. 6. Type 6/ complicated lesions/ complicated
atheroma:
Surface defect in endothelium
Presence of platelet plug and fibrin on the
lumen side = thrombus
There may by Hg. Blood comes from ruptured
vessels in plaque. Intra plaque hg enlarges and
blocks lumen of vessel
Growth of lesions 1-4 manily depends on
acculumation of lipid in lesion
Growth of 5 due to accumulation of SMC and
collagen
Growth of 6 by blood or thrombus
41.
42. MOST COMMON SITES OF ATHEROSCLEROSIS
1. Abdominal aorta (infra renal)
2. Coronary art
3. Popliteal art
4. Carotid art
5. Circle of willis
(in this order)
44. 1. Erosion and ulcerations:
When endothelium is removed and underlying
basement membrane of intima exposed.
This BM is highly thrombogenic and will attract
platelets.
2. Fissuring and rupture:
Damage goes deeper and exposes the lipid. (ie
both endothelium and BM lost)
When very narrow called fissure, when wide =
rupture
21
endothelium
Basement membrane