Pathophysiology of atherosclerosis. Arteriosclerois, monkeberg medical calcific sclerosis, arteriolosclerosis

1. ATHEROSCLEROSIS
Dr Subhasish Deb
Dept of General Medicine
Burdwan Medical College

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

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

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

10. Hyaline arteriolosclerosis
Hyperplastic arteriolosclerosis

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

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

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

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

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)

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

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

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

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)

43. COMPLICATIONS
1. Fibrosis
2. Calcification
3. Erosions
4. Ulcerations
5. Rupture
6. Platelet plug formation
7. Thrombus formation
8. Atheroembolism
9. Intra plaque haemorrhage

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

45. THANK YOU