Atherosclerosis

ATHEROSCLEROSISDr Subhasish DebDept of General MedicineBurdwan Medical College

ATHEROSCLEROSISA condition characterized by :

Hardening of arteries with loss of elasticity Characterized by intimal lesions called

atheroma that protrude into the vessel lumen

ARTERIOSCLEROSIS Hardening of arteries with loss of

elasticity 3 types:

1. Monckeberg medial calcific sclerosis2. Atherosclerosis3. Arteriolosclerosis

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

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

ARTERIOLOSCLEROSIS1. Hyaline arteriolosclerosis

Deposition of amorphous hyaline in media Seen in – senile changes, Essential HTN,

DM2. Hyperplastic arteriolosclerosis

Arterioles become narrow Media has concentric layers of smooth

muscle hypertrophy – onion skin Seen in Malignant hypertension

Hyaline arteriolosclerosis

Hyperplastic arteriolosclerosis

PATHOGENESIS OF ATHEROSCLEROSIS Hypothesis:

1. Intimal cellular proliferation2. Repetitive formation and organization of

thrombi3. Response - to – injury

A process of chronic inflammation in response to a chronic or acute injury

Key players:1. Modified lipoproteins2. Monocyte derived macrophage3. T lymphocytes4. Smooth muscles from media

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

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 flow1. Branch points2. Ostia of vessels3. Post wall of abd aorta

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

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 can now stick and release their products

3. LDL in intima gets oxidized and plays role in atheroma formation

Other risk factors causing endothelial injury:c) Smokingd) Toxins e) Microbes – CMV, chlamydia

Pneumoniaef) Homocystineg) Inflammatory cytokines

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

II. ACCUMULATION OF LIPOPROTEINS IN VESSEL WALL

Usually ldl It gets oxidized

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

They release cytokines that stimulates lymphocytes. These lymphocytes also produce chemical mediators that stimulate macrophages.

Macrophages release:1. IL 12. TNF 3. MCP 1 (monocyte chemotactic protein 1)

Lymphocytes release:1. Gamma IF

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

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

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

Fibrin cap is composed of: Smooth muscle cells Collagen, GAG Some lymphocytes Some macrophages

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)

RISK FACTORS FOR ATHEROSCLEROSIS Fixed risk factors:

1. Age2. Sex: M>>F (women protected until

menopause – estrogen)3. Genetics : htn, dm, hypercholesterlemia

have a genetic component

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 smoking4. DM5. Homocystinuria : some people develop

this due to folate & B6 def6. Chronic inflammation7. Obesity8. Type A personality

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

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

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

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

MOST COMMON SITES OF ATHEROSCLEROSIS

1. Abdominal aorta (infra renal)2. Coronary art3. Popliteal art4. Carotid art5. Circle of willis

(in this order)

COMPLICATIONS1. Fibrosis2. Calcification3. Erosions 4. Ulcerations 5. Rupture6. Platelet plug formation7. Thrombus formation8. Atheroembolism9. Intra plaque haemorrhage

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 2

1endothelium

Basement membrane

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