Atherosclerosis

Atherosclerosis

Normal arterial structure

Tunica intima Endothelial cells lying on basement membrane
Functions of endothelial cells:
• Contain blood
• Selective transport into tissue (fluids, gases, ions + proteins)
• Control of haemostasis
• Control of blood pressure
Endothelial cells in adults have long life span
• Average turnover time >5yrs
• Rarely divide (<1/10,000 dividing at any time)
• Resistant to apoptosis
However, they retain the latency to proliferate (angiogenesis) and remodel (this may
involve apoptosis)
Tunica media Layers of perforated elastic laminae with smooth muscle cells in between

Intimal side of the media is bound by the internal elastic lamina
Adventitial side is bound by the external elastic lamina
Tunica adventitia Consists of connective tissue
Contains fibroblasts, leucocytes (mainly macrophages) and nerves
Also contains lymphatic and blood vessels (vasa vasorum) supplying the artery wall

• Exact structure of arteries depends on size

Large arteries Classified as elastic arteries
Examples: Aorta, common carotid, common iliac
Prominent elastic laminae in the media (between internal and external laminae)
Exposed to high pressures
Elastic recoil assists their maintenance of continuous flow
Medium + small Muscular arteries
arteries Example: coronary arteries (medium sized)
Media = mainly smooth muscle cells (little elastic fibres)
Clear and separate internal and external elastic laminae are visible
Contraction of smooth muscle cells in media ⟶ regulation of blood pressure

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Definitions

Artherosclerosis Disease of intima of large and medium sized arteries
• Lesions = focal thickenings of intima (plaques)
o These are deposits of fibrous tissues and lipids
Arteriosclerosis Loss of elasticity and physical hardening of the arterial wall from any cause
• Often accompanied by calcification of the wall
• ≠ artheroscleosis

Epidemiology and risk factors in atherosclerosis

• Geographical variation:
o USA, UK > Asia, Africa + South America
• Positive risk factors (↑ risk)
o Four main risk factors:
1. Hyperlipidaemia (esp. ↑ cholesterol)
2. Cigarette smoking
3. Hypetension
4. Diabetes mellitus
o Additional risk factors:
5. ↑ age
6. Family history (polygenic inheritance, e.g. 5-lipoxygenase, CRP)
7. Male (oestrogens may protect pre-menopausal females)
8. High saturated fat diet
9. Stressful + sedentary life style
10. Obesity
11. Excess alcohol
12. Low birth weight
13. Low socioeconomic status
14. Infections (Chlamydia organisms)

• Negative risk factors (↓ risk)

1. High circulating high density lipoproteins
2. Moderate alcohol consumption (2 units/day)
3. Cardiovascular fitness

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Lipoproteins in atherosclerosis

• Lipoproteins
o Carry hydrophobic lipids in plasma
o Powerful risk modifiers for atherosclerosis
o Consist of:
§ Lipid core (triglycerides, cholesterol, cholesterol esters and phospholipids)
§ Surrounded by apolipoproteins
• Two receptor systems exist for lipoproteins to transfer lipids into cells:

LDL receptor • Most active in hepatocytes
pathway • Responsible for cholesterol breakdown
• Underactivity ⟶ hypercholesterolaemia
Scavenger • Used by macrophages to take up lipoproteins that have been modified
receptor pathway o Example of modification = oxidized with atherosclerotic plaques
• Leads to uncontrolled accumulation of cholesteron
o After this macrophages are known as foam cells (∵ appearance on
paraffin-embedded tissue sections)

• Dyslipoproteinaemia
o Abnormality in the constitution / concentration of lipoproteins in the blood
o May be:
§ Inherited (e.g. familial hypercholesterolaemia)
§ Secondary to other diseases (e.g. diabetes mellitus or hypothyroidism)
o Particular types of dyslipoproteinaemia ⟶ ↑ the risk of atherosclerosis
§ These include:
• ↑ cholesterol
- esp. important
- 10% ↓ in serum cholesterol ⟶ 15% ↓ in deaths from CHD
• ↑ total triglycerides
• ↑ low density lipoprotein
• ↑ lipoprotein a
• ↓ high density lipoprotein
o Studies using genetically-engineered mice have demonstrated the importance of
lipoproteins and cholesterol for atherosclerosis:

Lipoprotein Deficiency ⟶ development of advanced atherosclerotic lesions
component apoE
LDL receptor Deficiency ⟶ development of advanced atherosclerotic lesions
Scavenger receptor Deficiency ⟶ modest ↓ of atherosclerotic lesions
SR-A
Scavenger receptor Deficiency ⟶ modest ↓ of atherosclerotic lesions
CD36
Acyl-cholesterol Deficiency ⟶ cannot store cholesterol ⟶ ↓ atherosclerotic lesions
acyl transferase
(ACAT)

o Humans that have mutations ⟶ ↑ LDL or ↓ HDL ⟶ ↑ atherosclerosis

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Pathogenesis of atherosclerosis (atherogenesis)

• Progression of atherosclerosis involves several interacting processes in which most cellular
components of the vessel wall are disrupted
• This disruption ⟶ chronic inflammatory process
• Key changes in vessel walls are:
1. Endothelial cell injury/dysfunction
2. Monocyte migration into the plaque and maturation into macrophages
3. Smooth muscle cell activation
4. Lipoprotein infiltration
5. T-lymphocyte migration into the plaque
6. Platelet adherence

Endothelial cell Important initiator of atherosclerosis
injury/dysfunction Endothelial injury/dysfunction may be caused by:
• Haemodynamic forces
• Chemical insults
• Cytokines
This leads to:
• Altered permeability (∴ lipid infiltration)
• Adhesion of leucocytes (∵ enhanced expression of chemokines + adhesion molecules)
• Activation of thrombosis














Monocyte migration • Circulating monocytes are recruited by chemotactic factors
into the plaque and • They adhere to endothelial cells and enter the lesion where they mature
maturation into into macrophages
macrophages • Once in the lesion they phagocytose oxidised lipoproteins to become
foam cells

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Smooth muscle cell • Macrophages, platelets and endothelial cells produce:

activation o Growth factors (e.g. PDGF and FGF)
o Reactive oxygen intermediates
• These activate vascular smooth muscle cells
o Once activated - smooth muscle cells proliferate ⟶ migrate into
the intima ⟶ change from a contractile phenotype to a synthetic
phenotype (matrix-producing) ⟶ secrete extracellular matrix and
release enzymes that assist in matrix remodelling (such as
collagenase)
Lipoprotein • Lipoproteins (esp. LDL) become oxidised in plaques by reactive oxygen
infiltration intermediates and enzymes released by platelets, macrophages and
endothelial cells
• Oxidised lipoproteins:
o Chemoattractant for monocytes
o Phagocytosed by macrophages (which become foam cells)
o Stimulate release of cytokines + growth factors
- By various cells in plaque
o Induce dysfunction / apoptosis
- In smooth muscle, macrophages, endothelium
o Immunogenic
o Inhibit plasminogen activation
• Anti-oxidants (e.g. vitamin E and nitric oxide)
o Inhibit the formation of oxidised lipids and reduce the risk of
myocardial infarction
• cholesterol-lowering drugs (e.g. statins, which reduce liver synthesis of
cholesterol)
o ↓ frequency of coronary artery atherosclerosis
T-lymphocyte T-lymphocytes may recognise antigens such as oxidised lipoproteins, and
migration into the subsequently activate immune responses and cytotoxic killing of cells in the plaque
plaque
Platelet adherence In early lesions
• Evidence that platelets adhere transiently to the injured or dysfunctional
endothelial cells and release platelet-derived growth factor (PDGF), which
can activate smooth muscle cells.
In advanced lesions
• platelets are also involved in thrombosis that occurs if plaques ulcerate or
rupture

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Spectrum of intimal lesions

• Processes above result in a range of intimal lesions. Listed below in order of increasing severity:

Isolated Can be found in the intima soon after birth.
monocytes/macrophages
Fatty streaks (fatty dots) By the second decade of life
• These lesions can be found throughout the vascular tree but especially
at branch points
• Macroscopically
o Pale yellow streaks or dots
• Microscopically
o Clusters of lipid-laden smooth muscle cells and macrophages
(foam cells)
They cause no significant pathological effects themselves
Their relationship to subsequent atherosclerosis is controversial.
Fibro-fatty Seen mainly in:
atherosclerotic plaques • Abdominal aorta
• Coronary arteries
• Carotid arteries
• Circle of Willis
• Arterial branch points
Appear by the third or fourth decade in men and later in women
• Macroscopically
o Raised white-yellow plaques that may coalesce
• Microscopically
o Media may appear thinned (atrophic)
o In the intima there are three regions:
1. Fibrous cap
On the extreme intimal surface of the plaque
Composed of collagen, smooth muscle cells, macrophages
and T-lymphocytes
2. Lipid core
Contains foam cells, and in more advanced lesions
necrotic debris and extracellular lipid (in particular
cholesterol)
The shoulder of the cap
Contains foam cells, smooth muscle cells, T- lymphocytes
and new blood vessels (angiogenesis)
Complicated plaques Plaques may become calcified.
Plaques may expand due to haemorrhage from new vessels
Plaques may rupture / ulcerate, particularly if they are rich in leucocytes or
show haemorrhage
• May lead to thrombosis and embolisation of plaque fragments
Aneurysms may be formed as a consequence of thinning of the media and
fragmentation of the elastic laminae – seen particularly in the abdominal aorta.

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Consequences of atherosclerosis

• Atherosclerosis + sequelae ⟶ ~ 50% of all deaths in the Western world
• Under normal dietary conditions atherosclerosis is clinically significant only in humans and in
some large birds (e.g. turkeys)
• Atherosclerosis is silent until it reaches the stage (often suddenly due to rupture, haemorrhage
or thrombosis) when it causes symptoms and signs
• In smaller arteries, atherosclerosis causes gradual narrowing of the lumen (stenosis) or
occlusion due to plaque progression, haemorrhage, rupture or thrombosis.
• In larger arteries embolisation of thrombus formed on the plaque and aneurysm formation
(dilation) are common consequences of atheroma
• The most important clinical sequels of atherosclerosis are:
1. Ischaemic heart disease (leading to angina pectoris, myocardial infarction and cardiac
failure)
2. Peripheral vascular disease (leading to intermittent claudication, and gangrene)
3. Cerebrovascular disease (leading to transient ischaemic attacks and cerebral
infarction/stroke)
4. Aneuryms (especially in the abdominal aorta)
5. Renal failure