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What is atherosclerosis?

Formation of focal elevated lesions (plaques) in the intima of large and medium sized arteries


What does atheroma in the coronary arteries result in?

Narrowing of the lumen due to atheromatous plaques, this in turn causes ischaemia and angina and can be complicated by thromboembolism


What is arteriosclerosis?

Age-related change in the muscular arteries


What does arteriosclerosis result in?

Smooth muscle hypertrophy
Apparent reduplication of internal elastic laminae
Intimal fibrosis leading to decreased vessel diameter


What does arteriosclerosis contribute to in the elderly?

High frequency of cardiac, cerebral, colonic and renal ischaemia


When are the clinical effects of arteriosclerosis most apparent?

When CVS is further stressed by haemorrhage, major surgery, shock, infection etc.


What is atheroma?

Fatty streak
The earliest significant lesion in atherosclerosis
Yellow linear elevation of the intimal lining


What is an atheroma lesion comprised of?

Masses of lipid-laden macrophages


In what way is atheroma relevant?

No clinical significance, only relevant in patients at risk as it may develop into an atheromatous plaque


When are early atheromatous plaques seen?

Young adults onwards


What are the features of early atheromatous plaques?

Smooth yellow patches in the intima
Lipid-laden macrophages
Can progress to established plaques


What are the features of a fully developed plaque?

Central lipid core with fibrous tissue cap
Covered by arterial endothelium
Collagens in the cap provide structural strength
Inflammatory cells reside in the fibrous cap
Central lipid core is rich in cellular lipids and debris derived from the macrophages
Soft, highly thrombogenic ring of foamy macrophages
Extensive dystrophic calcification
Late stage plaques are confluent and cover large areas


What do macrophages in fully developed plaques have a foamy appearance?

Due to uptake of oxidised lipoproteins via specialised membrane bound scavenger receptors


What might provide a marker for atherosclerosis in angiograms and CT scans?

Dystrophic calcification


Where do calcifications form?

At arterial branching points and bifurcations due to turbulent flow


What are the features of a complicated atheroma?

Features of established atheromatous plaque plus;
Haemorrhage into the plaque, calcification
Plaque rupture/fissuring
Clinical consequences


What are the two steps involved in the development of atheromatous plaques? How do these steps result in formation of atheromatous plaques?

Injury to the endothelial lining of the artery
Chronic inflammatory and healing response of the vascular wall to the agent causing the injury

Chronic and episodic exposure of arterial wall to these processes is what results in the formation of atheromatous plaques


What is the order of events in atherosclerosis development?

Endothelial injury and dysfunction
Accumulation of lipoproteins in the vessel wall
Monocyte adhesion to the endothelium, migration into the intima and transformation to foamy macrophages
Platelet adhesion
Factor release from activated platelets and macrophages causing smooth muscle cell recruitment
Smooth muscle cell proliferation, ECM production and T-cell recruitment
Lipid accumulation


What are the most important causes of endothelial injury?

Haemodynamic disturbances e.g. turbulent flow, hypercholesterolaemia


How can chronic hypercholesterolaemia directly impair endothelial cell function?

By increasing local production of reactive oxygen species;

Lipoproteins aggregate in the intima and are modified by free radicals produced by inflammatory cells
Modified LDL accumulated by macrophages but not completely degraded
Foamy macrophages accumulate
These are toxic to endothelial cells plus release growth factor and cytokines


How are injured endothelial cells functionally altered?

Enhanced expression of cell adhesion molecules (ICAM-1, E-selectin)
High permeability for LDL
Increased thrombogenicity
Inflammatory cells and lipids accumulate in intimal layer and form plaques


In advanced plaque formation there are large number of what cells?

Macrophages and T-lymphocytes


What does response to endothelial injury involve?

The chronic inflammatory process


What do growth factors cause in the intimal smooth muscle cells?

Proliferation of the intimal smooth muscle cells and subsequent synthesis of collagen, elastin and mucopolysaccharides


What are growth factors secreted by?

Injured endothelium
Smooth muscle cells


In established plaques, what is plaque growth initiated by (besides growth factors)?

Small areas of endothelial loss
Microthrombi formed at denuded areas of the plaque surface are organised by the same rear process
Repeated cycles gradually increase the plaque volume


What are the main components of an atheromatous plaque?

Central lipid core
Fibrous tissue cap
Arterial endothelial lining
Collagen in fibrous cap
Inflammatory cells in fibrous cap
Rim of foamy macrophages


What is the most important risk factor for atheroma? Why?

It causes plaque formation and growth in the absence of other known risk factors


What proportion of Caucasians are heterozygous for a mutation resulting in genetically determined lack of cell membrane receptors for LDL?



What is the prognosis of patients who are homozygous for the mutation resulting in a genetically determined lack of cell membrane receptors for LDL?

Much higher cholesterol levels, these patients usually die from coronary artery atheroma in infancy or teens
1 in 1 million people - rare