Pathophysiology of Atheroma

Question 1

What is an atheroma/atherosclerosis?

Answer 1

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

Question 2

Give an example of the implications of an atheroma.

Answer 2

E.g. in coronary arteries, atheromatous plaques narrow lumen –> ischaemia.
Serious consequences - angina due to myocardial ischaemia.

Question 3

How can atheromas be complicated?

Answer 3

By thromboembolisms.

Question 4

What is arteriosclerosis?

Answer 4

Not atheromatous.
Age related change in muscular arteries.
Smooth muscle hypertrophy, apparent reduplication of internal elastic laminae, intimal fibrosis –> decrease in vessel diameter.

Question 5

What does arteriosclerosis contribute to?

Answer 5

High frequency of cardiac cerebral, colonic and renal ischaemia in elderly.

Question 6

When are clinical effects most apparent?

Answer 6

When CVS further stressed by haemorrhage, major surgery, infection, shock…

Question 7

What is the earliest significant lesion of an atheroma?

Answer 7

A fatty streak..

Question 8

When will this fatty streak develop?

Answer 8

Probably in childhood.

Question 9

What will this fatty streak look like?

Answer 9

Yellow, linear elevation of intimal lining.

Question 10

What is the fatty streak comprised of? What is the risk associated with this streak?

Answer 10

Masses of lipid laden macrophages. No clinical significance and may disappear but at risk of developing atheromatous plaques.

Question 11

When does an early atheromatous plaque develop? What does it look like and what is it composed of?

Answer 11

Young adulthood onwards.
Smooth yellow patches in intima.
Lipid-laden macrophages.
Progress to established plaques.

Question 12

What is the fully developed atheromatous plaque composed of?

Answer 12

Central lipid core (rich in cellular lipids/debris from macrophages (died in plaque)) with fibrous tissue cap, covered by arterial endothelium. 
Collagens (produced by smooth muscle cells) in cap provide structural strength. 
Inflammatory cells (macrophages, T-lymphocytes, mast cells), reside in fibrous cap - recruited from arterial endothelium.

Question 13

What often forms the rim of the fully developed atheroma?

Answer 13

Soft, highly thrombogenic foamy macrophages - foamy appearance due to uptake of oxidised lipoproteins via specialised membrane bound scavenger receptor.

Question 14

What may also happen to a fully developed atheromatous plaque?

Answer 14

Dystrophic calcification (occurs late) - (?marker for atherosclerosis in angiograms/CT). 
Form at arterial branching points/bifurcations (turbulent flow).

Question 15

What are late stage plaques like?

Answer 15

Confluent, cover large areas.

Question 16

Describe what a complicated atheroma is like.

Answer 16

Features of established atheromatous plaque plus haemorrhage into plaque (calcification), plaque rupture/fissuring, thrombosis –> clinical consequences.

Question 17

What is the most important risk factor for developing atheromas?

Answer 17

Hypercholesterolaemia - causes plaque formation and growth in absence of other risk factors.

Question 18

What is the prevalence of hypercholesterolaemia and how does it present?

Answer 18

1/500 Caucasians heterozygous for this type of mutation: decreased functional receptors on cell surfaces, elevated plasma LDL cholesterol levels.
Homozygous (1/mil) - much higher cholesterol levels, usually due from coronary artery atheroma in infancy/teens.

Question 19

What are the signs for major hyperlipidaemia?

Answer 19

Familial/primary vs acquired/secondary. 
Biochemical evidence - LDL, HDL, total cholesterol, triglycerides. 
Corneal arcus (premature)
Tendon xanthomata (knuckles, Achilles)
Xanthelasmata
Risk/premature/FH of MI/atheroma.

Question 20

What are the major risk factors for atheroma?

Answer 20

Hypercholesterolaemia
Smoking
Hypertension 
Diabetes mellitus
Male 
Elderly
Accelerate process of plaque formation driven by lipids.

Question 21

What are less strong risk factors for atherosclerosis?

Answer 21

Obesity
Sedentary lifestyle
Low socio-economic status
Low birth weight
?role of microorganisms

Question 22

Describe the two step process leading to the formation of atheromatous plaques.

Answer 22

Injury to endothelial lining of artery.
Chronic inflammation and healing response of vascular wall to agent causing injury.
Chronic/episodic exposure of arterial wall to these processes –> formation of atheromatous plaques.

Question 23

Describe the pathogenesis of atherosclerosis.

Answer 23

Endothelial injury and dysfunction
Accumulation of lipoproteins (LDL) in vessel wall
Monocyte adhesion to endothelium –> migration into intima and transformation to foamy macrophages
Platelet adhesion
Factor release from activated platelets, macrophages (smooth muscle recruitment)
Smooth muscle cell proliferation, extracellular matrix production and T-cell recruitment
Lipid accumulation (extracellular and in foamy macrophages).

Question 24

How are the injured endothelial cells functionally altered?

Answer 24

Enhanced expression of cell adhesion molecules (ICAM-1, E-selectin)
High permeability for LDL
Increased thrombogenicity.
Inflammation cells, lipids –> intimal layer –> plaques.

Question 25

Describe advanced plaque formation.

Answer 25

Large no.s of macrophages,T-lymphocytes
Lipid-laden macrophages die through apoptosis –> lipid into lipid core
Response to injury = chronic inflammation process 1. inflammation reaction 2. process of tissue repair
Growth factors (PDGF) –> proliferation intimal smooth muscle cells, subsequent synthesis collagen, elastin, mucopolysaccharide
Fibrous cap encloses lipid rich core
Growth factors secreted y platelets, injured endothelium, macrophages and smooth muscle cells.

Question 26

What are the consequences of an atheroma?

Answer 26

Many clinically unnoticed.
Clinical disease - relatively benign to life-threatening/fatal
Acute changes in plaques (complicated) –> serious.

Question 27

What is classed as progressive lumen narrowing due to high grade plaque stenosis? What does it cause?

Answer 27

Stenosis of >50-75% of vessel lumen –> critical reduction of blood flow in distal arterial bed –> reversible tissue ischaemia.

Question 28

Give examples of where this stenosis can occur and the symptoms experienced by the patient if it does.

Answer 28

Stenosed atheromatous coronary artery –> stable angina.
Very severe stenosis –> ischaemic pain at rest (unstable angina).
Ileal, femoral, popliteal artery stenosis –> intermittent claudication (peripheral arterial disease).
Longstanding tissue ischaemia –> atrophy of affected organ, e.g. atherosclerotic renal artery stenosis –> renal atrophy.

Question 29

What is the major complications of acute atherothrombotic occlusion?

Answer 29

Rupture of plaque –> acute event.
Rupture exposes highly thrombogenic plaque contents (collagen, lipid, debris) to bloodstream –> activation of coagulation cascade and thrombotic occlusion in v short time.

Question 30

What does total occlusion lead to?

Answer 30

Irreversible ischaemia and necrosis (infarction) of tissues, e.g. MI (coronary artery), stroke (carotid, cerebral artery), lower limb gangrene (ileal, femoral, popliteal).

Question 31

What does detachment of small thrombus fragments lead to?

Answer 31

Can embolism distal to ruptured plaque, which may lead to occlusion of smaller vessels and smart infarcts in organs.

Question 32

Give examples of where these fragments can embolise to and the problems they cause.

Answer 32

Heart, dangerous small foci of necrosis –> life-threatening arrhythmias.

Large ulcerating aorta plaques, lipid rich fragments of plaque –> cholesterol emboli in kidney, skin, leg.

Carotid artery atheromatous debris common cause of stroke (cerebral infarct/TIA).

Question 33

How can atheromatous plaques lead to aortic aneurysms?

Answer 33

Media beneath plaque gradually weakened (lipid-related inflammatory activity in plaque) –> gradual dilatation of vessel.

Question 34

Describe how aortic aneurysms develop and in which age group they are most common.

Answer 34

Slow but progressive.

Seen in elderly, often asymptomatic.

Question 35

What can sudden rupture of an aortic aneurysm lead to?

Answer 35

Massive retroperitoneal haemorrhage (high mortality).

Question 36

What size of aneurysms are at high risks of rupturing?

Answer 36

More than 5cm.

Question 37

What are the typical features of a vulnerable atheromatous plaque?

Answer 37

Typically thin fibrous cap, large lipid core, prominent inflammation.
High risk of developing thrombotic complications.

Question 38

What does inflammation lead to and why does it increase the risk of rupture?

Answer 38

Pronounced inflammatory activity leads to degradation, weakening of plaque and therefore increased risk of rupture.

Question 39

What kinds of secretions released by the inflammatory cells will cause the plaque to rupture?

Answer 39

Secretion of proteolytic enzymes, cytokines and reactive oxygen species.

Question 40

What is the appearance of highly stenotic plaques?

Answer 40

Often large fibrocalcific component with little inflammation.

Question 41

What are the preventative and therapeutic approaches to atherosclerosis?

Answer 41

Stop smoking, control BP, weight loss, regular exercise, dietary modifications.

Question 42

What are some drugs you may use in secondary prevention of atherosclerosis?

Answer 42

Cholesterol lowering drugs, aspiring (inhibits platelet aggregation to decrease risk of thrombosis on established atheromatous plaques).

Question 43

What other options may you consider in treatment?

Answer 43

Surgical options.