6. Atherosclerosis

Question 1

What is the difference between “arteriosclerosis” and “atheroma”?

Answer 1

• arteriosclerosis = thickening of walls of arteries and arterioles, usually as a result of hypertension or diabetes mellitus
• atheroma = thickening and hardening of arterial walls as a consequence of atherosclerosis

Question 2

What is “atherosclerosis”?

Answer 2

accumulation of intracellular and extracellular lipid in the intima and media of large- and medium-sized arteries

Question 3

What are the 3 macroscopic stages/features of atherosclerosis?

Answer 3

1. fatty streak
2. simple plaque
3. complicated plaque

Question 4

What is the difference between fatty streak, simple plaque and complicated plaque?

Answer 4

1. fatty streak
   - yellow, slightly raised
   - lipid deposits in intima
2. plaque
   - raised, yellow/white, irregular outline
   - widely distributed, enlarge and coalesce
3. complicated plaque
   - calcification
   - haemorrhage into plaque
   - thrombosis
   - aneurysm formation

Question 5

What are the common sites of atherosclerosis?

Answer 5

i) aorta - esp. abdominal
ii) coronary arteries (right, left anterior descending and circumflex)
iii) carotid arteries
iv) cerebral arteries
v) leg arteries

Question 6

Describe the microscopic features of atherosclerosis.

Answer 6

Early changes:

• proliferation of smooth muscle cells
• accumulation of foam cells
• extracellular lipid deposition

Later changes:

• fibrosis
• necrosis
• cholesterol clefts
• +/- inflammatory cells

Later changes:

• disruption of internal elastic lamina
• damage extends into media
• ingrowth of blood vessels
• plaque fissuring

Question 7

Describe the effects of severe atherosclerosis in ischaemic heart disease.

Answer 7

Can lead to:

1. sudden death
2. MI
3. angina pectoris
4. arrhythmias
5. cardiac failure

Question 8

Describe the effects of severe atherosclerosis in cerebral ischaemia.

Answer 8

Can lead to:

1. transient ischaemic attach (neurological symptoms similar to stroke but resolve in 24hrs)
2. cerebral infarction - stroke (often unilateral neurological probs that don’t resolve)
3. multi-infarct dementia (many small cerebral infarcts causing dementia)

Question 9

Describe the effects of severe atherosclerosis in mesenteric ischaemia.

Answer 9

Can lead to:

1. ischaemic colitis (pain and bleeding often at splenic flexure of large bowel due to poor blood supply)
2. malabsorption (if small bowel affected)
3. intestinal infarction (in mesenteric artery - affects all small bowel)

Question 10

Describe the effects of severe atherosclerosis in peripheral vascular disease.

Answer 10

Affects blood supply to legs causing:

1. intermittent claudication (pain in calves induced by exercise due to reduced arterial supply)
2. Leriche syndrome (pain in buttocks and impotence)
3. ischaemic rest pain (not enough blood supply even at rest)
4. gangrene

Question 11

Describe the effects of severe atherosclerosis in the abdominal aorta.

Answer 11

Can cause abdominal aortic aneurysm - rupture causes massive intraperitoneal haemorrhage.

Question 12

Name examples of risk factors for atherosclerosis.

Answer 12

1. age - slowly progressive throughout adult life
2. gender - post-menopausal women less at risk due to higher oestrogen levels
3. hyperlipidaemia - high plasma cholesterol associated with atherosclerosis: LDL most significant whilst HDL protective
4. genetics - genetic variations in ApoE associated with changes in LDL levels (6 ApoE phenotypes, polymorphisms can be used as risk markers for atherosclerosis)
5. smoking - uncertain mode of action: coagulation system? reduced prostaglandin I2? increased platelet aggregation? Risk falls after giving up. Powerful risk factor for IHD.
6. hypertension - uncertain mode of action: endothelial damage caused by raised BP? Strong link between IHD and high BP.
7. diabetes mellitus - uncertain MOA: related to hyperlipidaemia and hypertension? Doubles IHD risk, also associated with high risk of cerebrovascular and peripheral vascular disease. Protective effect in premenopausal women lost.
8. alcohol consumption - >5 units/day associated with increased risk of IHD. Smaller amounts may be protective.
9. infection - e.g. Chlamydia pneumoniae, Helicobacteri pylori, cytomegalovirus
10. other: lack of exercise, obesity, soft water, oral contraceptives, stress and personality type?

Question 13

Which inherited disease is associated with early dev of atherosclerosis? What are the physical signs of this?

Answer 13

familial hyperlipidaemia

i) corneal arcus
ii) tendon xanthomas
iii) xanthelasma

Question 14

What are the 4 hypotheses for atherosclerosis pathogenesis?

Answer 14

1- thrombogenic theory
2- insudation theory
3- monoclonal hypo.
4. reaction to injury hypo.

Question 15

Describe the thrombogenic theory.

Answer 15

(Karl Rokitansky 1852)

• plaques formed by repeated thrombi
• lipid derived and released from thrombi
• overlying fibrous cap

Question 16

Describe the insudation theory.

Answer 16

(Rudolf Virchow 1856)

- endothelial injury causes inflammation and increased permeability to lipid from plasma (moves into vessel wall)

Question 17

Describe the reaction to injury hypo.

Answer 17

(Ross and Glomset 1972)

• hypercholesterolaemia leads to endothelial damage (in experimental animals)…
• plaques form in response to endothelial injury…
• injury increases permeability and allows platelet adhesion…
• monocytes penetrate endothelium…
• smooth muscle cells proliferate and migrate

(Ross 1986)

• endothelial injury may be very subtle and be undetectable visually
• LDL, esp. oxidised, may damage endothelium

Question 18

Describe the monoclonal hypo.

Answer 18

(Benditt and Benditt)

• crucical role for smooth muscle proliferation- each plaque is monoclonal
• might represent abnormal growth control
• is each plaque a benign tumour?
• could atherosclerosis have a viral aetiology?

Question 19

Name the cell types involved in atherosclerosis.

Answer 19

1. endothelial cells
2. platelets
3. SM cells
4. macrophages
5. neutrophils
6. lymphocytes

Question 20

What is the role of endothelial cells in atherosclerosis?

Answer 20

1. key role in haemostasis
2. altered permability to lipoproteins
3. collagen production
4. stimulation of proliferation and migration of SM cells

Question 21

What is the role of platelets in atherosclerosis?

Answer 21

1. key role in haemostasis

2. stimulation of prolferation and migration of SM cells via PDGF

Question 22

What is the role of smooth muscle cells in atherosclerosis?

Answer 22

1. take up LDL and other lipids to become foam cells

2. synthesise collagen and proteoglycans

Question 23

What is the role of macrophages in atherosclerosis?

Answer 23

1. oxidise LDL
2. take up lipids to become foam cells
3. secrete proteases which modify matrix
4. stimulate proliferation and migration of SM cells

Question 24

What is the role of lymphocytes in atherosclerosis?

Answer 24

1. produce TNF which may affect lipoprotein metabolism

2. stimulate proliferation and migration of SM cells

Question 25

What is the role of neutrophils in atherosclerosis?

Answer 25

secrete proteases leading to continued local damage and inflammation

Question 26

Describe the unifying hypothesis to atherosclerosis.

Answer 26

1. Raised LDL, toxins (e.g. cigarette smoke), hypertension, haemodynamic stress cause endothelial injury. 2. Endothelial injury causes: i) platelet adhesion...PDGF release... SM cell proliferation and migration ii) insudation of lipid and LDL oxidation... uptake of lipid by SM cells and macrophages iii) migration of monocytes into intima 3. Stimulated SM cells produce matrix material. 4. Foam cells secrete cytokines causing further SM cell stimulation and recruitment of other inflammatory cells.

Question 27

How can atherosclerosis be prevented?

Answer 27

- no smoking - reduce fat intake (to some extent, trans vs untrans) - treat hypertension - not too much alcohol - regular exercise/weight control but some will still develop atherosclerosis