Atherogenesis

Question 1

modifiable risk factors for arterial disease

Answer 1

smoking, high BP, high cholesterol levels, diabetes

Question 2

non-modifiable risk factors for arterial disease

Answer 2

genetic abnormalities, family history, increasing age, male

Question 3

what is the fibrous cap in atherosclerotic plaque composed of

Answer 3

smooth muscle cells, foam cells, macrophages, lymphocytes, proteoglycans collagen, elastin, neovascularisation

Question 4

what is the necrotic core in an atherosclerotic plaque composed of

Answer 4

cell debris, cholesterol crystals, calcium salts, foam cells

Question 5

what did the lipid oxidation hypothesis did not explain?

Answer 5

the distribution of the atheroma in the arterial tree, the role of non-lipid risk factors (HTN, smoking, genetics), the complications of atherosclerosis, clinical trials with anti-oxidant drugs did not show any effect on the cause of atherosclerotic diseases

Question 6

what are the two types of mouse models used in lipid experiments

Answer 6

1. LDL receptor deficient mice- familial hypercholesterolaemia in humans
2. ApoE deficient mice- familial dysbetalipoproteinaemia in humans

Question 7

five stages of atherosclerosis

Answer 7

1. endothelial injury/dysfunction 2. lipoprotein accumulation 3. leukocyte adhesion and migration 4. lipid accmulation (foam cells) 5. smooth muscle recruitment + proliferation 6. ECM formation

Question 8

causes of endothelial dysfunction

Answer 8

-haemodynamic stress (high BP, arterial branch points) -toxins (e.g. cigarette smoke) -hyperlipidaemia -aging

Question 9

initial response to endothelial injury

Answer 9

• endothelial cells release cytokines -endothelial cells express adhesion molecules -allow leukocytes
  (monocytes) to bind and infiltrate macrophages -injury leads to decreased No production

Question 10

cytokines in atherosclerosis

Answer 10

small protein molecules, mediate/regulate inflammatory responses e..g, IL-1, TNF-a, IFN-y

Question 11

growth factors in atherosclerosis

Answer 11

stimulates growth of specific cell lines.eg., PDGF, VSMGF

Question 12

chemokines in atherosclerosis

Answer 12

attracts monocytes

Question 13

adhesion molecules in atherosclerosis

Answer 13

ICAM-1, VCAM-1

Question 14

lipoprotein accumulation in atherosclerosis

Answer 14

1. common lipoprotein abnormalities leads to high LDL, low HDL and high Lp(a)
2. endothelial injury causes: high O2 free radicals and low NO levels
3. in the intima, two lipid forms accumulate: oxidised LDL, cholesterol crystals
4. stimulate the release of inflammatory mediators

Question 15

what are foam cells

Answer 15

oxidised lipids are ingested by macrophages and become foam cells

Question 16

fatty streak formation

Answer 16

1. foam cells eventually undergo apoptosis
2. smooth muscle cells migrate from the media
3. SMCs and foam cells produce fatty streaks

Question 17

plaque development and stabilisation

Answer 17

SMCs migrates from the media and proliferate
SMCs synthesize ECM-mainly collagen-also elastin and proteoglycans
ECM stabilises the atherosclerotic plaque- controlled by a number of cytokines and growth factors: PDGF, FGF, TGF-a

Question 18

development of the plaques

Answer 18

SMC and ECM form a fibrous cap over foam cells. Foam cells degenerate to form the necrotic core which is lipid rich

Question 19

plaque progression

Answer 19

plaque grows-> raised from the vessel wall.
calcium salts deposited -> phosphate +hydroxypatite which causes hardening of arteries.
new vessels grow into the edge of the plaque-> neovascularisation
tunica media is thinned and weakened

Question 20

unstable plaques

Answer 20

activated inflammatory cells in plaques can cause SMC apoptosis and ECM breakdown which causes thinning of the fibrous plaques
development of unstable or vulnerable plaques

Question 21

clinical events related to plaques

Answer 21

rupture, erosion or ulceration –> exposes collagen + lipid core (thrombogenesis)
occulsion-> ST-elevation MI, stroke
atheroembolism- ruptures plaque material discharged into the circulation and lands in small vessels (e.g., legs)
aneurysm formation- weakening of the media leads to arterial dilation. if excessive, leads to vessel rupture or dissection

Question 22

physiology of a thrombus

Answer 22

thrombus may -> occulude the artery (e.g., MI) ->partially occulude the artery (unstable angina)–> becomes organised into the plaque –> plaque progression (e.g., stable angina) –> occulsion or progression can also follow bleeding into the plaque

Question 23

clinical consequences of atherosclerosis

Answer 23

Aorta-aneurysm formation (abdomen> thorax), renal artery stenosis
Coronary arteries- angina, MI, HF
Cerebral arteries- stroke, vascular dementia
Leg arteries- claudication, foot ulcers, gangrene

Question 24

atherosclerotic progression

Answer 24

normal –> fatty streak –> fibrous plaque –> occulsive atherosclerotic plaque –> plaque rupture