Atherogenesis Flashcards
modifiable risk factors for arterial disease
smoking, high BP, high cholesterol levels, diabetes
non-modifiable risk factors for arterial disease
genetic abnormalities, family history, increasing age, male
what is the fibrous cap in atherosclerotic plaque composed of
smooth muscle cells, foam cells, macrophages, lymphocytes, proteoglycans collagen, elastin, neovascularisation
what is the necrotic core in an atherosclerotic plaque composed of
cell debris, cholesterol crystals, calcium salts, foam cells
what did the lipid oxidation hypothesis did not explain?
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
what are the two types of mouse models used in lipid experiments
- LDL receptor deficient mice- familial hypercholesterolaemia in humans
- ApoE deficient mice- familial dysbetalipoproteinaemia in humans
five stages of atherosclerosis
- endothelial injury/dysfunction 2. lipoprotein accumulation 3. leukocyte adhesion and migration 4. lipid accmulation (foam cells) 5. smooth muscle recruitment + proliferation 6. ECM formation
causes of endothelial dysfunction
-haemodynamic stress (high BP, arterial branch points) -toxins (e.g. cigarette smoke) -hyperlipidaemia -aging
initial response to endothelial injury
- endothelial cells release cytokines -endothelial cells express adhesion molecules -allow leukocytes
(monocytes) to bind and infiltrate macrophages -injury leads to decreased No production
cytokines in atherosclerosis
small protein molecules, mediate/regulate inflammatory responses e..g, IL-1, TNF-a, IFN-y
growth factors in atherosclerosis
stimulates growth of specific cell lines.eg., PDGF, VSMGF
chemokines in atherosclerosis
attracts monocytes
adhesion molecules in atherosclerosis
ICAM-1, VCAM-1
lipoprotein accumulation in atherosclerosis
- common lipoprotein abnormalities leads to high LDL, low HDL and high Lp(a)
- endothelial injury causes: high O2 free radicals and low NO levels
- in the intima, two lipid forms accumulate: oxidised LDL, cholesterol crystals
- stimulate the release of inflammatory mediators
what are foam cells
oxidised lipids are ingested by macrophages and become foam cells
fatty streak formation
- foam cells eventually undergo apoptosis
- smooth muscle cells migrate from the media
- SMCs and foam cells produce fatty streaks
plaque development and stabilisation
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
development of the plaques
SMC and ECM form a fibrous cap over foam cells. Foam cells degenerate to form the necrotic core which is lipid rich
plaque progression
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
unstable plaques
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
clinical events related to plaques
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
physiology of a thrombus
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
clinical consequences of atherosclerosis
Aorta-aneurysm formation (abdomen> thorax), renal artery stenosis
Coronary arteries- angina, MI, HF
Cerebral arteries- stroke, vascular dementia
Leg arteries- claudication, foot ulcers, gangrene
atherosclerotic progression
normal –> fatty streak –> fibrous plaque –> occulsive atherosclerotic plaque –> plaque rupture