atherogenesis Flashcards
what is arteriosclerosis
hardening of the arteries - a generic term reflecting arterial wall thickening and loss of elasticity
what are the 3 patterns of arteriosclerosis
arteriolosclerosis; Monckeberg medial sclerosis; atherosclerosis
what is arteriolosclerosis and what can it cause
the hardening of small arteries and arterioles; it can be hyaline (thickening of the vessel wall) or hyperplastic (onion skin thickening of vessel wall); it can cause downstream ischaemic injury
what is monckeberg medial sclerosis
calcific deposits in muscular arteries; may undergo metaplastic change into bone; does not affect the vessel lumen
what is atherosclerosis characterised by?
characterised by intimal lesions (atheromas/atherosclerotic plaques) that protrude into the vessel lumens; plaques made of a rasied lesion with a soft, yellow lipid core covered by a fibrous cap
what can atherosclerosis cause?
plaque can obstruct blood flow; rupture can lead to vessel thrombosis; underlying media is weakened thus increasing risk of aneurysm
major targets of atherosclerosis
large elastic arteries (aorta, carotid); medium sized muscular arteries (coronary, popliteal)
what areas does atherosclerosis most affect
arteries supplying the brain, heart, kidneys, lower extremities
4 major consequences of atherosclerosis
MI; cerebral infarction (stroke); aortic aneurysm; PVD
non modifiable risk factors for atherosclerosis (4)
increasing age; being male; genetic abnormalities; family history
modifiable risk factors for atherosclerosis (5)
hyperlipidemia; hypertension; smoking; T2DM; high CRP levels
what is the contemporary view of artherogenesis
the response to injury hypothesis - endothelial injury leads to chronic inflammatory response, lesions progress due to the interaction of modified lipoproteins, monocyte derived macrophages, and t-lymphocytes with the normal cellular components of the arterial wall
atherosclerosis pathway (7)
- endothelial injury (increased vascular permeability, upreg of adhesion proteins resulting in enhances leukocyte adhesion, thrombosis)
- accumulation of lipoproteins (LDLs + oxidised LDLs are deposited in vessel wall)
- monocyte adhesion to endothelium (migration into the intima, transformation into foam cells)
- platelet adhesion
- factor release (from activated platelets/vessel wall cells, induce smooth muscle recruitment from media or circulating precursors, uptake of modified lipids)
- smooth muscle proliferation (and extra cellular matrix production)
- lipid accumulation (extracellularly and intracellularly, forms a well developed plaque)
examples of chronic endothelial injury (8)
hyperlipidemia; hypertension; smoking; homocysteine; haemodynamic factors; toxins; viruses; immune reactions
why are bifurcations more at risk of atherosclerosis
due to turbulent blood flow (disturbed shear) leading to increased endothelial injury (high EC turnover, poor alignment of EC, inflammatory genes, high permeability, oxidative stress)
what is turbulent blood flow known as
oscillatory flow - flow is slow and can be reversed during the cardiac cycle
properties of endothelial cells in areas of high lamina shear (5)
quisecent, anti-inflammatory phenotype; characterised by alignment and direction of flow; expression of anti-inflammatory genes; low levels of oxidative stress/turnover; protected from atherosclerosis
properties of endothelial cells in areas of disturbed lamina shear (5)
activated, pro-inflammatory phenotype; characterised by poor alignment; expression of inflammatory genes; high levels of oxidative stress/turnover; susceptible to atherosclerosis
what is a fatty streak
the earliest lesion in atherosclerosis; comprised of lipid filled macrophages; not significantly raised and so do not cause any flow disturbances
what is the relationship between fatty streaks and atherosclerosis
they may develop into precursors of plaques;
what is plaque ulceration
indentation, fissure, or erosion on the luminal surface of a plaque, exposing a portion of the inner plaque to direct contact with the circulating blood; often occur preceding ischaemic events
character of atherosclerotic lesions
patchy (only on a part of the wall); eccentric (rarely circular); focal and sparsely distributed at first
why are lesion focal?
due to the vagaries (unexpected changes) of vessel haemodynamic
arteries most commonly involved in atherosclerosis (descending order - 5)
lower abdominal aorta; coronary; popliteal; internal carotid; circle of willis
3 principle components of atherosclerotic plaques
- cells - smooth muscle, T lymphocytes, macrophages
- extra cellular matrix - collagen, elastic fibres, proteoglycans
- intracellular and extracellular lipids
components of a typical atherosclerotic lesion (4)
- superficial fibrous cap (smooth muscle cells, dense collagen)
- cellular area beneath and to side of cap (macrophages, T cells, smooth muscle cells)
- necrotic core (lipid, debris from dead cells, foam cells, fibrin, organised thrombus)
- neovascularisation
what often causes plaques to enlarge
cell death/degeneration, synthesis and degradation of ECM, thrombus organisation (calcification can also happen to atheroma - complication)
what does calcification make difficult?
angioplasty
what changes are atherosclerotic plaques susceptible to?
rupture, ulceration, erosion - leading to thrombosis; haemorrhage; atheroembolism; aneurysm formation
stable vs unstable plaque
stable - dense fibrous cap, minimal lipid accumulation, little inflammation
unstable - thin caps, large lipid cores, dense inflammatory filtrate
morphologic changes in an MI (3)
- ischaemic coagulative necrosis
- inflammation
- repair
progression of an MI pathology
<12hrs - recognition may be difficult -> 12-24hrs - red-blue area of trapped, stagnant blood -> more sharply defined, yellow-tan colour -> 10+ days infarct rimmed by zone of hyperaemic vascular granulation zone -> infarct replaced by fibrous scar
progression of an MI histology
changes of coagulative necrosis -> acute inflammation elicited by necrotic muscle fibres -> macrophages remove the necrotic muscle fibres -> damaged zone replaced by ingrowth of vascularised granulation tissue -> well developed scar tissue
