atherosclerosis Flashcards
lecture 33
what are the 3 layers of arteries
tunica intima
tunica media
tunica adventitia
the three layers communicate to form a system that regulates its function.
describe the intima
endothelial cells linked by tight junctions lying on a basement membrane.
resistant to apoptosis and rarely divide
describe the media
layers of perforated elastic laminae with smooth muscle cells in between.
bound by the internal and external elastic laminae
describe the adventitia
consists of connective tissue and contains fibroblasts, leucocytes, nerves, lymphatics and its vasa vasorum
describe large arteries
prominent elastic laminae in the media. so called elastic arteries. elastic recoil aids continuous flow
describe medium sized arteries and small
eg coronary.
classified as muscular arteries since the media is largely smooth muscle but little elastic.
define atherosclerosis
a disease of the intima of large and medium sized arteries. focal thickenings of intima called plawues are formed which are deposits of fibrous tissues and lipids.
define arteriosclerosis
loss of elasticity and physical hardening of the arterial wall from any cause. often accompanied by calcification. one cause is atherosclerosis.
name an epidemiological study that looked at the risk factors for atherosclerosis
the Framingham study
4 major positive risk factors for atherosclerosis
- hyperlipidaemia
- cigarette smoking
- hypertension
- diabetes mellitus
10 minor positive risk factors for atherosclerosis
1 - old age 2 - family history (polygenic inheritance) 3 - male gender (oestrogens may protect in premenopause) 4 - high sat fat diet 5 - stressful and sedentary lifestyles 6 - obesity 7 - excess alcohol 8 - low birth weight 9 - low socioeconomic status 10 - possibly infections like chlamidya
3 negative risk factors for atherosclerosis
1 - high levels of circulating HDLs
2 - moderate alcohol consumption of 2units a day
3 - cardiovascular fitness.
general structure of lipoproteins
a lipid core of triglycerides, cholesterol, cholesterol esters and phospholipids surrounded by apolipoproteins
what do lipoproteins do
transfer the lipids they carry into cells through 2 receptor systems
what are the 2 uptake systems for lipids carried by lipoproteins
1 - LDL receptor pathway - most active in hepatocytes. responsible for cholesterol breakdown. underactivity leads to hypercholesterolaemia.
2 - scavenger receptor pathway - used by macrophages to take up modified lipoproteins (eg oxidised in atherosclerotic plaques). pathway is unregulated and so leads to uncontrolled accumilation of cholesterol so macrophages - foam cells then burst.
what’s dyslipoproteinaemia?
a collective name for an abnormality in the constitution or concentration of lipoproteins in the blood. can be inherited - familial hypercholesterolaemia. or secondary to other disease (diabetes mellitus or hypothyroidism)
what types of dyslipoproteinaemia predispose for atherosclerosis
- increased: cholesterol, total triglycerides, LDL and lipoprotein a.
especially cholesterol - one study suggested a 10% drop in serum levels may result in a 15% drop in deaths due to CHD. - decreased HDL
3 atheroscerotic mice studies
1 - deficient in lipoprotein component of apoE or for the LDL receptor results in fast dev of atherosc.
2 - deficient in scavenger receptors SR-A or CD36 caused modest drop in atherosclerotic lesions.
3 - those that cannot store cholesterol due to deficiency in acyl-cholesterol acyl transferase (ACAT) also have a reduction in atherosclerotic lesions.
atherosclerosis pathogenesis overview
several interacting processes. ost components of cell wall disrupted. initiates chronic inflammation.
6 key changes in vessel walls in atherosclerosis
1 - endothelial cell injury or dysfunction
2 - monocyte migration into plaque and maturation to macrophages
3 - smooth muscle cell activation
4 - lipoprotein infiltration
5 - t-lymphocyte migration into the plaque
6 - platelet adherence
causes and results of endothelial damage/dysfunction in atherosclerosis
causes - haemodynamic forces, chemical insults, cytokines.
results - altered permeability (so lipid infiltration), adhesion molecules expression (selectins, VCAM-1, ICAM-1) chemokine/mitogn expression (MCP-1, IL1, IL8, M-CSF) so leukocyte infiltration, activation of thrombosis
cause of monocyte recruitment in atherosclerosis, effect?
cause - chemotaxis, adhesion, migration into intima, maturation to macrophage.
result - increase chemokine expression, present antigen to T cells, activate endothelial cells, oxidise and scavenge lipids, activate smooth muscle cells (PDGF, ROS), modify matrix with collagenase, promote coagulation (tissue factor)
what caused smooth muscle activation in the media and what results
macrophages, platelets and endothelial cells all produce growth factors (PDGF, FGF) and ROS that activate SMCs.
result - proliferation, migration to intima, change from contractile to synthetic (ECM producing) phenotype. secrete ECM and enzymes for matrix remodelling.
what oxidises lipoproteins in plaques
ROS and enzymes from platelets, macrophages and endothelial cells.
what do oxidised lipoproteins do
1- macrophage chemoattractants
2 - phagocytosed by macrophages -foam cells
3 - stim various cells to secrete cytokines and growth factors
4 - induce dysfunction/apoptosis in SM, macrophages, and endothelium
5 - may be immunogenic
6 - inhibit plasminogen activation
evidence for relevant role of lipoproteins
1 - anti-oxidants ie vitamin E and NO inhibit their oxidation and also reduce the risk of myocardial infarc
2 - cholesterol lowering drugs (eg statins) decrease freq of coronary artery atherosclerosis
result of T lymphocyte migration into the plaque
may recognise oxidised lipoproteins as antigens and hence activate immune responses inc cytotoxic killing of cells in the plaque. may be the cause of necrotic areas.
role of platelets in early and advanced lesions
early - evidence they adhere transiently to dysfunctional endothelium, release PDGF to activate SMCs.
advanced - if plaques ulcerate or rupture then they are involved in thrombosis
4 stages of atherosclerotic lesions
1 - isolated monocytes - from soon after birth
2 - fatty streaks or dots
3 - fibro-fatty plaques
4 - complicated plaques
describe fatty streaks
common by second decade of life. clusters of lipid laden SMCs and foam cells. no sig pathological effects
describe fibrofatty plaques
principally in abdominal aorta, coronary arteries, carotids, circle of willis. 3rd or 4th decade in men, later in women.
-raised yellow/white plaques. possibly atrophy of media. 3 regions in the intima:
1 - fibrous cap - collagen, SMCs, macrophages, T cells
2 - lipid core - foam cells, necrosis and extracellular lipid in more advanced lesions
3 - shoulder of the cap - foam cells, SCs, t cells and angiogenesis.
describe complicated plawues
- may become calcified
- may expand if new vessels haemorrhage
- may rupture or ulcerate, particularly if rich in leucocytes or angiogenesis. embolism.
- aneurysm due to thinning of the media and fragmentation of the elastic laminae.
what is diffuse intimal thickening
separate from atherosclerosis but can coexist. build up of SMCs, collagen and elastin due to advancing age, hypertension and chronic inflam.
atherosclerosis death?
its complications cause about 50% of all deaths in the western world.
the problem with atherosclerosis
its silent and progressive, only becoming symptomatic when somehting serious happens - rupture, ahemorrhage or embolism.
different results of atherosclerosis in small and large vessels?
small - gradual stenosis or occlusion
large - embolisation of thrombus formed on plaque, aneurysm.
5 most clinically important results of atherosclerosis
1 - ischaemic heart disease (angina, MI, heart failure)
2 - peripheral vascular disease (intermittent claudication, gangrene)
3 - cerebrovascular disease (transient ischaemia, infarc, stroke)
4 - aneurysm (esp abdominal aorta)
5 - renal failure
