What is arteriosclerosis?
What is atherosclerosis?
What are the 3 stages of atherosclerosis development?
Thickening of arterial wall which loses elasticity. Commonest = atherosclerosis.
Focal disease of large and medium sized arteries. Fatty plaques form in arterial walls.
1) Endothelial damage
2) Uptake of modified LDL particles, adhesion and infiltration of macrophages
3) SM proliferation and formation of a fibrous cap
What is the endothelial function?
What causes endothelial damage ("activation")?
1) vasomotor tone (make vasoconstrictors/dilators)
2) thrombosis: produce anti and procoagulants, platelet inhibitors/activators
3) Inflammatory factors
4) cellular adhesion molecules
Sheer stress (turbulant blood), toxic damage (free radicals react with lipid bilayer), high lipid levels, infection
What are lipoproteins, and what are the 5 types?
Which is made mainly of cholesterol?
Lipids transported through blood paired with protein. Chylomicrons, VLDL (very low), LDL, IDL (intermediate), HDL.
LDL. HDL is smaller and mainly protein.
After stage 1 of atherosclerosis (endothelial damage, causing vasoconstriction and activated endothelial cells), what happens in stage 2?
LDL modification, caused by oxidation (free radicals) and glycation (increased in diabetes mellitus). Oxidised LDL stimuates expression of inflammatory mediators inc. adhesion molecules for monocytes.
After endothelial damage, monocytes bind to endothelium, cross it and are transformed to macrophages. They accumulate large droplets of lipid to become foam cells -> fatty streak. (sub-endothelial lipid pool)
Normally macrophages recognise LDL via their LDL receptors recognising apolipoprotein B100 on LDL. -ve feedback (internal accumulation of LDL downregulates LDL receptor numbers. But modified LDL not recogonised by LDL-receptor - taken up via scavenger receptor. The is no negative feedback therefore form cells are formed.
Fatty streaks (yellow):
What is FS?
Fatty streak (foamy macrophages, few lymphocytes and rare SM cells) in sub intimal layer.
Describe stage 3 of atherosclerosis.
Endothelial cells and macrophages release growth factors especially PDGF. 2 types of SM: contractile and proliferating. PDGF converts cont. to prolif. Proliferating secretes collagen, starts to break down internal elastic lamina. Pressure on media causes muscle atrophy and collagen increase. Cytokines secreted by endothelium and macrophages stimulates migration of SM cells. Plaque bulges in lumen (=angina/claudication). Collagen forms fragile fibrous cap. Fragility increased by calcification, which makes artery rigid. Cap rupture exposes collagen to blood and triggers thrombus formation which can occlude vessel.
What are the commonest sites of atheroma formation?
Where high sheer stress or turbulant flow esp. junctions of arteries e.g. aortic bifucation. Also carotid bifurcation and at renal artery.
What can you see in this abdominal aorta?
Plaques all over endothelial layer. Has had bifurcation replaced. Huge aneurysm.
What is a stable plaque?
What effect does increasing plaque volume have on the lumen?
Why does the artery loose its elasticity around an intimal plaque?
Reduces blood flow but stable angina (exertional). Only when e.g. 80% of coronary artery lumen occluded is there a decrease in coronary flow.
Stenosis (and limits flow - 'stable angina')
SM migrates into plaque
What happns with an unstable plaque?
Fragile cap ruptures: hemorrhage from plaque (can still be covered by endothelium), release of tissue factor, collagen exposed causing platelet aggregation. Thrombus forms. Reduced Lumen diameter. May occlude lumen (MI)
Label A-C. What is happening?
A: endothelium B: hemorrhage C: plaque
Unstable plaque (still covered by endothelium)
Label A-C. What has happened in this post-mortem?
A: post mortem blood clot
C: atheromatous plaque
Thrombus has formed on plaque surface
List unmodifiable and modifiable risk factors for atherosclerosis.
What are desirable blood cholesterol levels for adults?
Unmodifiable: age, sex, race, family history e.g. familial hyperlipidaemia
Modifiable: Dyslipidaemia (eat less sat fat), smoking (toxic damage and free radicals), hypertension (increases sheer stress at vessel junctions), diabetes mellitus (hyperglycaemia), physical activity (converts LDL -> HDL)
TC (total chol) <200mg/dl, LDL <130mg/dl, HDL >40mg/dl, normally triglycerides 10-190mg/dl
What are the 3 emerging risk factors for atherosclerosis?
What is the treatment for atherosclerosis?
Two genetic: homocysteinaemia, lipoprotein a
Infection (can cause endothelial activation)
Treatment: modifiable risk factors, plasma lipid reduction using statins: inhibit HMG CoA = reduced intracellular cholestrol synthsis = reduced chol in cells = increased LDL receptors on macrophage surface = increased chol uptake = reduced plasma chol.
Polypil: drug combination of statin, 3 BP lowering drugs, folic acid and aspirin. Average reduction of chol and BP. Increases years free from IHD/stroke? WIP
What are some complications of atheromas?
Coronary artery disease (leading to angina/MI). Peripheral vascular disease (leads to ulcers, peripheral neuropathy, gangrene). Stroke. Aneurysm. Renal artery stenosis.
What happens in percutaneous transluminal coronary angioplasty?
Balloon catheter with uninflated balloon is threaded through to obstructed area in artery. Balloon inflated: stretches arterial wall and squashes artherosclerotic plaque. After lumen widened, balloon deflated and catheter withdrawn. Stent insertion may follow to maintain patency of BV.