Atherosclerosis & Lipid-lowering Drugs Flashcards
What defines if something is HDL or LDL?
APOPROTEINS
• A-1 = HDL
• B = LDL
Explain the exogenous pathways of lipid metabolism
When we eat food:
- It is broken down into chylomicrons (large)
- These are further broken down into FFAs + chylomicron remnants
- Chylomicron remnants –> deposit in vessels –> atheroma
Explain the endogenous pathways
MOST HDL/LDL comes from this pathway
• Lipoprotein lipase & Hepatic lipase metabolise the most
• IDL & LDLS are deposited in vessels to form atheromas
Explain what is meant by ‘Reverse Cholesterol Transport’
The REMOVAL of cholesterol from VESSEL WALLS
back to the liver by HDL!
Define atherosclerosis
An inflammatory fibro-proliferative disorder
Remnant cholesterol is PRO-inflammatory
8 general steps that leads to atherosclerosis?
- LDL enters endothelium (into tunica intima (media is VSMCs))
- LDLs are oxidised by macrophages and VSMCs
- Release of growth factors and cytokines
- Additional monocytes/macrophages recruited
- Foam cell accumulation (macrophages that contain lots of lipids)
- VSMC migration
- VSMC proliferation
- Plaque growth
Explain the ‘Endothelial Dysfunction’ part of Atherosclerosis
It is characterised by: Increased endothelial permeability Upregulation of adhesion molecules Leucocyte adhesion Migration of leucocytes into artery wall
Explain the ‘Fatty Streak Formation’ of Atherosclerosis
The earliest recognisable lesion of atherosclerosis
• caused my FOAM CELL aggregation
- derived from macrophages & T-cells within the tunica intima
• fatty streaks usually form in the DIRECTION of BLOOD FLOW
It is characterised by: Migration of VSMCs (included later on) Activation of T-cells Adherence & activation of platelets Formation of foam cells
Explain the ‘Plaque Formation’ of Atherosclerosis
It is characterised by:
Formation of fibrous cap
- VSMCs migrate to intima & lay-down collagen fibres
- separates the lipid-rich core from circulating platelets * coagulation factors
Accumulation of macrophages
Formation of necrotic core
- in STABLE atherosclerotic plaques
Foam cells die & rupture
What are the different types of Atherosclerotic lesions?
1. Lesion-prone location – Adaptive thickening. 2. Type 2 lesion – foam cells. 3. Type 3 lesion (preatheroma) – extracellular lipid. 4. Type 4 lesion (atheroma) – bigger core of extracellular lipid. 5. Type 5 lesion (fibroatheroma) – fibrous thickening. 6. Type 6 lesion (complicated lesion) – fissure & haematoma.
(onenote!!)
What effect does remnant lipids have on the endothelium
The remnant lipids are the CHYLOMICRON remnants that are very good at infiltrating the endothelial wall
Remnants include:
• VLDL
• Chylomicron remnants
• IDL
Note – remnants are MORE important than LDLs here!
What causes the INFLAMMATORY part of atherosclerosis?
Lipid remnants!
NOT LDL
Charactertics of a STABLE vs. UNSTABLE plaque?
Stable plaque
– thick fibrous cap
– sometimes have a thinner lumen but are less likely to rupture
Unstable plaque
– thin fibrous cap
– rich core of lipids & macrophages
– less evidence of VSMC proliferation
What normally happens if the atherosclerotic plaque is unstable?
Plaque
• ruptures
&
• exposes the thrombogenic lipid-rich core to circulating platelets & coagulation factors
Leads to THROMBOSIS
Note: the cell in the plaque also produces loads of factors that promotes inflammation & cause other cells to be attracted to the lesion causing:
• cells to proliferate
• plaque erosion
LDL vs. HDL?
LDL
– strongly associated with atherosclerosis & CHD events
– 10% increase LDL –> 20% increase in CHD events
o These events are modified by – smoking, low HDL, hypertension & diabetes
HDL
– protective effect for atherosclerosis & CHD events
o HDL tends to be low when TG are high
o HDL is lowered by – smoking, obesity, physical inactivity
