17. Atherosclerosis and lipo metabolism Flashcards
what is thought to be the main culprit of atherosclerosis and why?
LDLs
they get into the vascular wall to form a core of atheroma
what is the exogenous pathway of lipid metabolism?
- absorption of fats from the diet
- triglycerides are absorbed as chylomicrons into the blood
- chylomicrons are broken down by lipases into remnants
- some of this ends up as atheroma in the vascular wall
what is the endogenous pathway of lipid metabolism?
- the liver generates different lipoproteins which are broken down and converted
- some of the lipoproteins end up with the LDL receptor
- the endogenous pathway forms 80% of the cholesterol in the body
what is reverse cholesterol transport?
a process where cholesterol is taken out of blood vessels and foam cells
what are foam cells?
smooth muscle macrophages full of lipid (including cholesterol)
what converts HDL back to LDL?
cholesterol ester transfer protein
outline the process of atherosclerosis
LDL moves into the subendothelium and is oxidised by macrophages and smooth muscle cells
release of growth factors and cytokines attract inflammatory cells such as monocytes
foam cells form in the endothelium
proliferation of fibroblasts and smooth muscle cells expand the plaque
what is stage 1 of atherosclerosis?
ENDOTHELIAL DYSFUNCTION
- the endothelium becomes dysfunctional: increased permeability, up-regulation of leucocytes, endothelial adhesion molecules and migration of leucocytes into the artery wall
what is stage 2 of atherosclerosis?
FATTY STREAK FORMATION
- a fatty streak is the earliest recognisable lesion of atherosclerosis and forms due to the aggregation of lipid-rich foam cells
- the fatty streaks usually form in the direction of blood flow
- later on the lesions also include smooth muscle cells
what is stage 3 of atherosclerosis?
FORMATION OF THE ATHEROSCLEROTIC PLAQUE
- death and rupture of the foam cells in the fatty streak
- formation of a necrotic core
- migration of smooth muscle cells into the intima and laying down of collagen fibres results in the formation of a protective fibrous cap over the lipid core
- the cap separates the highly thrombogenic lipid-rich core from circulating platelets and coagulation factors
what do complicated lesions often contain, and so what scans can be done?
calcium
coronary artery disease can be detected by doing a CT scan of the heart to detect any calcium
what are remnant lipids? give examples
come from the breakdown of chylomicrons
e.g. VLDL, chylomicron remnant and IDL
what is the difference between vulnerable and stable plaques?
vulnerable: thin fibrous caps, a core rich in lipid and macrophages and less evidence of smooth muscle proliferation
a surge in BP could lead to the break down of the plaque –> THROMBOSIS
stable: very thick fibrous cap
obstruction of blood flow to the heart due to the thick cap –> PAIN
what is plaque rupture associated with?
greater influx and activation of macrophages, accompanied by the release of matrix metalloproteinases that are involved in the breakdown of collagen
outline the features of LDL cholesterol
- strongly associated with atherosclerosis and CHD
- 10% increase = 20% increase in CHD risk
- modified by other risk factors: low HDL, smoking, hypertension, diabetes
outline the features of HDL cholesterol
- protective for risk of atherosclerosis and CHD (promotes reverse cholesterol transport)
- low when triglycerides are high
- lowered by smoking, obesity, physical inactivity
- there are some types of HDL that are not good
what are the 5 classes of drugs used to treat dyslipidaemia?
- STATINS: 1st line treatment
- BILE ACID SEQUESTRANTS: cholesterol lowering drugs but compliance is a problem due to GI bloating, nausea and constipation
- NICOTINIC ACID: increases HDL but causes flushing, skin problems, GI distress, liver toxicity, hyperglycaemia and hyperuricaemia
- FIBRATES: triglyceride-lowering drugs
- PROBUCOL: lowers LDL (not as effective)
how do statins work?
they act on the mevalonate pathway to inhibit HMG-CoA Reductase
this pathway produces geranyl pyrophosphate and farnesyl pyrophosphate which are small lipids that are important in the cell function because they are involved in cell growth and proliferation
how do statins reduce elevated LDLs?
- if cholesterol synthesis is blocked in the liver the liver cells respond by making more LDL receptors
- these receptors bind to circulating LDL and lower it
name some statin drugs
- simvastatin
- fluvastatin
- atorvastatin
- rosuvastatin
- pravastatin
what is the selectivity ratio?
the higher the selectivity ratio, the greater the likelihood of the molecule being concentrated in the liver cell
what is potency?
the lower the number the more powerful the drug as an inhibitor of the enzyme
what is the ‘rule of 6’ with regards to statins?
if you double the dose of any of the statins you only get a 6% reduction in LDL cholesterol
what is meant by the ‘pleiotropic effects of statins’? give an example of an effect
effects that are not directly related to the reduction in cholesterol
e.g. anti-inflammatory action
