Atherosclerosis, lipoproteins and lipid lowering drugs Flashcards
What is thought to be ‘good’ and ‘bad’ cholesterol
LDL is thought to be the main culprit in atherosclerosis. LDL gets into the vascular wall, to form a core of atheroma. HDL is usually thought to be ‘good cholesterol’, in that it reduces and blocks atherosclerosis.
Outline the exogenous pathway of lipid metabilism
Fat in GI tract broken down into FA, MAG/DAG and cholesterol.
Incorporated into mixed micelles with bile acids (water soluble) for duodenal absorption
Absorbed into lymph, transferred to bloodstream via thoracic duct
Chylomicron is hydrolysed by the enzyme lipoprotein (LP) lipase releasing the triglyceride core, free fatty acids and mono- and diglycerides for energy production or storage
Residual chylomicron undergoes further delipidation, resulting in the formation of chylomicron remnants.
These are taken up by a number of tissues. In the liver they undergo lysomal degradation, and are either used for a variety of purposes (look at how in further card)
What proportion of cholesterol and TG is absorbed across duodenum from mixed micelle
Normally, virtually all triglyceride (TG) is absorbed, compared with only 50% of cholesterol.
How can chylomicrons remnants from exogenous pathway of lipid metabolism be used
remanufacture into new lipoproteins, production of cell membranes or excretion as bile salts
Outline the endogenous pathway of lipid metabolism
VLDL analogous to chylomicron, but transports TAGs, cholesterol, cholesterol ester and other lipoproteins from liver to rest of body in the blood stream
Delipidation of VLDL with lipoprotein lipase (similar to chlylomicron)… triglycerides removed from the core and replaced with cholesterol esters from HDL
VLDL transformed into LDL. But larger VLDL transformed into IDL (which is removed from plasma)
Lipoprotein lipase main enzyme for these larger VLDL.
Hepatic lipase reacts with small VLDL and IDL.
All ends up as LDL
What is the end product of the metabolic lipoprotein cascade. How does it exist in the plasma
LDL, exists in the plasma in the form of a number of subfractions; LDL I–IV
Which lipoprotein molecules are atherogenic and why
IDL and
LDL (most)
They are absorbed by macrophages within the arterial wall to form lipid-rich foam cells, the initial stage in the pathogenesis of atherosclerotic plaques
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What determines the density of lipoprotein
The amount of TAG (low density) to protein (higher density)
t/f cholesterol can be broken down within the body, and its metabolites are excreted via the enterohepatic circulation
F: Cholesterol is excreted intact
Outline reverse cholesterol transport
Cholesterol excreted intact.
Transported via HDL from peripheral tissues to be excreted.
HDL begins as lipid-deficient which then transforms into being lipid-rich.
It transfers the cholesterol it has acquired from the peripjhery to the liver directly, OR TO OTHER CIRCULATION LIPOPROTEINS (e.g. VLDL)
What is the action of HDL
HDL acts as a vehicle for the transport of cholesterol for elimination has led to the identification of HDL
a protective factor against the development of atherosclerosis
Give an overview of the inflammatory process in atherosclerosis
LDL enters subendothelium. Becomes oxidised (oxLDL) by macrophages and SMCs. Release GF/cytokines to attract more monocytes
Monocyte adheres to endothelial cells, and migrates through the endothelium into artery wall. Vessel wall must be leaky for this. Differentiates using M-CSF.
Macrophage takes up oxLDL, becoming foam cell
SMC proliferation –> plaque growth
When does endotheliam dysfunction occur in athersclerosis
Priot to clot formation
Outline endothelial dysfunction in atherosclerosis
Increased endothelial permeability
Upregulation of endothelial adhesion molecules
Leukocyte adhesion
Migration of leukocytes into the artery wall
When does formation of complicated atherosclerotic plaque occur.
Why does it happen
indicates an advanced stage in the atherosclerotic process
results from death and rupture of the lipid-laden foam cells in the fatty streak.
Explain how a complicated atherosclerotic plaque is made
What is the importance of VSMC
Foam cells containing the gobbled up LDL rupture, releasing LDL.
VSMC then migrates to the intima and secretes collagen fibres, which allows a fibrous cap to form over the lipid core.
results from death and rupture of the lipid-laden foam cells in the fatty streak.
What is a stable atherosclerotic plaque
characterised by a necrotic lipid core covered by a thick VSM-rich fibrous cap
State the 3 stages in Formation of the Complicated Atherosclerotic Plaque
Accumulation of
macrophages
Formation of
necrotic core
Formation of
the fibrous cap
T/F most fatty streaks develop into atherosclerotic plaques
F… Most fatty streaks don’t actually develop into serious atherosclerosis, but it is an early stage and begins very early in human life.
What affects the likelihood of being symptomatic when you have atherosclerotic plaquew
When is Ca2+ important in plaque
It is generally believed that the more calcium you have in the plaque, the more likely you are to be symptomatic
Higher Ca2+ also increases risk of CVD
Detected with CT scan of heart (non-invasive)
Calcification predominates after surface defect/haemoatoma/thrombosis so following complicated lesion
Give exmaples of remnant lipids
From break down of chylomicrons after a meal
VLDL, chylomicron remnant and IDL
Why are remnant lipids bad
They may be modified, and then macrophages may release cytokine adhesion molcules to recruit more macrophages
Which part of the atherosclerotic process are cholesterol remnants
High LDL alone causes atherosclerosis without inflammation
Inflammatory component of atherosclerosis is driven by elevated remnant cholesterol levels
Outline a vulnerable plaque and a stable plaque
Vulnerable: Thin fibrous cap, core rich in lipid and macrophages, less SM proliferation
Stable:relatively thick fibrous cap protecting the lipid core from the contact with blood
T/F the sae of the plaque seems to predict whether the plaque is prone to rupture
F… The size of the plaque does not appear to predict whether a plaque is prone to rupture, indeed clinical data suggest that stable plaques more often show luminal narrowing detectable by angiography than do vulnerable plaques
Where does rupture of atherosclerotic plaque usually occur
at sites of thinning (particularly at the shoulder area of the plaque)
How are macrophages involved in how likely a plaque is to rupture
Rupture is associated with greater influx and activation of macrophages, accompanied by release of matrix metalloproteinases that are involved with the breakdown of collagen
When would pain be experienced in atherosclerosis?
Someone with a stable plaque will probably have symptoms due to the thick cap obstructing blood flow to the heart –> PAIN.
What steps might lead to plaque rupture
VSMC apoptosis and matrix degrading enzymes
What happens when plaque ruptures
THROMBUS
What is LDL associated with
atherosclerosisand CHD events
By how much would a 10% increase in LDL change CHD risk
10% increase results in a 20% increasein CHD risk
What are the risk factors affecting LDL
low HDL cholesterol
smoking
hypertension
diabetes
How does HDL impact atherosclerosis and CHD
The lower the HDL cholesterol level, the higher the risk for atherosclerosis and CHD
What could lower HDL
when triglycerides are high
How can HDL be lowered
HDL cholesterol is lowered by smoking, obesity and physical inactivity
Increasing total cholesterol increases CHD risk factors, but this differs between country… why
Diet, ethnic background and social class
State the 5 drug classes used in lipid lowering and the problem in each case
- Statins- 1st line
- Bile salt sequestrants (effective, but poor compliance due to GI bloating, nausea and constipation)
- Nicotinic acid (increase HDL, but adverse actions of flushing, skin problems, GI distress, liver toxicity, hyperglycaemia
hyperuricaemia) - Fibrates (effective TAG lowering)
- Probucal (only modest effect in LDL lowering)
What is the mechanism of statin action
HMG-CoA reductase inhibitors
The cholesterol synthesis pathway is a complex process involving many biochemical pathways and feedback mechanisms in the liver. Statins inhibit the HMG-CoA reductase, the enzyme involved in the rate-limiting step in the formation of cholesterol, which is usually responsible for two-thirds of the body’s cholesterol
In response to this the hepatocytes up-regulate and increase the number of LDL receptors, increasing binding and removal of LDL cholesterol and LDL precursors from the plasma. This results in an increase in HDL levels although the mechanism involved has not been fully established
What must hepatocytes do when exposed to stains
geranyl pyrophosphate and farmesy; pyrophsophate are small lipids (not steroids) that are extremely important in the cell function, because they are involved in the modification and activation of proteins. So they are involved in cell growth, proliferation etc. (rho, ras)
The cell can’t function properly without these lipids but it can function properly without cholesterol. The cell must make these small lipids itself as taking statins will stop their production
Account for the differences in effectiveness of the different statins, despite them acting on the same enzyme (HMG-CoA reducase)
SELECTIVITY RATIO…. the higher the selectivity ratio, the greater the likelihood of the molecule being concentrated in the liver cell .
POTENCY… the lower the number the more powerful the drug as an inhibitor of the enzyme (to with antagonist, so you want low efficacy at the receptor?)
What is the rule of 6 with statins
If you double the dose of any of the statins, you only get a 6% reduction in LDL cholesterol.
Applies to all statins at all doses
When are statins most useful
In patients who have the greatest risk factors (i.e. for secondary prevention)
However, could also be useful for those without signs of heart disease yet
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What is the relationship between LDL and CHS risk
Studies have shown that the reduction in cardiovascular risk is directly proportional to the amount by which LDL is lowered.
This is not to say that LDL is the only factor in risk, but it seems to be an essential, indispensable factor.
What is meant by the pleitropic effects of statin ttreatment
Statins have several effects that are not directly related to lowering cholesterol (e.g. anti-inflammatory action).
Anti-inflammatory nature of statins might not just be with regard to reduction of inflammation of atherosclerosis, but also generalised reduced inflammation
What is the mechanism of action of fibrates
Main mechanism of action is activation of PPAR alpha receptors
PPAR = peroxisome proliferator activated receptors
PPAR gamma activators (different to the PPAR ALPHA we are talking about here) are the thiazolidinediones (glitazones) used
in diabetes
Where are PPAR found and what effect
NUCLEAR RECEPTOR on Liver and adipose tissue increases HDL
REDUCES INFLAMMATION
Mechanism of nitotinic acid
- It lowers LDL, it increases HDL, it lowers triglycerides and increases fibrinolytic activity (clot dissolution)
- But in the real world, it doesn’t work and isn’t used very much in clinical practice
- This is because it is NOT WELL TOLERATED (causes flushing, so it isn’t taken by patients)
Action of ezetimibe
- Inhibits cholesterol absorption
- Ezetimibe is absorbed and then activated as glucuronide
- They reduce LDL cholesterol a reasonable amount (15-20%)
- It has been useful as an additional treatment to statins
T/f if one has probably heart disease but quite a normal angiogram, they are probably sage
F…. the stable plaques are probably more likely to result in angina etc because the wall thick between the plaque and the blood vessel, so more chance for occlusion
Vulnerable plaques less likely to give angina as they are not that occlusive, but that also means there is a smaller barier between blood and lipid core
When might fibrates be useful in additin ot atherosclerosis
For people with very high triglycerides (e.g. diabetics) because these are at risk of acute pancreatitis
What are glitazones
PPAR gamma activators… signficiantly reduces triglycerides
T/F the helpful action of fibrates in atherosclerosis is the reduction in triglycerides
F.. they do reduce TGs a lot but the help in atherosclerosis is the increase in HDL
