Atherosclerosis and Lipometabolism Flashcards
What do LDLs and HDLs do?
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
What is the exogenous pathway of lipid metabolism?
The amount of the cholesterol that enters the circulation from the diet is very small. However, other lipids (such as triglycerides) are absorbed. 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?
There is a pathway in which the liver generates different lipoproteins, which are then broken down and converted. Some of the lipoproteins end up with the LDL receptor.
This endogenous pathway forms around 80% of the cholesterol in the body. Most circulating lipids are endogenous. A small proportion of the lipids end up in the walls of blood vessels.
What are foam cells?
smooth muscle macrophages that are full of lipid
What is reverse cholesterol transport?
This is a process where cholesterol is taken OUT of blood vessels and foam cells
There is a transformation of HDL (beneficial) back to LDL – by cholesteryl ester transfer protein
What are the stages of atherosclerosis?
- endothelium becomes dysfunctional -> greater permeability of endothelium, up-regulation of leukocytes, endothelium adhesion molecules and migration of leukocytes into artery wall
- fatty streat formed by aggregation of lipid-rich foam cells. later on lesions also include smooth muscle cells - fatty streaks usually formed in direction of blood flow
* most fatty streaks don’t actually develop into serious atherosclerosis - death and rupture of foam cells in fatty streak -> necrotic core
migration of smooth muscle cells into intima and laying down collagen fibres -> formation of protective fibrous cap over lipid core
How can coronary artery disease be detected?
complicated lesions often contain calcium - CT detects calcium
- The more calcium detectable in the coronary arteries, the higher the risk of CVD
What is the importance of remnant lipids?
- come from chylomicrons
e. g VLDL, chylomicron remnant and IDL
they are quite atherogenic
If there are lots of remnant lipoproteins in the blood (as a result of eating fatty meals), the individual is at a higher risk of CHD compared to blood with fewer remnants
What are the features of the vulnerable plaque?
- thin fibrous cap
- core rich in lipid and macrophages
- less evidence of smooth muscle proliferation
What are the consequences of an atheroma with a thick and thin cap?
Someone with a stable plaque will probably have symptoms due to the thick cap obstructing blood flow to the heart -> PAIN
Someone with a vulnerable plaque has only a very thin wall separating the lumen and lipid core. A surge in BP could lead to the breaking down of the thin fibrous cap -> THROMBOSIS.
What would a 10% increase in LDL cholesterol lead to?
20% increase in CHD release
What factors aggregate the effects of LDL cholesterol?
- low HDL cholesterol
- smoking
- hypertension
- diabetes
- If LDL is modified (particularly by oxidising it), it becomes much more atherogenic
What are the features of HDL cholesterol?
- HDL cholesterol is protective for risk of atherosclerosis and CHD (promotes reverse cholesterol transport)
- The lower the HDL cholesterol level, the higher the risk for atherosclerosis and CHD
- HDL cholesterol tends to be low when triglycerides are high
- HDL cholesterol is lowered by smoking, obesity and physical inactivity
What are the classes of drugs used to treat dyslipidaemia?
- Statins - first line treatment for dyslipidaemia, highly effective in lowering LDL cholsterol and they have a good tolerability profile
- Bile Acid Sequestrants - effective cholesterol-lowering drugs, however, compliance can be a problem because they tend to cause GI bloating, nausea and constipation
- Nicotinic Acid - effective at increasing HDL cholesterol, but adverse actions include flushing, skin problems, GI distress, liver toxicity, hyperglycaemia and hyperuricaemia
- Fibrates - effective triglyceride-lowering drugs
- Probucol - only has a modest effect in lowering LDL cholesterol
Describe the mechanism of action of statins
Statins act on the mevalonate pathway to inhibit HMG-CoA Reductase. Two of the main products of this pathway are geranyl pyrophosphate and farnesyl pyrophosphate. These are small lipids (not steroids) that are involved in the modification and activation of proteins (cell growth, proliferation etc.). The cell can’t function properly without these lipids but it can function properly without cholesterol. The cell must make these small lipids itself
If you block cholesterol synthesis in the liver then the liver cells respond by making more LDL receptors
These LDL receptors bind to circulating LDL and lower it
- The main target of statins is to lower LDL synthesis in the liver cells
How does selectivity ratio affects statins?
the higher the ratio, the greater the likelihood of the molecule being concentrated in the liver
How does potency affect the effects of statins?
the lower the number, the more powerful the drug as an inhibitor of the enzyme
What is the rule of 6 regarding statins?
if you double the dose of any statin you only get a 6% reduction in LDL cholesterol
What is a pleiotropic effect of statins?
- Pleiotropic effects of statins: effects that are not directly related to the reduction in cholesterol
Statins are anti-inflammatory in a vascular setting. They can be anti-inflammatory in other situations too (e.g. rheumatoid arthritis, IBD). It has been proposed that using statins in chronic inflammation will be useful
How do fibrates lower lipid levels?
activation of peroxisome proliferator activated receptor (PPAR) alpha receptors
- NOTE: PPAR gamma activators are the thiazolidinediones (glitazones) used in diabetes - often used in diabetics with high triglycerides
Fibrates lower plasma fatty acids and triglycerides (they are much better than statins are doing this)
- FIBRATES REDUCE INFLAMMATION
What does nicotinic acid do?
Why isn’t it used clinically?
- It lowers LDL
- it increases HDL
- it lowers triglycerides
- increases fibrinolytic activity (clot dissolution)
- NOT WELL TOLERATED (causes flushing, so it isn’t taken by patients)
What does ezetimibe do?
- Inhibits cholesterol absorption
- Ezetimibe is absorbed and then activated as glucuronide
- They reduce LDL cholesterol a reasonable amount (15-20%)
- Because of the rule of 6, you want to find something else that can be added to increase the effectiveness of statins at lowering cholesterol without just increasing the dose of the statin - ezetimibe decreases LDL further when given with a statin
What do CETP inhibitors do?
another process breaks down HDL -> LDL using cholesterylester transfer protein (CETP)
Had a positive effect in increasing HDL and decreasing LDL - when they expanded the clinical trial they found that it was actually killing people
- It MIGHT be due to activation of aldosterone synthesis leading to increased blood pressure
Other ‘rapibs’ do NOT have the same effects
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What is PCSK9?
proprotein convertase subtilisin/kexin type 9
an inhibitor of the LDL receptor so it stops the LDL from reaching the LDL receptor
LDLR and PCSK9 gene expression are coinduced by statins -> PCSK9 inhibition enhances the lipid-lowering effect statins
- Monoclonal antibodies are the most advanced PCSK9 inhibitors currently in development
When is PCSK9 inhibition used?
It protects the LDL receptor so that the LDL receptor can continue to work well
PCSK9 inhibitors given with atorvastatin causes a big decline in cholesterol
Familial hypercholesterolemia patients appear to have the greatest need for such therapies.
