Atherosclerosis, lipoproteins and lipid lowering drugs

Question 1

What is thought to be ‘good’ and ‘bad’ cholesterol

Answer 1

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.

Question 2

Outline the exogenous pathway of lipid metabilism

Answer 2

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)

Question 3

What proportion of cholesterol and TG is absorbed across duodenum from mixed micelle

Answer 3

Normally, virtually all triglyceride (TG) is absorbed, compared with only 50% of cholesterol.

Question 4

How can chylomicrons remnants from exogenous pathway of lipid metabolism be used

Answer 4

remanufacture into new lipoproteins, production of cell membranes or excretion as bile salts

Question 5

Outline the endogenous pathway of lipid metabolism

Answer 5

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

Question 6

What is the end product of the metabolic lipoprotein cascade. How does it exist in the plasma

Answer 6

LDL, exists in the plasma in the form of a number of subfractions; LDL I–IV

Question 7

Which lipoprotein molecules are atherogenic and why

Answer 7

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

Question 8

……..

Answer 8

………

Question 9

What determines the density of lipoprotein

Answer 9

The amount of TAG (low density) to protein (higher density)

Question 10

t/f cholesterol can be broken down within the body, and its metabolites are excreted via the enterohepatic circulation

Answer 10

F: Cholesterol is excreted intact

Question 11

Outline reverse cholesterol transport

Answer 11

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)

Question 12

What is the action of HDL

Answer 12

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

Question 13

Give an overview of the inflammatory process in atherosclerosis

Answer 13

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

Question 14

When does endotheliam dysfunction occur in athersclerosis

Answer 14

Priot to clot formation

Question 15

Outline endothelial dysfunction in atherosclerosis

Answer 15

Increased endothelial permeability

Upregulation of endothelial adhesion molecules

Leukocyte adhesion

Migration of leukocytes into the artery wall

Question 16

When does formation of complicated atherosclerotic plaque occur.

Why does it happen

Answer 16

indicates an advanced stage in the atherosclerotic process

results from death and rupture of the lipid-laden foam cells in the fatty streak.

Question 17

Explain how a complicated atherosclerotic plaque is made

What is the importance of VSMC

Answer 17

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.

Question 18

What is a stable atherosclerotic plaque

Answer 18

characterised by a necrotic lipid core covered by a thick VSM-rich fibrous cap

Question 19

State the 3 stages in Formation of the Complicated Atherosclerotic Plaque

Answer 19

Accumulation of
macrophages

Formation of
necrotic core

Formation of
the fibrous cap

Question 20

T/F most fatty streaks develop into atherosclerotic plaques

Answer 20

F… Most fatty streaks don’t actually develop into serious atherosclerosis, but it is an early stage and begins very early in human life.

Question 21

What affects the likelihood of being symptomatic when you have atherosclerotic plaquew

When is Ca2+ important in plaque

Answer 21

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

Question 22

Give exmaples of remnant lipids

Answer 22

From break down of chylomicrons after a meal

VLDL, chylomicron remnant and IDL

Question 23

Why are remnant lipids bad

Answer 23

They may be modified, and then macrophages may release cytokine adhesion molcules to recruit more macrophages

Question 24

Which part of the atherosclerotic process are cholesterol remnants

Answer 24

High LDL alone causes atherosclerosis without inflammation

Inflammatory component of atherosclerosis is driven by elevated remnant cholesterol levels

Question 25

Outline a vulnerable plaque and a stable plaque

Answer 25

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

Question 26

T/F the sae of the plaque seems to predict whether the plaque is prone to rupture

Answer 26

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

Question 27

Where does rupture of atherosclerotic plaque usually occur

Answer 27

at sites of thinning (particularly at the shoulder area of the plaque)

Question 28

How are macrophages involved in how likely a plaque is to rupture

Answer 28

Rupture is associated with greater influx and activation of macrophages, accompanied by release of matrix metalloproteinases that are involved with the breakdown of collagen

Question 29

When would pain be experienced in atherosclerosis?

Answer 29

Someone with a stable plaque will probably have symptoms due to the thick cap obstructing blood flow to the heart –> PAIN.

Question 30

What steps might lead to plaque rupture

Answer 30

VSMC apoptosis and matrix degrading enzymes

Question 31

What happens when plaque ruptures

Answer 31

THROMBUS

Question 32

What is LDL associated with

Answer 32

atherosclerosisand CHD events

Question 33

By how much would a 10% increase in LDL change CHD risk

Answer 33

10% increase results in a 20% increasein CHD risk

Question 34

What are the risk factors affecting LDL

Answer 34

low HDL cholesterol
smoking
hypertension
diabetes

Question 35

How does HDL impact atherosclerosis and CHD

Answer 35

The lower the HDL cholesterol level, the higher the risk for atherosclerosis and CHD

Question 36

What could lower HDL

Answer 36

when triglycerides are high

Question 37

How can HDL be lowered

Answer 37

HDL cholesterol is lowered by smoking, obesity and physical inactivity

Question 38

Increasing total cholesterol increases CHD risk factors, but this differs between country… why

Answer 38

Diet, ethnic background and social class

Question 39

State the 5 drug classes used in lipid lowering and the problem in each case

Answer 39

1. Statins- 1st line
2. Bile salt sequestrants (effective, but poor compliance due to GI bloating, nausea and constipation)
3. Nicotinic acid (increase HDL, but adverse actions of flushing, skin problems, GI distress, liver toxicity, hyperglycaemia
   hyperuricaemia)
4. Fibrates (effective TAG lowering)
5. Probucal (only modest effect in LDL lowering)

Question 40

What is the mechanism of statin action

Answer 40

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

Question 41

What must hepatocytes do when exposed to stains

Answer 41

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

Question 42

Account for the differences in effectiveness of the different statins, despite them acting on the same enzyme (HMG-CoA reducase)

Answer 42

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?)

Question 43

What is the rule of 6 with statins

Answer 43

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

Question 44

When are statins most useful

Answer 44

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

Question 45

………….

Answer 45

………

Question 46

What is the relationship between LDL and CHS risk

Answer 46

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.

Question 47

What is meant by the pleitropic effects of statin ttreatment

Answer 47

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

Question 48

What is the mechanism of action of fibrates

Answer 48

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

Question 49

Where are PPAR found and what effect

Answer 49

NUCLEAR RECEPTOR on Liver and adipose tissue increases HDL

REDUCES INFLAMMATION

Question 50

Mechanism of nitotinic acid

Answer 50

• 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)

Question 51

Action of ezetimibe

Answer 51

• 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

Question 52

T/f if one has probably heart disease but quite a normal angiogram, they are probably sage

Answer 52

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

Question 53

When might fibrates be useful in additin ot atherosclerosis

Answer 53

For people with very high triglycerides (e.g. diabetics) because these are at risk of acute pancreatitis

Question 54

What are glitazones

Answer 54

PPAR gamma activators… signficiantly reduces triglycerides

Question 55

T/F the helpful action of fibrates in atherosclerosis is the reduction in triglycerides

Answer 55

F.. they do reduce TGs a lot but the help in atherosclerosis is the increase in HDL