Atherosclerosis, Lipoproteins and Lipid-Lowering Agents

Question 1

What is the main difference in the composition of LDLs and HDLs?

Answer 1

They have different apoproteins

Question 2

What are dietary triglycerides and cholesterol packaged into once they are absorbed?

Answer 2

Chylomicrons

Question 3

What are chylomicrons broken down into?

Answer 3

When hydrolysed by lipoprotein lipase the chylomicron releases TG core, free FAs and mono and diglycerides. Then it undergoes delipidation forming ….

Chylomicron remnants

Question 4

Describe the exogenous pathway of lipid metabolism.

Answer 4

Exogenous pathway = transport and use of fats from diet.

1. Fats in GI broken into cholesterol, fatty acids, mono and diglycerides.
2. They become water soluble when combined with bile acids and can be absorbed in the duodenum.
3. Virtually all TG absorbed but only 50% cholesterol
4. Chylomicrons enter bloodstream via intestinal lymphatics and thoracic duct
5. When in plasma, chylomicrons are hydrolysed by lipoprotein lipase releasing TG core, FAs and mono and diglycerides for energy production or storage.
6. Residual chylomicron is delipidated forming chylomicron remnants, which are taken up by different tissues e.g. liver where they undergo lysomal degradation and are used for making new lipoproteins, cell membanes or excreted as bile salts.

Question 5

Describe the endogenous patway of lipid metabolism.

Answer 5

1. TGs, cholesterol, cholesterol ester and other lipoprotein particles are ransported in VLDL in bloodstream, where VLDL is delipidated using lipoprotein lipase = this is endogenous pathway of lipid metabolism.
2. TG is removed from core and exchanged for cholesterol esters (from HDL mainly)
3. Most VLDL is converted to LDL but the larger ones are lipolysed to IDL which is removed from plasma directly
4. LDL formed then leaves the plasma in the forms of a number of subfractions: LDL I-IV
5. Enterohepatic circulation provides a route of excretion of bile acids and cholesterol.

Question 6

Are most circulating lipids endogenous or exogenous?

Answer 6

Endogenous

Question 7

What forms of lipoprotein are the most atherogenic?Why?

Answer 7

• IDL and small dense LDL particles.
• They are absorbed by macrophages within the arterial wall to form lipid-rich foam cells, which is the initial stage in the pathogenesis of atherosclerotic plaques.

Question 8

What are the enzymes used for lipolysis of VLDL and IDL.

Answer 8

Large VLDL = lipoprotein lipase

Small VLDL and IDL = hepatic lipase

Question 9

Summarise reverse cholesterol transport.

Answer 9

• Cholesterol cannot be broken down within the body so is eliminated intact.
• It is transported via HDL from peripherl tissues -> liver to be excreted.
• HDL begins as a lipid-deficient precursor which changes into a lipid-rich lipoprotein which transfers cholesterol directly to liver or to other circulating lipoproteins to be transported to liver for elimination.

Question 10

Why is HDL identifed as a protective factor against development of atherosclerosis?

Answer 10

HDL acts as a vehicle for the transport of cholesterol for elimination in the process of reverese cholesterol transport so it is said to be protective against atherosclerosis.

Question 11

Define atherosclerosis.

Answer 11

Atherosclerosis is an inflammatory fibroproliferative disorder

Question 12

What cells are recruited in the process of atherosclerosis?

Answer 12

Macrophages (which turn into foam cells) Fibroblasts Smooth muscle cells

Question 13

What must initially happen for the process of atherosclerosis to begin?

Answer 13

ENODOTHELIAL DYSFUNCTION precedes lesion formation. This includes:

• Increase in permeability of the endothelium
• Upregulation of leukocytes and cell adhesion molecules
• Leukocyte adhesion
• Migration of leukocytes into arterial wall

Question 14

What is the name of the earliest recognisable lesion in atherosclerosis.?

Answer 14

Fatty streak = first visible sign of atherosclerosis to the naked eye

Happens early in human development but probably not all progress to atherosclerosis.

Question 15

Describe what happens in fatty streak formation in atherosclerosis.

Answer 15

Aggregation of lipid-rich foam cells ( from macrophages and T-lymph) occurs inside the tunica intima. Later lesions include smooth muscle cells.

Steps involved:

• smooth-muscle migration
• T-cell activation
• foam cell formation
• platelet adherence and aggregation

Question 16

Which cells are responsible for producing a protective fibrous cap over the fat core?

Answer 16

Smooth muscle cells lay down collagen fibres

Question 17

What can happen as the atheroma grows larger?

Answer 17

Some of the foam cells die and rupture, releasing their toxic contents to form a lipid necrotic core

Question 18

Describe how the complicated atherosclerotic plaque is formed in the advanced stages of atherosclerosis.

Answer 18

• Develops form a process of cell death and rupture of foam cells in the fatty streak.
• VSMCs migrate to the intima and lay down collagen fibres to form a protective fibrous cap over the lipid core.
• Fibrous cap separates the highly thrombogenic lipid-rich core from circulating platelets and other coagulation factors.
• Stable atherosclerotic plaques have a necrotic lipid core covered by a thick VSM-rich fibrous cap.
• Lesions expand at shoulders by continued leukocyte adhesion.

Question 19

What is an unstable atherosclerotic plaque?

Answer 19

The fibrous cap thins and eventually ruptures, exposing the thrombogenic lipid core to the platelets and coagulation factors

This causes THROMBOSIS

NOTE: plaque erosion is also associated with hardening of the arteries, leading to weakening and thickening of the vessel wall leading to aneurysm and possible haemorrhage

NB: a stable atherosclerotic plaque is characterised by a necrotic core covereb by a thick VSM-rich fibrous cap.

Question 20

What do complicated lesions often contain?

Answer 20

Calcium

Question 21

What type of scanning is used to look at atherosclerotic plaques?

Answer 21

electron beam CT

This looks at the levels of calcium

If calcification predominates then the patient is at high risk of cardiovascular disease.

Question 22

What is the significance of chylomicron remnants with regards to atherosclerosis? Which atherosclerosis pathway are they associated with?

Answer 22

• They are very good at getting into the tunica intima, therefore they are extremely atherogenic
• Can cause atherosclerosis in the same way as LDL but….
• Elevated levels of remnant cholesterol also causally associated with low-grade inflammation and IHD
• Elevated LDL is associated with IHD but not inflammation
• Indicating LDL doesn’t need an inflammatory component to cause atherosclerosis whereas remnant cholesterol does.

Question 23

What are some characteristics of vulnerable plaques?

Answer 23

• Thin fibrous cap
• A core rich in lipid and macrophages
• Less evidence of smooth muscle proliferation

NB: SIZE of plaque does not indicate whether it is prone to rupture.

Vulnerable plaques are prone to rupture and ulceration, followed by rapid development of thrombi.

Question 24

What are metalloproteinases associated with (released during plaque rupture)?

Answer 24

Breakdown of collagen

Question 25

What does plaque rupture lead to?

Answer 25

Thrombosis

Question 26

Where is rupture of a plaque most likely to occur?

Answer 26

Rupture usually occurs where there are * signs of thinning (particulary shoulder area) * few SMCs * abumndant macrophages and T cells Rupture -\> activation of macrophages -\> release of matrix metalloproteinases (involved in breakdown of collagen).

Question 27

What can modify LDL cholesterol?

Answer 27

_Risk factors for LDL aggrevation:_ * Low HDL * Diabetes * Smoking * Hypertension

Question 28

What do low HDL cholesterol levels tend to be associated with?

Answer 28

High triglyceride levels

Question 29

What factors can lower HDL cholesterol levels?

Answer 29

* Smoking * Obesity * Physical inactivity

Question 30

What is the relationship between triglycerides and HDL cholesterol?

Answer 30

HDL tends to be low when triglycerides are high.

Question 31

How much does a 10% increase in LDL increase the risk of CHD?

Answer 31

by 20%

Question 32

What is considered a normal triglyceride level?

Answer 32

\< 200 mg/dL or 2.3 mmol/L

Question 33

What did the Seven Countries Study of the relationship between serum cholesterol to mortality show?

Answer 33

There is linear relationship between serum cholesterol and death rate from CHD but large between country differences exist in terms of CHD mortality rates at given cholesterol levels. This suggests that other factors such as diet, ethnic background, social class might be at play,

Question 34

Other than heart disease, what else is a very high triglyceride level associated with?

Answer 34

Pancreatitis

Question 35

State some different drug therapies that have been used to treat high cholesterol.

Answer 35

* Bile acid sequestrants * Nicotinic acid * Fibrates * Statins * Eztimibe

Question 36

What are statins also known as?

Answer 36

inhibitors of HMG CoA reductase

Question 37

Describe the mechanism of action of statins.

Answer 37

* They are HMG-CoA reductase inhibitors - they inhibit the rate-limiting step in the formation of cholesteol which is responsible for two-thirds of the body's formation of cholesterol. * This causes hepatocytes to upregulate LDL receptors which increases removal of LDL * This leads to increase in HDL levels too ## Footnote *Basically starving the hepatocytes of cholesterol will cause them to try to get LDL out of the circulation which makes statins effective.*

Question 38

What are two important products of the cholesterol synthesis pathway?

Answer 38

* Geranyl pyrophosphate * Farnesyl pyrophosphate They are involved in the modification and activation of proteins(all of which begin with R)

Question 39

How do statins decrease plasma LDL levels?

Answer 39

Statins block the cholesterol synthesis pathway, which leads to the liver responding by producing more LDL receptors Having more LDL receptors means that more LDL can be removed from the blood

Question 40

What is the selectivity ratio of a statin?

Answer 40

The higher the selectivity ratio, the greater the likelihood of the molecule being concentrated in the liver cell

Question 41

What is the Rule of 6?

Answer 41

* With the initial dose of statin, LDL can be reduced by 20-50% * Doubling the dose of any statin after that will give a 6% reduction each time

Question 42

In what group of patients will drugs such as statins have the greatest effects?

Answer 42

High risk groups Reduction of risk is also proportional to the amount by which you lower LDL. Other studies show that absolute benefits are cheifly related to the individual's risk - the worse your situation the more you benefit.

Question 43

What are the effects of statins?

Answer 43

Lower LDL Increase HDL Anti-inflammatory

Question 44

How do fibrates act?

Answer 44

* Fibrates activate PPAR-alpha receptors (PPAR = peroxisome proliferator activated receptors - a term used in rat physiology\_ * They lower plasma fatty acids and lower triglycerides * PPAR gamma activators are the thiazolidinediones (glitazones) often used in diabetics with high triglycerides

Question 45

What are the effects of fibrates?

Answer 45

* Lower free fatty acids * Lower triglycerides

Question 46

Apart from use in individuals with risk of heart disease, what condition could fibrates be used to prevent?

Answer 46

Used to reduce the risks of pancreatitis

Question 47

What is the mechanism of action of nicotinic acid ?

Answer 47

1. Increases HDL 2. Decreases LDL 3. Lowers TG 4. Increases fibrinolytic activity 5. Decreases platelet adhesion and aggregation The mechanism may involve a **decrease in esterification and synthesis of hepatic triglycerides**. Niacin treatment also decreases the serum levels of **apo B**, the major protein component of the VLDL (very low-density lipoprotein) and LDL fractions, probably due to TG decrease.

Question 48

What is the major side effect of niacin?

Answer 48

Causes thrushing - so not very well tolerated This drg is therefore not used unless patients are resistant to other drugs.

Question 49

What is the mechanism of action of ezetimibe?

Answer 49

* Inhibits cholesterol absoprtion * Absorbed then activated by glucuronic acid/glucuronide

Question 50

Name an important drug that can be given with statins to further decrease LDL levels?

Answer 50

Ezetimibe – it inhibits cholesterol absorption Adding ezetimibe will further decrease LDL by 18% when a standard dose is given. Although uncertain if this is as good as just lowering it with statin (x5)

Question 51

What is ezetimibe activated as?

Answer 51

Glucuronide

Question 52

Which protein is involved in the transport of cholesteryl esters and triglycerides from HDLs to LDLs?

Answer 52

Cholesteryl Ester Transfer Protein (CETP)

Question 53

What was the result of attempted inhibition of CETP? (cholesteryl ester transfer protein in the reverse cholesterol transport pathway)

Answer 53

It increased HDL and decreased LDL but it had off target effects that led to increased mortality NOTE: the drug was called torcetrapib

Question 54

What are the possible causes of increased mortality with CETP inhibitors in patients?

Answer 54

* "off target" effects? * activation of aldosterone synthesis causing raised BP?

Question 55

What is PCSK9?

Answer 55

* It is a secreted inhibitor of LDL receptors * It stops the LDL in the plasma from binding to the LDL receptor and being taken up * PCSK9 inhibition can lead to a decrease in cholesterol levels * Giving statins increases LDLR and increases PCSK9- g**iving PCSK9 inhibitor can enhance effect of statins**

Question 56

What group of patients unexpectedly benefit from PCSK9 inhibitors?

Answer 56

Familial hypercholesterolaemia - should have no LDL receptors but somehoe benefit from this durg. So they are the key treatment group for this drug.

Question 57

How does PCSK9 inhibition work?

Answer 57

PCSK9 is usually produced in the cell and comes out into the membrane where it binds and stops cholesterol entering the cell. This is blocked.

Question 58

Should we give statins to people without established cardiovascular disease but with cardiovascular risk factors?

Answer 58

Secondary prevention - patients given statins to stop teh established disease from progressing. Primary prevention - looking at patients without disease with minimal or no risk factors, assuming they don't have the disease. It is UNKNOWN whether the benefits of statins apply to primary prevention too or not . Amount given to have benefiical effects woud also have to be considerable and would only reduce the risk of stroke in 1 in 150.

Question 59

What is stopping us from using PCSK9 inhibitors more?

Answer 59

The cost £4000 per patient per year compared to statins which cost only £30 a year.