16. Atherosclerosis and lipo metabolism

Question 1

What does the exogenous pathway of lipid metabolism involve?

Answer 1

• Dietary triglycerides and cholesterol are broken down and packaged into chylomicrons
• Chylomicrons broken into smaller lipids => chylomicron remnants
• These products can end up in adipose tissue and blood vessels

Question 2

What does the endogenous pathway of lipid metabolism involve?

Answer 2

• Most circulating lipids are endogenous (80%)
• Lipid generates different lipoproteins, which are broken down and converted
• Some end up with the LDL receptor

Question 3

Which part of the blood vessel wall are chylomicrons good at getting into?

Answer 3

Tunica intima

Question 4

What type of disorder is atherosclerosis?

Answer 4

Inflammatory fibro-proliferative

Question 5

What is reverse cholesterol transport?

Answer 5

• Process where cholesterol is taken out of the blood vessels and foam cells
• HDL => LDL, by cholesteryl ester transfer protein

Question 6

How are white blood cells involved in athersclerosis?

Answer 6

• Circulating monocyte enters leaky endothelium
• Converted into macrophage
• Ingest lots of lipid to become foam cells
• Foam cells also derived from T-lymphocytes

Question 7

Outline the progression of atherosclerosis

Answer 7

• LDL moves into the subendothelium
• Oxidised by macrophages and smooth muscle cells
• Release of growth factors and cytokines, which attract inflammatory cells (monocytes)
• Foam cells form in endothelium
• Proliferation of fibroblasts and smooth muscle cells - plaque expands

Question 8

Describe what happens in the first stage of atherosclerosis (endothelial dysfunction)

Answer 8

• Greater permeability of endothelium
• Up-regulation of leucocytes, endothelial adhesion molecules
• Migration of leucocytes into artery wall
• These all precede lesion formation

Question 9

Describe what happens in the second stage of atherosclerosis (fatty streak formation)

Answer 9

• Earliest recognisable lesion
• Caused by aggregation of foam cells
• Later on lesions include smooth muscle cells
• Fatty streaks usually formed in the direction of blood flow
• Early stage, and most don’t develop into serious athersclerosis

Question 10

Describe what happens in the third stage of atherosclerosis (formation of atherosclerotic plaque)

Answer 10

• Death and rupture of the foam cells in the fatty streak
• Necrotic core forms
• Migration of smooth muscle cells into the intima and laying down collagen fibres
• Protective fibrous cap forms over the lipid core
• Stable plaques are characterised by a necrotic lipid core covered by a thick vascular smooth muscle-rich fibrous plaque

Question 11

Why is the fibrous cap important in a plaque?

Answer 11

Separates the highly thrombogenic lipid-rich core from the circulating platelets and coagulation factors

Question 12

What characterises an unstable atherosclerotic plaque and what happens if it ruptures?

Answer 12

• Unstable plaque characterised by thin fibrous cap, rich core, less smooth muscle proliferation
• Thrombogenic lipid rich core exposed to circulating platelets and coagulation factors
• Associated with greater influx and activation of macrophages
• Accompanied by the release of matrix metalloproteinases involved in collagen breakdown
• Surge in BP => thrombosis
• Plaque erosion can also lead to the hardening, weakening and thinning of the arteries
• Aneurysm and haemorrhage possible

Question 13

How can you detect coronary artery disease using a common element/molecule?

Answer 13

• Complicated lesions often contain calcium
• CT scan of the heart can detect calcium
• More calcium in the plaque => more likely to be symptomatic

Question 14

Why are remnant lipids significant in atherosclerosis and what do remnants include?

Answer 14

• Quite atherogenic
• Lots of remnant lipoproteins in the blood (as a result of fatty meals) => higher risk of CHD
• Includes VLDL, IDL and chylomicron remnants

Question 15

Why does a stable plaque still cause symptoms?

Answer 15

• Obstruction of blood flow to the heart

* Leads to pain

Question 16

How does the modification of LDL (e.g. oxidisation) affect its atherogenicity and which molecule can protect it?

Answer 16

• Makes it more atherogenic

* HDL can protect LDL from oxidation

Question 17

How does a low level of HDL affect the risk for atherosclerosis and CHD?

Answer 17

Increases the risk

Question 18

What happens to the levels of HDL when triglycerides are high?

Answer 18

Tends to be low

Question 19

What environmental factors lower HDL levels?

Answer 19

Smoking, obesity and physical inactivity

Question 20

Can HDL cholesterol be bad?

Answer 20

Yes
• Protection of LDL
• Become bad when oxidised

Question 21

What is the first line of treatment for dyslipidaemia?

Answer 21

Statins
• Effective in lowering LDL
• Good tolerability profile

Question 22

How do bile acid sequestrants work and what are the problems with using them?

Answer 22

• Cause body to use more cholesterol to make bile
• Effective cholesterol-lowering drugs
• Compliance is an issue:
- GI bloating
- nausea
- constipation

Question 23

How does probucol and fibrates work?

Answer 23

• Probucol - modest effect in lowering LDL

* Fibrates - effective in lowering triglycerides

Question 24

How do statins work?

Answer 24

• Inhibit HMG-CoA reductase, in the mevalonate pathway
• 2 main products of the pathway = geranyl pyrophosphate + farnesyl pyrophosphate
• These are small lipids, involved in the modification and activation of proteins
• When cholesterol synthesis is blocked, liver makes more LDL receptors
• LDLR binds to circulating LDL, lowering it

Question 25

What does a higher ‘selective ratio’ mean in context of lipids?

Answer 25

Greater likelihood of the molecule being concentrated in the liver cell

Question 26

If the number for the potency of a drug is lower, what does this mean for statins?

Answer 26

It is more powerful as an inhibitor of the enzyme

Question 27

If you double the dose of any statins, how does this effect LDL cholesterol?

Answer 27

6% reduction

Question 28

What are ‘pleiotropic’ effects of statins?

Answer 28

Effects that are not directly related to the reduction of cholesterol
• e.g. anti-inflammatory

Question 29

How do fibrates work and who are they given to?

Answer 29

• Activation of PPAR alpha receptors (nuclear receptors)
• Lowers plasma fatty acids and triglycerides
• Reduces inflammation
• Often used in diabetics with high triglycerides
• Reduces inflammation
• Often used in diabetics with high triglycerides to reduce acute pancreatitis risk
• Given to patients with low HDL and LDL

Question 30

How does nicotinic acid work?

Answer 30

• Lowers LDL
• Increases HDL
• Lower triglycerides
• Increases fibrinolytic activity
• Not well tolerated, so not used much in clinical practice, despite effectiveness:
- flushing, skin problems, GI distress, liver toxicity, hyperglycaemia, hyperuricaemia

Question 31

How does ezetimibe work?

Answer 31

• Inhibits cholesterol absorption
• The drug is absorbed and activated as glucuronide
• Reduces LDL cholesterol
• Useful as an addition to statins

Question 32

What is responsible for the breakdown of HDL into LDL?

Answer 32

Cholesteryl ester transfer protein (CTEP)

Question 33

How effective were CETP inhibitors?

Answer 33

• Increase HDL and decrease LDL
• They were killing people in expanded clinical trials
• Torcetrapib had off-target adverse effects (i.e. unpredictable)
• Could have been due to the activation of aldosterone synthesis => increased BP

Question 34

What is PCSK9 and how is it significant in cholesterol lowering treatment

Answer 34

• Inhibitor of the LDLR
• Stops LDL from reaching the LDLR
• Unfortunately statins increase PCSK9 (as well as LDLR)
• Therefore, monoclonal antibodies have been produced to inactivate PCSK9
• This allows the LDL receptor to continue working, lowering the circulating LDL levels

Question 35

What patients appear to have the greatest need for PCSK9 inhibition therapy?

Answer 35

Familial hypercholesterolaemia patients