17. Atherosclerosis and lipo metabolism

Question 1

what is thought to be the main culprit of atherosclerosis and why?

Answer 1

LDLs

they get into the vascular wall to form a core of atheroma

Question 2

what is the exogenous pathway of lipid metabolism?

Answer 2

• absorption of fats from the diet
• 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

Question 3

what is the endogenous pathway of lipid metabolism?

Answer 3

• the liver generates different lipoproteins which are broken down and converted
• some of the lipoproteins end up with the LDL receptor
• the endogenous pathway forms 80% of the cholesterol in the body

Question 4

what is reverse cholesterol transport?

Answer 4

a process where cholesterol is taken out of blood vessels and foam cells

Question 5

what are foam cells?

Answer 5

smooth muscle macrophages full of lipid (including cholesterol)

Question 6

what converts HDL back to LDL?

Answer 6

cholesterol ester transfer protein

Question 7

outline the process of atherosclerosis

Answer 7

LDL moves into the subendothelium and is oxidised by macrophages and smooth muscle cells

release of growth factors and cytokines attract inflammatory cells such as monocytes

foam cells form in the endothelium

proliferation of fibroblasts and smooth muscle cells expand the plaque

Question 8

what is stage 1 of atherosclerosis?

Answer 8

ENDOTHELIAL DYSFUNCTION

• the endothelium becomes dysfunctional: increased permeability, up-regulation of leucocytes, endothelial adhesion molecules and migration of leucocytes into the artery wall

Question 9

what is stage 2 of atherosclerosis?

Answer 9

FATTY STREAK FORMATION

• a fatty streak is the earliest recognisable lesion of atherosclerosis and forms due to the aggregation of lipid-rich foam cells
• the fatty streaks usually form in the direction of blood flow
• later on the lesions also include smooth muscle cells

Question 10

what is stage 3 of atherosclerosis?

Answer 10

FORMATION OF THE ATHEROSCLEROTIC PLAQUE

• death and rupture of the foam cells in the fatty streak
• formation of a necrotic core
• migration of smooth muscle cells into the intima and laying down of collagen fibres results in the formation of a protective fibrous cap over the lipid core
• the cap separates the highly thrombogenic lipid-rich core from circulating platelets and coagulation factors

Question 11

what do complicated lesions often contain, and so what scans can be done?

Answer 11

calcium

coronary artery disease can be detected by doing a CT scan of the heart to detect any calcium

Question 12

what are remnant lipids? give examples

Answer 12

come from the breakdown of chylomicrons

e.g. VLDL, chylomicron remnant and IDL

Question 13

what is the difference between vulnerable and stable plaques?

Answer 13

vulnerable: thin fibrous caps, a core rich in lipid and macrophages and less evidence of smooth muscle proliferation

a surge in BP could lead to the break down of the plaque –> THROMBOSIS

stable: very thick fibrous cap

obstruction of blood flow to the heart due to the thick cap –> PAIN

Question 14

what is plaque rupture associated with?

Answer 14

greater influx and activation of macrophages, accompanied by the release of matrix metalloproteinases that are involved in the breakdown of collagen

Question 15

outline the features of LDL cholesterol

Answer 15

• strongly associated with atherosclerosis and CHD
• 10% increase = 20% increase in CHD risk
• modified by other risk factors: low HDL, smoking, hypertension, diabetes

Question 16

outline the features of HDL cholesterol

Answer 16

• protective for risk of atherosclerosis and CHD (promotes reverse cholesterol transport)
• low when triglycerides are high
• lowered by smoking, obesity, physical inactivity
• there are some types of HDL that are not good

Question 17

what are the 5 classes of drugs used to treat dyslipidaemia?

Answer 17

• STATINS: 1st line treatment
• BILE ACID SEQUESTRANTS: cholesterol lowering drugs but compliance is a problem due to GI bloating, nausea and constipation
• NICOTINIC ACID: increases HDL but causes flushing, skin problems, GI distress, liver toxicity, hyperglycaemia and hyperuricaemia
• FIBRATES: triglyceride-lowering drugs
• PROBUCOL: lowers LDL (not as effective)

Question 18

how do statins work?

Answer 18

they act on the mevalonate pathway to inhibit HMG-CoA Reductase

this pathway produces geranyl pyrophosphate and farnesyl pyrophosphate which are small lipids that are important in the cell function because they are involved in cell growth and proliferation

Question 19

how do statins reduce elevated LDLs?

Answer 19

• if cholesterol synthesis is blocked in the liver the liver cells respond by making more LDL receptors
• these receptors bind to circulating LDL and lower it

Question 20

name some statin drugs

Answer 20

• simvastatin
• fluvastatin
• atorvastatin
• rosuvastatin
• pravastatin

Question 21

what is the selectivity ratio?

Answer 21

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

Question 22

what is potency?

Answer 22

the lower the number the more powerful the drug as an inhibitor of the enzyme

Question 23

what is the ‘rule of 6’ with regards to statins?

Answer 23

if you double the dose of any of the statins you only get a 6% reduction in LDL cholesterol

Question 24

what is meant by the ‘pleiotropic effects of statins’? give an example of an effect

Answer 24

effects that are not directly related to the reduction in cholesterol

e.g. anti-inflammatory action

Question 25

how do fibrates work?

Answer 25

• activate PPAR (peroxisome proliferator activated receptors) alpha receptors
• lower plasma fatty acids and triglycerides
• reduce inflammation
• often used in diabetics

Question 26

how does nicotinic acid work?

Answer 26

• lowers LDL, increases HDL, lowers triglycerides and increases fibrinolytic activity (clot dissolution)
• not very well tolerated

Question 27

what is ezetimibe and how does it work?

Answer 27

• inhibits cholesterol absorption
• absorbed and then activates as glucuronide
• reduces LDL
• useful additional treatment of statins: because of the rule of 6 it is best to find something else that can be added to increase the effectiveness of statins without increasing the dose of statins

Question 28

what are CETP inhibitors and what are the problems with them?

Answer 28

cholesterol ester transfer protein inhibitors to prevent the breakdown of HDL –> LDL

they were killing people via adverse effects - may have been activation of aldosterone synthesis –> increased BP

Question 29

what is PCSK9?

Answer 29

an inhibitor of the LDL receptor so stops LDL from reaching the receptor (bad)

Question 30

how is PCSK9 inhibition being used?

Answer 30

PCSK9 inhibition enhances the lipid-lowering effect of statins

monoclonal antibodies have been produced to inactivate PCSK9 and protect the LDL receptor so that it can continue to work and reduce cholesterol