Atherosclerosis, Lipoproteins and Lipid-Lowering Agents Flashcards

1
Q

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

A

They have different apoproteins

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2
Q

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

A

Chylomicrons

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3
Q

What are chylomicrons broken down into?

A

Chylomicron remnants

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4
Q

Are most circulating lipids endogenous or exogenous?

A

Endogenous

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5
Q

What is the significance of chylomicron remnants with regards to atherosclerosis?

A

They are very good at getting into the tunica intima

- causes inflammation

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6
Q

Define atherosclerosis.

A

Atherosclerosis is an inflammatory fibro-proliferative disorder

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7
Q

What cells are recruited in the process of atherosclerosis?

A

monocytes–>Macrophages (which turn into foam cells)

Fibroblasts

Smooth muscle cells

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8
Q

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

A

Increase in permeability of the endothelium

Upregulation of leukocytes and cell adhesion molecules

adhesion of leukocytes

Migration of leukocytes into arterial wall

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9
Q

What can happen as the atheroma grows larger?

A

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

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10
Q

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

A

Smooth muscle cells lay down collagen fibres

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11
Q

What is an unstable atherosclerotic plaque?

A

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

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12
Q

What do complicated lesions often contain?

A

Calcium

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13
Q

What are some characteristics of vulnerable plaques?

A

Thin fibrous cap

A core rich in lipid and macrophages

Less evidence of smooth muscle proliferation

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14
Q

What can modify LDL cholesterol?

A
  • Low HDL
  • Diabetes
  • Smoking
  • Hypertension

All of these raise LDL

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15
Q

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

A

High triglyceride levels

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16
Q

What factors can lower HDL cholesterol levels?

A

Smoking

Obesity

Physical inactivity

17
Q

What is considered a normal triglyceride level?

A

< 200 mg/dL or 2.3 mmol/L

18
Q

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

A

Pancreatitis

19
Q

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

A

Bile acid sequestrants

Nicotinic acid

Fibrates

Statins

20
Q

Describe the mechanism of action of statins.

A

They are HMG-CoA reductase inhibitors

21
Q

What are two important products of the cholesterol synthesispathway?

A

Geranyl pyrophosphate —> Farnesyl pyrophosphate

They are involved in the modification and activation of proteins (Rho, Ras)

22
Q

How do statins decrease plasma LDL levels?

A

Statins block the cholesterol synthesis pathway (block HMG-CoA reductase), 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

23
Q

What is the selectivity ratio of a statin?

A

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

24
Q

What is the Rule of 6?

A

Doubling the dose of any statin will give a 6% reduction in the level of LDL cholesterol

25
Q

How do fibrates act?

A

They activate PPAR-alpha (this is a TF that makes a gene involved in FA uptake and metabolism.
They lower plasma fatty acids and lower triglycerides
They are often used in diabetics with high triglycerides

26
Q

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

A

Ezetimibe – it inhibits cholesterol absorption in small intestine

27
Q

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

A

Cholesteryl Ester Transfer Protein (CETP)

28
Q

What was the result of attempted inhibition of CETP?

A

It increased HDL and decreased LDL but it had off target effects that led to increased mortality and raised BP

NOTE: the drug was called torcetrapib

29
Q

What is PCSK9?

A

It is an inhibitor of LDL receptors

It stops the LDL in the plasma from binding to the LDL receptor and being taken up (in liver)

PCSK9 inhibition can lead to a decrease in cholesterol levels