Atherosclerosis, Lipoproteins and Lipid-Lowering Agents Flashcards
What is the main difference in the composition of LDLs and HDLs?
They have different apoproteins
What are dietary triglycerides and cholesterol packaged into once they are absorbed?
Chylomicrons
What are chylomicrons broken down into?
Chylomicron remnants
Are most circulating lipids endogenous or exogenous?
Endogenous
What is the significance of chylomicron remnants with regards to atherosclerosis?
They are very good at getting into the tunica intima
Define atherosclerosis.
Atherosclerosis is an inflammatory fibro-proliferative disorder
What cells are recruited in the process of atherosclerosis?
Macrophages (which turn into foam cells)
Fibroblasts
Smooth muscle cells
What must initially happen for the process of atherosclerosis to begin?
Increase in permeability of the endothelium
Upregulation of leukocytes and cell adhesion molecules
Migration of leukocytes into arterial wall
What can happen as the atheroma grows larger?
Some of the foam cells die and rupture, releasing their toxic contents to form a lipid necrotic core
Which cells are responsible for producing a protective fibrous cap over the fat core?
Smooth muscle cells lay down collagen fibres
What is an unstable atherosclerotic plaque?
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
What do complicated lesions often contain?
Calcium
What are some characteristics of vulnerable plaques?
Thin fibrous cap
A core rich in lipid and macrophages
Less evidence of smooth muscle proliferation
What can modify LDL cholesterol?
Low HDL
Diabetes
Smoking
Hypertension
What do low HDL cholesterol levels tend to be associated with?
High triglyceride levels
What factors can lower HDL cholesterol levels?
Smoking
Obesity
Physical inactivity
What is considered a normal triglyceride level?
< 200 mg/dL or 2.3 mmol/L
Other than heart disease, what else is a very high triglyceride level associated with?
Pancreatitis
State some different drug therapies that have been used to treat high cholesterol.
Bile acid sequestrants
Nicotinic acid
Fibrates
Statins
Describe the mechanism of action of statins.
They are HMG-CoA reductase inhibitors
What are two important products of the cholesterol synthesispathway?
Geranyl pyrophosphate
Farnesyl pyrophosphate
They are involved in the modification and activation of proteins
How do statins decrease plasma LDL levels?
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
What is the selectivity ratio of a statin?
The higher the selectivity ratio, the greater the likelihood of the molecule being concentrated in the liver cell
What is the Rule of 6?
Doubling the dose of any statin will give a 6% reduction in the level of LDL cholesterol
How do fibrates act?
They activate PPAR-alpha
They lower plasma fatty acids and lower triglycerides
by promoting absorption into cells They are often used in diabetics with high triglycerides
Anti atheromatous plaque formation by down-regulating genes for MMPs signalling molecules etc
Name an important drug that can be given with statins to further decrease LDL levels?
Ezetimibe – it inhibits cholesterol absorption
What is this drug activated as?
Glucuronide
Which protein is involved in the transport of cholesteryl esters and triglycerides from HDLs to LDLs?
Cholesteryl Ester Transfer Protein (CETP)
What was the result of attempted inhibition of CETP?
It increased HDL and decreased LDL but it had off target effects that led to increased mortality
NOTE: the drug was called torcetrapib
What is PCSK9?
It is an inhibitor of LDL receptors
It stops the LDL in the plasma from binding to the LDL receptor and being taken up
PCSK9 inhibition (mAb) can lead to a decrease in cholesterol levels
