Atherosclerosis and lipid metabolism Flashcards
Why is CVD and CHD becoming more common all over the world?
Due to the western diet
What is the main culprit in atherosclerosis?
LDL - it gets into the vascular wall to form a core of atheroma
What is the exogenous pathway of lipid metabolism?
- Lipids enter the blood in two ways, one of which is absorption of fats from the diet
- The amount of the cholesterol that enters the circulation from the diet is very small
- However, other lipids (such as triglycerides) are certainly absorbed
- Triglycerides are absorbed as chylomicrons into the blood
- If you ingest a very fatty meal and then take a blood sample, chylomicrons are present in the plasma
- Chylomicrons are broken down by lipases, into remnants
- Some of this ends up as atheroma, in the vascular wall
What is the endogenous pathway of lipid metabolism?
- There is a pathway in which the liver generates different lipoproteins, which are then broken down and converted
- Some of the lipoproteins end up with the LDL receptor
- This endogenous pathway forms around 80% of the cholesterol in the body
- Most circulating lipids are endogenous
What is the importance of chlylomicrons in atherosclerosis?
- Chylomicron remnants are lipids of lipoproteins that come about as the chylomicrons are broken down and become smaller and smaller
- These chylomicron remnants are very good at getting into the blood vessel wall - into the tunica intima
What is reverse cholesterol transport?
- This is a process where cholesterol is taken out of blood vessels and foam cells
- There is a transformation of HDL (beneficial) back to LDL – by cholesteryl ester transfer protein
What are foam cells?
Smooth muscle macrophages that are full of lipid (including cholesterol)
How can reverse cholesterol transport be inhibited?
We can block CETP (cholesteryl ester transfer protein) and thus increase HDL and reduce LD
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Atherosclerosis is an inflammatory process
What is the first stage in atherosclerosis?
ENDOTHELIAL DYSFUNCTION
ENDOTHELIAL DYSFUNCTION
- The endothelium becomes dysfunctional
- The endothelium is responsible for producing a lot of mediators
- Endothelial dysfunction in atherosclerosis is characterised by a series of early changes that precede lesion formation
- The changes include greater permeability of the endothelium, up-regulation of leucocytes, endothelial adhesion molecules and migration of leucocytes into the artery wall
- If the endothelium is not functioning properly, it is more likely that things will get through the endothelial layer of control
What are the changes that occur in the endothelium before atherosclerosis?
- The changes include greater permeability of the endothelium, up-regulation of leucocytes, endothelial adhesion molecules and migration of leucocytes into the artery wall
What happens in stage 2 of atherosclerosis?
FATTY STREAK FORMATION
FATTY STREAK FORMATION
- The fatty streak is the earliest recognisable lesion of atherosclerosis and is caused by the aggregation of lipid-rich foam cells (derived from macrophages and T lymphocytes within the tunica intima)
- Later on the lesions will also include smooth muscle cells
- The fatty streaks are usually formed in the direction of blood flow
- Most fatty streaks don’t actually develop into serious atherosclerosis
What happens in stage 3 of atherosclerosis?
FORMATION OF PLAQUE
FORMATION OF PLAQUE
- This results from the death and rupture of the foam cells in the fatty streak
- You get formation of a necrotic core
- The migration of smooth muscle cells into the intima and laying down collagen fibres results in the formation of a protective fibrous cap over the lipid core
- The fibrous cap is extremely important because it separates the highly thrombogenic lipid-rich core from circulating platelets and coagulation factors
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- LDL moves into the subendothelium and is oxidised by macrophages and smooth muscle cells
- You get release of growth factors and cytokines, which attract inflammatory cells such as monocytes
- Foam cells form in the endothelium (macrophages that contain lipid, cholesterol or cholesterol esters)
- There will also be proliferation of fibroblasts and smooth muscle cells – this expands the plaque
What do complicated lesion contain and how may this be detected?
- Complicated lesions often contain calcium
- Coronary artery disease can be detected by doing a CT scan of the heart - this will detect any calcium
What is the relationship between the amount of calcium in the plaque and how bad the atherosclerosis is?
It is generally believed that the more calcium you have in the plaque, the more likely you are to be symptomatic
Where do remnants come from and why are they important?
- Remnant lipids come from the chylomicrons
- The remnant lipids are important because they are quite atherogenic
- If there are lots of remnant lipoproteins in the blood (as a result of eating fatty meals), the individual is at a higher risk of CHD compared to blood with fewer remnants
Give examples of chylomicron remnants
VLDL, chylomicron remnant and IDL
How are stable atherosclerotic plaques characterised?
Necrotic lipid core covered by a thick vascular smooth muscle, has a thick fibrous cap