how has our view of atherosclerosis changed?
- We used to think of it as only a disease of lipid/cholesterol storage
- But now, it is thought of as an inflammatory disease (thanks to Ross)
- Develops slowly over many years - can be asymptomatic
how do atherosclerosis lesions begin developing?
- Starts with insult to the vascular endothelium - smoking, high shear stress, infection, diabetes
- Increased adhesion and transmigration of leukocytes - creates oxidant stress that can damage structures within the blood vessels, like connective tissue.
- This creates foam cells
-damage to endothelium
-focus of inflammation
what does damage to the endothelium result in?
increased permeability to lipids
inflammatory cells generating cytokines/oxidant stress
establishes a focus of inflammation
what processes are involved during the process of fatty streak formation?
- Platelet adhesion occurs
- Migration of smooth muscle cells as a result of PDGF to form a fibrous cap - this prevents the formation of a thrombus.
- Uptake of modified LDLs - LOX-1
- Formation of lipid-laden foam cells (monocytes-macrophages)
- Release of MMPs by macrophages
- Compensatory vessel remodelling
what happens in a more advanced/complicated lesion?
- Formation of fibrous cap - healing
- Foam cells burst/die due to continued, unregulated intake of lipids
- Necrotic core forms - lipid debris
- Further monocyte recruitment
- Oxidation of LDLs within plaque
what are the consequences of unstable fibrous plaques?
- Fibrous cap thins/ulcers - oxidation and shear stress
- Thrombus formation
- Intraplaque haemorrhage - increasing the size of the plaque, pushing it into the lumen of the vessel.
- Pulsatile, forceful, tortuous flow causes plaque to burst.
- Necrotic core leaks out which causes activation of coagulation cascade
- A serious rupture can lead to vessel occlusion, leading to myocardial infarction.
- Sometimes the plaques can break off and form an embolism.
what are vulnerable plaques?
- Liable to rupture at any time
- Easy to detect in pathological samples, more difficult to detect clinically
- Often occur in arteries without significant stenosis (<70%)
- Larger lipid core (>40% of total area)
- Thinner fibrous cap
- Abundance of inflammatory cells
- Paucity of smooth muscle cells
What could the issue be with angiography of coronary arteries?
normal CAG and abnormal coronory artery
IVUS showing large plaque
what is cholesterol essential for?
- Incorporating into cell membranes
- Maintaining membrane fluidity & permeability
- Production of steroids and fat-soluble vitamins
what is the role of the liver with cholesterol?
- Monitors levels of cholesterol
- Regulates this through synthesis, absorption and bile secretion
- Drugs to treat hyperlipidaeamia target this process in the liver/gut
what is the link between cholesterol and lipoproteins?
cholesterol is complexed in order to be carried around the blood
it is macromolecular complexes of lipids and apoproteins
what are lipids?
-cholesteryl ester
-triglycerides
-free cholesterol
-phospholipids
what are apoproteins?
-unique metabolic functions
-one or more per lipoprotein
facilitate the absorption and secretion of fat from the intestine, serve as activators of enzymes of lipoprotein metabolism and act as ligands for lipoprotein receptors on cell surfaces.
what are the different types of lipoproteins?
chylomicrons
VLDL
IDL
LDL
HDL
what are chylomicrons lipoproteins?
carry triglycerides from intestines to liver, muscle & adipose tissue
what are VLDL lipoproteins?
carry newly synthesised triglycerides from the liver to adipose tissue
what are IDL lipoproteins?
an intermediate between VLDL and LDL
what are LDL lipoproteins?
major reservoir of cholesterol. Taken up via LDL receptors by endocytosis
what are HDL lipoproteins?
adsorb cholesterol released by dying cells. Also act as ‘reverse transport’ to take cholesterol to liver.
what are the consequences od obesity?
- Clear link to insulin resistance + diabetes
- Adipose tissue not just a depot for fat storage - synthesises inflammatory cytokines
- Adipose tissue around blood vessels can affect function
- So, obesity can generate systemic inflammation
Outline the endogenous pathway of cholesterol transport
ADD MORE KNOWLEDGE HERE
the extent of LDL receptor expression on the liver is determined by the amount of cholesterol in the liver
what is familial hypercholesterolaemia?
Generally these patients have an inability to synthesise LDL receptors, so can’t take LDL back up into the liver, and thus have very high circulating levels of LDL.
- It therefore goes into peripheral tissue.
These patients tend to develop atherosclerosis much earlier in life
what are some of the signs of familial hyercholesterolaemia?
-xanthomas - fatty cholesterol rich deposits in the skin, usually found above the elbows, knees, buttocks and tendons
-xanthelasmas - fatty deposits in the eyelids
-arcus senilis- a white ring around the cornea
what is hyerlipoproteinaeamia?
less severe but more common
high circulating levels of feee and bound cholesterol and triglycerides
