atherosclerosis Flashcards
atherosclerosis
Atherosclerosis is the build-up of fatty deposits on the vessel wall, which ultimately restricts blood flow
endothelial dysfunction
Atheroma is initiated by endothelial injury or dysfunction
e.g. due to smoking, variable shear stress, infection, diabetes
Reduction in endothelial protective factors e.g. nitric oxide
initiation of atherosclerosis lesion
LDL (low density lipoproteins) particles cross the endothelium into the intima, where they become oxidised, promoting the expression of adhesion molecules
Circulating monocytes adhere and migrate, then mature into macrophages
Macrophages take-up oxidised-LDL via scavenger receptors to become large lipid-filled foam cells that form the fatty streak
Release of PDGF attracts SMC (smooth muscle cells) migration into intima
advanced lesion
SMCs secrete fibrous matrix (e.g. collagen) that form a protective cap
Over time, SMCs and macrophages divide and undergo cell death
Cellular debris accumulates forming the necrotic lipid-rich core
The ability of SMC to synthesise collagen is impaired by IFNγ from T-cells
Matrix metalloproteinases (MMPs) from macrophages degrade collagen
Thinning and weakening of the fibrous cap increase the susceptibility of the plaque to rupture
unstable fibrous plaque
Fibrous cap can rupture leading to coagulation in and around plaque
Thrombus formation can occlude the vessel or cause an embolism downstream triggering an acute ischaemic event e.g. MI, stroke
Thrombus may also be absorbed to form a healed plaque
warning signs
Easy to detect in pathological samples – more difficult in clinic
Can occur in arteries even without significant stenosis
Warning signs: -
Large lipid core (>40% of area)
Thin fibrous cap
Abundance of inflammatory cells
Paucity of smooth muscle cells
Microscopic or spotty calcification
risk factors
modifiable: obesity, hyperlipidemia, hypertension, diabetes
non-modifiable: genetics, age, gender, NAFLD
environmental: smoking, unhealthy diet, physical inactivity, stress
lifestyle: radiation, air pollution, heavy metals, free radicals
obesity- risk factor
Adipose tissue not just a depot for fat storage – it also synthesises inflammatory cytokines and hormones
Perivascular adipose tissue (PVAT) around blood vessels can also affect function and includes immune cells
Hence, obesity can generate systemic inflammation
consequences of atherosclerosis
carotid and cerebral arteries- stroke, vascular dementia
thoracic aorta- aortic rupture
renal arteries- worsening renal function
cholesterol
Cholesterol is essential for:
Incorporating into cell membranes
Maintaining membrane fluidity & permeability
Production of steroids and fat-soluble vitamins,
e.g. aldosterone, sex hormones, cortisol, vitamin D
The Liver
Monitors levels of cholesterol
Regulates cholesterol via synthesis, absorption and secretion of bile
Drugs to treat hyperlipidaemia target this process in the liver and gut
cholesterol transport- lipoproteins
Plasma is ~92% water, so lipids are transported in macromolecular complexes called lipoproteins
A core consisting of…
Cholesteryl ester
Triglycerides (TGs)
Surrounded by a coat of…
Phospholipids
Free cholesterol
Apoproteins
One or more per lipoprotein
Stabilises lipoproteins and is recognised by specific cells e.g. Apo B-100 is a ligand for the LDL receptor
exogenous cholesterol transport
- Cholesterol and TGs (triglycerides) are combined with apoproteins in the intestinal mucosa to form chylomicrons
- Chylomicrons pass into the bloodstream via the lymphatic system and bind to the capillary endothelium of tissues that express the enzyme lipoprotein lipase (LPL)
- LPL catalyses the hydrolysis of TGs to release glycerol and free fatty acids, which are taken up into the cells (for storage or use as fuel)
- While circulating in the blood, HDL (high density lipoproteins) donates apoE protein to chylomicrons leaving empty HDL
- ApoE is essential for the liver to recognise and rapidly remove chylomicron remnants from the blood
- The chylomicron remnants are broken down in the liver to yield cholesterol and free fatty acids
endogenous cholesterol transport
- The liver repackages cholesterol and fatty acids to form VLDLs, which are particularly rich in triglycerides and contain apoB-100 apoprotein
- These are released into the blood between meals and circulate until they bind to the capillary endothelium of target tissues expressing LPL (muscle and adipose)
3.The TGs cargo are hydrolysed into glycerol and free fatty acids by the enzyme lipoprotein lipase (LPL) and taken up by cells
4.After a VLDL has unloaded most of its fats it becomes smaller and is known as an intermediate density lipoprotein (IDL)
5.Empty HDL is produced as a byproduct (which can then collect LDL from the periphery).
- The liver absorbs IDL particles from the blood
7.IDLs are then broken down by hepatic lipase into LDLs (triglycerides are removed in this process, so LDL is enriched for cholesterol)
- LDL is released into the blood and circulates
9.Until absorbed by peripheral tissues via binding to LDL receptors (recognize apo-B100)
- Excess LDL is absorbed by the liver via LDL receptors.
signs of familial hypercholesterolaemia
Xanthomas - fatty cholesterol-rich deposits in the skin, often found around the elbows, knees, knuckles and Achilles tendon
Xanthelasmas - fatty deposits in and around the eyelids
Arcus senilis - a white ring around the cornea
HMG-CoA reductase inhibitors- statins
Competitive inhibitors of rate-limiting step in cholesterol biosynthesis
Decrease in cholesterol levels causes up-regulation of hepatic receptors for ApoB and ApoE = clearance of LDL, IDL and VLDL from plasma. Modest in HDL also observed
Can stabilise and even reduce plaque size
Side-effects: GI disturbances; hepatotoxicity (rare); myalgia is commonly reported, but true muscle toxicity is rare
