Pathophysiology of atheroma Flashcards
What is an atheroma/atherosclerosis?
- formation of focal eleveted lesions ( plaques) in T.intima of large + medium sized arteries
- hardening of artery
Describe features of arteriosclerosis
- umberella term
- when muscular arteries change with age due to hardening.
- atherosclerosis/arteriolosclerosis
Describe the formation of an atheroma
- Damage to the endothelium will cause the LDL to enter the endothelial cells. Monocytes (transforms into foamy macrophages) will follow the LDL and attempt to break them down through oxidation.
- High LDL means that macrophages will engulf too much LDL > death.
- dead macrophages(foamy macrophages) will deposit under the damaged endothelium and releases cytokines which signals other monocytes > dead.
- The foam cells will accumulate into a lesion = FATTY STREAK(earliest stage)
- This fatty streak is thrombogenic and can cause blood to clot on it.
- Platelet(activated) adhesion to endothelium and migrates to the damaged endothelium and release a growth factor which encourages growth of SM cells whichrecruit in the fatty streak in the T.intima.
- SM cells will release collagen, mucopolysaccharidess + elastin > ECM production ). This forms the FIBROUS CAP which encloses lipid rich core.
- Plaque prevents removal of Ca2+ by LDL due to HDL unable to do its job ( remove). In turn, calcium builds up in vessel wall + crystalises (calcification) on walls of artery.
- This process causes inflammation. C -reactive protein increases ( indication of infection/inflammation. Inflammatory reaction takes place and process of tissue repair.
- proteolytic ennzymes, cytokines and RAS will be produced by plaque inflammatory cells in attempt to degrade plaque
- Growth factors will also be secreted by platelets, SM, macrophages and injured endothelium
- endothelial loss can also cause plaque growth
When can fatty streaks be found? What is it?
- young children.
- can disappear
- Yellow linear elevation of intimal lining
- composed of lipid0laden macrophages
When can an early atheromatous plaque be formed and what is it?
- Young adults onwards
- smooth yellow patches in intima
- lipid laden macrophages
What may be found in the central lipid core of a fully developed atheromatous plaque?
- rich in cellular lipid/debris from dead macrophages ( died in plaque)
- fibrous tissue cap surrounds it
- collagen ( produced by SM cells) provide it structural strength.
- inflammatory cells such as macrophages, T.lymphocytes, mast cells ( C.reactive protein produced) reside in fibrous cap
Microthrombi in established plaques
-formed at plaque surface + organised by same repair process ( SM cell invasion, collagen deposition)
Why are the macrophages ‘Foamy’?
-due to the uptake of oxidised lipoproteins via specialised membrane bound scavenger receptor
When may calcification occur? And where?
- occurs in late plaque development and forms at arterial branching points/bifurcations(turbulent flow)
- late stage plaques cover large areas
Complicated atheroma
REMVOE
- features of established atheromatous plaque ( lipid-rich core, fibrous cap) + haemorrhage into plaque (calcification)
- plaque rupture/fissuring + thrombosis may occur
What is hypercholesterolaemia?
-high blood cholesterol
Effect of hypercholesterolaemia
-LDL deposits on the walls of arteries and macrophages engulf this. Overtime leads to astherosclerotic plaques.
Mutation of hypercholestorolaemia
- lack of LDL membrane receptors. Prevents uptake of LDL of peripheral cells so > high plasma LDL cholesterol
- caucasions is heterozygous for this mutation
- rare patients homozygous with a much higher cholesterol level and die from coronary artery atheroma in infancy/teens
Types of hypercholesterolaemia
hyperlipidaemia, hyperlipidproteinaemia..
Biochemical Signs of major hyperlipidaemia
Biochemical evidence: LDL, HDL, total cholesterol, triglycerides
What is hypercholeserolaemia(form)/hyperlipidaemia and state the types
- high level of cholesterol/triglycerides in blood
- familial/prmary vs acquired/secondary(idiopathic)
Symptoms + risk factors of major hyperlipidaemia
-corneal arcus - a white/grey line around the periphery. Can form a full circle ( premature)
- tendon xanthomata ( knuckles, achilles)
- Xanthelasmata ( eyelids)
Xanthomata= yellow skin lesions caused deposition of lipid
-family history of MI/atheroma due to disorders of lipid metabolism
risk factors for atheroma
Factors that accelarate process of plaque formation
- FMX of atheroma
- smoking
- hypertension
- DM
- male
- elderly
- accelerate process of plaque formation driven by lipids
Less strong:
- obesity
- lifestyle
- low socioeconomic status
- low birthweight
- role of microorganisms?
Causes of endothelial injury
- haemodynamic disturbances ( turbulent flow/hypertension)
- hypercholesterolaemia (if chronic, impairs endothelial cell function by increasing local production of free radicals)
- high LDL + free radicals modifies the intima > foamy macrophages > toxic to endothelial cells + release of growth factors, cytokines
- Free radicals from smoking ( aswell as produced by inflammatory cells)
- Inflammatory response to infection
- diabetes
Effect of damaged endothelial cells
- enhanced expression of cell adhesion molecules ( ICAM-1, E-selectin)
- high permeability for LDL
- increased liklihood of thrombus formation
-Inflammatory cells, lipids > intimal layer > plaques
In advanced plaque formation
- large numbers of macrophages, TLcytes
- Lipid laden macrophages will die through apoptosis in lipid into lipid core
Consequences of atheroma clinical manifestations
-plaque causes stenosis(50-75%) of lumen. This decreases BF in the distal arterial bed + leads to REVERSIBLE tissue isachemia
What can stenosed atheromatous coronary artery, ilial, femoral, poplitreal artery stenosis and atherosclerotic renal artery stenosis lead to?
-Stenosed athermatous coronary artery > stable angina(isachemic pain at rest).
Severe ‘’’’ > unstable angina
- ileal, femoral, popliteal artery stenosis >intermittent claudication ( peripheral arterial disease/iachemia?)
- athersclerotic renal artery stenosis leads to renal atrophy ( this applies to any organ affected)
Acute atherombotic occlusion + give examples
- rupture of plaque > acute event
- rupture exposes a highly thrombogenic plaque contents ( collagen, lipid, debris) into blood stream hich leads to activation of coagulation cascade and thrombotic occlusion very QUICKLY.
- Results in Total occlusion > irreversible ischaemia > necrosis ( infarction) of tissues
- Eg myocardial infarct ( coronary artery
- stroke ( carotid, cerebral artery)
- lower limb gangrene ( ileal, femoral, popliteal artery)
Embolisation of the distal arrterial bed + give examples
- detachment of small thrombus which > embolises in circulation
- embolic occlusion of small vessels >small infracts in organs
- Eg heart, small foci of necrosis > life threatening arrythmias (small isachemia?)
- large aortic plaques, lipid rich fragments in plaque > cholesterol emboli in kidney skin, leg
- carotid artery atheromatous debris>stroke ( cerberal infract ,TIA)
Ruptured atheromatous abdomoninal aortic aneurysm
- media beneath atheromatous plaques weakened ( lipid related inflammaotry activity in plaque)
- causes gradual dilaiton of vessel which is seen in elderly and asymptomatic.
- sudden rupture > massive retroperitoneal haemorrhage ( high mortality)
- aneurysms> 5.5cm diameter at high risk of rupture
- mural thrombus > emboli to legs
Vulnerable atheromatous plaques
-atheromatous plaques that rupture ( with thrombosis) has morphological features
- if we are able to recognise vulnerable plaques we prevent development of thrombotic compilations
- typically thin fibrous cap(more likely to rupture), large lipid core, prominent inflammation.
- Although inflammatory activity > degradation/weakening of plaque > increased risk of plaque rupture.
- secretion of proteolytic enzymes, cytokines and reactive oxygen species by plaque inflammatory cells
- highly stenotic plaques often large fibrocalcific component+ little inflammation
Preventation/therapy
Preventative approaches
- stop smoking
- regulate BP
- weight loss, excercise
- dietry modifications
Secondary preventation
-cholesterol lowering drugs, aspirin ( inhibits platelet aggregation to decrease risk of thrombosis on established athermatous plaques
Surgical options
