Pathophysiology of atheroma Flashcards
What is atheroma’s alternative clinical name?
Atherosclerosis
What is atheroma?
Formation of focal elevated lesions (plaques) in intima of large and medium-sized arteries
Why is atheroma damaging to health?
Atheromatous plaques narrow the lumen of the blood vessels
Narrow lumen can cause angina
Potential complications ie thromboembolism
What is arteriosclerosis?
Non atheromatous narrowing of lumen
Caused by Smooth muscle hypertrophy, apparent reduplication of internal elastic laminae, intimal fibrosis
What is the commonest cause of arteriosclerosis?
Old age
Arteriosclerosis contributes to ischaemia in the elderly in what areas?
cardiac, cerebral, colonic and renal ischaemia
What conditions can exacerbate the effects caused by arteriosclerosis?
Clinical effects most apparent when CVS further stressed by haemorrhage, major surgery, infection, shock
What are the layers of the wall of an artery?
Tunica Intima - inner
Tunica Media - Smooth muscle layer
Tunica Adventitia
What is the earliest significant stage/lesion of an atheroma?
What age group is this most likely to present in?
Fatty streak in the T. Intima
Young children - neonates
Describe the appearance & histology of a fatty streak
Yellow linear elevation of intimal lining
Comprises masses of lipid-laden macrophages
What is the clinical significance of a fatty streak?
It poses no immediate risk, and may just disappear
However, there is a risk that it will develop into an atheromatous plaque
What is the appearance & histology of an early atheromatous plaque?
Smooth yellow patches in intima
Lipid-laden macrophages
Who is at risk of developing an early atheromatous plaque?
Young adults onwards
Describe the basic components/structure of a Fully developed atheromatous plaque
Central lipid core
‘Fibrous cap’ between CLC & the lumen
Surrounded by arterial endothelium
What is contained/histologically visible in the central lipid core of a FD atheromatous plaque?
Rich in cellular lipids, LDL’s & debris derived from macrophages
May have:
“Foamy macrophages” - often present due to uptake of oxidised lipoproteins via specialised membrane bound scavenger receptor
Haemorrhage
Describe the structure of the fibrous cap, in a FDAP
Fibrous tissue:
Collagen - produced by smooth muscle cells
( + elastin )
Inflammatory cells - macrophages, T cells, mast cells - recruited from arterial endothelium
What process occurs in atheromatous plaques, late in their development, once they are very large?
Dystrophic calcification:
- This occurs in necrotic tissue (which a large plaque contains in the lipid core)
- Dystrophy = tissue wasting away (necrosis causes this)
Late stage plaques are often described as ‘confluent’
What does this mean?
Multiple plaques merging together
This means they cover extensive areas
Why might a plaque cause turbulent flow?
If they form at arterial branching points/bifurcations
Or probably if theyre just massive
What feature of a plaque can be identified in imaging?
Dystrophic calcification
Shows up in angiograms/CT
Marker for atherosclerosis
What is a risk associated with calcification of a plaque?
Haemorrhage into lipid core of plaque
What are the local risks associated with a very large plaque, that could cause a ‘complicated atheroma’?
Haemorrhage into LC
Plaque rupture / fissuring
Thrombosis
What are the main risk factors for Atheroma?
Hypercholesterolaemia & Hyperlipidaemia
Smoking
Hypertension
Diabetes Mellitus
Male
Elderly
What are the less important risk factors for atheroma?
Obesity
Sedentary lifestyle
Low socio-economic class
Low birthweight
^Many of the above basically just contribute to main risk factors - ie Low SE class tends to smoking & a diet high in fat leading to hyperlipidaemia etc
Micro-organisms:
- May have a role
Hypercholesterolaemia is the most important risk factor for atheroma
Describe what makes it such an important factor…
It can cause formation & growth of plaque in the absence of other risk factors
Also:
- Rare genetic mutation causing lack of cell membrane receptors for LDL cholesterol is present in 1/1500 caucasians (heteroz) & 1/1million (homoz)
- Homozygous sufferers have insanely high LDL cholesterol levels & usually die from coronary artery atheroma in their teens
If you suspect hypercholesterolaemia/hyperlipidaemia
What biochemical investigations should be undertaken?
Bloods
- LDL
- HDL
- Total cholesterol
- Triglycerides
What signs on examination are indicative of hyperlipidaemia/hypercholesterolaemia?
1) Inspection of the face:
Corneal arcus
- Banana shaped cloudy opacity on cornea of eye
Xanthalasmata (xanthalasma)
- Sharp bump on skin
- Deposit of cholesterol
- Yellowish
2) Inspection of rest of body:
Tendon xanthomata
- knuckles, achilles etc
- deposits of cholesterol stuff
What must happen in order for an atheroma to begin to form?
1) Injury to endothelial lining of artery
2) Chronic inflammatory & healing response of vascular wall to agent causing injury
Exposure of arterial wall allows LDL to accumulate & plaque to start forming
Describe the formation of an atheromatous plaque on an exposed arterial wall
1) Wall exposed ∴ accumulation of Lipoproteins (LDL)
2) Monocytes see injury:
- Adhese to endothelium (& release factors)
- Migrate into intima & become foamy macrophages
3) Platelets:
- Adhesion & activation
- Release factors
4) Factors released by Platelets & macrophages recruit smooth muscle cells
5) Smooth muscle cells proliferate, begin manufacturing ECM & recruit T cells
6) Lipids continue to accumulate in this mess, and form the lipid core
In order for a plaque to begin forming, there must be endothelial injury, which allows monocytes & lipoproteins to migrate and all that stuff
What are the main causes of endothelial damage?
Turbulent flow (haemodynamic disturbance)
Hypercholesterolaemia
How does hypercholestrolaemia damage the endothelium of arteries?
Chronic hypercholesterolaemia can increase production of reactive oxygen species
It can also cause accumulation of Lipoproteins in the T. intima:
- Lipiproteins are modified by free radicals
- Modified lipoPs accumulated by macrophages but not destroyed
- This makes foamy macrophages
- Foamy Macrophages are toxic to endothelium & also release growth factors, cytokines
Why is it easier for plaques to form on damaged endothelial cells?
Increased expression of adhesion molecules (ICAM-1 & E-selectin)
High permeability to LDL
Increased thrombogenicity
To put it simply
What two things move into the intimal layer to form plaques
Inflammatory cells & lipids
How do lipids get into the lipid core?
During plaque formation - large number of macrophages & T-cells:
- Macrophages accumulate lipids, and die through apoptosis
- The debris & lipids accumulate ∴ form the lipid core
The chronic injury response recruits more & more lymphocytes ∴ more lipids are ‘fed’ to the core
What causes smooth muscle cells to proliferate?
What is the effect of this?
Platelets, injured endothelium, macrophages & smooth muscle cells release growth factors (PDGF)…
Causes:
- growth of intimal SM
- Synthesis of collagen, elastin & mucopolysaccharides
What gives rise to the fibrous cap?
Platelets, injured endothelial cells, macrophages and Smooth muscle cells secrete Growth factors (PDGF)
One of the effects of growth factors is to stimulate collagen synthesis
Fuck ton of collagen - goes into fibrous cap
There are several clinical manifestations of atheromas, related to several different aspects of the disease
Summarise what can cause the clinical manifestations of atheromas
Stenosis
Acute atherothrombotic occlusion
Embolisation of atherothrombus
Ruptured atheromatous abdominal aortic aneurysm
What clinical manifestations of atheromas are ‘Stenosis’ related?
High grade stenosis of over 70% causes ischaemia of supplied tissue:
Reversible tissue ischaemia Stable angina Unstable angina Peripheral arterial disease Atrophy due to longstanding ischaemia
What clinical manifestations of atheromas are related to ‘atherothrombotic occlusion’
Thrombus from ruptured plaque = total occlusion = infarction of tissue:
Myocardial Infarction
Stroke
Lower limb gangrene
What clinical manifestations of atheromas are caused by embolisation of fragments of thrombosed atheromatous arteries?
Embolic occlusions of small vessels = small infarcts of organs:
Arrhythmia
Cholesterol emboli in kidney, liver, skin
Stroke
What clinical manifestations of atheromas are caused by aneurysms due to the ruptured plaque?
The media layer beneath the atheromatous plaque is weakened by inflammatory processes from the plaque:
Retroperitoneal haemorrhage
Mural thrombus - emboli to legs
Atheromatous plaques that are likely to rupture have distinct morphological features
What are these features?
Thin fibrous cap
Large lipid core
Prominent inflammation
(just think of a big red spot thats about to burst)
Inflammatory processes weaken atheromatous plaques and are a main reason for them becoming fragile and likely to burst
How do inflammatory cells weaken the plaque?
Secretion of proteolytic enzymes, cytokines and reactive oxygen species
Some plaques are highly stable, and cause problems through stenosis of the vessel in which they exist
How is the structure/activity of these cells different from that of an unstable plaque?
Highly stenotic, more stable plaques have a much larger fibrocalcific component & less inflammatory activity
What are the preventative & therapeutic measures for atheromas?
Smoking cessation BP control Weight loss Exercise Diet
Statins - if high cholesterol
Aspirin - stabilise plaque & reduce thrombosis risk
Surgery - if needed
