Pathophysiology of Atheroma Flashcards
What is an Atheroma/Atherosclerosis?
Formation of focal elevated lesions (plaques) in intima of large and medium sized arteries
What can an atheromatous plaque in coronary arteries lead to?
Ischaemia
What is the serious consequence of atheroma in coronary artery?
Angina due to myocardial ischaemia
Explain arteriosclerosis
Not atheromatous
Age-related change in muscular arteries
What happens in arteriosclerosis?
Smooth muscle hypertrophy, apparent reduplication of internal elastic laminae, intimal fibrosis - leads to decreased vessel diameter
When are clinical effects of arteriosclerosis more apparent?
When CVS is further stressed by haemorrhage, major surgery, infection and shock
What does the normal artery wall consist of?
Intima includes endothelium
Separated by internal elastic lamina
Media
Separated by external elastic intima
Adventitia
Describe the fatty streak in atheroma?
Earliest significant lesion, usually young children.
Yellow linear elevation of intimal lining and masses of lipid laden macrophages
What is the clinical significance of fatty streak atheroma?
No clinical significance
May disappear
Patients at risk of atheromatous plaque
Describe the early atheromatous plaque in atheroma?
Young adult onwards
Smooth yellow patches in intima and lipid-laden macrophages
Progress to established plaques
Describe fully developed atheromatous plaque in atheroma?
Central lipid core with fibrous tissue cap covered by arterial endothelium
Collagens in cap for strength
Inflammatory cells reside in fibrous cap
What inflammatory cells reside in fibrous cap and where are they recruited from?
Macrophages, T-lymphocytes and mast cells
Recruited from arterial endothelium
Describe a fully developed atheromatous plaque in atheroma?
Central lipid core rich in cellular lipids/debris derived from macrophages (died in plaque)
Soft, highly thrombogenic, often rim of foamy macrophages
What makes macrophages foamy?
Uptake of oxidised lipoproteins via specialised membrane bound scavenger receptor
What occurs late in plaque development?
Dystrophic calcification extensive - marker for atherosclerosis in angiograms and CTs
Form at arterial branching points/ bifurcations which can cause turbulent flow
Late stage plaques can cover large areas and confluent
What are the features of an established atheromatous plaque?
Lipid-rich core
Fibrous cap
Explain complicated atheroma?
Has features of established atheromatous plaque plus haemorrhage into plaque (calcification), plaque rupture/fissuring or thrombosis
What is the most important risk factor of atheroma?
Hypercholesterolaemia
What does hypercholesterolaemia cause?
Causes plaque formation and growth in absence of other known risk factors
What happen when there is a decrease un functional receptors on cell surfaces?
elevated plasma LDL cholesterol levels
What happens if patient has rare homozygous mutation causing hypercholesterolaemia?
Much higher cholesterol levels and usually die from coronary artery atheroma in teens/infancy
What are signs of major hyperlipidaemia?
Familial/primary or acquired/secondary
Biochemical evidence
Corneal arcus
Tendon xanthomata
Xanthelasmata
Premature, FH of MI/atheroma
What is Xanthelasmata?
Collections of foamy macrophages and lipids in skin
Often under eyes and are yellow plaques
What are some risk factors for atheroma?
Smoking, hypertension, diabetes mellitus, male, elderly
These accelerate process of plaque formation driven by lipids
What is the 2 step process of developing atheromatous plaques?
- injury to endothelial lining of the artery
- Chronic inflammation and healing of vascular wall to agent causing injury
Describe the pathogenesis of atherosclerosis
Endothelial injury and dysfunction
Accumulation of lipoproteins (LDL) in vessel wall
Monocyte adhesion - migration into intima and transformation to foamy macrophages
Platelets adhesion
Factor release from activated platelets and macrophages recruit smooth muscle cell
Smooth cell proliferation, EXM production and T-cell recruitment
Lipid accumulation
What are the most important endothelium injuries causing atheroma?
Haemodynamic disturbances causing turbulent flow instead of smooth
Hypercholesterolaemia
How does hypercholesterolaemia cause endothelium impair?
Increasing production of reactive O2 species
Lipoproteins aggregate in intima and are modified by free radicals which are produced from inflammatory cells
This leads to modified LDL accumulation by macrophages - foamy macrophages then toxic to endothelial cells
How are injured endothelial cells functionally altered?
Enhanced expression of cell adhesion molecules
High permeability for LDL
Increased thrombogenicity
Describe the formation of advanced plaque formation
Large numbers macrophages and T lymphocytes
Lipid-laden macrophages die through apoptosis lead lipid into lipid core
Response to injury - chronic inflammatory process
Growth factors (PDGF)
Fibrous cap encloses lipid rich core
What is the chronic inflammatory process?
- inflammatory reaction
- process of tissue repair
Where are growth factors secreted from?
By platelets, injured endothelium, macrophages and smooth muscle cells
What does secretion of growth factors (PDGF) cause?
Proliferation intimal smooth muscle cells, subsequent synthesis collagen, elastin and mucopolysaccharide
What does microthrombi formed at denuded areas of plaque surface lead to?
Organised by same repair process (smooth muscle cell invasion and collagen deposition)
Established plaques and plaque growth are also initiated by?
Small areas of endothelial loss
What are some clinical consequences of atheroma?
Progressive lumen narrowing due to high grade plaque stenosis
Acute atherothrombotic occlusion
Embolisation of distal arterial bed
Ruptured atheromatous abdominal aortic aneurysm
Describe progressive lumen narrowing due to high grade plaque stenosis?
Stenosis of more than 50-75% of vessel lumen leads to critical reduction of blood flow in distal artery so can get reversible tissue ischaemia
What can a stenosed atheromatous coronary artery cause?
Stable angina
What does very serious stenosis lead to?
Ischaemic pain at rest - unstable angina
Ex. ileal, femoral, popliteal artery stenosis
Longstanding tissue ischaemia
Describe acute atherothrombotic occlusion
Rupture of plaque - exposes highly thrombogenic plaque contents to blood stream - activation of coagulation cascade and thrombotic occlusion in very short time
What does total occlusion lead to?
Irreversible ischaemia then necrosis of tissues which is infarction
Ex. MI, stroke, lower limb gangrene
Describe embolisation of the distal arterial bed
Detachment of small thrombus fragments from thrombosed atheromatous arteries - embolise distal to ruptured plaque
Embolic occlusion of small vessels - small infarcts of organs
What are some examples of embolisation of the distal arterial bed?
Carotid artery atheromatous debris can lead to stroke as cerebral infarct
Cholesterol emboli in kidney, leg and skin due to large ulcerating aortic plaques
Life threatening arrhythmias due to small foci of necrosis in heart
Describe ruptured atheromatous abdominal aortic aneurysm?
Media beneath atheromatous plaques gradually weakened - gradual dilatation of vessels
Is slow but progressive, seen in elderly
Sudden rupture - retroperitoneal haemorrhage
Aneurysms > 5cm which are at high risk of rupture
Mural thrombus - emboli to legs
What are signs of a vulnerable plaque?
Typically thin fibrous cap, large lipid core and prominent inflammation
Pronounced inflammatory activity - degradation and weakening of plaque - increase risk of plaque rupture
What do plaque inflammatory cell secrete?
Proteolytic enzymes, cytokines and reactive oxygen species
What are the preventative and therapeutic approaches?
Stop smoking
Control blood pressure
Weight loss
Regular exercise
Dietary modifications
What are secondary prevention options?
Cholesterol lowering drugs which inhibit platelet aggregation of decrease risk of thrombosis on established atheromatous plaques
What are surgical options?
To remove or bypass atheromatous vessels
