Pathophysiology of Atheroma Flashcards
Atheroma/ atherosclerosis
Formation of focal elevated lesions (plaques) in intima of large and medium sized arteries
How is ischaemia caused in the coronary arteries?
Atheromatous plaques narrow lumen meaning that not enough oxygenated blood gets through
What is a serious consequence of myocardial ischaemia?
Angina
What can complicate atheroma?
Thromboembolism
Arteriosclerosis
Age-related change in muscular arteries
What is arteriosclerosis characterised by?
- Smooth muscle hypertrophy
- Apparent reduplication of internal elastic laminae
- Intimal fibrosis which leads to a decrease in vessel diameter
What doe arteriosclerosis contribute to?
High frequency of cardiac, cerebral, colonic and renal ischaemia in the elderly
When are the clinical effects of arteriosclerosis most apparent?
When the CVS is stressed:
- Haemorrhage
- Major surgery
- Infection
- Shock
What is the earliest significant lesion?
Fatty streak
How does the fatty streak appear?
Yellow linear elevation of intimal lining
What is the fatty streak comprised of?
Comprises masses of lipid-laden macrophages
What is the clinical significance of fatty streaks?
No clinical significance
What is the fate of fatty streaks?
- May disappear
- May form artheromatous plaques in patients at risk
Who do fatty streaks form in?
Young children
When do early artheromatous plaques form?
Young adults onwards
How do early artheromatous plaques appear?
Smooth yellow patches in intima
What are early artheromatous plaques compose of?
Lipid-laden macrophages
What is the fate of early atheromatous plaques?
Progress to established plaques
What is the composition of a fully developed atheromatous plaque?
Central lipid core, rich in cellular lipids/ debris derived from macrophages with fibrous tissue cap, covered by arterial enothelium
What produces collagen?
Smooth muscle cells
What does the collagens in the cap provide?
Structural strength
What resides in the fibrous cap?
Inflammatory cells including:
- Macrophages
- T lymphocytes
- Mast cells
Where are the inflammatory cells recruited from?
Arterial endothelium
How doe fully developed atheromatous plaques appear?
Soft, highly thrombogenic, often rim of foamy macrophages
Why do fully developed atheromatous plaques appear foamy?
Due to the uptake of oxidised lipoproteins via specialised membrane bound scavenger receptor
What occurs later in the development of fully developed atheromatous plaques?
Dystrophic calcification extensive
Where does calcification occur in plaques?
Form at arterial branching points/bifurcations (turbulent flow)
How can late stage plaques be described?
Confluent, cover large areas
What makes a complicated atheroma?
Features of established atheromatous plaque +
- Haemorrhage into plaque(calcification)
- Plaque rupture/ fissuring
- Thromobsis
What is the most important risk factor in the aetiology of atheroma?
Hypercholesterolemia
What does hypercholesterolemia cause?
Plaque formation and growth in the absence of other known risk factors
What usually happens to people who are homozygous for hypercholesterolemia?
Much higher cholesterol levels which leads to death from coronary artery atheroma in infancy/teens
What is the mutation which causes hypercholesterolemia?
Decreased functional receptors on cell surfaces which leads to elevated plasma LDL cholesterol levels
What are the different types of causes of hyperlipidaemia?
- Familial/primary
- Acquired/secondary
What is the biochemical evidence of hyperlipidaemia?
-LDL
-HDL
-Total cholesterol
Triglycerides
What are the signs of major hyperlipidaemia?
- Corneal arcus
- Tendon xanthomata
- Xanthelasmata
What other risk factors are there for atheroma?
- Smoking
- Hypertension
- Diabetes mellitus
- Male
- Elderly
- Accelerate process of plaque formation driven by lipids
What less strong risk factors are there for atheroma?
- Obesity
- Sedentary lifestyle
- Low socio-economic status
- Low birthweight
- Role of micro-organisms
What are the 2 steps in the development of atheromatous plaques?
- Injury to endothelial lining of artery
- Chronic inflammatory and healing response of vascular wall to agent causing injury
- It is chronic/ episodic exposure of arterial wall to these process which leads to the formation of atheromatous plaques
What is the pathogenesis of atherosclerosis?
- Endothelial injury and dysfunction
- Accumulation of lipoproteins (LDL) in vessel wall
- Monocyte adhesion to endothelium leads to the migration into intima and transformation to foamy macrophages
- Platelet adhesion
- Factor release from activated platelets, macrophages which leads to smooth muscle recruitment
- Smooth muscle cell proliferation, extracellular matrix production an T cell recruitment
- Lipid accumulation (extracellular an in foamy macrophages)
What is the most important cause of endothelial injury?
Haemodynamic disturbances (turbulent flow)
How can hypercholesterolemia directly impair endothelial cell function?
- By increasing local production of reactive oxygen species
- Lipoproteins aggregate in intima and are modified y free radicals produced by inflammatory cells
- Modified LDL accumulated by macrophages but not completely degraded
- Foamy macrophages
- Toxic to endothelial cells plus release of growth factors, cytokines
How are injured endothelial cells functionally altered?
- Enhance expression of cell adhesion molecules (ICAM-1, E-selectin)
- High permeability for LDL
- Increased thrombogenicity
What response to injury of the endothelial surface is there?
Chronic inflammatory process
- Inflammatory reaction
- Process of tissue repair
What doe growth factors stimulate?
Proliferation of the intimal smooth muscle cells with subsequent synthesis of collagen, elastin and mucopolysaccharides
What does the fibrous cap enclose?
Lipid rich core
What are growth factors secreted by?
- Platelets
- Injured endothelium
- Macrophages
- Smooth muscle cells
Where are microthrombi formed?
At denuded areas of plaque surface
What are the consequence of the clinical manifestations of atheroma?
- Progressive lumen narrowing due to high grade plaque stenosis
- Acute atherthrombotic occlusion
- Embolisation of the distal arterial bed
- Ruptured atheromatous abdominal aortic aneurysm
What does stenosis of >50-75% of the vessel lumen lead to?
Critical reduction of blood flow in distal arterial bed leading to reversible tissue ischaemia (stenosed atheromatous coronary artery leads to stable angina)
What will very severe stenosis lead to?
Ischaemic pair at rest ( unstable angina)
What can ileal, femoral or popliteal artery stenosis lead to?
Intermittent claudication (peripheral artery disease)
What can longstanding tissue ischaemia lead to
Atrophy of affected organ ( e.g. atherosclerotic renal artery stenosis leading to renal atrophy)
What are the major complications of acute atherothrombotic occlusion?
Rupture of plaques leading to acute event
What does rupture of plaque lead to?
Rupture exposes highly thrombogenic plaque contents (collagen, lipid, debris) to blood stream which leads to the activation of coagulation cascade and thrombotic occlusion in very short time
What does total occlusion lead to?
Irreversible ischaemia which leads to necrosis (infarction) of tissues
What are examples of necrosis due to irreversible ischaemia?
- Myocardial infarct caused by coronary artery
- Stroke caused by carotid/ cerebral artery
- Lower limb gangrene caused by ileal/femoral/popiteal artery
What leads to the embolization of the distal arterial bed?
- Detachment of small thrombus fragments from thrombosed atheromatous arteries leads to embolus distal to ruptured plaque
- Embolic occlusion of small vessels leads to small infarcts in organs
What are examples of consequences of embolic occlusion of small vessels?
- Heart, dangerous small foci of necrosis- life threatening arrhythmias
- Large ulcerating aortic plaques, lipid rich fragments of plaque leads to cholesterol emboli in kidney, leg and skin
- Carotid artery atheromatous debris, common cause of stroke
What causes an atheromatous abdominal aortic aneurysm to rupture?
- Media beneath atheromatous plaques gradually weakened leads to gradual dilatation of the vessel
- Sudden rupture leads to massive retroperitoneal haemorrhage
Which AAA are at risk of rupture?
> 5cm
Where do mural thrombus emboli to
Legs
What atheromatous plaques are vulnerable and at high risk of developing thrombotic complications?
Typically thin fibrous cap, large lipid core with prominent inflammation
What does pronounced inflammatory activity in vulnerable plaques lead to?
Degradation and weakening of plaque which increases the risk of plaque rupture
How do highly stenotic plaques usually appear/
Large firbrocalcific component with little inflammation
What do plaque inflammatory cells secrete?
- Proteolytic enzymes
- Cytokines
- Reactive oxygen species
What preventative and therapeutic measures are there?
- Stop smoking
- Control blood pressure
- Weight-loss
- Regular exercise
- Dietary modifications
What secondary prevention is there?
- Cholesterol lowering drugs
- Aspirin (inhibits platelet aggregation to decrease risk of thrombosis on established atheromatous plaques)
