Pathophysiology of atheroma 2 Flashcards
What two step process is involved in the development of atheromatous plaques?
- Injury to endothelial lining of artery
- Chronic inflammatory and healing response of vascular wall to agent causing injury
Chronic/episodic exposure of arterial wall to these processes cause the formation of atheromatous plaques
What are the first 3 in the order of events for pathogenesis of atherosclerosis?
- Endothelial injury and dysfunction
- Accumulation of LDL in vessel wall
- Monocyte adhesion to endothelium - they migrate into intima and transform to foamy macrophages
What are the last 3 in the order of events for pathogenesis of atherosclerosis?
- Platelet Adhesion
- Factor release from activated platelets, macrophages - smooth muscle cell recruitment
- Smooth muscle cell proliferation, extracellular matrix production and T-cell recruitment
- Lipid accumulation (extracellular and in foamy macrophages).
What are the most important causes of endothelial injury?
- Haemodynamic disturbances (turbulent flow)
- Hypercholesterolaemia
How can chronic hypercholesterolaemia directly impair endothelial cell function?
By increasing local production of reactive oxygen species
What can injured endothelial cells functionally alter?
- Enhanced expression of cell adhesion
- High permeability for LDL
- Increased thrombogenicity
- Inflammatory cells, lipids - intimal layer - plaques
What can advanced plaque formation cause?
- Large numbers macrophages, T-lymphocytes
- Lipid-laden macrophages die through apoptosis - lipid into lipid core
How does advanced plaque formation affect response to injury?
It causes a chronic inflammatory process
- Inflammatory process
- Alters process of tissue repair
How does advanced plaque formation affect growth factors?
- Stimulation of proliferation of smooth muscle cells
- It affects subsequent synthesis collagen
- Causes elastin degradation
- Alterations in Mucopolysaccharide deposition
What can plaque growth be initiated by?
Small areas of endothelial cells
What can advanced plaque formation affect?
Secretion of growth factors by cells such as platelets, injured endothelium, macrophages and smooth muscle cells
How does advanced plaque formation affect microthrombi formed at denuded areas of plaque surface?
- Increase in thrombus formation
- Altered repair process such as smooth muscle cell invasion and collagen deposition
What are the consequences of atheroma clinical manifestations?
- Progressive lumen narrowing due to high grade plaque stenosis
- Acute atherothrombotic occlusion
- Embolization of the distal arterial bed
- Ruptured atheromatous abdominal aortic aneurysm
What is progressive lumen narrowing due to high grade plaque stenosis?
Stenosis of > 50-75% of vessel lumen which leads to a critical reduction of blood flow in distal arterial bed, then causing reversible tissue ischaemia
E.g stenosed atheromatous coronary artery which leads to stable angina
What can very severe stenosis cause?
- Ischaemic pain at rest (very unstable angina)
- Severe stenosis in arteries such as ilea, femoral, popliteal arteries can lead to intermittent claudication (peripheral arterial disease
What can longstanding tissue ischaemia cause?
-Atrophy of affected organ eg atherosclerotic renal artery stenosis can lead to renal atrophy
What is acute atherothrombotic occlusion?
Rupture of plaque which is an acute event
- This rupture exposes highly thrombogenic plaque contents (collagen, lipid, debris) to blood stream leading to activation of coagulation cascade and thrombotic occlusion in very short time
What does total occlusion cause?
Irreversible ischaemia which leads to necrosis (infarction of tissues)
What are some arteries can acute atherothrombotic occlusion affect?
- Coronary artery which can lead to myocardial infarct
- Carotid and cerebral artery which can lead to stroke
- Ileal, femoral and popliteal artery which can lead to lower limb gangrene.
What is embolization of the distal arterial bed?
Detachment of small thrombus fragments from thrombosed atheromatous arteries can lead to embolization distal to ruptured plaque
Embolic occlusion of small vessels lead to small infarcts in organ.
What can embolization of the distal arterial bed lead to?
- In the heart, it can cause dangerous small foci of necrosis which can lead to life-threatening arrhythmias
- It can lead to large ulcerating aortic plaques, lipid rich fragments of plaque
- It can lead to cholesterol emboli in kidney, leg, skin
- It can lead to carotid artery atheromatous debris which is a common cause of stroke.
What is ruptured atheromatous abdominal aortic aneurysm?
- Media beneath atheromatous plaques gradually weakened (lipid-related inflammatory activity in plaque)
- It is a gradual dilation of vessel
- It is slow but progressive, seen in elderly, often asymptomatic.
What can a sudden rupture cause?
Massive retroperitoneal haemorrhage which has a high mortality
What can ruptured atheromatous abdominal aortic aneurysm lead to?
- Aneurysms > 5cm diameter at high risk of rupture
- Mural thrombus causing emboli to legs.
What are vulnerable atheromatous plaques?
-Ones that rupture with subsequent thrombosis and they have distinct morphological features
- Recognition of these plaques means a high risk of developing thrombotic complications
What can vulnerable atheromatous plaques cause?
- Pronounced inflammatory activities such as degradation and weakening of plaque which increases risk of plaque rupture
- Increased secretion of proteolytic enzymes, cytokines and reactive oxygen species by plaque inflammatory cells
- Highly stenotic plaques often large fibrocalcific component, little inflammation.
How to identify vulnerable atheromatous plaques?
- Typically thin fibrous cap
- Large lipid core
- Prominent inflammation
What are some preventative and therapeutic approaches?
- Stop smoking
- Control blood pressure
- Weight loss
- Regular exercise
- Dietary modifications
What are the secondary preventions?
- Cholesterol lowering drugs such as aspirin
- Surgical options
Why can aspirin be used in atheroma?
It inhibits platelet aggregation to decrease risk of thrombosis on established atheromatous plaques
