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What is atheroma/atherosclerosis?

Formation of focal elevated lesions (plaques) in intima of large and medium-sized arteries


What can atheromas cause?

Serious consequences: angina due to myocardial ischaemia
- Complicated by thromboembolism


What is arteriosclerosis?

- It is not atheromatous.
- Age-related change in muscular arteries
- Age-related change in muscular arteries
- Smooth muscle hypertrophy, apparent reduplicationof internal elastic laminae, intimal fibrosis causes a decrease in vessel diameter


How does arteriosclerosis affect the body?

Contributes to high frequency of cardiac, cerebral, colonic and renal ischaemia in elderly.


When are clinical features of arteriosclerosis most apparent?

They are most apparent when CVS further stressed by haemorrage, major surgery, infection, shock.


Is it possible to have arteriosclerosis and atheromatous together?



What is a Fatty streak in atherosclerosis?

- It is the earliest visible lesion of atherosclerosis
- It is due to an accumulation of lipid-laden foam cells in the intimal layer of the artery.


What is the main hallmark of established atherosclerosis?

Over time , the fatty streak evolves into a fibrous plaque, the hallmark of established atherosclerosis.
- Patients are at risk when there are atheromatous plaques


Features of a Fatty streak

- Earliest significant lesion
- Seen in young children
- Yellow linear elevation of intimal lining
- Comprises masses of lipid-laden macrophages
- No clinical significance
- May disappear


Features of early atheromatous plaque

- Seen in young adults onwards
- Smooth yellow patches in intima
- Lipid-laden macrophages
- Progress to established plaques


What does a fully developed atheromatous plaque contain?

- Central lipid core with fibrous tissue cap, covered by arterial endothelium
- Collagens (produced by smooth muscle cells) in cap provide structural strength
- Inflammatory cells (macrophages, T-lymphocytes, mast cells) reside in fibrous cap: recruited from arterial endothelium.
- Central lipid core rich in cellular lipids/debris derived from macrophages (died in plaque)
- Soft, highly thrombogenic, often rim of "foamy" macrophages


Features of complicated atheroma

- It has the same features of established atheromatous plaque (lipid-rich core, fibrous cap) plus:
- Haemorrhage into plaque (calcification)
- Plaque rupture/fissuring
- Thrombosis


What is calcified atheroma?

Aortic valve calcification is a condition in which calcium deposits form on the aortic valve in the heart.
- These deposits can cause narrowing at the opening of the aortic valve. This narrowing can become severe enough to reduce blood flow through the aortic valve — a condition called aortic valve stenosis.


Aetiology of atheroma

- Hypercholesterolaemia is the most important risk factor.
- Causes plaque formation and growth in absence of other known risk factors
- Importance of LDL cholesterol: studies of patients/animals with genetically determined lack of cell membrane receptors for LDL.


What is hypercholesterolaemia?

Hypercholesterolemia (high cholesterol), is the presence of high levels of cholesterol in the blood.
- It is a form of hyperlipidemia, high blood lipids, and hyperlipoproteinemia (elevated levels of lipoproteins in the blood).


What is the LDL cholesterol problem in 1/500 caucasians?

- Decreased functional receptors on cell surfaces.
- Elevated plasma LDL cholesterol levels.


What are signs of major hyperlipidaemia?

- Familial/primary vs acquired/secondary
- Biochemical evidence: LDL, HDL, total cholesterol, triglycerides
- Corneal arcus (premature)
- Tendon xanthomata (knuckles, achilles)
- Xanthelasmata
- Risk/premature/family history MI/atheroma


Risk factors for atheroma

- Smoking
- Hypertension
- Diabetes mellitus
- Being male
- Being old
These accelerate process of plaque formation driven by lipids.

Other risk factors: huge variation in disease severity among patients with same cholesterol levels.


Less strong risk factors for atheroma

- Obesity
- Sedentary lifestyle
- Low socio-economic status
- Low birthweight
- ?role of micro-organisms?


Two step process in the development of atheromatous plaques

1. Injury to endothelial lining of artery
2. Chronic inflammatory and healing response of vascular wall to agent causing injury

Chronic/episodic exposure of arterial wall to these processes causes formation of atheromatous plaques.


Order of events in the pathogenesis of atherosclerosis

- Endothelial injury and dysfunction
- Accumulation of lipoproteins (LDL) in vessel wall
- Monocyte adhesion to endothelium > migration into intima and transformation to foamy macrophages.
- 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 (chronic hypercholesterolaemia can directly impair endothelial cell function by increasing local production of reactive oxygen species)


In hypercholesterolaemia, how do lipoproteins aggregate?

- lipoproteins aggregate in intima and are modified by 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?

- Enhanced expression of cell adhesion molecules (ICAM-1, E-selectin)
- High permeability for LDL
- Increased thrombogenecity

Inflammatory cells, lipids → intimal layer → plaques


How does advanced plaque formation occur?

- Large numbers macrophages, T-lymphocytes
- Lipid-laden macrophages die through apoptosis > lipid into lipid core
- Response to injury = chronic inflammatory process: 1. Inflammatory reaction 2. Process of tissue repair
- Growth factors (PDGF) → proliferation intimal smooth muscle cells, subsequent synthesis collagen, elastin, mucopolysaccharide
- Fibrous cap encloses lipid rich core
- Growth factors secreted by platelets, injured endothelium, macrophages and smooth muscle cells.


What forms at denuded areas of plaque surface in development of atheromatous plaques?

- Microthrombi formed at denuded areas of plaque surface → organised by same repair process (smooth muscle cell invasion and collagen deposition

- Repeated cycles gradually increase plaque volume.


What are consequences of atheroma: clinical manifestations?

- Many plaques form over lifetime, many clinically unnoticed
- Clinical disease: relatively benign to life-threatening/fatal.
- Acute changes in plaques (complicated atheroma) → serious consequences


What occurs due to high grade plaque stenosis

This causes progressive lumen narrowing


What does acute atherthrombotic occlusion cause?

- Major complications: rupture of plaque → acute event
- rupture exposes highly thrombogenic plaque contents (collagen, lipid, debris) to blood stream → activation of coagulation cascade and thrombotic occlusion in a very short time.


What can a total occlusion cause?

Total occlusion → irreversible ischaemia → necrosis (infarction) of tissues

e.g. myocardial infarct (coronary artery), stroke (carotid, cerebral artery), lower limb gangrene (ileal, femoral, popliteal artery).


Who is at heightened risk for arterial embolisation?

Surgical and intensive care patients are at a heightened risk for arterial embolisation due to pre-existing conditions such as age, hypercoagulability, cardiac abnormalities and atherosclerotic disease.


Where do most arterial emboli originate and travel?

-Most are clots that originate in the heart and travel to distant vascular beds where they cause arterial occlusion, ischaemia, and potentially infarction.


How does ambolisation of the distal arterial bed occur?

- Detachment of small thrombus fragments from thrombosed atheromatous arteries → embolise distal to ruptured plaque.
- Embolic occlusion of small vessels → small infarcts in organs.


How does ruptured atheromatous abdominal aortic aneurysm occur?

- Media beneath atheromatous plaques gradually weakened (lipid-related inflammatory activity in plaque)
→ gradual dilatation of vessel
- Sudden rupture → massive retroperitoneal haemorrhage (high mortality)
- Aneurysms >5cm diameter are at high risk of rupture
- Mural thrombus → emboli to legs


What are vulnerable atheromatous plaques?

- Atheromatous plaques that rupture with subsequent thrombosis: distinct morphological features.
- Typically thin fibrous cap, large lipid core, prominent inflammation.


What causes an increase in risk of plaque rupture?

Pronounced infammatory 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


What are preventative and therapeutic approaches for atherosclerosis?

- Stop smoking
- Control blood pressure
- Weight loss
- Regular exercise
- Dietary modifications


Secondary prevention methods for atherosclerosis?

Cholesterol lowering drugs, aspirin (inhibits platelet aggregation to decrease risk of thrombosis on established atheromatous plaques)

- OR surgical options