Pathophysiology of Atheroma Flashcards
What is atherosclerosis?
Formation of focal elevated lesions (plaques) in the intima of large and medium sized arteries
What does atheroma in the coronary arteries result in?
Narrowing of the lumen due to atheromatous plaques, this in turn causes ischaemia and angina and can be complicated by thromboembolism
What is arteriosclerosis?
Age-related change in the muscular arteries
What does arteriosclerosis result in?
Smooth muscle hypertrophy
Apparent reduplication of internal elastic laminae
Intimal fibrosis leading to decreased vessel diameter
What does arteriosclerosis contribute to in the elderly?
High frequency of cardiac, cerebral, colonic and renal ischaemia
When are the clinical effects of arteriosclerosis most apparent?
When CVS is further stressed by haemorrhage, major surgery, shock, infection etc.
What is atheroma?
Fatty streak
The earliest significant lesion in atherosclerosis
Yellow linear elevation of the intimal lining
What is an atheroma lesion comprised of?
Masses of lipid-laden macrophages
In what way is atheroma relevant?
No clinical significance, only relevant in patients at risk as it may develop into an atheromatous plaque
When are early atheromatous plaques seen?
Young adults onwards
What are the features of early atheromatous plaques?
Smooth yellow patches in the intima
Lipid-laden macrophages
Can progress to established plaques
What are the features of a fully developed plaque?
Central lipid core with fibrous tissue cap
Covered by arterial endothelium
Collagens in the cap provide structural strength
Inflammatory cells reside in the fibrous cap
Central lipid core is rich in cellular lipids and debris derived from the macrophages
Soft, highly thrombogenic ring of foamy macrophages
Extensive dystrophic calcification
Late stage plaques are confluent and cover large areas
What do macrophages in fully developed plaques have a foamy appearance?
Due to uptake of oxidised lipoproteins via specialised membrane bound scavenger receptors
What might provide a marker for atherosclerosis in angiograms and CT scans?
Dystrophic calcification
Where do calcifications form?
At arterial branching points and bifurcations due to turbulent flow
What are the features of a complicated atheroma?
Features of established atheromatous plaque plus;
Haemorrhage into the plaque, calcification
Plaque rupture/fissuring
Thrombosis
Clinical consequences
What are the two steps involved in the development of atheromatous plaques? How do these steps result in formation of atheromatous plaques?
Injury to the endothelial lining of the artery
Chronic inflammatory and healing response of the vascular wall to the agent causing the injury
Chronic and episodic exposure of arterial wall to these processes is what results in the formation of atheromatous plaques
What is the order of events in atherosclerosis development?
Endothelial injury and dysfunction
Accumulation of lipoproteins in the vessel wall
Monocyte adhesion to the endothelium, migration into the intima and transformation to foamy macrophages
Platelet adhesion
Factor release from activated platelets and macrophages causing smooth muscle cell recruitment
Smooth muscle cell proliferation, ECM production and T-cell recruitment
Lipid accumulation
What are the most important causes of endothelial injury?
Haemodynamic disturbances e.g. turbulent flow, hypercholesterolaemia
How can chronic hypercholesterolaemia directly impair endothelial cell function?
By increasing local production of reactive oxygen species;
Lipoproteins aggregate in the intima and are modified by free radicals produced by inflammatory cells
Modified LDL accumulated by macrophages but not completely degraded
Foamy macrophages accumulate
These are toxic to endothelial cells plus release growth factor and cytokines
How are injured endothelial cells functionally altered?
Enhanced expression of cell adhesion molecules (ICAM-1, E-selectin)
High permeability for LDL
Increased thrombogenicity
Inflammatory cells and lipids accumulate in intimal layer and form plaques
In advanced plaque formation there are large number of what cells?
Macrophages and T-lymphocytes
What does response to endothelial injury involve?
The chronic inflammatory process
What do growth factors cause in the intimal smooth muscle cells?
Proliferation of the intimal smooth muscle cells and subsequent synthesis of collagen, elastin and mucopolysaccharides
What are growth factors secreted by?
Platelets
Injured endothelium
Macrophages
Smooth muscle cells
In established plaques, what is plaque growth initiated by (besides growth factors)?
Small areas of endothelial loss
Microthrombi formed at denuded areas of the plaque surface are organised by the same rear process
Repeated cycles gradually increase the plaque volume
What are the main components of an atheromatous plaque?
Central lipid core Fibrous tissue cap Arterial endothelial lining Collagen in fibrous cap Inflammatory cells in fibrous cap Rim of foamy macrophages
What is the most important risk factor for atheroma? Why?
Hypercholesterolaemia
It causes plaque formation and growth in the absence of other known risk factors
What proportion of Caucasians are heterozygous for a mutation resulting in genetically determined lack of cell membrane receptors for LDL?
1/500
What is the prognosis of patients who are homozygous for the mutation resulting in a genetically determined lack of cell membrane receptors for LDL?
Much higher cholesterol levels, these patients usually die from coronary artery atheroma in infancy or teens
1 in 1 million people - rare
Other than hypercholesterolaemia, what are some risk factors for atheroma?
Smoking Hypertension Diabetes mellitus Male Elderly
Less strong risk factors; Obesity Sedentary lifestyle Low socio-economic status Low birthweight Possible role of micro-organisms
What biochemical levels are needed in investigation of atheroma?
LDL
HDL
Total cholesterol
Triglycerides
Results in the above which are higher than expected are indicative of hyperlipidaemia
What features of a physical examination are indicative of atheroma?
Corneal arcus
Tendon xanthoma (knuckles, Achilles tendon)
Xanthelasmata
What changes in plaques have serious complications?
Acute changes
What will stenosis of 50-75% of the vessel lumen result in?
Critical reduction of blood flow in the distal arterial bed, resulting in reversible tissue ischaemia
What will a stenosed atheromatous coronary artery cause?
Stable angina and ischaemic pain when exercising
What does severe stenosis of a coronary artery result in?
Unstable angine - ischaemic pain at rest
What does iliac, femoral or popliteal artery stenosis result in?
Intermittent claudication (peripheral arterial disease)
What will longstanding tissue ischaemia result in?
Atrophy of the affected organ
What does rupture of an atheromatous plaque cause?
Exposure of the highly thrombogenic plaque contents to the blood stream, causing activation of the coagulation cascade and thrombotic occlusion in a very short time (thrombus formation)
What will total vessel occlusion result in?
Irreversible ischaemia resulting in necrosis or infarction of the affected tissues
e.g. MI in coronary artery
stroke in cerebral or carotid artery
lower limb gangrene in iliac, femoral or popliteal artery
What causes embolisation of the distal arterial bed?
Detachment of small thrombus fragments from thromboses atheromatous arteries which emolise distal to the ruptured plaque
What does embolic occlusion of small vessels cause?
Small infarcts in the affected organs
What can embolic occlusion of small vessels in the heart cause?
Dangerous small foci of necrosis leading to life-threatening arrythmias
What can lipid-rich fragments of large ulcerating aortic plaques cause?
Cholesterol emboli in the kidneys, legs and skin
What is atheromatous debris a common cause of in the carotid arteries?
Cerebral infarct or TIA
Why does the media beneath the atheromatous plaques gradually weaken?
Due to lipid related inflammatory activity in the plaque causing gradual dilatation of the vessel
What does sudden rupture of an atheromatous abdominal aortic aneurysm result in?
Massive retroperitoneal haemorrhage with a high mortality
When are abdominal aortic aneurysms at risk of rupture?
when > 5cm
What are the features typical of atheromatous plaques which are vulnerable to rupture?
Thin fibrous cap
Large lipid core
Prominent inflammation
Secretion of proteolytic enzymes, cytokines and reactive oxygen species by plaque inflammatory cells
What does pronounced inflammatory activity lead to?
Degradation and weakening of the plaque resulting in increased risk of plaque rupture
What is a typical feature of highly stenotic plaques?
Often have a large fibrocalcific component with little inflammation
What are some primary preventative measures that can be taken against atheromatous plaque development?
Smoking cessation BP control Weight loss Regular exercise Dietary modification
What are the options for secondary prevention of atheromatous plaques?
Cholesterol lowering drugs
Aspirin
Surgical options
