Pathophysiology of Atheroma Flashcards
What is an atheroma/atherosclerosis?
Formation of focal elevated lesions (plaques) in intima of large and medium sized arteries.
Give an example of the implications of an atheroma.
E.g. in coronary arteries, atheromatous plaques narrow lumen –> ischaemia.
Serious consequences - angina due to myocardial ischaemia.
How can atheromas be complicated?
By thromboembolisms.
What is arteriosclerosis?
Not atheromatous.
Age related change in muscular arteries.
Smooth muscle hypertrophy, apparent reduplication of internal elastic laminae, intimal fibrosis –> decrease in vessel diameter.
What does arteriosclerosis contribute to?
High frequency of cardiac cerebral, colonic and renal ischaemia in elderly.
When are clinical effects most apparent?
When CVS further stressed by haemorrhage, major surgery, infection, shock…
What is the earliest significant lesion of an atheroma?
A fatty streak..
When will this fatty streak develop?
Probably in childhood.
What will this fatty streak look like?
Yellow, linear elevation of intimal lining.
What is the fatty streak comprised of? What is the risk associated with this streak?
Masses of lipid laden macrophages. No clinical significance and may disappear but at risk of developing atheromatous plaques.
When does an early atheromatous plaque develop? What does it look like and what is it composed of?
Young adulthood onwards.
Smooth yellow patches in intima.
Lipid-laden macrophages.
Progress to established plaques.
What is the fully developed atheromatous plaque composed of?
Central lipid core (rich in cellular lipids/debris from macrophages (died in plaque)) 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.
What often forms the rim of the fully developed atheroma?
Soft, highly thrombogenic foamy macrophages - foamy appearance due to uptake of oxidised lipoproteins via specialised membrane bound scavenger receptor.
What may also happen to a fully developed atheromatous plaque?
Dystrophic calcification (occurs late) - (?marker for atherosclerosis in angiograms/CT). Form at arterial branching points/bifurcations (turbulent flow).
What are late stage plaques like?
Confluent, cover large areas.
Describe what a complicated atheroma is like.
Features of established atheromatous plaque plus haemorrhage into plaque (calcification), plaque rupture/fissuring, thrombosis –> clinical consequences.
What is the most important risk factor for developing atheromas?
Hypercholesterolaemia - causes plaque formation and growth in absence of other risk factors.
What is the prevalence of hypercholesterolaemia and how does it present?
1/500 Caucasians heterozygous for this type of mutation: decreased functional receptors on cell surfaces, elevated plasma LDL cholesterol levels.
Homozygous (1/mil) - much higher cholesterol levels, usually due from coronary artery atheroma in infancy/teens.
What are the signs for major hyperlipidaemia?
Familial/primary vs acquired/secondary. Biochemical evidence - LDL, HDL, total cholesterol, triglycerides. Corneal arcus (premature) Tendon xanthomata (knuckles, Achilles) Xanthelasmata Risk/premature/FH of MI/atheroma.
What are the major risk factors for atheroma?
Hypercholesterolaemia Smoking Hypertension Diabetes mellitus Male Elderly Accelerate process of plaque formation driven by lipids.
What are less strong risk factors for atherosclerosis?
Obesity Sedentary lifestyle Low socio-economic status Low birth weight ?role of microorganisms
Describe the two step process leading to the formation of atheromatous plaques.
Injury to endothelial lining of artery.
Chronic inflammation and healing response of vascular wall to agent causing injury.
Chronic/episodic exposure of arterial wall to these processes –> formation of atheromatous plaques.
Describe 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 recruitment)
Smooth muscle cell proliferation, extracellular matrix production and T-cell recruitment
Lipid accumulation (extracellular and in foamy macrophages).
How are the injured endothelial cells functionally altered?
Enhanced expression of cell adhesion molecules (ICAM-1, E-selectin)
High permeability for LDL
Increased thrombogenicity.
Inflammation cells, lipids –> intimal layer –> plaques.
Describe advanced plaque formation.
Large no.s of macrophages,T-lymphocytes
Lipid-laden macrophages die through apoptosis –> lipid into lipid core
Response to injury = chronic inflammation process 1. inflammation 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 y platelets, injured endothelium, macrophages and smooth muscle cells.
What are the consequences of an atheroma?
Many clinically unnoticed.
Clinical disease - relatively benign to life-threatening/fatal
Acute changes in plaques (complicated) –> serious.
What is classed as progressive lumen narrowing due to high grade plaque stenosis? What does it cause?
Stenosis of >50-75% of vessel lumen –> critical reduction of blood flow in distal arterial bed –> reversible tissue ischaemia.
Give examples of where this stenosis can occur and the symptoms experienced by the patient if it does.
Stenosed atheromatous coronary artery –> stable angina.
Very severe stenosis –> ischaemic pain at rest (unstable angina).
Ileal, femoral, popliteal artery stenosis –> intermittent claudication (peripheral arterial disease).
Longstanding tissue ischaemia –> atrophy of affected organ, e.g. atherosclerotic renal artery stenosis –> renal atrophy.
What is the major complications of acute atherothrombotic occlusion?
Rupture of plaque –> acute event.
Rupture exposes highly thrombogenic plaque contents (collagen, lipid, debris) to bloodstream –> activation of coagulation cascade and thrombotic occlusion in v short time.
What does total occlusion lead to?
Irreversible ischaemia and necrosis (infarction) of tissues, e.g. MI (coronary artery), stroke (carotid, cerebral artery), lower limb gangrene (ileal, femoral, popliteal).
What does detachment of small thrombus fragments lead to?
Can embolism distal to ruptured plaque, which may lead to occlusion of smaller vessels and smart infarcts in organs.
Give examples of where these fragments can embolise to and the problems they cause.
Heart, dangerous small foci of necrosis –> life-threatening arrhythmias.
Large ulcerating aorta plaques, lipid rich fragments of plaque –> cholesterol emboli in kidney, skin, leg.
Carotid artery atheromatous debris common cause of stroke (cerebral infarct/TIA).
How can atheromatous plaques lead to aortic aneurysms?
Media beneath plaque gradually weakened (lipid-related inflammatory activity in plaque) –> gradual dilatation of vessel.
Describe how aortic aneurysms develop and in which age group they are most common.
Slow but progressive.
Seen in elderly, often asymptomatic.
What can sudden rupture of an aortic aneurysm lead to?
Massive retroperitoneal haemorrhage (high mortality).
What size of aneurysms are at high risks of rupturing?
More than 5cm.
What are the typical features of a vulnerable atheromatous plaque?
Typically thin fibrous cap, large lipid core, prominent inflammation.
High risk of developing thrombotic complications.
What does inflammation lead to and why does it increase the risk of rupture?
Pronounced inflammatory activity leads to degradation, weakening of plaque and therefore increased risk of rupture.
What kinds of secretions released by the inflammatory cells will cause the plaque to rupture?
Secretion of proteolytic enzymes, cytokines and reactive oxygen species.
What is the appearance of highly stenotic plaques?
Often large fibrocalcific component with little inflammation.
What are the preventative and therapeutic approaches to atherosclerosis?
Stop smoking, control BP, weight loss, regular exercise, dietary modifications.
What are some drugs you may use in secondary prevention of atherosclerosis?
Cholesterol lowering drugs, aspiring (inhibits platelet aggregation to decrease risk of thrombosis on established atheromatous plaques).
What other options may you consider in treatment?
Surgical options.
