Pathophysiology of Atheroma Flashcards
What is Atheroma?
formation of focal elevated lesions (plaque) in intima of large and medium sized arteries
What does atheromatous plaque narrowing lumen lead to?
ischaemia
What are the serious consequences atheromatous plaque narrowing lumen?
myocardial ischaemia
What complicates atheroma?
thromboembolism
What is arteriosclerosis?
Not atheromatous
age related in muscular arteries
Smooth muscle hypertrophy, apparent reduplication of internal elastic laminae, intimal fibrosis → ↓ vessel diameter
What does arteriosclerosis contribute to?
Contributes to high frequency of cardiac, cerebral, colonic and renal ischaemia in elderly
When are clinical effects of arteriosclerosis most apparent?
Clinical effects most apparent when CVS further stressed by haemorrhage, major surgery, infection, shock
What are the parts of a normal artery wall?
intima- where atheroma forms
media-made up of smooth muscle
adventitia- fibrous tissue with blood vessels and nerves that’s on the outside. Separated by elastic lamina.
Characteristics of the atheroma?
Earliest significant lesion
Yellow linear elevation of intimal lining
Comprises masses of lipid-laden macrophages
No clinical significance
May disappear
But for patients at risk → atheromatous plaques
Characteristics of early atheromatous plaque?
Young adults onwards
Smooth yellow patches in intima
Lipid-laden macrophages
Progress to established plaques
Characteristics of fully developed atheromatous plaque?
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 (“foamy” due to uptake of oxidised lipoproteins via specialised membrane bound scavenger receptor)
What is a marker for athersclerosis in angiograms/CT?
Dystrophic calcification extensive, occurs late in plaque development
Where do atheromas commonly form?
Form at arterial branching points/bifurcations (turbulent flow)
Give characteristics of complicated atheroma?
Features of established atheromatous plaque (lipid-rich core, fibrous cap)
PLUS
Haemorrhage into plaque (calcification)
Plaque rupture/fissuring
Thrombosis
What causes atheroma?
hypercholesterolaemia- most important risk factor
Causes plaque formation and growth in absence of other known risk factors
Mutations which lead to a tendency to get atheroma?
Importance of LDL cholesterol: studies of patients/animals with genetically determined lack of cell membrane receptors for LDL
1/500 Caucasians heterozygous for this type mutation: ↓ functional receptors on cell surfaces, elevated plasma LDL cholesterol levels
Rare patients homozygous (1/million): much higher cholesterol levels, usually die from coronary artery atheroma in infancy/teens
What are the signs of major hyperlipidaemia?
Familial/primary vs acquired/secondary (?idiopathic)
Biochemical evidence: LDL, HDL, total cholesterol, triglycerides- test blood levels for these
Corneal arcus (premature)- pale ring in eye
Tendon xanthomata (knuckles, Achilles)- firm lumps of fatty material
Xanthelasmata- yellow spots under eye , cheek
Risk/premature/family history MI/atheroma
other risk factors for atheroma?
Other risk factors: huge variation in disease severity among patients with same cholesterol levels
Smoking
Hypertension
Diabetes mellitus
Male
Elderly
Accelerate process of plaque formation driven by lipids
What are the less strong risk factors for atheroma?
Obesity
Sedentary lifestyle
Low socio-economic status
Low birthweight
?role of micro-organisms
Order of events for development of atheromatous plaques?
Pathogenesis of atherosclerosis – order of events:
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 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)
(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
What is meant by injured endothelial cells being functionally altered?
enhanced expression of cell adhesion molecules (ICAM-1 , E-selectin)
High permeability for LDL
Increased thrombogenicity
Inflammatory cells, lipids → intimal layer → plaques
Describe advanced plaque formation?
large numbers of macrophages and T - lymphocytes
Lipid laden macrophages die through apoptosis (single cell death) and lipid gets 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
Characteristics of an established plaque?
Established plaques, plaque growth also initiated by small areas of endothelial loss
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 the clinical consequences of atheroma?
Many plaques form over lifetime, many clinically unnoticed
Clinical disease: relatively benign to life-threatening/fatal
Acute changes in plaques (complicated atheroma) → serious consequences
Clinical manifestations of atheroma? (PROGRESSIVE LUMNE NARROWING DUE TO HIGH GRADE PLAQUE STENOSIS)
Stenosis of > 50-75% of vessel lumen → critical reduction of blood flow in distal arterial bed → reversible tissue ischaemia
E.g. stenosed atheromatous coronary artery → stable angina (chest pain)
Very severe stenosis → ischaemic pain at rest (unstable angina)
E.g. 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
Clinical manifestations of atheroma (Acute atherothrombotic occlusion)?
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 very short time
Total occlusion → irreversible ischaemia → necrosis (infarction) of tissues
E.g. myocardial infarct (coronary artery)
E.g. stroke (carotid, cerebral artery)
E.g. lower limb gangrene (ileal, femoral, popliteal artery)
Clinical manifestations of atheroma( EMBOLISATION OF DISTAL ARTERIAL BED)
Detachment of small thrombus fragments from thrombosed atheromatous arteries → embolise distal to ruptured plaque
Embolic occlusion of small vessels → small infarcts in organs
E.g. heart, dangerous small foci of necrosis → life-threatening arrhythmias
E.g. large ulcerating aortic plaques, lipid rich fragments of plaque → cholesterol emboli in kidney, leg, skin
E.g. carotid artery atheromatous debris, common cause stroke (cerebral infarct/TIA)
Clinical manifestations of atheroma (RUPTURED ATHEROMATOUS ABDOMINAL AORTIC ANEURYSM)
Media beneath atheromatous plaques gradually weakened (lipid-related inflammatory activity in plaque)
→ Gradual dilatation of vessel
Slow but progressive, seen in elderly, often asymptomatic
Sudden rupture → massive retroperitoneal haemorrhage (high mortality)
Aneurysms > 5cm diameter at high risk of rupture
Mural thrombus → emboli to legs
Describe vulnerable atheromatous plaques?
Typically thin fibrous cap, large lipid core, prominent inflammation
Pronounced inflammatory activity → degradation, weakening of plaque → 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
Prevention/ therapy?
Preventative and therapeutic approaches:
Stop smoking
Control blood pressure
Weight loss
Regular exercise
Dietary modifications
Secondary prevention:
Cholesterol lowering drugs, aspirin (inhibits platelet aggregation to decrease risk of thrombosis on established atheromatous plaques)
Surgical options
