Pathophysiology of Atheroma

Question 1

What is Atheroma?

Answer 1

formation of focal elevated lesions (plaque) in intima of large and medium sized arteries

Question 2

What does atheromatous plaque narrowing lumen lead to?

Answer 2

ischaemia

Question 3

What are the serious consequences atheromatous plaque narrowing lumen?

Answer 3

myocardial ischaemia

Question 4

What complicates atheroma?

Answer 4

thromboembolism

Question 5

What is arteriosclerosis?

Answer 5

Not atheromatous
age related in muscular arteries
Smooth muscle hypertrophy, apparent reduplication of internal elastic laminae, intimal fibrosis → ↓ vessel diameter

Question 6

What does arteriosclerosis contribute to?

Answer 6

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

Question 7

When are clinical effects of arteriosclerosis most apparent?

Answer 7

Clinical effects most apparent when CVS further stressed by haemorrhage, major surgery, infection, shock

Question 8

What are the parts of a normal artery wall?

Answer 8

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.

Question 9

Characteristics of the atheroma?

Answer 9

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

Question 10

Characteristics of early atheromatous plaque?

Answer 10

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

Question 11

Characteristics of fully developed atheromatous plaque?

Answer 11

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)

Question 12

What is a marker for athersclerosis in angiograms/CT?

Answer 12

Dystrophic calcification extensive, occurs late in plaque development

Question 13

Where do atheromas commonly form?

Answer 13

Form at arterial branching points/bifurcations (turbulent flow)

Question 14

Give characteristics of complicated atheroma?

Answer 14

Features of established atheromatous plaque (lipid-rich core, fibrous cap)

PLUS

Haemorrhage into plaque (calcification)
Plaque rupture/fissuring
Thrombosis

Question 15

What causes atheroma?

Answer 15

hypercholesterolaemia- most important risk factor
Causes plaque formation and growth in absence of other known risk factors

Question 16

Mutations which lead to a tendency to get atheroma?

Answer 16

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

Question 17

What are the signs of major hyperlipidaemia?

Answer 17

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

Question 18

other risk factors for atheroma?

Answer 18

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

Question 19

What are the less strong risk factors for atheroma?

Answer 19

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

Question 20

Order of events for development of atheromatous plaques?

Answer 20

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)

Question 21

What are most important causes of endothelial injury?

Answer 21

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

Question 22

What is meant by injured endothelial cells being functionally altered?

Answer 22

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

Inflammatory cells, lipids → intimal layer → plaques

Question 23

Describe advanced plaque formation?

Answer 23

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

Question 24

Characteristics of an established plaque?

Answer 24

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

Question 25

What are the clinical consequences of atheroma?

Answer 25

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

Question 26

Clinical manifestations of atheroma? (PROGRESSIVE LUMNE NARROWING DUE TO HIGH GRADE PLAQUE STENOSIS)

Answer 26

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

Question 27

Clinical manifestations of atheroma (Acute atherothrombotic occlusion)?

Answer 27

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)

Question 28

Clinical manifestations of atheroma( EMBOLISATION OF DISTAL ARTERIAL BED)

Answer 28

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)

Question 29

Clinical manifestations of atheroma (RUPTURED ATHEROMATOUS ABDOMINAL AORTIC ANEURYSM)

Answer 29

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

Question 30

Describe vulnerable atheromatous plaques?

Answer 30

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

Question 31

Prevention/ therapy?

Answer 31

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