Pathophysiology of atheroma

Question 1

What is the definition of atheroma/atherosclerosis ?

Answer 1

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

Question 2

What are potential outcomes of atheroma ?

Answer 2

Ischaemia in coronary arteries - atheromatous plaques narrowing lumen
Angina due to myocardial ischaemia
Complicated thromboembolism

Question 3

What is the earliest significant lesion of atheroma ?

Answer 3

Fatty streak

Question 4

What makes up the yellow linear elevation of intimal lining of a fatty streak ?

Answer 4

Comprises masses of lipid - laden macrophages

Question 5

What is the clinical significance of fatty streaks ?

Answer 5

No clinical significance

Question 6

Who often gets fatty streaks ?

Answer 6

Young children

Question 7

Who often gets early atheromatous plaques ?

Answer 7

Young adults onwards

Question 8

What is the histological appearance of early atheromatous plaques ?

Answer 8

Smooth yellow patches in intima

Lipid-laden macrophages

Question 9

What can early atheromatous plaques progress to ?

Answer 9

Established plaques

Question 10

What are the features of a fully developed atheromatous plaque ?

Answer 10

Central lipid core with fibrous tissue cap, covered by arterial endothelium

Question 11

What is responsible for the collagen production in the cap ?

Answer 11

Smooth muscle cells

Question 12

What is the function of the fibrous cap that sits on the central lipid core ?

Answer 12

Provides structural strength

Question 13

What resides in the fibrous cap ?

Answer 13

inflammatory cells-

• Macrophages
• T-lymphocytes
• Mast cells

Question 14

What is contained within the central lipid core ?

Answer 14

Cellular lipids/debris derived from macrophages which have died in the plaque
Often a rim of foamy thrombogenic macrophages

Question 15

Why are some macrophages described as foamy ?

Answer 15

Due to the uptake of oxidised lipoproteins via specialised membrane bound scavenger receptor

Question 16

What marker in angiograms forms in late plaque development ?

Answer 16

Dystrophic calcification

Question 17

What is dystrophic calcification ?

Answer 17

Dystrophic calcification (DC) is the calcification occurring in degenerated or necrotic tissue

Question 18

What is a complicated atheroma ?

Answer 18

Haemorrhage into plaque causing plague rupture and potential thrombosis

Question 19

What is the most important risk factor for atheroma ?

Answer 19

Hypercholesterolaemia

Question 20

How does increased LDL cholesterol levels arise ?

Answer 20

Lack of cell membrane receptor for LDL

Question 21

What is the epidemiology for the decreased functional receptor mutation ?

Answer 21

1/500 Caucasians

Question 22

What are the signs of major hyperlipidaemia ?

Answer 22

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

Question 23

What are the risk factors for atheroma ?

Answer 23

Smoking 
Hypertension
Diabetes
Male
Elderly 
Accelerate process of plaque formation driven by lipids

Question 24

What are the less strong risk factors for atheroma ?

Answer 24

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

Question 25

What is arteriosclerosis ?

Answer 25

Not atheromatous Stiffening or hardening or the arterial walls which features smooth muscle hypertrophy, apparent reduplication of internal elastic laminae and intimal fibrosis leading to a decrease in vessel diameter

Question 26

What does arteriosclerosis contribute to ?

Answer 26

High frequency of cardiac cerebral, colonic and renal ischaemia in elderly Clinical effects most apparent when CVS further stressed by haemorrhage, major surgery, infection, shock

Question 27

Who commonly suffers from arteriosclerosis ?

Answer 27

The elderly

Question 28

What is the two step development process of atheromatous plaques ?

Answer 28

1. Injury to endothelial lining or artery 2. Chronic inflammation and healing repsonse of vascular wall to agent causing injury Chronic/episodic exposure of arterial wall to these processes-> formation of atheromatous plaques

Question 29

What is the steps of the pathogenesis of atherosclerosis ?

Answer 29

1. Endothelial injury and dysfunction 2. Accumulation of lipoproteins (LDL) in vessel wall 3. Monocyte adhesion to endothelium-> migration into intima and transformation to foamy macrophages 4. Platelet adhesion 5. Factor release from activated platelets, macrophages -> smooth muscle cell recruitment 6. Smooth muscle cell proliferation, extracellular matric production and T-cell recruitment Lipid accumulation (extracellular and in foamy macrophages)

Question 30

What are the possible causes of endothelial injury ?

Answer 30

Haemodynamic disturbances (turbulent flow) Hypercholesterolemia: - (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 31

How are injured endothelial cells functionally altered ?

Answer 31

Enhanced expression of cell adhesion molecules (ICAM-1, E-selectin) High permeability for LDL Increased thrombogenicity Inflammatory cells, lipids-> intimal layer-> plaques

Question 32

How does advanced plaques form ?

Answer 32

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

Question 33

What is the consequence of progressive lumen narrowing due to high grade stenosis ?

Answer 33

Stenosis of >50-75% of vessel lumen-> critical reduction of blood flow in distal arterial bed-> reversible tissue ischaemia E.g. Stenosed atheromatous cornonary artery-> stable angina Very severe stenosis-> ischamic pain at rest (unstable angina) E.g. Ileal, femoral, popliteal artery stenosis -> intermittent claudication (peripheral arterial disease) Longstanding tissue ischemia -> atrophy of affected organ e.g. Atherosclerotic renal artery stenosis-> renal atrophy

Question 34

What is the consequence of acute atherothrombotic occlusion ?

Answer 34

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 ischemia-> 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 35

What is the consequence of embolization of the distal arterial bed ?

Answer 35

Detachment if 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-> cholestrol emboli in kidney, leg, skin E.g. Carotid artery atheromatous debris, common cause stroke (cerebral infarct/ TIA)

Question 36

What is the consequence of ruptured atheromatous abdominal aortic anuerysm ?

Answer 36

Media beneath atheromatous plauqes 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 in legs

Question 37

What is the preventative and theraputic approaches to atheroma ?

Answer 37

``` Stop smoking Control blood pressure Weight loss Regular exercise Dietary modification ```

Question 38

What are the secondary prevention measures of atheroma's ?

Answer 38

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