Pathophysiology of Atheroma

Question 1

What is atherosclerosis?

Answer 1

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

Question 2

What does atheroma in the coronary arteries result in?

Answer 2

Narrowing of the lumen due to atheromatous plaques, this in turn causes ischaemia and angina and can be complicated by thromboembolism

Question 3

What is arteriosclerosis?

Answer 3

Age-related change in the muscular arteries

Question 4

What does arteriosclerosis result in?

Answer 4

Smooth muscle hypertrophy
Apparent reduplication of internal elastic laminae
Intimal fibrosis leading to decreased vessel diameter

Question 5

What does arteriosclerosis contribute to in the elderly?

Answer 5

High frequency of cardiac, cerebral, colonic and renal ischaemia

Question 6

When are the clinical effects of arteriosclerosis most apparent?

Answer 6

When CVS is further stressed by haemorrhage, major surgery, shock, infection etc.

Question 7

What is atheroma?

Answer 7

Fatty streak
The earliest significant lesion in atherosclerosis
Yellow linear elevation of the intimal lining

Question 8

What is an atheroma lesion comprised of?

Answer 8

Masses of lipid-laden macrophages

Question 9

In what way is atheroma relevant?

Answer 9

No clinical significance, only relevant in patients at risk as it may develop into an atheromatous plaque

Question 10

When are early atheromatous plaques seen?

Answer 10

Young adults onwards

Question 11

What are the features of early atheromatous plaques?

Answer 11

Smooth yellow patches in the intima
Lipid-laden macrophages
Can progress to established plaques

Question 12

What are the features of a fully developed plaque?

Answer 12

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

Question 13

What do macrophages in fully developed plaques have a foamy appearance?

Answer 13

Due to uptake of oxidised lipoproteins via specialised membrane bound scavenger receptors

Question 14

What might provide a marker for atherosclerosis in angiograms and CT scans?

Answer 14

Dystrophic calcification

Question 15

Where do calcifications form?

Answer 15

At arterial branching points and bifurcations due to turbulent flow

Question 16

What are the features of a complicated atheroma?

Answer 16

Features of established atheromatous plaque plus;
Haemorrhage into the plaque, calcification
Plaque rupture/fissuring
Thrombosis
Clinical consequences

Question 17

What are the two steps involved in the development of atheromatous plaques? How do these steps result in formation of atheromatous plaques?

Answer 17

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

Question 18

What is the order of events in atherosclerosis development?

Answer 18

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

Question 19

What are the most important causes of endothelial injury?

Answer 19

Haemodynamic disturbances e.g. turbulent flow, hypercholesterolaemia

Question 20

How can chronic hypercholesterolaemia directly impair endothelial cell function?

Answer 20

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

Question 21

How are injured endothelial cells functionally altered?

Answer 21

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

Question 22

In advanced plaque formation there are large number of what cells?

Answer 22

Macrophages and T-lymphocytes

Question 23

What does response to endothelial injury involve?

Answer 23

The chronic inflammatory process

Question 24

What do growth factors cause in the intimal smooth muscle cells?

Answer 24

Proliferation of the intimal smooth muscle cells and subsequent synthesis of collagen, elastin and mucopolysaccharides

Question 25

What are growth factors secreted by?

Answer 25

Platelets Injured endothelium Macrophages Smooth muscle cells

Question 26

In established plaques, what is plaque growth initiated by (besides growth factors)?

Answer 26

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

Question 27

What are the main components of an atheromatous plaque?

Answer 27

``` Central lipid core Fibrous tissue cap Arterial endothelial lining Collagen in fibrous cap Inflammatory cells in fibrous cap Rim of foamy macrophages ```

Question 28

What is the most important risk factor for atheroma? Why?

Answer 28

Hypercholesterolaemia | It causes plaque formation and growth in the absence of other known risk factors

Question 29

What proportion of Caucasians are heterozygous for a mutation resulting in genetically determined lack of cell membrane receptors for LDL?

Answer 29

1/500

Question 30

What is the prognosis of patients who are homozygous for the mutation resulting in a genetically determined lack of cell membrane receptors for LDL?

Answer 30

Much higher cholesterol levels, these patients usually die from coronary artery atheroma in infancy or teens 1 in 1 million people - rare

Question 31

Other than hypercholesterolaemia, what are some risk factors for atheroma?

Answer 31

``` Smoking Hypertension Diabetes mellitus Male Elderly ``` ``` Less strong risk factors; Obesity Sedentary lifestyle Low socio-economic status Low birthweight Possible role of micro-organisms ```

Question 32

What biochemical levels are needed in investigation of atheroma?

Answer 32

LDL HDL Total cholesterol Triglycerides Results in the above which are higher than expected are indicative of hyperlipidaemia

Question 33

What features of a physical examination are indicative of atheroma?

Answer 33

Corneal arcus Tendon xanthoma (knuckles, Achilles tendon) Xanthelasmata

Question 34

What changes in plaques have serious complications?

Answer 34

Acute changes

Question 35

What will stenosis of 50-75% of the vessel lumen result in?

Answer 35

Critical reduction of blood flow in the distal arterial bed, resulting in reversible tissue ischaemia

Question 36

What will a stenosed atheromatous coronary artery cause?

Answer 36

Stable angina and ischaemic pain when exercising

Question 37

What does severe stenosis of a coronary artery result in?

Answer 37

Unstable angine - ischaemic pain at rest

Question 38

What does iliac, femoral or popliteal artery stenosis result in?

Answer 38

Intermittent claudication (peripheral arterial disease)

Question 39

What will longstanding tissue ischaemia result in?

Answer 39

Atrophy of the affected organ

Question 40

What does rupture of an atheromatous plaque cause?

Answer 40

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)

Question 41

What will total vessel occlusion result in?

Answer 41

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

Question 42

What causes embolisation of the distal arterial bed?

Answer 42

Detachment of small thrombus fragments from thromboses atheromatous arteries which emolise distal to the ruptured plaque

Question 43

What does embolic occlusion of small vessels cause?

Answer 43

Small infarcts in the affected organs

Question 44

What can embolic occlusion of small vessels in the heart cause?

Answer 44

Dangerous small foci of necrosis leading to life-threatening arrythmias

Question 45

What can lipid-rich fragments of large ulcerating aortic plaques cause?

Answer 45

Cholesterol emboli in the kidneys, legs and skin

Question 46

What is atheromatous debris a common cause of in the carotid arteries?

Answer 46

Cerebral infarct or TIA

Question 47

Why does the media beneath the atheromatous plaques gradually weaken?

Answer 47

Due to lipid related inflammatory activity in the plaque causing gradual dilatation of the vessel

Question 48

What does sudden rupture of an atheromatous abdominal aortic aneurysm result in?

Answer 48

Massive retroperitoneal haemorrhage with a high mortality

Question 49

When are abdominal aortic aneurysms at risk of rupture?

Answer 49

when > 5cm

Question 50

What are the features typical of atheromatous plaques which are vulnerable to rupture?

Answer 50

Thin fibrous cap Large lipid core Prominent inflammation Secretion of proteolytic enzymes, cytokines and reactive oxygen species by plaque inflammatory cells

Question 51

What does pronounced inflammatory activity lead to?

Answer 51

Degradation and weakening of the plaque resulting in increased risk of plaque rupture

Question 52

What is a typical feature of highly stenotic plaques?

Answer 52

Often have a large fibrocalcific component with little inflammation

Question 53

What are some primary preventative measures that can be taken against atheromatous plaque development?

Answer 53

``` Smoking cessation BP control Weight loss Regular exercise Dietary modification ```

Question 54

What are the options for secondary prevention of atheromatous plaques?

Answer 54

Cholesterol lowering drugs Aspirin Surgical options