Atherosclerosis

Question 1

Where does atherosclerosis occur?

Answer 1

Atherosclerosis occurs in elastic arteries (such as aorta, carotid and iliac arteries) and large and medium sized muscular arteries (such as coronary and popliteal arteries). It is commoner in the abdominal rather than the thoracic aorta.

Atherosclerosis develops in patches of the intima often where flow is disturbed, e.g., around the opening of a branch.

It does not affect veins or capillaries.

Question 2

Briefly describe how atherosclerosis occurs

Answer 2

The key event is a focal accumulation of lipid and cells beneath the endothelium which forms a raised flat plaque. The plaque is usually about 1-2mm thick. It can be a major obstacle to flow in arteries with a lumen of approximately 3 mm, such as coronary arteries. The process of plaque formation takes many years.

Question 3

When does stenosis become significant?

Answer 3

Flow through a stenosed tube or artery is not significantly affected until the lumen is reduced by 70-80%. With lesser reductions in size the functional
reserve of the affected tissue is reduced, e.g., in moderate coronary artery atherosclerosis the heart may not get enough blood during exercise.

Question 4

What is arteriosclerosis?

Answer 4

Arteriosclerosis = hardening of the arteries. In this condition the walls of arteries are
thickened and lose their elasticity.

Question 5

Which diseases are included in arteriosclerosis?

Answer 5

It includes three diseases:

• Atherosclerosis
• Arteriolosclerosis
• Monkeberg’s disease

Question 6

What is atherosclerosis?

Answer 6

Atherosclerosis – a disease of large and medium sized arteries that begins in the intima. Plaques are formed in the arterial wall and these are filled with atheroma (a
necrotic gruel-like material. The plaques often calcify.

Question 7

What is arteriolosclerosis?

Answer 7

Arteriolosclerosis = hardening of the arterioles. This disease affects arterioles throughout the body but especially those of the kidney. It has little or no connection with atherosclerosis and usually occurs secondary to severe hypertension or in diabetes mellitus.

Question 8

What is Monkeberg’s disease?

Answer 8

Monkeberg’s disease – an uncommon disease where there is calcification of the media of large arteries.
Atheroma is the necrotic core of the atherosclerotic plaque. It consists of dead cells, debris and cholesterol crystals.

Question 9

What the atherosclerotic plaque?

Answer 9

The plaque is the basic lesion of atherosclerosis. It has three basic components:
● Cells – macrophages, leucocytes, smooth muscle cells,
● Intra- and extracellular lipid,
● Extracellular matrix – collagen, elastin, proteoglycans.

Question 10

What is the first stage in plaque formation?

Answer 10

1. Chronic endothelial insult from conditions such as hyperlipidaemia, hypertension, smoking or from haemodynamic factors result in endothelial dysfunction.

Question 11

What is the second stage in plaque formation?

Answer 11

2. Lipid droplets, mainly from low density lipoproteins (LDLs), and monocytes cross the endothelium and accumulate in the intima. The lipids become oxidised and the macrophages ingest the lipid. When they do so their cytoplasm appears bubbly microscopically and they are called foam cells.

Question 12

What is the third stage in plaque formation?

Answer 12

3. The crowded foam cells cause the endothelium to bulge. Smooth muscle cells migrate into the lesion from the media and start to proliferate. The lesion at this
   stage is called a fatty streak.

Question 13

What is the forth stage in plaque formation?

Answer 13

4. The plaque grows as the number of foam cells and smooth muscle cells increases. Some smooth muscle cells will also take up lipid and appear foamy. Some smooth muscle cells will lie over the plaque but beneath the endothelium forming a ‘roof’. This roof is reinforced by collagen, elastin and other matrix proteins and the result is a fibrous cap. As the endothelium stretches over the plaque gaps appear between
   the endothelial cells. Platelets adhere to the gaps.

Question 14

What is the final stage in plaque formation?

Answer 14

5. Cells in the centre of the plaque die and necrosis develops. The dead cells release cholesterol and cholesterol crystals appear in the plaque (these are removed during tissue processing for microscopy leaving behind linear holes in the tissue section =
   cholesterol clefts). Small blood vessels grow into the plaque from the adventitia and the plaque may undergo calcification.

Question 15

Describe the appearance of the fatty streak

Answer 15

The earliest lesion in atherosclerosis is the fatty streak. These are flat and cause no disturbance to blood flow. They occur early in life and can be seen in children.

Question 16

Describe the microscopic appearance of the fatty streak

Answer 16

Microscopically they consist of intimal foam cells, some smooth muscle cells and some extracellular lipid.

Question 17

Describe the appearance of plaques

Answer 17

As fatty streaks grow they become plaques. These are white to yellow in colour and impinge on the lumen of the artery. They usually measure between 0.3-1.5 cm in diameter and are usually only partly circumferential.

Question 18

Describe the microscopic appearance of plaques

Answer 18

Microscopically there is fibrosis, necrosis, cholesterol clefts, disruption of the internal elastic lamina, extension into the media and ingrowth of small vessels from the adventitia.

Question 19

How can plaques become complicated?

Answer 19

Plaques can become complicated in a number of ways:

• Ulceration
• Thrombosis on the plaque
• Spasm at the site of the plaque
• Embolisation
• Calcification
• Haemorrhage
• Aneurysm formation
• Rupture of the atherosclerotic artery

Question 20

Describe how ulceration occurs as a complication of a plaque

Answer 20

The fibrous cap is eroded from underneath and the core of the plaque is exposed to the blood. This core is highly thrombogenic.

Question 21

Where do thromboses on plaques occur?

Answer 21

Often on an ulcerated plaque, however it can sometimes occur on a plaque with intact endothelium. The thrombus may occlude the vessel lumen.

Question 22

What causes spasms at the site of a plaque?

Answer 22

Caused by vasoconstrictors released from thrombi.

Question 23

How can a plaque result in embolisation?

Answer 23

Pieces of exposed atheroma or overlying thrombus break away.

Question 24

Describe how calcification occurs as the result of a plaque

Answer 24

Occurs in and around the plaque making the artery even stiffer.

Question 25

Explain how haemorrhage can occur as the result of a plaque

Answer 25

Haemorrhage of one of the new vessels within the plaque. This suddenly expands the plaque which can result in vessel occlusion or the pressure from the haemorrhage may break the plaque open.

Question 26

Explain how a plaque may lead to aneurysm formation

Answer 26

A local dilatation may result when elastic tissue within the arterial wall is destroyed by the plaque. This weakens the wall and may result in rupture of the vessel.

Question 27

When might rupture of the atherosclerotic artery occur?

Answer 27

With resulting bleeding. This occurs as a result of a weakened media. It is especially seen in cerebral arteries when the patient has hypertension in addition to atherosclerosis.

Question 28

What is an aneurysm?

Answer 28

These are local dilatations of an artery due to weakening of the arterial wall. In large arteries they are almost always secondary to atherosclerosis. Like atherosclerosis, they are a disease of arteries. Dilatations in veins are called varices.

Question 29

What is a saccular aneurysm?

Answer 29

A saccular aneurysm is one that is shaped like a sac. They commonly occur in the abdominal aorta and can be 10-15cm in diameter. They are generally lined and/or filled by thrombus, which may be adventitious as it can protect the aneurysm from bursting.

Question 30

What is a fusiform aneurysm?

Answer 30

An fusiform aneurysm is one that is shaped like a spindle.

Question 31

What are the complications of aortic aneurysms?

Answer 31

Aortic aneurysms have two major complications; if large they may rupture and thrombus or plaque material within them may embolise.

Question 32

How does a dissecting aneurysm form?

Answer 32

Dissecting aneurysms occur virtually only in the aorta and its major branches. They form within a couple of minutes and survival is rare. The inner layer of the arterial wall tears open, blood enters the tear and separates the media into two layers. As the tear fills with blood the lumen of the artery can be occluded. Occasionally blood can push its way back into the lumen by means of a second tear.

Question 33

Describe the effects of atherosclerosis

Answer 33

Symptoms usually occur in the heart, brain, kidneys, legs or bowel. Atherosclerosis can cause conditions such as: ● Heart - myocardial infarction, chronic ischaemic heart disease, arrhythmias, cardiac failure and sudden cardiac death ● Brain – transient ischaemic attacks (TIAs), cerebral infarction, multi-infarct, dementia ● Kidneys – hypertension, renal failure ● Legs – peripheral vascular disease, gangrene, ● Bowel - ischaemic colitis, malabsorption, bowel infarction. These conditions are either due to narrowing/blockage of vessels or embolism of plaque material or thrombus that has formed on a plaque.

Question 34

What are the possible mechanisms of atherogenesis?

Answer 34

A number of mechanisms have been proposed. These include: ● The response to injury hypothesis ● The encrustation hypothesis ● The monoclonal hypothesis

Question 35

What is the response to injury hypothesis?

Answer 35

The response to injury hypothesis: this postulates that atherosclerosis is a chronic inflammatory response of the arterial wall initiated by injury to the endothelium. Lesion progression is sustained by interaction between modified lipoproteins, macrophages, T lymphocytes and cells of the arterial wall.

Question 36

What is the encrustation hypothesis?

Answer 36

The encrustation hypothesis: in this model plaques are formed by repeated thrombi overlying thrombi. The lipid core is derived from the thrombi.

Question 37

What is the monoclonal hypothesis?

Answer 37

The monoclonal hypothesis: this hypothesis arose following the finding that some plaques are monoclonal or oligoclonal. This raised the question of whether plaques are benign neoplastic growths, perhaps induced by cholesterol or a virus. However as some areas of normal arteries are clonal this theory hasn’t gained widespread popularity.

Question 38

What are the non-modifiable risk factors of atherosclerosis?

Answer 38

● Age, ● Gender - more common in men than in women but the incidence in women increases after the menopause as oestogen is protective ● Genetic predisposition – this most commonly results from a clustering of other risk factors but occasionally it is due to derangements in lipoprotein metabolism resulting in high lipid levels

Question 39

Explain why homozygous familial hypercholesterolaemia acts as a non-modifiable risk factor for atherosclerosis

Answer 39

People with this condition have defects in the LDL receptor which result in decreased hepatic uptake of LDL and therefore increased circulating LDL. Such people tend to have myocardial infarctions before the age of 20 years.

Question 40

Why do people with the apolipoprotein E genotype have an increased risk of developing atherosclerosis?

Answer 40

Some of the genotypes are associated with high LDL | levels and therefore a predisposition to atherosclerosis.

Question 41

What are the modifiable risk factors of atherosclerosis?

Answer 41

``` Modifiable Risk Factors ● Hyperlipidaemia ● Hypertension ● Cigarette smoking ● Geography ● Obesity ● Infection ```

Question 42

How does hyperlipidaemia act as a risk factor for atherosclerosis?

Answer 42

Hyperlipidaemia– (especially hypercholesterolaemia) results in premature and severe atherosclerosis. Any increase in LDL cholesterol (which delivers cholesterol to the peripheral tissues) is associated with an increased incidence of atherosclerosis. HDL removes cholesterol from atheromatous plaques and delivers it to the liver for excretion in bile. HDL is therefore protective. Levels of HDL are increased with exercise and moderate alcohol and decreased with obesity and smoking. The reason that diabetes mellitus is associated with atherosclerosis is that it causes hypercholesterolaemia.

Question 43

How is smoking a risk factor for atherosclerosis?

Answer 43

Via a number of mechanisms including inflammation in and damage to the blood vessel wall, increased predisposition to thrombosis and oxidation of lipids.

Question 44

How does geography act as a risk factor for atherosclerosis?

Answer 44

Atherosclerosis is ubiquitous among developed nations but has a lower incidence in South America, Africa and Asia. Migrants who immigrate to high risk locations and adopt the new lifestyles and diet will eventually have the same risk as the location to which they have moved.

Question 45

How is obesity a risk factor for atherosclerosis?

Answer 45

Produces hypertension, diabetes mellitus, hypertriglyceridaemia and reduced HDL.

Question 46

How does infection act as a risk factor for atherosclerosis?

Answer 46

E.g. with Chlamydia pneumoniae or CMV - has been reported by some to increase the risk of atherosclerosis.

Question 47

How is hypertension a risk factor for atherosclerosis?

Answer 47

The increased pressure damages blood vessel walls which predisposes an individual to plaque formation.

Question 48

What are the prevention strategies for atherosclerosis?

Answer 48

Prevention strategies should begin in childhood. They include: ● Decreasing total and LDL cholesterol and increasing HDL. This is probably the most important strategy and can generally be achieved with diet and lipid-lowering drugs. Dietary measures include a low fat and high fibre diet. Food high in soluble fibre reduces circulating lipid, ● Stopping smoking, ● Controlling hypertension, ● Controlling weight and regular exercise, ● Sensible alcohol intake. A moderate intake (1-2 units/day) appears protective. Excess alcohol produces secondary hyperlipidaemia ● Treating diabetes mellitus, ● Anti-oxidants, such as vitamin E, may be protective.

Question 49

What intervention strategies are there for atherosclerosis?

Answer 49

Intervention strategies include: ● Lipid-lowering drugs, e.g., statins, and aspirin prophylaxis, ● Thrombolysis, angioplasty, stents, and coronary artery bypass grafts (CABG).