Lecture 15 Atherosclerosis I

Question 1

Atherosclerosis is a chronic inflammatory disease T or F

Answer 1

T

Question 2

What is the significance of atherosclerosis in cardiovascular disease

Answer 2

Atherosclerosis is the principal cause of heart attack stroke and gangrene of the extremities. It is also one of the major causes of death in Europe USA and Japan

Question 3

What was atherosclerosis initially thought to be

Answer 3

A lipid storage disease

Question 4

What is the main problem caused by atherosclerosis

Answer 4

The main problem in atherosclerosis comes when the plaque ruptures leading to thrombus formation and ultimately death

Question 5

What factors influence atherosclerosis

Answer 5

It is influenced by a multitude of lifestyle choices medical conditions and haemodynamics of blood flow itself

Question 6

Atherosclerosis can begin before birth T or F

Answer 6

T – particularly if there is maternal hypercholesterolaemia

Question 7

Atherosclerosis often remains symptomless for the majority of the patients’ lifetime T or F

Answer 7

T

Question 8

What initial trigger is required to start the process of atherosclerosis

Answer 8

Insult or injury to the vessel wall that leads to endothelial cell dysfunction

Question 9

The risk factors of atherosclerosis can be subclassified into medical and behavioural factors give examples of medical risk factors

Answer 9

Medical risk factors include raised lipoprotein A levels high LDL and/or low LDL dyslipidaemia (high levels of circulating lipids) hypertension overweight/obese type 2 diabetes positive family history (genetically inherited) and infections (such as chlamydia pneumonia)

Question 10

The risk factors of atherosclerosis can be subclassified into medical and behavioural factors give examples of behavioural risk factors

Answer 10

Behavioural risk factors include a diet high in fat smoking physical inactivity and alcohol consumption

Question 11

What is the relationship between the behavioural risk factors of atherosclerosis and the trigger of the disease

Answer 11

Endothelial cell dysfunction linked to smoking dyslipidaemia and type 2 diabetes

Question 12

What is the significance of age in atherosclerosis

Answer 12

Age is also a risk factor as we get older the more likely that atherosclerosis can progress to late stage disease

Question 13

Where are atherosclerotic plaques found

Answer 13

In the peripheral and coronary arteries

Question 14

What factors can influence the localisation of atherosclerotic plaques

Answer 14

The distribution of plaques may be governed by haemodynamic factors. Changes in flow/turbulance (e.g. at bifurcations) cause the artery to adjust its wall thickness and develop a neointima.

Question 15

Where are atherosclerotic plaques often found

Answer 15

At bifurcations

Question 16

Outline the structure of atherosclerotic plaques

Answer 16

Atherosclerotic plaques are complex lesions consisting of lipids a fibrous cap made of connective tissue and smooth muscle cells a necrotic core buried within the lesion between the media of the vessel and the fibrous cap and then also connective tissue

Question 17

Discuss the fate of atherosclerotic plaques

Answer 17

Eventually the plaques will either occlude the vessel lumen resulting in a restriction of blood flow (angina) or they may rupture resulting in thrombus formation which can lead to death

Question 18

The atherosclerotic pathway is initiated by an injury to the endothelial cells which leads to endothelial dysfunction T or F

Answer 18

T

Question 19

What is the effect of endothelial dysfunction

Answer 19

Endothelial dysfunction can cause altered NO biosynthesis which affects blood pressure control regional blood flow and predisposes a vessel to atherosclerosis. Similarly the damaged endothelium sends signals to inflammatory cells which then accumulate and migrate into the vessel walls. These signals such as cytokines including IL-1 selectins and integrins act as chemoattractants for the invading immune system cells

Question 20

How does endothelial dysfunction lead to adhesion of immune cells to the vessel wall

Answer 20

The damaged endothelium releases chemoattractants that produce a concentration gradient that is recognised by leukocytes. The endothelial cells when also begin to upregulate cell adhesion molecules that promote the adhesion of the leukocytes

Question 21

What happens following leukocyte attraction to the damaged endothelium

Answer 21

In response to the chemoattractant gradient the leukocyte will become captured by the vessel. This is followed by rolling along the endothelium of the vessel. This rolling then slows down to become slow rolling. After rolling stops the leukocyte undergoes firm adhesion. This adhesion is then followed by transmigration across the vessel wall

Question 22

Outline the lipid stimulus in atherosclerotic plaque development

Answer 22

LDL can normally pass in and out of the arterial wall however in the presence of macrophages LDL is captured leading to an excess accumulation in the arterial wall. Endothelial cells and macrophages generate free radicals and these free radicals oxidise LDL to oxLDL. oxLDL is then engulfed by macrophages via scavenger receptors to form foam cells. Foam cells then release more pro-inflammatory cytokines and then incorporate into the vessel wall and atherosclerotic lesion

Question 23

Give examples of cytokines released by atherosclerotic plaques

Answer 23

IL-1 IL-6 IL-8 IFN-γ TGF-β MCP-1 and PDGF

Question 24

Give an overview of the process of atherosclerosis from initial plaque formation to thrombus formation

Answer 24

In the first instance excess LDL accumulates in the artery wall and is oxidised by free radicals produced by the damaged endothelium and macrophages. Oxidised LDL causes the endothelial cells to become inflamed and as a result they begin to express CAMs for leukocytes. Leukocytes move across the vessel wall into the intima where they begin to uptake some of the oxLDL. Upon taking up oxLDL the leukocytes transform into foam cells which incorporate into the lesion. Cytokines released by foam cells triggers the smooth muscle cells in the intima to proliferate and secrete extracellular matrix proteins such as collagen. Other smooth muscle cells from the media migrate into the intima to form the fibrous cap. Persistence of the risk factors causes growth of the plaque which triggers an inflammatory response. T lymphocytes that migrate into the plaque then activate macrophages and cause them to secrete matrix metalloproteases. These matrix metalloprotease enzymes breakdown the collagen of the fibrous cap and render the plaque prone to rupture. Rupture of the plaque subsequently causes thrombus formation by allowing the blood to contact the endothelium. This can then result in ischaemic events such as MI or stroke

Question 25

What is the first stage of lesion in atherosclerosis

Answer 25

Fatty streak formation where the accumulation of lipid–laden macrophages foam cells and T lymphocytes within the intimal layer of the vessel wall (below endothelium) has begun to form a lesion. This occurs at a very early age (around 10years) although won’t cause any symptoms

Question 26

Following fatty streak formation these lesions can progress to an intermediate stage. What is characteristic of atherosclerotic plaques at this stage

Answer 26

Intermediate lesions consist of layers of foam cells vascular smooth muscle cells isolated pools of extracellular lipid/cholesterol T lymphocytes and adhesions and aggregates of platelets to vessel wall

Question 27

Symptoms of atherosclerotic disease will being to occur at the intermediate lesion stage due to occlusion of the vessel lumen T or F

Answer 27

F – no symptoms will occur at this stage in the disease as no lumen occlusion will have occurred

Question 28

Why do most atherosclerotic plaques remain in the intermediate lesion stage

Answer 28

Due to the mechanism of reverse cholesterol transport

Question 29

Briefly describe the reverse cholesterol transport pathway

Answer 29

Circulating HDL contains Apo-A1 particles that interact with foam cells to collect cholesterol. This mature HDL then travels to liver to release its cholesterol which is then processed for excretion. HDL then recirculates back to heart to repeat process

Question 30

What factors are thought to provide the extra impetus for an intermediate atherosclerotic lesion to progress to advanced stage

Answer 30

The addition of another risk factor or area of disturbed flow

Question 31

What is seen in advanced atherosclerotic lesions

Answer 31

There is the formation of a dense fibrous cap overlying a lipid-rich core. This cap consists of extracellular matrix proteins including collagen (strength) and elastin (flexibility). The lipid core consists of necrotic and apoptotic debris smooth muscle cells foam cells cholesterol crystals macrophages and T-lymphocytes

Question 32

What is the name given to the cap and core of a late stage atherosclerotic lesion

Answer 32

Atheromatous plaque

Question 33

What additional step may advanced atheromatous lesions undergo

Answer 33

Calcification

Question 34

Advanced atheromatous plaques impede blood flow and are prone to rupture T or F

Answer 34

T

Question 35

Atherosclerotic plaques are constantly growing and receding this is why the majority of lesions remain in the intermediate stage T or F

Answer 35

T – there is a balance between LDL moving into the lesion and depositing cholesterol and HDL clearing some of the cholesterol

Question 36

As well as the lipid core growing and receding what is happening to the cap

Answer 36

The fibrous cap has to be resorbed and redeposited as well in order to be maintained. Macrophages stimulated by T cells are secreting matrix metalloproteases that breakdown the cap. Meanwhile a large number of VSMC and matrix proteins stabilise the cap.

Question 37

What can cause plaque rupture

Answer 37

Large numbers of macrophages predisposes plaque to rupture due to increased matrix metalloproteinases and gelatinase secretion that causes the cap to become weak. Similarly cholesterol crystals released by the necrotic and apoptotic foam cells also play a role in plaque rupture. These crystals can either tear directly out of the plaque or erode the plaque itself

Question 38

What is the result of plaque rupture

Answer 38

Plaque rupture provides a substrate for thrombus formation and vessel occlusion