L19 Atherosclerosis

Question 1

Atherosclerosis is a disease affecting…

Answer 1

the inner most layer of large and medium arteries

Question 2

Atherosclerosis is characterised by:

Answer 2

Focal thickenings of plaque which are deposits of fibrous tissues and lipids

Question 3

What are the three concentric layers?

Answer 3

Tunica intima, media, externa/adventitia

Question 4

The endothelial cells are seperated by

Answer 4

Tight junctionsWh

Question 5

What is the structure of tunica intima?

Answer 5

Single layer of endothelial cells on basement membrane

Question 6

What are myointimal cells?

Answer 6

Contractile cells scattered through the basement

Question 7

What are the five functions of endothelial cells?

Answer 7

• Provide barrier between blood and underlying tissues
• Act as a gatekeeper to the process of inflammation
• Regulate blood pressure by regulating contraction of vascular smooth muscle cells
• control haemostasis as they produce enzymatic and chemical inhibitors of platelet activation.
• Determine long term vessel regression vs new vessel growth (angiogenesis) in response to tissue needs.

Question 8

How does the tunica media regulate flow?

Answer 8

Via contraction of the muscle cells

Question 9

How does the tunica media stabalise endothelial cels?

Answer 9

Secrete ECM and activating TGF-b

Question 10

What does the elastic lamina look like when stained?

Answer 10

Wavy and pink

Question 11

In small vessels, where are elastic lamina layers found?

Answer 11

On either side of tunica media

Question 12

What is the function of elastic lamina?

Answer 12

To assist with continuous flow

Question 13

What is the tunica externa?

Answer 13

Tunica externa is connective tissue found on the very outside of the blood vessel

Question 14

What does the tunica externa contain?

Answer 14

Fibroblasts, leukocytes, nerves, lymphatics, blood vessels (vasa vasora)

Question 15

What is the structure of the tunica media in arterioles (small branches within tissues)?

Answer 15

Smallest, single later of smoth muscle cells (sometimes called pericytes).

Question 16

What is the structure of the tunica media in muscular arteries (i.e. coronary artery)

Answer 16

• Media contains large amounts of smooth muscle cells
• Few elastic fibres scattered through them
• Seperate internal/external elastic laminae on either side

Question 17

What is the structure of tunica media in large elastic arteries (i.e. aorta, common carotid)?

Answer 17

• Prominent elastic laminae in their media to support the immense pulsatile carotid.
• Internal/external elastic laminae continuous (thus, cannot be distinguished)
• Elastic recoil assists with continuous flow

Question 18

Is the aetiology of Atherosclerosis completely understood?

Answer 18

No

Question 19

What is the geographical variation of incidence of Atherosclerosis?

Answer 19

Western countries are more affected, but other regions are also affected

Question 20

What are the positive risk factors of atherosclerosis?

Answer 20

• Hyperlipidaemia (high conc of lipids esp cholesterol)
• cigarette smoking
• hypertension
• Diabetes
• Advancing age
• Polygenic inheritance
• Males > females due to oestrogen protection

Question 21

What are the negative risk factors of atherosclerosis?

Answer 21

• High levels of HDL –> carrying lipids away from B.V. to center of body)
• Low alcohol consumption
• Cardiovascular fitness (development of collateral vessels) - provide alternative routes for those that have Atherosclerosis.

Question 22

What is known to be the most important initiator of Atherosclerosis?

Answer 22

Endothelial cell injury

Question 23

What may cause endothelial cell injury?

Answer 23

Combination of:
- Hypertension leading haemodynamic forces of blood particularly at junctions/branch points
- Chemical insults (cigarette smoke, lipids)
- Cytokines

Question 24

What can endothelial cell injuries lead to?

Answer 24

• Altered permeability (lipid infiltration - contributing to accumulation of fats and cholesterol deposits)
• Adhesion of leukocytes (inflammation)
• Thrombosis
• Endothelial progenitors are recruited

Question 25

Leukocyte migration into the developing plaque is a form of ____ inflammation

Answer 25

Chronic

Question 26

What happens when monocytes enter Atherosclerosis plaque?

Answer 26

Differentiate into macrophages

Question 27

What happens when macrophages are in the plaque?

Answer 27

They ingest large amounts of oxidised lipoproteins which give them a foamy appearance, so they are called foam cells.

Question 28

What happens to the cell contents when macrophages die?

Answer 28

Cytoplasmic contents including digested lipids scape into extracellular space. If lipids are of a high concentration, they can crystalise, forming cholesterol clefts.

Question 29

What other types of cells might be present?

Answer 29

T-lymphocytes, mast cells, neutrophils, dendritic cells

Question 30

What causes activation of vascular smooth muscle cells?

Answer 30

Macrophages, platelets, and endothelial cells release growth factors - which activate smooth muscle cells.

Question 31

What happens once vascular smooth muscle cells are activated?

Answer 31

- They migrate into the tunica intima from media - Lay down ECM and thus contribute to atherosclerotic plaque - contributes to fibrous cap which may later be degraded by matrix-degrading protease enzymes - Ingest lipids and interact with other cell types in the plaque through adhesion molecules present on their surface and through the growth factors they secrete

Question 32

What may accelerate smooth muscle activation and activity?

Answer 32

- Failure of internal elastic laminae - Infection of vascular smooth muscle cells.

Question 33

What is CHIP?

Answer 33

Clonal hematopoiesis of indeterminate potential (CHIP)

Question 34

What happens in CHIP?

Answer 34

CHIP is a mutation in a single STEM cell in the bone marrow. These mutations gradually proliferate and take over the bone marrow, so that all or large portion of STEM cells carry CHIP. STEM cells that carry CHIP produce leukocytes in the periphery that can get inside atherosclerotic plaques. This drives the process of atherosclerosis more quickly than non-mutated, normal leukocytes. It is a modifiable factor of atherosclerosis.

Question 35

Which genes are affected in CHIP?

Answer 35

DNMT3A, TET2, ASXL1

Question 36

Which modifiable factors can increase or decrease the rate of Atherosclerosis?

Answer 36

- Presence of CHIP - Failure of internal elastic laminae

Question 37

Why don't lipoproteins enter the tunica media when it enters the plaque?

Answer 37

The internal elastic laminae forms a protective barrier

Question 38

What happens to lipoproteins in plaques?

Answer 38

Become oxidised

Question 39

What do oxidised lipoproteins induce?

Answer 39

Attract monocytes, release cytokines and growth factors, causing dysfunction and apoptosis in smooth muscle cells, macrophages and endothelial cells.

Question 40

In a pre-clinical phase, atheromas (Atherosclerosis plaque) are often...

Answer 40

Silent, fatty streak, fibrofatty plaque, advanced/vulnerable plaque

Question 41

Plaques become unstable due to...

Answer 41

High lipid content, inflammation, thin fibrous cap and luminal aspect of plaque

Question 42

Plaques can suddenly cause symptoms due to...

Answer 42

Rupture, haemorrage, occlusion by thrombus, critical stenosis.

Question 43

What are common clinical consequences of atherosclerosis?

Answer 43

Heart attack, peripheral vascular disease, strokes.

Question 44

What is haemorrage?

Question 45

What is occlusion by thrombus?

Question 46

What is critical stenosis?