Lecture 20: Atherosclerosis

Question 1

Define atherosclerosis:

Answer 1

Atherosclerosis is a disease affecting the innermost layer of large and medium sized arteries

• It appears as focal thickenings called plaques

Arteriosclerosis is a general term for hardening of arteries - atherosclerosis is a form of this.

Question 2

What are plaques made up of?

Answer 2

Fibrous tissues and lipids

Question 3

What are the 3 concentric layers of a vessel wall?

Answer 3

Tunica Intima
Tunica Media
Tunica Externa

Question 4

Describe the tunica intima:

Answer 4

• Endothelial cells seperated by tight junctions
• Scattered myointimal cells
• Basement membrane

Question 5

Describe the tunica media:

Answer 5

Smooth muscle cell layers

• Regulate flow by contraction
• Stabilise EC by secreting ECM and activating TGF-beta

Elastic lamina layers

Question 6

Describe tunica externa (Adventitia)

Answer 6

Connective tissue

Contains

• Fibroblasts
• Leucocytes
• Nerves
• Lymphatics
• Blood vessels (Vasa vasorum) (Too thick for diffusion)

Question 7

Describe how the size of the tunica media depends on the artery size and how function changes the constituents

Answer 7

Muscular artieres = Lots of smooth muscle

large elastic arteries = Mainly elastic laminae in their media. (recoil, exposed to high pressures)

Question 8

What sort of system are vessel walls and what happens in atherosclerosis?

Answer 8

Vessel walls are multi-cellular systems and in atherosclerosis the system malfunctions

Question 9

What is the aetiology of atherosclerosis?

Answer 9

• Positive risk factors increase risk
• Negative risk factors decrease risk
• Now now there is a possible contribution from mutations

Question 10

What are the positive risk factors for atherosclerosis?

Answer 10

• Hyperlipidemia (esp. inc. cholesterol)
• Cig smoking
• Hypertension (higher shear / wall stress)
• Diabetes mellitus

Question 11

What are negative risk factors for atherosclerosis?

Answer 11

• High levels of circulating HDL
• Moderate levels of alcohol (uncertain)
• Cardiovascular fitness

Question 12

What happens with risk factors in terms of disease risk?

Answer 12

They are mulpilicative i.e synergistic

Question 13

What is the pathogenesis of atherosclerosis?

Answer 13

Uncertain but;

• Initial endothelial cell injury
• Progression involves most components of the cell wall i.e is a process of chronic inflammation

Question 14

Endothelial cell injury is thought to be one of the most important initiators of atherosclerosis, what might it be the combination of?

Answer 14

• Heamodynamic force i.e shear/stress
• Chemical insults (smoking, lipids)
• Cytokines

Question 15

What can increased heamocydnamic load, chemical insults and cytokines lead to on endothelial cells?

Hint: PLTR

Plaque Leads To Risk

Answer 15

• Altered permeability (therefore lipid infiltration)
• Adhesion of leucocytes (Due to enhanced expression of chemokines and adhesion molecules)-> Inflammation
• Activation of thrombosis
• Recruitment of endothelial progenitors

Question 16

Describe the process of foam cell formation in atherosclerotic lesions

Hint: Circulating Monocytes

Answer 16

Chronic inflam

• Circulating monocytes adhere to endothelial cells and enter the atherosclerotic lesion
• These differentiate into macrophages
• Once in the plaque they ingest large amounts of oxidised lipoproteins which gives them the foamy appearance, hence called foam cells.
• When they die by necrosis or apoptosis their cytoplasmic contents (including digested lipids) escape into the extracellular space

EVERY CELL TYPE FOUND TO BE INVOLVED

Question 17

How does clonal hematopoiesis come into play with atherosclerosis?

Answer 17

• Clonal heamatopoiesis of indeterminate potential (CHIP) is an expanded blood cell ‘clone’ carrying somatic mutation in patient with no other hematological abnormality.
• Accumulates with age
• 1.9x more likely to have CAD

Question 18

What cells release factors that activate smooth muscle and How are smooth muscles involved in atherosclerosis?

Answer 18

• Macrophages, platelets and endothelial cells produce growth factors that activate vascular smooth muscle cells. (potentially infection too)
• Once activated they proliferate and migrate into the tunica intimate from media.
• This may be accelerated by failure of the internal elastic lamina

Question 19

How does lipoprotein entry and oxidation influence atherosclerosis? What do they attract and stimulate?

Answer 19

• Lipoproteins become oxidised in plaques
• Oxidised lipoproteins;
• > Attract monocytes
• > Stimulate intra-plaque cells to release cytokines and growth factors
• > These cause dysfunction and apoptosis in smooth muscle cells, macrophages and endothelial cells

Question 20

Describe the diagramatic atheroma lesion:

Answer 20

Fibrous cap:
- SM, Macros, Foam cells, Collagen, elastin, lymphocytes)
Necrotic center
- Cell debris, cholesterol crystals (cholesterol clefts), foam cells, calcium

Question 21

When do plaques become unstable?

Answer 21

• Thin fibrous cap
• High lipid content score
• Inflammation

Question 22

When do plaques cause symptoms?

Answer 22

When they cause:

• Rupture
• Heamorrhage
• Thrombosis
• Dissection

Question 23

What are vulnerable plaques characterised by?

Answer 23

Vulnerable plaques are characterised by high lipid and high inflammatory cells content, low content of vascular smooth muscle cells and collagen

Question 24

What are the common clinical consequences of atherosclerosis?

Answer 24

• MI
• Peripheral vascular disease
• Cerebrovascular disease ie strokes