BOD L6 Introduction to Athersclerosis

Question 1

What are the layers of the normal human artery?

Answer 1

Smooth muscle cells on outside.

Internal elastic lamina and extracellular matrix, then endothelial cells lining the inside (lumen).

Question 2

What is atherosclerosis?

Answer 2

Disease where a plaque(s) build up in the arteries. The plaque over time hardens and reduces blood flow through vessel.

Question 3

What is the plaque composed of?

Answer 3

Fat and cholesterol from lipid metabolism.

Calcium (calcification)

Other blood-borne substances.

Question 4

With progressive accumulation of atherosclerosis, what often occurs?

Where does this typically occur?

What does it lead to?

Answer 4

Lesions. In medium/large elastic and muscular arteries.

Occurs at branch points or bends in artery (from local mecahnical forces in area).

Leads to blockage and reduction in blood supply to other tissues/organs such as cardiac muscle, brain or extremeties (as arteries narrow).

Question 5

What disease state does a lesion bring about?

Answer 5

Ischaemia - reduction in blood supply to a tissue, from atheromatous plaques.

Question 6

How does atherosclerosis start? What can this be caused by?

Answer 6

May start by damage/injury to inner layer of an artery. Can be caused by high blood pressure, high cholesterol, dysregulated fat metabolism, irritant (such as nicotine). Certain diseases such as diabetes.

Question 7

Obesity and atherosclerosis are linked by what?

Answer 7

Regulation of lipid metabolis. (one of the causers of atherosclerosis, driven by obesity).

Question 8

What is hyperlipoproteinaemia?

Answer 8

Abnormally increased plasma lipoproteins - risk factor of atherosclerosis.

Question 9

What is hyperlipadaemia?

Answer 9

Increased levels of triglycerides

Question 10

How is atherosclerosis graded?

Answer 10

Based on classifications of lesions: Type I to type VI.

Type IV typically denotes the start of pathology, a core of extracellular lipid has formed.

Question 11

How are Type I lesions characterised?

Answer 11

Pre-atheroma, contains lipoprotien, macrophages and scattered foam cells.

Smooth muscle (intimal) undergoes adaptive thickening (bulge started to be seen).

Not necessarily pathological but this is where atheromas will develop.

Question 12

How are type II lesions characterised?

Answer 12

Layers of macrophage foam cells and lipid-laden smooth muscle cells seen. Known as fatty streaks.

The macrophages have started taking up lipid, (appear foamy) and started to burst.

Question 13

How are type III lesions chracterised?

Answer 13

Still pre-atheroma, but in addition to type II features, small extracellular lipid droplets seen (as well as other particles) that distrupt the continuity of intimal smooth muscle cells.

Question 14

How are type IV lesions characterlised?

Answer 14

Atheroma.

Extracellular lipid / cholesterol crystals make up a fatty core.

Question 15

How are Type V lesions characterised?

Answer 15

Formation of fibroatheroma (Va), a fibrous cap as protective or healing mechanism.

Vb - core is calcified

Vc - lipid core is absent and lipid is generally minimal.

Question 16

How are type VI lesions characterised?

Answer 16

The fibrous cap is disrupted, may have developed haematoma or haemorrhage.

These are known as complicated lisons, considered to be unstable.

Associated with severe ischaemic syndromes and atherosclerosis.

Question 17

What may occur as a result of a type VI lesion?

Answer 17

Blocked artery - plaque and thrombus.

Large occlusion of artery.

Question 18

What can occur when the plaque ruptures?

Answer 18

Sudden coronary death - heart attack and death.

Thrombus formation that can block coronary artery.

Question 19

By what three mechanisms does obesity infer disease, disability and eventually death upon a person?

Answer 19

Sex hormone imbalance,

Increased free fatty acids,

Mechanical stress

Question 20

What is familial hypercholesterolemia?

Answer 20

Congenital disease when LDL receptor not synthesised.

Concentration of cholesterol in blood markedly increases.

Severe atherosclerosis occurs.

Question 21

What is the healthy LDL/HDL ratio?

What can be evaluated from measuring this in a person

Answer 21

3.5 (less HDL)

Suseptibility to development of atherosclerosis

Question 22

In development of atherosclerosis, what are the early events that occur?

Answer 22

LDL cross endothelial barrier in arteries. They start to oxidise, and further oxidation causes disease progression.

Oxidised LDL leads to endothelial dysfunction, via release of monocyte chemotactic protein MCP.

This causes monocytes to force across endothelial wall which exacerbates damage. These cells take up oxidised LDL (OXLDL) and become foam cells. They eventually burst, and cause formation of lipid deposits.

Question 23

What effect does OXLDL have on endothelial cells?

Answer 23

Synthesis of many things, such as MCP, macrophage costimulating factors, and causes a reduction in nitric oxide (NO).

NO is a vasodilator which keeps arteries open.

Many other things,

synthesis of adhesion molecules, matrix metalloproteinase I, which activates PAR-1.
Reduced secretion of prostagladins, which are vasodilators that also inhibit platelet aggregation.

activation of clotting factors. secretion of endothelin.

Question 24

What effect does OXLDL have on monocytes/macrophages?

Answer 24

Expression of scavenger receptors and uptake of oxLDL.

Secretion of cytokines

Increased antigen presenting capacityy.

Question 25

What effect does OXLDL have on smooth muscle cells?

Answer 25

Proliferation, decreasing arteriole lumen volume.

Synthesis of various GF’s.

metalloproteinase expression, degrades ECM and facillitates smooth muscle migration.

Apoptosis.