Pathophysiology of Atherosclerosis

Question 1

What causes atherosclerosis?

Answer 1

The slow, excessive buildup of plaque on the arterial endothelium, which hardens and narrows the arteries.

Question 2

What are contained in the plaques?

Answer 2

Lipids, inflammatory cells, smooth muscle cells, and connective tissue.

Question 3

What are the narrowing of the arteries in the legs, arms, stomach, and head called?

Answer 3

Peripheral artery disease

Question 4

What is it called when there is narrowing of the arteries of the blood vessels that supply blood and oxygen to the heart?

Answer 4

Coronary artery disease, or CHD.

Question 5

Blood vessel anatomy: What is the outermost layer around the blood vessel called? What is it made up of?

Answer 5

The adventitia. It is made up of connective tissue.

Question 6

What is the first visible lesion in the development of atherosclerosis?

Answer 6

A fatty streak.

Question 7

Blood vessel anatomy: What is the middle layer around the blood vessel called? What is it made up of?

Answer 7

It is called the media. It is made up of an external elastic membrane and smooth muscle.

Question 8

Blood vessel anatomy: What is the innermost layer around the blood vessel called?

Answer 8

The intima. It contains an internal elastic membrane, and is located over the endothelium.

Question 9

What is the role of the endothelium?

Answer 9

• It acts as a barrier between the blood and the rest of the vessel wall.
• Also, it secretes proteins onto its surface to prevent clotting.

Question 10

What are the steps in atherosclerosis?

Answer 10

1. Irritants (lipids, toxins, hypertension)
2. Damage of endothelium
3. Cholesterol deposits in endothelium - LDL-c
4. Monocytes - macrophages - foam cells
5. Plaques

Question 11

What are form cells?

Answer 11

Monocytes that have become activated to macrophages, that have started to remove plaque and then “died.” These dead macrophages are called foam cells.

Question 12

What are fibrous caps?

Answer 12

Smooth muscle that has migrated into the blood vessel to cover the plaque formation. Smooth muscle cells also deposit calcium into the plaque which causes hardening of the arteries.

Question 13

What causes a fibrous cap to rupture?

Answer 13

A necrotic core forms if dead cells are not transported or disposed of properly. This includes the cholesterol, calcium, and foam cells. Growth factor secretions also contribute to the plaque rupture. Clotting factors are produced when the plaque is exposed to the blood, and a clot forms (thrombus), preventing blood flow through the vessel.

Question 14

What contributes to atherogenesis?

Answer 14

Excess of dietary fat and cholesterol.

Question 15

What does vascular endothelium do?

Answer 15

Important in vascular tone (through NO production), platelet aggregation, inflammation, oxidation, and cellular proliferation. permeability barrier, regulate thrombosis,

Question 16

What does migration and retention of lipoproteins in the arterial wall cause?

Answer 16

Helps initiate atherosclerosis.

Question 17

Do all plaques rupture? What makes them rupture?

Answer 17

Large necrotic core, many inflammatory cells, thin fibrous cap. Usually a cause of acute coronary syndrome.

Question 18

What does a thrombin consist of?

Answer 18

Platelets and fibrin

Question 19

What are some modifiable risk factors for atherosclerosis?

Answer 19

cigarette smoking
LDL <40
High HDL
Diabetes
Obesity
Physical inactivity

Question 20

What are some non-modifiable risk factor for atherosclerosis?

Answer 20

men>45 years
women post-menopause, >55 years
FH of CHD (male 1st degree <55yr, female 1st degree <65 yrs)

Question 21

What adjusted odds ratio is the most important for risk of MI?

Answer 21

ApoB/ApoA ratio

Question 22

What does an adjusted odds ration of >1 mean? <1?

Answer 22

> 1 means there is a risk, <1 means protective effect as long as the CI doesn’t cross one.

Question 23

What molecular markers are emerging?

Answer 23

Lipoprotein a = Lp(a)
High-sensitive creative protein (Hs-CRP)
small-dense LDL (metabolic syndrome)
Plasminogen Activator inhibitor-1
Apo-B
lipoprotein-associated phospholipase A2
Vitamin D deficiency

Question 24

What is the process of NO production?

Answer 24

1. eNOS releases NO (endothelium nitric oxide synthase)
2. NO activates guanylyl cyclase
3. Guanylyl cyclase catalyzes GTP to GMP
4. cGMP gets Ca into SR
5. Smooth muscle relaxer and vessel dilates

Question 25

What are the main factors affecting endothelial function?

Answer 25

Increased cholesterol (LDL-C) and decreased HDL-C

Question 26

What is the response to retention hypothesis?

Answer 26

There is a permeation and sub endothelial retention of Apo-B containing lipoproteins (such as LDL) in susceptible but still prelesional areas of the arterial wall.

Question 27

What are the four stages of the physiology of atherosclerosis?

Answer 27

1. Lesion initiation
2. Fatty streak
3. Fibrous plaque
4. Thrombosis

Question 28

What does minimally oxidized LDL’s induce?

Answer 28

Endothelium dysfunction
Decreased NO
Decreased guanylyl cyclase = vasoconstriction

Question 29

What do the macrophages ingest?

Answer 29

More extensively oxidized particles. This ingestion helps the macrophages give rise to foam cells.

Question 30

What can a stable lesion do?

Answer 30

• Accumulate more lipids (months to years)
• Remodel arterial wall
• smooth muscle cells produce dense extracellular matrix called cap over plaque
• Plaque may regress, remain static, grow slowly, and calcify

Question 31

What shows DIT?

Answer 31

Pre-lesional areas of the wall show diffuse intimal thickening.

Question 32

What type of interaction happens when lipoproteins bind to proteoglycans?

Answer 32

Ionic interaction. Apo B-100’s positive charges bind to the negative charges on glycosaminoglycans.

Question 33

What accessory molecule enhances adherence of lipoproteins to proteoglycans through a nonenzymatic bridging mechanism?

Answer 33

LpL

Question 34

What accessory molecule cleaves sphingomyelin on lipoproteins leading to lipoprotein fusion and aggregation.

Answer 34

SMase

Question 35

What accessory molecule increases lipoprotein fusion and increases affinity of lipoproteins to proteoglycans?

Answer 35

sPLA2

Question 36

What is efferocytosis?

Answer 36

The process by which apoptotic cells are removed by phagocytic cells. Efferocytosis is impaired in a necrotic core, where macrophage apoptosis is prevalent.

Question 37

What can a thin fibrous cap lead to?

Answer 37

Plaque rupture and thrombosis.

Question 38

What is the difference between early and late atherosclerosis?

Answer 38

Effercytosis occurs in early atherosclerosis, whereas it does not in late atherosclerosis.

Question 39

What is the Apo B lipoprotein physiology pathway?

Answer 39

1. Particle movement down the gradient through endothelium
2. Particle retention through lipoprotein binding to proteoglycans
3. Oxidative modification: oxidized lipoproteins taken up by scavenger receptors
4. Enhanced endothelial dysfunction: promotes inflammation and migration of monocytes
5. Maladaptive inflammation: foam cell formation, increased cytokine production, enhanced macrophage uptake of modified lipoproteins.
6. Defective efferocytosis leads to necrotic core, leading to thin fibrous cap and thrombosis