Fundamentals Of Atherogenesis

Question 1

What is the main problem of atherogenesis?

Answer 1

When the plaque ruptures, a thrombus will form, leading to arterial blockage and eventually death

Question 2

What are risk factors for atherogenesis?

Answer 2

Modifiable 
Tobacco smoking 
High serum cholesterol 
Hypertension 
Obesity 
Uncontrolled diabetes 
Unmodifiable  
Age 
Family history

Question 3

What is the distribution of atherosclerotic plaques?

Answer 3

Found within peripheral and coronary arteries. Focal distribution

Question 4

What is the distribution of atherosclerotic plaque distribution governed by?

Answer 4

Change in flow/turbulence - bifurcations cause the artery to alter endothelial cell pattern
Wall thickness change - leading to neointima (scar tissue)
Altered gene expression in the key cell types

Question 5

What does an atherosclerotic plaque consist of ?

Answer 5

Lipid
Necrotic core
Connective tissue
Fibrous “cap”

Question 6

What does the fibrous cap consist of?

Answer 6

Smooth muscle cell extracellular matrix

Question 7

Consequences of the plaque?

Answer 7

It can occlude (angina) or it may rupture (thrombus formation)

Question 8

What is the response to injury hypothesis of atherosclerosis

Answer 8

Injury to the endothelial cells leading to endothelial dysfunction
Signals sent to circulating leukocytes which then accumulate and migrate into the vessel wall
Inflammation ensures

Question 9

What initiates inflammation in the arterial wall?

Answer 9

LDLs and endothelial dysfunction

Question 10

How do LDLs initiate inflammation in the arterial wall?

Answer 10

They can pass in and out of the arterial wall in excess, accumulate in the arterial wall and undergoes oxidation and glycation

Question 11

What is the stimulus for adhesion?

Answer 11

Once initiated chemoattractants are released from endothelium and send signals to leukocytes. Chemoattractants are released from site of injury and a concentration gradient is produced

Question 12

Inflammatory cytokines found in plaques

Answer 12

IL-1, IL-6, IL-8, IFN-y, TGF-B, MCP-1 and CRP

Question 13

Role of IL-6

Answer 13

Pro-inflammatory cytokine and an anti-inflammatory myokine

Question 14

Role of IL-8

Answer 14

Attracts and activates neutrophils in inflammatory regions

Question 15

Role of IFN-y

Answer 15

Activator of macrophages and inducer of Class II MHC molecule expression

Question 16

Role of TGF-B

Answer 16

Transforming growth factor beta 1. Secreted protein that performs many cellular functions - cell growth, proliferation, differentiation and apoptosis

Question 17

Role of MCP-1

Answer 17

Monocyte chemoattractant protein-1

Question 18

Steps of leukocyte recruitment to vessel walls

Answer 18

Capture, rolling, slow rolling, firm adhesion and transmigration

Question 19

Type of molecules used during the steps of leukocyte recruitment to vessel wall

Answer 19

Capture, rolling and slow rolling - selectins

Firm adhesion and transmigration - integrins and chemoattractants

Question 20

Describe fatty streaks

Answer 20

Earliest lesion of atherosclerosis
<10 years
They consist of aggregations of lipid-laden macrophages and T lymphocytes within the intimal layer of the vessel wall

Question 21

Describe intermediate lesions

Answer 21

Composed of layers of:
Foam cells 
Vascular smooth muscle cells 
T lymphocytes
Adhesion and aggregation of platelets
Isolated pools of ECF

Question 22

Describe fibrous plaques/advanced plaques

Answer 22

Impedes blood flow 
Prone to rupture 
Covered by dense fibrous cap made of ECM proteins - collagen (strength) and elastin (flexibility) 
May be calcified 
Contains 
SMC 
Macrophages 
Foam cells 
T lymphocytes

Question 23

Describe plaque rupture

Answer 23

Plaques constantly growing and receding
Fibrous cap needs to be resorbed and redeposited in order to be maintained
if balance shifts towards inflammatory/enzymatic conditions the cap becomes weak and the plaque ruptures
Basement membrane, collagen and necrotic tissue exposure as well as haemorrhage of vessels within the plaques
thrombus clot formation and vessel occlusion

Question 24

Describe plaque erosion

Answer 24

Second most prevalent cause of coronary thrombosis
Lesion tends to be small early lesions
Fibrous cap does not disrupt
Luminal surface underneath the clot may not have endothelial present but is SMC rich
Prominent lipid core

Question 25

How do you treat coronary artery disease?

Answer 25

PCI - Percutaneous Coronary Intervention

more than 90% require this

Question 26

What is a major limitation of PCI?

Answer 26

Restenosis

Question 27

What is done to prevent restenosis?

Answer 27

Drug elution

Question 28

What is the purpose of drug elution?

Answer 28

Anti proliferation and inhibits healing

Question 29

What are examples of drug elution drugs?

Answer 29

Taxol and sirolimus

Question 30

What are other useful drugs for elution?

Answer 30

Aspirin, clopidogrel and statins

Question 31

What is the role of aspirin?

Answer 31

Irreversible inhibitor of platelets COX

Question 32

What is the role of clopidogrel?

Answer 32

Inhibitor of P2Y12 ADP Receptor on platelets

Question 33

What is the role of statins?

Answer 33

Inhibit HMG CoA reductase

Question 34

What does HMG CoA reductase do?

Answer 34

Rate-controlling enzyme of the mevalonate pathway, the metabolic pathway that produces cholesterol and other isoprenoids.