Fundamentals of Atherogenesis

Question 1

What is atherogenesis?

Answer 1

-the principle cause of heart attack, stroke & gangrene of extremities
-process of plaque formation in the intima layer of arteries
-eventually, the plaque will rupture or occlude the vessel lumen -> restriction of blood flow
-plaque ruptures -> thrombus formation -> death

Question 2

Risk factors for atherogenesis

Answer 2

Age - biggest risk factor
Tobacco smoking
High serum cholesterol
Obesity
Diabetes
Hypertension
Family history

Question 3

In which arteries are atherosclerotic plaques found?

Answer 3

Peripheral & coronary arteries
Focal distribution along artery length

Question 4

What governs atherosclerotic plaque distribution?

Answer 4

Bifurcations -> changes in blood flow/turbulence -> artery adjusts wall thickness -> neointima (new growth)

Question 5

Structure of an atherosclerotic plaque

Answer 5

-necrotic core
-lipid core
-connective tissue
-fibrous cap

Question 6

Angina

Answer 6

Restriction of blood flow

Question 7

Positive inflammation

Answer 7

-pathogens
-parasites
-tumours
-wound healing

Question 8

Bad inflammation

Answer 8

-atherosclerosis
-rheumatoid athritis
-ischaemic heart disease
-excessive wound healing

Question 9

What occurs as as response to inflammation in the arterial wall?

Answer 9

-LDLs can pass in/out of arterial wall in excess
-LDL accumulates in arterial wall
-LDL - oxidation & glycation

-endothelial dysfunction - large BV on the heart surface constrict instead of dilating

Question 10

How do leukocytes transmigrate into the arterial vessel wall?

Answer 10

ADHESION
-chemoattractants are releases from the endothelium
-chemoattractants send signals -> leukocytes
-leukocytes are released from the site of injury
-concentration-gradient is produced to guide more leukocytes into the arterial wall

LEUKOCYTES RECRUITMENT TO VESSEL WALL
-selectins on the vessel wall capture leukocytes
-selectins roll leukocyte along vessel wall
-integrins & chemoattractants are responsible for firm adhesion of leukocytes & transmigration -> vessel

Question 11

4 stages of atherosclerosis progression

Answer 11

1. fatty streaks
2. intermediate lesions
3. fibrous plaques of advanced lesions
4. plaque rupture

Question 12

Atherosclerosis - fatty streaks

Answer 12

-earliest lesion of atherosclerosis
-appear at early age <10 years
-aggregations of lipid-laden macrophages & T lymphocytes within intima

Question 13

Atherosclerosis - intermediate lesions

Answer 13

Layers of

-lipid laden macrophages
-vascular smooth muscle cells
-T lymphocytes
-adhesion & aggregation of platelets to vessel wall
-isolated pools of extracellular lipid

Question 14

Atherosclerosis - fibrous plaques or advanced lesions

Answer 14

-impedes blood flow
-prone to rupture
-smooth muscle cells, macrophages, foam cells, T lymphocytes
-covered by dense fibrous cap

Question 15

Atherosclerosis - plaque rupture

Answer 15

-fibrous cap has to be resorbed & redeposited in order to be maintained
-if balance shifts -> cap weakens -> plaque ruptures
-damage to vessel wall -> endothelial cells release TF
-TF -> coagulation cascade
-thrombus formation & vessel occlusion

Question 16

How is coronary artery disease treated?

Answer 16

PCI -percutaneous coronary intervention - stents

Question 16

How is coronary artery disease treated?

Answer 16

PCI - percutaneous coronary intervention - stents
Restenosis - artery opened with stent/angioplasty becomes narrowed again

Question 17

Drug-eluting stent

Answer 17

-improve duration of stents - reduce time to restenosis
-coated with time-release medication - anti-proliferative, inhbitis healing - vascular smooth muscle proliferation
-sirolimus

Question 17

Drug-eluting stent

Answer 17

-improve duration of stents - reduce time to restenosis
-coated with time-release medication - anti-proliferative, inhbitis healing - vascular smooth muscle proliferation

Question 18

Statins

Answer 18

-inhibit HMG CoA reductase
-reducing cholesterol synthesis

Question 19

Aspirin

Answer 19

Irreversible inhibitor of Cox-1 (platelet cyclo-oxygenase)

Question 20

Cox-1

Answer 20

Stimulates platelet aggregation & vasoconstriction

Question 21

Clopidogrel/ticagrelor

Answer 21

Inhibits P2Y-12 ADP receptor on platelets

P2Y-12 receptor - induces platelet aggregation

Question 22

Key cell types in atherosclerosis

Answer 22

-endothelial cells
-smooth muscle cells
-macrophages
-fibroblasts

Question 23

Arterial wall layers

Answer 23

Endothelium
Intima
Media
Adventitia

Question 24

What initiates atherosclerosis?

Answer 24

-endothelial injury -> endothelial dysfunction
-signals sent to circulating leukocytes -> leukocytes accumulate & migrate to vessel wall
-inflammation

Question 25

Fibrous cap

Answer 25

-ECM proteins - collagen (strength), elastin (flexibility)
-the ECM proteins are laid down by SMC that overlies lipid core & necrotic debris
-thin fibrous cap is prone to rupture

Question 26

Atherosclerosis - plaque erosion

Answer 26

-2nd most prevalent cause of coronary thrombosis
-more common in women
-thickened fibrous cap -> collagen triggers thrombosis (as opposed to TF triggering thrombosis in plaque rupture)
-platelet rich clot may overlie luminal surface
-often a small lipid core

plaque erosion -> erodes endothelial cells -> collagen exposed

Question 27

Plaque rupture vs plaque erosion

Answer 27

Rupture - disruption of a fibrous cap over a lipid core

Erosion - superficial disruption of a fibromuscular plaque without a core, fibrous cap intact

Question 28

Atherosclerosis

Answer 28

The buildup of fats, cholesterol & other substances in & on artery walls (plaque)

Question 28

Atherogenesis

Answer 28

The process of forming plaques in the intima layer of arteries