Fundamentals of Atherogenesis Flashcards
What are the three long-term results of atherosclerosis on the body
- Heart Attack
- Stroke
- Gangrene
What are the risk factors for atherosclerosis
- Age
- Smoking
- High serum cholesterol
- Obesity
- Diabetes
- Hypertension
- Family History
Where are atherosclerotic Plaques found
Peripheral and coronary arteries
What causes neointima
Scar tissue that forms within the blood vessels due to proliferation of smooth muscle cells in the MEDIA giving the appearance of fused intima and media layers
Wall Thickness changes generally lead to this
Define the term ‘atherogenesis’
The developmental process of atheromatous plaques
What is stenosis
Abnormal narrowing in a blood vessel caused by a lesion
What is the early atherogenesis characterised by
LPL in blood plasma INVADE endothelium and become oxidised and glycated
Monocytes in the blood adhering to the endothelium and migrating into sub-endothelial space
Monocytes -> Macrophages in subendothelial space
What happens after the endothelium has been initially damaged by the LPL
- Inflammatory response
2. Monocytes differentiate into macrophages and enter artery wall with platelets
Describe the role of Monocytes at the site of endothelial damage
Monocytes -> Macrophages
Macrophages ingest oxidised LDL and turn into FOAM CELLS - forms fatty streak
What are foam cells
Macrophages that have many vesicles containing lots of LDL
What happens to the foam cells
They dies and encourage further inflammation
What happens to the smooth muscle cells during plaque formation
They proliferate and migrate from media to intimate in response to cytokine released by damaged endothelial cells
- Forms fibrous capsule covering fatty streak
How is fibrosis of fatty streak prevented by the undamaged neighbouring endothelial cells
Release Nitric Oxide to prevent proliferation of smooth muscles
Describe the structure of an atherosclerotic plaque
- Lipid
- Necrotic Core
- Connective Tissue
- Fibrous ‘cap’
Define the calcification process of atherogenesis
- Calcification forms among vascular smooth muscle adjacent to atheroma
- As cells die, extracellular calcium deposits between muscular wall and outer portion of atheromatous plaques
- Atheromatous plaque interferes with calcium regulation causing it to accumulate and crystallise
Describe how the lipid part of the plaque forms
- LDL moves into vessel wall
- Cholesterol released from LDL and oxidised (causes inflammation)
- Foam cells and platelets cause smooth muscle proliferation and migration
- Smooth muscle cells during this process ingest lipids which gets replaced by collagen and transform into foam cells
- Lipid deposits (atheroma) produce enzymes that cause artery to enlarge over time
Why is LDL essential in inflammation of the arterial wall and not HDL, VLDL etc
LDL can pass in and out of there arterial wall in excess as it is small enough
What is the injury hypothesis of atherosclerosis
Injury to endothelial cells leads to endothelial dysfunction
Signals sent to monocytes which accumulate in the vessel wall
What inflammatory cytokines are found in plaques
IL-1 IL-6 IL-8 IFN-gamma TGF-beta MCP-1 C reactive protein
Describe the process of leukocyte (monocyte) migration in response to chemoattraction to the site of plaque formation
- Chemoattraction
- Carbohydrate ligans on circulating leukocytes bind to SELECTIN on inner vessel walls with only marginal affinity
- Leukocytes slow down and roll along inner wall
- Chemokines released by macrophages activate rolling leukocytes and cause surface intern molecules to go from low to high affinity
- Integrins bind tightly to receptors on endothelium
- Transmigration - leukocyte extend pseudopodia and pass through gaps between endothelial cells
At what age can fatty streaks begin to appear at
10
What do fatty streaks consist of
Lipid-Maiden Macrophages
T-Lymphocytes
Both in the intima
What do fatty streaks progress to
intermediate lesions
Structure of an intermediate lesion
- Foam Cells lipid-maiden macrophages)
- Smooth muscle cells
- T Cells
- Adhesion and aggregation of platelets
- Extracellular lipids
What do intermediate lesions progress to
Fibrous plaques
Problems caused by fibrous plaques
- Impeded blood flow
2. Prone to rupture
Structure of Fibrous Plaques
- Covered by dense fibrous cap
- Smooth muscle cell layer that overlies lipid and necrotic core
- Calcified
(SMC, Macrophages, Foam cells, T cells)
What is the progression from fibrous plaques
Plaque rupture
Describe the growth behaviour of a plaque
- Plaques are constantly growing and receding
How is the fibrous cap of a plaque maintained
- Fibrous cap has tone resorbed and redeposited to be maintained
How does plaque rupture occur
- If balance has shifted in favour of inflammatory conditions (increased enzyme activity), the cap weakens and ruptures
What is plaque rupture
Basement membrane, collagen and necrotic tissue is exposed and vessels undergo haemorrhage within the plaque
Thrombus forms and vessel occludes
What occurs after plaque rupture
Plaque Erosion
What is Plaque Erosion
- Fibrous cap does not disrupt
- Luminal surface underneath the clot may not have endothelium present but is SMC rich
- May be a prominent lipid core
What is PCI
Non-surgical procedure used to treat stenosis of coronary arteries via coronary catheterisation
Limitation of PCI
Restenosis
What is a drug-eluting stent
A peripheral coronary stent that releases a drug to block cell proliferation - prevents fibrosis
Two commonly used agents in Drug Elution
Taxol
Sirolimus
