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CVS > 17. Atherosclerosis > Flashcards

17. Atherosclerosis Flashcards

1
Q

What types of blood vessels does atherosclerosis affect?

A

Medium and large arteries

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2
Q

When does atherosclerosis start to progress and how does this affect prevention?

A
  • Changes in arteries early in life
  • Plenty of time for prevention
  • Clinical manifestations in middle and old age
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3
Q

What is the significance in the role of the macrophages compared to smooth muscle cells in atherosclerosis?

A
  • Macrophages - remove arterial tissue

* Smooth muscles - make more arterial tissue and protect plaque integrity

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4
Q

What are potentially modifiable risk factors for atherosclerosis?

A
  • Smoking
  • Blood pressure
  • Diabetes
  • Obesity
  • Lack of exericise
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5
Q

What are non-modifiable risk factors for atherosclerosis?

A
  • Age
  • Sex
  • Genetic background
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6
Q

Why do atherosclerotic lesions tend to appear on the outside of a bend?

A
  • Blood flow is laminar - faster in the middle
  • Blood goes around a bend - EDDYs (turbulent flow) is set up
  • Less flow on the outside
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7
Q

Where do LDLs deposit in the arteries?

A
  • Subintimal space
  • Bind to matrix proteoglycans in the subendothelial layer
  • Become susceptible to modification
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8
Q

How does atherosclerosis progress from the deposition of LDLs?

A
  • Inflammation (adaptive)
  • Macrophages ingest the endothelial fat - become foam cells
  • Extracellular lipids build up forming a core
  • Fibrous thickening - due to inflammation irritating the interior of the plaque
  • Macrophages produce growth factors - stimulate smooth muscle cells to grow, divide and make more collagen
  • Plaque ruptures - lipid core (thrombogenic) communicates with the lumen and stimulates clot formation
  • Layering effect - repeat episodes of plaque destabilisation
  • Thrombi form one after the other - lumen narrows and becomes too small
  • Angina or MI
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9
Q

What is the basic function of vascular endothelial cells?

A
  • Barrier (e.g. to lipoproteins)

* Leukocyte recruitment

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10
Q

What activates the macrophages?

A

T lymphocytes

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11
Q

What are matrix metalloproteinases and what forms them?

A
  • Enzymes that grade major extracellular proteins e.g. collagen
  • Produced by macrophages
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12
Q

What are the main inflammatory cells in atherosclerosis?

A
  • Macrophages

* Several subtypes - regulated by a combination of transcription factors

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13
Q

What are the 2 main classes of macrophages?

A
  • Resident - homeostatic, suppress inflammatory activity

* Inflammatory - adapted to kill microorganisms

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14
Q

What are oxidised LDLs?

A
  • Formed by action of free radicals (from macrophages) on LDLs
  • Families of highly inflammatory and toxic forms of LDL in vessel walls
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15
Q

What part of the LDL directs it and can be detected?

A

Apoproteins

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16
Q

What is Familial Hyperlipidaemia?

A
  • Autosomal recessive
  • Elevated cholesterol
  • Failure to clear LDL from the blood
  • Accumulation of foam cells - xanthoma in the skin
  • Early atherosclerosis => fatal MI before the age of 20 if untreated
17
Q

What were Brown and Goldstein’s findings?

A
  • Looked for the gene for Familial Hyperlipidaemia
  • Discovered LDL receptors
  • Found that their expression was negatively regulated by intracellular cholesterol
  • Also found that cholesterol synthesis is negatively regulated by cellular cholesterol
  • Led to the rationale of statins
18
Q

What is the scavenger receptor?

A
  • Second LDL receptor on macrophages
  • Not under feedback control
  • Accidentally binds to and takes up oxidised LDL
  • Macrophages accumulate cholesterol
19
Q

What is Macrophage scavenger receptor A?

A
  • CD204
  • Binds to oxidised LDL
  • Binds to gram-positive bacteria
  • Binds to dead cells
20
Q

What is Macrophage scavenger receptor B?

A
  • CD36
  • Binds to oxidised LDL
  • Binds to malaria parasites
  • Binds to dead cells
21
Q

What are the 2 different effects of arterial oxidised LDL deposits?

A

1) Interaction with macrophages - abnormal material removed safely
2) High levels of oxidised LDL - bug-detector pathways activated (scavenger receptors) - pathogen pattern recognition pathways activated, detect anything with fat in it that isn’t us - inflammatory

22
Q

What do activated macrophages secrete?

A
  • Cytokine mediators - recruit monocytes
  • Chemoattractants and growth factors for VSMCs
  • Proteinases - degrade the fibrous cap
  • Tissue factor - stimulates coagulation
23
Q

How do the macrophages contribute to the lipid rich core?

A
  • Apoptosis - usually clean

* Cytotoxic fat everywhere in atherosclerosis

24
Q

How do macrophages modify LDL with oxidative enzymes?

A
  • Macrophages take oxygen and reduce it (add electron) [NADPH oxidase]
  • Form a reactive superoxide (O2-)
  • Cascade - hydrogen peroxide + chloride => hypochlorous acid (HOCL) [myeloperoxidase]
  • HOCL is extremely toxic
  • Nitric oxide can form peroxynitrite (HONOO) which is even more unstable [myeloperoxidase]
25
Q

What happens to macrophages as they accumulate fat?

A
  • Start off small
  • Foam cells
  • Bloated with fat
  • Fat comes out of the solution - fat globules within the macrophages kill it
26
Q

Which cytokines do macrophages express and what are their roles in the arteries?

A
  • Interleukin-1 - upregulates vascular cell adhesion molecule-1 (VCAM-1)
  • VCAM-1 - mediates right monocyte binding
  • Lead to a viscous cycle (positive feedback)

(atherosclerosis is reduced in mice without these cytokines)

27
Q

Which chemokines do macrophages express and what are their roles in the arteries?

A
  • Monocyte chemoattractant protein-1 (MCP-1)
  • MCP-1 binds to a monocyte G-protein coupled receptor CCR2
  • Lead to a viscous cycle (positive feedback)

(atherosclerosis is reduced in mice without these chemokines)

28
Q

How do macrophages stabilise the plaque?

A

• Macrophages release complementary growth factors that recruit VSMCs
- Platelet derived growth factor (VSMC chemotaxis, survival and division)
- Transforming growth factor beta (increased collagen synthesis)
• Proliferation and deposition of extracellular material strengthens and stabilises the plaque

29
Q

How do VSMCs change to a synthetic phenotype?

A
  • PDGF and TGF-beta influences the change

* These atherosclerotic VSMCs make more ECM and have fewer contractile filaments

30
Q

How do metalloproteinases work?

A
  • (Matrix) metalloproteinases activate each other in a cascade
  • Mechanism is based on zinc
  • Degrade collagen
  • Weakens the fibrous cap - triggers rupture and thombus formation
  • Instant thrombosis when material meets blood - occlusive thrombus
31
Q

Which border normally defines the coronary artery?

A

Internal elastic lamina

32
Q

What are the characteristics of stable, rupture prone plaques?

A
  • Large, soft, eccentric, lipid-rich necrotic core
  • Thin fibrous cap
  • Reduced VSMC and collagen content (VSMC apoptosis)
  • Infiltrate of activated macrophages expressing MMPs
33
Q

What are the 3 main coronary arteries?

A

• Right Coronary Artery - runs down the right atrioventricular sulcus
• Left Main Coronary Artery
- Left Anterior Descending: supplies the anterior free wall and septum
- Left Circumflex: supplies the left ventricular free wall

34
Q

What do macrophages do when they apoptose?

A
  • Release macrophage tissue factor and toxic lipids into the lipid necrotic core
  • Accumulation of materials inside core
35
Q

What is endothelial erosion?

A
  • Loss of endothelial cells
  • Thrombosis occurs within the thick fibrous cap whilst the endothelial cells die
  • Less pronounced inflammatory infiltrated
  • Less association with a lipid/fatty core
  • Non-occlusive mural thrombus
36
Q

What is Nuclear Factor Kappa B?

A 
• Transcription Factor
• Master regulator of inflammation
• Activated by:
- Scavenger receptors
- Toll-like receptors
- Cytokine receptors
• Switches on:
- matrix metalloproteinases
- inducible nitric oxide synthase (for peroxynitrite)
37
Q

Why do endothelial cells become more sticky when activated?

A

Attract more monocytes => macrophages

38
Q

What are 4 of the harmful functions of macrophages?

A
  • Release free radicals
  • Recruit more monocytes
  • Express MMPs - destabilise the fibrous cap
  • Express tissue factor - stimulates thrombosis

CVS (21 decks)

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