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CVS > CVS 16 - Atherosclerosis > Flashcards

CVS 16 - Atherosclerosis Flashcards

1
Q

What are some risk factors for atherosclerosis?

A
  1. Smoking
  2. Lipids
  3. BP
  4. Obesity
  5. Diabetes
  6. Age
  7. Sex
  8. Genetics

Having multiple risk factors causes the risk to be multiplicated

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2
Q

Why do atherosclerotic plaques tend to form on outside of the bend rather than the inside?

A

When blood flows around a corner too quickly it forms an EDDY (turbulent flow).

This causes atherosclerotic lesions to appear on the outside of bend rather than the middle

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3
Q

Where do LDLs bind to form atherosclerotic plaques?

A

In the suboptimal space and binds to matrix proteoglycans.

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4
Q

Explain how an atherosclerotic plaque progresses

A
  1. LDLs enter subintimal layer.
  2. LDL accumulation brings in macrophages - these eat up endothelial fat and the macrophages become foam cells.
  3. Fat deposition continues - lesion accumulates pools of extracellular lipid (outside macrophages). Macrophages can no longer cope.
  4. Further fat buildup causes extracellular lipid core - fatty coalescence causes large fatty mass.
  5. Inflammation causes irritation in the interior of the plaque - which causes a fibrous thickening.
  6. Macrophages produce growth factors - stimulate SMC to grow and divide - making more collagen.
  7. Plaque eventually ruptures - lipid core can then stimulate clot formation in the lumen.
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5
Q

Describe the layering effect

A

Repeat episodes of plaque destabilisation. Small episodes of thrombus formation then stopping. The thrombi form one after another - lumen narrowed a little at a time.

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6
Q

What are the 5 main cell types and their roles, in relation to atherosclerosis?

A
  1. Vascular endothelial cells - barrier function and WBC recruitment
  2. Platelets - thrombus generation, cytokine and GF release
  3. Monocytes/macrophages - foam cell formation, cytokine/GF release, source of free radicals, metalloproteinases
  4. VSMC - Migration and proliferation, collagen synthesis, remodelling and fibrous cap formation
  5. T cells - macrophage activation
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7
Q

What are foam cells?

A

Macrophages that have consumed fat

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8
Q

What do matrix metalloproteinases do?

A

Degrade major EC proteins e.g collagen

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9
Q

What are the main inflammatory cells in atherosclerosis?

A

Macrophages

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10
Q

There are 2 main types of macrophages, and their formation is regulated by TFs binding to regulatory DNA sequences. What are the 2 classes?

A
  1. Resident - mainly homeostatic (suppress inflammatory activity, alveolar resident macrophages, osteoclasts, spleen)
  2. Inflammatory - kill microorganisms
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11
Q

Describe 3 types of lipoprotein.

A
  1. LDL - synthesised in liver. Carries cholesterol from liver to rest of body
  2. HDL - carries cholesterol from peripheral tissues back to liver
  3. Oxidised LDL/Modified LDL - caused by free radical action. Not one single substance - family of high inflammatory/toxic forms of LDL in vessel walls.
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12
Q

Describe LDL structure.

A
  1. Consist of lipid monolayer

2. Has apoproteins on outside telling it were to go

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13
Q

LDLs can leak through the endothelial layer. What happens if they leak?

A

They are trapped in the sub endothelial layer by sticking to sticky matrix carbohydrates.

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14
Q

How are the sub endothelial trapped LDLs modified?

A
  1. Free radicals oxidatively modify the LDLs.

2. Oxidised LDL is phagocytosed by macrophages, forming foam cells. This stimulates chronic inflammation.

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15
Q

What is familial hyperlipidaemia and what implication does it have?

A

Autosomal recessive genetic disease - causes massively elevated cholesterol levels (20mmol/L).

Failure to clear LDL from blood causes xanthomas (accumulations of foam cells).

May result in fatal MI by the age of 20.

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16
Q

How is FH caused?

A

LDLR expression is negatively regulated by intracellular cholesterol.

Cholesterol synthesis is negatively regulated by cellular cholesterol.

Ultimately led to statin discovery (HMG-CoA Reductase Inhibitors)

17
Q

In LDLR negative patients, there is still accumulation of cholesterol. How?

A

There is a second LDL receptor which isn’t under feedback control - it just scoops up oxidised LDL.

It is called Scavenger receptor.

Scavenger receptors are actually pathogen receptors that accidentally bind to oxidised LDLs.

18
Q

Explain the 2 effects that arterial oxidised LDL deposition can have.

A
  1. If there isn’t a high level of OxLDL, reverse cholesterol transport occurs (homeostasis), as the macrophage scoops up the OxLDL and clears it.
  2. If there are higher levels of OxLDL, bug receptor pathways are activated which causes an inflammatory response. The bug detector pathways use Macrophage Scavenger Receptors A and B.
19
Q

What are the differences between Macrophage Scavenger Receptors A and B?

A

A - binds to OxLDL but binds to gram positive bacteria and dead cells

B - binds to OxLDL but binds to malaria parasites and dead cells.

20
Q

Macrophages generate free radicals, which further oxidise lipoproteins. What knockon effects does this have?

A
  1. Macrophages phagocytose modified lipoproteins and become foam cells.
  2. Modified lipoproteins/free intracellular cholesterol activates macrophages.
  3. Activated macrophages secrete: cytokine mediators (recruit monocytes), chemoattractants and GFs for VSMC, proteinases that degrade tissue, tissue factor that stimulates coagulation on contact with blood.
21
Q

Why is apoptosis messy in atherosclerosis?

A

Cytotoxic fat is everywhere, which contributes to the rich lipid core of the plaque.

22
Q

Which oxidative enzymes do macrophages have that modifies native LDL?

A
  1. NADPH Oxidase - forms superoxide (O2-)
  2. Myeloperoxidase - forms HOCL (hypochlorous acid), peroxynitrite (HONOO).

HOCL is extremely toxic (produced by macrophages) and rapidly degrades the surface.

HONOO is even more unstable than HOCL.

23
Q

Which cytokines do macrophages secrete relating to atherosclerosis?

A
  1. IL-1. Upregulates Vascular Cell Adhesion Molecule (VCAM-1)
  2. VCAM-1 - mediates tight monocyte bonding
24
Q

Which chemokines (chemoattractants) do macrophages secrete relating to atherosclerosis?

A
  1. Monocyte Chemoattractant Protein-1 (MCP-1)

2. MCP-1 binds to CCR2 (monocyte G-protein coupled receptor)

25
Q

Both the chemokine secretion and cytokine secretion leads to a positive feedback loop which leads to?

A

Self perpetuating inflammation

26
Q

Macrophages release GFs that recruit VSMC and stimulates them to proliferate and deposit ECM. Which are the 2 main GFs involved?

A
  1. Platelet derived growth factor. Stimulates:
    - VSMC chemotaxis
    - VSMC survival in toxic environment
    - VSMC division
    - Attracts smooth muscle from tunica media to abnormal plaque
  2. Transforming Growth Factor Beta. It stimulates increases collagen synthesis which stabilises the plaque.
27
Q

What is the outcome of growth factors (in response to atherosclerosis) on VSMC?

A

Fewer contractile filaments are made and the atherosclerotic VSMC makes more ECM

28
Q

How do macrophages degrade plaque collagen?

A

They secrete matrix metalloproteinases (MMPs)

  1. They activate each other in a cascade.
  2. They use a mechanism based on zinc to degrade collagen.
  3. Degradation weakens fibrous cap. Once is it weak enough it ruptures and triggers thrombus formation - may lead to occlusive thrombus and ischaemia.
29
Q

What are the features of vulnerable plaques?

A
  1. Large, soft, eccentric lipid rich necrotic core.
  2. Reduced VSMC and collagen content
  3. Increased VSMC apoptosis
  4. Infiltrate of activated macrophages expressing MMPs
30
Q

Explain how macrophage apoptosis may occur.

A
  1. It occurs somewhat because OxLDL derived metabolites are toxic.
  2. The macrophage foam cells have protective systems that maintain survival even when toxic lipid loading occurs.
  3. When the amount of OxLDL is too much, they apoptose.
  4. They release macrophage tissue factor and toxic lipids to the central death zone called LIPID NECROTIC CORE.
  5. Thrombogenic and toxic materials accumulate until plaque rupture allows them to meet the blood.
31
Q

Describe endothelial erosion lesions.

A
  1. They are increasing as a proportion of plaque destabilisation.
  2. Caused by loss of endothelial cells.
  3. Less associated with developed lipid core or inflammatory infiltrate.
  4. Typically non-occlusive mural thrombus.
32
Q

Nuclear Factor Kappa B is a TF.
What is it the master regulator of?
What activates it?
Which genes does it switch on?

A

NFK-B is the master regulator of inflammation.

Activated by: Scavenger receptors, toll like receptors, cytokine receptors (all inflammatory stimuli)

Switches on: MMPs, NO synthase.

CVS (16 decks)

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