atherosclerosis

Question 1

What diseases does atherosclerosis contribute to?

Answer 1

Coronary disease, cerebrovascular disease, heart attack, stroke, lipids, diabetes, revascularisation (surgeries)

Question 2

What are modifiable and non-modifiable risks of atherosclerosis? What can you do for the modifiable ones?

Answer 2

• Modifiable –> smoking (cessation), lipid intake (statins), blood pressure (ABCD - ACEi –> beta blockers - calcium blockers - diuretics), diabetes (diet, weight loss, surgery, metformin, insulin), obesity, sedentary life (advice, exercise).
• Non-Modifiable –> age, sex, genetics.
• These risk factors multiply so big effect if one being treated

Question 3

why are people getting coronary heart disease at a later stage but more are dying of it?

Answer 3

Decrease in hyperlipidaemia due to statins and hypertension due to anti-hypertensives but increased diabetes due to increased obesity, with drugs having doubtful effects.

Question 4

Why is atherosclerosis focal and where does it happen?

Answer 4

Arteries affected by it are coronary, carotid, iliac.

• In coronary tree plaques occur at branches.
• In other arteries, mostly at ostea and bifurcation of aorta (because vortices formed by turbulent flow so endothelium senses turbulent flow as cause for inflammation)

Question 5

What is the structure of an artery and why?

Answer 5

Thick walls to maintain & resist bp. Elastic to cope with stroke volume & pulsatile pressure. Has internal elastic layer. Very thin endothelium that controls level of contraction & bp (inhibiting endothelium will increase blood pressure)

Question 6

In which region of the artery does atherosclerosis happen?

Answer 6

subendothelial space

Question 7

what is the progression of atherosclerosis (types)?

Answer 7

Type I: adaptive thickening (smooth muscle).
Type II: macrophage foam cells form.
Type III: pre-atheroma - small pools of extracellular lipid because macrophages die/overwhelmed.
Type IV (atheroma): core of extracellular lipid formed.
Type V (fibroatheroma): fibroblasts form abscesses reaction causing fibrous thickening (collagen).
Type VI (complicated lesion): thickened collagen breaks down due to inflammatory cells & thrombus formation.

Question 8

When is the opportunity for primary prevention? What interventions do you do when complications start (stenosis, plaque rupture)?

Answer 8

Normal - intermediate lesions - advanced lesions - complications.

Best window for primary intervention is at intermediate/advanced lesion stage.

When complications start secondary prevention with catheter based interventions, revascularisation surgery, treatment of heart failure.

Question 9

What are the main cells involved in atherosclerosis and their roles?

Answer 9

1. vascular endothelial cells (their barrier function damaged so lipoproteins can get into sub-endothelial space. Endothelial cells recruit leukocytes when activated)
2. platelets (thrombus generation, when activated release cytokine & growth factors).
3. monocyte/macrophages (accumulate and form foam cells, secrete cytokines, growth factors, free radicals, metalloproteinases).
4. vascular smooth muscle cells (migrate, proliferate, make collagen, remodel and cause fibrous cap formation)
5. T-lymphocytes (macrophage activation)

Question 10

What did CANTOS trial show?

Answer 10

Atherosclerosis has inflammatory basis. When injected patients with antibodies to IL-1 less CV events.

Question 11

What are foam cells and foam cell debris? What do they form?

Answer 11

Foam cells formed when macrophages ingest LDL.

Foam cell debris is material from dead foam cells which is thrombogenic and harmful

Question 12

What are the 2 functions of macrophages (& in different parts of the body)? What types of cells we see in atherosclerosis?

Answer 12

1. inflammatory macrophages adapted to kill
2. resident macrophages - normally homesostatic suppress inflammation eg. Alveolar resident macrophages (surfactant homeostasis take it up and back to Type 2 pneumocytes), osteoclasts (resorb bone releasing calcium & phosphate into blood), spleen (iron homeostasis by taking up old stiff RBC, taking them apart and sending iron back to liver).
   - In atherosclerosis we have macrophage inflammatory cells

Question 13

Where are macrophages derived from?

Answer 13

monocytes

Question 14

What is difference between LDL and HDL?

Answer 14

• LDL (bad cholesterol) made in liver and carries cholesterol from liver to rest of body including arteries.
• HDL (good) carries cholesterol from tissues including arteries back to liver (reverse cholesterol transport)

Question 15

How are LDLs modified and where? What happens to them?

Answer 15

LDLs modified in subendothelium.

• They leak through endothelium, trapped in subendthoellium by binding to sticky proteoglycans and susceptible to modification.
• Modified by oxidation (partial burning), by free radials.
• Oxidised LDL then phagocytosed by macrophages that become foam cells and stimulate chronic inflammation

Question 16

What is familial hyperlipidaemia FH? Inheritance? What does it cause?

Answer 16

• Autosomal (mostly dominant) condition causing extremely elevated cholesterol levels.
• Failure to clear LDL from blood leads to xanthomas and early atherosclerosis.
• Without treatment MI before 20yrs.

Question 17

What does LDL receptor do?

Answer 17

LDL receptor expressed on liver and takes up LDL into liver & switches off cholesterol synthesis

Question 18

What is relationship between LDL receptors and cell cholesterol levels?

Answer 18

low LDL receptors, high cholesterol levels

Question 19

What happens in those without LDL receptor?

Answer 19

Macrophages accumulate cholesterol

Question 20

What are scavenger receptors?

Answer 20

2nd LDL receptor not under feedback control. Hover up chemically modified LDL - accidentally bind oxidised LDL

Question 21

What are the different types of macrophage scavenger receptors and what do they do?

Answer 21

A: CD204 - binds to oxLDL, gram-negative bacteria (staph & strep), dead cells.

B: CD36 - binds oxLDL, malaria parasites & dead cells.

-Arterial oxidised LDL taken up by macrophages, activated bug detector pathways (inflammation). For homeostasis - macrophages will re-process this for reverse cholesterol transport

Question 22

What do macrophages have that can modify native LDL?

Answer 22

Oxidative enzymes.

1. NADPH oxidase (superoxide) 2. myeloperoxidases (eg hypochlorous acid from ROS + CK- HONOO perocynitrite)

Question 23

What happens to macrophages when they accumulate LDL?

Answer 23

become foam cells

Question 24

What inflammatory factors do plaque macrophages express that are involved in monocyte recruitment?

Answer 24

1. cytokines - activate endothelial cell adhesion molecules (IL-1 upregulates vascular cell adhesion molecule VCAM-1, which mediates tight monocyte binding. Atherosclerosis reduced in mice without IL-1 or VCAM-1).
2. chemokines - chemoattractant proteins to monocytes (monocyte chemotactic protein 1 (MCP-1) binds to monocyte G-protein coupled receptor CCR2 - atherosclerosis reduced in mice without MCP-1 or CCR2).

Positive feedback loop cycle drives inflammation

Question 25

What is the “wound healing” role of macrophages in atherosclerosis?

Answer 25

Macrophages release complementary protein growth factors that recruit VSMC & stimulate them to proliferate and deposit ECM.

1. platelet derived growth factor - vascular smooth muscle cell chemotaxis, survival, cell division
2. transforming growth factor beta - increases collagen synthesis and matrix deposition

Question 26

What do macrophages express that may degrade tissue?

Answer 26

Express proteinases that degrade tissue (eg metalloproteinases degrade collagen and activate eachother by proteinolysis).

Question 27

what is result of metalloproteases produced by macrophages?

Answer 27

Metalloproteases degrade collagen, weakening it and causing plaque erosion/rupture which can cause thrombus.

Question 28

What are characteristics of a vulnerable plaque? characteristics of stable plaque?

Answer 28

vulnerable : thin fibrous cap, large necrotic core, small ECM component, high number number macrophages (with MMPs)

stable: thick fibrous cap, small necrotic core, large ECM component, low macrophages

Question 29

When does macrophage apoptosis happen and what does this cause?

Answer 29

Usually have protective systems to maintain survival again toxic lipid loading (oxLDL derived metabolites are toxic eg. 7-keto cholesterol).

• But once overwhelmed apoptosis.
• Release macrophage tissue factors & toxic lipids into central death zone - necrotic core. T
• thrombogenic and toxic material accumulates until plaque ruptures and it meets blood

Question 30

what is nuclear factor kappa B? what is it activated by? What does it cause?

Answer 30

• Transcription factor that is master regulator of inflammation.
• Activated by inflammatory stimuli like scavenger receptors, toll-like receptors, cytokine receptors eg. IL1.
• switches on many inflammatory genes (matrix metalloproteinases, inducible nitric oxide synthase, IL-1 & also co-regulates many different inflammatory genes at same time.