atherosclerosis Flashcards
What diseases does atherosclerosis contribute to?
Coronary disease, cerebrovascular disease, heart attack, stroke, lipids, diabetes, revascularisation (surgeries)
What are modifiable and non-modifiable risks of atherosclerosis? What can you do for the modifiable ones?
- 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
why are people getting coronary heart disease at a later stage but more are dying of it?
Decrease in hyperlipidaemia due to statins and hypertension due to anti-hypertensives but increased diabetes due to increased obesity, with drugs having doubtful effects.
Why is atherosclerosis focal and where does it happen?
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)
What is the structure of an artery and why?
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)
In which region of the artery does atherosclerosis happen?
subendothelial space
what is the progression of atherosclerosis (types)?
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.
When is the opportunity for primary prevention? What interventions do you do when complications start (stenosis, plaque rupture)?
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.
What are the main cells involved in atherosclerosis and their roles?
- vascular endothelial cells (their barrier function damaged so lipoproteins can get into sub-endothelial space. Endothelial cells recruit leukocytes when activated)
- platelets (thrombus generation, when activated release cytokine & growth factors).
- monocyte/macrophages (accumulate and form foam cells, secrete cytokines, growth factors, free radicals, metalloproteinases).
- vascular smooth muscle cells (migrate, proliferate, make collagen, remodel and cause fibrous cap formation)
- T-lymphocytes (macrophage activation)
What did CANTOS trial show?
Atherosclerosis has inflammatory basis. When injected patients with antibodies to IL-1 less CV events.
What are foam cells and foam cell debris? What do they form?
Foam cells formed when macrophages ingest LDL.
Foam cell debris is material from dead foam cells which is thrombogenic and harmful
What are the 2 functions of macrophages (& in different parts of the body)? What types of cells we see in atherosclerosis?
- inflammatory macrophages adapted to kill
- 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
Where are macrophages derived from?
monocytes
What is difference between LDL and HDL?
- 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)
How are LDLs modified and where? What happens to them?
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
What is familial hyperlipidaemia FH? Inheritance? What does it cause?
- 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.
What does LDL receptor do?
LDL receptor expressed on liver and takes up LDL into liver & switches off cholesterol synthesis
What is relationship between LDL receptors and cell cholesterol levels?
low LDL receptors, high cholesterol levels
What happens in those without LDL receptor?
Macrophages accumulate cholesterol
What are scavenger receptors?
2nd LDL receptor not under feedback control. Hover up chemically modified LDL - accidentally bind oxidised LDL
What are the different types of macrophage scavenger receptors and what do they do?
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
What do macrophages have that can modify native LDL?
Oxidative enzymes.
1. NADPH oxidase (superoxide) 2. myeloperoxidases (eg hypochlorous acid from ROS + CK- HONOO perocynitrite)
What happens to macrophages when they accumulate LDL?
become foam cells
What inflammatory factors do plaque macrophages express that are involved in monocyte recruitment?
- 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).
- 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
What is the “wound healing” role of macrophages in atherosclerosis?
Macrophages release complementary protein growth factors that recruit VSMC & stimulate them to proliferate and deposit ECM.
- platelet derived growth factor - vascular smooth muscle cell chemotaxis, survival, cell division
- transforming growth factor beta - increases collagen synthesis and matrix deposition
What do macrophages express that may degrade tissue?
Express proteinases that degrade tissue (eg metalloproteinases degrade collagen and activate eachother by proteinolysis).
what is result of metalloproteases produced by macrophages?
Metalloproteases degrade collagen, weakening it and causing plaque erosion/rupture which can cause thrombus.
What are characteristics of a vulnerable plaque? characteristics of stable plaque?
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
When does macrophage apoptosis happen and what does this cause?
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
what is nuclear factor kappa B? what is it activated by? What does it cause?
- 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.
