atherosclerosis and peripheral vascular disease Flashcards
what are some modifiable risk factors for cardiovascular disease
smoking lipids uptake blood pressure diabetes obesity sedentary lifestyle
what are some non modifiable factors
age
sex
genetic background
what is the total risk if an individual smokes ,has high cholesterol and high blood pressure
x16 times more likely to die from heart attack
what are some changes in chd epidemiology over last decade
statins to reduce hyperlipidaemia
antihypertensive treatments
increased obesity leading to increased diabetes
new improvements in diabetes treatment have doubtful effect on cvd
why do atherosclerosis occur at bifurcations
turbulent blood flow
where does atherosclerosis usually take place
internal elastic lamina
where does ldl deposit in?
subintimal space and binds to matrix proteoglycans
briefly describe progression of atherosclerosis
adaptive thickening of smooth muscle at lesion prone site
type 2 lesion causes macrophage foam cells
in preatheroma - small pools of extracellular lipids
atheroma - core of extracellular lipids
fibroatheroma - fissure and haematoma, thrombosis
what are the main types of cells involved in atherosclerosis
vascular endothelial cells monocyte-macrophages vascular smooth muscle cells platelets t lymphocytes
what is the role of vascular endothelial cells
barrier function e.g to lipoproteins
leukocyte recruitment
what is the role of monocyte macrophages
foam cell formation
cytokine and growth faction release
major source of free radicals
metalloproteinases
what is role of platelets
thrombus generation
cytokine and growth factor release
what is the role of vascular smooth muscle cells
migration and proliferation
collagen synthesis
remodelling and fibrous cap formation
role of lymphocytes
macrophage activation and also activated by macrophages themselves
what are the main inflammatory cells in atheroclerosis
macrophages derived from blood monocytes
what are the main 2 classes of macrophages
inflammatory macrophages - adapted to kill microorganisms
resident - normally homeostatic - suppress inflammatory activity
alveolar resident macrophages - surfactant lipid homeostasis
osteoclasts - calcium and phosphate homeostasis
spleen - iron homeostasis
what is ldl
‘bad’ cholesterol - synthesised in liver
carries cholesterol from liver to rest of body incl arteries
what is hdl
‘good cholesterol’ - carries cholesterol from ‘peripheral tissues’ icl arteries back to liver
what are oxidised ldls/ modified ldls
families of highly inflammatory and toxic forms of ldl found in vessel walls
what happens when ldls leak through endothelial barrier by uncertain mechanisms
ldl is trapped by binding to proteoglycans in sub endothelial layer and becomes susceptible to modification e.g oxidation by free radicals - represents partial burning
phagocytosed by macrophages and stimulates chronic inflammation
what is familial hyperlipidaemia
autosomal genetic disease
massively elevated cholesterol >20mmol/l
failure to clear ldl from blood
causes xanthomas and early mi
treatment for fh
hmgcoa reductase inhibitor = statins
to lower plasma cholesterol
what are macrophage scavenger receptor a
known as cd204
binds to oxidised ldl
binds to gram positive bacteria like staph and strept
binds to dead cells
what are macrophage scavenger receptor b
aka cd36
binds to oxidised ldl
binds to malaria parasites
binds to dead cells
what are some oxidative enzymes that macrophages have that can modify native ldl
NADPH oxidase e.g superoxide 02
myeloperoxidase e.g HOCl (bleach) from ros+ and Cl, HONOO
what are macrophages 2 roles when it comes to arterial ox ldl deposits
- detects oxldls as bug causing activation of ‘bug detector’ pathways causing inflammation
- re process cholesterol and send back to hdl - reverse cholesterol transport
What is the effect of bleach HOCl on ldls
ldl gets into artery
activates macrophages
bleach damages inside of artery - plaques start falling apart
what are cytokines
protein immune hormones that activate endothelial cell adhesion molecules
what are chemokines
small proteins chemoattractant to monocytes
what are the cytokines involved in monocyte recruitment
IL1 upregulates vascular cell adhesion molecule 1 VCAM1
VCAM1 mediates tight monocyte binding
what are the chemokines involved in monocyte recruitment
monocyte chemotactic protein 1 - (mcp1) binds to monocyte g coupled receptor ccr2
what is the ‘wound healing’ role of macrophages in atherosclerosis
release complementary protein growth factors that recruit VSMC and stimulate them to proliferate and deposit ECM
what are the 2 main growth factors involved in wound healing
platelet derived growth factor
transforming growth factor beta
what is role of platelet derived growth factor
VSMC chemotaxis
VSMC survival
VSMC division - mitosis
role of transforming growth factor beta
increased collagen synthesis
matrix depostition
= thicker fibrous cap
overall what does pdgf and tgf beta cause
decrease in contractile filaments
increase in matrix deposition genes
what is the effect of plaque erosion/rupture
blood coagulation at site of rupture may lead to occulsive thrombus and cessation of blood flow
what are metalloproteinases
family of 28 homologous enzymes
activate each other by proteolysis
degrade collagen
catalytic mechanism is based on Zn
what are the characteristics of vulnerable and stable plaques
large soft eccentric liquid rich necrotic core
increased VSMC apoptosis
reduced VSMC and collagen content
thin fibrous cap
infiltrate of activated macrophages expressing MMPs
how does macrophage activation take place
oxldl metabolites are toxic
macrophage foam cells have protective systems that maintain survival in face of toxic lipid loading
once overwhelmed - macrophages die via apoptosis
release macrophage tf and toxic lipids into central death zone - lipid necrotic core
thrombogenic and toxic material accumulates - until plaque ruptures
what is nuclear factor kappa b
nfkb
transcription factor - major regulator of inflammation
-
what is nfkb activated by
scavenger receptors
toll like receptors
cytokine receptors e.g il1
what does nfkb switch on
matrix metalloproteinases
inducible nitric oxide synthase
il1
