atherosclerosis and peripheral vascular disease

Question 1

what are some modifiable risk factors for cardiovascular disease

Answer 1

smoking
lipids uptake
blood pressure
diabetes
obesity
sedentary lifestyle

Question 2

what are some non modifiable factors

Answer 2

age
sex
genetic background

Question 3

what is the total risk if an individual smokes ,has high cholesterol and high blood pressure

Answer 3

x16 times more likely to die from heart attack

Question 4

what are some changes in chd epidemiology over last decade

Answer 4

statins to reduce hyperlipidaemia
antihypertensive treatments
increased obesity leading to increased diabetes
new improvements in diabetes treatment have doubtful effect on cvd

Question 5

why do atherosclerosis occur at bifurcations

Answer 5

turbulent blood flow

Question 6

where does atherosclerosis usually take place

Answer 6

internal elastic lamina

Question 7

where does ldl deposit in?

Answer 7

subintimal space and binds to matrix proteoglycans

Question 8

briefly describe progression of atherosclerosis

Answer 8

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

Question 9

what are the main types of cells involved in atherosclerosis

Answer 9

vascular endothelial cells
monocyte-macrophages
vascular smooth muscle cells
platelets
t lymphocytes

Question 10

what is the role of vascular endothelial cells

Answer 10

barrier function e.g to lipoproteins

leukocyte recruitment

Question 11

what is the role of monocyte macrophages

Answer 11

foam cell formation
cytokine and growth faction release
major source of free radicals
metalloproteinases

Question 12

what is role of platelets

Answer 12

thrombus generation

cytokine and growth factor release

Question 13

what is the role of vascular smooth muscle cells

Answer 13

migration and proliferation
collagen synthesis
remodelling and fibrous cap formation

Question 14

role of lymphocytes

Answer 14

macrophage activation and also activated by macrophages themselves

Question 15

what are the main inflammatory cells in atheroclerosis

Answer 15

macrophages derived from blood monocytes

Question 16

what are the main 2 classes of macrophages

Answer 16

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

Question 17

what is ldl

Answer 17

‘bad’ cholesterol - synthesised in liver

carries cholesterol from liver to rest of body incl arteries

Question 18

what is hdl

Answer 18

‘good cholesterol’ - carries cholesterol from ‘peripheral tissues’ icl arteries back to liver

Question 19

what are oxidised ldls/ modified ldls

Answer 19

families of highly inflammatory and toxic forms of ldl found in vessel walls

Question 20

what happens when ldls leak through endothelial barrier by uncertain mechanisms

Answer 20

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

Question 21

what is familial hyperlipidaemia

Answer 21

autosomal genetic disease
massively elevated cholesterol >20mmol/l
failure to clear ldl from blood
causes xanthomas and early mi

Question 22

treatment for fh

Answer 22

hmgcoa reductase inhibitor = statins

to lower plasma cholesterol

Question 23

what are macrophage scavenger receptor a

Answer 23

known as cd204
binds to oxidised ldl
binds to gram positive bacteria like staph and strept
binds to dead cells

Question 24

what are macrophage scavenger receptor b

Answer 24

aka cd36
binds to oxidised ldl
binds to malaria parasites
binds to dead cells

Question 25

what are some oxidative enzymes that macrophages have that can modify native ldl

Answer 25

NADPH oxidase e.g superoxide 02 | myeloperoxidase e.g HOCl (bleach) from ros+ and Cl, HONOO

Question 26

what are macrophages 2 roles when it comes to arterial ox ldl deposits

Answer 26

1. detects oxldls as bug causing activation of 'bug detector' pathways causing inflammation 2. re process cholesterol and send back to hdl - reverse cholesterol transport

Question 27

What is the effect of bleach HOCl on ldls

Answer 27

ldl gets into artery activates macrophages bleach damages inside of artery - plaques start falling apart

Question 28

what are cytokines

Answer 28

protein immune hormones that activate endothelial cell adhesion molecules

Question 29

what are chemokines

Answer 29

small proteins chemoattractant to monocytes

Question 30

what are the cytokines involved in monocyte recruitment

Answer 30

IL1 upregulates vascular cell adhesion molecule 1 VCAM1 | VCAM1 mediates tight monocyte binding

Question 31

what are the chemokines involved in monocyte recruitment

Answer 31

monocyte chemotactic protein 1 - (mcp1) binds to monocyte g coupled receptor ccr2

Question 32

what is the 'wound healing' role of macrophages in atherosclerosis

Answer 32

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

Question 33

what are the 2 main growth factors involved in wound healing

Answer 33

platelet derived growth factor | transforming growth factor beta

Question 34

what is role of platelet derived growth factor

Answer 34

VSMC chemotaxis VSMC survival VSMC division - mitosis

Question 35

role of transforming growth factor beta

Answer 35

increased collagen synthesis matrix depostition = thicker fibrous cap

Question 36

overall what does pdgf and tgf beta cause

Answer 36

decrease in contractile filaments | increase in matrix deposition genes

Question 37

what is the effect of plaque erosion/rupture

Answer 37

blood coagulation at site of rupture may lead to occulsive thrombus and cessation of blood flow

Question 38

what are metalloproteinases

Answer 38

family of 28 homologous enzymes activate each other by proteolysis degrade collagen catalytic mechanism is based on Zn

Question 39

what are the characteristics of vulnerable and stable plaques

Answer 39

large soft eccentric liquid rich necrotic core increased VSMC apoptosis reduced VSMC and collagen content thin fibrous cap infiltrate of activated macrophages expressing MMPs

Question 40

how does macrophage activation take place

Answer 40

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

Question 41

what is nuclear factor kappa b | nfkb

Answer 41

transcription factor - major regulator of inflammation | -

Question 42

what is nfkb activated by

Answer 42

scavenger receptors toll like receptors cytokine receptors e.g il1

Question 43

what does nfkb switch on

Answer 43

matrix metalloproteinases inducible nitric oxide synthase il1