coronary heart disease and atherosclerosis

Question 1

what is about to be the world leading killer

Answer 1

ischemic heart disease

Question 2

what is cerebrovascular disease

Answer 2

stroke

Question 3

what is the main thing leading to stroke

Answer 3

atherosclerosis in carotids - inflammation driven by lipids

Question 4

epidemiology of ICH

Answer 4

used to be just in the developed world

developing world was ischemic - now it is on a western diet = obesity, hyperlipidaemia and hypertension

Question 5

what things does atherosclerosis result in, in different specialities

Answer 5

acute med - MI/stroke
metabolic medicine - lipids
endo - diabetes, aim to prevent atherosclerosis
vascular surgery - revascularisation
cardiac surgery - revascularisation, coronary artery bypass grafting - mammary artery/saphenous vein (leg) is used - connect aorta to distal coronary arteries bypass block in proximal coronary
cardiology = coronary disease

Question 6

modifiable risk factor

Answer 6

smoking
lipid intake/levels - reduce intake/used drugs
BP - reduce salt and use BP lowering drugs
diabetes - less sugar, lose weight, metformin/sulfonylurea
obesity - calory controlled diet/ drug reduce appetite, lipid absorption/gastric binding
sedentary lifestyle

Question 7

non-modifiable risk factors

Answer 7

age
sex
genetic background

Question 8

how do risk factors interact

Answer 8

they multiply

Question 9

how has the epidemiology changed

Answer 9

reduced hyperlipidaemia - statins
reduced hypertensions - antihypertensive treatment
increased obesity - diabetes - plaques more driven by this
new diabetes treatment little effect in macrovascular disease, metformin better effect in trials

Question 10

why is atherosclerosis focal.

Answer 10

when blood hits outer wall eddys formed = turbulent flow because of disturbance of geometry

Question 11

normal structure of bv

Answer 11

thick layer of sm - contracts to increase resistance and pressure and decrease flow
then have the endothelium and intima (joined by interstitial matrix)

Question 12

how does the bv allow endothelium deposition

Answer 12

risk factors 
endothelium leaky 
LDL enter 
bind to intima
set up inflammatory reaction

Question 13

describe the progression of atherosclerosis

Answer 13

increase in interstial matrix in intima
type 2 lesion - more inflammatory - population of macrophage foam cells
3 - macrophages die and release the fat - fat goes into the wall (small pool extracellular lipid)
4 - atheroma, core extracellular lipid formed by pools combining, dead macrophages - necrotic core
5 - fibroatheroma, inflammation = fibrotic thickening - cap, block coronaty artery = MI
6 - if not enough fissure = thrombosis, you can see stratification from multiple stepwise events

Question 14

what are the clinical interventions for thrombosis

Answer 14

percutaneous coronary intervention/cardiac surgery
secondary prevention 
catheter based interventions 
revasculation surgery 
treatment of heart failure 
squash cap flat - balloon angioplasty 
thrombolise/anticoagulated and clear 
bypass

Question 15

vascular endothelial cells

Answer 15

barrier function to LDL

leukocyte enter - it is an inflammatory disease

Question 16

platelets

Answer 16

thrombus generation

cytokine and growth factor release - influence plaque growth

Question 17

T lymphocytes

Answer 17

activated by macrophages and the plaque

they activate macrophages

Question 18

monocytes-macrophages

Answer 18

foam cell formation
cytokine and growth factor release
major source of free radicals
metalloproteinases - enzymes that degrade the cap = make it more rupture prone - the catalytic site depends on zinc

Question 19

vascular SM cells

Answer 19

migration into plaques and proliferation
collagen synthesis - make thicker
remodelling and fibrous cap formation

Question 20

process of inflammation- WBC

Answer 20

vascular dilation = influx WBC
some clear debris
some kill pathogens
some repair damage

Question 21

macrophages in atherosclerosis

Answer 21

can injure host
main inf cell
groups are regulated by TFs

Question 22

2 classes of macrophages

Answer 22

inf - kill microbes
resident - homeostatic so suppress inf, alveolar resident involved in surfactant lipid homeostasis, osteoclasts - they absorb calcified material - turn into serum ca, spleen - recycle iron

Question 23

LDLs

Answer 23

carry cholesterol from liver to body including arteries
bad at the level we have in our diet
all hyperlipidaemic
it is a j curve - low level mortality increases, then drops - min at 1-2mmol and then it increase at a high rate

Question 24

HDL

Answer 24

carry cholesterol from arteries to liver

‘reverse cholesterol transport’

Question 25

oxidised/modified LDLs

Answer 25

because of free radicals not a single substance family of toxic and inflammatory form found in vessel walls

Question 26

structure of LDL

Answer 26

outside is hydrophobic - has charged phosphotidyl choline inside is nonpolar micelles have targeting apoplipoproteins - tell cell where to go in body inside cholesterol and triglyceride - acts as cargo fat

Question 27

modification of the LDL

Answer 27

LDL leak through the endothelial barrier bind to proteoglycans oxidation LDL modified by free radicals - phagocytosed by macrophages = foam cells chronic inf because there is a wbc infiltrate

Question 28

what is familial hyperlipidemia

Answer 28

autosomal genetic disease - dominat/recessive mutation on the LDL receptor massively elevated cholesterol 20mmol/L failure to clear LDL from the blood - oxidised xanthomas and atherosclerosis - fatal MI before 20 if not treated

Question 29

explain the discovery of the LDL receptor

Answer 29

expression receptor -ve regulated by intracellular cholesterol led to discovery of HMG -coa reductase inhibitors - statins macrophages still accumulate cholesterol if LDLR -ve scavenger receptor - not under feedback control - take up modified LDL - actually pathogen receptors that accidently bind to LDL

Question 30

why isn't HDL involved in atherosclerosis

Answer 30

actively protective

Question 31

effect of clotting factor 8 deficiency

Answer 31

less likely to get thrombosis

Question 32

describe the scavenger receptor A

Answer 32

``` CD204 bind to oxLDL bind to gram +ve bacteria - staphylocci and streptococci bind to dead cells mistake LDL for germs try to kill = inflammation ```

Question 33

macrophage scavenger receptor B

Answer 33

``` CD36 bind oxLDL bind malaria bind to dead cells self clearance -reverse cholesterol transport, interact with HDL, suck cholesterol out of plaque and into liver - homeostasis or emigration, take thee cholesterol out of the plaque to lymph node ```

Question 34

roles of macrophages in plaques

Answer 34

generate free radicals that modify LDL phagocytose modified lipoproteins and become foam cells express cytokine mediators that recruit monocytes express chemoreceptors and growth factors for VSMC express proteinases that degrade tissue

Question 35

describe macrophages and the generation of free radicals

Answer 35

they have oxidative enzymes that modify naïve LDL = vicious cycle LDL oxidised, macrophages think it is a bug, oxidise further = inf - NADPH oxidase makes superoxide O2- - radical stick O onto LDL - make it more oxidised - myeloperoxidase eg HOCL (bleach) from ROS and Cl-, HONOO peroxynitrate from nitic oxide and hydrogen peroxide (unstable) - take superoxide derived oxidants (eg hydrogen peroxide) - convert to HOCL: the macrophages secrete bleach into the vessel wall which oxidises LDL

Question 36

describe macrophages phagocytising modified lipoproteins and become foam cells

Answer 36

they accumulate modified LDLs to become enlarged foam cells you can see this using a brown antibody to CD68 - a macrophage lysosome protein microphages die from lipid overload - toxic effect - release debris into lipid necrotic core

Question 37

describe the action of macrophages with cytokines

Answer 37

macrophages secrete cytokines - protein immune hormones activate endothelial cell adhesion molecules INL-1 upregulate vascular cell adhesion molecule 1 (VCAM1) - make sticky this mediates tight monocyte binding - make sticky for monocytes atherosclerosis reduced without this +ve feedback

Question 38

describe macrophages and chemokines

Answer 38

small proteins - chemoattractants to monocytes monocyte macrophages 'sniff' out chemotactic proteins MCP-1 this binds to monocyte G protein coupled receptor CCR2 allow more monocytes to be recruited atherosclerosis reduced when deficient - self perpetuating loop of inflammation

Question 39

explain how macrophages express chemoattractants and growth factors for VSMC

Answer 39

wound healing role - role of macrophage in atherosclerosis macrophage releases complementary protein growth factors that recruit VSMC and stimulate them to proliferate and deposit ECM platelet derived factor - VSMC chemotaxis - SM in to plaque from medius , survival, division - mitosis transforming growth factor beta - increased collagen synthesis and matrix deposition modified cells better make matrix and are less good at contracting

Question 40

describe macrophages expressing proteinases

Answer 40

metalloproteinases (MMPs) - 28 homologous enzymes activate each other by proteolysis degrade collagen catalytic mechanism is based on Zn where there are WBC there is no collagen - they eat the cells in the plaque causing it to degrade and rupture blood coagulation at site of rupture may lead to occlusive thrombus and cessation of flow

Question 41

the process of a ruptured plaque turning into a rupture

Answer 41

because macrophages have destroyed muscle and collagen - activated by lipid plaque is thin - collagen and sm is lost - infiltration of macrophages fat in the middle of the plaque touches blood procoagulation factors - so blood clots with it cause sudden coagulation of blood - completely stop blood flow MI and stroke

Question 42

characteristics of ruptured clot

Answer 42

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

Question 43

what colour is the heart normally

Answer 43

brown because of myoglobin

Question 44

what colour is the

Answer 44

pale because the myoglobin is released

Question 45

describe macrophage apoptosis

Answer 45

OxLDL derived metabolites are toxic eg 7-Keto cholesterol macrophage foam cells - protective systems, survive even in lipid toxicity once overwhelmed macrophages die - apoptosis release macrophages tissue factors and toxic lipids into central death zone called lipid necrotic core thrombogenic and toxic material accumulates - is walled off, until plaque rupture causes it to meet blood

Question 46

what is NFkB

Answer 46

TF | master regulator of inflammation

Question 47

what activates NFkB

Answer 47

scavenger receptors toll like receptors cytokine receptors

Question 48

what does NFkB switch on

Answer 48

inflammatory genes - MMP - inducible notric oxide synthase it directs multiple genes in concert it is an integration network hub activated by different things and activates downstream mechanisms

Question 49

summary of atherosclerosis

Answer 49

risk factors at branches in bv make endothelial more leaky attract monocytes LDL enter by binding to intima they are oxidised bind to scavenger receptors activation of macrophages (NFkB activation too) lipid accumulation in macrophages release reactive oxygen species, chemokines, MMP 1 attract more monocytes, MMPs - degrade collagen, make thinner = rupture GF (eg PDGF and TGFb make cap thicker and stable by making more collagen) - further oxidise LDL - vicious cycle secrete cytokines - active endo so sticky for more monocytes [HDL also made which reverses cholesterol transport] death - release and accumulation of tissue factor and toxic oxidised lipids tissue factor in plaque core - thrombosis made really quickly

Question 50

left anterior descending coronary artery

Answer 50

feeds biggest portion of the heart and goes all the way down the front