coronary heart disease and atherosclerosis Flashcards
what is about to be the world leading killer
ischemic heart disease
what is cerebrovascular disease
stroke
what is the main thing leading to stroke
atherosclerosis in carotids - inflammation driven by lipids
epidemiology of ICH
used to be just in the developed world
developing world was ischemic - now it is on a western diet = obesity, hyperlipidaemia and hypertension
what things does atherosclerosis result in, in different specialities
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
modifiable risk factor
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
non-modifiable risk factors
age
sex
genetic background
how do risk factors interact
they multiply
how has the epidemiology changed
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
why is atherosclerosis focal.
when blood hits outer wall eddys formed = turbulent flow because of disturbance of geometry
normal structure of bv
thick layer of sm - contracts to increase resistance and pressure and decrease flow
then have the endothelium and intima (joined by interstitial matrix)
how does the bv allow endothelium deposition
risk factors endothelium leaky LDL enter bind to intima set up inflammatory reaction
describe the progression of atherosclerosis
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
what are the clinical interventions for thrombosis
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
vascular endothelial cells
barrier function to LDL
leukocyte enter - it is an inflammatory disease
platelets
thrombus generation
cytokine and growth factor release - influence plaque growth
T lymphocytes
activated by macrophages and the plaque
they activate macrophages
monocytes-macrophages
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
vascular SM cells
migration into plaques and proliferation
collagen synthesis - make thicker
remodelling and fibrous cap formation
process of inflammation- WBC
vascular dilation = influx WBC
some clear debris
some kill pathogens
some repair damage
macrophages in atherosclerosis
can injure host
main inf cell
groups are regulated by TFs
2 classes of macrophages
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
LDLs
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
HDL
carry cholesterol from arteries to liver
‘reverse cholesterol transport’
oxidised/modified LDLs
because of free radicals
not a single substance
family of toxic and inflammatory form found in vessel walls
structure of LDL
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
modification of the LDL
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
what is familial hyperlipidemia
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
explain the discovery of the LDL receptor
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
why isn’t HDL involved in atherosclerosis
actively protective
effect of clotting factor 8 deficiency
less likely to get thrombosis
describe the scavenger receptor A
CD204 bind to oxLDL bind to gram +ve bacteria - staphylocci and streptococci bind to dead cells mistake LDL for germs try to kill = inflammation
macrophage scavenger receptor B
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
roles of macrophages in plaques
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
describe macrophages and the generation of free radicals
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
describe macrophages phagocytising modified lipoproteins and become foam cells
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
describe the action of macrophages with cytokines
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
describe macrophages and chemokines
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
explain how macrophages express chemoattractants and growth factors for VSMC
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
describe macrophages expressing proteinases
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
the process of a ruptured plaque turning into a rupture
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
characteristics of ruptured clot
large soft eccentric lipid rich necrotic core
increased VSMC apoptosis
reduced VSM and collagen content
thin fibrous cap
infiltration of activated macrophages expressing MMPs
what colour is the heart normally
brown because of myoglobin
what colour is the
pale because the myoglobin is released
describe macrophage apoptosis
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
what is NFkB
TF
master regulator of inflammation
what activates NFkB
scavenger receptors
toll like receptors
cytokine receptors
what does NFkB switch on
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
summary of atherosclerosis
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
left anterior descending coronary artery
feeds biggest portion of the heart and goes all the way down the front
