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cardiovascular system > coronary heart disease and atherosclerosis > Flashcards

coronary heart disease and atherosclerosis Flashcards

1
Q

what is about to be the world leading killer

A

ischemic heart disease

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2
Q

what is cerebrovascular disease

A

stroke

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3
Q

what is the main thing leading to stroke

A

atherosclerosis in carotids - inflammation driven by lipids

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4
Q

epidemiology of ICH

A

used to be just in the developed world

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

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5
Q

what things does atherosclerosis result in, in different specialities

A

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

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6
Q

modifiable risk factor

A

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

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7
Q

non-modifiable risk factors

A

age
sex
genetic background

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8
Q

how do risk factors interact

A

they multiply

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9
Q

how has the epidemiology changed

A

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

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10
Q

why is atherosclerosis focal.

A

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

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11
Q

normal structure of bv

A

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

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12
Q

how does the bv allow endothelium deposition

A 
risk factors 
endothelium leaky 
LDL enter 
bind to intima
set up inflammatory reaction
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13
Q

describe the progression of atherosclerosis

A

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

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14
Q

what are the clinical interventions for thrombosis

A 
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
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15
Q

vascular endothelial cells

A

barrier function to LDL

leukocyte enter - it is an inflammatory disease

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16
Q

platelets

A

thrombus generation

cytokine and growth factor release - influence plaque growth

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17
Q

T lymphocytes

A

activated by macrophages and the plaque

they activate macrophages

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18
Q

monocytes-macrophages

A

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

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19
Q

vascular SM cells

A

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

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20
Q

process of inflammation- WBC

A

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

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21
Q

macrophages in atherosclerosis

A

can injure host
main inf cell
groups are regulated by TFs

22
Q

2 classes of macrophages

A

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

23
Q

LDLs

A

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

24
Q

HDL

A

carry cholesterol from arteries to liver

‘reverse cholesterol transport’

25
Q

oxidised/modified LDLs

A

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

26
Q

structure of LDL

A

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

27
Q

modification of the LDL

A

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

28
Q

what is familial hyperlipidemia

A

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

29
Q

explain the discovery of the LDL receptor

A

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

30
Q

why isn’t HDL involved in atherosclerosis

A

actively protective

31
Q

effect of clotting factor 8 deficiency

A

less likely to get thrombosis

32
Q

describe the scavenger receptor A

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
33
Q

macrophage scavenger receptor B

A 
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
34
Q

roles of macrophages in plaques

A

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

35
Q

describe macrophages and the generation of free radicals

A

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
36
Q

describe macrophages phagocytising modified lipoproteins and become foam cells

A

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

37
Q

describe the action of macrophages with cytokines

A

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

38
Q

describe macrophages and chemokines

A

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

39
Q

explain how macrophages express chemoattractants and growth factors for VSMC

A

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

40
Q

describe macrophages expressing proteinases

A

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

41
Q

the process of a ruptured plaque turning into a rupture

A

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

42
Q

characteristics of ruptured clot

A

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

43
Q

what colour is the heart normally

A

brown because of myoglobin

44
Q

what colour is the

A

pale because the myoglobin is released

45
Q

describe macrophage apoptosis

A

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

46
Q

what is NFkB

A

TF

master regulator of inflammation

47
Q

what activates NFkB

A

scavenger receptors
toll like receptors
cytokine receptors

48
Q

what does NFkB switch on

A

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

49
Q

summary of atherosclerosis

A

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

50
Q

left anterior descending coronary artery

A

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

cardiovascular system (22 decks)

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