Case 5 Flashcards
what is atherosclerosis
refers to plaque formation which is the build up of fats and cholesterol inner artery walls that can restrict or block the blood flow
what happens when the blood flow is restricted or blocked,
tissues or organs can suffer from ischaemia which means lack of oxygen.
what is atherosclerosis described as
chronic inflammatory process triggered by the accumulation of cholesterol containing low-density lipoprotein LDL particles in the arterial wall
how common is it for death in males
most common cause of death in males
what does cigarette smoke cause in the arteries
endothelial dysfunction
when is pharmacotherapy recommend
if BP is over 140/90mmHg
Dyslipidemia mechanism
Hydrophobic fat molecules, such as triglycerides, phospholipids and cholesterol are transported to all the cells and tissues of the body in lipoprotein particles
Lipoprotein particles consist of a triglyceride and cholesterol centre, surrounded by a phospholipid outer shell
There is a special kind of protein, called apolipoprotein, embedded in the outer shell, to stabilise the complex and to give it a functional identity
Two main types of lipoproteins: the bad low density one (LDL) and the good high density one (HDL)
Lipoproteins are very low and intermediate densities are also considered bad.
In terms of apolipoproteins, apoliprotein B (ApoB) , is embedded in LDL and ApoA1 is in HDL
LDL in the circulation can be brought into the artery wall across the endothelial cells, for example by scavenger receptors
LDL will then be taken by macrophages to become foam cells, leading to plaque formation
On the other hand, HDLs transport the cholesterol back to the liver through reverse cholesterol transport (RCT)
In the liver, cholesterol will be excreted through the biliary route
For the ease of transporting via RCT, cholesterol is usually converted to cholesteryl ester
While reduction of LDL in the blood has proven to lower CAD risk, scientists had been wondering if increasing HDL, for example by taking Niacin, a form of vitamin B3, will help prevent CAD
When proper studies are conducted, increasing HDL levels don’t really show an effect on CAD
when genotyping what do most CAD patients tend to have
at the single nucleotide polymorphism they tend to have a C instead of. A T
what are the genes associated with CAD
PCSK9
how does PCSK9 affect CAD
- increases plasma LDL-C levels by downregulating LDL receptor (LDLR) expression after transcription.- when the 9p21 region is deleted, only the expression of CDKN2a and CDKN2b genes are reduced. without the 9p21 region, the proliferation and senescence of aortic smooth muscle cells are increased, both characteristics of smooth muscle cells in CAD
what are the layers of the arterial wall
- blood
- endothelial cells
- intima
- internal elastic lamina
- media
- adventitia
(1) infiltration and uptake modification of LDL
- at the hotspots of bifurcation, turbulent flow can happen and cause local recirculation and increase of the local conc of plasma LDL.
- LDL transport into the arterial wall radially and can be retained by proteoglycans
- the disturbed blood flow also causes shear stress on the endothelial cells leading to the activation of the pro inflammatory transcriptional programs I the cells
- given the injury and pro inflammatory activation, endothelial cells losing the function as the barrier, causing more influx of cholesterol and lipoproteins go into the arterial intimata
(2) uptake modification
- the LDL particles are retained in the intima and can be modified
- it is considered as sterile inflammation without external pathogens and so called danger associated molecular pattern against external pathogens
(3) endothelial adhesion molecule expression
- the oxidesed LDL particles can induce endothelial cell surface expression of the leukocyte adhesion molecules.
- these adhesion molecules bind to the ligands expressed on leukocytes
- the combinational expression of endothelial adhesion molecules and their ligands such as integrins and selectins lead to inflammatory process
(4) leukocyte recruitment
- leukocytes that are recruited to the atherosclerotic lesion produce a number of inflammatory mediators
- they amplify the inflammatory reaction through continuous activation of both leukocytes and endothelial cells and by recruiting further immune cells
(5) monocyte to macrophage differentiation
monocytes are the most numerous white blood cells recruited into atherosclerotic sites
They differentiate into macrophages under the influence of monocyte-colony stimulation factor (M-CSF) present in lesions
Two types of macrophages activated:
Classically activated or M1 macrophages. They further enrich the proinflammatory milieu through inflammatory proteins and lipid mediators such as cytokines and leukotrienes, to sustain inflammatory responses causing tissue damage
Alternatively activated or M2 macrophages that secrete anti-inflammatory mediators promoting the resolution of inflammation by means of clearance of apoptotic cells and dampening of immune responses. Therefore this type of macrophage promote tissue repair and healing
what is the stimulation factor that turns monocytes into macrophages
M-CSF
(6) Event of oxLDL uptake and foam cell production
- now the atherosclerotic lesion is emerging with retained LDL and activated leukocytes
- the oxidised LDL particles can bind to scavenger receptors on macrophages
- the macrophage then uptake the lipoprotein particles and become foam cells
- these lipid laden macrophages is a characteristic of the atherosclerotic lesion
(7) antigen presentation
the immune system is cracking up a level from innate to adaptive immunity
The uptake of oxLDL by macrophages and dendritic cells will lead not only to foam cell formation, but also antigen presentation
Leukocyte adhesion molecules and chemotactic factors, produced as a consequence of innate immune activation, can recruit effector CD4+ T cells
The antigen presentation by macrophages and dendritic cells can then activate or differentiate CD4+ T cells into helper T cells and regulatory T cells
Th1 cells promote macrophage activation and inflammation whilst Treg cells act by inhibiting immune responses and inflammation, therefore are considered atheroprotective
Th17 cell subtype promises fibrosis through action of its cytokine IL-17. Th17 activity can therefore enhance the formation of the fibrous cap and plaque stability
(8) macrophages apoptosis and necrotic core formation
in the atherosclerotic lesion, several factors, such as oxidative stress, induce macrophage death through apoptosis
Apoptotic cells are normally cleared by specific phagocytosis process, efferocytosis derived from the Greek word ‘to bury’.
Efferocytosis is important for the normal steady state of tissue and the resolution of inflammation
However, clearance of lipid-laden apoptotic macrophages in the atherosclerotic lesion can be defective and create a lipid necrotic core
(9) tertiary lymphoid organs
In addition to the inflammation happening in the intima, complex adaptive immune responses also develop in the adventitia
Inflammatory cells observed in the adventitia, include dendritic cells, macrophages, mast cells and lymphocytes. T and B cell activation is present in the adventitia and in advanced stages of atherosclerosis, large lymphoid structures, referred to as adventitial tertiary lymphoid organs, may develop
These adventitial tertiary lymphoid organs are sites of antibody production, including antibodies to plasma lipoproteins
what do malfunctioning endothelial cells release
vasoactive hormones such as nitric oxide and prostacyclin
what is secreted from the endothelial cells in the media
platelet derived growth factor
what is in the fibrous cap
bundles of muscle cells, macrophages, foam cells, lymphocytes, collagen and elastin
what radioactive drug is used to label inflammatory activities
18F flurodeoxyglucose
what do statins target
the HMG-CoA reductase in the mevalonate pathway
what transcription factor gets released when intercellular cholesterol levels are low
SREPB-2
what does SREP-B regular;ate
LDL receptor and PCSK9
how does PCSK9 control the amount of LDL receptors
by degrading them
how does LDL receptors reduce the level of LDL in circulation
by uptake of circulatory LDLs
mechanism of LDL receptors and PCSK9
- LDL receptors are binding and internalising circulatory LDLs on the liver cell surface
- PCSK9 is secreted and then binds to the LDL receptor to mediate the lysosomal degradation of the complex formed by the PSCK9, LDL receptor and LDL
- if we can inhibit PCSK9 by using inhibitors, LDL receptors will not be degraded and can be recycled to uptake more circulatory LDLs
what is the resting membrane potential set by
inward rectifying potassium channels
how do Sino-atrial node cells beat spontaneously
- resting membrane potential is around -60 and is less negative than ventricle resting potential because these SA node cells have fewer inner rectifying potassium channels
- it is not stable and spontaneously decays towards the pacemaker potential
- when it reaches the threshold potential we get the generation of an action potential
what ion channels are responsible for the pacemaker potential
opening of ‘funny’ currents (Na+ influx) and Ca channels (T and L types)
closing of outward channels - K channels slowly close
how does SA node action potential vary to ventricular
slow to rise - slow Ca channels
what do cardiac muscle cells form
a syncytium - intercalated discs
gap junction formation
six subunits of connexin form an ion channel
how does excitation spread through the heart
- positive charge moces through the excitation channels and depolarises the second cell
- on the outside of the cell, the positive charge moves back and decease negative charge on the first cell
- now there is an action potential in the second cell
- depolarises the third cell and the opposite happens back to the second
- channels only go in one direction - refractory
the movement of current through the heart
SAN - left and right atria - AVN - bundle of HIS - left and right bundle branches - purkinje system - ventricular myocardium
conduction velocity of the AP of the atrial myocardium
1m/s
what is the depolarisation in the atrial myocardium from
Na rapid entry
why does the action potential arise before the threshold is reached in the AVN
the action potential is generated before the pacemaker potential reaches the threshold potential - this is because in the heart the pacemaker potential in the AV node is very slow. So this is a shallow slope compared to that on the SA node. So what’s happening, is in the SA node, an action potential has been generated and the action potential in the SA node reaches threshold, the action potentials generated travels through the atrial myocardium and reaches the AV node at this point before the pacemaker potential in the AV node itself reaches threshold. So this pacemaker potential has nothing to do with the action potential I the AV node, the action potential is triggered here because of the SA node has produced an action potential much faster than the AV node because of the pacemaker potential in the SA node decays faster. That action potential pass through the atrial myocardium, its hit the AV node and its produced this action potential and then the pacemaker potential in the AV node is still sub threshold. So therefore the pacemaker potential in the AV node Is actually irrelevant because the SA node produces action potentials much faster
how fast is conduction through the AV node
0.05m/s
why does the purkinje fibres have a long refraction period
to prevent the conduction system from being re excited to prevent against arrhythmias
how fast is the action potential in the purkinje fibres
4m/s
how fast is the AP in the ventricular myocytte
1m/s
depolarisation wave travelling toward a positive electrode
postive deflection
depolarisation wave travelling away from a positive electrode
negative deflection
repolarisation wave travelling toward a positive electrode
negative deflection
repolarisation wave travelling away from a positive electrode
positive deflection
what is the atrial repolarisation masked by in the ECG
QRS wave
why is the T wave a positive deflection even though it is repolarisation
- because there are two ways to flip it and repolarisation is passing in the opposite direction
how does SNS affect the heart
- increase HR
- increases AVN conduction speed
- decreases AP duration
how does PSNS affect the heart
- decreases HR
- decreases AVN conduction speed
SNS effect on SA node
noradrenaline - B receptors - increase of cAMP and increasing depolarising current e.g funny current and Ca current
what does AV node do to the AVN
activates beta receptors
PNS activation on the SA node
- ACh acts on the muscarinic receptors
- K+ channels open causing hyperpolarisation and a pacemaker potential of a reduced slop
where is atheroma
in the intima of large and medium sized arteries
what are the three stages of atheroma
- fatty streak
- simple plaque
- complicated plaque
nature of simple atheromatous plaque
- fat in the intima
- extracellular
- within modified smooth muscle cells
- fibrous cap
- blood vessel proliferation and inflammatory cells
complicated athermatous plaque
- calcification
- plaque disruption
- haemorrhage into plaque
- thrombosis
encrustation
platelets
insudation
lipid from blood
monoclonal
proliferation of smooth muscle cells
response to injury
endothelial damage
infection
with Ag-Ab complexes deposition
what is infarction
reduced delivery of blood to an organ sufficient to lead to its death
cardiac arrhythmia
- atrial fibrillation
- heart block
- ventricular fibrillation
angina pectoris
- chest pain
- induced by exercise and relieved bt rest
stable angina
- lowish risk of infarct
unstable angina
- pain at rest
- increasing severity of attack
- pain lasting over 15 mins
acute myocardial infarction
- regional or circumferential
most common cause of MI
- rupture of an atherosclerotic plaque in a coronary artery
- formation of intracoronary thrombus
- causing infarction downstream of the occluded blood vessel
how many people who survive an MI will develop heart failure in next 5 years
20%
MI to heart failure
- blockage of coronary artery
- ischaemia and MI
- necrosis
- inflammatory response to remove dead cells
- infarct healing and scar formation
- hypertrophy, dilation and reduced function
- heart failure
how many cardiomyocytes in adult heart
5 billion
how many cardionyocytes die in large MI
1 billion
what do cells dying by necrosis release to initiate an inflammatory response and as a diagnostic tool
troponin
inflammatory response
- neutrophils infiltrate the infarct
- secrete MMPs and phagocytose debris
- pro inflammatory cytosine levels rise
- leads to recruitment of other inflammatory cells
- pro-reparative phase
infarct healing and scar formation
- cardiac fibroblasts -> myofibroblasts
- main function: secrete new ECM proteins
- clearance of myofibroblasts by apoptosis
glucose metabolism
glucose is a major fuel for cells
Once in cells its metabolised
Metabolised by a series of enzymes called glycolysis
Metabolise glucose from six carbon glucose to three carbon units
The end point of this glycolytic metabolism of this series of glycolytic enzymes is a three carbon acid called pyruvate
Pyruvate and lactate are closely related chemical substances because they’re connected by an equilibrium reaction which is catalysed by an enzyme
what is anaerobic respiration
Anaerobic metabolism is when pyruvate is concerted into lactate and doesn’t require any oxygen
Better way of metabolising the pyruvate and that is the mitochondrial oxidative metabolism
Only problem is you can’t do this without oxygen
back up glucose
can also get glucose from inside cell stores called glycogen.
It’s a back up storage version of glucose
If hypoxic the pathway is limited
Another problem; if ischaemic, you lose the ability to dump waste products outside the cell, like lactate
If there’s a build up of lactate then that in turn prevents metabolism
what are the metabolic changes in first minutes of cardiac victim.
No 02 - no oxidative (mitochondrial) metabolism
Cell consumes ‘high energy phosphate’ back-up
Phosphocreatine (PCr) to help maintain ATP level
Anaerobic metabolism switches on to maintain ATP - produces lactate + hydrogen ions
Lactic acid accumulates in extracellular space and cytosol
Contractility is impaired by metabolic changes
anaerobic glycolysis equation.
glycogen + lactate + H+
what does first degree heart block reflect
- a problem in conduction through the AV node and the bundle of HIS
- slowing in conduction that leads to an increased temporal separation between depolarisation in and contraction of the ratio and the depolarisation and contraction in the ventricles
what is complete heart block
no conduction through the AV node and the bundle of HIS down into the ventricles
Effectively two separate rhythms being established, one by a pacemaker in the atria and the second by a pacemaker in the ventricles
Each of the atrial depolarisation is associated then with the P wave - normal in ECG
there is a regular QRS but the rhythm is very slow and its come about because some portion of the ventricles have now become the pacemaker region for the ventricles
Its an abnormal shape as the depolarisation has started off in an abnormal position and will therefore be spreading throughout the ventricles in an abnormal way and finally
There is no relationship between the P waves from the QRS complexes
ventricles will be contracting much more slowly
Get about 15 beats per minute and also because the ventricle is contracting abnormally, it won’t be acting as efficiently as it would normally so won’t be a normal cardiac output
what is the sinus arrhythmia
completely normal and associated with breathing
ventricular extrasystole
- beat that has originated from the ventricles outside of the normal systolic heart beat and rhythm
atrial fibrillation
multiple depolarisation happening across the atria
Creating a series of P like waves in the recording
Relatively small effect on the ventricular filling and therefore ventricular function
Can also produce stagnant areas of blood as atria doesn’t empty completely and can therefore be associated with blood clotting
ventricular fibrillation
if contracting in an uncoordinated way, you won’t have the rhythmic or the contraction of the muscle and so therefore the stroke that the heart chambers will be contracting unevenly, generating uneven pressure unable to produce the normal cardiac output
what does myocardial ischaemia look like on an ECG
ST segment elevation/delressuin
- specifically interfere with ion channels mediating repolarisation of the ventricles
what are main components in plaque
foam cells
what is the role of the Lecithin Cholesterol Acyl Transferase enzyme
Esterifies free cholesterol in LDLs and HDLs
What is the type of angina caused by vasospasms
Prinzmetal
variant
What is not a role of NO (nitrous oxide)
Increases vascular permeability
Which of the following causes a side effect of coughing
Ramipril
CoA inhibitor
Atorvastatin
Which cholesterol transporter is the body’s main source of energy during prolonged
fasting
?
VLDL’s
Smoking one cigarette per day puts you at a ____ higher chance of developing
coronary heart disease
30%
What is Prinzmetal’s (variant) angina characterised by
Angina that occurs without provocation
What causes ST elevation in myocardial infarctions
Opening of K
+
channels
the main mechanism by which Nitric Oxide relieves an attack of angina
Dilating peripheral capacitance vessels
What is the fibrous cap of an atheroma mostly made up of
Smooth muscle cells and collagen
how does nitric oxide cause vasodilation
relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic-guanosine 3’,5’-monophosphate, which then leads to vasodilation.
first degree heart block on an ECG
complete heart block on an ECG
sinus arythmie on ECG
ventricular extrasystole on an ECG
atrial fibrillation on an ECG
ventricular fibrillation on an ECG
myocardial ischeamia and the ECG
ECG limb leads and what plane of the heart do they look at
each lead gives out two readings.
lead direction on limb leads diagram
12 lead ECG and where leads are placed diagram
