Download Cardiac Electrophysiology

Cardiac Electrophysiology
CMCs – atrial and ventricular
There is a tight association between the CMC transmembrane potential and the isometric
tension of cardiac muscle cell (CMC) contraction – both are initiated almost
simultaneously and last for roughly 250ms. This is enabled by an effective refractory
period (ERP) of 200ms which prevents the initiation of an AP before the decay of the
preceding one as well as the relative refractory period (RRP) which lasts 50ms and only
allows AP generation by a higher than normal stimulus (fig. 1). This way, tetanus cannot
be achieved in cardiac muscle, thereby, enabling the heart to relax during diastole and fill
up with blood. The cardiac AP comprises 4 distinct phases, each characterized by a
change in transmembrane voltage attributed to the activation of different ion channels (fig.
2).
Action potential
 250 ms, almost the same duration as myocardial muscle contraction to
prevent tetanus and to allow relaxation during diastole
 Effective refractory period the duration of which is 200 ms prevents
another AP being generated by another stimulus.
 Relative refractory period lasts 50ms following the end of the ERF during
which a bigger than normal stimulus can generate another AP.
 Maximum diastolic potential, the most negative transmembrane potential
during the refractory period, is -50 mV
 Resting membrane potential is -80 to -90 mV (due to impermeability of
negatively charged phosphates and amino acids in the cytosol) and
depolarisation reaches its peak at 20 mV.
 In skeletal muscle the AP is 5 ms long with a 10 ms ERP and RRP
while contraction duration is similar to the cardiac AP. This allows for
titanic stimulation
Phases and currents
 Phase 4 – resting membrane potential achieved by 3 background currents:
the inward rectifying K current (IK1) which leaks K out of the cell down
concentration gradient; the Na current (Ib) which takes Na into the cell
down an electrochemical gradient and the NaK pump which allows 2K
ions into the cell for an exchange of 3Na ions. These currents ensure a
resting potential above EK.
 Phase 0 – rapid depolarization when -60mV threshold reached, mediated
by the opening of Na channels and Na influx down the concentration
gradient. Na channels and ICa inactivate.
 Phase 1 – Initial (partial) repolarisation phase maintained by IK1.
 Phase 2 – initial plateau maintained by L-type Ca channels that allow a
small inward Ca current to oppose IK1. The late plateau phase is
maintained by the forward mode NCX electrogenic pump that allows 3Na
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ions into the cell for every Ca ion. This current is increased by high
sarcoplasmic Ca levels. The permeability of K channels decreases.
Phase 3 – rapid repolarisation. Ca currents cease and the delayed rectifier
(IK), also known as HERG, is slowly activated, expelling K ions out of the
cell and restoring the resting membrane potential. IK1 is also activated. It
is due to the HERG channel that the AP is long so as to prevent the
tendency to generate dysrhythmias.
Nodal cells – SAN, AVN and His bundle
Action potential
 Spontaneous
 Less negative resting potential (-60 mV) and less positive depolarisation
peak
 No inward rectification or Na channels
 Unlike CMCs nodal cells do not contribute to the ECG.
Phases and currents
 Phase 4 – pacemaker potential that contributes to automaticity of the cell:
slow depolarisation by influx of Na by non-selective If current.
 Phase 0 – rapid depolarisation by highly selective ICa which allows Ca
into the cell, driving membrane potential towards ECa.
 Phase 3 – Ca channels close and HERG opens causing efflux of K and
repolarising the cell back to – 60 mV which triggers the If channel,
repeating the cycle.
The AVN has some pacemaker activity as a potential compensatory mechanism in
case of SAN malfunction
EC coupling
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Nodal cells spindle shaped and mononucleate, with a low conduction velocity
across nexus ( 5 – 10 cm/s)
Purkinje cells binucleate with a 100 – 150 cm/s conduction velocity across
intercalated disc. They connect to endocardial CMCs and conduct impulses to
them.
CMCs are binucleate with a conduction velocity of 50 cm/s across intercalated
discs.
Only CMCs are packed with contractile proteins and mitochondria
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A nexus is an electrical link whereas zona adherans (CMCs and Purkinje cells) is
a mechanical link
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Orientation of CMCs changes throughout myocardial wall to ensure multidirectional impulse signal
Channels and contraction
 Physical coupling to DHP (L-type Ca channels) on t-tubule sarcolemma
opens them, causing an influx of Ca into the cell, activating RyR channels
on SR membrane to release Ca into the cytosol.
 Backward mode NCX pump transports a Ca ion in for 3 Na ions out due to
positive membrane potential.
 Ca in the cytosol binds to troponin C on the thin filament leading to cross
bridging and contraction.
 Ca is removed from the sarcomere into the mitochondrion via the Ca
uniporter, into the SR via SERCA (phospholamban) and out of the cell via
the sarcolemmal Ca ATPase pump and forward mode NCX.
 An increased frequency in stimulation causes an accumulation of Ca in the
cell due to the slow efflux via NCX and Ca ATPase, thus causing a
positive ionotropic effect.
Heart Anatomy
RA
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Right auricle allows RA to distend upon increased VR (in left atrium
auricle smaller)
Pectinate muscles in auricle prevent blood from accumulating and clotting
Fossa ovalis – a congenital septal hole that forms a membrane around after
birth
Ostium of coronary sinus drains blood from myocardium to the RA
Eustachian valve of IVC forces blood to middle of RA so as not to
accumulate below
Valves
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Tricuspid valve has 3 leaflets: anterior posterior and septal
Papillary muscles and chordae tendinae only in atrioventricular valves
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Semilunar valves have flaps around which blood flows, creating pressure
and forcing the flaps to shut to prevent backflow into atria.
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Infundibulum – outlet leadint to PA
Septomarginal trabeculations – septal and moderator bands that form the
nerve bundle. Moderator band conveys bundle branch to anterior papillary
to facilitate conduction time.
Trabeculae carnae – like pectinate muscles only in RV
RV
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Coronary arteries and Anastomoses
 Right dominance most common – PDA supplied by right coronary -> PDA
blocked
 Left dominance more severe as supplies LAD and PDA -> both blocked
and both usually supply anastomoses in the septum (septal perforators)
 Co-dominance most rare: PDA comes off whichever CA is dominant
Cardiac cycle
Starling’s law = ^ VR -> ^ Force Contraction -> ^SV
 ^ VR causes ^ VV which instantaneously causes ^ force contraction due to
myocardial stretch.
 10 -15 min contraction shows positive staircase where a slow increase in
CMC Ca levels causes increased and transient force of contraction.
 Increasing VP increases VR which increases VV and distends ventricles,
increasing contraction and SV as blood is pushed out due to decrease in
distension.
 SV increase shows Anrep effect – it progressively increases within 10-15
min due to a slow increase in force of contraction that pushes more blood
out (positive staircase)
 Starling’s proof in isolated dog heart experiment: increasing CVP
increased SV by 64% and decreasing ventricular distension had no effect
on SV meaning an increase in contractility played a role in increasing SV.
Cycle
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Cycle lasts 0.8 s of which, normally, 2/3 is diastole and 1/3 is systole.
Normal vitals: HR = 70bpm, BP =120/80, CO = 5 l/min, SV = 70 ml/min
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Heart muscles are relaxed as heart fills up with blood. AV valves are open.
Low pressure in heart but higher in atria so as to direct flow downwards
into ventricles
Diastole
Atrial systole
 Ventricles filled with blood
Ventricular systole
 Increase in ventricular volume causes distension and an increase in
pressure, causing AV valves to shut as ventricular pressure now exceeds
atrial.
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Isovolumetric contraction where volume in ventricles remains the same
due to both AV and semilunar valves being shut, but an increase in
pressure due to myocardial contraction. Semilunar valves are forced open
and blood is ejected into pulmonary arteries/aorta.
As ventricles empty, pressure in them is lower than beyond the semilunar
valvues causing them to shut (dicrotic notch).
Isovolumetric relaxation when end systolic volume in ventricles stays the
same while pressure decreases below atrial. This causes AV valves to open.
End systolic volume retained after each beat and end diastolic volume
retained before each beat.
PV loop
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Increased during exercise where VR is greater, increasing EDV, so force
of contraction is greater and SV is greater. Sympathetic output to heart
increases contractility but VV falls so loop increases but shifts to the left.
Decreased during hemorrhage when increased HR causes an increase in
circuitry, narrowing loop and a decrease in VR causes it to shift to the left.
Anoxia causes heart to dilate, shifting loop to right, and making it smaller
due to decreased contractility that exerts less pressure. The reason for this
is increased pH due to lactic acid produced from anaerobic respiration of
CMCs.
A loop shifted too much to the right means Starling’s law does not
apply and heart fails – dangerous for weak hearts.
ECG
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P wave: depolarization of atrial CMCs. PR interval (120-200ms)
represents time taken for SAN to activate AVN
QRS complex (80-120ms): depolarization of ventricular CMCs. ST
interval (80-120ms) interval represents isoelectric potential of depolarized
ventricular CMCs.
T wave (160ms): ERP/RRP of ventricular CMC repolarization. QT
interval (~250ms) is when there is risk of arrhythmias.
Defects and dysrhythmias
VSDs
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In isolated VSDs, where the perimembranous ventricular septum thins and
is disrupted by turbulent flow, blood is shunted from left to right as the
LV generates more power. VSDs of the muscular septum are rarer as that
part of the interventricular septum is the thickest.
Tetralogy of Fallot
 Initial left to right shunt but due to rapid RV hypertrophy the shunt
changes to right to left.
 Pulmonary stenosis
 Aorta overriding septum allowing deoxygenated RV blood to enter it
 As a result deoxygenated blood enters the systemic circulation during each
beat and in severe cases metabolic O2 demand is not met.
Dysrhythmias
 Classified by: Brady/tachy; ventricular/supraventricular/ transient/sustained;
altered impulse formation/conduction
 Benign e.g sinus arrhythmia (positive chronotropic effect on inspiration);
pathological e.g atrial fibrillation (risk of stroke, syncope, symptoms) and lifethreatening e.g ventricular fibrillation where defibrillation required to save life.
 Normal inward septal excitation followed by endocardial to epicardial excitation;
abnormal ectopic excitation disrupts pattern causing slow and ineffective
myocardial activation (shown by QRS complex of more than 140ms)
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Junctional ectopic tachycardia: impulse originates in AVN/His bundle
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Torsade de pointes: intermittent ventricular tachycardia
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AV nodal re-entrant tachycardia and SAN re-entrant tachycardia where SAN
is re-excited (in Wolf Parkinson White syndrome due to retrograde conduction
by fibrous flap)
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Long QT/Brugada syndrome: QT interval more than 250ms
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Atrial flutter/fibrillation and ventricular fibrillation
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AVN block
Causes
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Congenital structural e.g WPWS
Congenital channelopathies (due to polymorphisms in genes encoding
channels causing variation in Ca concentrations and AP amplitudes
Ischaemia e.g due to myocardial infarction
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Myocarditis causing poor beating
Enlarged hearts e.g in athelets
Electrolyte imbalance
Antiarrhythmic drug side effects
Self-perpetuating e.g atrial fibrillation causes more atrial fibrillation
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Catheter ablation (surgery)
Defibrillation
Antiarrhythmic drugs
Pacemaker implantation
Treatment
SAN automaticity
 Increased by ischaemia and sympathetic outflow (either during emotional
stress or exercise) -> beta receptors -> ^ pacemaker potential
 Decreased by vagal outflow -> M receptors -> decrease pacemaker
potential or cause escape rhythm where pacemaker shifted to another atrial
site due to SAN suppression.
Bundle of Kent
 An AV bypass tract conducts impulses directly from atrium to ventricles,
represented by delta wave which shortens the PR interval and shows early
ventricular excitation – WPWS