Cardiac Electrophysiology

JoePatlak

MedicalPhysiology 301

Cardiac Electrophysiology and

Electrocardiogram Interpretation

Cardiovasculardiseaseistheleadingkillerofall
Americans, accountingformorethan50%ofall
annual deaths. Thenormalfunctionofthisremarkable
organdepends onit's electricalactivity,andthe
influence ofthoseelectricaleventsoneachofitscells.
Whendiseased,itisoftendisturbancesinthat
electrical activity that leadstosuddendeath.
Inthesesectionswewillexaminethebasicelectrical
behavioroftheheart.

Cellular Excitation

Cell-to-cellelectrical transmission
Becauseionsmove freely from celltocell,electrical
activity incardiaccellsistransmittedtotheirneighbors.
Cardiacmuscleissaidtoactelectricallyasa
syncytium.

Consequences:

!
!
!
!

Excitationproceeds from cell to cell.

Cannotnormallyexcitejustonecell,ora
portionoftheheart.
Cannotadjustcontractionbasedonthenumber
ofcells.

Theheart is an excitabletissuebecause
itscellseach,individually,generateand
communicatethiselectrical activity. Each
myocyteintheheartiscapable ofsupporting
itsbasicpatternofelectricalbehavior. I n a
latersectionweexamine howthatbasic
cellularresponseis generated.
Further,theheartconsists ofspecialized
regions. Theelectricalactivityof theheartis
pacedbysomeoftheseregions,
communicatedbyothers,andmodifiedto
matchtheneedsofeachworkingregion. We
will thus also examine thechangeablenature
oftheheart'selectricalactivity.

Whenoneportionoftheheartisdamaged,the
wholeheartcanbeaffected.
Page 1

Cardiac Electrophysiology

JoePatlak

MedicalPhysiology 301

Cellular Structure of Cardiac Muscle

Cardiacmusclecomposedofahighlybranchednetworkof
small (approx.12X100micron)cells.

Cellmembrane and transverse tubules

Eachcellissurroundedbyathinmembrane--thesarcolemma.
Invaginationsofthesarcolemmaformtubules intotheinterior
ofthecell.ThesetransversetubulesoccurattheZlinesin
ventricularmuscle.

Contractile filaments
Striatedappearancecausedbyoverlappingarrayof
thick (myosin) and thin(actin) filaments
(myofilaments) asinskeletalmuscle.Sarcomeresare
basiccontractileunits;structureandterminology(A
band,Iband,Zline,Hzone)sameasinskeletal
muscle.

Intercalateddiscs

Myofibrils

Finger-likeprojectionsofadjacentcells"lock"
cellstogether atintercalateddiscs.Membranesof
two cellsarecloselyapposedhere. The
specialized regioncalledagapjunction,ornexus,
allowsionstomovefreelyfromcelltocell,
accountingforthelowcell-to-cellresistance.

Thecross-sectionof thecellismadeupofbundlesof
aboveproteinfilaments; thebundlesarereferredtoas
myofibrils.

Internal membrane system

TheSarcoplasmicReticulum,orSR,isspecialized
endoplasmicreticulumthatforms a membraneboundedintracellularcompartment.TheSRis a system
ofclosedtubulesandsacs.AtubularnetworkofSR
surroundsmyofibrils;enlargedsacs canbefound
wheretheSRcomesclosetothesurfacemembrane
(wheretheyarecalledsubsarcolemmal cisternae)or
wheretheSRapproachestransversetubules(theseare
calledterminal cisternaeor lateral sacs).

Page 2

Cardiac Electrophysiology

Basic Activation Sequence:

SA Node
Atria
AV Node

JoePatlak

Bundle o f His

MedicalPhysiology 301

Purkinje System

Ventricles

Sinoatrial (SA) node

The sinoatrialnode,orSAnode , is located atthejunction
ofthesuperiorvena cavaandtherightatrium.TheSA
nodeservesasthenormalpacemakeroftheheart,
initiatingeachnewwaveofexcitation.

Atrial muscle
Activityisconductedthroughatrialmuscletoexciteright
andleftatria.Therearepreferentialconductionpathways-anterior, middle,andposteriorinternodal tracts that
conduct activity rapidly fromtheSAtotheAVnode(see
below). Bachmann's bundle conductsactivityfromthe
righttotheleftatrium.

Atrioventricular (AV) node

TheAV nodeis located atthebaseoftheinteratrial
septum,neartheopeningofthecoronarysinus.Itconducts
electrical activity from theatriatothebundleofHis(see
below). Electrical conduction in t h e AV nodeisveryslow
(approx.0.05mm/ms); this ensures a delaybetween
activationoftheatriaandactivationoftheventricles.

Ventricular conducting system

Components, gross organization

Theventricularconductingsystem includesthe Bundle
ofHis(alsocalledtheAVbundle,the Hisbundle,or the
commonbundle),bundlebranches,andPurkinje
system .TheAVnodemergeswiththeBundleofHis,
whichisthefirstpartofasystemthatconducts
electrical activity intotheventricles.TheBundleofHis
enterstheinterventricularseptum,whereit subdivides
intothe left andrightbundle branches,whichactivate
the left and rightventricles. Inbothventricles,the
ventricularconductingsystem branches extensivelyto
becomethe Purkinjefibers. Thesecellsaretheonly
onesofthissystemthatactuallymake electricalcontact
withventricular cells.

Structure
Cellsoftheventricularconductingsystem arelarge,and
specialized for rapidconduction. Thesecolumnsof
electrically excitablecells(shownattheright)are
surroundedbythicksheathsofconnectivetissuewhich
insulatesthe excitablecells from the surrounding
ventricularmuscle.

Sequence of ventricular
activation
Asthewaveofelectricalexcitationleavesthe
Purkinjefibers,it spreads to the ventricular
muscleinmanyplacessimultaneouslysothat
the ventriclescanbestimulatedasquicklyas
possible. Nevertheless,thereisastandard
sequencebywhichtheexcitationpasses
throughtheventricles. First, theventricular
septumisstimulated. Next, theapexofthe
heart,andthenexcitationspreads upwards
towards thebase. Ingeneral,the ventricles
are stimulatedontheirendocardialsurface,
andtheexcitationspreads throughthewallto
the epicardium. Remember: Apexbefore
Base,EndocardiumtoEpicardium.

Page 3

Cardiac Electrophysiology

JoePatlak

MedicalPhysiology 301

Cardiac Action Potentials, Fast and Slow

Ventricular Muscle
RestingPotential:
Therestingmembranepotential of
ventricularmuscleis-80mVto-90mV,
associatedwithahighKconductance. In
healthyventricularmuscle,theresting
potentialis stableanddoesnotchange
untilthemuscleisgivenanadequate
stimulus.

CardiacActionPotentials
Slow Phase0: SANode,AVNode
Fast Phase0: Atria,ConductingSystem,Ventricles
RestingPotentials
DiastolicDepolarization: SANode,AVNode,BundleofHis
StableRestingPotential: Atria,PurkinjeFibers,Ventricles

FastActionPotentials:
Theactionpotentialofventricular muscle
is quitedifferentfrom that ofanerveor
skeletal muscle. Whileitdoeshavea
rapidupstrokeandovershoot,likeina
nerve,therepolarizationis muchmore
prolonged(hundredsofms),withan
extendedplateauatabout0mV.

Overall,ventricularpotentialscanbedescribedbyfivephases,0-4.
Phase0: Aninitialrapiddepolarizationoccursshortlyafteranadequatestimulus.Themembranevoltage
actuallychangessignwithin1-2ms;attheendofthisinitialdepolarizationthemembranevoltageis
approximately +30 m V. This initial rapiddepolarizationisreferredtoasphase0,andiscausedbyarapid
increaseinNa conductanceof themembrane.
Phase1: Aninitialrepolarizationnext occursthatpartiallyrepolarizesthecellmembranetoa voltagenear
zero.This portionoftheactionpotentialiscalledphase1. Phase1iscausedbytheinactivationofNachannels,
andthetransientopeningof Kchannels.
Phase2: Afterphase 1,repolarizationslowsdramaticallytoformtheplateauorphase2ofthecardiacaction
potential.Duringtheplateau,thecellsrepolarizegraduallyfor100-200ms. The plateau isprimarilydominated
byCaconductance. Thisistheperiodwhentheventriclescontract.
Phase3: Astheactionpotentialcontinues,repolarizationacceleratestobringabout finalrepolarization,or
phase3.Phase3bringsthemembranepotentialbacktotherestingpotential. Phase3iscausedprimarilyby
increased K conductanceofthemembrane
Phase4: Theintervalbetweenactionpotentials,whenthemembranepotentialofaventricularcellisatthe
restingpotential,isoftencalleddiastoleorphase4.(Thevoltageisstableduringdiastoleinventricularand
atrial cells; inothercardiaccellsgradualdepolarizationmayoccurduringdiastole.) During p h a s e 4 t h e K
conductanceofthemembraneishigh.
Page 4

Cardiac Electrophysiology

JoePatlak

MedicalPhysiology 301

S A a n d A V NodePotentials:
ActionPotential: Theactionpotential oftheSA
Node(andtheAVnode)hasaverydifferentform
fromthatofventricular muscle. Phase0isslower,
the peakpotential isnotasgreat,andthereisno
markedplateau. Repolarization(Phase3)gradually
occursfrom peakbacktorest.
RestingPotential: Unlikeventricularmuscle,the
restingpotential ofnodaltissuesisnotstable. The
potentialis most negativeimmediatelyfollowingan
actionpotential,butgraduallydepolarizesuntilthe
thresholdforanewactionpotentialis reached. This
diastolicdepolarizationis duetotheactionof
cation channels(calledI,mainlyNapermeable)
f
duringPhase4andagradualdecreaseintheK
conductance.

Ventricular Muscle

AV Node

SA Node

Refractory Periods
Duringtheactionpotentialofcardiactissues,an
additionalstimuluswillbeincapable ofinitiatinga
new actionpotential. Thisiscalledinheartthe
EffectiveRefractoryPeriod or ERP. This
periodis followedbyabrieftimewhereanother
largestimuluscangenerateanewactionpotential-the RelativeRefractoryPeriod orRRP.
Inventricular muscle, theERPisduetothe
inactivationofNa channels. Itlasts untilthe end
ofPhase3.
Innodaltissues,theERPisduetotheinactivation
ofCachannels. Notethattheirslowrecovery
causestheERPandRRPofthenodestolastlonger
thantheactionpotentialitself.

Conduction Velocity
Measuresthedistance thatthespreadingexcitationcoversinagivenamountoftime.Itis
primarilydeterminedby:

!
!
!

Cell diameter:Thetissue'sinternalresistanceisinverselyproportional todiameter.

dV/dtofupstroke :Fastupstrokedepolarizes adjacentcellstothresholdquickly.Fast actionpotentials
will beconductedfasterthanslowactionpotentials.
Amplitudeofthe upstroke:Largeamplitudeactionpotentials(e.g.ventrical muscle) producelarge
voltagedifferencebetweenactiveandadjacent resting cells.

Conduction velocitychanges inthedifferentpartsoftheheart.

!
!
!

ConductingSystem(BundlesandPurkinjeFibers) : Largecells,fastupstrokes,largeovershoots cause

veryrapidconductionof2-5mm/ms.
Atrial and ventricularmuscle: Intermediateconductionvelocityofabout 1 mm/ms.
AV node: Very small cells, slowupstrokes,smallovershoots.Conductionvelocityisroughly0.05mm/ms.
Page5

The EKG and its relation to the heart's excitation

Theelectrocardiogram(EKGor
ECG)isarecordingofthehearts
electrical activity asseenfromthe
surfaceof thebody.Whencurrents
spreadthroughtheheartasthe
tissuedepolarizesor repolarizes,
small voltagescanbepickedupon
the skin. Theseprovideacritical,
non-invasivewaytoviewthe
healthoftheheartselectrical
conduction system.
Thissectionprovidesbasic
information aboutwhat you see
in anEKG. A secondhandout
detailsrhythmdisturbancesyou
areresponsibleforrecognising.

EKG Electrodes andtheirelectrical o r ientation

aroundthe heart:

EKG SignalAmplitude
Proportionalto:

AnEKGcanbemeasuredwithasfewastwoleads, i.e.wires
withelectricalcontacttotheskin. However,byconvention,
recordingpointsareestablishedatthearmsandoneleg. When
combinedinvariousways,sixelectricalviewsoftheheartcanbe
obtainedthatprovideaverticalcrosssectionoftheexcitation
pattern. Inaddition,recordings areoftenmadefromelectrodes
positionedhorizontallyaroundtheheart,providingahorizontal
crosssectionof theheart'sexcitation.All 12viewsare
commonlypresentedtogetherinaprintedEKG.

+ Amount oftissue
changing potential
+ Directionofpropagation
compared to the
electrode orientation.
+ Size of potential change
+ Speed of propagation

aVR

aVL

I
V6

V5
V1
III

II

V2 V3

V4

aVF
Page6

Cardiac Electrophysiology

JoePatlak

MedicalPhysiology 301

Relationshipbetween:
ActionPotentials and theEKG
ActionPotentials and contraction.
Normal and abnormalvalues for
heartrate
AtrialContraction

Ventricular Contraction
(Systole)

Normal SinusRhythm
Sinus Bradycardia
SinusTachycardia

BPM
60-100
<60
>100

Phases of the EKG

correspond to cardiac
excitation.
P wave
Spreadofexcitationthroughatria.

P-R interval
AtriaContract
ExcitationwithinAV node

QRS Complex
Spreadofexcitationthrough
ventricles

Q-T interval
VentriclesContract
APphase2

T wave
VentriclesRepolarize
Page 7

Cardiac Electrophysiology

JoePatlak

MedicalPhysiology 301

Measuring intervalsand rates in EKG strips:

TheEKGisusuallytracedontographpaperataconstantrate. ForstandardEKGtracings,the
following apply:

One largebox=0.2second,eachsmallbox = 0.04 seconds.

Thelarge and smallboxes canbeusedtomeasureintervalsbetweensegmentsoftheEKG.

Normal intervals include:

+ PRinterval :0.12-0.20sec(3-4smallboxes)
+ QRS interval: 0.08-0.12 sec(2-3smallboxes)
+ QT interval: 0.30-0.46 sec(normalrange,varieswithheartrate)

Measuring the Heart Rate

Theheart rate(inbeatsperminute,BPM)canbe
determinedquicklybydividing300bythenumber
oflargeboxesbetweensuccessiveR-wavepeaks

Number
of large
boxes
1
2
3
4
5
6

Heart
Rate
300
150
100
75
60
50

150

100

75

60
Page 8

Cardiac Electrophysiology

JoePatlak

MedicalPhysiology 301

Ionic Basis for the Cardiac Action Potential

Theactionpotentialsinatrialandventriculartissues
are caused, asinnerve,bythemovementsofseveral
different ionsthroughspeciallyadaptedchannelsin
the membrane.
Inheart,aricherarrayofionsandchanneltypesis
involved ingeneratingthe complex signalsneededto
signalandcontrol thecardiaccontraction.
Manyofthedrugsthatmodifycardiacelectrical
behaviorare targeted to act onthesechannels. We
are alsobecomingaware ofanumberofchannel
mutationsthatleadtodisruptionofnormalcardiac
electrical stimulation.
Inthissectionwestudytheionsandchannels
involved.

REMEMBER:
TochangeVm, a net current must flow.
If Vm ischanging, then a currentis
flowing.

Exampleofcurrentsandgenesresponsiblefor the
ventricularactionpotential. FromNature,V.415,P
215. (simplifieddiagramonnextpage).

Inward Current ==Depolarization

Outward Current=Hyperpolarization
Page 9

Cardiac Electrophysiology

JoePatlak

MedicalPhysiology 301

Ion currents depend on membrane potential

Whenionchannels areopen,specificcurrents will
flowthroughthem. Thedirectionandmagnitudeof
thiscurrentdependsonthedrivingforceforionic
movement.,andonhowmanychannels areopen.

I
Outward
Currents

Drivingforcedependsonthedifferencebetweenthe
membrane potential and theequilibrium (Nernst)
potentialfor that ion.

EK

If themembranepotential ismorepositivethanthe
equilibrium potential,thencations like Na a n d K
will flowoutofthecell. Ifitismorenegative,they
will flowin.

Inward
Currents

E Na

VM

Noteatrightthatduringtheentirecardiacaction
potential(superimposed),Kcurrents areoutward,
while Nacurrentsareinward.

Ion currents during the ventricular action potential

E Na
1

VM
EK

IK1
ITO
IK
INa
ICa

Duringtheactionpotential,
depolarizationiscausedbyinward
currents,andrepolarizationdue to
outwardcurrents.

2
3
4

Time

}
}

ThefastNacurrentgives thepowerful
initialdepolarizationinphase0,while
the slowercurrentsthroughtheL-typeCa
channel maintain that depolarization
throughtheplateau.

Outward
Currents

Severaldifferent K currentsmediate
different phasesof repolarization: A fast
transientcurrentcontributestophase1,
andtwoslowercurrents(IK-randIK-s,
calledheresimplyIK)helpendthe
plateau. Finally,theinwardrectifyingK
current,IK1,ishighduringphase4,and
low during theactionpotential.

Inward
Currents

Page 10

Cardiac Electrophysiology

JoePatlak

MedicalPhysiology 301

Thefollowing table summarizes theioniccurrents thatplay an importantrole i n

thecardiac action potential. Each currentcorresponds to a different channel type,
withthe gating andpermeability properties as shown:

Page 11

Cardiac Electrophysiology

JoePatlak

MedicalPhysiology 301

Long QT Syndrome
Whenphase2oftheactionpotentialisprolonged,thenthereisanincreaseddelaybetween
depolarizationandrepolarizationof theventricles,i.e.alongQTsegment. If NaorCacurrents
are increased (or dontinactivateat theirnormalrates),oriftheKcurrentsdontturnon
sufficiently, thentheventricularcellswillstaylongerattheirplateau.
Thisconditioncanbeacquiredviadrugtoxicityor electrolyteimbalance. However, it isnow
recognizedthatfamilialsusceptibility tothisdiseaseisnotrare. Approximatelyoneinevery
5000personsmayhavevariationsinchannelstructurethatgiverise to thiscondition,andit
appearstocause3000to4000suddendeathsinchildrenandyoungadultseachyear.
Thereareanumberofdifferent formsof familialdominant disease, causedbymutations in
cardiacionchannels:
! LQT-1 -->IK-s
! LQT-2 -->IK-r
! LQT-3 -->INa
Thechart below illustrateshow a familial patternofdisease wasdiscoveredfollowingsudden
deathofachild.
(ClinicianReviews,V.13#1,P.40).

QT>0.46s

Page 12

Cardiac Electrophysiology

If

JoePatlak

MedicalPhysiology 301

ICa
Gs

Gi

Stimulates
Stimulates

Pacemakecurrents and Autonomic

Control of the Heart:
Severaltissues intheheartnormallyhave anunstableresting
potential(diastolic depolarization)duringphase 4. Thisis
dueprimarilytothepresence ofthePacemaker current, If,
whichisactivateduponhyperpolarizationfollowingphase3
oftheactionpotential.
Stimulation o f t h e Beta-1receptors causescyclic-AMP
production,whichleadstothestimulationofIf and the
inhibition o f Ik. Diastolicdepolarizationbecomessteeper,
andtheheartreachesitsnextthresholdmorequickly. The
heartrateincreases.
Conversely, stimulationofthe muscarinicreceptors
increasesI,whichslowsdepolarizationbyopposingI.
The
k
f
heartslows.
Sympatheticsinnervateall portionsof theheart.They
increaseautomaticityandstrengthofcontractionthroughout
the heart.
Parasympatheticsinnervateabovetheventricles(SAnode,
atria, a n d AVnode). Theyslowautomaticityinallthese
tissues.
SA Node, rate > 60

AtrialFoci,rate60-80
AV Junction, Rate 4 0 - 6 0
Ventricular Foci, rate 20-40

AfterParasympathetic

Time

After Sympathetic

Time

OverdriveSuppression
Eachactionpotentialresetsthediastolic
depolarizationtoitsmosthyperpolarized
level. TheSAnodeisusuallythefastest
pacemakerintheheart,soalltheslower
pacemakers are resetbythenode eachbeat .
Thesesecondarypacemakers thereforedont
normallycontributeextrabeats.
If theSAnodestopspacing(orslows
dramatically),thenasecondarypacemaker
cantakeovergeneratingregularheartbeats.
Theatriaareoftenthenexttobeat. If they
slow, t h e AV junction can t a k e o v e r a t a
lowerrate(40-60bpm),oreventhe
ventricles(20-40bpm).

Page13

Cardiac Electrophysiology

JoePatlak

MedicalPhysiology 301

Reentrant Rhythms
Theactionpotentialconductionthroughthe
ventricalsisfastenoughsothatallpartsofthe
heartare normallystimulatedandintheir
refractoryperiodsatthesametime. ThelongERP
oftheAVnodealsopreventstheventricularaction
potentialfromreexcitingtheatria.

However,whenventricularorconductingtissueisdiseasedordamaged,itsconductingvelocityslowsdown
anditsrefractoryperiodlengthens.
Forexample,this couldmeanthatasegmentofPurkinjetissueisnotreadytoconductthenormalaction
potentialwhenitarrives. However,thatactionpotentialcanlaterspreadbackintothisdamagedtissuefrom
the ventricle side. Ifthisreversepropagationisslow,thenthe"backwards"signalcanarrivebackincontact
withhealthytissue AFTER thathealthytissuehasrecoveredfromitsrefractoryperiod.
Inthiscase,thisregionoftheheartrepeatedlystimulatesitself(andtherestoftheheartaswell). This is
called a reentrantrhythm,whichresultsinperiodicactivitygeneratedoutside thenormalpacemaker system
(an"EctopicFocus"). Such an area,whenstimulatingat a high r a t e c a n l e a d t o "VentricularTachycardia"
or"Atrial Flutter". Ifseveral(ormany)suchregionsbegintotakeoverstimulationontheirown,the
cardiacelectrical behavior becomeschaotic. Thisiscalled"fibrillation",whichcanoccurineithertheatria
ortheventricles.

ReentrantRhythminAtrial Flutter
Theestablishment ofacircularpattern
ofactivitywithintherightatriumis
shown. Conductionvelocityisslow
enoughheretopermitpartsofthe
atriatorepolarizewhileothersare
stillactive. Theactivationproceeds
in a circle(inthiscasearoundthe
rightatrium).
Duringsomecycles,theAVnodeis
repolarizedandreadytoconduct. The
ventriclesarethusstimulatedviatheir
normalpathway(narrowcomplex).
However, the AVnode stays
refractory for severalcycles.
PWaves

[Illustrationsfrom
www.blaufuss.org]

TheEKGshowsregular,fastPwaves
superimposedonamuchslowerQRSTpattern.

Page 14
AV Noderefractoryperiods

Cardiac Electrophysiology

JoePatlak

MedicalPhysiology 301

Excitation-contraction coupling
inventricular muscle.
Excitation-contraction coupling is theprocess
wherebythesurfacemembraneactionpotentialis
communicatedtothemyofibrilstructuresthatcause
the contraction. Although similar to the processin
skeletal muscle,therearesomeimportant
differences.

EC-Coupling Sequence:
?A.
?B.

Anactionpotentialdepolarizesthe surfacemembraneof thecardiaccell.

Thesurfacemembraneinvaginates attheleveloftheZlinesinventricularmuscletoformtransverse
tubules(t-tubules).Asthesurface membranesurroundingat-tubuledepolarizes,themembraneofthetubule
depolarizes.
?C. Duringtheplateauofthecardiacactionpotential,calciumchannelsinthesarcolemma and t-tubules
open.Calciuminfluxthroughthesechannelsprolongstheplateau(phase2)oftheactionpotential.Because
intracellularcalcium is extremelylow atthebeginningofthe actionpotential,thisinfluxalsoslightly
increases theintracellularcalciumconcentration.
?D. Theslight riseofintracellularcalcium causedbyICatriggersthereleaseofadditionalcalciumfromthe
SarcoplasmicReticulum. Thereleasetakes placethroughspecialcalciumreleasechannels (ryanodinesensitive)intheportionoftheSRmembrane thatfacesthet-tubularorsarcolemmalmembrane.
?E. Calcium diffusestothemyofilaments,andbindstocalciumbindingsitesontroponinC,activating
contraction.Someof thiscalcium wasderivedfromCaentryviaICa,butmostwasreleasedfrom theSR
stores.
?F. TheSRmembranecontainhigh-affinityATP-drivenCapumps.TheseuseATPtoprovide theenergyfor
"uphill"transportof CafromthemyoplasmintotheinterioroftheSR.Asthesepumpsreducemyoplasmic
calcium,calciumdissociates from troponinC,endingcontraction.
?G. Asodium-calciumexchanger(antiporter)is primarily responsiblefor extrudingCa;thisexchanger
allows3Na+toenter,downthesodiumconcentrationgradient,inexchangeforextrusionofonedoubly
chargedCaion.AnATP-utilizingCapumpinthesarcolemmaalsoextrudesCa;thispumphasalower
capacitythanthesodium-calciumexchanger.

Page 15

Cardiac Electrophysiology

JoePatlak

MedicalPhysiology 301

Ca-activatedCa release
Inskeletalmuscle,theSRCa-release
channel isactivatedbythevoltage
sensorsofaT-tubuleCachannel. In
heart,it is theCathatentersthrough
the L-typeCachannelthatstimulates
release. This iscalledCa-activatedCa
release.
CathatisreleasedfromtheSRhelps
enhanceopeningofotherrelease
channels. Thismakesthe Carelease
all-or-nothing, muchlikeanaction
potential. It alsohasinactivationand
a refractoryperiod!

Important functionaldifferences betweencardiac and skeletal ECcoupling.

?Caentryandextrusion: About10% ofthetotalriseinintracellularCaentersviaCachannelsduring
each cardiacactionpotential.This amount,byitself, isnotenoughtofullyactivatethemyofilaments,
butitisrequiredtoreplenish theintracellularCastoresthatdoprovidemostofthecalciumfor
activation (seediscussionbelow ontheCapool).
?Carelease mechanismdifferent: CardiacmusclereleasesCabya"calcium-inducedcalcium
release" mechanism.Thismechanism staysrefractoryfor a timeaftereachrelease.Thisiswhythecells
cannot producesustainedtetaniccontractions.
?Carelease not normally sufficienttosaturatetroponin: In cardiaccellscontractingundernormal
conditions,theamountofCareleasedwitheachstimulusisnotsufficienttoactivatethemyofilaments
fully.IfthecalciumcontentoftheSRrises,Careleasecanincrease,andcontractioncanincrease.

Ca extrusion a n d t he early afterdepolarization:

Caleavesthecytoplasmaftereachbeat(duringphase4)viapumps
thatreturnittothesarcoplasmicreticulum,andvia extrusion from
the cell usingprimarilytheNaXCaexchanger.
TheNaXCaexchanger iselectrogenic. ThreeNasflowintothe cell
for eachCathatleaves,leadingtoanetinward(depolarizing
current). IfCalevelsinthecytoplasmbecometoohigh(theCa
pool),thisNaXCadepolarizationcanbringthecelltothreshold,and
stimulateasecondAPjustafterthefirst. Inthesubsequentbeats,the
Caloadbecomes evenhigher,becausephase4was much
foreshortened. Thiseffectcansetuprapidrepeatsofaction
potentials.
Such delayedafterdepolarizationsare important sourcesof
ventriculartachycardia,andcanleadtosyncopeorsuddendeath.
Page 16

Cardiac Electrophysiology

JoePatlak

MedicalPhysiology 301

The Ca Pool
AlltheCawithinthecell(withintheSRandfree)constitutetheCapool. Duringdiastole,mostofthis
Caissequesteredwithinthe SR andtheheartisrelaxed. Duringsystole,thisCaisfree,anddetermines
the strengthofcontraction. ChangesintheCapoolthusdeterminethestrengthofeachbeat.
ThesizeoftheCapoolultimatelydependsonthebalance betweenCaentryduringphase2andits
extrusionduringphase4. At fasterheartrates,theCapoolincreasesbecausethere islesstimebetween
beatstoextrudetheCa. TheheartbeatsharderandfasterduetothislargerCapool.
Athighheartrates,theactionpotentialshortens duetothishighCapool. Thisadaptationhelpsprevent
Caoverloadathighheartrates.

Autonomic Adjustment of
Contraction
SympatheticandParasympathetic
stimulation alters the strengthand
speedofcontractionintwoways.
First,bychangingtheheartrate,the
sizeoftheCapoolchanges.
Second,theactivationofsympathetic
Beta-1receptorsleadstothe
productionofcyclic-AMP. This
secondmessengeralsoalterstheSR
andthecontractileproteins to further
enhancecontractionstrenght. This
lattereffectis called an increaseinthe
hearts contractility.
Page 17