Basis and Treatment of Cardiac Arrhythmias

359 Pages·2006·5.69 MB·English

by  M.J. Janse

Handbook of
Experimental Pharmacology
Volume 171
Editor-in-Chief
K.Starke,Freiburgi.Br.
EditorialBoard
G.V.R.Born,London
M.Eichelbaum,Stuttgart
D.Ganten,Berlin
F.Hofmann,München
W.Rosenthal,Berlin
G.Rubanyi,Richmond,CA
Basis and Treatment
of Cardiac Arrhythmias
Contributors
M.E.Anderson,C.Antzelevitch,J.R.Balser,P.Bennett,
M.Cerrone,C.E.Clancy,I.S.Cohen,J.M.Fish,I.W.Glaaser,
T.J.Hund,M.J.Janse,C.January,R.S.Kass,J.Kurokawa,
J.Lederer,S.O.Marx,A.J.Moss,S.Nattel,C.Napolitano,
S.Priori,G.Robertson,R.B.Robinson,D.M.Roden,
M.R.Rosen,Y.Rudy,A.Shiroshita-Takeshita,K.Sipido,
Y.Tsuji,P.C.Viswanathan,X.H.T.Wehrens,S.Zicha
Editors
Robert S. Kass and Colleen E. Clancy
123
RobertS.KassPh.D.
DavidHosackProfessorandChairman
ColumbiaUniversity
DepartmentofPharmacology
630W.168St.
NewYork,NY10032
USA
e-mail:[email protected]
ColleenE.ClancyPh.D.
AssistantProfessor
DepartmentofPhysiologyandBiophysics
InstituteforComputationalBiomedicine
WeillMedicalCollegeofCornellUniversity
1300YorkAvenue
LC-501E
NewYork,NY10021
e-mail:[email protected]
With60Figuresand11Tables
ISSN 0171-2004
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Preface
In thepastdecade,major progresshasbeenmadeinunderstandingmecha-
nismsofarrhythmias.Thisprogressstemsfrommuch-improvedexperimen-
tal,genetic,andcomputationaltechniquesthathavehelpedtoclarifytheroles
of specific proteins in the cardiac cycle, including ion channels, pumps, ex-
changer,adaptorproteins,cell-surfacereceptors,andcontractileproteins.The
interactionsofthesecomponents,andtheirindividualpotentialastherapeu-
tictargets,havealsobeenstudiedindetail,viaanarrayofnewimagingand
sophisticatedexperimentalmodalities.Thepast10yearshavealsoledtothe
realizationthatgeneticsplaysapredominantroleinthedevelopmentoflethal
arrhythmias.
Many of the topics discussed in this text reflect very recently undertaken
researchdirectionsincludingthegeneticsofarrhythmias,cellsignalingmole-
culesaspotentialtherapeutictargets,andtraffickingtothemembrane.These
newapproachesandimplementationsofanti-arrhythmictherapyderivefrom
manydecadesofresearchasoutlinedinthefirstchapterbythedistinguished
professorsMichaelRosen(ColumbiaUniversity)andMichielJanse(University
ofAmsterdam).Thetextcoverschangesinapproachestoarrhythmiatherapy
over time, in multiple cardiac regions, and over many scales, from gene to
proteintocelltotissuetoorgan.
NewYork,May2005 ColleenE.ClancyandRobertS.Kass
ListofContents
HistoryofArrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . 1
M.J.Janse,M.R.Rosen
PacemakerCurrentandAutomaticRhythms:
TowardaMolecularUnderstanding . . . . . . . . . . . . . . . . . . . . 41
I.S.Cohen,R.B.Robinson
Proarrhythmia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
D.M.Roden,M.E.Anderson
CardiacNa+ChannelsasTherapeuticTargets
forAntiarrhythmicAgents . . . . . . . . . . . . . . . . . . . . . . . . . 99
I.W.Glaaser,C.E.Clancy
StructuralDeterminantsofPotassiumChannelBlockade
andDrug-InducedArrhythmias . . . . . . . . . . . . . . . . . . . . . . 123
X.H.T.Wehrens
SodiumCalciumExchangeasaTargetforAntiarrhythmicTherapy . . . 159
K.R.Sipido,A.Varro,D.Eisner
ARoleforCalcium/Calmodulin-DependentProteinKinaseII
inCardiacDiseaseandArrhythmia . . . . . . . . . . . . . . . . . . . . 201
T.J.Hund,Y.Rudy
AKAPsasAntiarrhythmicTargets? . . . . . . . . . . . . . . . . . . . . 221
S.O.Marx,J.Kurokawa
β
-BlockersasAntiarrhythmicAgents . . . . . . . . . . . . . . . . . . . 235
S.Zicha,Y.Tsuji,A.Shiroshita-Takeshita,S.Nattel
ExperimentalTherapyofGeneticArrhythmias:
Disease-SpecificPharmacology . . . . . . . . . . . . . . . . . . . . . . 267
S.G.Priori,C.Napolitano,M.Cerrone
Mutation-SpecificPharmacologyoftheLongQTSyndrome . . . . . . . 287
R.S.Kass,A.J.Moss
VIII ListofContents
TherapyfortheBrugadaSyndrome . . . . . . . . . . . . . . . . . . . . 305
C.Antzelevitch,J.M.Fish
MolecularBasisofIsolatedCardiacConductionDisease . . . . . . . . . 331
P.C.Viswanathan,J.R.Balser
hERGTraffickingandPharmacologicalRescue
ofLQTS-2MutantChannels . . . . . . . . . . . . . . . . . . . . . . . . 349
G.A.Robertson,C.T.January
SubjectIndex . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357
ListofContributors
(Addressesstatedatthebeginningofrespectivechapters)
Anderson,M.E. 73 Moss,A.J. 287
Antzelevitch,C. 305
Napolitano,C. 267
Balser,J.R. 331 Nattel,S. 235
Cerrone,M. 267 Priori,S.G. 267
Clancy,C.E. 99
Cohen,I.S. 41 Robertson,G.A. 349
Robinson,R.B. 41
Eisner,D. 159 Roden,D.M. 73
Rosen,M.R. 1
Fish,J.M. 305 Rudy,Y. 201
Glaaser,I.W. 99 Shiroshita-Takeshita,A. 235
Sipido,K.R. 159
Hund,T.J. 201
Tsuji,Y. 235
Janse,M.J. 1
January,C.T. 349 Varro,A. 159
Viswanathan,P.C. 331
Kass,R.S. 287
Kurokawa,J. 221 Wehrens,X.H.T. 123
Marx,S.O. 221 Zicha,S. 235
HEP(2006)171:1–39
©Springer-VerlagBerlinHeidelberg2006
HistoryofArrhythmias
M.J.Janse1((cid:1))·M.R.Rosen2
1TheExperimentalandMolecularCardiologyGroup,AcademicMedicalCenter,M051,
UniversityofAmsterdam,Meibergdreef9,1105AZAmsterdam,TheNetherlands
[email protected]
2CenterforMolecularTherapeutics,DepartmentofPharmacology,CollegeofPhysicians
andSurgeons,ColumbiaUniversity,630W168thStreet,PH7West-321,
NewYorkNY,10032,USA
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
2 MethodstoRecordtheElectricalActivityoftheHeart . . . . . . . . . . . . . 4
2.1 TheElectrocardiogram . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2.2 TheInterpretationofExtracellularWaveforms . . . . . . . . . . . . . . . . . 6
2.3 TheRecordingofTransmembranePotentials . . . . . . . . . . . . . . . . . . 10
2.4 MappingoftheSpreadofActivationDuringArrhythmias . . . . . . . . . . . 11
3 SomeAspectsofCardiacAnatomyRelevantforArrhythmias . . . . . . . . . 12
3.1 AtrioventricularConnections . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
3.2 SpecializedInternodalAtrialPathways . . . . . . . . . . . . . . . . . . . . . . 14
4 MechanismsofArrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
4.1 Re-entry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
4.2 AbnormalFocalActivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5 SomeSpecificArrhythmias . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
5.1 AtrialFibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23
5.2 AtrioventricularRe-entrantTachycardia . . . . . . . . . . . . . . . . . . . . . 24
5.3 AtrioventricularNodalRe-entrantTachycardia . . . . . . . . . . . . . . . . . 26
5.4 VentricularTachycardia,FibrillationandSuddenDeath . . . . . . . . . . . . 28
6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Abstract A historical overview is given on the techniques to record the electrical activ-
ityoftheheart,someanatomicalaspectsrelevantfortheunderstandingofarrhythmias,
generalmechanismsofarrhythmias,mechanismsofsomespecificarrhythmiasandnon-
pharmacologicalformsoftherapy.Theunravellingofarrhythmiamechanismsdepends,
of course, on the ability to record the electrical activity of the heart. It is therefore no
surprisethatfollowingtheconstructionofthestringgalvanometerbyEinthovenin1901,
which allowed high-fidelity recording of the body surface electrocardiogram, the study
ofarrhythmiasdevelopedinanexplosiveway.Still,papersfromMcWilliam(1887),Gar-
rey(1914)andMines(1913,1914)inwhichneithermechanicalnorelectricalactivitywas
recordedprovidedcrucialinsightsintore-entryasamechanismforatrialandventricular
2 M.J.Janse·M.R.Rosen
fibrillation,atrioventricularnodalre-entryandatrioventricularre-entranttachycardiain
heartswithanaccessoryatrioventricularconnection.Thecomponentsoftheelectrocardio-
gram,andofextracellularelectrogramsdirectlyrecordedfromtheheart,couldonlybewell
understoodbycomparingsuchregistrationswithrecordingsoftransmembranepotentials.
Thefirstintracellularpotentialswererecordedwithmicroelectrodesin1949byCoraboeuf
andWeidmann.Itisremarkablethattheinterpretationofextracellularelectrogramswas
stillcontroversialinthe1950s,anditwasnotuntil1962thatDowershowedthatthetrans-
membrane action potential upstroke coincided with the steep negative deflection in the
electrogram.Formanydecades,mappingofthespreadofactivationduringanarrhythmia
wasperformedwitha“roving”electrodethatwassubsequentlyplacedondifferentsites
onthecardiacsurfacewithasimultaneousrecordingofanothersignalastimereference.
Thismethodcouldonlyprovidereliableinformationifthearrhythmiawasstrictlyregular.
Whenmultiplexingsystemsbecameavailableinthelate1970s,andopticalmappinginthe
1980s, simultaneousregistrationscouldbemade frommanysites. Theanalysis of atrial
andventricularfibrillationthenbecamemuchmoreprecise.Theoldquestionwhetheran
arrhythmiaisduetoafocalorare-entrantmechanismcouldbeanswered,andforatrial
fibrillation,forinstance,theansweristhatbothmechanismsmaybeoperative.Theroad
fromunderstandingthemechanismofanarrhythmiatoitssuccessfultherapyhasbeen
long: the studies of Mines in 1913 and 1914, microelectrode studies in animal prepara-
tionsinthe1960sand1970s,experimentalandclinicaldemonstrationsofinitiationand
terminationoftachycardiasbyprematurestimuliinthe1960sand1970s,successfulsurgery
inthe1980s,thedevelopmentofexternalandimplantabledefibrillatorsinthe1960sand
1980s,andfinallycatheterablationattheendofthepreviouscentury,withsuccessrates
thatapproach99%forsupraventriculartachycardias.
Keywords Electrocardiogram·Extracellularelectrograms·Transmembranepotentials·
Re-entry·Focalactivity·Tachycardias·Fibrillation
1
Introduction
Thediagnosisofcardiacarrhythmiasandtheelucidationoftheirmechanisms
depend on the recording of the electrical activity of the heart. The study
of disorders of the rhythmic activity of the heart started around the fifth
centuryb.c.inChinaandinEgyptaround3000b.c.withtheexaminationof
theperipheralpulse(fordetailsseeSnellen1984;Acierno1994;Lüderitz1995;
ZiskindandHalioua2004).Inretrospect,itiseasytorecognizeatrioventricular
(AV) block, represented by the slow pulse rate observed by Gerber in 1717
(seeMusicetal.1984),oratrialfibrillationmanifestedbytheirregularpulse
described by de Senac (1749). The recording of arterial, apical and venous
pulsations, notably by MacKenzie (1902) and Wenckebach (1903), provided
a more rational basis for diagnosing many arrhythmias. Still, the concept
that disturbances in the electrical activity of the heart were responsible for
abnormalarterialandvenouspulsationswasnotuniversallyknownattheturn
ofthenineteenthcentury.Forexample,MacKenzieobservedthattheAwave
disappearedfromthevenouscurveduringirregularheartaction,andwrote,in
HistoryofArrhythmias 3
1902undertheheadingof“Thepulseinauricularparalysis”,“Ihavenoclear
ideaofhowthestimulustocontractionarises,andsocannotdefinitelysayhow
theauriclemodifiestheventricularrhythm.ButasamatterofobservationI
canwithconfidencestatethatthehearthasaverygreattendencytoirregular
actionwhentheauricleslosetheirpowerofcontraction.”
The first demonstration of the electrical activity of the heart was made
accidentally by Köllicker and Müller in 1856. Following the experiments of
Matteuci in 1842, who used the muscle of one nerve-muscle preparation as
a stimulus for the nerve of another, thereby causing its muscle to contract
(seeSnellen1984),theyalsostudiedanerve-musclepreparationfromafrog
(sciaticnerveandgastrocnemiusmuscle).Accidentally,thesciaticnervewas
placedin contactwiththeexposedheartof another frog, andtheyobserved
thegastrocnemiusmusclecontractinsynchronywiththeheartbeat.Theysaw
immediately before the onset of systole a contraction of the gastrocnemius,
and in some preparations a second contraction at the beginning of diastole.
AlthoughMarey(1876)firstusedLipmann’scapillaryelectrometertorecord
theelectricalactivityofthefrog’sheart,theexplanationforthisactivitywas
provided by the classic experiments of Burdon-Sanderson and Page (1879,
1883). They also used the capillary electrometer together with photographic
equipment to obtain recordings of the electricalactivity of frog and tortoise
hearts.Theyplacedelectrodesonthebasalandapicalregionsofthefrogheart
and observed two waves of opposite sign during each contraction. The time
intervalbetweenthetwodeflectionswasintheorderof1.5s.Byinjuringthe
tissue under one of the recording sites, they obtained the first monophasic
action potentials and showed how, in contrast to nerve and skeletal muscle,
thereisintheheartalongperiodbetweenexcitationandrepolarization[“...
if either of the leading-off contacts is injured ... the initial phase is followed
by an electrical condition in which the injured surface is more positive, or
less negative relatively to the uninjured surface: this condition lasts during
the whole of the isoelectric period ...” (Burdon-Sanderson and Page 1879)].
Asecondimportantobservationwasthatbypartiallywarmingthesurface“...
theinitialphase(i.e.oftheelectrogram)isunalteredbuttheterminalphase
beginsearlierandisstrengthened”(Burdon-SandersonandPage1879).
Heidenhainintroducedthetermarrhythmiaasthedesignationforanydis-
turbanceofcardiacrhythmin1872.Withtheintroductionofbettertechniques
torecordtheelectricalactivityoftheheart,thestudyofarrhythmiasdeveloped
inanexplosiveway.Wewilllimitthisbriefaccounttothosestudiesinwhich
theelectricalactivitywasdocumented,eventhoughwewillmakeanexception
foranumberofseminalpapersonthemechanismsofarrhythmiasinwhich
neithermechanicalnor electricalactivity wasrecorded(McWilliam1887a,b,
1889; Garrey 1914; Mines 1913b, 1914). We will pay particular attention to
theearlystudies,nowadaysnoteasilyaccessible,andwillnotattempttogive
acompletereviewofallarrhythmias.