Molecular and Cellular Mechanisms Review of Cardiac Arrhythmias

12 Pages·2001·0.64 MB·English

Cell,Vol.104,569–580,February23,2001,Copyrightª 2001byCellPress
Molecular and Cellular Mechanisms Review
of Cardiac Arrhythmias
MarkT.Keating*‡andMichaelC.Sanguinetti†‡ thenslowlyrepolarize,whichisdenotedastheTwave
*HowardHughesMedicalInstitute ontheECG,leadingtocardiacrelaxationandcomple-
DepartmentofCellBiology tionofonecardiaccycle.
HarvardMedicalSchool The rhythmic activity of the human heart is clearly
DepartmentofCardiology apparentbyultrasoundafteronlyfiveweeksofgesta-
Children’sHospital tion. It is remarkable to think how flawlessly the heart
Boston,Massachusetts02115 performsinthecourseofone’slife,beatingz70times
†DepartmentofMedicine perminuteoveracourseof75to90years.One’sheart
DivisionofCardiology mustbeat,therefore,z36milliontimesayear,aremark-
EcclesPrograminHumanMolecularBiology ablefeatconsideringthatthereisvirtuallynotolerance
andGenetics forfailure.
UniversityofUtahHealthSciencesCenter
SaltLakeCity,Utah84112 CardiacArrhythmiasandSuddenDeath
Althoughmostheartsbeatwithremarkablefidelityand
resilience, under certain circumstances the rhythm of
Introduction theheartcanfail.Thisisknownasacardiacarrhythmia.
The heart is a pump (Figure 1). Through coordinated When the heartbeat is too slow (bradyarrhythmia or
contractionoftheatria,bloodispumpedintotheventri- bradycardia) blood pressure cannot be maintained,
cles.The ventricles,whichdomost ofthework ofthe leading to loss of consciousness and death. Bradyar-
heart,contractsynchronouslytopumpbloodtotherest rhythmias often result from disease or death of pace-
of the body. The right ventricle pumps deoxygenated makerandotherspecializedconductingcellsandcan
bloodtothelungsforgasexchange.Theleftventricle, beeffectivelytreatedwithartificial,electronicpacemak-
the most forceful chamber of the heart, pumps blood ers.Similarly,iftheheartrhythmistoorapid(tachyar-
to the rest of the organs, including the brain, kidneys, rhythmia or tachycardia), blood pressure cannot be
liver, skeletal muscle, and other vital organs. Through maintained,leadingtosyncopeandsuddendeath.The
this pumping action, the left ventricle maintains sys- most dangerous tachyarrhythmias are focused in the
temicbloodpressureatapproximately120over80milli- ventriclesandareknownasventriculartachycardia,tor-
metersofmercury.Thebrainisparticularlysensitiveto sadesdepointesventriculartachycardia,andventricu-
bloodpressureandflow.Ifthecoordinatedcontraction lar fibrillation (Figure 1). Torsades de pointes means
ofventricles isstopped foronly afewseconds, blood twistingaroundthepoint,anallusiontothealternating
pressuredropsandconsciousnessislost.Thissudden axisoftheQRScomplexaroundtheisoelectriclineofthe
lossofconsciousnessiscalledsyncope.Ifthemechani- ECGduringthisarrhythmia(Lazzara,1997)(Figure1).
calactivityoftheheartislostformorethanafewmin- Cardiacarrhythmiasarealeadingcauseofmorbidity
utes,permanentbraindamageanddeathensue. and mortality. More than 300,000 individuals in the
Themechanicalactivityoftheheartiscontrolledby United States die suddenly every year, and in most
electricalimpulses(Figure1).Theseimpulsesareintrin- casesitisassumedthattheunderlyingcauseofsudden
sic to the heart but are also modulated by neuronal deathisventriculartachyarrhythmia(Kanneletal.,1987;
activitythroughtheautonomicnervoussystem.Special- Willich et al., 1987). Despite their importance, until re-
ized cells in the right atrium known as the sino-atrial centlytheunderstandingofthemolecularmechanisms
node act as the pacemaker, spontaneously firing z70 underlyinglife-threateningventriculartachyarrhythmias
times per minute at rest and up to about 200 times waspoor.Theabilitytopredict,prevent,andtreatthese
per minute during rigorous exercise. This impulse is disordersremainsamajorscientificandmedicalchal-
conveyedtoallatrialmyocytes,leadingtocoordinated lenge.
depolarizationandcontractionoftheatria.Onasurface An exampleof anindividual withcardiac arrhythmia
electrocardiogram (ECG) atrial depolarization can be may provide insight into these disorders (Splawski et
visualized as a P wave. The electrical activity of the al.,1997a).A25-year-oldwomanwasseenforroutine
pacemaker is also conveyed to specialized cells that evaluationbyherobstetrician.Shewashealthyandin
connecttheatriaandtheventricles,knownastheatrio- her 35th week of gestation in an apparently uncompli-
ventricularnode.Here,theelectricalactivityisdelayed cated pregnancy. During examination the physician
forabout20milliseconds,givingtheatriatimetopump notedabradyarrhythmiainthefetus.Thefetus’sheart
blood into the ventricles. Then, the electrical activity rate was only 70–80 beats per minute, approximately
is conveyed to specialized fibers known as bundle half the normal rate. Ultrasonic examination, however,
branches,leadingtorapiddepolarizationofallventricu- revealednormalfetaldevelopment,andthepregnancy
larmyocytesandcoordinatedcontractionoftheventri- wasallowedtocometoterm.Thechildwasbornwithout
cles.Depolarizationoftheventriclescanbevisualized complicationat39weeksgestation.
ontheECGastheQRScomplex.Ventricularmyocytes Duringthefirstfeeding,thechildexperienceddistress
andturnedblue.Shewasrushedtotheneonatalinten-
sivecareunit,whereaseriesoftestswereperformed.
‡E-mail:[email protected] AllofthesetestswerenormalexceptfortheECG,which
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570
(Moss,1995)(Figure1).Itcanbeassociatedwithsyn-
copeandsuddendeathduetoepisodiccardiacarrhyth-
mias,particularlytorsadesdepointesventriculartachy-
cardia and ventricular fibrillation (Vincent et al., 1992;
Schwartz et al., 1993). Most individuals with long QT
syndromehavenoothersymptomsorsignsofdisease,
and arrhythmias are relatively rare except in severe
cases. As noted above, however, some cases of long
QTsyndromeareassociatedwithcongenitaldeafness
andthisdisorderhasalsobeenassociatedwithsyndac-
tyly,anabnormalwebbingoffingersortoes(Markset
al.,1995).
The long QT syndromes can be divided on clinical
grounds into two main types: familial and acquired.
There are at least two familial forms of long QT syn-
drome.One,whichwasdescribedabove,wasbelieved
tobeinheritedasanautosomalrecessivetraitandasso-
ciatedwithcongenitaldeafness,theJervellandLange-
Nielsensyndrome(JervellandLange-Nielsen,1957).A
second, more common familialform is inherited as an
autosomaldominanttraitwithnootherphenotypicab-
normalities. This form, which is sometimes referred to
Figure1. TheHeartIsanElectricallyActivatedPump as the Romano Ward syndrome (Romano et al., 1963;
(A)Aschematicrepresentationofafour-chamberedheartincluding Ward,1964),isusuallyassociatedwithlessarrhythmia
specializedcellsthatactasapacemaker(thesino-atrialnode,SAN)
riskthantheautosomalrecessiveform.Themostcom-
andconductingtissuessuchastheatrio-ventricularnode(AVN)and
therightandleftbundlebranches(RBB,LBB).RA5rightatrium; monformof longQTsyndromeis acquired.Thereare
LA5leftatrium;RV5rightventricle;LV5leftventricle.(B)Normal many different causes of acquired long QT syndrome,
electrocardiogram(ECG)andanECGshowingQTintervalprolonga- including heart diseases such as cardiomyopathy and
tion.NotethatvoltageisontheYaxisandtimeisontheXaxis.The cardiac ischemia, bradycardia, and metabolic abnor-
Pwaverepresentsatrialdepolarization,QRScomplexrepresents malities like reduced serum potassium concentration
ventricular depolarization and the T wave represents ventricular
(Rodenetal.,1996).Treatmentwithmanymedications,
repolarization.AnormalQTcintervalisz0.40s.QTcintervalprolon-
includingcertainantibiotics,antihistamines,andantiar-
gationresultsfromabnormalcardiacrepolarization.(C)ECGshow-
ingnormalsinusrhythmconvertingtotorsadesdepointesventricu- rhythmicsisthemostcommoncauseofacquiredlong
lartachycardiaandventricularfibrillation,alife-threateningcardiac QTsyndrome(Roden,1998).
arrhythmia. When molecular studies of long QT syndrome were
initiated,thereweretwomaintheoriesinvokedtoexplain
showed bradycardia with a heart rate of 82 beats per thepathogenesisofthisdisorder.Onewastheautonomic
minute and a prolonged QTc interval of z0.60 s. The imbalancehypothesis.Thistheorywasbasedonstudies
rate-correctedQT(QTc)intervalisatemporalmeasure showing that manipulation of the autonomic nervous
ofventricularrepolarizationandisnormallyabout0.40 systemindogscouldleadtoQTprolongationandcar-
s. Because of these findings, a pediatric cardiologist diacarrhythmias(Abildskov,1991).Asecondhypothe-
was consulted, who ordered audiographic evaluation. sis,thecardiacionchannelhypothesis,suggestedthat
Thesetestsshowedseverebilateralhearinglossanda inherited or acquired dysfunction of cardiac ion chan-
tentative diagnosis of Jervell and Lange-Nielsen syn- nelscouldleadtothisdisorder.Whileitisclearthatthe
dromewasmade.Thisdisorder,aformoflongQTsyn- autonomic nervous system plays a secondary role in
drome,isafamilialcardiacarrhythmiaassociatedwith manycardiacarrhythmias,thecardiacionchannelhy-
congenital deafness. It was previously believed to be pothesis has proved to be the primary mechanism of
inheritedasanautosomalrecessivetrait.Thechildwas arrhythmia susceptibility in studies reported to date
placed on beta-blockers, drugs that reduce the auto- (Figure2).
nomic nervous activity of the heart, and observed for
severaldayswithoutcomplication.Shewassenthome MutationsinCardiacIonChannelGenesCause
after10dayswithamonitor.BecauseJervellandLange- ArrhythmiaSusceptibility
Nielsensyndromewasthoughttobepurelyrecessive, Todefinegenesthat contributetoarrhythmiasuscep-
no clinical evaluation of the child’s parents or other tibility, familial forms of this disorder were examined,
family members was performed. Several months after particularlylongQTsyndrome.Overthelastsixyears,
thebirthofthechild,heroverstressedmotherwasawak- six arrhythmia susceptibility genes were discovered:
enedbyanalarmclock,stoodup,hadacardiacarrest, KVLQT1, HERG,SCN5A, minK,MiRP1, RyR2(Table 1)
anddied.Shehadpreviouslyenjoyedexcellenthealth, (Curran et al., 1995; Wang et al., 1995a, 1995b, 1996;
andhadnohistoryofsyncope. Splawskietal.,1997a,1997b;Chenetal.,1998;Abbott
etal.,1999;Priorietal.,2000).KVLQT1wasdiscovered
LongQTSyndrome,aFamilialCardiacArrhythmia usingpositionalcloning.HERG,SCN5A,andRyR2were
LongQTsyndromeisagroupofdisordersthatisusually identified using the positional cloning–candidate gene
characterized by a prolonged QT interval on the ECG approach,andminKandMiRP1werediscoveredusinga
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571
and Lange-Nielsen syndrome was previously believed
tobeanautosomalrecessivedisorder.Phenotypiceval-
uationofthisfamily,however,revealedamorecompli-
cated picture (Splawski et al., 1997a). Many members
ofthefamily,includingtheproband’sfather,hadsubtle
prolongation of the QT interval with normal hearing.
Someindividualsgaveahistoryofoneortwosyncopal
episodes, but no cases of sudden death were noted.
Furthermore, pedigreeanalyses revealed thatthe pro-
bandresultedfromaconsanguineousmarriageinthat
herparentsweresecondcousins.Thisledtothehypoth-
esisthathomozygousmutationsofanautosomaldomi-
nant long QT syndrome gene might cause Jervell and
Lange-Nielsen syndrome. This proved to be the case,
anditisnowclearthathomozygousmutationsofeither
KVLQT1 or minK can cause this disorder (Neyroud et
al., 1997; Splawski et al., 1997b; Duggal et al., 1998).
Themoleculargeneticsalsohelpedtodefinetheclinical
picture. One aspect of Jervell and Lange-Nielsen syn-
drome,congenitaldeafness,isinheritedasanautoso-
mal recessive trait in that heterozygous carriers have
noobvioushearingdeficit.However,arrhythmiasuscep-
tibilityisinheritedasasemidominanttrait.Thatis,het-
erozygotesandhomozygotesbothhavearrhythmiasus-
ceptibility,buttheriskofarrhythmiainhomozygotesis
much greater. Homozygous mutations of HERG have
alsobeenreported(Hoorntjeetal.,1999).Thiscondition
alsocausesseverearrhythmiasusceptibility,butisnot
associatedwithotherphenotypicabnormalities.
AutosomaldominantlongQTsyndromegenesbecame
candidatesforinvolvementinotherfamilialarrhythmia
susceptibility syndromes. Although the familial occur-
renceofvirtuallyeveryarrhythmiahasbeenreported,in
mostcases,themodeofinheritanceisunclear.Familial
ventricularfibrillation,bycontrast,canbeinheritedasa
clear,autosomaldominanttrait.AsinlongQTsyndrome,
peoplewithfamilialventricularfibrillationoftenappear
healthy(Martini,1989).Electrocardiographicevaluation
of these individuals shows no evidence of QT interval
prolongation.Insomecases,subtleprolongationofthe
QRScomplexcanbedemonstrated.Adistinctelectro-
cardiographic feature of elevation of the ST segment
hasbeendescribedinsomeindividualsandreferredto
astheBrugadasyndrome(Brugadaetal.,1997).Some
forms of familial ventricular fibrillation have also been
associatedwithconductionabnormalities.Inallcases,
Figure2. IonChannelMutationsCauseCardiacArrhythmias theseindividualsareatincreasedriskforepisodicven-
Schematicrepresentationofionchannelsencodedbyarrhythmia tricularfibrillation,aparticularlylethalarrhythmia.When
susceptibilitygenesincludingKVLQT1potassiumchannelasub- ventricularfibrillationoccurs,thereisnocardiacoutput,
units,HERGpotassiumchannelasubunits,SCN5Asodiumchannel andpermanent braindamageanddeath ensueunless
asubunits,minKpotassiumchannelbsubunits,MiRP1potassium
the arrhythmia is controlled. As noted above, SCN5A
channelbsubunits,andRyR2ryanodinereceptor/calciumrelease
mutationscancausearrhythmiasusceptibilityincertain
channel. Missense mutations are indicated by red dots, and the
location of frameshifts or intragenic deletions are indicated by familial forms of long QT syndrome (Table 1). Recent
bluedots. molecular genetic studies have demonstrated that
SCN5A mutations can also cause familial ventricular
fibrillation (Chen et al., 1998). Thus, SCN5A mutations
candidategeneapproach.AseventhlongQTsyndrome cancauseseveraldifferentformsofarrhythmiasuscep-
locuswasmappedtochromosome4,butthisgenehas tibility.
not yet been identified (Schott et al., 1995). Additional Thegeneticbasisforathirdfamilialcardiacarrhyth-
locus heterogeneity was described and several addi- mia,catecholaminergicventriculartachycardia,hasre-
tional arrhythmia genes await discovery (Jiang et al., centlybecomeapparent.Thisdisorderischaracterized
1994).Thesestudiesprovidedthefirstmolecularinsight by syncope and sudden death in otherwise healthy
intothepathogenesisofcardiacarrhythmias. youngindividualsduetoepisodicventriculartachycar-
Asnotedinthecasereportdescribedabove,Jervell dia. Recent studies demonstrate that this disorder is
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Table1. MolecularandCellularMechanismsofCardiacArrhythmias
Diseasea Inheritance Geneb(alternatename) Protein Mechanism
LQT autosomaldominant KVLQT1(KCNQ1) I K1channelasubunit repolarizationabnormality
Ks
HERG(KCNH2) I K1channelasubunit repolarizationabnormality
Kr
SCN5A I K1channelasubunit repolarizationabnormality
Na
LQT4 ? ?
minK(KCNE1) I K1channelbsubunit repolarizationabnormality
Ks
MiRP1(KCNE2) I K1channelbsubunit repolarizationabnormality
Kr
LQT7 ? ?
autosomalrecessive KVLQT1 I K1channelasubunit repolarizationabnormality
Ks
(withdeafness)
minK I K1channelbsubunit repolarizationabnormality
Ks
syndactylyassociated ? ? ?
acquired(druginduced) HERG I K1channelasubunit repolarizationabnormality
Kr
MiRP1 I K1channelbsubunit repolarizationabnormality
Kr
IVF autosomaldominant SCN5A I Na1channelasubunit conductionabnormality
Na
IVF2 ? ?
CVT autosomaldominant RyR2 Ryanodinereceptor/ calciumoverload
Ca21releasechannel
aLQT5longQTsyndrome;IVF5familialidiopathicventricularfibrillation;CVT5catecholaminergicventriculartachycardia.
bLQT4,LQT7,IVF2:genesnotidentified.
caused by mutations in RyR2, the ryanodine receptor L-typecalciumchannelsandgraduallyincreasingout-
gene(Priorietal.,2000). wardcurrentthroughseveraltypesofpotassiumchan-
Insummary,thegeneticbasisofarrhythmiasuscepti- nels. The total amount of current during the plateau
bilityhasbeguntoemerge.Sixarrhythmiageneshave phaseofthecardiacactionpotentialissmall.Asacon-
beenidentifiedtodate:SCN5A,KVLQT1,minK,HERG, sequence,relativelysmallchangesinioncurrentduring
MiRP1,RyR2.SCN5AmutationscancausebothlongQT thisphasecanhaveamajorimpactonactionpotential
syndrome and familial ventricular fibrillation. KVLQT1, duration.AtthispointinthecardiaccycletheECGhas
minK, HERG, and MiRP1 mutations have been impli- returned to baseline. Phase 3 represents myocellular
catedinlongQTsyndrome.RyR2mutationscausecate- repolarization,aneffectmediatedbyoutwardpotassium
cholaminergic ventricular tachycardia. In general, ar- currents.Physiologic andpharmacologic studieshave
rhythmiasusceptibilityismoresevereinhomozygotes defined two main repolarizing potassium currents, I
Kr
thaninheterozygotes.Althoughsomefamilialformsof and I , that sum to terminate the plateau phase and
Ks
arrhythmiasusceptibilityareassociatedwithadditional initiatefinalrepolarization(SanguinettiandJurkiewicz,
obviousphenotypicabnormalities(e.g.,congenitalneu- 1990).Othercurrentssuchastheplateaudelayedrecti-
ral deafness in Jervell and Lange-Nielsen syndrome), fier K1 current (I ) and the inward rectifier K1 current
Kp
mostoftheseindividualsappeargrosslynormalandgo (I ) also contribute to repolarization. I is the rapidly
K1 Kr
undetecteduntiltheirfirstarrhythmiastrikes. activating delayed rectifier potassium current that is
specifically blocked by methanesulfonanilide drugs.
IonChannelsandtheCardiacActionPotential WhenI currentisblockedbythesedrugs,I theslowly
Kr Ks,
Like other excitable cells, including neurons, skeletal activatingdelayedrectifierpotassiumcurrent,remains.
muscle,andsmoothmuscle,cardiacmyocyteexcitabil- TherepolarizationphasecorrelateswiththeTwaveon
ityresultsfromactionpotentials.Thecardiacmyocyte surface ECG. Phase 4 is the final phase of the action
action potential,however, is distinctive inits duration, potentialandsignalsareturnofmembranepotentialto
whichismuchlongeratz300ms.Bycontrast,theaction itsbaselinenear285mV.Thisphaserepresentsventric-
potentials of neurons and skeletal muscle last a few ularrelaxationordiastoleandisindicatedontheECG
milliseconds. The cardiac action potential consists of asareturntobaseline.Thus,thecoordinatedopening
five phases, numbered 0–4 (Figure 3). Phase 0 repre- andclosingofionchannelsmediatesthecardiacaction
sentsdepolarizationofthemyocyte.Thisphaseisiniti- potential.DurationoftheQTintervalonsurfaceECGis
atedbytherapidopening(activation)ofvoltage-gated relatedtothelengthofventricularactionpotentials.
sodiumchannels.Depolarizationofallventricularmyo-
cytesismeasurableastheQRScomplexonthesurface SodiumChannelDysfunctionCanCauseSeveral
ECG. Phase 1 of the cardiac action potential occurs DifferentTypesofArrhythmia
immediatelyafterthepeakofdepolarizationandisrec- InvestigatorshadpreviouslydemonstratedthatSCN5A
ognized as a partial repolarization of the membrane. encodes the a subunits of sodium channels that are
Thissmallrepolarizingeffectisduetotheclosure(inacti- responsibleforinitiatingcardiacactionpotentials(Gel-
vation) of cardiac sodium channels, and activation of lensetal.,1992).Thisgeneislocatedonchromosome
transient outward potassium current. Phase 2 of the 3p21-p24andencodesaproteinwithapredictedtopol-
actionpotentialistheplateauphase.Therelativelylong ogy of four major domains, DI through DIV (Figure 2).
durationofthisphaseisuniquetoventricularandPur- Eachofthese domainsisbelievedto haveastructure
kinjefibermyocytes.Theplateauisgeneratedprimarily similar to a voltage-gated potassium channel with six
by slowlydecreasing inward calciumcurrents through membrane-spanning domains (S1–S6) and pore do-
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573
logicconsequences.Theoretically,reductionofsodium
current would be expected to slightly shorten action
potential duration and slow conduction velocity. It is
also not yet clear exactly how reduction in the total
numberoffunctionalsodiumchannelsandexpression
ofaheterogeneouspopulationofsodiumchannelslead
to arrhythmia. Clues may come from pharmacologic
studies, which show that inhibition of sodium channel
currentcancauseheterogeneityinactionpotentialcon-
Figure3. TheCardiacActionPotentialIsMediatedbyIonCurrents figurationintherightventricularepicardium,leadingto
Schematicrepresentationofacardiacactionpotentialwithvoltage marked dispersionof repolarizationand refractoriness
ontheYaxisandtimeontheXaxis.Notethatthecardiacaction (Krishnan and Antzelevitch, 1991). This creates a sub-
potentialdurationisquitelong,forexample,200millisecondsfor strate for the development of reentrant arrhythmias.
theventricularmyocyteshownhere.Inwardsodiumcurrentmedi- SomefamilialventricularfibrillationmutationsofSCN5A
atestherapidphase0depolarization.TransientoutwardK1currents
maycauseanabnormalityofconduction,andinsome
(I )mediaterapidphase1repolarization.TheL-typeinwardcalcium
to cases,baselineelectrocardiogramsinaffectedindividu-
current contributesto thelong plateauduration (phase2). Many
outward potassium currents are responsible for repolarization of als show conduction abnormalities. In summary, both
thecardiacactionpotential(phase2and3),includingI ,I ,and gain- and loss-of-function mutations of SCN5A can
Kr Ks
I .Thus,thecoordinateopeningandclosingofcardiacionchannels causearrhythmiasusceptibility.Gainoffunctioncauses
K1
isresponsibleforcardiacexcitability. prolongationofactionpotentials,whereasloss-of-func-
tionmutationslikelyshortenactionpotentialsandslow
mains located between S5 and S6. The a subunit can conductionvelocity.
formfunctionalchannels,butaccessorybsubunitshave
alsobeenidentifiedthataltersomebiophysicalproper- KVLQT1andminKCoassembletoFormCardiac
tiesofthechannel.Mutationalanalyseshaverevealed I PotassiumChannels
Ks
14 distinct mutations of SCN5A associated with long KVLQT1islocatedonchromosome11p5.5(Keatinget
QTsyndrome(Splawskietal.,2000). al.,1991)inaregionassociatedwithBeckwith-Weide-
Based on the location of these mutations and the mann syndrome (Lee et al., 1997). Northern analyses
physiologyofthedisease,itwashypothesizedthatgain- indicatethatKVLQT1isexpressedintheheart,placenta,
of-function mutations in SCN5A would cause long QT lung,kidney(Wangetal.,1996),innerearandpancreas,
syndrome. Normally, cardiac sodium channels open with greatest expression in the pancreas (Yang et al.,
briefly in response to membrane depolarization. The 1997). KVLQT1 and other genes in the region are im-
channelistheninactivatedandremainsclosedforthe printed, with paternal silencing in most tissues. How-
remainderoftheactionpotential.Sodiumchannelinacti- ever, KVLQT1 is not imprinted in the heart (Lee et al.,
vation is mediated by an intracellular domain located 1997).TwohomologsofKVLQT1(KCNQ2,KCNQ3)have
betweenDIIIandDIV.Thisdomainisreferredtoasthe beenidentifiedinthebrainandassociatedwithbenign
inactivationgateandisthoughttophysicallyblockthe familialneonatalseizures,aninheritedformofepilepsy
innermouthofthechannelpore.SeveralSCN5Amuta- (Charlier et al., 1998; Singh et al., 1998; Yang et al.,
tionsassociatedwithlongQTsyndromewereidentified 1998).
in this region. Physiologic characterization of one of ThecDNA-predictedaminoacidsequenceofKVLQT1
these mutants (D KPQ) led to the discovery that the suggeststhatthisgeneencodesvoltage-gatedpotas-
mutationsdestabilizedtheinactivationgate(Bennettet siumchannelasubunits.Ithassixputativemembrane-
al.,1995).Activationofthesemutantsodiumchannels spanning domains, S1–S6, including a voltage sensor
is normal and the rate of inactivation appears slightly (S4)andapotassiumchannelporesignaturesequence
fasterthannormal,butmutantchannelscanalsoreopen betweenS5andS6(Figure2).TheintracellularN-termi-
during the plateau phase of the action potential. The nal segment of KVLQT1 is short. Mutational analyses
net effect is a small, maintained depolarizing current have revealed 85 mutations of KVLQT1 coding se-
thatismodeledtobepresentduringtheplateauphase quences, representing z40% of known arrhythmia-
oftheactionpotential(Bennettetal.,1995;Dumaineet associatedmutationsdiscoveredtodate.Mostofthese
al.,1996).Thislengthensactionpotentialduration.Other mutationsaremissensemutationslocatedinmembrane
longQTsyndrome-associatedmutationsofSCN5Ahad spanningregionsaswellastheporeregion.
slightlydifferenteffectsonmutantchannelsatthesingle Heterologous expression of KVLQT1 in mammalian
channellevel,butallledtomaintaineddepolarizingcur- cellsandXenopusoocytesrevealedthatthisgeneen-
rents and action potential prolongation, setting up a codes a subunits that form voltage-gated potassium
substrateforarrhythmia. channels (Barhanin et al., 1996; Sanguinetti et al.,
SCN5Amutationsalsocausefamilialventricularfibril- 1996b). However, the biophysical properties of the in-
lation (Table 1). In some cases, these mutations are ducedcurrentwereunlikeanypotassiumcurrentidenti-
clearlyloss-of-function.Forexample,anonsensemuta- fied in cardiac myocytes. This observation led to the
tionofSCN5Ahasbeenassociatedwithventricularfi- hypothesisthatKVLQT1subunitsmightassemblewith
brillationinanotherwisehealthyindividualwhohasno subunits encoded by another gene to form a cardiac
obviouselectrocardiographicabnormalities(Chenetal., potassiumchannel.
1998).Othermutationsthathavebeenassociatedwith minK,whichislocatedonchromosome21,received
thisdisorderarelessclear-cutintermsoftheirphysio- thisnamebecauseitwasthoughttoencodetheminimal
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574
potassiumchannelsubunit.Only129aminoacidslong, andmutantsubunitshavereducedornofunction.The
this predicted amino acid sequence has room for one net effect is a greater than 50% reduction in channel
putativemembrane-spanningdomain.Itcontainsnopo- function,adominant-negativeeffect.Theseverityofthe
tassiumchannelporesignaturesequenceandnoputa- dominant-negative effect varies considerably depend-
tivevoltage-sensingdomain.Althoughitisnotacom- ingonthesiteandtypeofmutation.Insomecases,the
moncauseofarrhythmiasusceptibility,mutationsinthis dominant-negativeeffectisrelativelysmallwhereasin
genehavebeenassociatedwithlongQTsyndromeand otherstheeffectiscomplete,leadingtomarkedreduc-
homozygous mutations cause Jervell and Lange-Niel- tionofI eveninheterozygotes.Missensemutationsin
Ks
son syndrome (Schulze-Bahr et al., 1997; Splawski et theporesequencesseemtobeparticularlypotent.The
al.,1997a,1997b).Tenarrhythmia-associatedmutations severity of the dominant-negative effect likely has an
of minK have beenidentified. This represents z5% of impact on the severity of arrhythmia susceptibility in
longQTsyndromemutationsidentifiedtodate. individuals.However,therearemanyfactorsthataffect
minKwasinitiallyclonedbyfunctionalexpressionin arrhythmiasusceptibility,andextensivephenotypicvari-
Xenopusoocytes(Takumietal.,1988).Thebiophysical ability can be seen between family members carrying
propertiesofthecurrentelicitedbyexpressionofminK thesameprimarygeneticmutations.
were similar to cardiac IKs, one of the main currents KVLQT1andminKarebothexpressedintheinnerear.
responsibleforterminationofthecardiacactionpoten- Here,thechannelfunctionstoproduceapotassium-rich
tial. Thus, investigators concludedthat minK encoded fluidknownasendolymphthatbathestheorganofCorti,
subunits that formed cardiac IKs channels. However, thecochlearorganresponsibleforhearing.Individuals
therewereseveralproblemswiththishypothesis.First, withJervellandLange-Nielsensyndromehavehomozy-
as noted above, the structure of minK was unusual. gousmutationsofKVLQT1orminK,andthereforehave
The typical voltage-gated potassium channel has six nofunctionalI channels.Asnotedabove,theseindivid-
Ks
membrane-spanningdomainsandfoursubunitsarere- ualshaveseverearrhythmiasusceptibilityandcongeni-
quired for assembly andformation of functional chan- talneuraldeafness.Themechanismofdeafnessinthese
nels.BecauseminKwassmallandonlyhadoneputative individuals is that the lack of I leads to inadequate
Ks
membrane-spanningdomain,investigatorshypothesized endolymph production and deterioration of the organ
thatmany subunitsmightassembleto formfunctional of Corti (Vetter et al., 1996). Deafness can also result
channels. Some experiments, however, suggest that frommutationsinKCNQ4,agenethatencodesahomo-
onlytwounitswererequiredforexpression(Wangand logofKVLQT1thatishighlyexpressedwithinsensory
Goldstein, 1995; Tai et al., 1997). Second, physiologic outerhaircellsoftheinnerear(Kubischetal.,1999).
studiesindicatedthatexpressionofminKinmammalian
cells failed to induce a current. Finally, expression of HERGEncodestheaSubunitofCardiacI
increasingamountsofminKinXenopusoocytesdidnot Kr
PotassiumChannels
leadtoincreasingcurrent,indicatingsaturability.
HERG,locatedonchromosome7q35-q36,isexpressed
It is now clear that minK b subunits assemble with
primarily in the heart (Curran et al., 1995). HERG was
KVLQTasubunitstoformcardiacI channels(Barhanin
Ks originally identified from a human hippocampal cDNA
etal.,1996;Sanguinettietal.,1996b).Heterologousex-
library (Warmke and Ganetzky, 1994) and is also ex-
pression of minK alone in mammalian cells produced
pressedinneuralcrest–derivedneuronsandmicroglia.
no current. By contrast, heterologous expression of
Ninety-fourdistinctmutationsofHERGhavebeeniden-
KVLQT1 and minK together led to a large potassium
tified (Splawski et al., 2000). These represent 45% of
current with the biophysical properties of cardiac I .
Ks thetotalnumberoflongQTsyndromemutationsfound
Although the stoichiometry of coassembly is not yet
known,itislikelythatfourKVLQT1asubunitsassemble todate.
withfourminKbsubunitstoformthesechannels. Basedonitspredictedaminoacidsequence,HERG
was thought to encode a typical voltage-gated potas-
How is it that minK alone can be functionally ex-
siumchannelasubunitwith6membrane-spanningdo-
pressedinXenopusoocytes?Theexplanationisthata
mains(S1–S6),avoltagesensor(S4),andaK1-selective
homolog of KVLQT1, XKVLQT1, is constitutively ex-
porebetweenS5andS6.HERGhasalargeintracellular
pressedinXenopusoocytes,butatarelativelylowlevel
(Sanguinetti et al., 1996b). This homolog can interact C-terminalregioncontainingacyclicnucleotidebinding
withminK,forminganI -likechannel. domain.HERGalsohasalargeN-terminaldomain,the
Ks
At least two molecular mechanisms account for re- first135aminoacidsofwhicharehighlyconservedwith
ducedKVLQT1functioninthelongQTsyndrome(Woll- comparabledomainsinrelatedchannels.Thestructure
niketal.,1997;Wangetal.,1999).Inthefirst,disease- oftheN-terminaldomainhasbeensolvedandhasstruc-
associated intragenic deletions of one KVLQT1 allele tural similarity to PAS (Per-Arnt-Sim) domains (Morais
result in syntheses of abnormal subunits that do not etal.,1998).ProteinswithPASdomainsarefrequently
assemblewithnormalsubunits.Asaresult,onlynormal involvedinsignaltransduction.AnalysisoflongQTsyn-
subunits form the functional tetrameric channels. This drome-associated missense mutations located in the
loss-of-functionmechanismresultsina50%reduction PASdomainofHERGrevealedthatthisregionisimpor-
in the number of functional channels. In the second tantinmediatingtheslowrateofchanneldeactivation
mechanism, missense mutations result in synthesis of (Chenetal.,1999).
KVLQT1 subunits with subtle structural abnormalities. Expressionof HERGinheterologoussystems ledto
Manyofthesesubunitscanassemblewithnormalsub- the discovery that this gene encodes a subunits that
units,formingheterotetramerswithvaryingstoichiome- formcardiacI potassiumchannels,thesecondofthe
Kr
try. Channels formed from the coassembly of normal two channels primarily responsible for termination of
Review
575
the plateau phase of the action potential (Sanguinetti ofthecontractileapparatus.Thefourmutationsidenti-
et al., 1995; Trudeau et al., 1995). One of the unusual fiedinRyR2todatearemissensemutations.Thefunc-
biophysical properties of I channels that was repro- tional consequences of these mutations are not yet
Kr
ducedbyHERGinXenopusoocytesisthebell-shaped known.Alikelypossibility,however,isepisodic,stress-
current–voltage relationship, a rectification caused by inducedCa21overloadincardiacmyocytes,leadingto
C-type inactivation (Smith et al., 1996). This property asubstrateforarrhythmia.
accountsfortherelativeimportanceofI duringphase Insummary,allknownarrhythmiasusceptibilitygenes
Kr
3 of the cardiacaction potential. During repolarization encodecardiacionchannels.SCN5Aencodessodium
oftheactionpotential,HERGchannelsrapidlyrecover channelsthatareresponsibleforinitiatingcardiacaction
frominactivationintotheopenstate.Thisresultsinan potentials. HERG encodes a subunits that assemble
increase in the magnitude of I during the first half of with MiRP1 b subunits to form cardiac I potassium
Kr Kr
phase3repolarizationdespiteadecreaseintheelectro- channels,whereasKVLQT1assembleswithminKtoform
chemicaldrivingforceforoutwardfluxofK1(Spector, cardiacI potassiumchannels.I andI areresponsible
Ks Kr Ks
1996). for termination of the plateau phase and contribute to
AlthoughmanyofthebiophysicalpropertiesofHERG finalrepolarizationofthecardiacactionpotential.RyR2
current in heterologous systems were nearly identical encodestheryanodinereceptor/calciumreleasechan-
tocardiacI ,twopropertieswereoutofline(Sanguinetti nel crucial for excitation–contraction coupling. Muta-
Kr
etal.,1995;Abbottetal.,1999).First,althoughdeactiva- tionsofSCN5AassociatedwithlongQTsyndromede-
tion of cardiac I was relatively slow, deactivation of stabilize the channel inactivation gate, resulting in
Kr
HERGchannelswasmuchslower.Second,thekinetics repetitivereopeningofmutantchannelsandabnormal
andvoltagedependenceofI blockbymethanesulfo- depolarizing sodium current during the plateau phase
Kr
nanilidedrugsweredifferentthanHERGchannels.This oftheactionpotential.Thus,gain-of-functionmutations
problemledtothehypothesisthatHERG,likeKVLQT1, ofthecardiacsodiumchannelcauselongQTsyndrome.
might assemble with an unknown b subunit to form By contrast, loss-of-function mutations of the cardiac
cardiacI channels. sodiumchannelcauseidiopathicventricularfibrillation
Kr
MiRP1,orminK-relatedprotein1,islocatedonchro- withorwithoutbaselineconductionabnormalities.Mu-
mosome21,just70kbfromminK(Abbottetal.,1999). tations of KVLQT1, HERG, minK, and MiRP1 cause a
The two genes have significant homology at the DNA lossoffunction,oftenwithadominant-negativeeffect
and amino acid level and likely resulted from a recent that leads to a reduction in repolarizing current. RyR2
duplication. Missense mutations of MiRP1 have been mutations probably lead to abnormal intracellular cal-
associated with long QT syndrome, indicating that it ciummetabolism.Takentogether,thesestudiesdemon-
isanarrhythmia-susceptibilitygene.WhenMiRP1was stratethatmutationsofcardiacionchannelscausear-
expressedwithHERGinheterologoussystems,thebio- rhythmia susceptibility through multiple molecular
physicalandpharmacologicpropertiesoftheresultant mechanisms.
currentwerenearlyidenticaltoI incardiacmyocytes
Kr
(Abbottetal.,1999).Thus,HERGasubunitsassemble Reentry,aFundamentalMechanismofArrhythmia
withMiRP1bsubunitstoformcardiacIKrchannels. Togetherwithpreviousphysiologicstudies,recentgenetic
ManyHERGmutationsclusteraroundthemembrane- advancesprovideapictureofcardiacarrhythmiasatthe
spanningdomainsandtheporeregion.Someofthese molecular,cellular,andorganlevels.Gain-of-functionmu-
mutations, such as early nonsense mutations, have a tationsofcardiacsodiumchannelsandloss-of-function
pure loss-of-function effect. Oftentimes the encoded mutationsofpotassiumchannelsdelaymyocyterepo-
mutantproteinsmisfoldandarerapidlydegraded(Zhou larization.Loss-of-functionmutationsofsodiumchan-
et al., 1998), leading to a dominant-negative effect or nels cause conduction abnormalities. Calcium release
haploinsufficiency.However,manylongQTsyndrome– channeldysfunctionprobablycausescalciumoverload.
associatedmutationsinHERGaremissensemutations. Thesechannelsareexpressedatvaryinglevelsindiffer-
BecausefunctionalIKrchannelsarecomprisedofhetero- entregionsoftheheart,sotheeffectofchanneldysfunc-
multimers with several HERG subunits, it is possible tion has regional variability. Regional abnormalities of
thatmanyofthesemutationshaveadominant-negative cardiacrepolarizationorconductionprovideasubstrate
affect on channel function. Heterologeous expression forarrhythmia.Forexample,duringaprolongedaction
studies indicate that this is a common effect and that potential,myocytesarerelativelyrefractorytoelectrical
different mutations lead to a spectrum of dominant- excitation by neighboring myocytes. Dispersion of re-
negativesuppressionofchannelfunction(Rodenetal., fractorinesscanleadtounidirectionalblockofawave
1996;Sanguinettietal.,1996a;Lietal.,1997). ofelectricalexcitation(Figure4A).Thus,pocketsofcells
thataretemporarilyunabletoconductthenormalflow
RyR2EncodestheCalciumReleaseChannel of electrical activity in the heart create a substrate for
RyR2 encodes the ryanodine receptor, a calcium- arrhythmia.
inducedcalciumreleasechannellocatedincardiacsar- Althoughunidirectionalblockcanincreasetheriskof
coplasmic reticulum. RyR2 channels are activated by arrhythmia, it is not sufficient; a triggering mechanism
Ca21 that transiently enters the cell through plasma is still required. The trigger for arrhythmia in the long
membrane–boundL-type calciumchannels duringde- QTsyndromeisbelievedtobespontaneoussecondary
polarizationofthecardiacmyocyte.ThisCa21triggers depolarizations that arise during or just following the
thereleaseofCa21storedinthesarcoplasmicreticulum plateauphaseofactionpotentials.Secondarydepolar-
through RyR2 channels that in turn initiates activation izations appear as premature, small action potentials
Cell
576
Figure5. UnintendedBlockofHERGChannelsbyDrugsIsaCom-
monMechanismofAcquiredLongQTSyndrome
(A)PartialsequenceoftheS6transmembranedomainforseveral
Figure4. UnidirectionalBlockandReentry,aFundamentalMecha- voltage-gatedpotassiumchannels.Twounusualstructuralfeatures
nismofArrhythmia ofHERGnotsharedbyothervoltage-gatedK1channelsarerespon-
(A)Abnormalcardiacrepolarization,conduction,orintracellularcal- sibleforcommon,nonspecificdruginteractions.Theseincludea
ciumhomeostasiscanleadtoepisodicunidirectionalblock,asub- lackofprolineresiduesintheS6transmembranedomain,andthe
strateforarrhythmia.Greenarrowsrepresentthenormalconduction presenceoftwoaromaticresidues(Y,F)inthisdomainthatface
inabifurcatedpathway.Conductionisblockedinanareaofrefrac- theinnercavityoftheHERGchannel.Thesearomaticresiduesform
torytissue(unidirectionalblock).Ifconductionvelocityisslowed, thedrugbindingsite.(B)Thelackofprolineresiduesincreasesthe
thenreentrythroughareaofrefractorytissuecanoccur(redarrows). sizeoftheHERGinnercavity,therebycreatingalargespacefor
(B)Multiplereentrantcircuits(multiplecurvedarrows)isamecha- channel–drug interactions in this channel, but not other voltage-
nismofventricularfibrillation,thecauseofsuddendeath. gatedpotassium(KvX)channels.
andare mediatedbydepolarizinginward calciumcur- AcommoncauseofacquiredlongQTsyndromeisa
rents through L-type calcium channels. This cellular sideeffectofnumerouscommonmedicationsofdiverse
mechanismpredictsthattheautonomicnervoussystem therapeuticandstructuralclasses(Roden,1998).Exam-
can have a significant impact on arrhythmia suscepti- plesofdrugsassociatedwithlongQTsyndromeinclude
bility. Heightened sympathetic tone can substantially terfenadine,cisapride,erythromycin,amiodarone,quini-
increase spontaneous inward current through L-type dine,phenothiazines,tricyclicantidepressants,andcer-
calcium channels, increasing the likelihood that the taindiuretics(thelattermediatedthroughdrug-induced
spontaneous repolarization will trigger an arrhythmia. hypokalemia). Most of these medications block HERG
Oncetriggered,thearrhythmiaismaintainedbyaregen- channels, leading to reduced repolarizing potassium
erativecircuitofelectricalactivityaroundrelativelyinex- current and delayed myocellular repolarization. These
citabletissue,aphenomenonknownasreentry(Figure findingsshow,therefore,thatcardiacionchanneldysfunc-
4A). The development of multiple reentrant circuits tionunderliesbothinheritedandacquiredarrhythmias.
withintheheart(Figure4B)causesventricularfibrillation, The problem of medication-induced long QT syn-
thearrhythmiaofsuddendeath. dromeisasignificantissuetothepharmaceuticalindus-
try and the Food and Drug Administration. Why are
CardiacIonChannelDysfunctionUnderlies HERGchannelssosusceptibletononspecificblockby
InheritedandAcquiredArrhythmias such a wide variety of medications, and why isn’t ac-
Abnormal cardiac repolarization, aberrant conduction, quired long QT syndrome commonly caused by block
and arrhythmia susceptibility are most commonly ac- ofpotassiumchannelsotherthanHERGthatcontribute
quired and not primarily genetic. Common acquired tocardiacrepolarization?Theanswertothesequestions
causesofarrhythmiaincludecardiacischemiaresulting is just beginning to unfold through structural studies
fromthesuddendisruptionofbloodflowtoaregionof ofHERGchannelsexpressedinheterologoussystems
theheart,structuralheartdiseaseslikecardiomyopathy, (Lees-Milleretal.,2000;Mitchesonetal.,2000a)(Figure
developmental abnormalities of the heart such as ar- 5).Thereareatleasttwoimportantstructuralfeatures
rhythmogenicrightventriculardysplasia,metabolicab- that account for the unusual susceptibility of HERG
normalitieslikeabnormalserumpotassium,calciumor channelstoblockbydiversedrugs.First,theinnercavity
magnesiumlevels,andmedications. of the HERG channel appears to be much larger than
Review
577
anyothervoltage-gatedK1channel.Almostallvoltage- andcentralneurons.Together,thesestudieshavede-
gated K1 channel asubunits, except HERG, have two finedanewclassofdisease,ionchannelopathies(Ash-
proline residues in the S6 domains that line the inner croft,2000).
cavityofthechannel.Theseprolinescauseakinkinthe
S6andapparentlyreducethevolumeoftheinnercavity TheFuture:Prediction,Prevention,andTreatment
(delCaminoetal.,2000).ThelargeinnercavityofHERG ofCardiacArrhythmias
channels can accommodate and trap large drugs that Despiterecentadvances,thefieldsofarrhythmiagenet-
otherK1channelscannottrap(Mitchesonetal.,2000b). ics, physiology, and therapy are still immature. Major
Second, the S6 domains of HERG channels, but not problemsthatappearmostprominentincludetheidenti-
other voltage-gated K1 channels, have two aromatic ficationofallarrhythmiasusceptibilitygenes,theidenti-
residues that face into the inner cavity that may bind fication of common geneticvariants that contribute to
large aromatic drugs by a p-stacking interaction (Mit- arrhythmiasusceptibilityinthegeneralpopulationand
chesonetal.,2000a).Thetwoaromaticresidueslocated the implementation of reliable, cost-effective genetic
ineachsubunit(Tyr652,Phe656)provideatotalofeight testing.Genomicsandthehumangenomeprojecthave
residuesthatcanformavariablereceptorsitethatcan alreadyhadamajorimpactonthisfield,andthatinflu-
accommodatedrugsfromdiversetherapeuticandstruc- encewillcontinuetogrowinthenearfuture.Earlyge-
tural classes. In addition, the binding affinity of drugs netic studies involved tedious methods of positional
isenhancedbyinactivationoftheHERGchannel(Ficker, cloning, becauserelatively littleof thehuman genome
1998). The net effect of the structural peculiarities of wasmapped,geneticallyorphysically,andfewhuman
HERGchannelsisheightenedsensitivityofIKrtostruc- genes were defined. The limitations of the technology
turally diverse drugs. Continued structural analysis of availableadecadeagoaddedtothedifficultiesofthese
HERGchannelscoupledwithstructure–activityrelation- experiments.Theearlygeneticlinkageanalyses,forex-
shipanalysisofmedicationswillhelpimproveourability ample, required the use of restriction fragment length
topredictdrugsthatarelikelytocauseasignificantrisk polymorphisms(RFLPs)andSouthernblots.Thesitua-
ofcardiacarrhythmia. tioniscompletelydifferenttoday,andintheverynear
Geneticpredispositionmayplayanimportantrolein future genomics and the human genome project will
drug-inducedlongQTsyndrome.Forexample,lessthan empowerthesefieldstoanevengreaterextent.Genetic
5%ofpatientsreceivingadruglikequinidinehavear- mapswillbeatthelimitsofresolution,allhumangenes
rhythmiaasasideeffect,irrespectiveofdoseandother will be defined and available in online databases, and
riskfactorssuchashypokalemia.Recentstudiesindi- genetictechnologies,particularlyDNAsequenceanaly-
cate that drug-induced arrhythmia can be associated sis, will be robust, reliable, and inexpensive. DNA se-
withsporadicmutations(Abbottetal.,1999)andcom- quenceanalysis,inparticular,willgreatlyfacilitatethe
mon polymorphisms (Sesti et al., 2000) in MiRP1. It is implementation of effective genetic testing for large
likelythatmutationsorpolymorphismsinallofthegenes populations using existing information regarding ar-
associatedwiththeinheritedformsoflongQTsyndrome rhythmiasusceptibilitygenes.
willeventuallybeshowntoincreasetheriskoftheac- Althoughprospectsforfutureresearcharepromising,
quiredformofthisdisease. atleastonesignificanthurdleremains—ascertainment
andphenotypiccharacterizationofindividualswithar-
MultipleEventsAreRequiredtoInduce rhythmia susceptibility and appropriate controls. The
CardiacArrhythmias identification of novel arrhythmia genes and common
Studiesofinheritedandacquiredarrhythmiashaveled arrhythmia susceptibility variants will involve genetic
ustohypothesizeamulti-hitmechanismforthisdisease. epidemiology—the genotypic characterization of large
It is clear that at least three things have to go wrong numbersofcarefullyphenotypedindividuals.Forthemost
simultaneously for a life-threatening arrhythmia to oc- part,theprocessofascertainingandphenotypicallychar-
cur.Forexample,mostindividualscarryingonemutant acterizingindividualshasbeenslowtochange,involving
allele of an arrhythmia susceptibility gene have few, if agreatdealofone-on-oneeffortinaprocessthatisnot
any,arrhythmias.Bycontrast,individualscarryingtwo easily scalable. Even here, however, new technology
mutant alleles (e.g., Jervell and Lange-Nielson syn- holdsthepromiseforsignificantimprovement.Thein-
drome) have many arrhythmias and usually die during ternetrevolutionhasconnectedpopulationsofindividu-
childhood unless effective treatment is implemented. alsseparatedbylargedistancestoinstantaneouslyand
Thattheseindividualsneverthelessliveintoearlychild- effortlessly meet and communicate about many sub-
hood,evenwhenuntreated,indicatesthatanadditional jects, including disease. Many for- and not-for-profit
event,suchastheintroductionofamedication,hypoka- organizationshavecreatedwebsitesaimedatunifying,
lemia,orasinuspause,isrequiredforanarrhythmia.It organizing,empowering,andinformingindividualswith
is clear, however, that a genetic mechanism is not a virtually every imaginable health concern. By creating
prerequisiteforanarrhythmia.Itisknown,forexample, andworkingwiththesewebsites,investigatorsmayac-
thatarrhythmiacanbeinducedinvirtuallyanyonewith celerate the rate-limiting step of the human molecular
therightcombinationofdrug,hypokalemia,andalong geneticprocess.
sinuspause. Functional genomics, thus far largely limited to ex-
Arrhythmiageneticsandphysiologyhaveconverged pression and protein–protein interaction studies, will
withagrowingbodyofevidenceimplicatingionchan- also have an impact on this field. It is already clear
nels in episodic diseases of excitable cells, including that by examining the expression of arrhythmia genes
disordersofskeletalmuscle,vascularsmoothmuscle, intissuesotherthantheheart,onecanhypothesizethe
Cell
578
existence of pathology in other tissues that were not lecularmechanismforaninheritedcardiacarrhythmia.Nature376,
apparent from previous clinical studies. The clinical 683–685.
worldtendstofocusonthemostsevere,life-threaten- Brugada, J., Brugada, R., and Brugada, P. (1997). Right bundle
ing, and obvious phenotypic features of the disorder. branchblock,STsegmentelevationinleadsV1–V3:amarkerfor
suddendeathinpatientswithoutdemonstrablestructuralheartdis-
It is hard to ignore congenital deafness and sudden
ease.Circulation96,1151.
arrhythmic death. However, many of these genes are
Charlier,C.,Singh,N.A.,Ryan,S.G.,Lewis,T.B.,Reus,B.E.,Leach,
expressed in other tissues and evidence of pathology
R.J.,andLeppert,M.(1998).AporemutationinanovelKQT-like
in these tissues is beginning to emerge. KVLQT1, for potassiumchannelgeneinanidiopathicepilepsyfamily.Nat.Genet.
example, is expressed in the pancreas and it may be 18,53–55.
discovered that mutations in this gene cause a subtle Chen,J.,Zou,A.,Splawski,I.,Keating,M.T.,andSanguinetti,M.C.
riskfactorforpancreatitis. (1999). Long QT syndrome-associated mutations in the Per-Arnt
Asmostionchannelsareheteromultimers,andmay Sim(PAS)domainofHERGpotassiumchannelsacceleratechannel
be modulated by interaction with signaling molecules, deactivation.J.Biol.Chem.274,10113–10118.
databases of protein–protein interactions will also be Chen,Q.,Kirsch,G.E.,Zhang,D.,Brugada,R.,Brugada,J.,Brugada,
P.,Potenza,D.,Moya,A.,Borggrefe,M.,Breithardt,G.,etal.(1998).
valuable.Itislikely,however,thateachinteractionwill
Geneticbasisandmolecularmechanismforidiopathicventricular
requirevalidation.Itisalreadyknown,forexample,that
fibrillation.Nature392,293–296.
minKcaninteractwithKVLQT1andHERGwhenoverex-
Compton,S.J.,Lux,R.L.,Ramsey,M.R.,Strelich,K.R.,Sanguinetti,
pressed in heterologeous systems (McDonald et al., M.C., Green, L.S., Keating, M.T., and Mason, J.W. (1996). Gene
1997). It is not clear, however, that the interaction of derivedtherapyininheritedlongQTsyndrome:correctionofabnor-
minK with HERG has physiologic relevance (Abbott et malrepolarizationbypotassium.Circulation94,1018–1022.
al.,1999).Nevertheless,broadfunctionaldatabaseswill Curran,M.E.,Splawski,I.,Timothy,K.W.,Vincent,G.M.,Green,E.D.,
havegreatvalue,atleastasastartingpoint. andKeating,M.T.(1995).Amolecularbasisforcardiacarrhythmia:
Recentmolecularandcellularstudieshaveimportant HERGmutationscauselongQTsyndrome.Cell80,795–803.
implicationsforthepreventionandtreatmentofarrhyth- delCamino,D.,Holmgren,M.,Liu,Y.,andYellen,G.(2000).Blocker
protectionintheporeofavoltage-gatedK1channelanditsstruc-
mias. Identification and characterization of arrhythmia
turalimplications.Nature403,321–325.
susceptibilitygenesprovidethefoundationforpreven-
Duggal, P., Vesely, M.R., Wattanasirichaigoon, D., Villafane, J.,
tion thorough genetic testing. The observation that
Kaushik,V.,andBeggs,A.H.(1998).MutationofthegeneforIsK
HERGchannelfunctionisparadoxicallysensitivetoex-
associatedwithbothJervellandLange-NielsenandRomano-Ward
tracellularpotassiumconcentrationshighlightstheim- formsofLong-QTsyndrome.Circulation97,142–146.
portance of maintaining normal electrolyte levels and Dumaine,R.,Wang,Q.,Keating,M.T.,Hartmann,H.A.,Schwartz,
providesanewstrategyfortreatment(Comptonetal., P.J.,Brown,A.M.,andKirsch,G.E.(1996).Multiplemechanismsof
1996).Themostimportanttherapeuticconsequenceof sodiumchannel-linkedlongQTsyndrome.Circ.Res.78,914–924.
thiswork,however,isthemessageitdeliverstophysi- Ficker,E.(1998).MoleculardeterminantsofdofetilideblockofHERG
ciansandtothepharmaceuticalindustry:theobserva- K1channels.Circ.Res.82,386–395.
tions that gain- and loss-of-function mutations of the Gellens,M.,George,A.,Chen,L.,Chahine,M.,Horn,R.,Barchi,R.,
cardiacsodiumchannelbothcausearrhythmiasuscep- andKallen,R.(1992).Primarystructureandfunctionalexpression
of the human cardiac tetrodotoxin-insensitive voltage-dependent
tibility indicate that drugs that modulate cardiac ion
sodiumchannel.Proc.Natl.Acad.Sci.USA89,554–558.
channel function may reduce the risk of one type of
Hoorntje,T.,Alders,M.,vanTintelen,P.,vanderLip,K.,Sreeram,
arrhythmia but increase the risk of another. Thus,
N.,vanderWal,A.,Mannens,M.,andWilde,A.(1999).Homozygous
chronicuseofcardiacionchannelblockerscanbedan- prematuretruncationoftheHERGprotein:thehumanHERGknock-
gerous.Thefutureofarrhythmiatherapymaybedevices out.Circulation100,1264–1267.
thatmeasurecardiacconductionandrepolarization,de- Jervell,A.,andLange-Nielsen,F.(1957).Congenitaldeaf-mutism,
liver appropriate antiarrhythmic drugs when needed, functionalheartdiseasewithprolongationoftheQTinterval,and
andprovideasafetynetintheformofautomaticinternal suddendeath.Am.HeartJ.54,59–68.
defibrillation(Moss,1997). Jiang,C.,Atkinson,D.,Towbin,J.,Splawski,I.,Lehmann,M.,Li,H.,
Timothy,K.,Taggart,R.,Schwartz,P.,Vincent,G.,etal.(1994).Two
Acknowledgments longQTsyndromelocimaptochromosome3and7withevidence
forfurtherheterogeneity.Nat.Genet.8,141–147.
We thank I. Splawski for advice, D. Atkinson for help preparing Kannel,W.,Cupples,A.,andD’Agostino,R.(1987).Suddendeath
figures,andL.Morelliforassistancepreparingthemanuscript. riskinovertcoronaryheartdiseases:theFraminghamstudy.Am.
HeartJ.113,799–804.
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