mechanisms of sudden cardiac death...mechanisms of sudden cardiac death michael rubart1,2 and...
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Mechanisms of sudden cardiac death
Michael Rubart, Douglas P. Zipes
J Clin Invest. 2005;115(9):2305-2315. https://doi.org/10.1172/JCI26381.
Despite recent advances in preventing sudden cardiac death (SCD) due to cardiacarrhythmia, its incidence in the population at large has remained unacceptably high. Betterunderstanding of the interaction among various functional, structural, and genetic factorsunderlying the susceptibility to, and initiation of, fatal arrhythmias is a major goal and willprovide new tools for the prediction, prevention, and therapy of SCD. Here, we review therole of aberrant intracellular Ca2+ handling, ionic imbalances associated with acutemyocardial ischemia, neurohumoral changes, and genetic predisposition in thepathogenesis of SCD due to cardiac arrhythmia. Therapeutic measures to prevent SCD arealso discussed.
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Science in medicine
TheJournalofClinicalInvestigationâ â â http://www.jci.orgâ â â Volumeâ115â â â Numberâ9â â â Septemberâ2005â 2305
Mechanisms of sudden cardiac deathMichael Rubart1,2 and Douglas P. Zipes1
1Krannert Institute of Cardiology and 2Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Despiterecentadvancesinpreventingsuddencardiacdeath(SCD)duetocardiacarrhythmia,itsincidenceinthepopulationatlargehasremainedunacceptablyhigh.Betterunderstandingoftheinteractionamongvariousfunctional,structural,andgeneticfactorsunderlyingthesuscep-tibilityto,andinitiationof,fatalarrhythmiasisamajorgoalandwillprovidenewtoolsfortheprediction,prevention,andtherapyofSCD.Here,wereviewtheroleofaberrantintracellularCa2+handling,ionicimbalancesassociatedwithacutemyocardialischemia,neurohumoralchanges,andgeneticpredispositioninthepathogenesisofSCDduetocardiacarrhythmia.TherapeuticmeasurestopreventSCDarealsodiscussed.
Suddenâcardiacâdeathâ(SCD)âfromâanyâcauseâclaimsâ300,000â400,000âlivesâaâyearâinâtheâUnitedâStates.âTheâmostâcommonâsequenceâofâeventsâleadingâtoâSCDâappearsâtoâbeâtheâdegenera-tionâofâventricularâtachycardiaâ(VT;âabnormalâaccelerationâofâventricularârate)âintoâventricularâfibrillationâ(VF),âduringâwhichâdisorganizedâcontractionsâofâtheâventriclesâfailâtoâejectâbloodâeffectively,â oftenâ followedâ byâ asystoleâ orâ pulselessâ electricalâactivity.âPreexistingâcoronaryâarteryâdiseaseâandâitsâconsequenc-esâ(acuteâmyocardialâischemia,âscarringâfromâpreviousâmyocar-dialâinfarction,âheartâfailure)âareâmanifestâinâ80%âofâSCDâvic-tims.âDilatedânonischemicâandâhypertrophicâcardiomyopathiesâaccountâforâtheâsecondâlargestânumberâofâSCDs,âwhereasâotherâcardiacâdisorders,âincludingâcongenitalâheartâdefectsâandâtheâknownâgeneticallyâdeterminedâionâchannelâanomalies,âaccountâforâ5â10%âofâSCDsâ(1).
Whileâ theâ implantableâ cardioverterâ defibrillatorâ (ICD)âimprovesâ survivalâ inâ high-riskâ patientsâ (2),â standardâ anti-arrhythmicâ drugâ therapyâ hasâ failedâ toâ reduce,â andâ inâ someâinstancesâhasâincreased,âtheâincidenceâofâSCDâ(3).âInâfact,âtheâgreatestâreductionâinâcardiovascularâmortalityâ(includingâSCD)âinâpatientsâwithâclinicallyâmanifestâheartâdiseaseâhasâresultedâfromâtheâuseâofâbetaâblockersâ(4)âandânon-antiarrhythmicâdrugs,âi.e.,âthoseâwithoutâmajorâdirectâelectrophysiologicalâactionâinâcardiacâmuscleâorâtheâspecializedâconductionâsystem,âsuchâasâangiotensin-convertingâenzymeâ(ACE)âinhibitors,âangiotensinâreceptorâblockingâagents,âlipid-loweringâagents,âspironolac-tone,âthrombolyticâandâantithromboticâagents,âandâperhapsâmagnesiumâandâomega-3â fattyâacidsâ (forâ review,â seeâ ref.â5).ââTheseâdrugsâmostâlikelyâexertâtheirâantiarrhythmicâpotentialâindirectlyâ byâ inhibitingâ orâ delayingâ adverseâ functionalâ andâstructuralâremodelingâinâtheâdiseasedâheart,âi.e.,âbyâaffectingâ
âupstreamâeventsââthatâcontributeâtoâtheâdevelopmentâofâelec-trophysiologicalâinstability.
Clinicalâtrials,âinâgeneral,âhaveâfailedâtoâdefineâSCDâriskâmark-ersâ forâspecificâ individualsâ inâtheâ largerâgeneralâpopulation,âwhereâtheârelativeâriskâofâSCDâisâlowâbutâtheâabsoluteânumberâofâdeathsâisâhigh.âRiskâmarkersâincludeâabnormalitiesâinâcardio-vascularâfunctionâ(left-ventricularâejectionâfraction),âelectrocar-diographicâvariablesâ(e.g.,âlateâpotentials,âT-waveâalternans,âQRSâduration,âdispersionâofârepolarization),âresultsâofâelectrophysi-ologicalâtestingâ(programmedâelectricalâstimulation),âandâmea-suresâofâcardiacâautonomicâfunctionâ(heartârateâatârestâandâdur-ingâexercise,âheartârateâvariability,âandâbaroreflexâsensitivity),âasâwellâasâambientâventricularâarrhythmiasâ(prematureâventricularâdepolarizations,ânonsustainedâandâsustainedâVT).
Acquiredâfunctionalâandâstructuralâchangesâoccurringâinâtheâdiseasedâheartâasâwellâasâgeneticâfactorsâ(e.g.,âmutationsâofâionâchannelâencodingâgenes,âpolymorphismâofâcoagulationâfactorsâorâβ-adrenergicâreceptors)âmayâcontributeâtoâanâincreasedâriskâofâdyingâsuddenly,âbutâtheseâfactorsâaloneâcannotâexplainâtheâapparentârandomnessâofâtheâoccurrenceâofâfatalâarrhythmias.âTheânatureâofâtheâimmediate precipitating eventâthatâtriggersâtheâfatalâventricularâtachyarrhythmiaâatâaâspecificâtimeâinâanâotherwiseâstableâpatientâremainsâasâtheâmajorâunansweredâquestion.âBet-terâunderstandingâofâtheâinteractionâamongâvariousâfunction-al,âstructural,âandâgeneticâfactorsâthatâareâthoughtâtoâunderlieâtheâsusceptibilityâto,âandâinitiationâof,âfatalâarrhythmiasâisâtheâmajorâgoalâofâfutureâresearchâandâshouldâprovideânewâtoolsâforâtheirâprediction,âprevention,âandâtherapy.âThisâreviewâwillâhigh-lightâtheâroleâofâsomeâofâtheseâfactors,âwithâaâfocusâonâalteredâintracellularâCa2+âdynamics,âacuteâmyocardialâischemia,âneuro-humoralâchanges,âand,âbriefly,âgeneticâpredisposition.âAdditionalâmechanismsâasâwellâasâtherapeuticâandâdiagnosticâapproachesâareâdiscussedâinâotherârecentlyâpublishedâreviewâarticlesâ(6â9).
The normal electrocardiogram and its relation to the transmembrane action potential and activities of cardiac ion channelsBothâtheâanatomyâandâphysiologyâofâtheâspecializedâconductionâsystemâandâworkingâcardiacâmuscleâdetermineâhowâtheâheartâisâactivated.âOneâcycleâofâaânormalâECGâisâshownâinâFigureâ1A.âTheâPâwaveâisâproducedâbyâtheâelectricalâactivationâofâtheâatria,âandâtheâPRâintervalârepresentsâtheâdurationâofâconductionâfromâtheâsinusânode,âthroughâtheâatriaâtoâtheâventricles;â theâQRSâcomplexâisâgeneratedâbyâelectricalâactivationâofâtheâventricles;â
Nonstandardabbreviationsused:âACE,âangiotensin-convertingâenzyme;ââ[Ca2+]i,âintracellularâCa2+âconcentration;âCASQ2,âcalsequestrinâ2;ââCPVT,âcatecholaminergicâpolymorphicâVT;âDAD,âdelayedâafter-depolarization;âEAD,âearlyâafter-depolarization;âFKBP12.6,â12.6-kDaâFK506-bindingâprotein;ââICa.L,âL-typeâCa2+âcurrent;âICD,âimplantableâcardioverterâdefibrillator;ââINa/Ca,âNa+/Ca2+âexchangeâcurrent;âIP3,âinositol-1,4,5âtriphosphate;ââIto,âtransientâoutwardâK+âcurrent;âLQTS,âlong-QTâsyndrome;â[Na+]i,ââintracellularâNa+âconcentration;âRAS,ârenin-angiotensinâsystem;ââRyR2,âryanodineâreceptorâ2;âSCD,âsuddenâcardiacâdeath;âSR,âsarcoplasmicââreticulum;âVF,âventricularâfibrillation;âVm,âmembraneâpotential;ââVT,âventricularâtachycardia.
Conflictofinterest:âTheâauthorsâhaveâdeclaredâthatânoâconflictâofâinterestâexists.
Citationforthisarticle:âJ. Clin. Invest.â115:2305â2315â(2005).ââdoi:10.1172/JCI26381.
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andâtheâST-Tâwaveâreflectsârecovery.âDuringâaânormalâcardiacâcycle,âelectricalâexcitationâstartsâinâtheâsinusânode,âthenâmovesâtoâtheâatria,âcrossingâtheâatrioventricularânodeâandâHisâbundle,âandâfinallyâreachesâtheâventricles.âTheâQRSâcomplexâreflectsâtheâsumâofâtheâspatialâpatternsâofâventricularâactivation.âVentricularâexcitationârapidlyâspreadsâ alongâ theâ specializedâ intracar-diacâ conductionâ systemâ (His-Purkinjeâsystem)âinâtheâendocardium,âresultingâinâdepolarizationâofâmostâofâtheâendocardialâsurfacesâofâbothâventriclesâwithinâseveralâmilliseconds.âTheâactivationâfrontâthenâmovesâfromâendocardiumâtoâepicardium,âstartingâatâtheâPurkinjeâmuscleâcellâjunc-tionsâandâproceedingâbyâcell-to-cellâcon-ductionâthroughâtheâmuscleâtowardâtheâepicardium.â Ventricularâ recovery,â likeâactivation,âoccursâinâaâstereotypicalâgeo-metricalâpattern.âDifferencesâinârecoveryâtimingâoccurâbothâacrossâtheâventricularâwallâandâbetweenâregionsâofâtheâleftâandârightâventriclesâandâgiveâriseâtoâtheâchar-acteristicâmorphologyâofâtheâST-Tâwaveâinâtheâelectrocardiogram.
Transmembraneâionicâcurrentsâareâulti-matelyâresponsibleâforâtheâelectricalâactivityârecordedâinâtheâECG.âShownâinâFigureâ1Bâareâtheâmajorâionâfluxesâduringâaânormalâven-tricularâactionâpotential.âInitialâNa+âinfluxâthroughâopenâNa+âchannelsâcausesârapidâmembraneâdepolarization,âwhichâinâturnâactivatesâCa2+âchannels.âTheâensuingâinflowâofâCa2+âcausesâCa2+âreleaseâchannelsâinâtheâsarcoplasmicâreticulumâ(SR)âmembraneâtoâopen,âincreasingâtheâcytosolicâcalciumâlevelâandâcausingâcontraction.âFinally,âanâincreaseâinâK+âeffluxâthroughâactivatedâK+âchannelsârestoresâtheârestingâmembraneâpotentialâ(Vm;ârepolarization),âandâremovalâofâCa2+âfromâtheâcytosolâdeactivatesâcontractileâproteins,âtherebyârelaxingâtheâcardiacâmuscle.
The emerging role of altered intracellular Ca2+ dynamics in cardiac arrhythmogenesisAlterationsâinâintracellularâcalciumâhomeostasisâplayâanâimportantâroleâinâtheâdevelopmentâofâventricularâtachyarrhythmiasâinâtheâfailingâheartâ(10),âasâwellâasâinâsomeâinheritedâsyndromesâleadingâtoâSCD.âCongenitalâCa2+âhandlingâanomaliesâinâtheâheartâincludeâdefectiveâfunctionâofâtheâryanodineâreceptorâ2â(RyR2)âinâcatechol-aminergicâpolymorphicâVTâ(CPVT)â(11);âaâloss-of-functionâmuta-tionâinâankyrin-Bâcausingâtypeâ4âlong-QTâcardiacâarrhythmiasâ(12);âandâaâmissenseâmutationâofâcalsequestrinâ2â(CASQ2)âcaus-ingâstress-inducedâpolymorphicâVTâ(13).âDisruptionâofâtheâgeneâencodingâtheâ12.6-kDaâFK506-bindingâproteinâ(FKBP12.6),âwhichâreversiblyâassociatesâwithâandâmodulatesâtheâactivityâofâRyR2,âcausesâsimilarâalterationsâinâintracellularâCa2+âsignalingâinâcardio-myocytesâofâmaleâandâfemaleâmiceâbutâresultsâinâhypertrophyâinâmaleâmiceâonlyâ(14).âItâisâcurrentlyânotâknownâwhetherâsimilarâgen-
Figure 1Temporal relationship between ECG and single cardiomyocyte action potential. (A) The waves and intervals of a normal ECG. (B) Sche-matic representation of a ventricular action potential and its major underlying ionic currents. The downward arrow indicates influx; the upward arrow, efflux.
Figure 2Schematic illustration of intracellular Ca2+ cycling and associated second messenger pathways in cardiomyocytes (figure modified from ref. 84). AC, adenylyl cyclase; a, G protein subunit a; a-receptor, a-adrenergic receptor; β, G protein subunit β; β-receptor, β-adrenergic recep-tor; g, G protein subunit g; LTCC, L-type Ca2+ channel; CAMKII, Ca2+-calmodulin kinase II; I-1, inhibitor 1; NCX, Na+/Ca2+ exchanger; P, phosphate group; PLC, phospholipase C; PLN, phospholamban; PP1, protein phosphatase 1; PP2A, protein phosphatase 2A; SERCA2a, SR Ca2+-ATPase isoform 2a; T-tubule, transverse tubule.
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TheJournalofClinicalInvestigationâ â â http://www.jci.orgâ â â Volumeâ115â â â Numberâ9â â â Septemberâ2005â 2307
derâdifferencesâexistâforâtheâsusceptibilityâtoâarrhythmiasâinâheartsâexhibitingâinheritedâdisordersâofâCa2+âhandlingâproteins.
Cardiac arrhythmogenesis associated with RyR2 dysfunction in CPVT and heart failure.âRyR2âisâtheâmajorâCa2+âreleaseâchannelârequiredâforâexcitation-contractionâcouplingâinâcardiomyocytes.âDepolar-izationâofâtheâcardiomyocyteâcellâmembraneâcausesâCa2+âinfluxâthroughâ activatedâ voltage-dependentâ L-typeâ Ca2+channels,âwhichâ inâ turnâ initiatesâ Ca2+â releaseâ viaâ RyR2sâ fromâ theâ SRââ(Figureâ2),âknownâasâCa2+-inducedâCa2+âreleaseâ(15).âRyR2-medi-atedâCa2+âreleaseâactivatesâcontractileâproteins,âwhichâresultsâinâcardiacâcontractionâduringâsystole.âDuringâdiastole,âcytosolicâCa2+âre-sequestersâintoâtheâSRâviaâtheâphospholamban-regulatedâSRâCa2+-ATPaseâisoformâ2aâ(SERCA2a);âbindingâofâFKBP12.6â(alsoâknownâasâcalstabin2)âtoâtheâRyR2âcomplexâmaintainsâtheâchannelâinâaâclosedâstateâtoâpreventâleakageâofâSRâCa2+âintoâtheâcytoplasm.âPhosphorylationâofâRyR2sâbyâPKAâduringâadrenergicâstimulationâ(e.g.,âexercise)âdissociatesâFKBP12.6âfromâtheâRyR2âchannelâcom-plex,âwhichâresultsâinâincreasedâRyR2âopenâprobability,âdefinedâasâtheâfractionâofâtimeâtheâchannelâisâinâtheâopen,âi.e.,âconducting,âstate.âRyR2âmutationsâinâpatientsâwithâCPVTâreduceâtheâaffin-ityâofâtheâSRâCa2+âreleaseâchannelâforâFKBP12.6,âwhichâcausesâCa2+âtoâleakâoutâofâtheâSRâduringâdiastoleâ(11).âTheâelectrocar-
diographicâphenotypeâofâclinicalâCPVTâisâmimickedâinâtransgenicâmiceâdeficientâinâFKBP12.6â(16).âIncreasingâtheâbindingâaffinityâofâFKBP12.6âforâtheâRyR2âcomplexâpreventsâexercise-âandâcatechol-amine-inducedâpolymorphicâVTâandâSCDâinâFKBP12.6-deficientâmiceâ(16).âInâheartâfailure,âtheâRyR2âchannelâFKBP12.6âcomplexâhasâbeenâshownâtoâbeâdepletedâofâFKBP12.6âdueâtoâchronicâPKA-mediatedâhyperphosphorylation,âwhichâresultsâinâanâabnormalâincreaseâinâRyR2âopenâprobabilityâduringâdiastoleâ(10).
WhereasâtheseâobservationsâprovideâcompellingâevidenceâthatâabnormalitiesâinâintracellularâCa2+âhomeostasisâplayâaâprimaryâroleâinâcausingâSCDâdueâtoâcardiacâarrhythmias,âtheâmechanismâbyâwhichâspontaneousâCa2+âreleaseâfromâtheâSRâcanâtriggerâfatalâarrhythmiasâhasâremainedâelusive.
Congenitalâand/orâacquiredâfactorsâcanâcauseâaâdiastolicâCa2+âleakâthroughâRyR2â(Figureâ3A),âgivingâriseâtoâlocalizedâincreasesâinâcytosolicâcalciumâ(Figureâ3B,âii)âinâaâsingleâcardiomyocyteâloadedâwithâaâCa2+-sensitiveâfluorescentâdye.âTheâfocallyâelevatedâCa2+âthenâdiffusesâtoâadjacentâjunctionalâSRâtoâactivateâCa2+âreleaseâchannelsâandâinduceâreleaseâofâCa2+âthatâcanâthenâpropagateâthroughoutâtheâcell.âThisâregenerativeâpropagatingâprocessâhasâpreviouslyâbeenâtermedâaâCa2+âwaveâ(17).âDiastolicâCa2+âwavesâdepolarizeâtheâcar-diomyocyteâmembrane,âtriggeringâaâdelayedâafter-depolarizationâ
Figure 3Proposed scheme of events leading to DADs and triggered tachyarrhythmia. (A) Congenital (e.g., ankyrin-B mutation) and/or acquired factors (e.g., ischemia, hypertro-phy, increased sympathetic tone) will cause a diastolic Ca2+ leak through RyR2, result-ing in localized and transient increases in [Ca2+]i in cardiomyocytes. (B) Representa-tive series of images showing changes in [Ca2+]i during a Ca2+ wave in a single car-diomyocyte loaded with a Ca2+-sensitive fluorescent dye. Images were obtained at 117-ms intervals. Focally elevated Ca2+ (ii) diffuses to adjacent junctional SR, where it initiates more Ca2+ release events, resulting in a propagating Ca2+ wave (iiiâviii). Repro-duced with permission from Biophysical Journal (85). (C) The Ca2+ wave, through activation of Ca2+-sensitive inward currents, will depolarize the cardiomyocyte (DAD). In cardiomyocytes, the inward INa/Ca is the major candidate for the transient inward current underlying DADs, although the role of the Ca2+-activated Clâ current [ICl(Ca)] and a Ca2+-sensitive nonspecific cation current [INS(Ca)] cannot be excluded. If of sufficient magnitude, the DAD will depolarize the cardiomyocyte above threshold resulting in a single or repetitive premature heartbeat (red arrows), which can trigger an arrhyth-mia. Downregulation of the inward rectifier potassium current (IK1), upregulation of INa/Ca, or a slight increase in intercellular electrical resistance can promote the generation of DAD-triggered action potentials. S, stimulus. Modified with permission from Circulation Research (26) and Nature (12).
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(DAD)âviaâtransientâactivationâofâaâCa2+-dependentâinwardâcurrentâ(18)â(Figureâ3C).âCandidatesâforâtheâtransientâinwardâcurrentâareâtheâelectrogenicâNa+/Ca2+âexchangeâcurrentâ(INa/Ca)âoperatingâinâitsâforwardâmodeâ(extrudingâCa2+âandâtakingâupâNa+âinâaâ1:3âstoi-chiometry);âtheâCa2+-activatedâClââcurrentâ(ICl(Ca));âandâaâCa2+-acti-vatedânonselectiveâcationâcurrentâ(INS(Ca)).âMoreârecentâworkâhasâsupportedâaâmajorâroleâofâINa/CaâinâcausingâDADsâinâventricularâmyocytes,âwithâICl(Ca)âandâINS(Ca)âcontributingâonlyâaâlittleâorânotâatâallâtoâDADâinitiationâ(18).
OnlyâwhenâspontaneousâCa2+âreleaseâeventsâoccurâatâmultipleâsitesâsynchronouslyâwithinâtheâcellâwillâtheirâspatialâandâtempo-ralâsummationâresultâinâaâriseâinâintracellularâCa2+âconcentrationâ([Ca2+]i)âofâsufficientâmagnitudeâtoâtriggerâanâactionâpotential.âIncreasesâinâ[Ca2+]iâexceedingâ1âmmol/lâareârequiredâforâactionâpotentialâactivationâinâisolatedâventricularâcardiomyocytesâ(18),âwhichâcanâthenâpropagateâthroughoutâtheâventriclesâtoâinduceâanâextraâheartbeat,âleadingâtoâVTâandâVFâ(Figureâ3C).âWhileâfactorsâdeterminingâwhetherâaâDADâtriggersâanâactionâpotentialâinâiso-latedâcardiomyocytesâhaveâbeenâcharacterized,âwhatâdeterminesâwhetherâaâDADâproducesâaâpropagatingâactionâpotentialâinâtheâintactâmyocardiumâisâlessâwellâknown.
Inâtheâintactâheart,âtheâchangeâinâVmâinâresponseâtoâaâgivenâincreaseâinâinwardâcurrentâactivatedâbyâtheâlocalâincreaseâinâ[Ca2+]iâisâusuallyâlessâthanâthatâinâanâisolatedâcardiomyocyteâbecauseâmoreâpassiveâoutwardâcurrentâopposesâtheâdepolarizingâeffectâofâlocallyâactivatedâNa+âchannelâcurrentâinâcardiacâtissue.âIndi-vidualâcardiomyocytesâareâelectricallyâcoupledâtoâtheirâneighbors,âasâopposedâtoâisolatedâcardiomyocytes,âwhichâareâdisconnected.âTherefore,âtoâinduceâmembraneâdepolarizationâinâaâsufficientânumberâofâcardiomyocytesâsimultaneouslyâtoâeffectivelyâincreaseâtheâcurrentâload,âactionâpotentialâinitiationâfromâaâDADâinâtheâwholeâheartâwouldâprobablyârequireâthatâspontaneousâCa2+âwavesâoccurâalmostâsynchronouslyâinâmultiple,âcloselyâadjacentâcardio-myocytesâorâthatâaâsingleâCa2+âwaveârapidlyâpropagateâacrossâcellâborders.âHowever,âCa2+âwavesâinâintactâcardiacâpreparationsârarelyâspreadâtoâtheirâneighboringâcellsâunderâphysiologicalâconditionsâandâdoânotâappearâtoâoccurâsynchronouslyâinâmultipleâcontigu-ousâcardiomyocytesâ(17,â19,â20).âElectrophysiologicalâchangesâoccurringâ inâ theâ failingâheart,â suchâasâdoublingâofâNa+/Ca2+ââexchangerâexpressionâandâreductionâinârepolarizingâK+âcurrentsâ(18),âcouldâfacilitateâactionâpotentialâinitiationâfromâaâDADâ(6).âThus,âforâanyâgivenâincreaseâinâ[Ca2+]i,âtheâinwardâcurrentâcar-riedâbyâtheâNa+/Ca2+âexchangerâwillâbeâdoubled,âandâtheâreduc-tionâofâoutwardlyâdirectedâK+âcurrentsâwillâenhanceâtheâdepolar-izingâeffectâofâaâgivenâINa/Ca.âFurthermore,âreducedâintercellularâelectricalâcouplingâinânonischemicâfailingâmyocardiumâ(21)âandâredistributionâofâgapâjunctionsâbetweenâcardiomyocytesâinâtheâepicardialâborderâzoneâofâchronicâinfarctsâ(22)âmayâbluntâelectro-tonicâinteractionsâbetweenâDAD-generatingâcardiomyocytesâandâtheirâneighbors,âreducingâtheâinwardâcurrentârequiredâtoâdepolar-izeâtheâcardiomyocytesâaboveâthreshold.âHowever,âanâincreaseâinâintercellularâresistanceâmayâpreventâtheâpropagationâofâtriggeredâactionâpotentials.âFinally,âincreasedâadrenergicâactivationâinâfail-ingâmyocardiumâleadsâtoâSRâCa2+âoverload,âresultingâinâenhancedâactivityâofâRyR2âchannelsâduringâdiastoleâ(23)âandâtheâenhancedâprobabilityâofâCa2+âwaveâoccurrence.
Collectively,âtheseâresultsâstronglyâsuggestâthatâdefectiveâRyR2âgatingâandâassociatedâaberrantâCa2+âreleaseâfromâtheâSRâduringâdiastoleâmayâconstituteâtheâmolecularâtriggerâforâarrhythmiaâini-tiationâinâtheâfailingâheartâ(Figureâ3).
Three-dimensionalâmappingâstudiesâinâintactâheartsâsupportâtheâhypothesisâthatâspontaneousâSRâCa2+âreleaseâeventsâactâasâfocalâtriggersâofâarrhythmiasâbyâshowingâthatânearlyâallâVTâinânonischemicâheartâfailureâandâapproximatelyâ50%âofâthoseâinâischemicâheartâfailureâariseâfromâabnormalâautomaticityâ(ectopicâpacemakerâfiringâatâaârateâgreaterâthanâtheâsinusânodeârate)âorâtriggeredâactivity,âsuchâasâDADsâandâearlyâafter-depolarizationsâ(EADs)â(24â26).âHowever,âopticalâmappingâstudiesâinâisolatedâperfusedâleft-ventricularâwedgeâpreparationsâhaveârevealedâthatâelectricalâreentryâwasâtheâprimaryâmechanismâresponsibleâforâVTâduringâacuteâmyocardialâischemiaâ(27,â28).âReentrantâexcitationâcanâoccurâwhenâmyocardiumânotâactivatedâduringâaâprecedingâwaveâofâdepolarizationârecoversâexcitabilityâ inâtimeâtoâbeâdis-chargedâbeforeâtheâimpulseâdiesâout.
Ankyrin-B mutation in long-QT4 syndrome.âAâ loss-of-functionâmutationâinâankyrin-Bâ(alsoâknownâasâankyrinâ2),âaâmemberâofâaâfamilyâofâmembraneâadaptorâproteins,âcausesâtypeâ4âlong-QTâsyndromeâ(LQTS)âcardiacâarrhythmiasâandâSCDâ(12).âTheâcon-genitalâLQTSâisâcharacterizedâbyâprolongationâofâtheâQTâintervalâ(seeâFigureâ1),ârecurrentâsyncope,âandâlife-threateningâVT/VF.âInâadditionâtoâtheâmutationâinâtheâgeneâencodingâankyrin-B,âloss-âorâgain-of-functionâmutationsâinâaânumberâofâdifferentâionâchan-nelâencodingâgenes,âincludingâcardiacâNa+âandâK+âchannelâgenes,âhaveâbeenâidentifiedâinâinheritedâLQTS.âAnkyrin-BâisâtheâfirstâproteinâtoâbeâimplicatedâinâLQTSâthatâisânotâanâionâchannelâorâauxiliaryâionâchannelâsubunit.
Transgenicâ miceâ heterozygousâ forâ theâ ankyrin-Bâ mutation,âwhichâresultsâinâsubstitutionâofâglycineâforâaâglutamicâacidâatâaminoâacidâresidueâ1425â(E1425G),âexhibitâaâcardiacâphenotypeâthatâisâveryâsimilarâtoâthatâseenâinâtypeâ4âLQTSâpatients,âincludingâQTâprolongation,âintermittentâsinusâbradycardia,âandâSCDâfromâstress-inducedâpolymorphicâVTâ(seeâFigureâ3C)â(12).âAnkyrin-Bâmutationsâdisruptâtheâcellularâorganizationâofâankyrin-Bâbindingâpartnersâinâcardiomyocytes,âincludingâtheâNa+/Ca2+âexchanger,âtheâNa+/K+âATPaseâ(anâelectrogenicâpumpâinâtheâouterâmembraneâextrudingâNa+âionsâandâtakingâupâK+âionsâinâaâ3:2âstoichiometry),âandâtheâinositol-1,4,5âtriphosphateâ(IP3)âreceptorâ(aâCa2+âreleaseâchannelâinâtheâSRâthatâisâactivatedâbyâbindingâofâIP3),âresultingâinâreducedâtargetingâofâtheseâproteinsâtoâtheâtransverseâtubulesâ(Figureâ2)âasâwellâasâreducingâtheirâoverallâexpressionâlevels.âPeakâamplitudesâofâdepolarization-inducedâ[Ca2+]iâtransientsâareâmark-edlyâincreasedâinâsingleâcardiomyocytesâisolatedâfromâheterozygousâankyrin-Bâmutantâ(AnkB+/â)âmice.âItâisâconceivableâthatâreducedâactivityâofâtheâNa+/K+âATPaseâincreasesâintracellularâNa+âconcentra-tionâ([Na+]i),âwhichâinâturnâinhibitsâCa2+âextrusionâbyâtheâNa+/Ca2+ââexchangerâintoâtheâextracellularâspaceâ(seeâFigureâ2).âAsâNa+/Ca2+ââexchangerâ expressionâ isâ reduced,â totalâ cellularâ Ca2+â contentâbecomesâelevated.âCellularâCa2+âoverloadâcanâleadâtoâincreasedâinci-denceâofâDAD-generatingâCa2+âwaves.âTransmembraneâpotentialârecordingsâinâsingleâAnkB+/ââcardiomyocytesâduringâβ-adrenergicâreceptorâactivationârevealedâextrasystolesâarisingâfromâDADsâasâwellâasâfromâEADsâ(12),âwhichâsuggestsâthatâtheseâmechanismsâareâresponsibleâforâatâleastâsomeâofâtheâVT/VFâinâLQTSâpatients.
Whereasâ itâ isâgenerallyâacceptedâthatâDADsâareâ initiatedâbyâspontaneousâCa2+âreleaseâfromâtheâSR,âtheâinvolvementâofâSRâCa2+âreleaseâinâtheâgenerationâofâEADsâoccurringâinâtheâplateauâphaseâofâtheâactionâpotentialâisâcontroversial.âSomeâEADsâareâattributableâtoârecoveryâfromâinactivationâandâreactivationâofâvoltage-depen-dentâL-typeâCa2+âchannelsâduringâprolongedâactionâpotentials,âwhileâEADsâoccurringâlateâduringârepolarizationâmayâariseâfromâ
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spontaneousâSRâCa2+âreleaseâandâtransientâactivationâofâaâdepo-larizingâinwardâcurrent.âTheâroleâofâCa2+âhandlingâinâtheâinitia-tionâofâEADsâandâpolymorphicâVTâ(torsadeâdeâpointesâ[TdP])âhasârecentlyâbeenâstudiedâbyâtheâsimultaneouslyâmappingâofâVmâandâ[Ca2+]iâinâanâanimalâmodelâofâtypeâ2âLQTSâ(29).âItâwasâshownâthatâatâtheâsitesâofâoriginâofâEADs,âincreasesâinâ[Ca2+]iâprecededâmem-braneâdepolarization,âwhereasâawayâfromâtheseâsites,âincreasesâinâ[Ca2+]iâcoincidedâwithâorâfollowedâmembraneâdepolarization.âConceivably,âspontaneousâCa2+âreleaseâfromâinternalâstoresâacti-vatesâinwardâcurrentsâtoâgenerateâanâEADâandâaâpropagatedâactionâpotential.âIschemiaâcanâenhanceâtheâdevelopmentâofâEADsâunderâsomeâcircumstancesâ(30).
CASQ2 mutation in CPVT.â Aâ missenseâ mutationâ inâ theâ geneâencodingâCASQ2,âaâCa2+-bindingâproteinâinâtheâcardiacâluminalâSR,âcausesâtheârecessiveâformâofâCPVT.âSequenceâanalysesâofâtheâCASQ2âgenesâofâCPVTâpatientsârevealedâsubstitutionâofâhistidineâforâanâasparticâacidâatâaminoâacidâresidueâ307â(D307H).âSimulta-neousârecordingsâofâVmâandâ[Ca2+]iâinâsingleâcardiomyocytesâwithâadenovirus-mediatedâexpressionâofâCASQ2âcarryingâtheâCPVT-linkedâmutationâD307Hâ(CASQ2D307H)ârevealedâCa2+âwavesâandâassociatedâDADsâduringârapidâpacingâandâβ-adrenergicâreceptorâstimulationâ(13).âPrimaryâalterationsâinâcellularâCa2+âhomeosta-sis,âsimilarâtoâthoseâunderlyingâCPVTâandâlong-QT4âarrhythmias,âcouldâconstituteâtheâtriggerâforâtheseâarrhythmogenicâevents.
SR Ca2+ cycling in VF and electrical alternans.â Atâ normalâ heartârates,â[Ca2+]iâreliablyâandâconsistentlyâtracksâchangesâinâVm.âMap-pingâstudiesâhaveâdemonstratedâthatâSRâCa2+âcyclingâmayâexhibitâintrinsicâdynamicsâandâmayâbecomeâindependentâofâchangesâinâVmâduringâVF.âNonâvoltage-gatedâSRâCa2+âreleaseâevents,âthroughâmodulationâofâCa2+-sensitiveâmembraneâcurrents,âthenâcauseâlocalâalterationsâinâactionâpotentialâdurationâandâmyocardialârefractori-ness,âwhichâinâturnâpromoteâtheâmaintenanceâofâfibrillatoryâactiv-ityâ(31).âThus,âspatialâheterogeneityâofâ[Ca2+]iâsignalingâmayâactânotâonlyâasâaâtriggerâbutâalsoâasâaâstabilizerâofâVT/VF.
Beat-to-beatâvariationsâinâT-waveâmorphologyâand/orâpolarityâ(T-waveâalternans),âaâmarkerâofâincreasedâelectricalâinstabilityâandâfibrillationâ(32),âariseâfromâalternationâinâactionâpotentialâdura-tion.âSimultaneousâmeasurementsâofâ[Ca2+]iâandâVmâinâsingleâcar-diomyocytesâasâwellâasâinâwholeâheartsâduringârapidâpacingâprovideâevidenceâthatâprimaryâalternansâinâtheâamplitudeâandâdurationâofâ[Ca2+]iâtransientsâcanâdriveâactionâpotentialâdurationâtoâalternateâsecondarily,âbyâinfluencingâseveralâkeyâmembraneâcurrentsâthatâareâsensitiveâtoâchangesâinâ[Ca2+]iâ(33â35).
Collectively,âtheseâobservationsâsupportâtheâconceptâthatâSRâCa2+âcyclingâplaysâanâimportantâroleâinâcontributingâtoâactionâpotentialâdynamicsâduringâVT/VF.
Intracellular calcium regulates second messenger pathways and ion chan-nel gene transcription.âIntracellularâCa2+âionsâinfluenceâtheâactivityâofâionâchannelsâand/orâtransportersâviaâdirectâinteractionâwithâtheâion-conductingâmoleculeâandâindirectlyâviaâmodulationâofâCa2+-sensitiveâintracellularâsignalingâpathways.âCa2+âcanâdirectlyâbindâtoâaâsubunitâofâtheâvoltage-dependentâNa+âchannel,âwhichâresultsâinâalteredâNa+âchannelâgatingâ(36).âCa2+âalsoâactivatesâCa2+-calmodulinâkinaseâIIâ(CaMKII)â(seeâFigureâ2),âwhichâinâturnâtargetsâkeyâmole-culesâthatâcontrolâintracellularâCa2+âhomeostasisâinâcardiomyocytes,âandâincreasedâCaMKIIâactivityâmayâtriggerâarrhythmia-initiatingâafter-depolarizationsâbyâactivatingâL-typeâCa2+âchannelsâorâincreas-ingâinwardâcurrentâcarriedâbyâtheâNa+/Ca2+âexchangerâ(37,â38).ââDeterminingâwhetherâalterationsâinâtheâsensitivityâofâtheâtargetâmoleculesâtoâchangesâinâintracellularâCa2+âlevelsâand/orâalterationsâ
inâintracellularâsecondâmessengerâsignalingâcascadesâcontributeâtoâarrhythmogenesisâinâconditionsâofâabnormalâintracellularâCa2+âhandlingâwillâbeâimportant.
Collectively,âtheseâstudiesâhighlightâtheâfundamentalâimportanceâofâinvestigatingâtheâspatialâandâtemporalârelationshipâofâmem-braneâvoltageâandâintracellularâCa2+âdynamicsâinâtheâwholeâheart.âTechniquesâforâsimultaneouslyâmappingâtransmembraneâvoltageâandâ[Ca2+]iâwithâhighâtemporalâresolutionâinâtheâintactâheartâhaveârecentlyâbeenâdevelopedâ(29)âandâwillâprovideânovelâinsightsâintoâtheâfactorsâthatâfacilitateâtheâdevelopmentâofâDAD-âorâEAD-relatedânon-reentrantâarrhythmiasâasâwellâasâtheâroleâofâ[Ca2+]iâinâreentrantâarrhythmiasâinâanimalâmodelsâofâSCD.
Inâadditionâtoâtheâtransientâeffectsâofâincreasedâ[Ca2+]iâonâcardio-myocyteâexcitability,âchronicâchangesâinâ[Ca2+]iâinâtheâregulationâofâionâchannelâexpressionâinâcardiomyocytesâcanâeffectâlastingâaltera-tionsâinâelectricalâpropertiesâ(39).âForâexample,âlong-termâchangesâinâintracellularâCa2+âhandlingâinâtransgenicâmiceâoverexpressingâSERCA1aâcausedâdownregulationâofâK+âchannelâexpressionâinâtheâabsenceâofâcardiacâhypertrophyâandâfailure,âleadingâtoâactionâpotentialâprolongationâ(39).âDeterminingâtheâmolecularâunderpin-ningsâofâtheseâremodelingâprocessesâwillâpotentiallyâcreateânovelâtargetsâforâantiarrhythmicâprevention.
Acute myocardial ischemiaIonic imbalances during acute myocardial ischemia.âManyâSCDsâfromâVT/VFâoccurâduringâacuteâmyocardialâischemiaâ(40).âAbruptâces-sationâofâmyocardialâbloodâflowâcausesâredistributionâofâaânumberâofâions,âincludingâH+,âNa+,âCa2+,âandâK+,âacrossâtheâcardiomyocyteâmembrane,âanâeventâthatâhasâprofoundâelectrophysiologicalâcon-sequencesâthroughâitsâinfluenceâonâtheâactivityâofâaâvarietyâofâionâchannelsâandâtransporters.âHowever,âtheâdetailsâofâtheirâinterac-tionsâvis-Ă -visâ initiationâofâtheâtriggeringâprematureâbeatâandâmaintenanceâofâarrhythmiasâhaveâremainedâlargelyâelusive.
NetâcellularâK+âlossâandâsubsequentâextracellularâK+âaccumulationâduringâacuteâmyocardialâhypoxiaâand/orâischemiaâcausesâsustainedâmembraneâdepolarizationâthatâleadsâtoâaâslowingâofâconductionâandâalteredârefractoriness,âwhichâinâcombinationâwithâotherâfactorsâpromoteâVT/VFâandâSCDâ(27,â28).âDespiteâtheâfactâthatâK+âlossâisâanâimportantâpathogenicâfactorâinâischemia-associatedâarrhythmogen-esis,âtheâunderlyingâmechanismsâareânotâcompletelyâunderstood.âNetâK+âlossâinâpartâreflectsâpassiveâintracellularâNa+âgainâduringâmyo-cardialâhypoxia/ischemiaâ(41).âNetâintracellularâNa+âgainâimpliesâthatâtheâNa+/K+âATPaseâisâunableâtoâcompensateâforâtheâamountâofâNa+âionsâenteringâtheâcardiomyocytesâthroughâtheâmajorâNa+âinfluxâpathways,âincludingâvoltage-gatedâNa+âchannels,âNa+/Ca2+ââexchanger,âNa+/H+âexchanger,âandâpotentiallyâplasmalemmalâcon-nexin-43âhemichannelsâ(42)â(Figureâ4).âItâisâunknownâwhetherâtheâinflux/effluxâmismatchâresultsâfromâaâprimaryâincreaseâinâNa+âuptakeârateâbeyondâtheâmaximalâNa+/K+âATPaseâpumpâcapac-ity,âprimaryâinhibitionâofâtheâpump,âorâboth.âIschemia-inducedâdecreaseâinâintracellularâATPâcontentâmayâinhibitâNa+/K+âATPase.âIncreasedâintracellularâprotonâgenerationâincreasesâNa+âinfluxâviaâincreasedâactivityâofâtheâNa+/H+âexchanger.âBuild-upâofâtheâischemicâmetaboliteâlysophosphatidylcholineâenhancesâNa+âinfluxâthroughâvoltage-dependent,âtetrodotoxin-sensitiveâNa+âchannelsâ(43).âMajorâK+âeffluxâpathwaysâduringâhypoxia/ischemiaâinvolveâATP-depen-dentâK+âchannels,âinwardârectifierâK+âchannels,âasâwellâasâotherâvolt-age-gatedâK+âchannels,âandâpotentiallyâconnexin-43âhemichannelsâ(42).âNetâcellularâK+âlossâisâthoughtâtoâmaintainâelectroneutralityâofâchargeâmovementâandâcellularâosmolarity.âIncreasesâinâ[Na+]iâ
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mayâhaveâdetrimentalâelectrophysiologicalâeffects.â[Na+]iâregulatesâcardiacâ[Ca2+]i.âAnâincreaseâinâ[Na+]iâwillâresultâinâanâincreaseâinâ[Ca2+]i,âdueâtoâanâincreaseâinâCa2+âinfluxâviaâtheâNa+/Ca2+âexchangerâoperatingâinâtheâreverseâmodeâandâdepolarization-activatedâL-typeâCa2+âchannels,âandâpossiblyâdirectâCa2+âinfluxâthroughâconnexin-43âhemichannelsâ(42)â(Figureâ4).
Role of intracellular calcium in ischemia-associated arrhythmias.âCellu-larâCa2+âoverloadâsecondaryâtoâNa+âoverloadâcanâincreaseâtheâprob-abilityâthatâDAD-generatingâCa2+âwavesâwillâbeâinduced.âWhileâtheârelationshipâbetweenâtheâamountâofâCa2+âreleasedâfromâinternalâstoresâduringâaâwaveâandâtheâmagnitudeâofâtheâassociatedâchangeâinâVmâhasâbeenâcharacterizedâinâisolatedâcardiomyocytesâunderânormalâconditions,âitâhasânotâbeenârigorouslyâquantifiedâinâpar-tiallyâdepolarizedâcardiomyocytesâtypicallyâfoundâinâtheâischemicâmyocardium.âItâhasâalsoâremainedâunknownâwhetherâspontane-ousâCa2+âreleaseâthroughâryanodine-insensitiveâCa2+âreleaseâchan-nelsâ(e.g.,âIP3âreceptors;âseeâFigureâ2)âcontributesâtoâtheâinductionâofâCa2+âwavesâinâtheâsettingâofâacuteâischemiaâandâwhichâmem-braneâconductancesâareâinvolvedâinâtheâgenerationâofâtheâtransientâinwardâcurrentâunderlyingâaâDAD.
EvenâmoreâimportantâareâtheâfactorsâthatâdetermineâwhetherâaâDADâresultsâinâaâpropagatingâactionâpotentialâinâtheâsettingâofâacuteâmyocardialâischemia.âAlthoughâspontaneousâCa2+âwavesâoccurâinâbuffer-perfusedâisolatedâheartâpreparationsâunderâphysi-ologicalâconditionsâasâwellâasâfollowingâinjuryâ(17,â19,â20,â44),ââitâisânotâknownâwhetherâCa2+âwavesâtriggerâarrhythmiasâunderâisch-emicâconditions.âConceivably,âanâincreaseâinâtheâelectricalâresistanceâ
betweenâcardiomyocytesâinâtheâacutelyâ ischemicâ myocardiumâ(45)âinitiatesâDAD-relatedâextraâbeatsâbecauseâreducedâintercel-lularâcouplingâwouldâdiminishâtheâopposing,âi.e.,ârepolarizing,âeffectâofâpassiveâoutwardâcurrentâgeneratedâbyâneighboringâcar-diomyocytes.âItâisâalsoâpossibleâthatâ ischemiaâ inducesâcellularâchangesâthatâcauseâeitherâmoreâCa2+âtoâbeâreleasedâfromâinternalâstoresâorâgreaterâdepolarizationsâforâ aâ givenâ increaseâ inâ [Ca2+]i,âresultingâinâanâincreasedâpropen-sityâ forâtriggeredâarrhythmias.âBecauseâintracellularâNa+âgain,âthroughâitsâsecondaryâeffectsâonâcardiacâ[Ca2+]iâandâextracellularâ[K+],â appearsâ toâ actâ asâ aâ pri-maryâarrhythmogenicâfactorâinâtheâsettingâofâacuteâischemia,âitâwillâbeâimportantâtoâdefineâtheâspatio-temporalâ relationshipsâbetweenâ Vmâ andâ intracellularâconcentrationsâofâNa+âandâCa2+â(andâextracellularâ [K+])â inâani-malâmodelsâofâacuteâischemiaâinducedâ cardiacâ arrhythmiasâandâ SCDâ byâ simultaneouslyâmappingâtransmembraneâvolt-ageâandâionâconcentrations.
Althoughâ VT/VFâ occurringâduringâreperfusionâcanâbeâreproduciblyâinducedâinâtheâexperi-mentalâsettingâ(46),âtheâroleâofâspontaneousâreperfusionâinâtrig-geringâSCDâfromâcardiacâarrhythmiasâremainsâtoâbeâdefined.âTheâpathogenicâmechanismâunderlyingâreperfusionâarrhythmiasâisâlargelyâunknown,âbutâanâincreaseâinâ[Na+]iâduringâischemiaâand/orâearlyâreperfusionâappearsâtoâplayâaâmajorâroleâ(47).âIntracellularâNa+âaccumulationâcanâthenâgiveâriseâtoâ[Ca2+]iâoverload,âwhichâinâturnâincreasesâtheâpropensityâforâDAD-relatedâarrhythmiasâbyâtheâmechanismsâdescribedâabove.
Whereasâthereâisâexperimentalâevidenceâforâtheâroleâofâspontaneousâincreasesâinâ[Ca2+]iâinâinducingâEADsâandârelatedâventricularâarrhyth-miasâinâtheânonischemicâsettingâ(29),âtheâinvolvementâofâEADsâinâischemia/reperfusionâinducedâarrhythmiasâhasâyetâtoâbeâdemon-stratedâexperimentally.âOtherâfactorsâpredisposingâtoâEADsâmayâhaveâtoâbeâpresent,âincludingâactionâpotentialâprolongationâ(30,â48)ââorâslightâreductionâofâtheâelectricalâconductivityâbetweenâcellsâ(45).âSinceâfailingâasâwellâasâhypertrophicâmyocardiumâexhibitâbothâdelayedârepolarizationâandâincreasedâelectricalâresistanceâ(21,â22),âacuteâischemiaâoccurringâinâtheâelectricallyâremodeledâfailingâheartâmayâindeedâgiveâriseâtoâEAD-relatedâventricularâtachyarrhythmias.
Relationship between Vm and SR Ca2+ cycling in the acutely isch-emic myocardium.âAâstudyâutilizingâsimultaneousârecordingsâofâchangesâinâmembraneâvoltageâandâintracellularâcalciumârecentlyâshowedâthatâacuteâischemiaâexertsâcontrastingâeffectsâonâtheâkineticsâofâVmâandâ[Ca2+]iâtransientsâ(49).âIschemiaâwasâassociat-edâwithâmarkedâshorteningâofâactionâpotentialâdurationâbutâsig-nificantâprolongationâofâtheâ[Ca2+]iâtransient.âChangesâinâactionâ
Figure 4Proposed scheme of events leading to transmembrane ionic imbalances during myocardial ischemia. Net intracellular Na+ gain due to a mismatch of Na+ influx and efflux will cause net cellular K+ loss, extracellular K+ accumulation, and an increase in intracellular Ca2+ due to activation of the Na+/Ca2+ exchanger operating in the reverse mode. Cellular Ca2+ overload will cause triggered arrhythmias by the mechanisms illustrated in Figure 3. Lysophosphatidylcholine is a product of diacyl phospholipid catabolism generated by the enzyme phospholipase A2 during ischemia. Question marks indicate that the pathway/mechanism is hypothetical. [ATP]i, intracellular concentration of adenosine triphosphate; Cx43, connexin-43; [H+]i, intracellular proton concentration; IK, delayed rectifier K+ current; IK,ATP, ATP-sensitive potassium current; IK1, inward rectifier K+ current; INa, fast Na+ current; Na/H, sodium-hydrogen exchanger; [K+]o, extracellular K+ concentration; TTX, tetrodotoxin (a specific blocker of the fast sodium current).
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potentialâdurationâwereâspatiallyâmoreâheterogeneousâthanâwasâlengtheningâofâ[Ca2+]iâtransientâduration.âMoreover,âoccurrenceâofâ[Ca2+]iâtransientâalternansâwasânotâconsistentlyâassociatedâwithâalternansâofâtheâactionâpotentialâduration.âThus,âinâcontrastâtoâsimilarâopticalâmappingâstudiesâperformedâunderânonischemicâconditions,âthisâstudyâdeemphasizesâtheâprimaryâroleâofâalter-nationâofâ[Ca2+]iâtransientâmagnitudeâand/orâdurationâinâdeter-miningâactionâpotentialâdurationâandâactionâpotentialâdurationâalternansâinâtheâsettingâofâacuteâischemia.
Neurohumoral changesRole of cardiac sympathetic innervation.â Activationâ ofâ cardiacââβ-adrenergicâreceptorsâbyâtheâneurotransmittersâepinephrineâandânorepinephrineâhasâseveralâphysiologicalâeffects,âincludingâincreasingâsystolicâcontractilityâandâdiastolicârelaxationârateâasâwellâasâacceleratingâheartârateâandâatrioventricularâconduction.âAtâtheâcardiomyocyteâlevel,âstimulationâofâβ-adrenergicâreceptorsâaltersâtheâactivityâofâaânumberâofâionâchannelsâandâtransportersâviaâactivationâofâtheâGâprotein/adenylylâcyclase/cAMP/PKAâpath-wayâ(seeâFigureâ2).âThisâinâturnâresultsâinâanâincreaseâinâbothâpeakâamplitudeâandârateâofâdeclineâofâtheâ[Ca2+]iâtransientâviaâstimula-tionâofâkeyâCa2+âhandlingâproteinsâasâwellâasâshorteningâofâactionâ
potentialâdurationâviaâaugmentationâofâK+âoutwardâcurrents.âTheâobservationâthatâpharmacologicalâbetaâblockadeâconfersâaâsurvivalâbenefitâonâpatientsâafterâmyocardialâinfarctionâsug-gestsâanâimportantâroleâofâtheâautonomicânervousâsystemâinâtheâpathogenesisâofâSCDâfromâVT/VF.âFurtherâevidenceâforâaâneuralâcomponentâinâSCDâcomesâfromâ2ârecentâexperimentalâstudies.âInâtheâfirstâstudy,âchronicâinfusionâofânerveâgrowthâfactorâ(NGF)âtoâtheâ leftâstellateâganglionâinâdogsâwithâchronicâmyocardialâinfarctionâandâcompleteâatrioventricularâblockâcausedâspatiallyâheterogeneousâ sympatheticâ cardiacâ hyperinnervationâ (nerveâsprouting)âandâdramaticallyâ increasedâtheâ incidenceâofâSCDâfromâVT/VFâ(50).âInâaâsecondâstudy,âLiuâetâal.â(51)âreportedâthatâaâhigh-cholesterolâdietâresultedâinâmyocardialâhypertrophyâandâcardiacâsympatheticâhyperinnervationâinârabbitsâinâtheâabsenceâofâcoronaryâarteryâstenosesâandâinfarction.âFurthermore,âtheyâfoundâaâmarkedâincreaseâinâtheâincidenceâofâVF,âwhichâwasâasso-ciatedâwithâenhancedâdispersionâofârepolarization,âprolongationâofâactionâpotentialâdurationâandâtheâQTâinterval,âandâincreasedâL-typeâCa2+âcurrentâ(ICa.L)âdensityâ(definedâasâtheâpeakâICa.Lâampli-tudeânormalizedâtoâtheâcellâsurfaceâarea).âAlthoughâresultsâofâtheseâstudiesâdoânotâconstituteâanâultimateâproof,âtheyâstronglyâsuggestâaâcausalârelationshipâbetweenâalteredâautonomicâinner-vationâandâSCDâdueâtoâVT/VF.âIntriguingly,âexplantedâhumanâheartsâfromâtransplantârecipientsâwithâaâhistoryâofâarrhythmiasâexhibitedâaâsignificantlyâhigherâandâalsoâmoreâheterogeneousâdensityâofâsympatheticânerveâfibersâthanâthoseâfromâpatientsâwithoutâarrhythmiasâ(52),âwhichâindicatesâthatâheterogeneousâovergrowthâofâcardiacânerveâmayâoccurâinâhumanâheartsâwithâmyocardialâinfarctionsâevenâinâtheâabsenceâofâexogenousâNGF.âWhetherâneuralâremodelingâalsoâinvolvedâparasympatheticânerveâfibersâinâtheâheartâwasânotâexaminedâinâtheseâstudies.
Theâpreciseâmechanismâbyâwhichâsympatheticâhyperinnerva-tionâpromotesâcardiacâarrhythmiaâisâspeculativeâatâpresent.âTheâultimateâmanifestationâofâtheâarrhythmiaâisâprobablyâtheâendâresultâofâaâvarietyâofâinteractingâfactors,âasâschematicallyâillus-tratedâinâFigureâ5.âIncreasedâdensityâofâsympatheticânerveâend-ingsâcouldâaugmentâreleaseâofâandâconsequentlyâresultâinâhigherâthanânormalâtissueâconcentrationsâofâsympatheticâneurotrans-mittersâ(e.g.,ânorepinephrine,âneuropeptideâY)âduringâsympa-theticâexcitation.âThisâautonomicâremodelingâisâassociatedâwithâ
Figure 5Factors contributing to arrhythmogenesis in hearts with heteroge-neous sympathetic innervation. Myocardial injury (e.g., myocardial infarction) or chronic hypercholesterolemia (51) will cause a spatially uneven increase in sympathetic nerve density in the heart, resulting in regional variations in release and, consequently, variations in tis-sue levels of sympathetic neurotransmitters. Chronic, nonuniform elevations of neurotransmitters, through alterations in the expression of L-type Ca2+ channels and K+ channels, create spatial dispersion of action potential duration. Action potential prolongation and aug-mented Ca2+ influx through L-type Ca2+ channels combine to increase the susceptibility to EAD- and/or DAD-triggered activity in hyperinner-vated regions. If the triggered beat propagates throughout the rest of the heart, the preexisting spatial dispersion of action potential duration and, thus, myocardial refractoriness facilitate the initiation of tachyar-rhythmias. Locally elevated levels of neuropeptide Y and norepineph-rine may increase coronary artery tone, thereby critically reducing the coronary perfusion reserve under conditions of increased oxygen demand (e.g., physical and/or emotional stress) and causing regional ischemia, which contributes to the development of an arrhythmia.
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spatiallyâheterogeneousâelectricalâremodelingâofâtheâcardiomyo-cytes,âincludingâanâincreaseâinâICa.Lâdensityâ(51)âandâdecreasesâinâK+âcurrentâdensitiesâ(53),âresultingâinâactionâpotentialâprolonga-tionâinâhyperinnervatedâregionsâ(Figureâ5).âAlongâwithâelectri-calâremodelingâofâaânumberâofâionâchannelsâandâtransportersâinâtheâsurvivingâmyocardiumâalongâtheâinfarctâborderâ(i.e.,âtheâinfarctâborerâzone),âacuteâreleaseâofâsympatheticâneurotransmit-ters,âthroughâtheirâeffectsâonâCa2+,âK+,âandâClââchannelsâandâCa2+âtransportersâandâenzymes,âisâlikelyâtoâaccentuateâtheâpreexistingâheterogeneityâofâexcitabilityâandârefractoriness,âwhichâinâturnâisâlikelyâtoâcontributeâtoâarrhythmiaâsusceptibilityâinâtheseâmodels.âNorepinephrine-âand/orâneuropeptideâYâinducedâarterialâcon-strictionâcanâinduceâmyocardialâischemiaâinâhyperinnervatedâregionsâduringâemotionalâand/orâphysicalâstress,âfurtherâpro-motingâvulnerabilityâtoâarrhythmicâevents.
Myocardialâ ischemiaâandâ infarctionâareâknownâtoâresultâ inâinjuryâofâsympatheticânervesâandâsympatheticâdenervationâofânoninfarctedâ myocardiumâ inâ areasâ distalâ toâ theâ infarctâ (54).âSympatheticâdenervationâpotentiatesâadrenergicâresponsivenessâtoâcatecholamines,âaâprocessâtermedâdenervationâsupersensitiv-ityâ(55).âDiffusionâofâneurotransmittersâfromânormalâregionsâtoâneighboringâdenervatedâareasâduringâsympatheticâexcitationâisâlikelyâtoâcreateâsteepâlocalâgradientsâofârefractorinessâandâexcit-ability,âfurtherâcontributingâtoâtheâarrhythmogenicâsubstrate.âFurthermore,âsuperimposedâuponâprolongationâofâactionâpoten-tialâdurationâandâincreasedâICa.Lâdensity,âsympatheticâstimulationâisâlikelyâtoâleadâtoâintracellularâCa2+âoverload,âwhichâinâturnâcouldâgiveâriseâtoâtriggeredâactivity,âwhichâmayâunderlieâtheâspontaneousâoccurrenceâofâVFâinâtheseâanimalâmodels.
Futureâstudiesâonâtheâmechanismsâbyâwhichâneuralâremodelingâcontributesâtoâarrhythmiaâsusceptibilityâwillâhaveâtoâaddress:â(a)âtheâmolecularâandâcellularâmechanismsâregulatingâsympatheticâ(andâparasympathetic)ânerveâprocessingâinâtheânormalâandâdis-easedâheart;â(b)âtheâeffectsâ(bothâshort-âandâlong-term)âofânon-cholinergic,ânonadrenergicâneurotransmitters,âincludingâneuro-peptideâY,âcalcitoninâgeneârelatedâproduct,âvasoactiveâintestinalâpeptide,âandâsubstanceâP,âonâcardiomyocyteâelectrophysiologyâandâCa2+âhandling;âandâ(c)âtheâsecondâmessengerâpathwaysâinvolved.âAllâ4âpeptidesâhaveâprofoundâphysiologicalâeffects.âNeuropeptideâY,âforâexample,âisâaâpotentâvasoconstrictorâ(56)âandâalsoâappearsâtoâbeâanâessentialâinâvivoâregulatorâofâcardiacâICa.Lâduringâpostnatalâdevelopmentâ(57).âOtherâquestionsâincludeâtheâfollowing:âwhatâareâtheâalteredâelectricalâpropertiesâofâpre-/postganglionicâsympa-thetic/parasympatheticâneuronsâinâtheâdiseasedâstateâthatâresultâinâalteredâexcitation-secretionâcoupling?âwhatâareâtheâmechanismsâunderlyingâsympatheticallyâinducedâventricularâtachyarrhythmiasâinâanimalâmodelsâofâSCD?âdoesâsympatheticânerveâstimulationâacutelyâexaggerateâanyâpreexistingâelectricalâheterogeneityâinâtheâdiseasedâheart?âand,âfinally,âdoesâsympatheticâstimulationâincreaseâtheâincidenceâofâabnormalitiesâinâintracellularâCa2+âhandlingâinâtheâwholeâheartâ(Ca2+âwaves,âbeat-to-beatâvariationsâinâCa2+âamplitudeâand/orâdurationâ[alternans])âthatâmayâactâasâtriggersâofâventricularâarrhythmias?âToâanswerâtheâlatterâquestion,âopticalâmappingâtech-niquesâwillâbeârequiredâtoâsimultaneouslyâmeasureâmembraneâvolt-ageâandâ[Ca2+]iâinâwholeâheartsâduringâautonomicâstimulation.
Role of the renin-angiotensin systemAngiotensin II.âTheârenin-angiotensinâsystemâ(RAS)âisâanâenzymaticâcascadeâthatâcontrolsâconversionâofâangiotensinogenâintoâangio-tensinâII.âTheâfinalâstepâinâthisâprocessâisâmediatedâbyâACE.âFor-
mationâofâangiotensinâIIâoccursâsystemicallyâandâalsoâlocallyâinâtheâheart.âIncreasedâlevelsâofâangiotensinâIIâhaveâseveralâadverseâeffectsâonâtheâcardiovascularâsystem,âincludingâcardiomyocyteâhypertrophy,âfacilitationâofânorepinephrineâreleaseâfromâitsâpre-junctionalâsites,âfibroblastâandâsmoothâmuscleâproliferation,âandâvasoconstriction.âInâcardiomyocytes,âchronicâstimulationâofâtheâangiotensinâreceptorâcoupledâGaq/phospholipaseâC/PKCâpath-wayâcanâdownregulateâtheâactivityâofâseveralâkeyâCa2+-handlingâproteinsâviaâphosphatase-mediatedâdephosphorylationâ(Figureâ2).ââInterruptionâofâRASâbyâmeansâofâpharmacologicâinhibitionâofâACEâand/orâangiotensinâIIâreceptorâblockadeâdecreasesâcardio-vascularâmorbidityâandâmortalityâinâpatientsâwithâleft-ventricularâdysfunctionâ(58â61).âHowever,âwhetherâtheâreductionâinâmortalityâresults,âatâleastâinâpart,âfromâaâdecreaseâinâtheâincidenceâofâdeathâfromâarrhythmiasâwasânotâdemonstrated.âExperimentalâstudiesâshowâthatâabnormalâregulationâofâRASâinâcardiovascularâdiseaseâmayâincreaseâtheâsusceptibilityâtoâarrhythmias.âMiceâinâwhichâangiotensinâIIâwasâelevatedâviaâgeneticâclampingâexhibitâmarkedâcardiacâhypertrophy,âbradycardiaâdueâtoâatrioventricularâconduc-tionâdefects,âT-waveâalternans,âandâaâhighâfrequencyâofâSCDâfromâarrhythmiasâ(62).âMiceâwithâcardiomyocyte-specificâoverexpressionâofâACE-relatedâcarboxypeptidaseâcapableâofâcleavingâangiotensinâIIâexhibitâdownregulationâofâconnexin-40âandâconnexin-43,âcom-pleteâatrioventricularâblock,âandâanâincreasedârateâofâSCDâfromâventricularâarrhythmias,âwhichâsuggestsâthatâRASâcontrolsâcon-nexinâexpressionâinâtheâheartâ(63).
Intriguingly,âalterationsâinâtheâRASâalsoâaffectâperipheralâandâcentralâsympatheticâfunction.âInâratâpostganglionicâsympatheticâneurons,âangiotensinâIIâacutelyâinhibitsâvoltage-dependentâN-typeââCa2+âcurrentsâandârepolarizingâK+âcurrentsâ(64),âpossiblyâresultingâinâalteredâexcitation-secretionâcouplingâofâperipheralâsympatheticâneu-rons.âTransgenicâratsâdeficientâinâbrainâangiotensinogenâexhibitedâbetterâpreservationâofâleft-ventricularâfunction,âarterialâbaroreflexâcontrol,âandârenalâsympatheticânerveâactivityâfollowingâmyocardialâinfarctionâthanâdidânontransgenicâratsâ(65).âInârabbitsâwithârapidâpacingâinducedâchronicâheartâfailure,âblockadeâofâangiotensinâIIâreceptorsâcombinedâwithâadministrationâofâexogenousâNOâreducesâelevatedârenalâsympatheticânerveâactivity,âwhichâsuggestsâthatâbothâlossâofâNOâandâanâincreaseâinâangiotensinâIIâareânecessaryâforâsym-pathoexcitationâinâchronicâheartâfailureâ(66).âItâisâstillâunknownâwhetherâpreservationâofânormalâsympatheticâfunctionâtranslatesâintoâaâreductionâinâtheâincidenceâofâcardiacâarrhythmias.
Effect of angiotensin II on ion channels and transporters.âAngiotensinâIIâhasâalsoâbeenâshownâtoâdirectlyâmodulateâionâchannelsâandâtrans-porters.âInhibitionâbyâangiotensinâIIâofâvoltage-dependent,ârepolar-izingâK+âcurrentsâinâarterialâsmoothâmuscleâcausesâvasoconstrictionâ(67,â68),âpossiblyâleadingâtoâreducedâmyocardialâbloodâflowâinâcon-ditionsâassociatedâwithâelevatedâangiotensinâII.âInâcardiomyocytes,âenhancementâofâICa.L;âreductionâofâtheâdelayedârectifierâK+âcurrent,âIK,âandâtheâtransientâoutwardâK+âcurrent,âIto;âandâelectrogenicâNa/KââATPaseâactivityâactâsynergisticallyâtoâprolongâactionâpotentialâdura-tionâandâtoâincreaseâintracellularâCa2+âload,âtherebyâpromotingâarrhythmiaâsusceptibility.âACEâinhibitors,âasâwellâasâangiotensinâreceptorâblockers,âreduceâSCDâinâheartâfailureâandâpostinfarctionâpatientsâ(58â61).âPassiveâstretchâelicitsâanâoutwardlyârectifyingâClââcurrentâinâventricularâmyocytesâbyâaâmechanismâthatâinvolvesâreleaseâofâangiotensinâIIâandâactivationâofâangiotensinâIIâtypeâ1âreceptorâinâanâautocrine/paracrineâloopâ(69).
Aldosterone.âAngiotensinâIIâalsoâenhancesâreleaseâofâaldosteroneâfromâtheâadrenalâcortex.âAldosteroneâhasâpotentâsodium-retainingâ
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propertiesâandâcanâexertâadverseâcardiovascularâeffects,âincludingâmyocardialâhypertrophyâandâfibrosis.âLikeâangiotensinâII,âaldo-steroneâregulatesâcardiacâionâchannels.âChronicâexposureâofâratâventricularâmyocytesâtoâaldosteroneâreducesâandâincreases,ârespec-tively,âItoâandâICa.Lâ(70).âTheâtemporalârelationshipâofâtheâchangesâinâcurrentâdensitiesâandâtheâeffectâofâblockersâofâtheâICa.Lâareâconsis-tentâwithâtheâCa2+-dependentâreductionâofâItoâexpression.âInâaâpostâmyocardialâinfarctionâmodelâofâheartâfailureâinârats,âaldosteroneâantagonismâhadâaânumberâofâeffects,âincludingâinhibitingâfibro-sis,âreducingâmyocardialânorepinephrineâcontent,âandâincreasingâtheâVFâthresholdâ(71).âClinically,âtreatmentâwithâtheâaldosteroneâreceptorâantagonistsâspironolactoneâorâeplerenoneâhasâbeenâdem-onstratedâtoâreduceâSCDâinâheartâfailureâpatientsâ(72,â73).
Collectively,âtheseâobservationsâsuggestâthatâelevatedâangioten-sinâIIâand/orâaldosteroneâlevelsâexertâadverseâelectrophysiologicalâeffectsâthatâmayâcontributeâtoâtheâdevelopmentâofâaâproarrhythmicâsubstrateâinâconditionsâthatâareâtypicallyâassociatedâwithâabnormalâactivationâofâtheâRASâ(e.g.,âheartâfailure).âAntagonizingâtheirâeffectsâcouldâreduceâtheâextentâofâadverseâelectricalâremodelingâandâhasâbeenâshownâtoâpreventâSCD.âBecauseâRASâsignalingâalsoâhasâprofoundâeffectsâonâheartâstructure,âincludingâinductionâofâhypertrophyâandâinterstitialâfibrosis,âitâwillâbeâimportantâtoâdetermineâwhetherâantiar-rhythmicâeffectsâofâRASâsignalingâantagonistsâderiveâindirectlyâfromâpreservationâofâtheâstructuralâintegrityâofâtheâheart,âdirectlyâfromâmodulationâofâionâchannelsâandâtransporters,âorâboth.
Genetic predispositionInâadditionâtoâwell-knownâheritableâgeneticâdisordersâsuchâasâLQTS,âgeneticâvariationsâexistâthatâdetermineâanâindividualâsâriskâforâfatalâarrhythmias.âInâtheâParisâProspectiveâstudy,âaâhistoryâofâSCDâinâ1âparentâwasâshownâtoâincreaseâtheâriskâofâfatalâarrhythmiaâinâtheâoff-springâbyâ80%;âaâhistoryâofâSCDâinâbothâparentsâleadsâtoâanâapproxi-mateâ9-foldâincreaseâinâtheâriskâofâSCDâforâtheâoffspringâ(74).âInâanotherâpopulation-basedâstudy,âtheârateâofâSCDâinâfirst-degreeârelativesâofâSCDâvictimsâwasâ50%âgreaterâthanâtheârateâinâcontrolâsubjectsâand,âimportantly,âwasâindependentâofâotherâriskâfactorsâsuchâasâdiabetes,âhypertension,âorâcigaretteâsmokingâ(75).âItâisâveryâlikelyâthatâaânumberâofâgenesâcontributeâtoâtheâphenotypicâmani-festationâofâSCD.âContributorsâmayâincludeâknownâorâunknownâgenesâassociatedâwithâmyocardialâischemia,âneurohumoralâsignal-ing,âcardiomyocyteâCa2+âhandling,âandâcardiacâelectricalâproperties.âOnceâgeneticâfactorsâhaveâbeenâidentifiedâbyâgenomicâscreening,âtheâmajorâchallengeâwillâbeâtoâdetermineâwhetherâaâspecificâgeneâvariantâconstitutesâaâspecificâmarkerâofâtheâriskâforâSCDâindependentlyâofâtheâunderlyingâstructuralâheartâdiseaseâandâwhatâroleâthisâvariantâplaysâinâtheâpathogenesisâofâfatalâarrhythmias.
Prevention of SCD from arrhythmiaChronicâbeta blockadeâimprovesâsurvivalâinâpatientsâafterâmyo-cardialâinfarctionâ(4,â76),âreducingâtheâincidenceâofâSCD,âpar-
ticularlyâ inâpatientsâwithâ impairedâ left-ventricularâ function.âTheâuseâofâsomeâcompounds,âsuchâasâencainide,âflecainide,âandâD-sotalol,âthatâblockâspecificâcardiacâionâchannels,âi.e.,ââclassicââantiarrhythmicâdrugs,âhasâbeenâshownâtoâbeâassociatedâwithâanâadverseâoutcomeâinâpatientsâwithâchronicâmyocardialâinfarctionâ(3,â77).âAmiodarone,âanâantiarrhythmicâagent,âwhichâatâclinicallyârelevantâconcentrationsâblocksâaâvarietyâofâcardiacâionâchannelsâandâtransporters,âincludingâsodiumâchannels,âL-typeâcalciumâchannels,âseveralâtypesâofâpotassiumâchannels,âandâtheâsodium-calciumâexchanger,âandâwhichâinhibitsâa-âandâβ-adrenergicârecep-torsâ(78),âalsoâdoesânotâimproveâsurvivalâ(79â81).âTherefore,âpro-phylacticâuseâofâspecificâionâchannelâblockersâdoesânotâreduceâmortalityâorâmayâevenâincreaseâit.âInâcontrast,âICDsâconferâsur-vivalâbenefitâcomparedâwithâdrugsâinâhigh-riskâpopulationsâ(2).âICDâtherapyâisânowâstandardâcareâforâpatientsâwhoâhaveâsurvivedâlife-threateningâarrhythmiasâ(2).
Patientsâwithâheartâfailureâcommonlyâhaveâregionsâofâdelayedâmyocardialâactivationâandâcontraction,âwhichâleadsâtoâcardiacâdys-synchrony.âCardiacâresynchronization,âwhichâentailsâplacementâofâaâright-atrial,âaâright-ventricular,âandâaâleft-ventricularâlead,ârestoresâatrio-biventricularâsynchronyâresultingâinâimprovedâleft-ventricularâfunctionâandâ(withoutâconcomitantâICDâtherapy)âcanâimproveâsurvivalâinâpatientsâwithâheartâfailureâ(ejectionâfractionâ<35%)âandâcardiacâdyssynchronyâ(82).
ConclusionTheâpurposeâofâthisâreviewâwasâtoâconsiderâsomeâofâtheâmanyâeventsâthatâcanâtransformâanâelectricallyâstableâheartâintoâoneâthatâisâunstable,âinâorderâtoâanswerâtheâclinicalâquestionâofâwhyâaâpar-ticularâpatientâdiedâatâaâparticularâtimeâonâaâparticularâdayâandânotâatâanotherâtime.âThisâisâoneâofâtheâmostâimportantâ(andâvexing)âquestionsâinâclinicalâcardiologyâtoday,âasâitâentailsâexplorationâofâtheâproximateâprecipitatorsâofâSCDâ(83)âinâorderâtoâhelpâidentifyâtheâindividualâatârisk.âBecauseâofâspaceâconstraints,âweâhaveâonlyâdiscussedâseveralâofâtheâmanyâfactorsâthatâmayâbeâimportant.âTheâlistâisâlongâandâcanâbeâapproachedâbyâconsideringâfundamentalâmolecularâmechanisms,âcellularâchanges,âwholeâheartâelectrophys-iology,âandâclinicalâriskâfactors.âNevertheless,âitâisâanâareaârichlyâdeservingâintenseâinvestigationâifâweâareâeverâgoingâtoâreduceâtheâhorrendousâtollâclaimedâbyâSCD.
AcknowledgmentsThisâworkâwasâsupportedâbyâgrantsâfromâtheâHermannâC.âKran-nertâFundâandâtheâNIHâ(HL075165âtoâM.âRubart).
Addressâcorrespondenceâto:âMichaelâRubart,âHermanâB.âWellsâCenterâforâPediatricâResearch,âIndianaâUniversityâSchoolâofâMedi-cine,â1044âWestâWalnutâStreet,â Indianapolis,â Indianaâ46202-5225,âUSA.âPhone:â(317)â274-2207;âFax:â(317)â278-5413;âE-mail:â[email protected].
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