High%Density%Mapping%Of%Ventricular%Scar7%Insights% Into%Mechanisms%Of%Ventricular%Tachycardia%%

Transcription

1 High%Density%Mapping%Of%Ventricular%Scar7%Insights% Into%Mechanisms%Of%Ventricular%Tachycardia%% By% Sachin%Nayyar% MBBS,%MD,%DM% % Centre%for%Heart%Rhythm%Disorders% University%of%Adelaide%and%Royal%Adelaide%Hospital% % % % A%thesis%submitted%to%the%Faculty%of%Health%Science,%University%of% Adelaide%in%total%fulfillment%of%the%requirements%of%the%degree%of%% DOCTOR%OF%PHILOSOPHY% % % % Department%of%Cardiology,%Royal%Adelaide%Hospital% Discipline%of%Medicine,%University%of%Adelaide,% Adelaide,%South%Australia% Australia% December%2013%

2 TomywifePallavi &Parents UrmilaandRajKumarDham

3 ABSTRACT Ventricular tachyarrhythmias related to structural heart disease are the most common cause of sudden cardiac death. Many of these occur in patients with ventricular scarring, related predominantly to coronary artery disease or dilated cardiomyopathies. These regions of scarring remodel over time with ongoing collagen turnover and do not stay stable, such that patients are often subject to repeatedepisodesofthearrhythmia. Ventricularscarsarecomposedofvariableregionsofdenseinterstitialfibrosisthat createconductionblock,interspersedwithviablemyocytechannelswithdiminished coupling which produce substrate for circuitous slow conduction pathways that promote reentry. During sinus rhythm, these channels can be identified by the presence of late potentials and long stimulus to QRS intervals during pacing in the channel. A high density of sampling in the left ventricle allows recording of small amplitude electrograms that are of fundamental emphasis in ventricular substrate mapping. Several studies have characterized channels in patients with ventricular scar and ventricular tachycardia (VT). However, there has been no assessment on the functional characteristics of these channels and whether channels that are criticaltothevtcircuitdifferfromnongvtchannels. Chapter1reviewsliteratureonarrhythmicburdenandepidemiologyofscarrelated VT, its cellular mechanisms, substrate characterization, techniques of VT mapping and gaps in the current knowledge. Chapter 2 presents the high density characterizationofsubstrateinischemiccardiomyopathy(icm)patientswithvtand comparesthefeaturesofvtsupportingchannelswithchannelsthatdonotsupport VT. This study showed that compared to nongvt channels, VT channels are more oftenlocatedinthedensescar,longerinlength,havelongstimulustoqrslatencies and slower conduction velocity. Chapter 3 describes the electrogram properties in i

4 regions of VT channels, and development of a stepwise model from multiple electrogrampropertiestoensembleregionssupportingvt(s)duringsinusrhythm.it also discusses the application of Shannon entropy, a fundamental measure of informationcontentinsignals,tomapvtchannelsinsinusrhythm.thissystemof ablationalongwithhighdensitymappingwillsignificantlyadvancevtmappingand helpindividualizesubstratebasedablation.chapter4presentsdataonhighdensity characterizationofsubstrateinicmpatientswithvtandcompareswiththosewho donothavespontaneousvt.itshowedthatpatientswithoutspontaneousvthave fewerchannelswithshorterlengthsandfasterconduction,comparedtovtpatients. These observations partly explain the relative higher predilection of few selected survivingmyocytechannelsinthepostinfarctventriclestosustainvt. Structural heterogeneity in the scar produces spatial and temporal disturbances in ventricularrepolarizationovermultipletimescales.chapter5evaluatestheroleof acute autonomic modulation on beatgtogbeat QT variability in patients with heart failurewithandwithoutvt,andcontrastsitwithpatientswithoutstructuralheart disease. It showed that acute pacing and humoral modulation including betag blockade fail to bring down high repolarization instability in heart failure patients andvt. Catheterablationisthemainstayfortreatmentofrecurrentventriculararrhythmias inpatientswithstructuralheartdisease.chapter6analysespublishedliteratureon ventricular arrhythmia storm ablation in a systematic review and metaganalysis. It showedthattheinterventionsaresafeandpatientsoftenneedmultipleprocedures including nongradiofrequency ablation measures. Although patients who had successfulablationhadgoodlonggtermoutcomes,afailedprocedureportendedan earlyandhighrateofmortalitycomparedwithmedicallymanagedhistoriccontrols. Itraisedapertinentconcernofpossibleharmfuleffectsofcatheterablationinahigh riskpatientpopulation. Insummary,thisthesishasdevelopedinnovativeinsightsintothesurvivingmyocyte channels in patients with ischemic cardiomyopathy. It describes a novel tool for ii

5 ventricularsubstratemappingthatisreadilyapplicableintheclinicallaboratory.the repolarizationinstabilityiselevatedinthesepatientsandisresistanttomodulation by acute betagblocker treatment. Finally, catheter ablation is safe and should be advised in most patients with ventricular arrhythmia storm. iii

6 DECLARATION Icertifythatthisworkcontainsnomaterialwhichhasbeenacceptedfortheaward ofanyotherdegreeordiplomainanyuniversityorothertertiaryinstitutionand,to the best of my knowledge and belief, contains no material previously published or writtenbyanotherperson,exceptwhereduereferencehasbeenmadeinthetext.i certifythatnopartofthisworkwill,inthefuture,beusedinasubmissionforany other degree or diploma in any university or other tertiary institution without the prior approval of the University of Adelaide and where applicable, any partner institutionresponsibleforthejointgawardofthisdegree. The work was performed at Centre for Heart Rhythm Disorders, University of AdelaideandRoyalAdelaideHospital,Adelaide,Australia. I certify that the writing of this thesis, the results, interpretation, opinions and suggestions are entirely my own work. This thesis does not exceed the length of 80,000wordsexclusiveoftables,figuresandbibliography. I give consent to this copy of my thesis, when deposited in the University Library, being made available for loan and photocopying, subject to the provisions of the Copyright Act The author acknowledges that copyright of published works contained within this thesis resides with the copyright holder(s) of those works. I alsogivepermissionforthedigitalversionofmythesistobemadeavailableonthe web, via the University s digital research repository, the Library catalogue and also throughwebsearchengines,unlesspermissionhasbeengrantedbytheuniversity torestrictaccessforaperiodoftime. Signature..Date (SachinNayyar) iv

7 ACKNOWLEDGEMENTS IwouldliketothankProfessorPrashanthanSanders,DrKurtRobertsGThomsonand Dr Anthony Brooks for their guidance, support and encouragement as my supervisorsandmentorsoverthisexcitingperiod.ithasindeedbeenaprivilegeto work side by side with distinguished clinical researchers. Their dedication to work and research continues to inspire me. I am also grateful to Professor Jaganmohan Tharakan, a renowned scholar and a clinician, and Professor Mohan Nair, a distinguished cardiologist, from my training institutes back in India for their workmanshipanddirectiverolesthathasculminatedinundertakingthisthesis. IamalsogratefultotheUniversityofAdelaideforaffordingmeascholarshipforthe durationofmyphdstudies.thesestudiescouldnothavebeenperformedifnotfor the many patients, who often at times of significant illness, participated in our understandingofthedisease. I want to acknowledge the important role of Dr Glenn Young, whose teaching, appreciationandencouragementmotivatedme,andwhoalsoprovidedmanyofthe patientsandsessiontimesforstudyprotocols. I wish to advance special sincere thanks to Dr Kurt RobertsGThomson for his stupendousplanning,prudenceandpatienceinhelpingconductthisdifficultstudyin highriskpatients.specialthankstodrpawelkuklikforhisexceptionalsupport,and developing a novel computational model to enable signal mapping, that singularly addedclinicalapplicationfromotherwiseobservationalresults.thankstothomas Sullivan for his statistical advice and support. A very special appreciation for Dr AnandGanesan,whosedisruptiveintelligenceandperseverancehelpedmenurture as a diligent and intensive researcher focused on goals. My sincere thanks to Dr Mathias Baumert from School of Electrical and Electronic engineering, who helped me build a scientific grasp in the technique and interpretation of body surface electrocardiography. I am also thankful to all other cogfellows, who helped me v

8 developaspiritedinsightwhilelearningelectrophysiology,andmademerecognize valueofentitlement. My sincere appreciation to the electrophysiology laboratory technical team at the Royal Adelaide Hospital, Lauren Wilson, Ksenya Wojewidka, Simon Stolcman, and industrysupportstaff,dariuschapman,rayedkutielehwhosedeterminedsupport and organization helped conducting these cases. A sincere thanks to the nursing staff,judith,karen,christine,jake,sam,arun,reeba,ravish,crystal,juliaandmany otherspecialpeopleassociatedwiththelaboratoryforthroughoutselflesssupport. MywarmgratitudetomyesteemedparentsDrRajKumarDhamandUrmilaDham, whosetremendousencouragementandbeliefhelpedmecommissionandcomplete this work. Without their youthful feelings and inspirations, it was virtually unmanageabletoundertakeandperformattheexpectedlevels. Most importantly, I wish to thank my beloved wife Pallavi, who despite her own brightcareerprospects,hasalwaysendeavoredtostaybymyside.iappreciateher for her unconditional love and understanding throughout the trying times. The masterfulroleofmysonsabeeroverthelastthreeyearscannotbeundervaluedfor hisintelligencesoverstressmanagement.icannothelpbutthankhimtohavethis littleangelwhoforgothispleasurestohelpmeachievemyacademicambitions. vi

9 TABLE%OF%CONTENTS Abstract...i Declaration...iv Acknowledgements...v TableofContents...vii PublicationsAndCommunicationstoLearnedSocieties...xiv Abbreviations...xvi Chapter1.ReviewofLiterature...1 Abstract Epidemiology: Arrhythmic Burden of Ventricular Tachycardia In Ischemic CardiomyopathyandItsRiskAssessment VentricularArrhythmiaandSuddenCardiacDeath TimecourseofVentricularArrhythmiasinIschemicCardiomyopathy IdentificationofPatientsAtRiskofVentricularArrhythmia TheSubstrate:MechanismofVentricularImpulsePropagationandArrythmogenesis Introduction ActionPotentialGenerationBySingleMyocytes PrinciplesofPropagation...12 A.NormalContinuousPropagation...12 B.Discontinuouspropagation...13 C.TheSafetyofPropagation...14 D.PropagationAlongaCurvature FactorsaffectingActionPotentialPropagation:StructuralBasisofAnisotropy...16 A.OrientationofMuscleFibers...16 B.CellularShapeandSize...16 C.ConnexinExpression...17 D.IonChannelClustering...18 E.CellGtoGCellInteractionsBetweenMyocytesandNonmyocytes ActionPotentialPropagationandExtracellularElectrogramGeneration LocalActivationAnalysesFromExtracellularElectograms...20 vii

10 1.2.7MechanismsofSlowConduction...20 A.SlowConductionDuetoReducedMembraneExcitability...21 B.SlowConductionDuetoReducedCellGtoGCellCoupling...22 C.SlowConductionRelatedtoTissueStructureGEffectofLengthandBranching MechanismsofUnidirectionalConductionBlock...25 A.HeterogeneityinMembraneExcitabilityandRefractoriness...26 B.HeterogeneityinTissueArchitectureandDiscontinuousConduction BasicPrinciplesofReentry...28 A.Leadingcircleconcept,Scrollwaves,Vortexshedding...28 B.Phasesingularity(Rotortip)...30 C.RoleofExcitableGap MappingofScarRelatedVentricularTachycardiaInIschemicCardiomyopathy RelevantAnatomy DefinitionofScar RelationshipBetweenScarAndBorderzone RoleoftheEpicardium RoleoftheEndocavitaryStructures ChannelsInTheScarAndTheirLocalization...37 A.EntrainmentMapping...37 B.SubstrateMapping Indicationsofventriculartachycardiaablation...49 Ventriculartachycardiastorm Biophysicsofcatheterablationintheventricle Recent Advances and New Technologies in Mapping of Scar Related Ventricular Tachycardia NewImagingTechnologies...53 A.ContrastEnhancedMagneticResonanceImaging...53 B.BodySurfaceMapping HumanStemCellsasBenchModelsforVentricularTachycardiaMapping GeneTransfer LimitationsinTheCurrentKnowledgeAndResearchObjectives ElectricalResolutionWithinScar PoorClinicalOutcomesWithCatheterAblation ResearchObjectives...58 Figures...60 viii

11 Chapter2.HighDensityMappingofVentricularScarInIschemicCardiomyopathy7 A Comparison of Channels That Support Ventricular Tachycardia With Channels ThatdoNotSupportVT...65 Abstract Introduction Methods Patientpopulation Electrophysiologicstudy Radiofrequencyablation PostGprocessingofmaps FollowGup Statisticalanalysis Results BaselineClinicalCharacteristics InducibleVentricularTachycardia LeftVentricularEndocardialVoltageMapping MappingofChannels...74 A.Pacemapping...74 B.Entrainmentmapping...74 C.VTchannels...75 D.NonGVTchannels RelationshipofChannelsandScarRelatedElectrograms AblationOutcomes...77 InducibleVentricularTachycardiaDuringRepeatProcedures Discussion Majorfindingsofthestudy Previousstudies ScarrelatedelectrogramsandVTchannels IsletsofpreservedvoltagesandVTchannels ClinicalImplications StudyLimitations Conclusion...83 Tables...84 Figures...88 ix

12 Chapter 3. Defining arrhythmogenic ventricular scar using time7 and voltage7 domainanalysis:anovelapproachtoventriculartachycardiachannellocalization duringsinusrhythm...96 Abstract Introduction Methods Substratecharacterization...99 A.PatientPopulation...99 B.ElectrophysiologicStudyandAblation...99 C.FollowGup TimeGandVoltageGDomainAnalysisofElectrograms A.LateMeanActivationTime B.HighDispersioninActivationTimes C.LowShannonEntropy D.ChannelRegionValidation ProspectiveApplication StatisticalAnalysis Results BaselineClinicalCharacteristics InducibleVentricularTachycardia LeftVentricularEndocardialVoltageMapping MappingofVentricularTachycardiaChannels RelationshipofChannelsandScarRelatedElectrograms AblationOutcomes TimeandVoltageDomainElectrogramProperties ValidationofVTChannelsIdentifiedbyNovelElectrogramProperties Prospectivecases Discussion MajorFindings SubstrateAblation ConceptofMultipleGDeflectionMappinganditsRelationtoVTChannels ContemporaryMethodsandFutureDirectives StudyLimitations Conclusion Tables x

13 Figures Chapter 4. A Systematic Insight Into Channels In Ischemic Cardiomyopathy With AndWithoutSpontaneousVentricularTachycardiaUsingHighDensityMapping132 Abstract Introduction Methods Patientpopulation Electrophysiologicstudy A.VentricularTachycardiaPatients B.ControlGroup C.PostGprocessingofmaps Statisticalanalysis Results BaselineClinicalCharacteristics InducibleVentricularTachycardia LeftVentricularEndocardialVoltageMapping MappingofChannels A.Pacemapping B.Entrainmentmapping C.VTchannels D.NonGVTchannelsinVTpatients E.NonGVTchannelsinControlPatients RelationshipofChannelsandScarRelatedElectrograms Discussion Majorfindings Earlierstudies RelationshipBetweenScarAndBorderzone ConceptofChannels ElectrogramProperties ClinicalImplications StudyLimitations Conclusion Tables Figures xi

14 Chapter 5. Autonomic Modulation of Repolarization Instability In Patients With HeartFailureProneToVentricularTachycardia Abstract Introduction Methods Patientpopulation ECGrecording A.PatientsundergoingVTablation B.PatientsundergoingICDimplantation C.Patientsundergoingelectrophysiologicalstudy QTintervalvariabilityanalysis Statisticalanalysis Results Patientcharacteristics Heartrateresponse Heartratevariability QTResponse QTvariability QTVariability/Heartratevariabilityratio Discussion Majorfindings Previousstudies RelationwithHeartRateVariability ClinicalSignificanceandFutureDirections Studylimitations Conclusion Tables Figures SupplementaryData Chapter6.VentricularArrhythmiaStormAblation7ASystematicReviewandMeta7 analysis Abstract Introduction Methods xii

15 6.2.1IdentificationOfResearch QualityAssessmentAndSelectionOfStudies DataExtraction DataSynthesisAndStatisticalAnalysis Results IdentificationOfLiterature BasicClinicalAndDemographicData ProceduralStrategy ElectrophysiologicCharacteristics ProceduralResult A.DefinitionOfSuccess B.AcuteProceduralResult FollowGUp,RecurrenceOfVAAndMortality Impact Of Incessant VA On Procedural Outcome, Mortality And VA Recurrence OtherDemographicPredictorsOfMortalityAndVARecurrence RelationshipBetweenProceduralOutcome,MortalityAndVARecurrence Discussion AppraisingAvailableMulticenterStudies,MetaGAnalysisAndReviews MajorFindingsFromTheSystematicReview A.PalliationOrMortalityBenefit B.PredictorsOfOutcomes:MortalityAndVARecurrence StudyLimitations Conclusion Tables Figures Chapter7.FinalDiscussion Chapter8.FutureDirections Bibliography xiii

16 PUBLICATIONS+AND#COMMUNICATIONS*TO*LEARNED&SOCIETIES Chapter2 Manuscript accepted for publication in Circulation Arrhythmia Electrophysiology PresentedasanoralatAnnualHeartRhythmSocietymeeting,2012&2013, USA, and published in abstract form (Heart& Rhythm.2012;9:S329GS356) (Heart&Rhythm.2013;10:S85) Best Clinical paper award at Annual Asia Pacific Heart Rhythm Society meeting,2012,taiwan. Best Poster Award at Annual Cardiac Society of Australia and New Zealand meeting,2012,andpublishedinabstractform(heart,lungandcirculation, 2012;21:S1GS330) Ralph Reader Young Investigator Award, Clinical, Finalist at Annual Cardiac SocietyofAustraliaandNewZealandmeeting,2013 Chapter3 PresentedasanmoderatedandinnovationpostersatAnnualHeartRhythm Society meeting, 2013, USA, and published in abstract form (Heart& Rhythm.2013;10:S482) NIMMOFirstPrize,2013forFullTimeResearch,RoyalAdelaideHospital xiv

17 Best Poster award, Catheter ablation at Annual Asia Pacific Heart Rhythm Societymeeting,2013,HongKong Manuscriptorganizedforpublication Chapter4 Manuscriptorganizedforpublication Chapter5 PresentedasaposteratAnnualHeartRhythmSocietymeeting,2013,USA, andpublishedinabstractform(heart&rhythm.2013;10:s388gs433) Manuscript published as Original Research article in American Journal of Chapter6 PhysiologyG Heart and Circulatory Physiology:. Autonomic& modulation& of& repolarization& instability& in& patients& with& heart& failure& prone& to& ventricular& tachycardia. Nayyar S, RobertsGThomson KC, Hasan MA, et al. Am J Physiol HeartCircPhysiol.doi: /ajpheart Manuscript published as Clinical Update & Reviews in European Heart Journal:Venturing&into&ventricular&arrhythmia&storm:&a&systematic&review&and& meta>analysis. Nayyar S, Ganesan AN, Brooks AG, et al.european Heart Journal2013;34:560G569 Presented as a poster at Annual Heart Rhythm Society meeting, 2012, Boston,andpublishedinabstractform,HeartRhythm.2012;9:S357 S388 PresentedasaposteratAnnualAsiaPacificHeartRhythmSocietymeeting, 2012,Taiwan. xv

18 ABBREVIATIONS AP:Actionpotential ECG:Electrocardiogram EF:Ejectionfraction ICD:Implantablecardioverterdefibrillator ICM:Ischemiccardiomyopathy DCM:Dilatedcardiomyopathy LV:Leftventricle QTV:QTvariability RV:Rightventricle ShEn:Shannonentropy SGQRS:StimulusGQRS VA:Ventriculararrhythmia VF:Ventricularfibrillation VT:Ventriculartachycardia xvi