Originalarticle
Predictors of an adverse clinical outcome in patients with long-term right ventricular apical pacing
Jihyun Sohn (MD, PhD)a, Young Soo Lee (MD, PhD)b,*, Hyung Seob Park (MD, PhD)c, SeongwookHan(MD, PhD)c,Yoon-Nyun Kim(MD, PhD)c
aKyungpookNationalUniversityMedicalCenter,Daegu,RepublicofKorea
bDaeguCatholicUniversityMedicalCenter,Daegu,RepublicofKorea
cKeimyungUniversityDongsanMedicalCenter,Daegu,RepublicofKorea
Introduction
Cardiacpacingistheonlyeffectivetreatmentforsymptomatic atrioventricularblock (AVB).However, therehave been several studiesthathaveindicatedthatlong-termrightventricular(RV) apicalpacingisassociatedwithleftventricular(LV)dilatation[1]
oradecreasedLVejectionfraction[2].Large-scaledrandomized studiesalsoshowedanincreasedhospitalizationrateduetoheart failure(HF)inpatientswithlong-termRVapicalpacing[3,4].The decreased LV function may be due to abnormal electrical and mechanicalactivationpatternsoftheventriclesduetochronicRV pacing[5].Therehavebeenstudiesthathavesuggestedthatthe QRS duration and left-axis deviation could be related to the development of HF [6]. Nevertheless, there are no robust
electrocardiographic (ECG) features that can predict cardiac outcomes.ThisstudyaimedtoinvestigatethepacedQRSfeatures thatcouldhelppredictthecardiacoutcomeafterchronicRVapical pacinginpatientswithacquiredAVB.
Materialsandmethods Studypopulation
Thisstudycomprised247consecutivepatientswhounderwent long-term (>90% ventricular pacing with atrioventricular syn- chronyformorethanayear)RVapicalpacingforacquiredhigh degreeAVBfromOctober1995toDecember2012.Weonlyincluded patientswhowere implantedwithaDDDorVDDpacemakerto maintain atrioventricular sequential pacing. We excluded the patientswithanLVejectionfractionoflessthan50%,significant valvulardisease,oranytypeofcardiomyopathyoratrialfibrillation beforethe pacemakerimplantation. Thedemographiccharacter- istics, laboratory findings, ECG findings, and echocardiographic ARTICLE INFO
Articlehistory:
Received5January2017
Receivedinrevisedform19April2017 Accepted25April2017
Availableonline25May2017
Keywords:
Rightapicalpacing Heartfailure Electrocardiography
ABSTRACT
Background:Right ventricular (RV) apical pacing can result in progressive left ventricular (LV) dysfunctionandcontributetothedevelopmentofheartfailure(HF).Thisstudyaimedtopredictthe outcomeafterlong-termRVapicalpacinginpatientswithacquiredatrioventricular(AV)blockwho requiredpermanentpacing.
Methods:We included 247 patients who underwent long-term (>90% ventricular pacing with atrioventricularsynchronyformorethan1year)RVapicalpacingforacquiredAVblock.Weexcluded patientswithareducedLVsystolicfunction[ejectionfraction(EF)<50%].ThepacedQRSduration, degreeoftheaxis,clinicalcharacteristics,laboratoryfindings,andechocardiographicparameterswere recorded.WeevaluatedthemortalityandhospitalizationduetoHF.
Results:Themeanfollow-updurationwas6.9years.MortalityandhospitalizationduetoHFoccurredin 8.1%and17%,respectively.Inamultivariateanalysis,awiderpacedQRSdurationandlesssuperiorpaced QRSaxisatthetimeoftheimplantationwereindependentriskfactorsforadverseevents.Thepatients withapacedQRSdurationof163msandaxisof 658hada5.8timeshigherriskforadverseevents comparedtothosewithapacedQRSdurationof<163msandaxisof< 658.
Conclusions: ThepacedQRSdurationandaxiscouldhelpuspredictadverseclinicaloutcomesafter permanentRVapicalpacinginpatientswithhigh-degreeAVblock.
ß2017JapaneseCollegeofCardiology.PublishedbyElsevierLtd.Allrightsreserved.
* Correspondingauthorat:DepartmentofCardiology, CatholicUniversityof Daegu,Daemyung-4-dong,Nam-gu,Daegu3056-6,RepublicofKorea.
E-mailaddress:mdleeys@cu.ac.kr(Y.S.Lee).
ContentslistsavailableatScienceDirect
Journal of Cardiology
j our na l ho me pa g e : w ww . e l se v i e r . com / l oca t e / j j cc
http://dx.doi.org/10.1016/j.jjcc.2017.04.008
0914-5087/ß2017JapaneseCollegeofCardiology.PublishedbyElsevierLtd.Allrightsreserved.
findings were collected retrospectively. The current study was conductedinaccordancewiththedeclarationofHelsinki,andthe Institutional Review Board of the Daegu Catholic University MedicalCenterapprovedthestudyprotocol.
Electrocardiography
AllECGswererecordedata speedof25mm/s.TheECGwas sequentiallyobtainedrightaftertheimplantationofapermanent pacemakerand repeatedeveryyear aftertheimplantation. We collecteddataintermsofthepacedQRSdurationandaxis.The pacedQRSdurationwasassessedatthewidestQRSdurationatall pacedQRS leads. The paced QRS axiswas calculated from the voltageofleadIandleadaVFusingtrigonometry.Allinterrogated datafromthepacemaker,whichwereobtainedevery6months, werereviewedtoconfirmtheproportionofventricularpacing.
Echocardiography
Echocardiographywasdonebeforethepacemakerimplanta- tionandfollowedupayearafter.Wealsoperformedechocardi- ographyinsituations ofcardiacevents aswell.TheLV ejection fraction, LV end-diastolicand end-systolic dimensions,and left atrial diameter were obtained and recorded. The LV ejection fraction was measured by Simpson’s method using apical 4chamberviewandapical2chamberview.
Pacemakerimplantation
Allpatients wereimplanted witha pacemakerlead in right ventricularapex.Underfluoroscopicguidance,thepacingleadwas insertedtorightventricleviasuperiorvenacavaandrightatrium.
AfteradvancementofleadasfaraspossibletowardtheRVapex, weconfirmedwhetherthetipofleadwasstablylodgedinRVapex influoroscopicimaging.ECGwasalsocheckedtofindoutnegative QRSaxisinleadII,III,andaVF.Aftertheprocedure,wecheckedchest X-raydailytoconfirmthepositionofleadfor5days.Thecardio- thoracicratioininitialchestX-raywascalculatedandrecorded.
Clinicaloutcomes
Asa primary outcome, thecomposite of the cardiac events includingtheall-causemortalityandhospitalizationduetoHFwere evaluated.Further,eachoftheall-causemortalityandhospitaliza- tionsduetoHFwereanalyzedseparatelyassecondaryoutcomes.
Statisticalanalysis
ThestatisticalevaluationwasperformedusingSPSSsoftware packageversion18.0forWindows(SPSSInc.,Chicago,IL,USA).A chi-square and t-test were used to compare the demographic characteristic,andlaboratory,electrocardiographicandechocar- diographicfindings between thegroups withevents and those withoutevents. A logistic regression analysis wasused for the detectionoftheriskfactorsofcardiacevents.Areceiver-operating characteristic(ROC)curvewasusedtodeterminethecut-offvalues oftheQRSdurationandaxisforthedevelopmentofevents.We usedaKaplan–Meiercurvetodescribetheevent-freesurvivalrate indifferentriskgroupsdeterminedbythepacedQRSdurationand axisdeviation.Allanalysesrequiredap-value<0.05forstatistical significance.
Results
Thefollow-updurationwas6.73.9years.Amongthepatients, 51 (20.6%) developed events that were adjudicated as primary
outcomes.Deathfromanycauseoccurredin20(8.1%)patients,and hospitalization due to HF occurred in 42 (17.0%) patients. The characteristics of the patients who developed events or not are describedinTable1.Theage,gender,andpresenceofhypertension, diabetes,orcoronaryarterydiseasedidnotdifferbetweenthegroups with events andthose without events. There was no significant difference in the medications suchas betablockers, angiotensin- converting enzyme inhibitor, or angiotensin receptor blockers.
Among the ECG parameters, the paced QRS duration was longer (167.318.2msvs.158.617.9ms,p=0.002)andthedegreeofthe paced QRS axis was less superior ( 64.27.2 vs. 68.410.6, p=0.001)inthepatientswhodevelopedcardiacevents.Amongthe conventionalrisk factorsforpoor cardiovascularoutcomes,theLV ejectionfractionwasconfirmedtobeanindependentriskfactorfor events.Also,alongerQRSdurationandalessersuperioraxiswere independentriskfactorsofevents(Table2).TheoddsratiooftheQRS durationwas1.029(CI1.001–1.058,p=0.045)fordeathsand1.047 (CI1.010–1.053,p=0.004)forhospitalizationsduetoHF,respective- ly.TheoddsratiooftheQRSaxiswas1.031(CI1.002–1.093,p=0.038) fordeathsand1.054(CI1.018–1.091,p=0.003)forhospitalizations duetoHF,respectively.
Fig.1describestheROCcurveshowingtheQRSdurationand axisforthedevelopmentofcardiacevents.Thebestcut-offvalues oftheQRSdurationandaxisforpredictingcardiaceventswere 163msand 658,respectively.Amongthepatientswithapaced QRSdurationof163ms,29.3%developedcardiacevents.Inthose withapacedQRSaxisof 658,28.4%developedcardiacevents.
The paced QRS duration and axis were also independent risk factorsforcompositecardiaceventsincludingall-causemortality andhospitalizationsduetoHF.Usingthebestcut-offvaluesofthe QRSdurationandaxisforthedevelopmentofcardiacevents,we divided all patients into four different groups: group I, which included patients witha QRS duration of <163ms and axis of
< 658,groupII,whichincludedpatientswithaQRSdurationof
<163msandaxisof 658,groupIII,whichincludedpatientswith aQRSdurationof163msandaxisof< 658,andgroupIV,which included patients witha QRS duration of 163ms and axis of Table1
Thecharacteristicsofpatientswithcardiacevents.
Event(+) (n=51)
Event( ) (n=196)
p-value
Ageatimplantation,years 66.412.2 65.513.5 NS
Female,n(%) 31(60.8) 201(61.2) NS
Hypertension,n(%) 22(43.1) 83(42.3) NS
Diabetes,n(%) 11(21.6) 36(18.4) NS
CAD,n(%) 5(9.8) 15(7.7) NS
Medication,n(%)
Betablocker 7(13.7) 22(11.2) NS
ACEi/ARB 16(31.4) 45(23.0) NS
ECGafterimplantation
PacedQRSduration,ms 167.318.2 158.617.9 0.002 PacedQRSaxis,8 64.27.2 68.410.6 0.001 Initialcardio-thoracicratio,% 53.04.6 51.85.8 NS Initialechocardiography
LVEF,% 60.07.8 62.97.0 0.012
LVEDD,mm 51.97.4 50.56.1 NS
LVESD,mm 34.77.6 32.15.6 0.008
LAdimension,mm 41.57.7 39.16.7 0.023
NewonsetAF,n(%) 15(28.3) 72(35.3) NS
Follow-upechocardiography
LVEF,% 49.915.5 58.88.9 <0.001
LVEDD,mm 53.610.1 48.510.0 0.003
LVESD,mm 38.711.9 31.97.9 <0.001
LAdimension,mm 43.77.6 39.28.3 <0.001 CAD, coronary artery disease; AF, atrial fibrillation; ACEi, angiotensin- convertingenzymeinhibitor;ARB,angiotensinreceptor blocker;LVEF,left ventricular ejection fraction; LVEDD/LVESD, left ventricular end-diastolic/
systolicdimension;LA,leftatrium.
658. The populations of group Ito IV were 88, 43, 78, and 38patients,respectively.Therewasasignificantgradualincrease intheriskofcardiaceventsfromgroupItogroupIV(Table3).In the patients of the paced QRS duration of <163ms, the less superiorQRSaxis( 658)had higherriskofcompositecardiac eventsby2.6-foldcomparedtopatentswhohadthepacedQRS durationof<163msandthemoresuperiorQRSaxis(< 658).In addition,thepatientsofthewiderpacedQRSduration(163ms) andthelesssuperiorQRSaxis( 658)presentedincreasedriskby 5.8-foldcomparedtothepatientswiththelesswidepacedQRS duration(<163ms)and themoresuperiorQRSaxis(< 658).A
Kaplan–Meiercurvedemonstratedthedifferenceintheevent-free survival rate of the different risk groups using the paced QRS durationandaxisasshowninFig.2.Theevent-freesurvivalrate gradually decreased from group I to group IV with statistical significance.
Discussion
Inthisstudy,wefoundtheriskfactorsthatcouldpredictapoor clinicaloutcomeafterpermanentRVapicalpacinginpatientswith acquired AVB. Because all patients included maintained AV synchrony (DDD or VDD pacing mode) and had a cumulative ventricular pacing rate of >90%, we could provide reliable parametersintermsofpacingrhythmwhichwererelatedwith poorclinicaloutcome.ApacedQRSdurationofmorethan163ms andaxisofmorethan 658forRVapicalpacingincreasedtherisk oflong-termoutcomesby5.8-fold.
Pacingmodesandclinicaloutcomes
ChronicRVpacingisreportedtodecreasetheLVfunction[2].It is possiblydue tothenon-physiologic activationpattern ofthe interventricularseptumandabnormalelectricalandmechanical Table2
Theriskfactorsofcardiacevent.
Univariateanalysis Multivariateanalysis
OR CI p-value OR CI p-value
Age 1.005 0.981–1.029 NS
Hypertension 1.033 0.554–1.925 NS
CAD 1.312 0.453–3.796 NS
NewonsetAF 0.724 0.373–1.404 NS
InitialLVEF 0.947 0.907–0.988 0.013 0.953 0.912–0.996 0.031
InitialLVESD 1.070 1.016–1.126 0.010
InitialLAD 1.053 1.007–1.102 0.024 1.048 1.001–1.097 0.047
QRSduration 1.030 1.010–1.051 0.003 1.025 1.007–1.043 0.007
QRSaxis 1.037 1.008–1.067 0.012 1.012 1.003–1.020 0.007
CAD,coronaryarterydisease;AF,atrialfibrillation;LVEF,leftventricularejectionfraction;LVESD,leftventricularend-systolicdimension;LAD,leftatrialdimension.
Fig.1.Receiver-operatingcharacteristiccurveofpacedQRSdurationandQRSaxisforcardiacevent.ThepacedQRSdurationandQRSaxiswererelatedwiththecomposite cardiaceventsincludingmortalityandadmissionfromcongestiveheartfailure.AUC,area-under-the-curve.
Table3
GradualincreaseofriskaccordingtopacedQRSdurationandaxis.
OR CI p-value
GroupI(QRSd<163msandaxis< 658), n=88
1
GroupII(QRSd<163msandaxis 658), n=43
2.647 0.942–7.440 0.065
GroupIII(QRSd163msandaxis< 658), n=78
3.448 1.421–8.371 0.006
GroupIV(QRSd163msandaxis 658), n=38
5.833 2.187–15.561 <0.001
QRSd,QRSduration.
activationpatternsof theventriclessuchas leftbundle branch block [5]. The abnormal electrical and mechanical activation causesLV dyssynchrony,which couldcause theLV systolicand diastolicfunctiontodeteriorate [7].Andersenet al.[8] demon- strated that physiologic pacing maintaining AV synchrony can significantly reduce the rate of heart failure compared to ventricular pacing in patients with sick sinus dysfunction.
Howevertherehadbeenstudiesshowingthatphysiologicpacing withdual-chamberdeviceswasnotrelatedwithoutcomes[9]or evenassociatedwithahigherincidenceofnew-onsetHF[10].In thepresentstudy,weenrolledallpatientswithonlyphysiologic pacingwithdual-chamberdevicestoavoidtheexpectedbias.
Cumulativeventricularpacingrate
RV apical pacing causes chronic changes in the regional myocardialperfusion[11],cellularstructure[12],andventricular geometry[13]thatmayimpairtheventricularperformancesuch asleftbundlebranchblock.Someclinicaltrialshavereportedthat a higher cumulative RV pacing rate was associated with an increasedriskofHF,especiallyamongpatientstowhomRVapical pacingisnot essential[14,15].In thesub-analysis oftheMode SelectionTrial(MOST)[16],cumulativeventricularpacingof>40%
ofthetimeinthedual-chamberpacingmodewasassociatedwitha 2.6-foldincreasedriskofheartfailurehospitalizationscompared topacingof<40%ofthetime.Inaddition,theMOSTtrialreported 12%ofheartfailurehospitalizationsamong361patientswitha cumulativeventricularpacingrateof>90%asthesameinclusion criteriaasthepresentstudy.ConsistentwiththeMOSTstudy,the rateofHFhospitalizationswas17%duringthemeanfollow-upof 7.8yearsinourstudy.
PacedQRSdurationasapredictorofcardiacevents
PermanentRV apicalpacing resemblesa left bundle branch blockpatternandcausesprolongationoftheQRSduration.Awide QRS width has been suggested as a potentialpredictor of the developmentofLVdyssynchronyincardiacpacing[17]aswellas anindicatorofLVdyssynchonyitself.Miyoshietal.[18]reported thataprolongedpacedQRSdurationof190mswasassociated
withasignificantincreaseintheoverallmorbidityofcongestiveHF duringameanfollow-upperiodof53months,intheirstudywhich enrolled some elderly patients (mean age 73 years) including single-chamberpacing(14.1%).Ontheotherhand,Zhangetal.[10]
demonstrated that a paced QRS duration of 165ms was associatedwithanincreasedriskofHFafterRVapicalpacingin patients with high degree AVB. Consistent with the previous studies,wefoundthatalongerQRSdurationwasassociatedwith anincreasedriskofcardiacevents.
PacedQRSaxisasapredictorofcardiacevents
ThepacedQRSaxiscoulddifferaccordingtothelocationofthe RVleadaswell.ThepacedQRSaxisanddurationwerenotsimilar totheoriginalQRSduetothealteredintraventricularactivation sequence. The development of left-axis deviation has been reported to predict the mortality in patients with left bundle branchblock[17].However,littlewasknownaboutthemecha- nism oftheoutcomefromtheleft-axisdeviationanddegreeof deviationthatisrelatedtoapooroutcome.Astudypreviouslyhad suggestedleft-axisdeviationasacomponentoftheriskscorefor interventriculardyssynchronyinpatientswithchronicRVapical pacing[6].AleadplacementintheRVapexresultsinasuperior pacedaxis(i.e.negativeintheinferiorleads),andthedegreeofthe superiorpacedaxiscouldchangeaccordingtothelocationofthe RVleadbetweentheseptumandfreewalloftheRVapex.Amore superioraxisresultsfrombeingclosertotheseptumoftheRV.We foundthattheQRSaxisaswellastheQRSdurationwasrelatedto theclinicaloutcome.Inthepresentstudy,wefoundthata less superioraxis,thatis 658,wasassociatedwithcardiacevents.
Althoughallpatientshadleft-axisdeviation,between 87.38and 21.08,becauseallofthemwereimplantedwithapacemakerlead intheRVapex,wecouldcalculatethebestcut-offvalueoftheQRS axisforpredictingapooroutcome.
PlacementoftheRVlead
Recentlytheplacementofpacemakerleadsatalternativesites such as RV outflow tract instead of the RVapex hasgathered consensus[19].Therationaleforthealternativepacingsiteisthat maintainingAVsynchronycouldpreventventriculardyssynchro- nization.However,therehavebeendatathathaveshownthata wide QRS duration wasassociated with poor outcomesalso in patients with an implanted pacemaker with a lead in the RV outflowtract[20],andthemortalityratewassimilarinRVapical pacingandseptalpacing[21].Inourstudy,about80%ofpatients withapacedQRSdurationoflessthan160msandanaxisofless than 708,hadnoadverseeventsoverthelong-termfollow-up.
WecansuggesttheRVapicalpacingwouldbefavorableoutcomeif thepacedQRSdurationisnarrowandthemoresuperioraxisright afterleadimplantation.
Limitations
Thepresentstudywasaretrospectivestudyincludingarelative smallnumberofpatients.Becausethemeanagewas65.7years, therewasarelativelyhighmortalityrateof8.1%.Insomepatients thecauseofdeath couldnotbeidentifiedbecausetheydiedat homewithoutvisitingthehospital.However,concerningtheodd ratiosofdeathsandhospitalizationsduetoHF,themajorcauseof highercardiaceventrateinpatientswithwiderQRSdurationand lesssuperiorQRSaxiscouldbeconsideredtoresultfromhigher hospitalizationrateduetoHF.Althoughwecouldnotfindoutall causesofdeathsinthisstudy,itcouldprovideinsightintothelong- term outcome in patients with chronic RV pacing and the predictorsoftheoutcomeafterapacemakerinsertion.
Fig.2.Event-freesurvivalrateaccordingtoQRSdurationandaxisdeviation.The longerpacedQRSdurationandlesssuperiorQRSaxishadincrementaleffecton cardiacevents.
