Triple-site pacing for cardiac resynchronization in permanent atrial fibrillation : acute phase results from a prospective observational study

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www.revportcardiol.org

Revista

Portuguesa

de

Cardiologia

Portuguese

Journal

of

Cardiology

ORIGINAL

ARTICLE

Triple-site

pacing

for

cardiac

resynchronization

in

permanent

atrial

ﬁbrillation

---

Acute

phase

results

from

a

prospective

observational

study

Pedro

Marques

∗

,

Miguel

Nobre

Menezes,

Gustavo

Lima

da

Silva,

Ana

Bernardes,

Andreia

Magalhães,

Nuno

Cortez-Dias,

Luís

Carpinteiro,

João

de

Sousa,

Fausto

J. Pinto

CardiologyDepartment,UniversityHospitalSantaMaria,CentroHospitalardeLisboaNorte,CCUL,UniversityofLisbon,Portugal

Received28October2015;accepted20December2015

Availableonline30May2016

KEYWORDS Cardiac resynchronization therapy; Multi-sitepacing; Triple-sitepacing; Heartfailure; Atrialﬁbrillation; Cardiacoutput; QRSduration; Ejectionfraction Abstract

IntroductionandAim:Multi-sitepacingisemergingasanewmethodforimprovingresponseto cardiacresynchronizationtherapy(CRT),buthasbeenlittlestudied,especiallyinpatientswith atrialﬁbrillation.Weaimedtoassesstheeffectsoftriple-site(Tri-V)vs.biventricular(Bi-V) pacingonhemodynamicsandQRSduration.

Methods:Thiswasaprospectiveobservationalstudyofpatientswithpermanentatrial ﬁbrilla-tionandejectionfraction<40%undergoingCRTimplantation(n=40).Onerightventricular(RV) leadwasimplantedintheapexandanotherintherightventricularoutﬂowtract(RVOT)septal wall.Aleftventricular(LV)leadwasimplantedinaconventionalvenousepicardialposition. Cardiacoutput(usingtheFloTracTM _VigileoTM _system),_mean_QRS_and_ejection_fraction_were calculated.

Results:Meancardiacoutputwas4.81_±0.97l/minwithTri-V,4.68_±0.94l/minwithRVOTseptal andLVpacing,and4.68±0.94l/minwithRVapicalandLVpacing(p<0.001for Tri-Vvs.both BiV).Meanpre-implantationQRSwas170±25ms,123±18mswithTri-V,141±25mswithRVOT septalpacingandLVpacingand145±19withRVapicalandLVpacing(p<0.001forTri-Vvs.both BiVandpre-implantation).MeanejectionfractionwassigniﬁcantlyhigherwithTri-V(30±11%) vs.Bi-Vpacing(28_±12%withRVOTseptalandLVpacingand28_±11withRVapicalandLVpacing) andpre-implantation(25±8%).

Conclusion: Tri-VpacingproducedhighercardiacoutputandshorterQRSdurationthanBi-V pacing.ThismayhaveasigniﬁcantimpactonthefutureofCRT.

∗_{Corresponding}_author.

E-mailaddress:[email protected](P.Marques).

http://dx.doi.org/10.1016/j.repc.2015.12.006

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PALAVRAS-CHAVE Terapêuticade ressincronizac¸ão cardíaca; Pacingmulti-site; Pacingtriple-site; Insuﬁciência cardíaca;

Fibrilhaçãoauricular; Débitocardiaco; DuraçãoQRS; Fraçãodeejeção

Pacingtriple-sitepararessincronizaçãocardíacanafibrilhaçãoauricularpermanente

--- resultadosdafaseagudadeumestudoprospetivoobservacional

Resumo

Introduçãoeobjetivo: O pacing multi-site está a emergir como um novo método de ressincronizaçãocardíaca. Todavia,foi poucoestudado, sobretudo em fibrilhaçãoauricular. EsteestudovisaaferiroefeitohemodinâmicoenaduraçãodoQRSdepacingTri-VversusBi-V.

Métodos: Estudoprospetivoobservacionaldedoentescomfibrilhaçãoauricularpermanentee fraçãodeejeção<40%submetidosaimplantaçãodeCRT(n=40).Implantou-seumeletrocateter direitonoápex,outronaparedeseptaldotratodesaídadireitoeoutroemposiçãovenosa epicárdicaesquerdaconvencional.Calcularam-seodébitocardíaco(usandoosistemaVigileo Flotrac®_),_o_QRS_médio_e_a_frac_¸ão_de_ejec_¸ão.

Resultados: Odébitocardíacomédiofoi4,81_±0,97L/minemTri-V,4,68_±0,94L/mincom

pacingseptaleesquerdoe4,68±0,94L/mincompacingapicaleesquerdo(p<0,001para Tri-VversusambosBiV).OQRSpré-implantaçãomédiofoi170±25ms,123±18msemTri-V, 141±25msempacingseptaleesquerdoe145±19empacingapicaleesquerdo(p<0,001 paraTri-VversusambosBiVepré-implantação).Afraçãodeejeçãomédiafoiestatisticamente superioremTri-V(30_±11%)versusBi-V(28_±12%empacingseptaleesquerdoe28_±11em

pacingapicaleesquerdo),eversuspré-implantac¸ão(25±8%).

Conclusão:OpacingemTri-VproduziuumdébitocardíacosuperioreQRSmaisestreitodoque emBi-V.Estesresultadospoderãomodificarofuturodaterapêuticaderessincronização. ©2016SociedadePortuguesadeCardiologia.PublicadoporElsevierEspaña,S.L.U.Todosos direitosreservados.

Listofabbreviations AF atrialﬁbrillation AV atrioventricular Bi-V biventricularpacing

CRT cardiacresynchronizationtherapy ECG electrocardiographic

EF ejectionfraction LV leftventricular

NYHA NewYorkHeartAssociation RV rightventricular

RVOT rightventricularoutﬂowtract Tri-V triple-siteventricularpacing

Introduction

Cardiac resynchronization therapy (CRT) is an established therapyforpatientswithdrug-refractoryheartfailureand electrical evidenceof dyssynchrony. Several large clinical trials have demonstrated that biventricular (Bi-V) pacing signiﬁcantlyreducesall-causemortalityandheart failure-relatedhospitalizationsandsymptoms,andimprovesquality oflife,exercisetoleranceandleftventricular(LV)systolic performance.1_However,_even_when_{appropriately}_selected,

20-30%ofpatientsdonotrespondtoCRT.Thismaybedueto incompleteresynchronization,asintraventricularand inter-ventriculardyssynchrony canpersist in 25-30%of patients despiteCRT.2_For_such_{non-responders,}_multi-site_and

multi-point pacing are emerging as new methods of CRT. The

fewpreviouslypublishedstudiesregardingthesenovel pac-ingmodalitieshaveshownimprovedLVhemodynamicsand synchrony.3---6_However,_doubts_remain_concerning_their

indi-cations andshort-termand long-term efﬁcacyand safety, andthustheoptimalmethodofresynchronizationremains unknown.

Inthesubgroup ofpatientswithatrial ﬁbrillation(AF), nofewerthan23%ofallthosewithimplantedCRTdevices,7

studiesarestillscarce,andthesepatientsareparticularly challenging.However,currentlyavailableevidencesuggests CRT may be of beneﬁt. A meta-analysis8 _of _prospective

cohortstudiescomparingresponsetoCRTinpatientswith sinus rhythmvs.AFshowednotonlythat CRTwas beneﬁ-cialinboth groups, butalsothatthe AFgroupperformed betterintermsofreverseremodeling(assessedas improve-mentinejectionfraction[EF]),albeitwithworsefunctional outcomes.Becauseachievinghighlevelsofpacingisharder inpatientswithAF,thereis evidencethatatrioventricular (AV)junction ablation may further enhance CRT response and improve not only remodelingresponse but also func-tionaloutcomes.9_{Interestingly,}_there_is_evidence_that_even

AFpatients without severelydepressedEF,prolongedQRS or severe heart failure (i.e. in New York Heart Associa-tion[NYHA]class≤II)maybeneﬁtfromCRT.Arandomized trial10 _assessing_patients_who_underwent_AV_junction

abla-tion due to severely symptomatic permanent AF showed thatCRTwasmorebeneﬁcialthanconventionalright ven-tricular (RV) apical pacing both in patients who met the current recommendations for CRT implantation regarding EF,QRSdurationandfunctionalclassandinthosewhodid not. Finally, only one trial of multi-site pacing has been undertaken in the subgroup of AF patients,11 _with _good

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Thus,todate,theoptimalmethodofcardiac resynchro-nization remains tobe established, especially in patients with AF. We are currently undertaking an observational prospectivetrialtoassessthisissue.Inthispaperwepresent our results from the acute post-implantation phase, with particularfocusonhemodynamicperformance.

In this study cardiac resynchronization with multi-site pacingwasachievedbymeansoftworightventricular(RV) leads.Moststudiesonmulti-sitepacingusedtwoLVleads andoneRVlead.12-14_Only_two_trials_using_two_RV_leads_have

beenpublishedthusfar.5,13_Given_that_the_former_approach

has shown to have greater procedure duration, radiation exposure and LV pacing threshold12,15 _and _that _multi-site

pacing using two RV leads has never been assessed in patientswithAF,wechosetousethelatterapproach.

Sincethebeneﬁtofrightventricularoutﬂowtract(RVOT) septal pacing is still regarded as controversial,14 _we _also

assessedtheperformanceofRVOTseptalpacingvs.RV api-calpacingasasecondaryobjective,inordertoshedfurther lightonthisquestion.

Objective

Theprimaryaimof thisstudywastoassesstheeffectsof triple-siteventricular(Tri-V)pacingvs.Bi-Vpacingon hemo-dynamicperformanceandQRSduration.Thesecondaryaim wastoassesstheeffectsofRVOTseptalpacingvs.RVapical pacingonhemodynamicperformanceandQRSduration.

Methods

Patientselection

Patientsmeeting all thefollowing criteria wereincluded: (1)permanentAF;(2)EF<40%; (3)heartfailureNYHA≥II despite appropriate medical treatment and baseline QRS >120msorneedforanti-bradycardiapacingwithan antic-ipatedpercentageofventricularpacing>40%;(4)cognitive capacitytounderstandthestudyandhencegiveinformed consent.

Implantationandconnectionmethod

When a CRT defibrillatordevice wasimplanted, the defi-brillator leadwaspositioned inthe RV apex,andfor CRT pacemaker implantation, one conventional RV lead was implantedintheRVapex.Inbothcases,asecondRVlead wasimplantedintheRVOTseptalwallmeetingfluoroscopic criteria14 _combined_with_{electrocardiographic}_(ECG)

crite-riaforcorrectplacement,16_ensuring_avoidance_of_the_RVOT

anterioror freewall. Finally,a coronarysinus leadfor LV pacing was implanted as usual for CRT pacing (i.e. in a posterolateralmid-basal position).The RVapicalleadwas connected tothe RV channel. If the LV lead wasbipolar, withapacingthresholdbelow2.5Vandnodiaphragmatic stimulation,theLVleadwasconnectedtotheatrial chan-nelandtheRVOTleadconnectedtotheLVchannel.Ifthe LVlead wasquadripolar, if the pacing thresholdwasover 2.5V,if speciﬁcLVvector programmingwasnecessary,or if therewas any type of diaphragmatic stimulation, then

theLVleadwasconnectedtotheLVchannelandtheRVOT leadwasconnectedtotheatrialchannelonthegenerator. Anydeviceandleadbrandcouldbeused.Programmingwas settoDDDRwiththelowestpossibleAVinterval(25-40ms dependingondevicebrand)andaVVintervalof0ms.

Hemodynamicassessment

Uptoonemonthafterimplantation,allpatientsunderwent minimally invasive hemodynamic assessment with place-mentofaradialarteriallineusingtheFloTracIIITM_VigileoTM monitoringsystem(EdwardsLifesciences,Irvine,CA,USA), whichcalculatescardiacoutputbasedonthearterial pres-sure waveform. This system is widely used in peri- and intraoperative settings as well as in intensive care units, andisusefulindetectingsuddenchangesincardiacoutput andvolumestatusprovidedthecardiacrhythmisregular.17

Cardiacoutputandsystolicvolumewereassessedat70 beatsper minute in the following configurations: RV api-cal,RVRVOT,LV,Bi-VpacingusingtheRVapical(RVA)and LVleads (Bi-VRVA-LV), Bi-V pacing usingtheRVOT andLV leads (Bi-V RVOT-LV), and Tri-V. The assessment was per-formedunder≥99%pacing.Inordertoachievetheselevels, AVnodesuppressionwasachievedpreviously bymeans of pharmacotherapyorbyAVnodeablationindrug-refractory cases.Eachconfigurationwasassessedfor15mintoachieve stablemeasurements.Duringtransitions,toavoida poten-tialcarry-overeffect,thefirst5minofmeasurementswere disregarded,andonlymeasurementsfromthefollowing15 minwereconsidered.Theoperatorperformingthe hemody-namicassessmentwasblindedtothepacingmodeused.

Electrocardiographicassessment

Simultaneously with the hemodynamic assessment, all patients underwent standard 12-lead ECG assessment in each of the following conﬁgurations: RV apical,RV RVOT, LV,Bi-V RVA-LV, Bi-V RVOT-LV and Tri-V. QRS duration was measured in each of these conﬁgurations by two blinded operators.

Echocardiographicassessment

TheechocardiographicstudywasperformedwithaVivid7 device(GeneralElectric®₎_in_each_of_the_following conﬁgu-rations:Tri-V,Bi-VRVA-LVandBi-VRVOT-LV.The studywas undertakensimultaneously with the hemodynamic assess-ment.

EFwasestimatedbytheSimpsonbiplanemethod deter-mined from the cine loops acquired in two-dimensional mode,end-diastolic and latesystolicvolumes being mea-suredinthreeconsecutive cardiac cycles.Post-processing analysiswas performed by two operatorsusing EchoPAC© software(GeneralElectric).

Statisticalanalysis

Meancardiacoutput,QRS andEFwerecalculatedin each group.Differenceswereassessedbyapairedsamplesttest.

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Table1 Patientpopulationdetails.

n 40

Age,years(mean±SD) 73±11

Male,n(%) 37(97.5) Ischemiccardiomyopathy,n(%) 10(25) NYHAI,n(%) 3(7.5) NYHAII,n(%) 14(34) NYHAIII,n(%) 24(58.5) NYHAIV,n(%) 0(0) ACEinhibitor,n(%) 34(85)

Aldosteronereceptorblocker,n(%) 3(7.5) Mineralocorticoidreceptorantagonist,n(%) 23(57.5)

Beta-blocker,n(%) 34(85) Diuretic,n(%) 36(90) Digoxin,n(%) 11(27.5) Amiodarone,n(%) 7(17.5) Antithrombotics,n(%) 6(15) VitaminKantagonist,n(%) 24(60) Neworalanticoagulant,n(%) 11(27.5)

Pre-implantationQRS,ms 170±25

Pre-implantationEF,%(mean±SD) 27±6

CRT-D,n(%) 26(65)

CRT-P,n(%) 14(35)

AVnodeablation,n(%) 6(17.5)

ACE:angiotensin-convertingenzyme;CRT-D:cardiac resynchro-nizationtherapydeﬁbrillator;CRT-P:cardiacresynchronization therapypacemaker;EF:ejectionfraction;NYHA:NewYorkHeart Association;SD:standarddeviation.

In order to assess differences in procedure duration, ﬂuoroscopyduration and radiation dosage, the additional amountsoftheseparametersrequiredfor implantationof the second RV lead were quantiﬁed, and the differences betweenBi-VandTri-Vwereassessedbythettest.

Ethicalconsiderations

This paperconforms with the Helsinki Declaration onthe EthicalPrinciplesforMedicalResearchInvolvingHuman Sub-jects and was approved by our local ethics committee. Writteninformedconsentwasobtainedfromallpatients.

Results

Population

A total of 40 patients were included. Baseline pre-implantation characteristics are summarized in Table 1. Mostpatients were severely symptomatic, with markedly depressedEF and a signiﬁcantly prolonged QRS. AV node ablationwasnecessaryinsixpatientspriortohemodynamic assessment.

Hemodynamicresults

The hemodynamic results are depicted in Table 2 and

Figures 1A and B. Cardiac output wassigniﬁcantly higher duringTri-VcomparedtoBi-Vpacing.Therewasno statis-tically signiﬁcant differencebetweenthe twoBi-V pacing

Table2 Cardiacoutputindifferentpacingconﬁgurations. Pacingconﬁguration Cardiacoutput,

l/min(mean±SD)

Tri-V 4.81±0.97

Bi-VwithRVOTseptalpacing 4.68±0.94 Bi-VwithRVapicalpacing 4.66_±0.91

RVOTseptalpacing 4.56±0.93

RVapicalpacing 4.44_±0.84

LVpacing 4.47±0.92

Bi-V: biventricularpacing; LV: leftventricular; RV: right ven-tricular;RVOT:rightventricularoutﬂowtract;Tri-V:triple-site pacing. 5

A

B

p<0.001 Pacing configuration Pacing configuration Tri-V Bi-V (RVOT) RVOT Bi-V (apical) Rv apical LV Tri-V Bi-V (RVOT) RVOT Bi-V (apical) Rv apical LV p<0.001 p=NS p=NS p=NS p=0.007 4.9 4.8 4.7 4.6 4.5 4.4 4.3 4.2 4.1

Cardiac output (l/min)

4 5 4.9 4.8 4.7 4.6 4.5 4.4 4.3 4.2 4.1 4

Figure1 DifferencesincardiacoutputbetweenTri-Vand Bi-Vpacing(A),betweenBi-VpacingandRVOTseptalpacing,and between RVOT septalpacing and RV apical pacing (B). Bi-V: biventricularpacing;LV:leftventricular;RV:rightventricular; RVOT:rightventricularoutﬂowtract;Tri-V:triple-sitepacing.

conﬁgurations, nor between Bi-V pacing and RVOT septal pacing. The latter produced a signiﬁcantly higher cardiac output than RV apical pacing. These differences remain acrossischemicandnon-ischemiccardiomyopathygroups.

Electrocardiographicresults

MeanQRSdurationineachpacingconﬁgurationisdepicted in Table 3 and Figures 2A, B and C. Tri-V pacing pro-duced a signiﬁcantly shorter QRS than pre-implantation

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Table3 QRSdurationineachpacingconﬁguration. Pacingconﬁguration MeanQRS,ms(mean_±SD)

Tri-V 123±18

Bi-VwithRVOTseptalpacing 141±25 Bi-VwithRVapicalpacing 145±19 RVOTseptalpacing 158_±20 RVapicalpacing 187±18

LVpacing 201_±22

Bi-V: biventricularpacing; LV:left ventricular; RV:right ven-tricular;RVOT:rightventricularoutﬂowtract;Tri-V:triple-site pacing. p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 p<0.001 p=NS p<0.001 p<0.001 p<0.001 p<0.001 Pacing configuration Pacing configuration Pacing configuration Tri-V Pre-implantation Bi-V (RVOT) RVOT Bi-V (apical) Rv apical LV QRS (ms) 100 120 140 160 180 200 220

A

B

C

QRS (ms) 100 120 140 160 180 200 220 QRS (ms) 100 120 140 160 180 200 220 Tri-V Pre-implantation Bi-V (RVOT) RVOT Bi-V (apical) Rv apical LV Tri-V Pre-implantation Bi-V (RVOT) RVOT Bi-V (apical) Rv apical LV

Figure2 DifferencesinmeanQRSbetweenpre-implantation andpacing(A),betweenTri-VandBi-Vpacing(B),betweenBi-V andRVOTseptalpacing,andbetweenthelatterandRVapical pacing(C).Bi-V:biventricularpacing;LV:leftventricular;RV: rightventricular;RVOT: rightventricularoutﬂowtract;Tri-V: triple-sitepacing.

QRS and both Bi-V pacing configurations.Bi-V pacing also significantly shortened QRS duration compared with pre-implantation QRS. There was no statistically significant difference between the two Bi-V pacing configurations. RVOTseptalpacingproducedasignificantlyshorterQRSthan

Table4 Echocardiographicejectionfractionineach pac-ingconﬁguration.

Pacingconﬁguration Ejectionfraction, %(mean±SD)

Pre-implantation 25±8

Tri-V 30_±11

Bi-VwithRVOTseptalpacing 28±12 Bi-VwithRVapicalpacing 28_±11

Bi-V:biventricularpacing;RV:rightventricle;RVOT:right ven-tricularoutﬂowtract;Tri-V:triple-sitepacing.

Pacing configuration Pacing configuration Tri-V Pre-implantation Bi-V (RVOT) Bi-V (apical) Ejection fr action 20 22 24 26 28 30 32 34

A

B

Ejection fr action 20 22 24 26 28 30 32 34 Tri-V Pre-implantation Bi-V (RVOT) Bi-V (apical) p<0.001 p=0.07 p=0.018 p=0.005 p=NS p=0.0017

Figure3 Differencesinmeanejectionfractionbetween pre-implantation and cardiac resynchronization therapy (A) and betweenTri-VandBi-Vpacing(B).Bi-V:biventricularpacing; RVOT:rightventricularoutﬂowtract;Tri-V:triple-sitepacing.

pre-implantationQRS andRVapicalpacingQRS,buta sig-niﬁcantly longer QRS than Bi-V pacing. These differences remainacross ischemic and non-ischemic cardiomyopathy groups.

Echocardiographicresults

EFresultsaredepictedinTable4andFigures3AandB.All modesof CRTproduceda statisticallysigniﬁcant improve-mentinEF.Tri-Vproducedthegreatestimprovement,with asigniﬁcantdifferencecomparedtoBi-V.Thesedifferences remainacross ischemic and non-ischemic cardiomyopathy groups.

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Table5 ProcedureandﬂuoroscopytimesandradiationdoseinTri-Vpacingvs.conventionalBi-Vpacing.

Tri-V Bi-V p

Proceduretime,min(mean±SD) 81±34 75±31 NS

Fluoroscopytime,min(mean±SD) 15±11 14±12 NS

Radiationdose,␮Gy/cm2_(mean_±_SD) _0.61_±_0.38 _0.58_±_0.32 _NS

Bi-V:biventricularpacing;Tri-V:triple-sitepacing.

Meanﬂuoroscopyandproceduretime

AlthoughimplantationoftheTri-Vsystemresultedinlonger procedure and ﬂuoroscopy times, the difference wasnot signiﬁcant compared to conventional Bi-V implantation (Table5).

Discussion

In this study, Tri-V pacing produced a superior hemody-namicperformancecomparedtoconventionalBi-Vpacing, asdemonstratedbyincreasedcardiac outputand EF.This islikelyanimmediateconsequenceofimproved resynchro-nization,giventhatQRSdurationwassignificantlyshorterin Tri-Vpacingvs.conventionalBi-Vpacing,andthatthiswas anacutephasestudy,inwhichreverseremodelingcouldnot yethaveoccurred.ThereductioninQRSdurationobtained byTri-V pacingis especiallyremarkable,QRShaving been shortenedalmosttonormallength.Ourfluoroscopyand pro-ceduretimeswerescarcelyprolongedbythistechnique,and assuchwerenotasignificantlimitation.

There havebeen few studies onmulti-sitepacing,and themethodologyhasbeenveryheterogeneousregardingnot only pacingand implant techniques, but also themethod usedforassessinghemodynamicresponse.MostusedtwoLV leadsandoneRVlead.Inonenon-randomizedtrialoneof theLVleadswasconnectedtotheatrialchannel(allpatients hadpermanentAF),andtheothertwoleadswereconnected asusual. Triple-sitepacing yieldedhigherEF andreduced end-systolicvolume,withoutclinicalimprovement,atthree months.11 _Of_course,_by_connecting_an _LV_lead_to_an _atrial

channel,theuseofvectorsislimited.Twootherrandomized trialsusedasimilarapproachbutconnectedbothLVleads withaY-connector.Theydemonstratedanadditionalclinical beneﬁt,but greaterprocedure length, radiation exposure andLVpacingthreshold.12,15_Regarding_safety,_none_of_these

trialshave shown signiﬁcant differences between Tri-V or Bi-Vpacing,andOganoetal.18_recently_demonstrated_that

dualLVpacingmightevenhaveaprotectiveeffectagainst ventriculararrhythmias.3

Only three trials using two RV leads and one LV lead alonehavebeenpublished.5,13,19_However,_in_two_of_these,

theconnection technique wasdifferent,asboth RV leads were connected to the atrial channel by means of a Y-connector. Systolic function was assessed invasively by determiningpeakLVdP/dt(usingamicromanometer-tipped pigtailangiographiccatheter)andalsocardiacoutputwith aSwan-Ganzcatheter.Dyssynchronywasassessedwith tis-sueDoppler echocardiographicimaging. QRSduration was alsoassessedineachpacingconﬁguration.Triple-site pac-ingwassuperiorregardingallfourparameterscomparedto

conventional BiV pacing.Therewere alsonosafetyissues regardingthismethod.Finally,onetrialusedbothtypesof triple-sitepacing(i.e.onegroupreceivedtwoRVleads,and anothertwoLVleads),withbetterclinicalandhemodynamic results in triple-site pacing compared toconventional Bi-Vpacing.20 _A_very_recent_randomized_trial_compared_Tri-V

pacingwithconventionalBi-Vpacingintermsofclinicaland echocardiographicdataat12-monthfollow-up.Therewere nodifferencesinadverseeventsorclinicalbeneﬁt,however Tri-VdidproducehigherEFat12months.5,13,19

Despite the heterogeneity of the studies, and the unique methodologyof ourstudy,all of these trialsusing triple-sitepacinghavedemonstratedsuperiorhemodynamic performanceandincreasedresynchronizationcomparedto conventional Bi-V pacing. The beneﬁtwasalsopresent in AFpatients.11_Thus,_our_results_are_consistent_with_previous

studies.

Itisworthnotingthatnoprevioustrialhaseverassessed theuse oftriple-sitepacingwithtwoRVleadsin patients withpermanentAF.Giventhatthesepatientsrepresentan understudiedandparticularlychallenginggroup,ourstudy adds pioneeringscientiﬁcdataonthismodalityofcardiac resynchronizationtherapyinthissubgroup.

Regardingtheresultsofsingle-sitepacing,ourstudy pro-duced interesting results. RVOT septal pacing wasclearly superior toRV apical pacing, with improved cardiac out-put and much shorter QRS duration. RVOT septal pacing aloneevendecreasedbaselineQRSlengthinourpatients. Studies comparing these two pacing modalities have pro-ducedconﬂictingresults.14 _However,_the_{discrepancies}_are

largelydue tothesigniﬁcant heterogeneity inlead place-ment technique:fewstudies havebeen carefulenoughto ensure proper lead placement in both the RVOT and the septalwall. This wasa criticalconcernin ourstudy. Sev-eraltrials in which theRV lead wasplaced undercareful ﬂuoroscopic and/or electrocardiographicguidance yielded superior results for RVOT septalpacing.14 _Our _study _adds

furtherweighttothisevidence.

Finally,theabsenceof astatisticaldifferencebetween cardiacoutputwithBi-VpacingandRVOTseptalpacingwas anunexpectedfinding,especiallyconsideringthattheQRS wassignificantlyshorterwithBi-Vpacing.Theclinical signif-icanceofthisfindingisunclear,giventhatwewerenot com-paringtheclinicalperformanceofthesetwopacing modali-ties.Studiescomparingsingle-siteRVpacingvs.Bi-Vpacing used echocardiographic and clinical endpoints obtained sometimeafterimplantation,andnotimmediate hemody-namicdata.21_In_addition,_the_majority_of_these_studies

com-pareRVapicalpacingratherthanRVOTseptalpacing.Thus, nostudycanbedirectlycomparedtoours,andwhilemost studiesfavorBi-Vpacing,theabove-mentionedlimitations regardingRVpacingsitemaybeofgreaterimportancethan

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previouslythought.Therefore,whatevertheinterpretation ofourparticularresults,theyhighlighttheimportanceand potentialofRVOTseptalpacing.Indeed,inpatientsinwhom theCRTindicationisbasedonneed forpacingratherthan primarily onheart failure,could RVOTseptalpacing be a sustainable alternative to Bi-V pacing? Our trial was nei-ther designed nor statistically powered to answer such a question,butaddsfurtherevidencetotheissue.

Limitations

Ourstudy has several limitations. Use of the FloTracIIITM VigileoTM_monitoring_system_is_{time-consuming}_and_while_it hasbeen wellvalidatedinavarietyofclinicalscenarios,17

thisisthefirsttimethatithasbeentestedinthissetting. Also,ischemiccardiomyopathywasfoundinonly25%ofall patients.Despitethefactthatstatisticalresultswere sim-ilaracross thissubgroupof patients,theabsolute number of patients is small, and as such this heterogeneity may haveinfluencedourresults.Finally,althoughthe echocar-diographicresultswerestatisticallysignificant,theresulting differences are small and within the inter- and intraob-server variabilityof thetechnique. Thus,theseparticular results should be interpreted with caution. The observed differences in cardiacoutput were alsosmall,and there-fore we cannot yet be absolutely sure of their clinical significance.

Future

directions

The factthat multipletechniques, includingours, yielded beneﬁt suggests that multi-site pacing should be further developed.Theoptimalmethod,whetherwithtwoRVleads, twoLVleads,asingleleadwithmulti-pointpacing capabil-itiesoracombinationof theseremains tobedetermined. Webelieve thatifthreeventricularleads aretobeused, two RV leads are much faster and probably more stable. The development of CRT generators designed speciﬁcally for multi-site pacing may also be important. So far only onemanufacturerhasproducedsuchadevice,whichwillbe testedinnon-respondersinarandomizedtrial.22_It_is_worth

pointing out,however, that in ourpopulation we deliber-ately did not select a subset of non-responders, and still achievedsuperiorresultswiththisnewpacingmodality.This raisesthepossibilityoforganizingalargetrialofmulti-site pacing as a ﬁrst-line treatment in candidates for cardiac resynchronizationtherapy.

Conclusion

Triple-site pacing produced a superior hemodynamic per-formance with shorter QRS duration, which is likely the consequence of improved resynchronization. RVOT septal pacingwasclearlysuperiortoRVapicalpacing,withshorter QRSandgreatercardiacoutput.

Ethical

disclosures

Protection of human and animal subjects.The authors declare thatthe procedures followedwere in accordance

withtheregulationsoftherelevantclinicalresearchethics committeeandwiththoseoftheCodeofEthicsoftheWorld MedicalAssociation(DeclarationofHelsinki).

Conﬁdentialityofdata.Theauthorsdeclarethattheyhave followedtheprotocolsoftheirworkcenteronthe publica-tionofpatientdata.

Righttoprivacyandinformedconsent.Theauthorshave obtainedthe written informed consentof the patients or subjectsmentionedinthearticle.Thecorrespondingauthor isinpossessionofthisdocument.

Funding

Nospeciﬁcfundinggrantswereusedregardingthisstudy.

Conﬂicts

of

interest

Theauthorshavenoconﬂictsofinteresttodeclare.

References

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