www.revportcardiol.org
Revista
Portuguesa
de
Cardiologia
Portuguese
Journal
of
Cardiology
ORIGINAL
ARTICLE
Does
permanent
atrial
fibrillation
modify
response
to
cardiac
resynchronization
therapy
in
heart
failure
patients?
Ana
Abreu
a,∗,
Mário
Oliveira
a,
Pedro
Silva
Cunha
a,
Helena
Santa
Clara
b,
Guilherme
Portugal
a,
Inês
Gonc
¸alves
Rodrigues
a,
Vanessa
Santos
b,
Luís
Morais
a,
Mafalda
Selas
a,
Rui
Soares
a,
Luísa
Branco
a,
Rui
Ferreira
a,
Miguel
Mota
Carmo
c,
on
behalf
of
BETTER-HF
investigators
aServic¸odeCardiologia,HospitaldeSantaMarta,CentroHospitalarLisboaCentral,CHLC,Lisboa,Portugal
bCentroInterdisciplinardeEstudodaPerformanceHumana,CIPER,FaculdadedeMotricidadeHumana,UniversidadedeLisboa,
Portugal
cCentrodeEstudosdeDoenc¸asCrónicas,CEDOC,FaculdadedeCiênciasMédicas,UniversidadeNova,Lisboa,Portugal
Received16June2016;accepted21February2017 Availableonline12October2017
KEYWORDS Heartfailure; Cardiac resynchronization; Atrialfibrillation; Responder Abstract
Introduction:The benefits ofcardiacresynchronization therapy(CRT) documentedinheart failure(HF)maybeinfluencedbyatrialfibrillation(AF).WeaimedtocompareCRTresponsein patientsinAFandinsinusrhythm(SR).
Methods:Weprospectivelystudied101HFpatientstreatedbyCRT.Ratesofclinical, echocar-diographicandfunctionalresponse,baselineNYHAclassandvariation,leftventricularejection fraction, volumes andmass, atrialvolumes, cardiopulmonary exercise test(CPET) duration (CPETdur),peakoxygenconsumption(VO2max)andventilatoryefficiency(VE/VCO2slope)were
comparedbetweenAFandSRpatients,beforeandatthreeandsixmonthsafterimplantation ofaCRTdevice.
Results:Allpatientsachieved≥95%biventricularpacing,and5.7%underwentatrioventricular junctionablation.PatientsweredividedintoAF(n=35)andSR(n=66)groups;AFpatientswere older,withlargeratrialvolumesandlowerCPETdurandVO2maxbeforeCRT.Thepercentages
ofclinicalandechocardiographicrespondersweresimilarinthetwogroups,buttherewere morefunctionalrespondersintheAFgroup(71%vs.39%inSRpatients;p=0.012).InSRpatients, leftatrialvolumeandleftventricularmassweresignificantlyreduced(p=0.015andp=0.021, respectively), whereasinAFpatients,CPETdur(p=0.003)andVO2max(p=0.001; 0.083
age-adjusted)showedlargerincreases.
∗Correspondingauthor.
E-mailaddress:[email protected](A.Abreu).
http://dx.doi.org/10.1016/j.repc.2017.02.016
Conclusion:ClinicalandechocardiographicresponseratesweresimilarinSRandAFpatients, withabetterfunctionalresponseinAF.Improvementinleftventricularfunctionandvolumes occurredinbothgroups,butleftventricularmassreductionandleftatrialreverseremodeling were seen exclusively inSR patients (ClinicalTrials.gov identifier: NCT02413151; FCTcode: PTDC/DES/120249/2010).
©2017SociedadePortuguesadeCardiologia.PublishedbyElsevier Espa˜na, S.L.U.Allrights reserved. PALAVRAS-CHAVE Insuficiência cardíaca; Ressincronizac¸ão cardíaca;
Fibrilhac¸ãoauricular; Respondedor
Afibrilhac¸ãoauricularmodificaarespostaàterapêuticaderessincronizac¸ãocardíaca emdoentescominsuficiênciacardíaca?
Resumo
Introduc¸ão:Osbenefíciosdaterapêuticaderessincronizac¸ãocardíaca(TRC),documentadosna insuficiênciacardíaca(IC),poderãoserinfluenciadospelafibrilhac¸ãoauricular(FA). Pretende-mosavaliarcomparativamenteefeitosTRCemdoentesemFAeemritmosinusal(RS).
Métodos: Foramestudadosprospetivamente101doentessubmetidosaTRC.Percentagensde respondedores clínicos, ecocardiográficos e funcionais, valores basais e variac¸ão de classe NYHA, frac¸ão de ejec¸ão, volumes e massa ventriculares esquerdos, volumes auriculares, durac¸ãodaprovadeesforc¸ocardiorrespiratória(PECRdur),consumopicodeoxigénio(VO2p) eeficiênciaventilatóriadeesforc¸o (VE/VCO2)foramcomparadosentregruposFAeRS, pré-implantac¸ãoTRCenosseismesesapósimplantac¸ão.
Resultados: Os doentes tiveram percentagens de pacing biventricular ≥95%, com 5,7% de ablac¸ãoauriculoventricularjuncional.DefinimosgrupoFA(n=35)egrupoRS(n=66),tendoos doentescomFAidadesuperior,maioresvolumesauriculares,menoresPECRdureVO2ppré-CRT. Percentagensderespondedoresclínicoseecocardiográficosforamidênticasnosdoisgrupos, masderespondedoresfuncionaisforamsuperioresnosdoentesFA(71versus39%nogrupoRS; p=0,012).NosdoentesRSverificou-seareduc¸ãosignificativadovolumeauricularesquerdoeda massaventricularesquerda(p=0,015ep=0,021,respetivamente)enosdoentescomFAmaior aumentodaPECRdur(p=0,003)eVO2p(p=0,001;p=0,083ajustadoparaidade).
Conclusão:Asrespostasclínicae ecocardiográficaàTRC foramsemelhantesnosdoentesFA e RS,com respostafuncional superior em FA. A melhoria de func¸ão e dimensões ventricu-laresesquerdasfoiidênticanosdoisgrupos,contudoreduc¸ãodemassaventricularesquerda eremodelageminversaauricularesquerdaforamexclusivasdedoentesRS(ClinicalTrials.gov Identifier:NCT02413151;FCTcode:PTDC/DES/120249/2010).
©2017SociedadePortuguesadeCardiologia.PublicadoporElsevierEspa˜na,S.L.U.Todosos direitosreservados.
Introduction
Cardiac resynchronization therapy (CRT) is an important device-based, non-pharmacological treatment for chronic heartfailure(HF).ThemultiplebenefitsofCRTinselected HFpatientsunderoptimizedpharmacologictherapyinclude improvementinsymptomsandqualityoflife,left ventric-ular(LV)remodelinganddecreased mortalityandhospital admissions for HF, and have been established by mul-tiple large trials,1---5 leading to its recommendation in
current guidelines.6 An important feature in HF is the
presence of atrial fibrillation (AF), the arrhythmia most frequently associated with HF, which affects up to 45%-50% of patients, depending on the severity of HF.7,8 For
HF patients still in sinus rhythm (SR), the annual inci-denceofAFisapproximately5%.9AFisnegatively related
toprognosis, althoughsome authorsdonotconsiderit an
independent prognostic predictive factor after correction forageandcomorbidities.10Atrialarrhythmias,ifnot
appro-priately managed, may have a negative impact on the clinicalbenefitsofCRT,11since,inAFpatients,CRTcanonly
correctintra-andinterventriculardyssynchrony.CRTisalso hamperedbyhighintrinsicventricularratesandirregularity, leadingtoreducedcapture,fusionandpseudo-fusion,and hencelesseffectivebiventricularpacing.12
Althoughtheevidencefromlargerandomizedcontrolled trials is weak,13,14 and some authorshave argued that HF
patientsinAFmayrespondlesswelltoCRT,15---20 the
Euro-peanSocietyofCardiology(ESC)guidelinesrecommendthat thistherapyshouldalsobeusedforAFpatients,aslongas atrioventricular(AV)junctionablationisaddedinpatientsin whomcontinuousbiventricularpacingislost.6Recently,the
CERTIFY study21 showedthat long-termsurvival after CRT
thatobservedamongpatientsinSR,andthatmortalityinAF patientstreatedwithrate-reducingdrugsishigher.Whether CRT is effective in the context of AF is still an impor-tantquestiontobeaddressed.Thepurposeofthepresent studywastoprospectivelyassesstheresponsetoCRTinHF patientswithpermanentAFcomparedtothoseinSR.
Methods
Studydesign
Aprospectivecohortstudywasperformedinasingle hospi-tal center, includingconsecutiveHFpatients withsystolic dysfunction selected for CRT according to current guide-lines,overaperiodof36months.
Thestudyprotocolwasapprovedbythehospital’sEthics CommitteeandcomplieswiththeDeclaration ofHelsinki. Writteninformedconsentwasobtainedfromallpatients. Patientselection
ThepatientswereconsecutivelyselectedforCRTbetween 2012and2014,basedoncurrentguidelines6andaccording
tothefollowinginclusionandexclusioncriteria:
Inclusioncriteria:
• Moderate to severe HF (New York Heart Association [NYHA]classIII-IV)underoptimalmedicaltherapy • Age>18and<80years
• Moderate tosevere LV systolic dysfunction(LV ejection fraction[LVEF]<35%)
• QRSduration≥120ms
• Ischemicornon-ischemicetiology • Cardiacrhythm:SRorAF
• Stableconditionfor>1month(nohospitalizationforHF, nochange inmedication, nochange inNYHA functional class).
Exclusioncriteria:
• Refusaltoparticipateinthestudyforanyreason • Inability to perform cardiopulmonary exercise testing
(CPET)
• Inabilitytosigninformedconsent • Unstableangina
Optimal medical therapy for HF was considered to include an angiotensin-converting enzyme inhibitor or an angiotensinreceptorblockerandabeta-blocker,as recom-mendedbytheguidelines,unlesscontraindicated.
Patientsweredividedintwogroupsaccordingtobaseline cardiacrhythm,SRorpermanentAF,confirmedby electro-cardiogram(ECG).
Technicalprocedures
Implantation was performed as previously described.22
PatientswithpermanentAFunderwentradiofrequency AV junctionablationwhenevercaptureoccurredlessthan95%
of the time. The percentage of biventricular pacing was identifiedbydevice counters, ECGand Holterin doubtful cases.Allpatientsinthecurrentstudywereprovidedwith similarHFmanagementfollowingCRTimplantation, includ-ingcomparableandoptimalpharmacologictreatment. Assessmentprotocol
Clinical, echocardiographic and CPET parameters were assessedin the48 hoursbefore(T1)and at threeandsix monthsafter CRT implantation(T2 and T3,respectively), andtheirvariationovertime(T2-T1andT3-T1)was deter-minedandcomparedbetweenthetwogroups.
Clinicalandelectrocardiographicparameters Age, gender, HF etiology and NYHA functional classwere recorded.Cardiacrhythm,heartrate(HR)andQRSduration weredeterminedfromtheECGatinclusionandconfirmed atimplantation.
Cardiopulmonaryexercisetesting
Symptom-limited CPET was performed under HF medica-tion,accordingtoamodifiedBruceprotocolonatreadmill (MortaraMultisyn190),withbreath-by-breathgasexchange measurements (Innocor). Testing supervisors encouraged patientstoexercisetoexhaustion,guidedbytherespiratory exchangeratio(RER),withagoalofRER>1.10.Exercisetest duration(CPETdur),peak oxygenconsumption (VO2max),
ventilatoryefficiencyasmeasuredbytheslopeofthelinear relationshipbetweenventilationandCO2output(VE/VCO2
slope),andHRweredetermined. Echocardiographicstudy
Transthoracicechocardiography(GEVivid9)wasperformed toassessLVEF(bySimpson’smethod),LVend-diastolicand end-systolic volume (LVEDV and LVESV, respectively), LV mass(LVM), andleftandrightatrialvolume(LAVandRAV, respectively).
Clinicalandechocardiographicresponders tocardiacresynchronizationtherapy
TheproportionofCRTrespondersineachgroupwas calcu-latedandcomparedbetweenthetwogroups.
CRTresponsewasdefinedaccordingtoclinical, echocar-diographicandfunctionalparameters,asfollows:
• ClinicalresponsetoCRT---sustainedimprovementof at leastoneNYHAclass;
• Echocardiographic response --- a minimum absolute 5% increaseinLVEF;
• Functional response --- an absolute increase of >1ml/kg/mininVO2max.
Response to CRT was defined by clinical, echocardio-graphic or functional improvement between T1 and T2 (sustainedatT3)orT1andT3.
Statisticalanalysis
Continuous variables wereexpressed asmean ± standard deviation(SD)andcategoricalvariablesasabsolutevalues and percentages. Variations in continuous variables were determinedandcomparedbythepairedttestandthe non-parametricWilcoxontest, whenappropriate,forvariables withand without normal distribution, respectively. Cate-gorical variables were compared by the chi-square test. Differencesin mean ± SDbetween the AF and SR groups weretested withtheunpairedttestor theMann-Whitney test,accordingtodistribution.Multivariatelinearregression wasusedforage adjustmentandfor baselineadjustment forVO2maxregardingchangeinVO2maxafterCRTintheAF
group.Apvalue<0.05wasconsideredsignificant.SPSS22.0 (IBMSPSS,Armonk,NY)wasusedforthestatisticalanalysis.
Results
Populationsample
Atotal of 101HF patients referredfor CRTimplantation, inclassNYHAIIIor IVandwithLVEF<35%,wereincluded,
Table1 Characteristics of patients in sinus rhythm and atrialfibrillationatbaseline,beforecardiac resynchroniza-tiontherapy. Baseline SR(n=66) AF(n=35) p Age,years 67.4±11.8 71.4±8.9 0.024 Male 41(62.1%) 28(80%) 0.066 NYHAII 16(24.2%) 7(20%) 0.316 NYHAIII 48(72.7%) 24(68.6%) NYHAIV 2(3.0%) 3(8.6%) BMI(kg/m2) 26±5 27±4 0.730 Ischemic etiology 18(27.3%) 10(28.6%) 0.890 LVEF<25% 26(39.4%) 13(38.2%) 0.910 LVEF,% 25.8±7.1 26.6±7.3 0.638 LVEDV,ml 202.2±68.2 222.3±70.5 0.188 LVESV,ml 149.8±53.4 166.0±63.4 0.288 LVM,g 315.86±82.16 362.31±103.69 0.06 LAV,ml 68.1±34.6 106.9±50.8 0.006 RAV,ml 29.5±16.2 64.0±51.6 0.0001 CPETdur,s 432.9±250.7 242.2±183.4 0.001 HRbas,bpm 78.6±11.6 76.6±12.7 0.48 HRmax,bpm 123±23 122±31 0.585 VO2max, ml/kg/min 15.8±5.4 11.9±4.3 0.001 Predicted VO2max,% 52.88±18.52 39.67±16 0.004 QRS,ms 143.2±20.7 145.8±24.3 0.790
AF:atrialfibrillationgroup;BMI:bodymassindex;bpm:beats perminute;CPETdur:cardiopulmonaryexercisetestduration; HRbas:baselineheartrate;HRmax:maximumheartrate;LAV: leftatrialvolume;LVEDV:leftventricularend-diastolicvolume; LVEF:leftventricularejectionfraction;LVESV:leftventricular end-systolicvolume;NYHA:NewYorkHeartAssociationclass; RAV:rightventricularvolume;SR:sinusrhythmgroup;VO2max:
peakoxygenconsumption.
Dataareexpressedasmean±SDforcontinuousvariablesand asnumberandproportion(%)forcategoricalvariables.
71male(70%),meanage68years,27.5%ischemicetiology. Of these,35 patients (34%) were in permanentAF at the timeofCRTimplantation.
To achieve effective biventricular capture, two AF patients (5.7%) underwent radiofrequency AV junction ablation, while the other 33 (94.3%) were successfully treated with negative chronotropic drugs only (digoxin, beta-blockers, amiodarone) for rate control, maximizing biventricularpacingdelivery.
Thecharacteristicsofthepopulationsampleand differ-encesbetweengroupsareshowninTable1.Patientsinthe AFgroup wereolderandmore oftenmale. Also, echocar-diographicandfunctionaldatashowmoreLVhypertrophy, atrialdilatationandworsefunctionalcapacityinthisgroup, reflectedbyhighermeanLVM,LAVandRAV,andlowermean CPETdur,VO2maxandpercentagepredictedVO2compared
totheSRgroup.
Clinicaleffectsofcardiacresynchronization therapy
NYHA functional class improved significantly over time (T2-T1andT3-T1)in both groups, withno significant dif-ferencebetweenSRandAF,asdisplayedinTable2. Echocardiographiceffectsofcardiac
resynchronizationtherapy
Changes over time after CRT (T2-T1 and T3-T1) in sev-eralechocardiographicvariablesshowedsignificanceinboth rhythmgroups(Table2).MeanLVEFandventricularvolumes, especiallyLVESV,improvedsignificantlyafterCRTinbothSR andAFpatients,withoutstatisticaldifferencebetweenthe groups.However,meanLVmassandLAVchanged significan-tly,butonlyinSRpatientsatsixmonths.
Functionaleffectsofcardiacresynchronization therapy
ImprovementsinCPETdurandVO2maxwereonlysignificant
inAFpatients.ChangeinVE/VCO2slopewassignificantinAF
andatthreemonthsinSR(Table2).Thereweresignificant differencesin variationinVO2maxandCPETdur between
thegroups.Whenadjustedforage,thedifferenceinVO2max
variationlosesstatisticalsignificance,butCPETdurchange remainssignificantlydifferentinAF,evenafterage adjust-ment.Pre- andpost-CRTbaselineHRwasnotsignificantly differentinthetwogroupsandpost-CRTmaximumHRwas alsosimilar.
Responderstocardiacresynchronizationtherapy Proportions of clinical, echocardiographic and func-tional responders at six months in the SR and AF groups are summarized in Table 3, which shows similar percentagesforclinicalresponders(78.6%forSRand80.7% forAF)andforechocardiographicresponders(77.4%forSR and 82.1% for AF).However, the proportion of functional responderswassignificantlylargerinAFpatients(71.4%vs. 39.3%inSR,p=0.012).
Table2 Differencesinclinical,echocardiographicandfunctionalvariablesofcardiopulmonaryexercisetestingaftercardiac synchronizationtherapyinpatientsinsinusrhythmandinatrialfibrillation.
Variable SR(n=66) p AF(n=35) p pSR/AF NYHAclassT1-T2 -0.97±0.78 0.0001 -0.96±0.72 0.0001 0.884 NYHAclassT1-T3 -1.14±0.85 0.0001 -1.07±0.94 0.0001 0.873 LVEFT1-T2,% 10.71±10.44 0.0001 7.97±11.15 0.001 0.269 LVEFT1-T3,% 12.9±11.3 0.0001 10.9±9.8 0.0001 0.305 LVEDVT1-T2,ml -5.90±63.60 0.393 -9.74±50.58 0.212 0.790 LVEDVT1-T3,ml -12.25±43.60 0.040 -15.07±45.51 0.036 0.694 LVESVT1-T2,ml -13.27±46.68 0.021 -27.14±59.50 0.067 0.487 LVESVT1-T3,ml -23.40±39.94 0.0001 -25.97±40.50 0.003 0.681 LVMT1-T2,g -7.51±89.87 0.922 5.66±87.19 0.778 0.867 LVMT1-T3,g -31.05±88.39 0.021 -12.13±95.80 0.527 0.486 LAVT1-T2,ml -10.2±28.81 0.093 -16.63±48.82 0.483 0.919 LAVT1-T3,ml -15.81±29.83 0.015 13.77±39.13 0.249 0.022 RAVT1-T2,ml -6.10±17.44 0.067 -9.63±19.46 0.208 0.722 RAVT1-T3,ml -4.46±15.04 0.247 -4.58±33.70 0.255 0.307 HRbasT1-T3,bpm 1.7±2.3 0.77 4.8±2.9 0.09 0.451 HRmaxT1-T3,bpm 1.09±3.7 0.77 9.5±5.5 0.99 0.61 VO2maxT1-T2, ml/kg/min 0.92±4.74 0.246 2.18±3.81 0.021 0.225 VO2maxT1-T3, ml/kg/min -0.42±4.92 0.493 3.72±2.91 0.001 0.005 CPETdurT1-T2,s 44.17±181.7 0.178 160.64±193.3 0.001 0.018 CPETdurT1-T3,s 39.10±202.7 0.343 152.62±235.7 0.003 0.009 VE/CO2slopeT1-T2 -5.31±9.21 0.006 -8.54±8.82 0.005 0.220 VE/CO2slopeT1-T3 -3.1±11.6 0.36 -6.4±10.9 0.08 0.322
AF:atrialfibrillationgroup;bpm:beatsperminute;CPETdur:cardiopulmonaryexercisetestduration;HRbas:baselineheartrate;HR max:maximumheartrate;LAV:leftatrialvolume;LVEDV:leftventricularend-diastolicvolume;LVEF:leftventricularejectionfraction; LVESV:leftventricularend-systolicvolume;NYHA:NewYorkHeartAssociationclass;RAV:rightventricularvolume;SR:sinusrhythmgroup; T1:beforecardiacresynchronizationtherapy(CRT);T2:3monthsafterCRT;T3:6monthsafterCRT;VO2max:peakoxygenconsumption.
Dataexpressedasmean±SD.
Table 3 Proportions of clinical, echocardiographic and functionalrespondersinsinusrhythmandatrialfibrillation patients. Total population (n=101) SR(n=66) AF(n=35) p Clinical responders, n(%) 44(78.6%) 46(80.7%) NS Echocardiographic responders, n(%) 24(77.4%) 23(82.1%) NS Functional responders, n(%) 26(39.3%) 25(71.4%) 0.012
AF:atrialfibrillationgroup;SR:sinusrhythmgroup. Dataexpressedasnumbersandproportions(%).
Discussion
Inthepresentstudy,patientswithpermanentAF,onethird ofthestudypopulation,showedgoodresponsetoCRTinthe
majorityofcaseswithouttheneedforAVjunctionablation, incontrasttoseveralpreviousstudies.19
To date, randomizedstudies on CRT have been mainly restrictedtopatientsinSR,excludingpatientsinpermanent AF.ThiscontrastswiththehighprevalenceofCRTuseinAF patientsinroutineclinicalpractice,asobservedinourdata (35%)andaspreviouslyindicatedbyESCsurveys,23,24which
indicateaprevalenceof23%.23
ItiswellknownthatthelikelihoodofcoexistentAFand HFisstronglyrelatedtotheseverityofthedisease repre-sentedbyNYHAfunctionalclass:prevalenceof5%forNYHA classI,10%-25% for classII/III,and 50%for classIV.10 The
probablereasonforthehigherprevalenceofAFobservedin ourstudy populationis theirgreater clinicalseverity(95% NYHAclassIII/IV, 5%classII) compared topatientsin the Europeancardiacresynchronizationregistry(78%classIII/IV, 22% class I/II).23 In our sample, AF patients were older,
withworsefunctionalcapacity,asinpreviousstudies,which mayhaveinfluencedtheeffectsofCRTinAFcomparedto SRpatients.25,26 Ourdataarealsoin accordancewiththe
greaterproportionofmenamongAFpatients,aspreviously demonstrated,27 andadditionallyshowedahigher
percent-ageofnonischemiccardiomyopathy.
Regarding the managementof our patients, which fol-lowedtheconsensusformandatorycontinuousbiventricular
capture, it assured rate control and rhythm regulariza-tion,inordertomaximizetheclinicalbenefitandimprove prognosis of patients with permanent AF.28 This requires
AVjunction ablationinsome cases,sincepharmacological treatmentmaybeinadequatetocontrolventricularrateat rest andduring exercise.In the second ESCCRT survey,24
74%ofEuropeancentersimplantingCRTdevicesscheduled AVjunction ablation onlyin the presence of uncontrolled HR,andonlyaminorityofcenters(11%)proceededdirectly toAVjunctionablation,regardlessof HR.Frequent biven-tricularpacing,aspreviouslydefined,wastakenas≥95%of biventricularcapture.29Inourstudy,only5.7%ofAFpatients
underwentAVjunctionablationduringthefirstsixmonths afterimplantation,theother94.3%beingtreatedwith phar-macologicaltherapyfor HRcontrol.Thelow proportionof patients needing AV junction ablation could be explained bygood pharmacologicHRcontrolwith adequate dosages ofbeta-blockers,digoxinandotherdrugswithbradycardia effects,carefullytitratedandincreasedwheneverneeded. Furthermore,someofthesepatientsunderwentCRT implan-tation due to left ventricular dysfunction, heart failure andindicationforpacingduetobradyarrhythmia.However, therewasnocontrolgrouptocomparetheseeffects,since theothergroupwasmadeupofSRpatients,whomightnot needthesamedrugsorthesamedosages.Atthispoint,it isimportanttonotethatpre-andpost-CRTbaselineHRand maximum HRduring CPETwerenot significantlydifferent betweenSRandAFpatients.
ConcerningtheeffectsofCRTinthisreal-lifestudy, sev-eralclinical,echocardiographicandfunctionalvariablesof exercisetesting changedsignificantlyafterCRT inbothSR andAFpatients:NYHAclass,LVEF,LVESVandVE/VCO2slope
(atthreemonths),andLVEDVandVE/VCO2(atsixmonths).
Similarly,someauthorshaveshownthatCRTinAFpatients improves symptoms,14,30 while others suggest that CRT is
only effective after AV junction ablation, which was cer-tainlynotthecaseinourpatients.Incontrasttoourresults, some previous studies in AF patients demonstrated that, despitesimilarchangesinLVEF,therewaslessimprovement inNYHAfunctionalclass.25,26,31
An important issue is the CRT response rate, bearing in mindthat definitions of CRT responsein the literature differwidely.32 It isinterestingtoobservethatneitherSR
norpermanent AF significantly influencedthe percentage ofresponders inthis sample, either clinical (SR 78.6%vs. AF 80.7%) or echocardiographic (SR 77.4% vs. AF 82.1%). Somestudies, however,have showndifferentresults. Ina meta-analysisby Wilton etal., which included 33 studies (7495patients),alowerrateofCRTresponsewasobserved in AF patients than in SR, with no response in 34.5% vs. 26.7%,respectively(p=0.01).26 Also,amorerecentstudy33
confirmedthebenefitofCRTinHFpatientswithAF,although inferior to that of SR patients, with more frequent non-response.Incontrasttotheresultsofthesetwopublications andtoourowndata,single-centerrandomizedstudieshave demonstratedlittleevidenceregardingCRTeffectivenessin AF.34 TheRAFTstudy35 includedmorepatientswith
perma-nent AF than all other published studies combined. RAFT failed, however, to demonstrate a clear improvement in anyclinicalorsurrogateoutcomewithCRTinpatientswith permanent AF, despite a trend for fewer HF hospitaliza-tions.Thispooroutcomemightbeattributedtosuboptimal
deliveryofCRT,becauseonlyonethirdofpatientsreceived ≥95% ventricular pacing.35 It should benotedthat in this
studymanypatientswereinNYHAclassII.Toincreasethe percentageofpacinginAF,AVjunctionablationwasapplied inourstudy,increasingCRTresponse.26
In the present study, there was a significant mean increase in LVEF at three and six months in both groups, which wasnot statisticallygreaterin SRpatients. Despite the significant decrease in both groups in mean LVESV and LVEDV (only at six months), other authors found less improvementinLVESV inAFpatients.26 MeanLVMandLAV
decreased significantly at six months, but only in the SR group. It is known that HF facilitates atrial remodeling, whichpromotesthedevelopmentandmaintenanceofAF,36
explaining thelarger LAV in AFpatients. LAV was smaller in SR patients, and consequently the changes were less marked,whichfacilitatedreverseremodelingafterCRT.We mayhypothesizethatLAreverseremodelingandmore pro-foundLVreverse remodelingtake longer(morethanthree months)untilasignificantchangeisachievedafterCRT,and areprobablypositivelyinfluencedbythepresenceofSR.
On theother hand, regardingthe functional effectsas assessedbyCPET,althoughVE/VCO2slopedecreased
signifi-cantlyinbothgroups,onlypatientswithAFhadasignificant increaseinCPETdur(anabsoluteincreasethreetimesthat ofSR)andalsoinVO2maxthreemonthsafterCRT.
Interest-ingly,after adjustingfor ageand baselineVO2max (which
washigher in SR andlower inAF patients), therewasno longerastatisticallysignificantimprovementinVO2maxin
AF patients(multivariate linearregression,p=0.083).This shows the importanceof baseline VO2max andage in the
VO2maxresponseobservedafterCRTinAF.
Aprevious study37 demonstrated that treatment of HF
patients with CRT improves exercise capacity and that this increase is most substantial among patients with a lowerbaselineVO2max(percentagepredictedforage),the
authorsconcludingthatbaselineCPETcanthereforebeused toidentifypatientswhoaremorelikelytoexhibitfunctional improvementafterCRT.ThosewithpredictedVO2max<40%
had muchgreater improvement in VO2max. In agreement
withthis,ourAFpatientshadlowermeanpre-CRTVO2max
(probablyrelatedtoolderage,andalsopredictedVO2max)
and more improved VO2max after CRT than SR. Also, HF
patientswithmeanbaselineVO2max<14ml/kg/min,which
was the case in our AF group, benefited most from the implantationofaCRTdevice.39Thepercentageoffunctional
CPETresponderswassignificantlyhigherinAFpatientsthan in SR patients, for the reasons mentioned above. Despite thesebettervalues,post-CRTmeanVO2maxin AFdidnot
exceedthatinSR,andvaluesatsixmonthsweresimilarin thetwostudygroups.
InpatientswithadvancedHF,variationinVO2maxisan
important predictor of outcomes, including clinical dete-rioration or death, especially in patients with ischemic cardiomyopathy or not receiving beta-blockers.39
Exer-cise capacityis objectively quantifiedby measurement of VO2max, carbon dioxide production (VCO2), and minute
ventilation.40 Not surprisingly,VO
2maxhasa strong linear
correlation withboth cardiac output and skeletal muscle bloodflow.41Peakexercisecapacityisdefinedasthe
maxi-mumabilityofthecardiovascularsystemtodeliveroxygen toexercisingskeletalmuscleandoftheexercisingmuscleto
extractoxygenfromtheblood.42Asaresult,exercise
capac-ityisdeterminedbythreefactors:pulmonarygasexchange; cardiovascular performance,including theperipheral vas-cular tree; and skeletal muscle metabolism. It has been demonstrated that CRT significantly improves all ventila-tion and metabolic parameters of patients with HF and ventricularconductiondelay.Patientswithmoredepressed metabolicandventilationparametersandhigherHRat base-lineseemtobenefitmostfromthistherapeuticapproach.38
Theseresultsareinagreementwiththoseobservedinour study. AF patients were more deconditioned, with worse physical condition andlowerexercisecapacity, relatedto severeHFandaging,asdemonstrated,andafterCRTthey had greater improvement in cardiovascular performance. Mean CPET dur increased in both groups, early at three months,withamorethanthree-foldchangeinAFpatients, inwhom thechange wasstatisticallysignificant (unlikein SR patients), attaining similar values for CPET dur after CRT.CRTdidnotsignificantlyalterexercisecapacityinSR patients,butthisfindingisnotsurprisinginpatientswhose exercisecapacitywasnotsoseverelyimpairedatbaseline. This observation is consistent with the study referred to above,whichdemonstratedthatHFpatientswithrelatively preservedexercisecapacityatbaselineachieveonlyminor improvementinexercisecapacityduringCRT.38
As mentioned above, the mean decrease in VE/VCO2
slopewassignificantatthreemonthsinbothgroups,which isalsoanimportantbeneficialeffectofCRT,sincealower VE/VCO2slopeinHFisassociatedwithbetterprognosis.43
In conclusion, beneficial effects of CRT were demon-strated in HF patients, both in permanentAF and in SR, withsimilar proportionsof clinical andechocardiographic responders.
BothgroupsshowedLVreverseremodelingindependently ofcardiacrhythm,toalargerextentinSRpatients,whoalso showedLVmassreductionandLAreverseremodeling,which werenotpresent inAFpatients.Additionally, AFpatients, initiallywithlessexercisefunctionalcapacity,hadagreater improvement,withmorefunctionalresponders.According toourresults,permanentAFshouldnotbyitselfbe consid-eredafactoragainstdecidingtotreatselectedHFpatients withCRT.
Study
limitations
Thiswork, analyzingtheuseof CRTinHFpatientsin per-manentAF,hastheinherentlimitationsofanobservational study.Itinvolvesamedium-sizedpopulationsample,sothe presentresultsneedtobetreatedwithcautionandshould bereproducedinalargerpermanentAFpopulation, prefer-ablyinaprospectivecontrolledclinicaltrial onCRTinAF, toconfirmitsresults.Longerfollow-upstudiesareneeded.
Ethical
disclosures
Protection of human and animal subjects.The authors declarethatnoexperimentswereperformedonhumansor animalsforthisstudy.
Confidentialityofdata.Theauthorsdeclarethatnopatient dataappearinthisarticle.
Right to privacy and informed consent.The authors declarethatnopatientdataappearinthisarticle.
Funding
This work was supported by an FCT grant (PTDC/DES/120249/2010).
Conflicts
of
interest
Theauthorshavenoconflictsofinteresttodeclare.
Acknowledgments
WearegratefultoProf.AnaLuisaPapoilaandProf.Marta Alves(ResearchUnit,CentralLisbonHospitalCenter,CHLC, Lisbon,Portugal)fortheiradvisorysupportwiththe statis-ticalanalysis.
References
1.Cazeau S, Leclercq C, Lavergne, et al. Effects of multisite biventricularpacingin patientswithheartfailureand intra-ventricularconductiondelay.NEnglJMed.2001;344:873---80.
2.AbrahamWT,FisherWG,SmithAL,etal.Cardiac resynchroniza-tioninchronicheartfailure.NEnglJMed.2002;346:1845---53.
3.AuricchioA,StellbrinkC,SackS,etal.Long-termclinicaleffect ofhemodynamicallyoptimizedcardiacresynchronization ther-apyinpatientswithheartfailureand ventricularconduction delay.JAmCollCardiol.2002;39:2026---33.
4.Bristow MR, Saxon LA, Boehmer J, et al. Cardiac-resynchronization therapy with or without an implantable defibrillatorinadvancedchronicheartfailure.NEngl JMed. 2004;350:2140---50.
5.ClelandJGF,DaubertJC,ErdmannE,etal.Theeffectofcardiac resynchronizationonmorbidityandmortalityinheartfailure. NEnglJMed.2005;352:1539---49.
6.BrignoleM,Auricchio,Baron-Esquivias,etal.2013ESC guide-linesoncardiacpacingandcardiacresynchronizationtherapy: thetaskforceoncardiacpacingandresynchronizationtherapy oftheEuropeanSocietyofCardiology(ESC).Developedin col-laborationwiththeEuropeanHeartRhythmAssociation(EHRA). EurHeartJ.2013;34:2281---329.
7.Khan NK, Goode KM, Cleland JG, et al. ECG abnormalities inaninternationalsurvey ofpatientswithsuspectedor con-firmedheartfailure atdeathor discharge.EurJHeartFail. 2007;9:491---501.
8.KhandAU,RankinAC,KayeGC,etal.Systematicreviewofthe managementofatrialfibrillationinpatientswithheartfailure. EurHeartJ.2000;21:614---32.
9.Maisel WH, StevensonLW. Atrial fibrillationin heartfailure: epidemiology,pathophysiology,and rationalefortherapy.Am JCardiol.2003;91:2D---8D.
10.CrijnsHJ,TjeerdsmaG,deKamPJ,etal.Prognosticvalueofthe presenceanddevelopmentofatrialfibrillationinpatientswith advancedchronicheartfailure.EurHeartJ.2000;21:1238---45.
11.GaspariniM,RegoliF,GalimbertiP,etal.Cardiac resynchroniza-tiontherapyinpatientswithheartfailureinatrialfibrillation. Europace.2009;11Suppl5:v82---6.
12.LeyvaF,NisamS,AuricchioA.20yearsofcardiac resynchro-nizationtherapy.JAmCollCardiol.2014;64:1047---58.
13.Brignole M, Botto G, Mont L, et al. Cardiac resynchroniza-tion therapy inpatientsundergoing atrioventricular junction
ablationforpermanentatrialfibrillation: arandomizedtrial. EurHeartJ.2011;32:2420---9.
14.LeclercqC,WalkerS,LindeC,etal.Comparativeeffectsof per-manentbiventricularand right-univentricularpacinginheart failure patientswith chronic atrial fibrillation. EurHeart J. 2002;23:1780---7.
15.Khadjooi K, FoleyPW, Chalil S, et al. Long-term effects of cardiac resynchronizationtherapy inpatientswithatrial fib-rillation.Heart.2008;94:879---88.
16.GaspariniM,AuricchioA,RegoliF,etal.Four-yearefficacyof cardiac resynchronization therapyon exercise tolerance and diseaseprogression:theimportanceofperforming atrioventric-ularjunctionablationinpatientswithatrialfibrillation.JAm CollCardiol.2006;48:734---43.
17.Gasparini M,AuricchioA, MetraM,etal. Long-termsurvival inpatientsundergoingcardiacresynchronizationtherapy:the importance of performing atrioventricular junction ablation in patients with permanent atrial fibrillation. Eur Heart J. 2008;29:1644---52.
18.GaspariniM,SteinbergJS,ArshadA,etal.Resumptionofsinus rhythm in patients with heart failure and permanent atrial fibrillationundergoingcardiacresynchronizationtherapy:a lon-gitudinalobservationalstudy.EurHeartJ.2010;31:976---83.
19.Gasparini M,LeclercqC,LunatiM,et al.Cardiac resynchro-nizationtherapyinpatientswithatrialfibrillation:theCERTIFY study(CardiacResynchronizationTherapyinAtrialFibrillation PatientsMultinationalRegistry).JCHF.2013;1:500---7.
20.YancyCW,JessupM,BozkurtB,etal.2013ACCF/AHAGuideline forthemanagementofheartfailure:areportoftheAmerican CollegeofCardiologyFoundation/American HeartAssociation TaskForceonPracticeGuidelines.Developedincollaboration withtheAmericanCollegeofChestPhysicians,HeartRhythm SocietyandInternationalSocietyforHeartandLung Transplan-tation.Circulation.2013;128:e240---327.
21.DicksteinK,VardasPE,AuricchioA,etal.2010FocusedUpdate ofESCGuidelinesondevicetherapyinheartfailure:anupdate of the2008 ESC Guidelines for thediagnosis and treatment of acute and chronic heart failure and the 2007 ESC guide-lines for cardiac and resynchronization therapy, Developed withthespecialcontributionoftheHeartFailureAssociation andtheEuropeanHeartRhythmAssociation.EurJHeartFail. 2010;12:1143---53.
22.DaubertJC,SaxonL,AdamsonPB,etal.2012EHRA/HRSexpert consensusstatementoncardiac resynchronizationtherapyin heart failure: implant and follow-up recommendations and management.HeartRhythm.2012;9:1524---76.
23.Dickstein K, Bogale N, Priori S, et al. The European cardiac resynchronization therapy survey. Eur Heart J. 2009;30:2450---60.
24.Sciaraffia E, Dagres N, Hernandez-Madrid A, et al. Do car-diologists follow the European guidelines for cardiac pacing andresynchronizationtherapy?ResultsoftheEuropeanHeart RhythmAssociationsurvey.Europace.2015;17:148---51.
25.Upadhyay GA, Choudry NK, Auricchio A, et al. Cardiac resynchronizationin patientswithatrialfibrillation: a meta-analysis of prospective cohort studies. J Am Coll Cardiol. 2008;52:1239---46.
26.Wilton SB,Leung AA, Ghali WA,et al. Outcomesof cardiac resynchronizationtherapyinpatientswithversusthose with-outatrialfibrillation: asystematicreviewandmeta-analysis. HeartRhythm.2011;8:1088---94.
27.KannelWB,AbbottRD,SavageDD,etal.Epidemiologicfeatures ofchronic atrialfibrillation:theFraminghamstudy.NEngl J Med.1982;306:1018---22.
28.Ferreira AM, Adragao P, Cavaco DM, et al. Benefit of car-diacresynchronizationtherapyinatrialfibrillationpatientsvs. patientsinsinusrhythm:theroleofatrioventricularjunction ablation.Europace.2008;10:809---15.
29.KoplanBA,Kaplan AJ,WeinerS, etal.Heartfailure decom-pensation and all-cause mortality in relation to percent biventricularpacing inpatients withheartfailure: is a goal of 100% biventricular pacing necessary? J Am Coll Cardiol. 2009;53:355---60.
30.Linde C,Leclercq C, Rex S, et al., on behalf of the MUlti-site STimulation InCardiomyopathies (MUSTIC) StudyGroup. Long-term benefits of biventricular pacing in congestive heart failure: results from the Multisite Stimulation in car-diomyopathy (MUSTIC) study. J Am Coll Cardiol. 2002;40: 111---8.
31.WeinS,VoskoboinikA,WeinL,etal.Extendingtheboundariesof cardiacresynchronizationtherapy:efficacyinatrialfibrillation, NewYorkHeartAssociationclassII,andnarrowQRSheartfailure patients.JCardFail.2010;16:432---8.
32.FornwaltBK,SpragueWW,BeDellP,etal.Agreementispoor amongcurrentcriteriausedtodefineresponsetocardiac resyn-chronizationtherapy.Circulation.2010;121:1985---91.
33.LopesC,PereiraT,BarraS.Cardiacresynchronizationtherapy inpatients withatrial fibrillation: a meta-analysis.Rev Port Cardiol.2014;33:717---25.
34.Prinzen FW, Vernooy K, Auricchio A. Cardiac resynchro-nization therapy: state-of-the-art of current applications, guidelines,ongoingtrials,andareasofcontroversy.Circulation. 2013;128:2407---18.
35.HealeyJS,HohnloserSH,ExnerDV,etal.,onbehalfoftheRAFT Investigators. Cardiac resynchronization therapy in patients withpermanentatrialfibrillation:resultsfromthe Resynchro-nizationforAmbulatoryHeartFailureTrial(RAFT).CircHeart Fail.2012;5:566---70.
36.Darby AE, DiMarco JP. Management of atrial fibrillation in patients with structural heart disease. Circulation. 2012;125:945---57.
37.Arora S, Aarones M, Aakhus S, et al. Peak oxygen uptake duringcardiopulmonaryexercise testingdetermines response to cardiac resynchronization therapy. J Cardiol. 2012;60: 228---35.
38.AuricchioA,KlossM,TrautmannSI,etal.Exerciseperformance following cardiac resynchronization therapy in patientswith heartfailureand ventricularconductiondelay.AmJCardiol. 2002;89:198---203.
39.MacGowanGA,PohwaniA,MuraliS.Dynamicanalysisof exer-ciseoxygenconsumptionpredictsoutcomesinadvancedheart failure.CongestHeartFail.2007;13:313---8.
40.McElroy PA, Janicki JS, Weber KT. Cardiopulmonary exer-cisetestingin congestiveheartfailure. AmJCardiol. 1988; 62:35A.
41.Reddy HK, Weber KT, Janicki JS,et al. Hemodynamic, ven-tilatoryand metabolic effects oflight isometricexercise in patientswithchronic heartfailure.JAmCollCardiol.1988; 12:353.
42.DennisC.Rehabilitationofpatientswithcoronaryartery dis-ease.In: Braunwald E,editor. Heart disease, a textbook of cardiovascularmedicine.4thed.Philadelphia:Saunders;1992. p.1382.
43.FrancisDP,Shamin W, CeriDavies L, etal. Cardiopulmonary exercisetestingforprognosisinchronicheartfailure: continu-ousandindependentprognosticvaluefromVE/VCO2slopeand peakVO2.EurHeartJ.2000;21:154---61.
