www.revportcardiol.org
Revista
Portuguesa
de
Cardiologia
Portuguese
Journal
of
Cardiology
ORIGINAL
ARTICLE
The
arterial
baroreflex
effectiveness
index
in
risk
stratification
of
chronic
heart
failure
patients
who
are
candidates
for
cardiac
resynchronization
therapy
João
Fernandes
Serôdio
a,∗,
Mário
Martins
Oliveira
a,b,
Sérgio
Matoso
Laranjo
a,
Cristiano
Tavares
a,
Pedro
Silva
Cunha
b,
Ana
Abreu
b,
Luísa
Branco
b,
Sandra
Alves
b,
Isabel
Rocha
a,
Rui
Cruz
Ferreira
baInstituteofPhysiology,FacultyofMedicine,UniversityofLisbon,Lisbon,Portugal bDepartmentofCardiology,SantaMartaHospital,Lisbon,Portugal
Received1September2015;accepted22November2015
KEYWORDS Heartfailure; Cardiac resynchronization therapy; Arterialbaroreflex Abstract
Introduction:Baroreflexfunctionisanindependentmarkerofprognosisinheartfailure(HF). However,littleisknownaboutitsrelationtoresponsetocardiacresynchronizationtherapy (CRT).The aimofthisstudy istoassessarterialbaroreflexfunction inHFpatients whoare candidatesforCRT.
Methods:Thestudypopulationconsistedof25patients withindicationforCRT,aged65±10 years,NYHAfunctionalclass≥IIIin52%,QRSwidth159±15ms,leftventricularejection frac-tion(LVEF)29±5%,leftventricularend-systolicvolume(LVESV)150±48ml,B-typenatriuretic peptide(BNP)357±270pg/ml,andpeakoxygenconsumption(peakVO2)18.4±5.0ml/kg/min.
Anorthostatictilttestwasperformedtoassessthebaroreflexeffectivenessindex(BEI)bythe sequencemethod.Thisgroupwascomparedwith15age-matchedhealthyindividuals.
Results:HF patients showed asignificantly depressed BEIduring tilt (31±12% vs. 49±18%, p=0.001).AlowerBEIwasassociatedwithhigherBNP(p=0.038),lowerpeakVO2 (p=0.048),
andhigherLVESV(p=0.031).Byapplyingacut-offvalueof25%forBEI,twoclustersofpatients were identified: lower risk cluster (BEI >25%) QRS 153ms, LVESV 129 ml, BNP 146 pg/ml, peakVO219.0ml/kg/min;andhigherriskcluster(IEB≤25%)QRS167ms,LVESV189ml,BNP
590pg/ml,peakVO216.2ml/kg/min.
Conclusions:CandidatesforCRTshowdepressedarterialbaroreflex function.LowerBEIwas observedinhigh-riskHFpatients.BaroreflexfunctioncorrelatedcloselywithotherclinicalHF parameters.Therefore,BEImayimproveriskstratificationinHFpatientsundergoingCRT. ©2016SociedadePortuguesa deCardiologia.Publishedby ElsevierEspa˜na,S.L.U.All rights reserved.
∗Correspondingauthor.
E-mailaddress:jserodio@campus.ul.pt(J.FernandesSerôdio). http://dx.doi.org/10.1016/j.repc.2015.11.021
PALAVRAS-CHAVE Insuficiência cardíaca; Ressincronizac¸ão cardíaca; Reflexobarorrecetor arterial
Oíndicedeeficáciadobarorreflexonaestratificac¸ãoderiscodedoentescom insuficiênciacardíacacrónicacandidatosàterapêuticaderessincronizac¸ãocardíaca
Resumo
Introduc¸ão:O barorreflexo arterial é comprovadamente um marcador independente de prognósticonaIC.Contudo,poucosesabesobrearelac¸ãoentreafunc¸ãodobarorreflexoe arespostaàTRC.Assim,oobjetivodesteestudoéavaliarafunc¸ãobarorreflexaemdoentes comICcandidatosaTRC.
Métodos: Apopulac¸ãodesteestudoprospetivoconsistiuem25doentescom65±10anos,classe NYHA≥IIIem52%,QRS159±15ms,frac¸ãodeejec¸ãodoventrículoesquerdo(FEVE)29±5%, vol-umetelessistólicodoventrículoesquerdo(VTSVE)150±48mL,péptidonatriuréticotipo-B(BNP) 357±270pg/ml,consumomáximodeoxigénio(VO2max)18,4±5,0ml/kg/min.Foi implemen-tadoumtestedeortostatismopassivoparaavaliaroíndicedeeficáciadobarorreflexo(IEB), atravésdométodo sequencial.Ogrupocontrolo foi constituídopor15 indivíduossaudáveis emparelhadosparaaidade.
Resultados:OsdoentescomICapresentaramumIEBsignificativamentereduzidoduranteotilt (31±12%versus49±18%,p=0,001).UmIEBdiminuídoassociou-seaumBNPelevado(p=0,038), aumVO2diminuído(p=0,048)eaumVTSVEaumentado(p=0,031).Aplicandoumcut-off25% paraoIEB,foramidentificadosdoisclustersdedoentes:clusterderiscomenorrisco(IEB>25%) QRS153ms,VTSVE129mL,BNP146pg/mL,VO2max19,0mL/kg/min;clusterdemaiorrisco (IEB≤25%)QRS167ms,VTSVE189mL,BNP590pg/mL,VO2max16,2mL/kg/min.
Conclusões:Doentescandidatos aTRC apresentambarorreflexodeprimido. OBEIdiminuído foi observadonosdoentes demaiorrisco. Obarorreflexo correlacionou-se bemcomoutros parâmetrosdegravidadedeIC.Destaforma, oBEIpodecontribuirparaaestratificac¸ãode riscodosdoentescomICsubmetidosaTRC.
©2016SociedadePortuguesadeCardiologia.Publicado porElsevier Espa˜na, S.L.U.Todosos direitosreservados.
Listofabbreviations
ACE angiotensin-convertingenzyme ANS autonomicnervoussystem BEI baroreflexeffectivenessindex BNP brain-typenatriureticpeptide BP bloodpressure
CRT cardiacresynchronizationtherapy HF heartfailure
HR heartrate
HRV heartratevariability LBBB leftbundlebranchblock LV leftventricular
LVEDV leftventricularend-diastolicvolume LVEF leftventricularejectionfraction LVESV leftventricularend-systolicvolume NBR numberofbaroreflexeventsperminute NYHA NewYorkHeartAssociation
RR R-Rintervalonelectrocardiogram SBP systolicbloodpressure
VO2 oxygenconsumption
Introduction
Chronicheartfailure(HF)isaclinicalsyndromethataffects millions of people worldwide1 and is responsible for high
mortality and morbidity and decreased quality of life.2 AlthoughHF affects1% oftheadult population,its preva-lence reaches 6-10% of people over the age of 65 years1 anditisresponsiblefor atleast20%ofallhospital admis-sions among the elderly.3 Nearly 30% of patients with HF withdecreasedejectionfractionalsopresentleft ventricu-lar(LV)electricaldyssynchronythatresultsinaQRSinterval greater than 120 ms, most commonly with a left bundle branch block (LBBB) pattern.4 LV electrical dyssynchrony resultsindecreaseddiastolictime,anomalousseptalmotion andincreasedmitralregurgitation,withanoverallreduction inleftventricularejectionfraction(LVEF).1,5
Cardiac resynchronization therapy (CRT) has shown importantclinicalbenefitsinthetreatmentofHFpatients withsystolicdysfunction(LVEF<35%)andelectrical dyssyn-chrony(QRS>120ms).4,6Byreducingventricularelectrical dyssynchrony, CRT improves LV systolic function while reducing myocardial oxygen consumption,7 which results in improvement of symptoms and qualityof life and in a significant reductionin mortality.4,8,9 However, up to 30% of patients do not respond to CRT (nonresponders).10---12 CRT responders undergo LV reverse remodeling, which is characterized by decreases in intraventricular conduc-tion delay and LV end-systolic volume (LVESV) and reduction in mitralregurgitationarea, witha consequent increase inLVEF.8,12,13 LVreverse remodelingis thoughtto beresponsible for theclinical improvementin responders toCRT,butthemechanismsunderlyingreverseremodeling arenotwellunderstood.
The autonomic nervous system (ANS) may play an important role in reverse remodeling. The ANS has an important role in cardiovascular functional and struc-turalregulation,14,15 butANSfunctionisalsorecognizedas a prognostic marker in HF.16 Furthermore, CRT induces a reductioninmeanheartrate(HR)andanincreaseinheart rate variability(HRV).17---19 Najem et al. alsoshowed that therewasanacuteincreaseincardiacsympatheticactivity afterbiventricularpacingwasswitchedoff.20Morerecently, an improvement in cardiac sympatheticactivity has been demonstratedin responders toCRT, assessed by 123I-MIBG scintigraphy.21,22
Nevertheless, little is known of the impact of CRT on arterial baroreflexfunction. The arterial baroreflex (with afferentsfromaortic andcarotidbaroreceptors)iscrucial in thehomeostatic regulation of blood pressure(BP).23 It isalsoawell-establishedindependentprognosticmarkerin HF;thereisevidencethatlowbaroreflexsensitivityis asso-ciatedwithincreasedcardiovascularmorbidityandoverall mortality.24 However, it is not known whether baroreflex functionbeforeCRTcorrelateswithseverityofHFor with theresponsetocardiac resynchronization.Therefore,the aimofthepresentstudywastoassessbaroreflexfunctionin HFpatientswhowerecandidatesforCRT,andtocompareit withotherclinicalandlaboratoryparametersofHFseverity.
Methods
Population
Patients of both sexes with class I recommendation for CRT were included. We thus included patients in sinus rhythmwithsymptomaticHFrefractorytooptimalmedical treatment,inNewYorkHeartAssociation(NYHA)functional class II or III or outpatients in class IV, with LVEF <35% and QRS width >120 ms.6 Patients in NYHA class II with wider QRS and lower LVEF (QRS >130 ms and LVEF <30%) were included.6,13 Patients with atrial fibrillation/flutter, second or third degree atrioventricular block or frequent supraventricular or ventricular ectopic beats, and those with a pacing rhythm were excluded from this study, as sinusrhythmisaprerequisiteforreliablearterialbaroreflex measurement.25 Patientswererecruitedat theCardiology Departmentof SantaMartaHospital.Allpatients provided writteninformedconsentaccordingtotheprinciplesofthe HelsinkiDeclaration.
Protocol
Thiswasanexploratory clinicalstudy.BeforeCRT implan-tation,allpatientsunderwentclinicalassessmentincluding NYHAfunctional class, laboratory testing including deter-minationofbrain-typenatriureticpeptide(BNP),a12-lead electrocardiogram (ECG) (Philips TRIM III), transthoracic echocardiogramandcardiopulmonaryexercisetest(CPET). Anorthostatictilttestwasusedtostudybaroreflexfunction.
Transthoracicechocardiography
Transthoracic echocardiographic images were obtained usingVivid7equipment(GeneralElectric-Vingmed, Milwau-kee,WI).Theechocardiographicassessmentwasperformed
in M-mode, biplane and Doppler modes. LVEF, LVESV and LV end-diastolic volume (LVEDV) were determined using Simpson’sbiplanemethod.26,27Asemi-quantitativeDoppler methodwasusedtoassessmitralregurgitationgrade.
Cardiopulmonaryexercisetest
Patientswereinstructedtoavoidanyintensephysical acti-vity and not to smoke or ingest any caffeine-containing drinks in the three hours preceding the exam. CPET was performed ona treadmillaccordingtothemodified Bruce protocol.28 Patients exercised until maximal fatigue was reached.29 During thetest an ECG anda respiratory mass spectrometerwithcapnography wereusedtocontinuously monitor HR, ventilation, oxygen consumption and carbon dioxideproduction.Usingthese,peakHRandpeakoxygen consumption(peakVO2)weredetermined.
Orthostatictilttestandbaroreflexfunctionassessment
Tilttestprotocol. Orthostatictilttestingwasperformedin atemperature-controlledautonomicfunctionlab.Patients wereinstructedtoavoidanykind ofintensephysical acti-vity beforethe test andto avoidsmokingor drinkingany caffeine-containingdrinksinthethreehoursprecedingthe exam. No peripheral venous catheters were used and no drugs were administeredduring theentire exam. All sub-jectsunderwenta10-minbasalrestingperiodinthesupine position,or slightlyinclined inaccordancewithindividual sleeping habits to prevent respiratory discomfort.25 Sub-jects weretilted upto 70◦ using apassive electronictilt
table. The orthostatic period wasmaintainedfor 10 min, afterwhichsubjectsreturnedtotheirbasalinclinationfor a10-minrecoveryperiod.30,31
Dataacquisitionandanalysis. ECGandperipheralBPwere continuouslyandnoninvasivelyrecordedduringthetilttest (Task Force Monitor, CNSystems, Graz, Austria). Hemody-namicdatawerethenanalyzedusingsoftwaredevelopedin ourlab(FisioSinal32).Thissystemusesanalgorithmtodetect systolicbloodpressure(SBP)peaksandR-wavepeaksineach QRScomplexoftheECGfromwhichtheRRintervalcanbe calculated. In thisway, signals depicting the evolution of SBPovertime(systogram)andRRinterval(tachogram)were reconstructed.33,34 The reconstructedsignalswereusedto calculatethebaroreflexeffectivenessindex(BEI).
Baroreflex effectiveness index measurement. To assess arterial baroreflex function, the BEI was calculated by the sequence method.35,36 Briefly, the BEI is calculated on the basis of beat-to-beat analysis of cardiovascular signals. The algorithm identifies SBP ramps of three or more consecutive beats characterized by a progressive increase (up-ramp) or decrease (down-ramp) of at least 1 mmHg. Spontaneous baroreflex sequences (baroreflex events)weredefinedasSBPrampsfollowedbyconcomitant and concordant lengthening or shortening of RR inter-vals of at least 5 ms. The RR intervals were scanned with a lag from the SBP ramp of 0, 1 or 2 beats, each sequence being included only once.36 Baroreflex events wereonlyconsideredreliablewhentherewasastrong cor-relation between SBP ramps and concomitant RR-interval ramps (correlation coefficient >0.835). The total number of baroreflex events per minute (NBR) of the analysis was calculated, as well as the BEI, which is defined as
the ratio between baroreflex events and the total num-ber of SBP ramps. The higher the BEI, the greater the effectiveness of the arterial baroreflex in hemodynamic adaptationtochangesinbloodpressure.36,37
As assessment of baroreflex function is ideally per-formed under stationary conditions,37 baroreflex analysis wasdividedintothreeperiodsforeachpatient:
1) Basal:5minofbasalperiodinsupineposition; 2) Tilt:10minat70◦orthostaticposition;
3) Recovery:5minofrecoveryinbasalsupineposition. Statisticalanalysis
ThestatisticalanalysiswasperformedinSPSSsoftware (ver-sion 20, IBM, USA). Categorical variables were expressed aspercentages orfrequencies andcontinuousvariables as means± standarddeviation.TheKolmogorov-Smirnovtest was used to test the normal distribution of continuous variables.Thenon-parametricMann-Whitneytestwasused to compare groups. Pearson’s correlation coefficient was appliedtotest thecorrelationbetween BEIand theother continuousvariablesusedtodescribeHFseverity.The divi-sionofpatientsaccordingtoHFseveritywasperformedby k-meansclustering.Apvalue<0.05wasconsidered statisti-callysignificant.
Results
Population
In this study, 25 HF patients with a mean age of 65±10 years were included, of whom 20% were female. Table 1
summarizes the patients’ demographic and clinical char-acteristics. In approximately half of the population (13 patients, 52%) ischemic cardiomyopathy was the etiology of HF, theremaining12 (48%)patients havingHFof other causes.Intotal,11patientswereinNYHAfunctionalclass
Table 1 Clinicalcharacteristics ofheart failurepatients whowerecandidatesforcardiacresynchronizationtherapy.
n 25 Female 5(20%) Age(years) 65±10 HFetiology Ischemic 13(52%) Non-ischemic 12(48%)
NYHAclassII/III/IV 11/13/1
QRSduration(ms) 159±15 LVEF(%) 29±5 LVESV(ml) 150±48 LVEDV(ml) 207±60 PeakVO2(ml/kg/min) 18.4±5.0 BNP(pg/ml) 357±250
BNP: brain-typenatriureticpeptide;HF:heartfailure;LVEDV: leftventricularend-diastolicvolume;LVEF:leftventricular ejec-tionfraction;LVESV:leftventricularend-systolicvolume;NYHA: NewYorkHeartAssociation;VO2:oxygenconsumption.
Table2 Comorbiditiesandpharmacologictreatment.
Comorbidities
Hypertension 88%
Dyslipidemia 80%
Diabetes 32%
Obesity 28%
Chronickidneydisease 20%
Medication ACEinhibitors/ARBs 96% Beta-blockers 96% Diuretics 80% Spironolactone 52% Digoxin 12%
ACE:angiotensin-convertingenzyme;ARBs:angiotensin recep-torblockers.
II,13inNYHAclassIIIandoneinclassIV.MeanQRS dura-tion was 159±15 ms. All patients had depressed systolic functionwithseverelydilatedleftcardiacchambers(mean values:LVEF 29±5%,LVESV 150±48 ml andLVEDV 207±60 ml).Thepopulationwasalsocharacterizedbyasignificant limitationofphysical activity,asdemonstratedbyamean peakVO2of18.4±5.0ml/kg/min.MeanBNPwas357±270 pg/ml.Mostpatientshadmultiplecomorbiditiesandother cardiovascularriskfactors,notablyhypertension(88%), dys-lipidemia(80%),diabetes (32%),obesity(28%)andchronic kidneydisease(20%).Allpatientswereunderoptimal medi-caltreatment(Table2).
Controls
Thegroupofpatientswerecomparedwithacontrolgroup of15age-matchedindividuals(age58±8years,p=0.08).In thecontrolgroup,eightindividuals(53%)werefemale.None hadahistoryofcardiorespiratorydiseaseor dysautonomia orwastakingcardiovascularmedication.
Baroreflexfunction
Baroreflex function was significantly depressed in HF patientscomparedtocontrols.Figure1summarizes barore-flexfunctioninHFpatientsintermsofNBRandBEI.Itshows asignificantreductionofNBRinHFpatientsbothduringthe basal period (NBR HF:2.7±2.3 vs. NBR controls: 3.9±1.6 events/min, p=0.017), and during tilt (NBR HF: 2.7±2.8 vs.NBRcontrols:5.0±2.5events/min,p=0.001).Moreover, HF patients had a lower BEI. In basal supine position, patients’ BEI (34±14%) was significantly lower (p=0.001) thancontrols’(51±15%).Similarresultswerefoundforthe orthostatic tilt period (BEI HF: 31±12% vs. BEI controls: 49±18%,p=0.001).Interestingly,nodifferences in barore-flexfunctionwerefoundduringrecovery.
Associationbetweenbaroreflexfunctionandother clinicalparametersofheartfailureseverity
Ofalltheparametersassessed,thefollowingwereselected tobettercharacterize HFseverity:NYHAfunctionalclass, QRSduration,BNP,peakVO2,LVEF,LVESV,LVEDVandmitral
60.00 50.00 40.00 30.00 20.00 10.00 0.00 6.00 5.00 4.00 3.00 2.00 1.00 0.00 % p=0.001 p=0.001 NS p=0.017 p=0.001 BEI NBR NS HF patients Controls Ev ents/min
Basal Tilt Recovery Basal Tilt Recovery
Figure1 Baroreflexfunctionincandidatesforcardiacresynchronizationtherapy(green)comparedtohealthycontrols(blue), measuredby BEIandNBR.Heartfailurepatients havesignificantdecreased baroreflexfunction. Statisticalsignificancep<0.05 (Mann-Whitneytest).BEI:baroreflexeffectivenessindex;NBR:numberofbaroreflexeventsperminute;NS:non-significant.
Table3 Correlationbetweenbaroreflexfunctionandparametersofheartfailureseverity.
Baroreflexfunction NYHAclass QRS BNP PeakVO2 LVEF LVESV LVEDV MR
BasalBEI Pearson’sr -0.177 -0.19 -0.505 0.206 0.022 -0.221 -0.129 -0.111
p 0.431 0.398 0.033 0.428 0.926 0.428 0.646 0.65
TiltBEI Pearson’sr -0.251 -0.287 -0.435 0.472 0.195 -0.541 -0.486 -0.021
p 0.248 0.184 0.038 0.048 0.385 0.031 0.056 0.931
BasalNBR Pearson’sr -0.059 -0.071 -0.314 0.256 0.193 -0.314 -0.243 -0.162
p 0.779 0.736 0.191 0.304 0.366 0.22 0.348 0.482
TiltNBR Pearson’sr -0.265 -0.187 -0.537 0.428 0.354 -0.392 -0.331 0.007
p 0.201 0.371 0.018 0.077 0.09 0.12 0.195 0.977
BEI:baroreflexeffectivenessindex;BNP:brain-typenatriureticpeptide;LVEDV:leftventricularend-diastolicvolume;LVEF:left ven-tricularejectionfraction;LVESV:leftventricularend-systolicvolume;MR:mitralregurgitation;NBR:numberofbaroreflexeventsper minute;NYHA:NewYorkHeartAssociation.
regurgitationgrade.Table3 showsthe calculated correla-tioncoefficientsbetween the abovevariables andNBR or BEI.Duringtilt,alowerBEIwasassociatedwithhigherBNP values(r=-0.435,p=0.038),higherLVESV(r=-0.541,p=0.031)
and lower peak VO2 (r=0.472, p=0.048) (Figure 2). Fur-thermore, there was a significant negative correlation between basal BEI and BNP (r=-0.505, p=0.033), as well as between NBR during tilt and BNP (r=-0.517, p=0.018),
800 35.0 265 215 165 115 65 15 30.0 25.0 20.0 15.0 10.0 5.0 0.0 600 400 200 0 0 20 40 60 80 0 20 40 60 80 0 20 40 60 80 BNP (pg/ml)
BEI vs. BNP BEI vs. peak VO2
P eak V O2 (ml/kg/min) LVESV (ml) BEI vs. LVESV
BEI % BEI % BEI %
r=–0.435
p=0.038 p=0.048r=0.472 r=–0.541p=0.031
Figure2 AlowerBEIwasassociatedwithhigherBNPvalues,lowerpeakoxygenconsumptionandincreasedcardiacvolumes. Statis-ticalsignificancep<0.05(Pearson’srlinearcorrelationcoefficient).BEI:baroreflexeffectivenessindex;BNP:brain-typenatriuretic peptide;LVESV:leftventricularend-systolicvolume;VO2:oxygenconsumption.
Cluster 1 (BEI >25%) QRS 153 ms LVESV 129 ml BNP 146 pg/ml Peak VO2 19.0 ml/kg/min Cluster 2 (BEI ≤25%) QRS 167 ms LVESV 189 ml BNP 590 pg/ml Peak VO2 16.2 ml/kg/min
Figure3 Applyingacut-offvalueof25%forBEI,twoHFriskclusterswereobtained.Incluster2HFpatientswhopresentlow baroreflexfunctionhavewiderQRScomplexes,higherLVESVandBNPvaluesandreducedfunctionalstatusasshownbypeakVO2.
ThisisthereforethepatientgroupwithhigherHFclinicalrisk(K-meansclustering,variablesexpressedasmeans).BEI:baroreflex effectivenessindex;BNP:brain-typenatriureticpeptide;HF:heartfailure;LVESV:leftventricularend-systolicvolume;VO2:oxygen
consumption.
demonstratingthatdepressedbaroreflexfunctionis associ-atedwithincreasedBNPvalues.Duringtilt,theassociations between BEIand LVEDV (r=-0.486, p=0.056) and between NBRandpeakVO2werenon-significant(r=0.428,p=0.077). Inviewoftheaboveresults,BEIduringtiltwasusedto stratifypatients,asitwasthebaroreflexfunction measure-mentthatcorrelatedwithmostHFseverityvariables(LVESV, BNPandpeakVO2).Applyingk-meansclustering,acut-off valueof25%forBEIduringtiltwasfoundtostratifypatients intotwoclustersofdifferentHFseverity(Figure3):a low-risk cluster(BEI>25%)withQRS durationof153ms,LVESV 129ml,BNP146pg/ml,andpeakVO219.0ml/kg/min;anda high-riskcluster(BEI≤25%)withQRSduration167ms,LVESV 189ml,BNP590pg/ml,andpeakVO216.2ml/kg/min.These clustersdemonstrate thatbaroreflexfunction canbeused tobetterstratifyHFpatientswhoarecandidatesforCRT.
Discussion
Our resultsshow that HFpatients whoarecandidates for CRT have depressedbaroreflexfunction. This is in agree-ment with the literature, since this population consisted of selected HF patients and HF is a syndrome classi-callycharacterizedbycompensatorychronicneurohormonal hyperstimulation, with hypersympathetic activation and attenuation of the arterial baroreflex.38,39 The extent of thereductioninbaroreflexfunctionhasimportant progno-sticvalueinHF,lowervaluesofbaroreflexsensitivitybeing associatedwithincreasesinoverallmortality, cardiovascu-lar morbidity and mortalityand HF hospital admissions.24 Moreover, BEI correlated well with other variables of HF severity.PatientswithlowerBEIwerethosewithincreased cardiacvolumes(LVESVandLVEDV),increasedBNPandlower functionalcapacity(peakVO2).BNPandpeakVO2aretwo independentprognosticmarkersinHF.28,40Theyarewidely usedin riskstratification of HFpatients,40 withimportant implications for HF clinical management and treatment, includingtheutilityof peakVO2 instratifyingpatientsfor cardiactransplantation.41Besidestheimportanceof barore-flexfunctionasaprognosticmarkerinHF,24ourresultsshow that it correlates well withother risk stratification varia-bles includingBNPandpeakVO2,supporting theideathat baroreflexfunctionitselfmaybeusedinHFrisk stratifica-tion.WefoundthatBEIduringtilt couldbeusedtodivide patientsintolow-riskandhigh-riskHFgroups(Figure3).In
ourstudy,patientswithBEIlowerthan25%hadmoresevere HF.Wesuggestfurtherstudiestousethiscut-offvaluefor BEIinordertoidentifypatientsselectedforCRTthathave moresignificantHFrisk.
TheimportanceofthebaroreflexinCRTisstillnotclear astherearefew studiesonthis subjectinthe literature. However,Bragaetal.reportedonepatientwhofully reco-vered baroreflex function to normal values three months after CRT.39 Moreover, Gademanetal. demonstrated that therewasanacuteincreaseinbaroreflexsensitivityandHRV afterthe implantationofa biventricularpacemaker25 and thatthisincreasewaspredictiveof theresponsetoCRT.42 However,inthesestudiesbaroreflexfunctionwasassessed onlyaftertheimplantationofaCRTdevice,25,42with biven-tricularpacing switched onand off. Itwould be valuable toassess baroreflexfunction beforeandafter CRTdevice implantationtobetterunderstandtheautonomicimpactof CRToncardiovascularfunction.Moreover,theimportanceof apredictiveindexisgreaterwhenassessedbefore implanta-tion.Likewise,therearenostudiesdemonstratingthatthe increaseinbaroreflexfunctionissustainedchronically,nor ifthisincreasecorrelateswithcardiacreverseremodeling. Furtherfollow-upstudiesarenecessarytobetteranswerall thesequestions.
Ourmethodologicalapproachis basedonthesequence method,35 which measures baroreflex function through a non-invasive beat-to-beat measurement of HR and SBP. Although the studies that established the prognostic value of the baroreflex used the classic method for measurement of baroreflexsensitivity (the phenylephrine technique),24thereissignificantevidencethatnon-invasive methodsgivesimilarresultstothoseobtainedthroughthe phenylephrinetechniqueandobviatetheuseofvasoactive drugs.43,44ThesequencemethodisusedtocalculateBEI,a newbaroreflexfunctionindexthatmeasuresthe effective-ness withwhich the HR responds to SBPvariations.36,37,45 BEIis lessliabletobeinfluencedby ectopicbeats,which werequitefrequentinourpatients,thanbaroreflex sensiti-vity.Recently,theassessmentofbaroreflexfunctionthrough non-invasivemethodsbytheuseofprovocativemaneuvers has been extended to different clinical entities including reflexsyncope,30,37atrialfibrillation,31andHF,25inwhichit appearstoimprovespecificity. Ourworkisthefirsttouse atilt testin HFpatientsandtheresultsduringthe ortho-staticperiodprovidedmoreconsistentdatathanduringthe supinebasalperiod,asBEIduringtiltcorrelatedwithmore
HFseverityvariables.Ourapproachisinnovativeintheuse oftilttestinginpatientswithHFandourresultsshowthat itisareproducible,consistentandwell-toleratedtest.
Thesizeofourstudygroup(n=25)isthemainlimitation ofthiswork.Moreover,thecontrolgroupalsopresentssome limitations,asitwasage-matchedbutnotgender-matched. Furthermore,thefactthatallpatientswereunderoptimal medicaltreatmentmayalsobeconsideredalimitationtoa workthataimstoassessbasalbaroreflexfunction,as96%of patientsweretakingabeta-blockingagent.Nevertheless,La Rovereetal.haverecentlyshowninaprospectivestudythat therearenosignificantdifferencesinbaroreflexsensitivity betweenHFpatientstreatedwithbeta-blockersandthose thatarenot.46
Ourworkshowstheimportanceofbaroreflexassessment inriskstratificationof HFpatients whoarecandidatesfor CRT.Inthefuture,prospectivestudies withat leasta six-monthpost-CRTfollow-upareneededinorderto demons-tratetheexistenceofautonomicremodelingassociatedwith CRTandtoassess whetherbaroreflexmeasurementshave predictivevalueconcerningresponsetoCRT.
Ethical
disclosures
Protection of human and animal subjects.The authors declarethat the proceduresfollowed were in accordance withtheregulationsoftherelevantclinicalresearchethics committeeandwiththoseoftheCodeofEthicsoftheWorld MedicalAssociation(DeclarationofHelsinki).
Confidentialityofdata.Theauthorsdeclarethattheyhave followedtheprotocolsoftheirworkcenteronthe publica-tionofpatientdata.
Righttoprivacyandinformedconsent.Theauthorshave obtainedthe written informed consentof the patients or subjectsmentionedinthearticle.Thecorrespondingauthor isinpossessionofthisdocument.
Conflicts
of
interest
Theauthorshavenoconflictsofinteresttodeclare.
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