www.revportcardiol.org
Revista
Portuguesa
de
Cardiologia
Portuguese
Journal
of
Cardiology
ORIGINAL
ARTICLE
Impact
of
cardiac
resynchronization
therapy
on
inflammatory
biomarkers
and
cardiac
remodeling:
The
paradox
of
functional
and
echocardiographic
response
Luís
Almeida-Morais
∗,
Ana
Abreu,
Mário
Oliveira,
Pedro
Silva
Cunha,
Inês
Rodrigues,
Guilherme
Portugal,
Pedro
Rio,
Rui
Soares,
Miguel
Mota
Carmo,
Rui
Cruz
Ferreira
CentroUniversitáriodeCardiologia,HospitaldeSantaMarta,CentroHospitalardeLisboaCentral,Lisbon,Portugal
Received1January2017;accepted29June2017 Availableonline2March2018
KEYWORDS Heartfailure; Cardiac resynchronization therapy; B-typenatriuretic peptide; C-reactiveprotein Abstract
Introduction:Responsetocardiacresynchronizationtherapy(CRT)cancurrentlybeassessed byclinicalorechocardiographiccriteria,andthereisnostrongevidencesupportingtheuseof oneratherthantheother.ReductionsinB-typenatriureticpeptide(BNP)andC-reactiveprotein (CRP)havebeenshowntobeassociatedwithCRTresponse.Thisstudyaimstoassessvariation inBNPandCRPsixmonthsafterCRTandtocorrelatethisvariationwithcriteriaoffunctional andechocardiographicresponse.
Methods:PatientsundergoingCRTwere prospectivelyenrolledbetween2011and2014. CRT responsewasdefinedbyechocardiography(15%reductioninleftventricularend-systolic vol-ume)andbycardiopulmonaryexercisetesting(10%increaseinpeakoxygenconsumption)from baselinetosixmonthsafterdeviceimplantation.
Results:A total of 115 patients were enrolled (68.7% male, mean age 68.6±10.5 years). Echocardiographic responsewasseenin51.4% and59.2% werefunctionalresponders.There was no statisticalcorrelation between thetwo. Functionalresponse was associated with a significantlygreaterreductioninBNP(-167.6±264.1vs.-24.9±269.4pg/ml;p=0.044)andCRP levels(-1.6±4.4vs.2.4±9.9mg/l;p=0.04).Nonetheless,anon-significantreductioninBNPand CRPwasobservedinechocardiographicresponders(BNP-144.7±260.2vs.-66.1±538.2pg/ml andCRP-7.1±24.3vs.0.8±10.3mg/l;p>0.05).
Conclusion: AnincreaseinexercisecapacityafterCRTimplantationisassociatedwith improve-ment in myocardial remodeling and inflammatory biomarkers. This finding highlights the importanceofimprovementinfunctionalcapacityafterCRTimplantation,notcommonly con-sideredacriterionofCRTresponse.
© 2018SociedadePortuguesade Cardiologia.Publishedby ElsevierEspa˜na,S.L.U.Allrights reserved.
∗Correspondingauthor.
E-mailaddress:[email protected](L.Almeida-Morais).
https://doi.org/10.1016/j.repc.2017.06.017
PALAVRAS-CHAVE Insuficiência cardíaca; Terapiade ressincronizac¸ão cardíaca; Péptidonatriurético tipo-B; ProteínaC-reactiva
Impactodaressincronizac¸ãocardíacanosbiomarcadoresinflamatórios ederemodelagemcardíaca
Resumo
Introduc¸ão: Aavaliac¸ãodarespostaàterapêuticaderessincronizac¸ãocardíaca(CRT)assenta emcritériosclínicoseecocardiográficos,semevidênciainequívocaqueapoieousodeunsem relac¸ãoaos outros.Reduc¸ões dopéptidonatriuréticotipo-B (BNP)e daproteínaC-reactiva (PCR)associaram-seàrespostaàCRT.Oobjetivodesteestudoéavaliaravariac¸ãodoBNPe PCRapósseismesesdeCRTerelacionaressavariac¸ãocomcritériosderespostafuncionale ecocardiográfica.
Métodos: De2011a2014,doentescomindicac¸ãoparaCRTforamincluídosprospetivamente. ArespostaàCRTfoidefinidaporecocardiograma(reduc¸ãoem15%novolumetelessistólicodo ventrículoesquerdo)eporprovacardiorrespiratória(aumentode10%noconsumodeoxigénio máximo),aosseismeses.
Resultados: Foram incluídos 115 doentes (género masculino: 68,7%, idade média 68,6±10,5anos);51,4% apresentaram respostaecocardiográficae 59,2%resposta funcional. Nãoseverificouumacorrelac¸ãoestatisticamentesignificativaentreesses.Osrespondedores funcionaisapresentaramreduc¸õesestatisticamentesignificativasdeBNP(-167,6±264,1versus -24,9±269,4;p=0,044)ePCR(-1,6±4,4versus2,4±9,9;p=0,04).Nogrupoderespondedores ecocardiográficosessareduc¸ãonãoatingiusignificânciaestatística[BNP(-144,7±260,2versus -66,1±538,2)ePCR(-7,1±24,3versus0,8±10,3;p>0,05)].
Conclusão:Umaumentodacapacidade funcionalapósimplantac¸ãodeCRTestáassociadoa uma melhoria dos biomarcadoresinflamatórios e de remodelagem reversaventricular. Essa ideiaenalteceaimportânciadamelhoriadacapacidadefuncionalapósimplantac¸ãodeCRT, poucoconsideradacomocritérioderespostaàressincronizac¸ão.
©2018SociedadePortuguesadeCardiologia.PublicadoporElsevierEspa˜na,S.L.U.Todosos direitosreservados.
BNP B-typenatriureticpeptide CHF chronicheartfailure
CPET cardiopulmonaryexercisetesting CRP C-reactiveprotein
CRT cardiacresynchronizationtherapy ICC intraclasscorrelationcoefficient LVEDV leftventricularend-diastolicvolume LVEF leftventricularejectionfraction LVESV leftventricularend-systolicvolume NYHA NewYorkHeartAssociation
VO2max peakoxygenuptake
VE/VCO2 minute ventilation-carbon dioxide produc-tionslope
Introduction
Cardiac resynchronization therapy (CRT) is an established treatment for patients with symptomatic chronic heart failure(CHF)andprolongedQRSdespiteoptimal pharmaco-logicaltherapy.Byrestoringtheheart’selectromechanical synchrony, CRT improves self-reported symptoms and reducesmortalityandrehospitalizationforheartfailure.1---4 ResponsetoCRTisassociatedwithleftventricularreverse remodeling,whichisobjectivelyassessedthrough echocar-diographic parameters, particularly improvement in left ventricular ejection fraction (LVEF) and reduction in left
ventricular end-systolic volume (LVESV).5 Nonetheless, up to 40% of CRT recipientsare considered non-responders.6 Improvement in New York Heart Association (NYHA) func-tionalclassandsix-minutewalktestdistancehavealsobeen proposedasclinicalresponsecriteriainseveralstudies.7,8 Improvement inpeakoxygen uptake(VO2 max), amarker
of functionalstatusandactivity,hasbeendescribed after CRT device implantation in a small cohort of patients.9 However,thereislittleagreementbetweenthecriteriaof response,whichsuggeststhatclinicalorfunctional improve-ment can occur without changes in echocardiographic parameters.10
B-typenatriureticpeptide(BNP)is amarkerofvolume and pressure overload that has been proposed as a diag-nostic and prognostic tool in CHF, in which it correlates wellwithseverity.Moreover,pharmacologicaltherapiesthat improve CHF symptoms and outcomes have been shown toreduce BNPlevels.11 Studies have alsoreported signif-icant reductions in plasma BNP levels after CRT device implantation.12---14 Systemic inflammation is also knownto playaroleinCHF,15 andincreasedserumlevelsof inflam-matorymarkers suchasC-reactive protein(CRP) confera dismalprognosisforCHFpatients.16,17
Nonetheless,thereareconflictingdataconcerning reduc-tions in BNP and CRP as markers of neurohormonal and inflammatory status after CRT device implantation.11,12 Moreover,theirassociationwithCRTresponsecriteriathat assess differentpathological pathways of thesyndrome is notfullyunderstood.
Hence, thisstudy aimsprimarily toassessvariationsin BNPandCRPsixmonthsafterCRTdeviceimplantation,and secondarily to assess the association between changes in theselaboratory variables andfunctional and echocardio-graphicresponsetoCRT.
Methods
Populationandstudydesign
Between April 2011 and December 2014, consecutive patients referred for CRT device implantation in a ter-tiarycenter weresystematicallyincludedina prospective cohortstudy.IndicationsforCRTfollowedcurrent interna-tionalguidelines.18Allpatientshadbeenonoptimalmedical therapyforatleastsixmonthsandwerefollowedbya spe-cialized heart failure team. A comprehensive assessment includingdemographic,clinical, laboratory, electrocardio-graphic, echocardiographic and cardiopulmonary exercise testing (CPET) wasperformed anddatawere collectedat baselineandsixmonthsafterdeviceimplantationand sub-sequentlyanalyzed.Theethicscommitteeofouruniversity hospital center approved the study protocol and written consentwasobtainedforallpatients.
Demographicandclinicaldata
Demographicandclinicaldatawereobtainedthrough medi-cal consultation at baseline and at six-month follow-up. Demographic variables included age and gender. Clinical variables included heart failure etiology, classical cardio-vascularriskfactors,comorbidities,ongoingmedicationand NYHAfunctionalclass.A12-leadelectrocardiogramwasalso obtainedtodetermineheartrhythm,QRSwidthand intra-ventricularconductionpattern.
Laboratorydata
Blood samples were collected through peripheral venous catheterization into blood collection tubes with (serum) or without (plasma) anticoagulant (EDTA). All laboratory tests were performed after at least six hours fasting and at rest in a supine position in the same laboratory using hospital protocol, and assays were determined according tothemanufacturer’srecommendations.BNPwasanalyzed from plasma on a Spinchron DLX 800 (Beckman Coulter) centrifuge usinga two-step chemiluminescenceassay and serumCRP wasdeterminedwithanephelometer (Siemens BNProSpecT).
Transthoracicechocardiography
Acompletetransthoracicechocardiogramwasperformedin allpatients usingaVivid E9scanner (GE Healthcare)with a3MHzprobe,atbaselineandatsix-monthfollow-up. M-mode,two-dimensional,color,pulsed,continuouswaveand tissue Doppler data were obtained from parasternal and apical views, and the standard echocardiographic param-eterswere calculated. Acquired cine-loop imageswithat least threecardiaccycles wereanalyzed offline(EchoPAC
software, GE Healthcare) for additional measures. LVEF, LVESV and left ventricular end-diastolic volume (LVEDV) weredeterminedfromapical4-and2-chamberviewsusing Simpson’sbiplane method.19 The meanof three measure-mentswasconsideredforanalysis.Endocardialborderswere manually traced and the left ventricular papillary mus-cleswereincludedinvolumeacquisition.Allmeasurements werereviewedbythesameechocardiographicoperator.The intraclass correlation coefficient (ICC) was calculated for LVESVtoassessintraobservervariability.Echocardiographic response to CRT was established as a ≥15% reduction in LVESVfrombaselinetosixmonthsafterCRTdevice implan-tation,aspreviouslypublished.20
Cardiopulmonaryexercisetesting
CPETwithventilatoryexpired gasanalysis wasperformed in all patients at baseline and at six-month follow-up usingthemodifiedBruce protocol. Exercisetestduration, VO2maxandminuteventilation-carbondioxideproduction
slope(VE/VCO2)weredetermined.Asignificantfunctional
responsetoCRTwasdefinedasa≥10%increaseinVO2max
frombaselinetosix-monthfollow-up.21
Cardiacresynchronizationtherapydevice implantation
CRT device implantation was performed through a transvenous approach, using the subclavian and cephalic veins.Therightatrialleadwaspositionedintherightatrial appendageandtherightventricularleadwasactivelyfixed in the right ventricular apex or interventricular septum. Theleftventricularleadwasintroducedusingalong guid-ing sheath in order to cannulate the coronary sinus. An angiogramwasperformedandthentheleadwaspositioned preferablyinalateralorposterolateralvein.
Statisticalanalysis
Baselinedemographicandclinicaldatawere expressedas meansandstandarddeviationforcontinuousvariablesand aspercentages for categorical variables. Changes in BNP andCRP(BNPandCRP)wereestablishedbythe arith-metic subtraction of their values at six-month follow-up frombaseline.Normality(Gaussiandistribution)wastested inall continuous variables usingthe Shapiro-Wilk test. To assesstheassociationbetweencontinuousvariables, Pear-son’s or Spearman’scorrelation was usedfor normally or non-normally distributed data, respectively. BNP and CRP were separately compared between echocardio-graphicandfunctionalrespondersandnon-respondersusing theStudent’storMann-Whitneytestsfornormallyor non-normallydistributedvariables,respectively.Thechi-square testwasusedtocomparedichotomousvariables.Thelevel of significance considered was ␣=0.05. Data were ana-lyzedusingSPSS forWindows, version20.0 (IBMSPSSInc, Chicago,IL).
Table1 Baselinecharacteristicsofechocardiographicandfunctionalrespondersandnon-responders.
Variables LVESV≤15% VO2max≥10%
R(59) NR(56) p R(68) NR(47) p
Demographic
Age(years)(mean±SD) 68.5±14.3 66.5±8.3 NS 68.5±9.6 67.4±10.9 NS
Female(%) 30.6 29.4 NS 31 17.2 NS Clinical Ischemicetiology(%) 16.7 29.4 NS 23.8 27.6 NS AF(%) 20 23 NS 19 24 NS NYHAII/III/IV(%) 31.4/62.9/2.9 21.9/75.0/3.1 NS 28.6/66.7/2.4 25.9/70.4/3.7 NS Smoker(%) 13.9 11.8 NS 11.9 20.7 NS Diabetes(%) 27.8 44.1 NS 33.3 41.4 NS Hypertension(%) 75.0 70.6 NS 73.8 82.8 NS Dyslipidemia(%) 61.1 55.9 NS 59.5 62.1 NS Obesity(%) 27.8 20.6 NS 26.2 13.8 NS Familyhistory(%) 33.3 26.5 NS 33.3 31 NS Medication Anticoagulants(%) 61.1 58.8 NS 59.5 58.6 NS Beta-blockers(%) 69.4 76.5 NS 73.8 79.3 NS ACEIs/ARBs(%) 80.6 73.5 NS 73.8 89.7 NS Diuretics(%) 80.6 79.4 NS 83.3 79.3 NS Laboratory CRP(mg/l)(mean±SD) 10.6±24.1 5.1±7.18 NS 4.55±5.3 3.0±3.6 NS BNP(pg/ml)(mean±SD) 530.9±528.1 636.0±657.7 NS 520.7±439.7 404.3±485.1 NS Cr(mg/dl)(mean±SD) 1.16±0.55 1.10±0.35 NS 1.07±0.67 1.15±0.83 NS Hb(g/dl)(mean±SD) 12.1±0.87 11.8±0.79 NS 11.9±0.57 12.3±0.68 NS Electrocardiography QRSwidth(ms)(mean±SD) 172.0±24.3 165.8±38.9 NS 166±25.7 176.6±25.1 Echocardiography LVEF(%)(mean±SD) 24.8±6.5 26.3±7.7 NS 25.6±7.9 26.7±5.9 NS LVEDV(ml)(mean±SD) 231.8±69.9 202.4±61.8 NS 225.6±68.7 218.5±84.0 NS LVESV(ml)(mean±SD) 173.8±58.9 143.6±59.9 0.03 165.0±64.4 163.3±68.3 NS CPET VO2max(ml/min/kg) 15.1±6.6 23.0±15.4 NS 12.1±4.1 18.6±5.2 0.04 VE/VCO2slope 38.9±9.9 61.7±37.4 NS 42.3±11.7 33.2±10.9 0.003 Duration(min) 3.63±2.62 3.8±2.5 NS 3.02±1.96 5.0±2.5 <0.001
ACEIs:angiotensin-convertingenzymeinhibitors;AF:atrialfibrillation;ARBs:angiotensinreceptorblockers;BNP: B-typenatriuretic peptide;CPET:cardiopulmonaryexercisetest;Cr:creatinine;CRP:C-reactiveprotein;Hb:hemoglobin;NR:non-responder;LVEDV:left ventricularend-diastolicvolume;LVEF:leftventricularejectionfraction;LVESV:leftventricularend-systolicvolume;NYHA:NewYork HeartAssociationfunctionalclass;R:responder;SD:standarddeviation;VE/VCO2:minuteventilation-carbondioxideproductionslope;
VO2max:peakoxygenconsumption.
Results
Baselinecharacteristics
A total of 115 patients underwent CRT device implanta-tion for whom complete data were collected at baseline and six-month follow-up. Mean age was 68.6±10.5 years and 68.7% were male. Ischemic heart failure etiology was reported in 29.1%. Mean QRS width at baseline was 172.1±28.8 ms and complete left bundle branch block was present in 56% of patients. Beta-blockers were pre-scribed in 86.2%of patients and 88.6%were treated with renin-angiotensinsysteminhibitors(angiotensin-converting enzyme inhibitors or angiotensin receptor blockers). At
baseline, 74.3%patients were in NYHA functionalclass III or IV. Clinical improvement of at least one NYHA class wasobservedin81.3%ofpatients.CRPandBNPpresented a statistically significant reduction from baseline to six-monthfollow-up(CRP7.0±15.6to6.5±15.3mg/l,p<0.001, and BNP 533.6±553.6 to 404.9±530.3 pg/ml, p<0.001). Echocardiographicresponsewasobservedin51.4%and func-tional response in 59.2%, assessed by the above criteria. Response asassessed byechocardiography wasnot statis-ticallycorrelatedwithfunctionalresponse(r=0.14,p=0.433 andchi-square=0.063,p=0.80).
Table1delineatesthebaselinedemographicandclinical characteristics of respondersandnon-responders assessed by both sets of criteria independently. Table 2 details
Table2 Laboratory,electrocardiographic,echocardiographicandcardiopulmonaryexercisetestdataatbaselineandsix-month follow-up.
Baseline Six-monthfollow-up p
Laboratory CRP(mg/l)(mean±SD) 7.0±15.6 6.5±15.3 p<0.001 BNP(pg/ml)(mean±SD) 533.6±553.6 404.9±530.3 p<0.001 Electrocardiography QRSwidth(ms)(mean±SD) 172.1±28.8 169.4±13.5 p<0.001 Echocardiography LVEF(%)(mean±SD) 26.4±7.0 38.7±11.2 p<0.001 LVEDV(ml)(mean±SD) 208.6±69.5 201.3±81.6 p<0.001 LVESV(ml)(mean±SD) 158.1±57.7 140.4±66.1 p<0.001 CPET VO2max(ml/min/kg) 16.4±4.11 14.5±5.2 p<0.001 VE/VCO2slope 38.0±11.6 32.4±7.1 p<0.001 Duration(min) 3.7±2.4 4.7±2.2 p<0.001
BNP:B-typenatriureticpeptide;CPET:cardiopulmonaryexercisetesting;CRP:C-reactiveprotein;LVEDV:leftventricularend-diastolic volume;LVEF:leftventricularejectionfraction;LVESV:leftventricularend-systolicvolume;VE/VCO2:minuteventilation-carbondioxide
productionslope;VO2max:peakoxygenconsumption.
laboratory,echocardiographicandCPETdataatbaselineand atsix-monthfollow-up.
Echocardiographicresponse
In our cohort, severely reduced mean LVEF at baseline was observed (26.4±7.0%). A significant improvement in mean LVEF andreduction in mean LVEDV andLVESV were noted after CRT device implantation. Additionally, 63.4% of patients showed more than 10% improvement in LVEF and in 51.4% of patients LVESV decreased by more than 15%comparedtobaseline(echocardiographicresponders). AnICCof0.89atbaselineand0.87at six-monthfollow-up wascalculated for intraobserver variability of LVESV. BNP reductionwasmorepronouncedinrespondersthanin non-respondersasassessed byechocardiography,although this did not achieve statistical significance (-144.7±260.2 vs. -66.1±538.2pg/ml, p>0.05)(Figure1).Echocardiographic responders also presented a non-significant reduction in serumCRP levelsafterCRT(-7.1±24.3vs.0.7±10.3mg/l, p>0.05)(Figure2).
Functionalresponse
VO2 max during CPET wasseverely depressedat baseline
(mean 14.5±5.2 ml/min/kg). However,a statistically sig-nificant improvement (14.5±5.2 to 16.4±4.1 ml/min/kg, p<0.001) was observed after CRT device implantation. Improvement in exercise capacity was also shown by a significant reduction in VE/VCO2 slope and longer CPET
duration(38.0±11.6vs.32.4±7.1and3.7±2.4vs.4.7±2.2 ms,respectively,allp<0.001)atsix-month follow-up.BNP reductionwassignificantlymorepronouncedinthose clas-sified as functional responders (-167.6±264.1 pg/ml vs. -24.9±269.4pg/ml,p=0.044)(Figure3).CRPreductionwas seen in functional responders, while non-responders pre-sentedelevation inmeanCRP levelssixmonthsafterCRT
deviceimplantation(-1.6±4.4vs.2.4±9.9mg/l, p=0.040) (Figure 4). A significant reduction in VE/VCO2 slope was
alsonotedinfunctionalresponders(-9.8±10.5vs.1.9±7.2, p=0.001).
Discussion
Inourstudypopulation asignificant reductionof CRPand BNP was observed six months after CRT (CRP 7.0±15.6 to 6.5±15.3 mg/l, p<0.001 and BNP 533.6±553.6 to 404.9±530.3pg/ml,p<0.001).TheCRPandBNPreductions weresignificantlyhigherinthefunctionalrespondergroup, whereastheydidnotachievestatisticalsignificanceinthe echocardiographicrespondergroup.
Heartfailureisasystemicconditionwithincreased lev-elsof natriuretic peptidesand inflammatory markers.12,13 Therapies targeting these pathways have shown positive prognosticimpactinthissyndrome.11,17
Asdescribed,ourcohortrepresentsasevereheartfailure population characterized by poor self-reported functional status,reducedexercisecapacityandlowmeanLVEF. More-over,comparedtootherstudies,ourpopulationpresented ahigher proportionof nonischemic heart failure etiology, such as idiopathic, valvular and alcoholic, only 29.1% of patientshavingischemic heartfailure.18 The heartfailure etiology didnot significantlydiffer between functional or echocardiographicrespondersandnon-responders.Patients inourpopulationpresentedadvancedage,whichexcludes themfromahearttransplantationprogram,andtheywere alreadyonoptimalmedicaltherapy.Additionally, thehigh meanBNPandCRPlevelspresentedatbaselinesupportthe conceptofan advanced heartfailurepopulation, and sig-nificantreductionsinBNPandCRPlevelswereobservedat six-monthfollow-upafterCRTdeviceimplantation,whichis inlinewithpreviousstudies.22---24,12
ResponsetoCRT isthesubjectofconsiderabledebate, since there is no established definition for therapeutic
r=-0.10, p=0.483 1000 0 -1000 Δ BNP -2000 No Yes ≥15% LVESV reduction
Figure1 CorrelationbetweenB-typenatriureticpeptide(BNP)levelsandechocardiographicresponsetocardiacresynchronization therapy.Responsewasdefinedasa≥15%reductioninleftventricularend-systolicvolume(LVESV).BNP:variationinBNPlevels.
r=-0.21, p=0.128 0 50 -50 -100 -150 Δ CRP No Yes ≥15% LVESV reduction
Figure 2 Correlation between C-reactive protein (CRP) levels and echocardiographic response to cardiac resynchronization therapy.Responsewasdefinedasa≥15%decreaseinleftventricularend-systolicvolume(LVESV).CRP:variationinCRPlevels.
response.20 Improvement in LVEF andreductions in LVESV andLVEDVaretheresultofleftventricularreverse remod-eling.Pharmacologicaltherapiestargetingthiseffecthave been shown to be associated with better long-term out-comesinheartfailurepatients.25---28 Thecut-offofa≥15% reduction in LVESV has been described as a more spe-cificsurrogateof leftventricularreverse remodelingthan LVEF, and has been used to define those responding to CRT therapy by echocardiography.10,11,14,21 In our study, only 51.4% of patients achieved this demanding criterion at six months.These echocardiographic respondershad a morepronouncedreductioninBNPat six-monthfollow-up than non-responders, but this did not achieve statistical
significance. Despite targeting the same mechanism, the demanding cut-off for LVESV reduction, the short follow-uptimeforstructuralchangesandvariabilityinBNPcould explainthisphenomenon.RegardingthechangesinCRP,a widelyusedmarkerofsystemicinflammation,therewasno significantassociationwithreducedLVESV,perhapsbecause theyreflectdifferentpathwaysofthepathologicaldisease process.Theassociationreportedintheliteraturebetween reducedLVESVandchangesinBNPorCRPafterCRThasin factbeenvariable.14,28,29
Exercise capacity, measured through VO2 max during
CPET,isknowntobeamajorprognosticindicatorinheart failurepatients.30,31Ithasbeenassessedinconjunctionwith
Figure 3 Correlation between B-type natriuretic peptide (BNP)levels and functional response to cardiacresynchronization therapy.Responsewasdefinedasa≥10%increaseinpeakoxygenconsumption(VO2max).BNP:variationinBNPlevels.
Figure4 Correlation betweenC-reactive protein (CRP) levels andfunctionalresponse tocardiac resynchronizationtherapy. Responsewasdefinedasa≥10%increaseinpeakoxygenconsumption(VO2max).CRP:variationinCRPlevels.
pharmacologicaltherapiesforheartfailurepatients.32 How-ever,itsusefordeterminingfunctionalresponseafterCRT isnotroutinelyconsideredandlacksclinicalevidence.We usedacut-offof≥10%improvementin VO2 maxtodefine
functionalresponders,andourstudyrevealed significantly greater reductionsin BNPandCRP amongCRT patientsin whomVO2maximprovedsubstantiallyatsix-month
follow-up. An association between reductions in neurohormonal and inflammatory levelsand a ≥10% improvement in VO2
max has not previously been reported in this population. Volume overload in heart failureis responsible for raised leftventricular and atrial pressure and consequently ele-vation of pulmonary capillary wedge pressure, which is
associatedwithfunctionalexerciseimpairment.13Moreover, systemic inflammatory markers increase oxygen demand, depressmyocardialfunctionanddisturbhomeostasisinthe pulmonaryvasculature,influencingtheinteractionbetween heartandlungs.33Thisfindingsuggeststhat electromechan-icalresynchronization mayhave a rolein reversing these pathologicalprocesses,whichhighlightstheimportanceof consideringimprovementinVO2maxafterCRTasaresponse
criterion.
Inourstudy,theassociationbetweenreducedLVESVand improvedVO2maxwasnon-significant,suggestingthatthose
whoimproved byonecriterionmaynothave improvedby theother.Similarly,Fornwaltetal.showedthatagreement
between criteria of clinical, echocardiographic and func-tionalexercise response after CRT device implantation is poor,11indicatingthatCRTmayleadtoimprovementsin dif-ferentparametersindifferentpatients.Functionalresponse supportedbyreductioninBNPandCRPcouldberelatedto CRT responseindependently of significant leftventricular reverseremodelingatsix-monthfollow-up.
Study
limitations
Follow-up time in this study was set at six months after CRTimplantation,which maybeinsufficient toassessthe long-term structural changes of left ventricular reverse remodeling.Moreover,inferencescannotbemadeaboutthe lastingclinical,laboratoryorechocardiographicalterations inthis populationafter thistime.Additionally, CRP levels aresusceptibletovariability,andongoinginflammatory pro-cessesthatinfluencedCRPlevelscannotbeexcluded.
Conclusion
CRTwasassociatedwithimportant reductions inBNPand CRP levels at six-month follow-up. Patients presenting significantlyimprovedfunctionalcapacity,considered func-tionalresponders, showed significant reductions in serum BNPand CRP levels at six-month follow-up, reflecting its benefit on ventricular remodeling and inflammation. In echocardiographic respondersthis effect wassmaller and non-significant,whichcallsattentiontotheimportanceof assessingfunctionalresponseinCRTpatients.
Conflicts
of
interest
Theauthorshavenoconflictsofinteresttodeclare.
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