Adaptive servo ventilation improves Cheyne-Stokes respiration, cardiac function, and prognosis in chronic heart failure patients with cardiac resynchronization therapy

ContentslistsavailableatSciVerseScienceDirect

Journal

of

Cardiology

j o u r n al hom ep ag e :w w w . e l s e v i e r . c o m / l o c a t e / j j c c

Original

article

Adaptive

servo

ventilation

improves

Cheyne-Stokes

respiration,

cardiac

function,

and

prognosis

in

chronic

heart

failure

patients

with

cardiac

resynchronization

therapy

Makiko

Miyata

(MD)

_,

_Akiomi

_Yoshihisa

_(MD,

_PhD)

_,

_Satoshi

_Suzuki

_(MD,

_PhD)

_,

Shinya

Yamada

(MD)

_,

_Masashi

_Kamioka

_(MD,

_PhD)

_,

_Yoshiyuki

_Kamiyama

_(MD,

_PhD)

_,

Takayoshi

Yamaki

(MD,

PhD)

_{, Koichi}

_Sugimoto

_(MD,

_PhD)

_{, Hiroyuki}

_Kunii

_(MD,

_PhD)

_,

Kazuhiko

Nakazato

(MD,

PhD)

_,

_Hitoshi

_Suzuki

_(MD,

_PhD)

_,

_Shu-ichi

_Saitoh

_(MD,

_PhD)

_,

Yasuchika

Takeishi

(MD,

PhD,

FJCC)

a_{DepartmentofCardiologyandHematology,FukushimaMedicalUniversity,Fukushima,Japan}

b_{DepartmentofAdvancedCardiacTherapeutics,FukushimaMedicalUniversity,Fukushima,Japan}

a

r

t

i

c

l

e

i

n

f

o

Articlehistory:

Received9August2011

Receivedinrevisedform

13December2011

Accepted10January2012

Availableonline20June2012

Keywords:

Heartfailuretreatment

Non-pharmacologicaltherapy

Obesity Ventilation

Brainnatriureticpeptides

Outcomesassessment

a

b

s

t

r

a

c

t

Background:Cheyne-Stokesrespiration(CSR-CSA)isoftenobservedinpatientswithchronicheartfailure (CHF).Althoughcardiacresynchronizationtherapy(CRT)iseffectiveforCHFpatientswithleftventricular dyssynchrony,itisstillunclearwhetheradaptiveservoventilation(ASV)improvescardiacfunctionand prognosisofCHFpatientswithCSR-CSAafterCRT.

Methodsandresults:TwentytwopatientswithCHFandCSR-CSAafterCRTdefibrillator(CRTD) implan-tationwereenrolledinthepresentstudyandrandomlyassignedintotwogroups:11patientstreated withASV(ASVgroup)and11patientstreatedwithoutASV(non-ASVgroup).Measurementofplasma B-typenatriureticpeptide(BNP)levels(before3,and6monthslater)andechocardiography(beforeand 6months)wereperformedineachgroup.Patientswerefolloweduptoregistercardiacevents(cardiac deathandre-hospitalization)afterdischarge.IntheASVgroup,indicesforapnea-hypopnea,centralapnea, andoxyhemoglobinsaturationwereimprovedonASV.BNPlevels,cardiacsystolicanddiastolicfunction wereimprovedwithASVtreatmentfor6months.Importantly,theevent-freeratewassignificantlyhigher intheASVgroupthaninthenon-ASVgroup.

Conclusions:ASVimprovesCSR-CSA,cardiacfunction,andprognosisinCHFpatientswithCRTD.Patients withCSR-CSAandpostCRTDimplantationwouldgetbenefitsbytreatmentwithASV.

©2012JapaneseCollegeofCardiology.PublishedbyElsevierLtd.Allrightsreserved.

Introduction

Chronic heart failure (CHF) is a major cause of death of the elderly in developed countries. A number of randomized large-scale clinical trials have demonstrated optimal medical management including angiotensin-converting enzyme (ACE) inhibitors,␤-blockers,aldosteroneantagonists,etc.improve clin-icalsymptoms,cardiacfunction, andevent-free survivalin CHF [1–3].However,CHFisstill associatedwitha highrateof mor-tality.Identificationoffactorscontributingtohighmortalitymay

∗ Correspondingauthorat:DepartmentofAdvancedCardiacTherapeutics,

FukushimaMedicalUniversity,1Hikarigaoka,Fukushima960-1295,Japan.

Tel.:+81245471190;fax:+81245481821.

E-mailaddress:[email protected](A.Yoshihisa).

leadtothedevelopmentof anewstrategy totreatCHF. Sleep-disorderedbreathingisoftenobservedinpatientswithCHF[4].The presenceofsleep-disorderedbreathing,either obstructivesleep apneaorCheyne-Stokesrespirationwithcentralsleepapnea (CSR-CSA),hasadverseprognosticimpactsinCHF[5–7].Therespiratory center’sinstabilityisthoughttobethemajorcauseofCSR-CSA, andadaptiveservoventilation(ASV)isaventilatorsupportsystem specificallydesignedtonormalizeventilationinpatientswith CSR-CSA[5–8].ASVcanregulatetheairwayventilationvolumeupon demandbasedonthevariabletidalvolumethroughouttheperiod ofCSR[5–8].Inaddition,ASVautomaticallyprovidespositive pres-sureventilationduringapnea,whennecessary.

Cardiac resynchronization therapy (CRT) with biventricular pacingisaneffectiveadjunctivetherapytopharmacological man-agementinCHF.CRTimprovesfunctionalstatus,exercisecapacity, qualityoflife,andmortalityinCHFpatientswithleftventricular

0914-5087/$–seefrontmatter©2012JapaneseCollegeofCardiology.PublishedbyElsevierLtd.Allrightsreserved.

systolicdysfunctionandintra-ventricularconductiondelay[5–7]. Althoughsustainedeffective therapy forCHF includingoptimal pharmacotherapyandCRThasbeenshowntoreducetheseverity ofCSR-CSA,CSR-CSAisfrequentlyobservedinCHFpatientswith CRT[5–7].Inaddition,theeffectofASVonCSR-CSAremainedafter CRTimplantationhasnotbeenpreviouslystudied.

Therefore,weexaminedwhetherASVimprovedCSR-CSA, car-diacfunction,andprognosisinCHFpatientswithCRT.

Methods

Subjectsandstudyprotocol

In the present study, 22 patients with CHF and CSR-CSA whohadimplantedCRTwithdefibrillator(CRTD)wereenrolled. At 12 months after CRTD implantation, polysomnography was performed.Theinclusioncriteriawere(1)thepresenceof symp-tomaticHF, which wasdefined asNew YorkHeart Association (NYHA)classIIorgreater,(2)standardpharmacotherapy(including ACEinhibitors,angiotensinIIreceptorblockers,␤-blockers, aldos-teroneantagonists,anddiuretics)basedonaguideline,(3)stable clinicalstatus, whichwasdefined asreceivingoptimalmedical therapyandwithoutworseningofCHFforatleast6monthsprior tostudyenrollment,and(4)diagnosedashavingmoderate-severe CSR-CSA,whichwasdefinedasapnea-hypopneaindex(AHI)>15 [5–7]. Theexclusion criteriawere(1) age<20or >80years, (2) severevalvularheartdisease,(3)thepresenceofseverechronic pulmonarydisease,(4)ondialysis,and(5)historyofstrokewith neurologicaldeficit[5–7].Thepatientswererandomlyassigned into2groupsbylotmethod:11patientstreatedwithASV(ASV group) and 11 patientstreated without ASV (non-ASV group). Writteninformedconsentwasobtainedfromallstudysubjects. The study protocol was approved by theethical committee of FukushimaMedicalUniversity.

PlasmaB-typenatriureticpeptide(BNP)levels(before3,and 6 monthslater) and echocardiographicparameters (before and 6 monthslater)were determinedin each group.Patients were followed upfor cardiac eventsincluding cardiacdeath and re-hospitalizationduetoworseningofheartfailureafterdischarge. Polysomnography

Allsubjectsunderwentovernightpolysomnographywiththe useofstandard techniquesandscoringcriteriafor sleepstages and arousals from sleep as previously reported [9,10]. Briefly, overnight complete polysomnography was performed using a computerizedsystem(Alice5,PhilipsRespironics,Murrysville,PA, USA)thatconsistedofmonitoringoftheelectro-encephalogram, electro-oculogram, submental electromyogram, electrocardio-gram,thoracoabdominalmotion,oronasalairflowby anairflow pressuretransducer,andarterialoxyhemoglobinsaturation(SPO2) bypulseoximetry[9,10].Sleep-disorderedbreathing specialists analyzedthedata.Apneawasdefinedasanabsenceof inspira-tionwithoutribcageand abdominalmotionformorethan 10s. Hypopneawasdefinedasa>30%reductioninmonitoredairflow accompaniedbyadecreaseinSaO2of>4%[9,10].Arousalresponses weredefinedaccordingtotherecommendationsoftheAmerican SleepDisordersAssociation.TheAHIwasdefinedasthenumberof apneaandhypopneaepisodesperhourofsleep.Acentralapnea wasdefinedastheabsenceoforonasalairflowfor>10sassociated withanabsentinspiratoryeffort.ACSR-CSAeventwasconsidered whenpolysomnographyrevealed awaxing andwaningpattern ofventilationwithanarousalatpeakventilation,followedbya periodofapneawithabsenceofrespiratoryeffort[9,10].Finally,

CSR-CSAwasdefinedasAHIover15times/h,andaratioofCSR-CSA tototal apnea eventsover 50%[8,9,19].The major polysomno-graphic parameters investigatedwere AHI,central apnea index (CAI),obstructiveapneaindex(OAI),minimalpulseoxygen satura-tion(MinSPO2),3%oxidativedesaturationindex(3%ODI),arousal index,slow wavesleep(SWS),total sleeptime(TST),rapideye movement(REM)sleep/TST(%),%time<SPO290%/TST(CT90),and %time<SPO295%/TST(CT95)aspreviouslyreported[9,10]. Echocardiography

Echocardiography was performed using the standard tech-niquesaspreviously reported[9,10].Twodimensional echocar-diographicimageswereacquiredfromtheparasternallongand shortaxis,apicallongaxis,andapicalfourchamberviewsbyan experiencedechocardiographerwhowasblindtothepatients’ clin-icaldata.Weexaminedleftventricularend-diastolicvolumeindex (LVEDVI),leftventricularend-systolicvolumeindex(LVESVI),left ventricularejectionfraction(LVEF),leftatrialvolumeindex(LAVI), estimatedrightventricularsystolicpressure(RVPS),andtheratio ofthepeaktransmitralvelocityduringearlydiastoletothepeak mitralvalveannularvelocityduringearlydiastole(E/E).LVEDVI, LVESVI,andLVEFwerecalculatedbyamodificationofSimpson’s method.TheratioofE/E wascalculatedbytransmitralDoppler flowandtissueDopplerimaging.Allrecordingswereperformed on the ultrasound system(Acuson Sequoia, Siemens,Erlangen, Germany)[19].

MeasurementofplasmaB-typenatriureticpeptidelevel

PlasmaBNPlevelwasmeasuredusingaspecific immunoradio-metricassay(ShionoriaBNPkit,Shionogi,Osaka,Japan)asreported previously[9,10].

Settingofadaptiveservoventilation

We used two types of ASV (HEART PAP or BiPAP autoSV, PhilipsRespironics)asreportedpreviously[9,10].Then,patients underwent a titration of the device overnight attended by polysomnography.Atthetimeoftitration,wesetexpiratory pos-itiveairwaypressuretoeliminateobstructiveapnea,andnextset pressuresupportandinspiratorypositiveairwaypressureto elim-inateCSR-CSA[9,10].

Statisticalanalysis

Data arepresentedasmean+SD,unlessotherwise statedfor continuous variables. Weused thechi-squaretest for categori-calvariablesandtheindependentt-testforcontinuousvariables betweentwogroups.LevelsofBNParepresentedasmedians(inter quartile range)and analyzedbythe Mann–WhitneyUtest and Wilcoxonsigned-ranktest.Event-freeratewasanalyzedbythe Kaplan–Meiermethodandcomparedbythelog-ranktest.Avalue ofp<0.05wasconsideredsignificantforallcomparisons.All analy-seswereperformedusingastatisticalsoftwarepackage(StatView version5.0,SASInstituteInc.,AbacusConcepts,Berkeley,CA,USA). Results

Clinicalcharacteristicsofstudysubjects

TheclinicalcharacteristicsoftheASVandnon-ASVgroupsare showninTable1.CRTresponderwasdefinedasreductionofLVESVI morethan15%postCRTimplantationover6months[11].There werenodifferencesinbaselineclinicaldatasuchasage,gender,

Table1

ComparisonsofclinicalcharacteristicsbetweenASVandNon-ASVgroups.

ASV(n=11) Non-ASV(n=11) p-Value Physical Age(years) 62.5±8.0 61.5±14.5 0.86

Male(n,%) 10(90.9) 10(90.9) –

NYHA(I/IIs/IIm/III/IV) 0/0/4/7/0 0/0/4/6/1 0.58 Etiology Dilatedcardiomyopathy(n,%) 8(72.7) 7(63.6) 0.65 Ischemic(n,%) 2(18.2) 3(27.3) 0.61 Congenital(n,%) 1(9.1) 1(9.1) –

CRTresponder 6(54.5) 6(54.5) –

Medication ACEinhibitors(n,%) 8(72.7) 7(63.6) 0.65

ARBs(n,%) 2(18.2) 2(18.2) – ␤-Blockers(n,%) 11(100) 11(100) – Diuretics(n,%) 11(100) 11(100) – Aldosteroneantagonist(n,%) 9(81.8) 10(90.9) 0.53 Digitalis(n,%) 0(0) 1(9.1) – Amiodarone(n,%) 9(81.8) 8(72.7) 0.61 Pimobendan(n,%) 4(36.4) 3(27.3) 0.65 Laboratorydata BNP(pg/ml) 482.0(530.1) 385.0(349.0) 0.54 PaO2(mmHg) 98.1±16.6 90.8±16.7 0.33 PaCO2(mmHg) 37.2±4.9 36.6±2.5 0.75 Hb(g/dl) 12.8±2.0 12.1±1.5 0.37 eGFR(ml/min/1.73cm2_{) 59.3±12.2 47.4±19.0 0.21} ECG QRSpreCRT(ms) 144.1±28.8 146.9±25.0 0.86 QRSpostCRT(ms) 138.5±21.1 140.5±21.6 0.82 Af(n,%) 6(54.5) 5(45.5) 0.82

ASV,adaptiveservoventilation;NYHA,NewYorkHeartAssociation;CRT,cardiacresynchronizationtherapy;ACE,angiotensin-convertingenzyme;ARB,angiotensinII receptorblocker;BNP,B-typenatriureticpeptide:median(interquartilerange);eGFR,estimatedglomerularfiltrationratebytheMDRDformula;ECG,electrocardiography.

Table2

Baselineechocardiographicparameters.

ASV Non-ASV p-Value LVEDVI(ml/m2_{) 114.8±48.3 107.5±45.9 0.72} LVESVI(ml/m2_{) 81.7±42.2 78.2±34.8 0.84} LVEF(%) 30.5±13.9 30.2±9.0 0.73 LAVI(ml/m2_{) 50.7±21.0 61.6±23.9 0.29} RVPS(mmHg) 38.1±16.8 40.9±11.7 0.67 E/E _{16.5±6.5 18.0±11.0 0.70}

ASV,adaptive servoventilation;LVEDVI, left ventricularend-diastolicvolume index;LVESVI,leftventricularend-systolicvolumeindex;LVEF,leftventricular ejec-tionfraction;LAVI,leftatrialvolumeindex;RVPS,rightventricularsystolicpressure; E/E,aratioofthepeaktransmitralvelocityduringearlydiastoletothepeakmitral valveannularvelocityduringearlydiastole.

NYHA functional status,etiologies of heartfailure, CRT respon-ders,medications,andlaboratorydataincludingplasmaBNPlevels betweentheASVandnon-ASVgroups.

Baselinedataof echocardiographyareshown inTable 2.All echocardiographic parameters including LVEDVI, LVESVI, LVEF, LAVI,RVPS,andE/E weresimilarbetweentheASVandnon-ASV groups.

Resultsofpolysomnographicrecordingsatthetimeof enroll-ment(baseline)areshowninTable3.Baselinepolysomnographic datawerenotsignificantlydifferentbetweentheASVandnon-ASV groups.

Changesinmedicationatbaselineand6monthslaterareas follows:IntheASVgroup,diureticswerereducedin4patients,and wereincreasedin2patients.Inthenon-ASVgroup,diureticswere reducedin1patient,andwereincreasedin6patients.Furthermore, pimobendanwasaddedin3patientsinthenon-ASVgroup. Effectsofadaptiveservoventilationonpolysomnographicdata

In the ASV group, allpatients were successfully titrated on ASV.ChangesinpolysomnographicdataatbaselineandonASV intheASVgroupareshowninTable3.AHI(p<0.01),CAI(p<0.01),

arousalindex(p<0.01),3%ODI(p<0.01),lowestSPO2 (p<0.01), CT90(p=0.02),andCT95(p<0.01),butnotOAI,SWS,REMsleep, andsleepefficacy,weresignificantlyimprovedonASV.

After6monthswithASV,complianceand efficacydatawere downloadedfromtheASVdevice.TherecordedaverageAHIwas 4.6±2.0times/h,meandevice%usageofdayswasmean82.3%of days,meanusagetimewas324.5min/day,and4h>usage(aratio oftheusedaysmorethan4h)was65.6%.

Effectsofadaptiveservoventilationoncardiacfunction

In the ASV group, plasma BNP levels were significantly decreased from baseline to 3months [482 (530)pg/ml vs. 252 (373)pg/ml, p<0.05], and 6 months [482 (530)pg/ml vs. 221 (217)pg/ml,p<0.01]asshowninFig.1.However,plasmaBNP lev-elswerenotchangedfrombaselineto6months[385(349)pg/ml vs.388(628)pg/ml,n.s.]inthenon-ASVgroup.

Thetimecourseofcardiacfunctiondeterminedby echocardi-ographyisshowninTable4.LVESVIwasdecreasedandLVEFwas increasedinbothgroupsafter6months.RVPSwasdecreasedin theASVgroup(p=0.04),butnotinthenon-ASVgroup.E/E was significantlyimprovedinonlytheASVgroup(p<0.01).

Comparisonsofevent-freeratebetweentheASVandnon-ASV groups

Duringthefollow-upperiod(mean349days,rangeof185–985 days), there were 7 re-hospitalizations for worsening of heart failure. In the ASV and non-ASV groups, 1 patient and 6 patientswere re-hospitalized,respectively. Asshown in Fig.2, Kaplan–Meieranalysisdemonstratedthatevent-freeratewas sig-nificantly higher in theASV group than in thenon-ASV group (p<0.05).

Table3

PolysomnographicdataatbaselineandonASV.

Baseline On-ASV p-Value

AHI(times/h) ASV Non-ASV

39.0±20.7 33.0±17.8

5.9±6.3 <0.01 CAI(times/h) ASV

Non-ASV

14.8±13.6 19.2±19.3

0.6±1.5 <0.01 OAI(times/h) ASV

Non-ASV

1.3±3.0 5.3±7.1

0.5±1.3 0.07 Arousalindex ASV

Non-ASV

21.9±4.2 27.8±13.9

13.6±6.6 <0.01 3%ODI(times/h) ASV

Non-ASV

30.5±19.6 18.8±15.8

3.3±3.7 <0.01 LowestSPO2(%) ASV

Non-ASV 77.3±12.0 85.8±7.3 87.8±8.9 <0.01 CT90(%) ASV Non-ASV 20.4±24.3 3.9±5.1 1.9±4.1 0.02 CT95(%) ASV Non-ASV 50.8±40.3 17.4±19.7 15.6±27.6 <0.01 SWS(%) ASV Non-ASV 2.2±2.0 2.1±3.9 8.9±13.7 0.12 REMsleep(%) ASV

Non-ASV

22.1±6.4 15.3±5.2

16.9±4.9 0.26 Sleepefficacy(%) ASV

Non-ASV

76.0±10.6 61.3±8.3

75.0±11.5 0.93

ASV,adaptiveservoventilation;AHI,apnea-hypopneaindex;CAI,centralapneaindex;OAI,obstructiveapneaindex;ODI,oxidativedesaturationindex;LowestSPO2,lowest

oxyhemoglobinsaturation;CT90,%time<SPO290%/totalsleeptime;CT95,%time<SPO295%/totalsleeptime;SWS,slowwavesleep;REM,rapideyemovement.

ASV

No

n-AS

V

Baseline 3 months 6 months

0 200 400 600 800 1000 1200 1400 1600

Baseline 3 months 6 months

P<0.01

P<0.05

Median 482 (530) 252 (373) 221 (217) Median 385 (349) 286 (385) 388 (628)

(pg/ml)

(pg/ml)

(inter quartile range)

Fig.1. ChangesinplasmaB-typenatriureticpeptide(BNP)levels:Comparisonsbetweenadaptiveservoventilation(ASV)andnon-ASVgroupsatbaseline,3,and6months. LevelsofBNParepresentedasmedians(interquartilerange)andanalyzedbytheMann–WhitneyUtestandWilcoxonsigned-ranktest.

0 20 40 60 80 100 0 1000 Follow up period

Event free rate (%)

(days) ASV (n=11)

Non-ASV (n=11)

Log rank P<0.05

500

Fig.2.Kaplan–Meieranalysisforallcardiaceventsbetweenpatientsinadaptive servoventilation(ASV)andnon-ASVgroups.

Discussion

Inthepresentstudy,theeffectsofASVonCSR-CSA,cardiac func-tion,andprognosisofCHFpatientswithCRTwereexamined.ASV treatmentduringsleepreducedplasmaBNPlevels,RVPS,andE/E inCHFpatientswithCSR-CSAafterCRT,suggestingthatcardiac overloadanddiastolicfunctionswereamelioratedinCHFpatients withCRTbyASVtreatment.Furthermore,theevent-freerateinthe ASVgroupwassignificantlyhigherthanthatinthenon-ASVgroup inCHFpatientspostCRTDimplantation.

CRTtotreatCSR-CSA

EffectivetherapiesforCHFsuchasoptimalpharmacotherapy includingACEinhibitorsand␤-blockersandCRTpartiallyimprove theseverityofCSR-CSA,buttheeffectsofsuchtherapiesforCHFare notsufficienttotreatCSR-CSA[12–14].Sinhaetal.reportedthat

Table4

Changesindataofechocardiographyafter6months.

Baseline 6months p-Value LVEDVI(ml/m2₎ ASV 114.8±48.3 89.0±48.6 0.06 Non-ASV 107.5±45.9 87.6±49.1 0.07 LVESVI(ml/m2₎ ASV 81.7±42.2 56.3±36.1 0.04 Non-ASV 78.2±34.7 62.1±38.2 0.03 LVEF(%) ASV 30.5±13.9 36.0±11.2 0.03 Non-ASV 30.2±9.0 32.2±8.8 0.02 LAVI(ml/m2₎ ASV 50.7±21.0 45.6±17.1 0.39 Non-ASV 61.6±23.9 56.7±20.3 0.67 RVPS(mmHg) ASV 38.1±16.8 27.4±18.4 0.04 Non-ASV 40.9±11.7 40.0±12.8 0.43 E/E ASV 16.5±6.5 9.2±4.1 <0.01 Non-ASV 18.0±11.0 16.6±9.3 0.35 ASV,adaptive servoventilation;LVEDVI, left ventricularend-diastolicvolume index;LVESVI,leftventricularend-systolicvolumeindex;LVEF,leftventricular ejec-tionfraction;LAVI,leftatrialvolumeindex;RVPS,rightventricularsystolicpressure; E/E_{,aratioofthepeaktransmitralvelocityduringearlydiastoletothepeakmitral}

valveannularvelocityduringearlydiastole.

CRTimprovedCSAinCHFpatients[12–14].Theirstudysubjects wereCHFpatientswithmildtomoderateCSA(averageAHI19.2/h) beforeCRTimplantation.AlthoughCRTledtoasignificantdecrease inAHIfrom19.2/hto4.6/h(average)at17weeksafterCRT,4out of14patientsstillhadAHI>5/hafterCRT.Inaddition,sinceCRT candidatesareassociatedwithseverelydepressedleftventricular functionandhighrateofCSR-CSA,CSR-CSAisfrequentlyobserved inCHFpatientsafterCRTimplantation.Furthermore,eventhough whenpatientsareselectedaccordingtotheaforementionedCRT criteria,approximately30%donothaveabeneficialresponsefor improvingheart failure[11].In thepresent study,CRT respon-derswere54.5% and tendedtobelower thanusually reported inbothgroups.Takentogether,thesedatasuggestthatCSR-CSA remainsevenafteroptimalmedicationandCRTimplantation,and specifictherapyforCSR-CSAincludingASVisrequiredtotreatsuch patients.Therefore,weexaminedtheeffectsofASVonCSR-CSA, cardiacfunction,andprognosisofCHFpatientswithCRTinthe presentstudy.Wedemonstratedforthefirsttime,tothebestof ourknowledgethatASV improvedcardiacfunctionand clinical outcomesinCHFpatientsafterCRTD.

At12monthsafterCRTDimplantation,polysomnographywas performedinthepresentstudy.Allstudysubjectshadstable clini-calstatus,whichwasdefinedasreceivingoptimalmedicaltherapy andwithoutworseningofCHFforatleast6monthspriortothe studyenrollment.Inthenon-ASVgroup,althoughplasmaBNP lev-elswereunchanged,LVESVIwasreducedandLVEFwasincreased after6months.Thesechangesmightbeexplainedbyalong-term beneficialeffectofCRToncardiacfunctionandventricularreverse remodeling[15].

ASVforCSR-CSAinCHF

Recently,arandomizedcontrolledprospectivestudyintreating CHF andCSR-CSA hasshown that ASVimprovesAHIand com-pliance (average usage time) more effectively than continuous positiveairwaypressure[16].WehaverecentlyshownthatASV improvescardiacsystolicanddiastolicfunctionaccompaniedby areductioninleftventricularvolume[16].Ourpresentdatawere concordantwithapreviousreportbyOldenburgetal.showingthat ASVimprovedLVEF(28.2–35.2%)[8].ASVimprovescardiac func-tionregardlessofsleep-disorderedbreathing severityandtype.

WehavealsodemonstratedthatASVimprovestheevent-freerate inpatientswithCHFandCSR-CSA[19].Inthepresentstudy,we studied22patientswithAHI>15/hatleast12monthsafterCRT implantation.

SeveralpossiblemechanismsforASVtoimproveCHFand CSR-CSAhavebeensuggested:(1)reducetheupperairwayobstruction, (2)increaseend-expiratorypulmonaryvolumeandalveolar pres-sure,(3) assist inspiratorymuscles [16],(4) reduce cardiacpre andafterload[17],(5)decreaseleftventricularvolume[18,19], (6)attenuatesympatheticnervousactivityresultinginthe sup-pressionoflethalarrhythmias,and (7)anti-inflammatoryeffect [20].Inthepresentstudy,ASVmighthaveimprovedCSR-CSA, car-diacfunction,andevent-freesurvivalofCHFpatientswithCRTby thesemechanisms.Inparticular,attenuationofsympathetic ner-vousactivitymightleadtodecreasingtherateofre-hospitalization duetoworseningofCHF.ASVshouldbeusedtotreatCSR-CSAin CHFpatientswithCRT.

Studylimitations

Thenumbersofstudysubjectsweresmall,sincethisstudywas performedinasingleinstitution.Patientswererandomlyassigned intotwogroupsinthepresentstudy.Clinicalbackground, labo-ratory,andechocardiographicdataweresimilarbetweenthetwo groups.Polysomnographicdatatendedtobesomewhatworsein theASVgroupcomparedtothenon-ASVgroup,althoughthese werenotstatisticallysignificant.Inthisstudy,sinceweexamined CHFpatientsmorethan12monthsafterCRTDimplantation,we cannotcompletelydenytheinfluenceofCRT.Furtherstudieswith alargerpopulationarenecessarytoestablishASVasapromising therapyforCHFwithCRT.

Conclusions

ASVimprovesCSR-CSA,cardiacsystolicanddiastolicfunction, and event-free survival in CHF patients with CRT. After CRTD implantation,CHFpatientswithCSR-CSAareatincreasedriskof re-hospitalizationandmaywarrantadditionaltherapywithASV. Acknowledgment

Thisstudywassupportedinpartbygrants-in-aidforScientific Research(Nos.21590935and21790737)fromJapanSocietyforthe PromotionofScience.

References

[1]Effectsofenalaprilonmortalityinseverecongestiveheartfailure.Resultsof

theCooperativeNorthScandinavianEnalaprilSurvivalStudy(CONSENSUS).

TheCONSENSUSTrialStudyGroup.NEnglJMed1987;316:1429–35.

[2]PfefferMA,StevensonLW.Beta-adrenergicblockersandsurvivalinheart

fail-ure.NEnglJMed1996;334:1396–7.

[3]PittB.Effectofaldosteroneblockadeinpatientswithsystolicleft

ventricu-lardysfunction:implicationsoftheRALESandEPHESUSstudies.MolCell

Endocrinol2004;217:53–8.

[4]FurukawaT,SuzukiM,FunatogawaI,IsshikiT,MiyazawaY,TeramotoT,Yano

E.Screeningmethodforseveresleep-disorderedbreathinginhypertensive

patientswithoutdaytimesleepiness.JCardiol2009;53:79–85.

[5]SinDD,FitzgeraldF,ParkerJD,NewtonG,FlorasJS,BradleyTD.Riskfactorsfor

centralandobstructivesleepapneain450menandwomenwithcongestive

heartfailure.AmJRespirCritCareMed1999;160:1101–6.

[6]WangH,ParkerJD,NewtonGE,FlorasJS,MakS,ChiuKL,RuttanaumpawanP,

TomlinsonG,BradleyTD.Influenceofobstructivesleepapneaonmortalityin

patientswithheartfailure.JAmCollCardiol2007;49:1625–31.

[7]JavaheriS,ShuklaR,ZeiglerH,WexlerL.Centralsleepapnea,rightventricular

dysfunction,andlowdiastolicbloodpressurearepredictorsofmortalityin

systolicheartfailure.JAmCollCardiol2007;49:2028–34.

[8] OldenburgO,SchmidtA,LampB,BitterT,MunteanBG,LangerC,HorstkotteD.

Adaptiveservoventilationimprovescardiacfunctioninpatientswithchronic

[9]SulgIA.ManualEEGanalysis.ActaNeurolScand1969;45:431–58.

[10]EEGarousals:scoringrulesandexamples:apreliminaryreportfromtheSleep

DisordersAtlasTaskForceoftheAmericanSleepDisordersAssociation.Sleep

1992;15:173–84.

[11]BaxJJ,AbrahamT,BaroldSS,BreithardtOA,FungJW,GarrigueS,Gorcsan3rd

J,HayesDL,KassDA,KnuutiJ,LeclercqC,LindeC,MarkDB,MonaghanMJ,

NihoyannopoulosP,etal.Cardiacresynchronizationtherapy:part1—issues

beforedeviceimplantation.JAmCollCardiol2005;46:2153–67.

[12] TamuraA,KawanoY,KadotaJ.Carvedilolreducestheseverityofcentralsleep

apneainchronicheartfailure.CircJ2009;73:295–8.

[13] TamuraA,KawanoY,NaonoS,KotokuM,KadotaJ.Relationshipbetween

beta-blockertreatmentandtheseverityofcentralsleepapneainchronicheart

failure.Chest2007;131:130–5.

[14]SinhaAM,SkobelEC,BreithardtOA,NorraC,MarkusKU,BreuerC,HanrathP,

StellbrinkC.Cardiacresynchronizationtherapyimprovescentralsleepapnea

andCheyne-Stokesrespirationinpatientswithchronicheartfailure.JAmColl

Cardiol2004;44:68–71.

[15]LindeC,AbrahamWT,GoldMR,StJohnSuttonM,GhioS,DaubertC.

Ran-domizedtrialofcardiacresynchronizationinmildlysymptomaticheartfailure

patientsandinasymptomaticpatientswithleftventriculardysfunctionand

previousheartfailuresymptoms.JAmCollCardiol2008;52:1834–43.

[16]KasaiT,UsuiY,YoshiokaT,YanagisawaN,TakataY,NaruiK,YamaguchiT,

YamashinaA,MomomuraSI,JASVInvestigators.Effectofflow-triggered

adap-tiveservo-ventilationcomparedwithcontinuouspositiveairwaypressurein

patientswithchronicheartfailurewithcoexistingobstructivesleepapneaand

Cheyne-Stokesrespiration.CircHeartFail2010;3:140–8.

[17]ShirakabeA,HataN,YokoyamaS,ShinadaT,KobayashiN,TomitaK,Kitamura

M,NozakiA,TokuyamaH,AsaiK,MizunoK.Predictingthesuccessof

noninva-sivepositivepressureventilationinemergencyroomforpatientswithacute

heartfailure.JCardiol2011;57:107–14.

[18]LanfranchiPA, BraghiroliA,Bosimini E,MazzueroG,ColomboR, Donner

CF,GiannuzziP.PrognosticvalueofnocturnalCheyne-Stokesrespirationin

chronicheartfailure.Circulation1999;99:1435–40.

[19] KasaiT,NaruiK,DohiT,TakayaH,YanagisawaN,DunganG,IshiwataS,Ohno

M,YmaguchiT,MomomuraS.Firstexperienceofusingnewadaptive

servo-ventilationdeviceforCheyne-Stokesrespirationwithcentralsleepapnea

amongJapanesepatientswithcongestiveheartfailure:reportof4clinical

cases.CircJ2006;70:1148–54.

[20]KoyamaT,WatanabeH,KobukaiY,MakabeS,MunehisaY,IinoK,KosakaT,

ItoH.Beneficialeffectsofadaptiveservoventilationinpatientswithchronic