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RESEARCHOpenAccessNasalcontinuouspositiveairwaypressureimprovesmyocardialperfusionreserveandendothelial-dependentvasodilationinpatientswithobstructivesleepapneaPatriciaKNguyen1*,ChandraKKatikireddy2,MichaelVMcConnell1,CleteKushida3,PhillipCYang1AbstractBackground:Obstructivesleepapnea(OSA)hasbeenassociatedwithcardiovasculardisease(CVD),butwhetherOSAisanindependentriskfactorforCVDiscontroversial.
ThepurposeofthisstudyistodetermineifpatientswithOSAhavesubclinicalcardiovasculardiseasethatisdetectablebymulti-modalitycardiovascularimagingandwhethertheseabnormalitiesimproveafternasalcontinuouspositiveairwaypressure(nCPAP).
Results:Ofthe35consecutivesubjectswithnewlydiagnosedmoderatetosevereOSArecruitedfromtheStanfordSleepDisordersClinic,20patientswererandomizedtoactivevs.
shamnCPAP.
ActivenCPAPwastitratedtopressuresthatwouldpreventsleepdisorderedbreathingbasedoninpatientpolysomnography.
OSApatientshadbaselinevascularfunctionabnormalitiesincludingdecreasedmyocardialperfusionreserve(MPR),brachialflowmediateddilation(FMD)andnitroglycerin-inducedcoronaryvasodilation.
PatientsrandomizedtoactivenCPAPhadimprovementofMPR(1.
5±0.
5vs.
3.
0±1.
3,p=0.
02)andbrachialFMD(2.
5%±5.
7%vs.
9.
0%±6.
5%,p=0.
03)aftertreatment,butthoserandomizedtoshamnCPAPshowednosignificantimprovement.
Therewerenosignificantchangesseeninchambersizes,systolicanddiastolicfunction,valvularfunctionandcoronaryvasodilationtonitroglycerin.
Conclusions:PatientswithmoderatetosevereOSAhaddecreasedMPRandbrachialFMDthatimprovedafter3monthsofnCPAP.
ThesefindingssuggestthatreliefofapneainOSAmayimprovemicrovasculardiseaseandendothelialdysfunction,whichmaypreventthedevelopmentofovertcardiovasculardisease.
Furtherstudyinalargerpatientpopulationmaybewarranted.
BackgroundObstructivesleepapnea(OSA)hasbeenassociatedwithanincreasedincidenceofcardiovasculardisease(CVD)andthesepatientsare,thus,likelytohaveahighburdenofsubclinicaldisease[1,2].
However,theextentofsub-clinicalCVDhasnotbeensystematicallyevaluated.
Previousstudieshaveusedsinglemeasuresofsubclinicaldisease[3-7].
Inaddition,whetherOSAplaysaninde-pendentroleinthedevelopmentofCVDremainscon-troversialsincemostpreviousstudiesarecrosssectionalandnotrandomized,and,thus,maynotadequatelycontrolforconfoundingfactors.
Weusemulti-modalitycardiovascularimaging(CVI)toevaluatesubclinicalCVDinpatientswithOSAbeforeandafterrandomizationtoactiveorshamnasalcontin-uouspositiveairwaypressure(nCPAP).
Wewill(1)determinethefrequencyofsubclinicalCVDusingmulti-modalityimaginginadultswithnewlydiagnosedmoderatetosevereOSAand(2)testthehypothesisthatnCPAPtherapy,thestandardtreatmentforOSA,improvestheseabnormalities.
*Correspondence:pnguyen@cvmed.
stanford.
edu1DepartmentofMedicine,DivisionofCardiovascularMedicine,StanfordUniversity,Stanford,CA,USAFulllistofauthorinformationisavailableattheendofthearticleNguyenetal.
JournalofCardiovascularMagneticResonance2010,12:50http://www.
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com/content/12/1/502010Nguyenetal;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
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0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
MethodsSubjectsAtotalof35consecutivepatientswererecruitedfromthepatientpopulationseenattheStanfordSleepDisor-dersClinic.
Theinclusioncriteriainclude:1)newlydiag-nosedmoderatetosevereOSAasdefinedbytheAmericanAcademyofSleepMedicine[8],2)RDI≥15eventsperhourbyinpatientpolysomnography,and3)EpworthSleepinessScalescore>10.
Theexclusioncri-teriainclude:1)priortreatmentforOSA,2)anoxygensaturation10%ofthediagnosticsleepstudyor25%ofthefirst4hoursofthediagnosticsleepstudy,3)clinicalsymptomsordiagnosisofcoron-aryarterydisease,congestiveheartfailure,cardiacrhythmdisturbance,Raynaud'sdisease(whichisacon-traindicationforflowmediateddilation),respiratorydis-ease,diabetes,chronicneurologicaldisorders,cancernotinremission,andrenalfailure,4)metalobjects,devicesorimplantsinoronthebodyincludingpacemakers,aneurysmclips,prostheses,bullets,buckshot,shrapnel,andanymetalfragmentsfromworkingaroundmetal(whicharecontraindicationsforcardiovascularmagneticresonanceimaging)and5)contraindicationstoadeno-sineornitroglycerin.
Sevenparticipantsfailedtheinitialscreeningforeligibility,and8withdrewpriortorando-mization.
TheStanfordInstitutionalReviewBoardapprovedthestudy.
Allsubjectsgavewritteninformedconsent.
Recruitment,RandomizationandBlindingSubjectswereidentifiedforrecruitmentafterundergoingastandardovernightinpatientrespiratorypolysomno-graphicsleepstudy.
Thediagnosticpolysomnogramservedasthebaselinemeasure.
Patientsalsocompletedastandardquestionnairetoevaluatethedegreeofsleepi-nessandunderwentbaselineechocardiography,cardiacmagneticresonanceimaging,andvascularultrasound.
Afterbaselineassessments,subjectswererandomizedtoeitheractive(therapeutic)orsham(subtherapeutic)nCPAPandthenadmittedforasecondnightofpolysom-nographyfornCPAPtitration.
DuringthenCPAPtitra-tionnight,ifpatientswererandomizedtoactivenCPAP,pressureswerevariedthroughoutthenighttocontrolthepatients'sleepdisorderedbreathing.
ForthoseonshamnCPAP,pressuresfluctuatedslightlybutnomorethan0.
5cmH2Opressure,whichwasachievedbyinsertingaflowrestrictingconnectoratthemachineoutletandsixextra4mmholesinthecollarofthemaintubingattheendofthemasktoallowairtoescapeandtopreventre-breathingofcarbonmonoxide.
AcertifiedtechnicianreviewedthepolysomnogramsthenextdaytodeterminetheoptimaltherapeuticpressuretocontrolsnoringandsleepapneaforpatientsintheactivenCPAPgroup.
PatientsassignedtoshamnCPAPreceivedasimilarnCPAPdevicebutthemachinedeliveredairpressureinsufficienttopreventsleepdisorderedbreathing.
Inallotherways,thenCPAPmachinesweresimilar.
Thepatients,techniciansconductingthetitrationstudiesandinvestigatorsassessingtheimagingstudieswerenotawareoftreatmentgroupassignments.
Thus,thestudywaseffectivelydouble-blind.
Within7daysaftertheassessment,thepatientsweregiventheirnCPAPmachinesandinstructedhowtousethemachinesathome.
Studystaffcontactedpatientsmonthlytoassessadherencetothedevices.
Patientsreturnedafterthreemonthsforrepeatpolysomnogramandmulti-modalityCVIstudies.
Informationoncompli-ancewasdownloadedfromtheassignednCPAPmachinesattheendofthestudy.
PolysomnographyOvernightrespiratorypolysomnographicsleepstudieswereperformedatbaseline,fornCPAPtitration,andaftertreatment.
Anobstructedbreathingeventconsistedofanobstructiveapnea,hypopnea,orrespiratoryeffort-relatedarousals[9].
Moderateorsevereapneawasdefinedasarespiratorydisturbanceindex>15eventsperhourofsleep.
EchocardiographyEchocardiographicimageswereobtainedinstandardviewsbythesameexperiencedsonographer(HewlettPackard,Sonos,5500).
LeftventriculardiastolicfunctionandpulmonaryarterialpressurewasassessedbyDop-plerechocardiographyinaccordancewiththeAmericanSocietyofEchocardiographyrecommendations[10].
CardiovascularmagneticresonanceCardiovascularmagneticresonance(CMR)includedanassessmentofstructureandfunction,adenosinestressmyocardialperfusion,andcoronaryarteryvasodilationtonitroglycerin(NTG).
ImaginganalysiswasperformedusingReportCard,theGEsoftware.
Scanswereperformedusinga1.
5TSignaMRscanner(GEHealthcare,Milwaukee,WI)equippedwithhigh-performancegradients(40mT/m,150mT/m/ms).
Acommercial4-channelcardiacphased-arraysurfacecoilprovidedsignalreception(GEHealthcare,Milwau-kee,WI).
Areal-timeinteractivesystem(iDrive,GEHealthcare,Milwaukee,WI)wasusedforlocalization.
AssessmentofcardiacfunctionwasobtainedusinganECG-triggeredretrospectivelygatedcineSSFPsequence(20phasespercardiaccycle,TR=3.
6ms,TE=1.
6ms,FOV=280to390mmandflipangle=40°).
First-passmyocardialperfusionimagingwasperformedusingasegmentedecho-planarimagingpulsesequencewithaNguyenetal.
JournalofCardiovascularMagneticResonance2010,12:50http://www.
jcmr-online.
com/content/12/1/50Page2of10notchedsaturationpulse[11].
Forstressimaging,adeno-sinewasadministeredintravenouslyatarateof140mcg/kg/minfor4minutes,followedbyfirst-passmyocardialperfusionimagingduringintravenousinjec-tionof0.
1mmol/kggadolinium-DPTAatarateof5ml/s.
Restperfusionimageswereacquiredapproxi-mately10minutesafterstressimages.
Thefollowingperfusionpulsesequenceparameterswereused:TR=2.
4ms,TE=1.
2ms,inversiontime=158to211ms,echotrainlength=4to8ms,FOV=34to37*25to27cm,matrix=128*128,flipangle=25°,andslicethickness=10mm.
Therestperfusionimagesweregenerallyacquiredwiththesamegraphicprescriptionusedforthestressimages.
Foranalysisofmyocardialperfusion,signalintensitywasdeterminedforeachofthethreecontiguousslicesrepresentingthebase,midandapexoftheleftventricle.
Thesignalintensitybeforecontrastagentadministrationwassubtracted,andtheupslopeoftheresultingsignalintensitytimecurvewasdetermined.
Aperfusionscorewasgeneratedbyaddingtheupslopeofeachofthethreeslices.
Themyocardialperfusionreserve(MPR)wascalculatedastheratiobetweenthemyocardialperfusionscoreatstressdividedbythemyocardialperfusionscoreatrest.
NTG-inducedcoronaryvasodilationwasthenper-formed.
Usingareal-timeinteractivesystem,in-planeviewsoftherightcoronaryartery(RCA)wereprescribed.
Across-sectionalviewofthemostlinearportionoftheproximaltomidRCAwasprescribed.
Multi-slicehigh-resolutionspiralcoronarymagneticresonanceangiogra-phywasperformedwithcardiacgating,breath-holding,andacquisitionduringdiastole(FOV=22cm,in-planespatialresolution=0.
7mm,slicethickness=5mm,3slices,TR=1heartbeat,TE=2.
5ms,18interleaves,andflipangle=60°).
Cross-sectionalspiralhigh-resolu-tioncoronarymagneticresonanceangiographyimages[12]wereacquiredbeforeand5minutesafteradminis-trationof0.
4mgsublingualNTGwhilethepatientwasinsidethemagnet.
Usingthecross-sectionalRCAimages,themostcircu-larandcorrespondingsliceswereidentifiedonthepre-andpost-NTGimages.
Theseimageswereallpooledandthenrandomized,withneitherpatientnorNTGinformationprovidedontheimages.
Weusedacustomdesignedsoftwareprogramtoanalyzethecrosssectionalimages.
Imagesweremagnifiedtwo-fold,andanovoidregionofinteresttoolwasusedtotracearoundtheRCA,yieldingthecross-sectionalarea.
VascularUltrasoundEndothelialfunctionwasassessednon-invasivelyusingvascularultrasoundtomeasurebrachialarteryflowmediateddilation(FMD)followingreactivehyperemiainaccordancewithpublishedguidelines[13].
Studieswereperformedbyoneoftwotrainedoperators.
Studieswereperformedatthesametimeofdayandinthefast-ingstate.
Vasoactivemedicationswereheld24hourspriortothestudy.
Brachialarterydiametersweremeasuredusinganautomatedsoftwaresystemtodetectnearandfarwalledgesandmeasurevesseldiameterforeachframeinthe10-secondloop(VascularAnalysisTools,MedicalIma-gingApplications,Iowa,USA).
Allanalyseswereper-formedbyoneoftwotrainedoperators.
Previousreproducibilitystudiesindicatehighoperatoragreement.
SampleSizeCalculationThesamplesizewasestimatedbasedonapreviousran-domizedstudycomparingFMDinpatientswithmoder-atetosevereOSArandomizedto3monthsofnCPAPandnonCPAP[14].
FMDwassignificantlylowerinpatientsrandomizedtonCPAP(nCPAP8.
9±1.
9%,nonCPAP5.
0±0.
7%,p=0.
02).
Usingatwotaileda=0.
01andpowerof0.
90,anattritionrateof20%,theesti-matedsamplesizeis10subjectspereachgroup(totalnumberofsubjectsis20).
StatisticalAnalysisContinuousvariableswerereportedasmeanswithstan-darddeviations.
Categoricalvariableswerereportedasfrequenciesandcounts.
Standardthresholdsforabnor-malvalueswereusedforallparameters.
AnMPR70%)hadaflowreservelessthan2.
5[15].
AnMPRof0.
75and1cm/s10%(1/10)0%(0/10)10%(1/10)20%(2/10)pvalue1.
01.
01.
00.
25E/Aratio≤0.
7540%(4/10)10%(1/10)0%(0/10)20%(2/10)>0.
75&240ms40%(4/10)20%(2/10)10%(1/10)30%(3/10)pvalue0.
620.
331.
001.
00E'≤8cm/s11%(1/9)20%(2/10)11%(1/9)40%(4/10)>8cm/s89%(8/9)80%(8/10)89%(8/9)60%(6/10)pvalue0.
920.
301.
000.
25E/e'150%(0/10)0%(0/10)0%(0/10)0%(0/10)pvalue0.
900.
660.
50.
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doi:10.
1186/1532-429X-12-50Citethisarticleas:Nguyenetal.
:Nasalcontinuouspositiveairwaypressureimprovesmyocardialperfusionreserveandendothelial-dependentvasodilationinpatientswithobstructivesleepapnea.
JournalofCardiovascularMagneticResonance201012:50.
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