TIMI Frame Count and Adverse Events in Women with No Obstructive Coronary Disease: A Pilot Study fro mthe NHLBI-Sponsore...

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Title:
TIMI Frame Count and Adverse Events in Women with No Obstructive Coronary Disease: A Pilot Study fro mthe NHLBI-Sponsored Women's Ischemia Syndrome Evaluation (WISE)
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Journal Article
Creator:
Petersen, John W.
Johnson, B. Delia
Kip, Kevin E.
Anderson, R. David
Handberg, Eileen M.
Sharaf, Barry
Mehta, Puja K.
Kelsey, Sheryl F.
Merz, C. Noel Bairey
Pepine, Carl J.
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Public Library of Science (PLoS ONE)
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Background: TIMI frame count (TFC) predicts outcomes in patients with obstructive coronary artery disease (CAD); it remains unclear whether TFC predicts outcomes in patients without obstructive CAD. Methods: TFC was determined in a sample of women with no obstructive CAD enrolled in the Women’s Ischemia Syndrome Evaluation (WISE) study. Because TFC is known to be higher in the left anterior descending artery (LAD), TFC determined in the LAD was divided by 1.7 to provide a corrected TFC (cTFC). Results: A total of 298 women, with angiograms suitable for TFC analysis and long-term (6–10 year) follow up data, were included in this sub-study. Their age was 55611 years, most were white (86%), half had a history of smoking, and half had a history of hypertension. Higher resting cTFC was associated with a higher rate of hospitalization for angina (34% in women with a cTFC .35, 15% in women with a cTFC #35, P,0.001). cTFC provided independent prediction of hospitalization for angina after adjusting for many baseline characteristics. In this cohort, resting cTFC was not predictive of major events (myocardial infarction, heart failure, stroke, or all-cause death), cardiovascular events, all-cause mortality, or cardiovascular mortality. Conclusions: In women with signs and symptoms of ischemia but no obstructive CAD, resting cTFC provides independent prediction of hospitalization for angina. Larger studies are required to determine if resting TFC is predictive of major events in patients without obstructive coronary artery disease.
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Collected for University of Florida's Institutional Repository by the UFIR Self-Submittal tool. Submitted by Haeden Roberson.
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TIMIFrameCountandAdverseEventsinWomenwithNo ObstructiveCoronaryDisease:APilotStudyfromthe NHLBI-SponsoredWomen’sIschemiaSyndrome Evaluation(WISE)JohnW.Petersen1* ,B.DeliaJohnson2,KevinE.Kip3,R.DavidAnderson1,EileenM.Handberg1, BarrySharaf4,PujaK.Mehta5,SherylF.Kelsey2,C.NoelBaireyMerz5,CarlJ.Pepine11 DivisionofCardiovascularMedicine,UniversityofFlorida,Gainesville,Florida,UnitedStatesofAmerica, 2 GraduateSchoolofPublicHealth,UniversityofPittsburgh, Pittsburgh,Pennsylvania,UnitedStatesofAmerica, 3 CollegeofNursing,UniversityofSouthFlorida,Tampa,Florida,UnitedStatesofAmerica, 4 DivisionofCardiology, BrownUniversity,Providence,RhodeIsland,UnitedStatesofAmerica, 5 DivisionofCardiology,BarbraStreisandWomen’sHeartCenter,HeartInstitute,Cedars-Sinai MedicalCenter,LosAngeles,California,UnitedStatesofAmericaAbstractBackground:TIMIframecount(TFC)predictsoutcomesinpatientswithobstructivecoronaryarterydisease(CAD);it remainsunclearwhetherTFCpredictsoutcomesinpatientswithoutobstructiveCAD.Methods:TFCwasdeterminedinasampleofwomenwithnoobstructiveCADenrolledintheWomen’sIschemiaSyndrome Evaluation(WISE)study.BecauseTFCisknowntobehigherintheleftanteriordescendingartery(LAD),TFCdeterminedin theLADwasdividedby1.7toprovideacorrectedTFC(cTFC).Results:Atotalof298women,withangiogramssuitableforTFCanalysisandlong-term(6–10year)followupdata,were includedinthissub-study.Theiragewas55 6 11years,mostwerewhite(86%),halfhadahistoryofsmoking,andhalfhada historyofhypertension.HigherrestingcTFCwasassociatedwithahigherrateofhospitalizationforangina(34%inwomen withacTFC 35,15%inwomenwithacTFC # 35,P 0.001).cTFCprovidedindependentpredictionofhospitalizationfor anginaafteradjustingformanybaselinecharacteristics.Inthiscohort,restingcTFCwasnotpredictiveofmajorevents (myocardialinfarction,heartfailure,stroke,orall-causedeath),cardiovascularevents,all-causemortality,orcardiovascular mortality.Conclusions:InwomenwithsignsandsymptomsofischemiabutnoobstructiveCAD,restingcTFCprovidesindependent predictionofhospitalizationforangina.LargerstudiesarerequiredtodetermineifrestingTFCispredictiveofmajorevents inpatientswithoutobstructivecoronaryarterydisease.Citation: PetersenJW,JohnsonBD,KipKE,AndersonRD,HandbergEM,etal.(2014)TIMIFrameCountandAdverseEventsinWomenwithNoObstructive CoronaryDisease:APilotStudyfromtheNHLBI-SponsoredWomen’sIschemiaSyndromeEvaluation(WISE).PLoSONE9(5):e96630.doi:10.1371/journal .pone. 0096630 Editor: AlexanderGObukhov,IndianaUniversitySchoolofMedicine,UnitedStatesofAmerica Received January16,2014; Accepted April9,2014; Published May6,2014 Copyright: 2014Petersenetal.Thisisanopen-accessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense,whichpermits unrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalauthorandsourcearecredited. Funding: ThisworkwassupportedbycontractsfromtheNationalHeart,LungandBloodInstitutes,nos.N01-HV-68161,N01-HV-68162,N01-HV-68163,N01-HV68164,grantsU0164829,U01HL649141,U01HL649241,T32HL69751,1R03AG032631fromtheNationalInstituteonAging,GCRCgrantMO1-RR00425fromthe NationalCenterforResearchResourcesandgrantsfromtheGustavusandLouisPfeifferResearchFoundation,Danville,NJ,TheWomen’sGuildofCedar s-Sinai MedicalCenter,LosAngeles,CA,TheLadiesHospitalAidSocietyofWesternPennsylvania,Pittsburgh,PA,andQMED,Inc.,LaurenceHarbor,NJ,theEd ytheL. BroadWomen’sHeartResearchFellowship,Cedars-SinaiMedicalCenter,LosAngeles,California,theBarbraStreisandWomen’sCardiovascularRese archand EducationProgram,Cedars-SinaiMedicalCenter,LosAngelesandTheSocietyforWomen’sHealthResearch(SWHR),Washington,D.C.Dr.CarlPepinere ceives supportfromtheNIHandNCRRCTSAgrantUL1TR000064.Thefundershadnoroleinstudydesign,datacollectionandanalysis,decisiontopublish,or preparationofthemanuscript. CompetingInterests: Drs.NoelBaireyMerz,EileenHandberg,andCarlPepinedeclarethattheyworkedwithQMED,Inc.,LaurenceHarbour,NJ,acommercial funderforthisstudy,inthecontextofreceivingdigitalHoltermonitorsfreeofchargeforseveralotherWomen’sIschemicSyndromeEvaluation(WIS E)studies. ThisdoesnotalteradherencetoPLOSONEpoliciesonsharingdataandmaterials. *E-mail:john.petersen@medicine.ufl.eduIntroductionWomenwithsymptomsandsignsofischemia,referredfor invasivecoronaryevaluation,oftenhavenoevidenceofobstructivecoronaryarterydisease(CAD)[1].Weandothershave identifiedthatsymptomaticpatientswithnon-obstructiveCAD haveanelevatedriskofadverseoutcomesandall-causemortality comparedwithcohortswithoutsymptomsand/orsignsof ischemicheartdisease[2,3].About45%to60%ofsuchpatients havecoronaryvasculardysregulation(endothelialornon-endothelialdependentmacro-ormicrovasculardysfunction)capableof causingischemiawithinvasiveprovocativetesting[1,4].Additionally,weandothershavelinkedcoronaryvasculardysregulationwithadverseoutcomes.Thus,additionalindicesofcoronary vasomotorfunction,beyondstandardanatomyfromangiography, PLOSONE|www.plosone.org1May2014|Volume9|Issue5|e96630

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wouldbeusefultoimproveriskstratificationofthesepatients[5– 9]. TheThrombolysisinMyocardialInfarction(TIMI)framecount (TFC)providesasimpleangiographicindexofcoronaryblood flowthatdoesnotrequireadditionalcoronaryarteryinstrumentation[10].Theintra-andinter-observerreproducibilityofTFCis good,anddyeinjectionrateandcathetersizedonotaffectits measurement[11,12].TheTFChascorrelatedwithotherinvasive andnon-invasivemeasuresofcoronarybloodflow[13–16]. Further,TFCestimatesofcoronaryflowafterreperfusionfor acutemyocardialinfarctionpredictshort-andlong-termclinical outcomes[17–19].However,theprognosticimplicationofan abnormalTFCinpatientswithoutacutemyocardialinfarctionor obstructiveCADandwithsuspectedmicrovasculardysfunction remainsunclear.Accordingly,weaimedtodetermineifTFCat restispredictiveofadverseoutcomesinpatientswithout obstructiveCAD.Methods PatientsTheWomen’sIschemiaSyndromeEvaluation(WISE)study (clinicaltrials.govIdentifierNCT00000554)isaNationalHeart, LungandBloodInstitute–sponsoredstudyaimedatimproving diagnosticevaluationandunderstandingofpathologicalmechanismsofischemicheartdiseaseinwomen.TheWISEprotocolwas approvedbytherelevantinstitutionalreviewboards(IRB) (UniversityofFloridaIRB,AlleganyGeneralHospitalIRB, UniversityofPittsburghIRB,UniversityofAlabamaatBirminghamIRB),andhaspreviouslybeendescribed[20].Allparticipants providedwritteninformedconsenttoparticipateinthisstudy.The consentprocedureandformwereapprovedbythelocalIRBs listed.Briefly,womenolderthan18yearsofagewithsymptoms andsignsofischemiaundergoingclinicallyindicatedangiograms werefollowedforclinicaloutcomes.Majorexclusioncriteria includedcomorbiditieslikelytocompromisefollowup.Initial evaluationinadditiontocoronaryangiographyincludedcollection ofdemographics,medicalhistory,symptomdata,physical examination,andbloodsamplingforlipids,reproductivehormones,andinflammatorymarkers.CoronaryAngiographyandTIMIframecountsCoronaryangiographywasperformedattheclinicalsites accordingtostandardmethods.Qualitativeandquantitative coronaryangiographicanalyseswereconductedbyacore laboratorymaskedtopatientdata[21].Aspreviouslydescribed, theTFCwasdeterminedasthenumberofcineframesrequired forcontrasttoreachstandardizeddistalcoronarylandmarks[10]. ThefirstframeusedforTFCistheframeinwhichdyefullyenters thearteryofinterest.Thelastframethatiscountedistheframe whendyeentersthedistallandmarkbranch(Figure1).Thedistal landmarkbranchoftheleftanteriordescending(LAD)arterywas thedistalbifurcation.Innormalcoronaries,theTFCintheLAD isonaverage1.7timeslongerthantheTFCintheothercoronary arteries.Therefore,theLADframecountsweredividedby1.7to provideacorrectedTFC(cTFC)[10].Thosepatientswhohadan angiogramrecordedinawaythatallowedthedeterminationof TFCbythecorelabandwerefoundnottohaveobstructiveCAD areincludedinthisanalysis.Follow-upforadverseeventsAfterthebaselineangiogramandcoronaryreactivitytesting,the WISEwomenhadprotocol-directedyearlyfollow-up.During telephonecontact,ascriptedinterviewwascompletedbyan experiencednurseorphysicianattherespectivecenter.Each patientorfamilymemberwasqueriedforoccurrenceofmajor adversecardiaceventsorhospitalizations.Telephonefollow-up wasterminatedatamaximumof8years,withamedianfollow-up of6years.Additionally,afterthephonefollow-upperiod,asecond phaseoffollow-upwasperformedwithasearchoftheNational DeathIndexforthosepatientsstillaliveatlastcontactwhohad notwithdrawnconsent.Thisextendedthefollow-upformortality toapproximately10years.Intheeventofdeath,adeath certificateand/orphysiciannarrativewasobtained.Alldeaths wereadjudicatedascardiovascular(CV)ornon-CVbya committeeofseniorWISEinvestigatorsblindedtoangiographic findings.Womensustainingmultipleeventswerecountedonly onceandbytheinitialevent.StatisticalAnalysisBaselinecharacteristicsaredescribedbymeanandstandard deviationforcontinuousvariablesandpercentagesforcategorical variables.TheKaplan-Meiermethodwasusedtoestimate10-year CVeventsratesbytertilesofcTFC,andcomparedbyuseofthe log-rankstatistic.TodeterminethecTFCcutpointforpredicting hospitalizationforangina,wegeneratedareceiver-operator characteristic(ROC)curveusinglogisticregression.ThecTFC valuecorrespondingtothepointofthecurveclosestto100% sensitivityandspecificitywasselectedandverifiedinsubsequent runsofincrementalcut-pointsnearthatvalue.MultivariateCox proportionalhazardsregressionwasusedtoexaminethe relationshipbetweenbaselinecharacteristicsandadverseoutcomes.Baselinecharacteristicswerechosenforentryinto multivariableCoxmodelsonthebasisoftheirdiscrimination betweenthosepatientsaboveandbelowtheoptimalcTFC cutpoint,aswellasonunivariateassociationswithadverse outcomesofP 0.20.Acombinationofforwardandbackward selectionprocedureswereusedtoaidindeterminingthebest modelofindependentpredictors.Thiswasfollowedbyforcing potentialconfoundersintothemodelsanddeterminingtheireffect ontherelationshipofinterest.Thelikelihoodratiotestwasusedto comparetheincrementalgoodnessoffitofnestedmodels.Alltests were2-sided,andP # 0.05wasconsideredstatisticallysignificant. AllanalyseswereperformedwithSASsoftwareversion9.3(SAS Institute). SampleSizeConsiderations .Usingpreviouslypublisheddata forwomenintheWISEwithnon-obstructivecoronarydisease[9], weassumedareference6-yearevent-freesurvivalrateof91%for suchwomenwithoutcoronarymicrovasculardysfunction(e.g. normalcTFC).Event-freesurvivalwastakenasfreedomfromfirst occurrenceofdeath(all-cause),nonfatalMI,non-fatalstroke,or hospitalizationforheartfailure.Weassumedthatwomenwith abnormalcoronarymicrovascularfunction(e.g.highcTFC)would havereducedevent-freesurvival.Thiswasexpressedasahazard ratioof2.5(correspondingtoa6-yeareventfreesurvivalrateof approximately79%)withproportionalhazardassumption. Assuming5%censoring,wewouldneed300womentoachieve 80%powerandneed500womentoachieve95%power,usinga two-sidedlog-ranktestwithalphalevelof0.05.SASprocedure PROCPOWERwasusedtoperformthepoweranalysis.We suspectedwewereunderpoweredinourcomparisonofthe incidenceofthebinaryoutcomeofmajoreventsbetweenTFC groups,andweusedtheKaplan-Meierestimatedratesofmajor eventsbetweenourtwoTFCgroupsinthispilotstudy(20%vs. 13%)todeterminethesamplesizenecessarytodetectastatistically significantdifferenceatapowerof80%andanalphaof0.05using theSASprocedurePROCPOWERwithtwo-sidedPearson’schi squaretest.TIMIFrameCountinWomenwithNoObstructiveCAD PLOSONE|www.plosone.org2May2014|Volume9|Issue5|e96630

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Results BaselineCharacteristicsWereportonasubgroupof298womenwithoutobstructive CAD(nostenosis $ 50%diameterreduction),whoseangiograms couldberetrievedandweresuitableforanalysisbyTFC,andfor whomclinicaloutcomedatawereavailable.Theirbaseline demographicsareshowninTable1.Theirmeanagewas 55 6 11years,mostwerewhite(86%),nearlyhalfhadahistoryof smoking,andhalfhadahistoryofhypertension.AngiographyandTFCThesewomen,inaggregate,hadnormaloverallleftventricular systolicfunctionwithameanejectionfractionof66 6 10%.The meancTFCwas33.9 6 10.0witharangeof18to91.AdverseOutcomesAdverseeventrateswerecomparedbetweenpatientsinthe variouscTFCtertiles(cTFC # 28,29–37,and 37).Duringa medianfollowupof6years,theKaplan-Meiereventratefor anginahospitalizationwashighestforthosewomeninthehighest cTFCtertile(35%,vs.24%inthemiddlecTFCtertile,and19% inthelowestcTFCtertile,P=0.022).However,theratesofmajor events(myocardialinfarction,heartfailure,stroke,orall-cause death),CVevents(myocardialinfarction,heartfailure,stroke,or CVdeath),all-causemortality,orCVmortalitywerenot statisticallydifferentbetweenwomeninthevariouscTFCtertiles. ByROCanalysis,acTFCof 35providedthebestcut-point forpredictinghospitalizationforangina,withasensitivityof61% andaspecificityof66%.Theareaunderthecurvewas0.63(95% confidenceinterval[CI]0.57to0.7).Adverseeventratesinthose patientsaboveversusatorbelowacTFCof35areshownin Table2.ThirtyfourpercentofwomenwithacTFC 35were hospitalizedforangina,whereasonly15%ofwomenwithacTFC # 35werehospitalizedforangina(P 0.001)(Figure2). Baselinecharacteristicswereexaminedfortheirpredictionof hospitalizationforangina.Patientswithwhiteracehadalower riskofhospitalizationforangina(age-adjustedHR=0.43[95%CI 0.24,0.76],P=0.004),whereasahistoryofunstableanginainthe preceding6weekspredictedhospitalizationforangina(ageadjustedHR1.79[95%CI1.05,3.03],P=0.03).Further,theuse ofvariousmedicationsatbaselinewaspredictiveofangina hospitalization:anti-hypertensives(age-adjustedHR1.96[95%CI 1.15,3.35],P=0.014);ACEinhibitors(age-adjustedHR2.17 [95%CI1.22,3.86],P=0.009);anddiuretics(age-adjustedHR 2.09[95%CI1.2,3.62],P=0.009). WhenaddedtoapredictivemodelthatincludedcTFCatcutpoint35,ahistoryofunstableanginaanddiureticusewerenot independentlyassociatedwithhospitalizationforangina.In contrast,whenwhiteracewasincludedinamodelthatcontained cTFCatcut-point35,itdidprovideanindependentpredictorof lowerriskofhospitalizationforangina(HR0.53[95%CI0.3, 0.94],P=0.03).Additionally,whenACEinhibitorusewas includedinamodelthatcontainedcTFCatcut-point35,itwas associatedwithahigherriskofhospitalizationforangina(HR2.04 [95%CI1.15,3.59],P=0.014).However,whenACEinhibitor use,whiterace,andcTFCatcut-point35wereallincludedina predictivemodelofhospitalizationforangina,onlycTFC providedindependentpredictionofhospitalizationforangina.DiscussionMicrovascularcoronarydysfunctionisprevalentinpatients presentingwithchestpainwhohavenoevidenceofobstructive CADonstandardangiography,andisassociatedwithadverse outcomes.Microvascularcoronarydysfunctioniscommonly diagnosedbyevaluatingcoronarybloodflowbeforeandafter administrationofadenosinewithaDoppler-tippedguidewirein thecoronary.TFCdoesnotrequireplacementofawireinthe coronaryartery,andhasbeenshowntocorrelatewithcoronary bloodflowandprognosisinpatientswithacutecoronaryevents. ThecorrelationofTFCwithadverseoutcomesinpatientswithno obstructivediseasebutsuspectedmicrovascularcoronarydysfunctionislessclear. Inthe298womenincludedinthisstudywhohadchestpainbut noevidenceofobstructiveCAD,ahighcTFCwasassociatedwith anincreasedriskofhospitalizationforangina.Moreover,ahigh cTFCremainedthestrongestpredictorofhospitalizationfor anginaaftercontrollingforbaselinecharacteristics.Interestingly, ACEinhibitorusewasalsoassociatedwithanincreasedriskof anginahospitalization.Wehavepreviouslyshownthatpatients randomizedtoanACEinhibitorhadgreaterimprovementin anginaseverityascomparedtothosewhoreceivedplacebo[22]. SothesedataarebiasedbyWISEinvestigatorslikelyprescribing Figure1.TIMIFrameCount. ThefirstframeusedtodeterminetheTIMIFrameCountistheframeinwhichdyefullyentersthearteryofinterest (left,arrow).Thelastframethatiscountedistheframewhendyeentersthedistallandmarkbranch(right,arrow). doi:10.1371/journal.pone.0096630.g001 TIMIFrameCountinWomenwithNoObstructiveCAD PLOSONE|www.plosone.org3May2014|Volume9|Issue5|e96630

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Table1. Baselinecharacteristicsandriskfactors.Characteristic Allwomen (n=298) cTFC # 35 n=179 cTFC 35 n=119 P(unadjusted)P(age-adjusted) Demographics Age(y)55 6 1156 6 1154 6 100.20Postmenopausal(%)**210/296(71)72690.53Whiterace(%)257(86)90800.0090.013 HSeduc.ormore(%)243/294(83)82830.970.94 Bodysize Waistcircumference(in)36.8 6 6.836.0 6 5.538.2 6 8.50.0270.020 BMI30.3 6 7.129.8 6 6.631.0 6 7.80.170.20 Waist/hipratio0.85 6 0.120.85 6 0.110.87 6 0.140.200.18 Self-reportedriskfactors Hxdiabetes(%)42/297(14)11190.070.053 FamilyhxofCAD(%)181/290(62)59670.160.18 Hxhypertension(%)143/296(48)47510.480.34 Hxdyslipidemia(%)116/275(42)43400.650.74 Eversmoker(%)151/297(51)54470.240.20 Currentsmoker(%)58/297(20)20190.750.50 Highstress(%)117(39)40390.860.70 Hemodynamicmeasures SystolicBP(mmHg)133 6 20134 6 20131 6 190.210.33 DiastolicBP(mmHg)76 6 1077 6 1176 6 100.370.34 Pulsepressure57 6 1658 6 1656 6 160.250.44 Meanarterialpressure95 6 1296 6 1294 6 110.220.28 Labvalues LDL-C(mg/dl)111 6 37112 6 39109 6 330.520.58 HDL(mg/dl)53 6 1353 6 1353 6 130.990.82 Triglycerides(mg/dl) (medians[IQR])* 113[72,169]122[76,169]96[70,172]0.370.55* Totalcholesterol191 6 43192 6 44191 6 410.920.94 Fastingbloodglucose104 6 39103 6 381076 400.330.31 Creatinine(mg/dl)0.79 6 0.180.80 6 0.190.78 6 0.160.480.61 Hemoglobin(g/dl)13.0 6 1.413.1 6 1.412.9 6 1.30.250.21 Medicationuse Anyantihypertensiveuse(%)167/283(59)60570.620.74 Anylipidloweringmeds(%)52/297(18)19150.410.45 EverHRTuse(%)160/293(55)56520.420.55 CurrentHRTuse(%)116/294(39)40380.700.83 Statins(%)39/297(13)13140.860.77 ACEinhibitors(%)51/269(19)18200.660.51 Betablockers(%)89/297(30)29310.670.65 Aspirin(%)138/296(47)49420.230.27 Diuretics(%)63/297(21)19240.250.19 Othervariables CADseverityscore(medians[IQR])*5.0[5.0,7.5]5.0[5.0,7.5]5.0[5.0,6.2]0.570.72* Functionalcapacity(DASI)21.4 6 14.922.6 6 15.319.7 6 14.20.110.10 Unstableanginapast6wks74/266(28)27290.720.81 cTFC=correctedTIMIframecount;HSeduc=HighSchooleducation;BMI=bodymassindex;Hx=history;HRT=hormonereplacementtherapy;CAD=coronary arterydisease. *Becauseofskeweddistribution,medians[interquartileranges]aregivenandLogtransformationswereusedtoestimatetheage-adjustedp-values **Forfrequencies,wherethereweremissingvalues,thestatisticgivenis:no.withthecondition/no.available(%). doi:10.1371/journal.pone.0096630.t001TIMIFrameCountinWomenwithNoObstructiveCAD PLOSONE|www.plosone.org4May2014|Volume9|Issue5|e96630

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anACE-Iforthosewithmoresevereangina.Additionally,followupbloodpressureforourcurrentcohortwashigherthanthe baselinebloodpressureinthosepatientsrandomizedtoanACE inhibitorinthePaulyetaltrial[22].WesuspectthatbaselineACE inhibitoruseinourcurrentcohortislikelyamarkerofmore advancedvasculardisease,whichmayhavecontributedtoan increasedriskofanginahospitalization.Inthispilotinvestigation, cTFCwasnotassociatedwithastatisticallysignificantincreasein riskofmajorevents(myocardialinfarction,heartfailure,stroke,or all-causedeath),CVevents,all-causemortality,orCVmortality. StudiescomparingTFCtomoreinvasivemeasuresofcoronary vasomotion(endothelialornon-endothelialdependentmacro-or microvascularfunction)haveprovidedvariousresults.Many studieshaveshownthatTFCdoescorrelatewithmeasuresof coronaryvasomotion[23–26],whereasothershaveshownno correlationofTFCandcoronaryflowreserve[27].Mostofthese studiesweresmall.Someofthesestudiesincludedpatientswith obstructiveCADandothersexcludedpatientswithobstructive CAD.SomeofthesestudiesdeterminedthechangeinTFCfrom baselinetotheTFCathyperemia,andcorrelatedthischangein TFCwithmeasuresofcoronaryvasomotion,whereassomelooked atonlythecorrelationofTFCatrestwithmeasuresofcoronary vasomotion.Therefore,itremainsunclearifTFCatrestcan replaceevaluationofcoronaryvasomotionwithmoretraditional methods.BecauseTFCatrestdoesnotrequireinstrumentationof thecoronaryarterynorvasoactivemedication,futurestudy evaluatingthecorrelationofTFCatrestwithCFRdetermined afteradministrationofadenosineandchangeincoronaryartery diameterandcoronarybloodflowafteracetylcholineinpatients withoutobstructiveCADremainswarranted. Themajorlimitationofourstudyistherelativelysmallnumber ofmajorevents.Becauseofthesmallnumberofevents,the currentanalysisprovideslowstatisticalpowertofindarelationship betweenTFCandmajorevents.Inordertohaveappropriate powertodetermineifthereisasignificantdifferenceinmajor eventratesbetweenTFCgroups,weestimatethatwewouldneed approximately880patients. Inconclusion,inwomenwithsignsandsymptomsofischemia butnoobstructiveCAD,restingcTFCprovidesindependent predictionofhospitalizationforangina.Largerstudiesare requiredtodetermineifrestingcTFCispredictiveofmajor eventsinpatientswithoutobstructivecoronaryarterydisease. Figure2.Survivalfreeofhospitalizationforanginaaccording toTIMIFrameCountgroups. Kaplan-Meieranalysisofsurvivalfree ofhospitalizationforangina. doi:10.1371/journal.pone.0096630.g002 Table2. AdverseEventRatesbetweenTIMIFrameCountGroups.Event* AllWomen(n=298)cTFC # 35n=179cTFC 35n=119 P(unadjusted) # EventsK-MRate** # EventsK-MRate** # EventsK-MRate** Majorevent3816%1913%1920%0.30 CVevent3313%1812%1515%0.70 All-causemortality2411%1210%1212%0.55 CVmortality136%75%67%0.88 Anginahospitalization6026%2417.5%3538%0.0005 6-yearCVeventoranginahospitalization7326%3119%4237%0.001 cTFC=correctedTIMIFrameCount;K-M=Kaplan-Meier;Majorevent=MI,heartfailure,stroke,orall-causedeath;CV(cardiovascular)Event=MI,hea rtfailure,stroke,orCVdeath. *Mortalityisestimatedforupto10yearsoffollowup.Non-fataleventsareestimatedforupto6yearsoffollowup. **NotethattheK-Mestimatedrateisnotequivalenttothenumberofeventspernofwomen. doi:10.1371/journal.pone.0096630.t002 TIMIFrameCountinWomenwithNoObstructiveCAD PLOSONE|www.plosone.org5May2014|Volume9|Issue5|e96630

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