Does patent foramen ovale closure improve exercise ... · and breathing 100% O2 (PFO/ASD blood flow...

Doespatentforamenovaleclosureimproveexercisecapacity&preventbloodflowthroughintrapulmonaryshunt?

NCTID:Notassigned

Date:12/11/18

StudyTitle:Doespatentforamenovaleclosureimproveexercisecapacity&preventbloodflowthroughintrapulmonaryshunt?ProtocolNumber: #12132016.027

PrincipalInvestigator: AndrewTLovering,PhD

A. IntroductionandBackground

Apatentforamenovale(PFO)ispresentin~30%ofthegeneralpopulation.ThePFOhashistoricallybeenconsideredtobetrivial.However,recentworkbyourgroupandothershasidentifiedthat,comparedtoindividualswithoutaPFO,thosewithaPFOhaveahighercorebodytemperature,significantlyworsepulmonarygasexchangeefficiency,bluntedventilatoryresponsestochronichypoxiaandacutecarbondioxideandincreasedsusceptibilitytoaltitudeillnessessuchasacutemountainsickness,andhighaltitudepulmonaryedema(Lovering,Elliott&DavisJApplPhysiol2016).Specifictothisapplication,subjectswithaPFOmaybeworsepulmonarygasexchangeefficiencybecauseaPFOisapotentialsourceofright-to-leftshuntthatwillmakepulmonarygasexchangeefficiencyworse.Iftrue,thenthismaynegativelyimpactexercisecapacityand/orexercisetolerance.

Ourlabgrouphasdemonstratedthathypoxemiaincreasesbloodflowthroughintrapulmonaryarteriovenousanastomoses(IPAVA)inhealthyandsubjectswithCOPD(Lovering,Duke&ElliottJPhysiol,2015;NorrisetalExpPhysiol,2016).Whenthesesubjectsbreathe100%O2itpreventsorreducesbloodflowthroughIPAVA.ThissuggeststhathypoxemiaperseinducesbloodflowthroughIPAVA.ThebloodflowthroughIPAVAandpresenceofaPFOisalsoassociatedwithincreasedriskofstrokeand/ortransientischemicattack(Duke,Elliott,LoveringEchocardiography2015).Inaddition,anatrialseptaldefect(ASD)isaholewithintheinteratrialseptum,andisconsideredacongenitalheartdefect.AnASDistypicallylargerthanaPFO,andthus,thesymptomsmaybeworseinthosewithanASD,comparedtothosewithaPFO.Thus,somehypoxemicpatientswhohavehadastrokeortransientischemicattack,whoalsohaveaPFO/ASDmayundergosurgicalclosureoftheirPFO/ASDtopreventsubsequentneurologicalsequelae.ThissurgicalclosuremayalsopreventthehypoxemiatherebyreducingorpreventingbloodflowthroughIPAVA.Ofnote,bloodflowthroughIPAVAhasbeendemonstratedtobestronglycorrelatedwithTIAand/orstrokeandhasnotpreviouslybeentakenintoconsiderationinrandomizedclinicaltrialsmentionedbelow(AbushoraetalJASE,2013).

ThreerandomizedclinicaltrialshavedeterminedthatPFOclosureisnotsuperiortoregularmedicalmanagement,forthepreventionofsubsequentstrokeand/orTIA.Nevertheless,theAmericanHeartAssociationstillrecommendsthat“inpatientswithcryptogenic[unexplained]TIAorstroke,aPFO,andDVT,guidelinesfromtheAmericanCollegeofChestPhysicianscurrentlyrecommendvitaminKantagonisttherapyfor3monthsandconsiderationofPFOclosureratherthannovitaminKantagonisttherapyoraspirintherapy.”(Whitlocketal.,CHEST2012;141(2)(Suppl):e576S–e600S,Kernanetal.,Stroke.2014;45:2160-2236).Additionally,inthelargestsinglecenterretrospectivestudyperformedtodate,PFOclosureforthepurposeofpreventinghypoxemiawasfoundtoresultin“improvementinechocardiographicevidenceofrighttoleftshunt,NewYorkHeatAssociationfunctionalclass,andoxygenrequirement.”(FensteretalAmJCardiol2013).

Thus,PFO/ASDclosureremainsapotentiallybeneficialoptionforbothhypoxemicandstroke/TIApatients.

Lastly,preliminarydataalsosuggestgreaterlevelsofplasmainflammatorymediatorsinsubjectswithaPFOandsystemicinflammationisassociatedwithincreasedriskofcardiovasculardiseases.Importantly,exerciseisknowntoreducesoofthesesystemicinflammatorymediatorlevels.Thus,PFO/ASDclosuremayallowforgreaterexercisecapacityandasubsequentreductionininflammation.

Thus,althoughaPFOhasbeentraditionallyconsideredtohaveaminimalimpactofphysiologyandpathophysiology,emergingevidencesuggeststhismaynotbethecase.Ourlabisfocusedonunderstandinghowandwhyarelativelysmallholeintheheart(PFO/ASD)canhavearelativelylargeimpactoncardiopulmonaryandrespiratoryphysiology.

B. SpecificAims/StudyObjectives

TheoverarchinggoalofthisstudyistoexaminecardiopulmonaryandrespiratoryphysiologypreandpostPFO/ASDclosureinpatientswhoareundergoingsurgicalclosureoftheirPFO/ASD.

PreandpostPFO/ASDclosure,wewill:

1)Quantifypulmonarygasexchangeefficiency(alveolartoarterialO2difference)andarterialoxygenationatrestandduringexercise.

2)Quantifyaerobicexercisecapacity,dailyactivity,six-minutewalktest.

3)QuantifyQIPAVAatrestandassessrecurrenceofstrokeorTIAat3months.

4)Quantifyplasmainflammatorymarkers(TNFa,IL-1,6&CRP)

5)Measurehypercapnicventilatoryresponse

6)Quantifycorebodytemperature

Hypotheses:WehypothesizethatclosureofPFO/ASDwillimprovepulmonarygasexchangeefficiency,improveexercisecapacity,andreducebloodflowthroughPFO/ASDandIPAVAtherebypreventingsubsequentstroke.PFO/ASDclosurewillalsoreduceplasmainflammatorymediators,increaseventilationinresponsetoahypercapnicchallenge,andwillresultinalowercorebodytemperature.

C. Methods,MaterialsandAnalysis

Thisstudywillbeperformedoverthecourseof7daysattheCardiopulmonaryandRespiratoryPhysiologyLabattheUniversityofOregon.Days1-3arePre-PFO/ASDclosureprocedureandDays4-7repeatallresearchactivitiesbeginningat3monthspostPFO/ASDclosureprocedure.Thoseclearedforexercisebytheircardiologists(seerecruitmentbelow)

willparticipateinallaspectsofthestudy,Days1-7.Thosenotclearedforexercisebytheircardiologistswillparticipateinallnon-exerciseaspectsofthestudyDays1-4[grayhighlightfornon-exercisesubjectinformation].

SpecialnoteonpostPFO/ASDclosureprocedures:ThetimingofpostPFO/ASDclosureprocedurevisitswerecarefullyselected(i.e.,3and6months)basedonrecommendationsfromthereferringphysicians(Dr.RichardPadgettandDr.SamuelLau).Itistheircollectiverecommendationthat6months(andinsomecases3months)issufficienttoallowforphysicalclosure/endothelializationofthePFO/ASD.However,ifisitdeterminedat6monthspostPFO/ASDclosureprocedurethatthePFO/ASDhasbeendeemedNOTPHYSICALLYCLOSED/ENDOTHELIALIZEDbythereferringphysician,thesubjectwillnotpartakeinthepost-closurevisit(s)scheduledat6months,ANDtheywillbeexcludedfromthestudy.

Screeningateachstudyvisit:Femalesubjectswillberequiredtotakeaurinepregnancytestbeforeeachvisitbegins.Apositivetestatanytimewillresultinexclusion.AModifiedAllen’stestwillbeperformedonDay1forallsubjectsandduringeachdaywhenanarteriallineisplaced.FailingtheModifiedAllen’stestatanytimewillresultinexclusion.

ProtectedHealthInformation(PHI):ParticipatingPhysiciansDr.PadgettandLauwillprovidePHItotheinvestigators.ThePHIprovidedwillinclude:thereason(s)forPFO/ASDclosureprocedure(e.g.,TIA,Stroke,dyspneauponexertion,etc.),whenthePFO/ASDhasphysicallyclosed/endothelializedperreferringphysician(e.g.,at3or6months),currentandpastmedicationinformation,andresultsfromclinicalexercisestudiesastheypertaintodeterminingthereason(s)forclosure(e.g.,arterialoxygensaturationatrestandduringexercise,ratingofperceivedexertion,etc).SubjectswillbeaskedtosignaHIPAAauthorizationformonDay1.ThePHIwillbeusedforresearchpurposesonly.Ofnote,thisinformationisonlysolicitedviaself-reportfromthosewhohavereportedapriorhistoryatthetimeofenrollment.

ThefollowingFigures(i.e.,1&2)aremeanttoassistindeterminingthepaththroughthestudydays,andshouldbeusedinconjunctionwiththedetailedstudy-daydescriptions.

Thisportionleftintentionallyblank

Figure1.Exercise

PFO Closure Procedure

3 months

PFO Physically Closed/Endothelialized per Physician?

YES NO

Visits 4 - 6a

Visit 7a OR 5 - 7b

Visit 4b

6 months

Timing


YES NO

You will be excluded from the study

Consent to Participate in Study

Visits 1 - 3Pre-Procedure

PFO/ASD

PFO/ASD

PFO/ASD

Figure2.Non-Exercise

PFO Closure Procedure

3 months


YES NO

Visit 3a

Visit 4a OR 4b

Visit 3b

6 months

Timing


YES NO

You will be excluded from the study

Consent to Participate in Study

Visits 1 & 2Pre-Procedure

PFO/ASD

PFO/ASD

PFO/ASD

EXERCISESUBJECTS

Whatfollowsisadetaileddescriptionofthestudydays.Forconvenience,pleaserefertoFigure1.Exercise(page4)toassistindeterminingthetimingofstudydays.

Visit1PrePFO/ASDClosureProcedure(~2.5hrs)AND:

Visit4a(PFO/ASDPhysicallyClosed/Endothelialized)(~2hours)OR,

Visit4b(PFO/ASDNotPhysicallyClosed/Endothelialized)(~30min)

Visit4a(IfPFO/ASDisphysicallyclosed/endothelializedat3monthsperreferringphysician)

Subjectswillundergoinformedconsent,fillouthealthhistoryquestionnaire,signaHIPAAauthorizationformandperformaModifiedAllen’sTest(~45min)

Subjectswillbecomprehensivelyscreenedforanycardiacabnormalities.AmountofbloodflowtravellingthroughthePFO/ASDandIPAVAwillbegradedusingsalinecontrastechocardiographywhilethesubjectisbreathingroomair(PFO/ASDandIPAVAbloodflow)andbreathing100%O2(PFO/ASDbloodflowonly).Pulmonaryarterypressurewillalsobemeasuredusingultrasound.Intravenousblooddraw,wewilltake21mls(~2Tablespoons)ofivblood(~1.25hrs)

Subjectswillperformpulmonaryfunction,plethysmographyanddiffusingcapacity(30min)

Visit4b(IfPFO/ASDisnotphysicallyclosed/endothelializedat3monthsperreferringphysician)

Subjectswillreceiveandintravenousblooddraw,andwewilltake21mls(~2Tablespoons)ofIVblood(30min).

Visit2PrePFO/ASDClosureProcedure(~2.5hrs)AND:

Visit5a(PFO/ASDPhysicallyClosed/Endothelialized)(~2.5hrs)OR,

Visit5b(PFO/ASDNotPhysicallyClosed/Endothelialized)(~2hrs):

Visit5a(IfPFO/ASDphysicallyclosed/endothelialized)at3monthsperreferringphysician)

Subjectswillundergoahypercapnicbreathingchallenge(~1hr)

Subjectswillbegivenanactivitymonitorandgiveninstructionsonhowandwhentouseit(~30min)(DetailedInstructionsonVisit2ONLY.OnVisit5,theywillberemindedoftheinstructions,withdetailsasrequired)

Subjectswillperforma6minutewalktest(~15min)

SubjectswillperformaVO2maxtest(~30min)

Visit5b(IfPFO/ASDnotphysicallyclosed/endothelializedat3monthsperreferringphysician)

Subjectswillundergoinformedconsent,fillouthealthhistoryquestionnaire,signaHIPAAauthorizationformandperformaModifiedAllen’sTest(~45min)



Visit3PrePFO/ASDClosureProcedure(~5hrs)AND:

Visit6a(PFO/ASDPhysicallyClosed/Endothelialized)(~5hrs)OR,

Visit6b(PFO/ASDNotPhysicallyClosed/Endothelialized)(~2.5hrs)

Visit6a(IfPFO/ASDphysicallyclosed/endothelializedat3monthsperreferringphysician)

SubjectswillbeinstrumentedwitharadialarterycatheterbyDr.JerryHawn,MD.Anesophagealtemperatureprobeandanivforsalinecontrastinjectionswillalsobeplaced.(~1hr)

Arterialbloodwillbetakenatrestwhilesubjectisbreathingroomairand100%O2for10-20minutestocalculateshuntfraction(~30min).

Subjectswillexerciseonacycleergometerfor4minutesperstageat25,50,75and90%ofVO2maxbreathingroomair.Subjectswilltakeupto15minutebreaksbetweenexercisestages(~1.5hr)

Afterexercisebreathingroomair,subjectswilltakea30-minutebreak.(~30min)

Subjectwillrepeattheexerciseprotocolabovewhilebreathing40%O2(~1.5hrs);note60%O2isthemaximallevelofoxygenthatcanbebreathedandstillgetmetabolicdatarequiredforcalculatingtheAaDO2.



Subjectswillbegivenanactivitymonitorandgiveninstructionsonhowandwhentouseit(~30min)(DetailedInstructionsonVisit2ONLY.OnVisit6b,theywillberemindedoftheinstructions,withdetailsasrequired)

Subjectswillperforma6minutewalktest(~15min)

SubjectswillperformaVO2maxtest(~30min)

Visit7a(PFO/ASDPhysicallyClosed/Endothelialized)(~30mins)OR,

Visit7b(PFO/ASDNotPhysicallyClosed/Endothelialized)(~5hrs)


Intravenousblooddraw.Wewilltakeroughly21mls(~2Tablespoons)ofIVblood.


SubjectswillbeinstrumentedwitharadialarterycatheterbyDr.JerryHawn,MD.Anesophagealtemperatureprobeandanivforsalinecontrastinjectionswillalsobeplaced.(~1hr)


Subjectswillexerciseonacycleergometerfor4minutesperstageat25,50,75and90%ofVO2maxbreathingroomair.Subjectswilltakeupto15minutebreaksbetweenexercisestages(~1.5hr)

Afterexercisebreathingroomair,subjectswilltakea30-minutebreak.(~30min)

Subjectwillrepeattheexerciseprotocolabovewhilebreathing40%O2(~1.5hrs);note60%O2isthemaximallevelofoxygenthatcanbebreathedandstillgetmetabolicdatarequiredforcalculatingtheAaDO2.

NON-EXERCISE

Whatfollowsisadetaileddescriptionofthestudydays.Foryourconvenience,pleaserefertoFigure2.Non-Exercise(page5)toassistindeterminingthetimingofstudydays.

Visit1PrePFO/ASDClosureProcedure(~2.5hrs):

Subjectswillundergoinformedconsent,fillouthealthhistoryquestionnaireandperformaModifiedAllen’sTest(~45min)



Visit2PrePFO/ASDClosureProcedure(~3hrs):


Subjectswillbegivenanactivitymonitorandgiveninstructionsonhowtouseit(~30min)(DetailedInstructionsonVisit2ONLY.OnVisit3,theywillberemindedoftheinstructions,withdetailsasrequired)

SubjectswillbeinstrumentedwitharadialarterycatheterbyDr.JerryHawn,MD.Anesophagealtemperatureprobeandanivforsalinecontrastinjectionswillalsobeplaced.(~1hr).

Arterialbloodwillbetakenatrestwhilesubjectisbreathingroomairand100%O2for10-20minutes(~30min).

Visit3a(PFO/ASDPhysicallyClosed/Endothelialized)(~4.5hrs)OR,

Visit3b(PFO/ASDNotPhysicallyClosed/Endothelialized)(~30min)








Subjectswillundergoanintravenousblooddraw,andwewilltake21mls(~2Tablespoons)ofIVblood(30min).

Visit4a(PFO/ASDPhysicallyClosed/Endothelialized)(~30min)OR,

Visit4b(PFO/ASDNotPhysicallyClosed/Endothelialized)(~4.5hrs)


Subjectswillundergoanintravenousblooddraw,andwewilltake21mls(~2Tablespoons)ofIVblood(30min).







DescriptionofDataCollectionProcedures(timingoftheseprocedurescanbefoundinTable1and2below:

• ModifiedAllen’sTest(Days1,3&6aOR7bExercise;Days1,2&3aOR4bNON-Exercise):

Thistestexaminescollateralbloodflowinthehand,andisperformedonthefirstdayandeachdaythereisanarteriallineplaced.Thesubjectclenchestheirfistfor~30secondswhiletheradialandulnararteriesareoccludedbytheinvestigator.Theulnararteryisreleasedandthereturnofcirculation(colortothehand)isexamined.Ifthecolordoesn'treturn,thenthisisconsideredanegativetest(fail).Bothhandswillbetested,twofailures(rightandlefthand)isexclusionary.

• Comprehensiveultrasoundscreening(Days1&4aOR5bExercise;Days1&3aOR4bNON-Exercise):

Anintravenouscatheterwillbeplacedinthesubject.Subjectswillsitintheleftlateraldecubitispositionforultrasoundscreening.Anagitatedsalinecontrastinjectionwillbemadewhiletransthoracicsalinecontrastechocardiography(TTSCE)isperformedonthesubjecttoevaluateextentofbloodflowthroughIPAVAandPFO/ASD.Thiswillberepeatedwhilebreathing100%O2for10minutes.SubjectwillbeaskedtoperformaValsalvamaneuverwhilebreathingroomairand100%O2.ThismaneuverenhancesbloodflowacrossthePFO/ASD.Multiplesalinecontrastinjections(upto3)maybeperformedtoverifybubblegrades/presenceofaPFO/ASD.

PulmonaryFunctionTests(Days1&4aOR5bExercise;Days1&3aOR4bNON-Exercise):

• Subjectswillperformstandardnon-invasivespirometrytomeasureamaximalinspiratoryandexpiratoryflow-volumeloop,forcedvitalcapacity(FVC),forcedexpiratoryvolumein1sec(FEV1),andmidexpiratoryflow(FEF25-75%).Thesetestswillrequirethesubjecttoblowinandoutofamouthpiececonnectedtoacomputerizedflowmeter(pneumotachometer).ThisisaroutineclinicaltestperformedinpulmonaryfunctionlabsintheUnitedStates.

• DiffusingCapacity(DLCO)(Days1&4aOR5bExercise;Days1&3aOR4bNON-Exercise):

Thisisastandardnon-invasivetestfordiffusioncapacityforcarbonmonoxide(CO)usingthesinglebreath,breath-holdtechnique.Itrequiresthesubjecttobreatheinasinglebreathofacommerciallyavailable(MedGraphics/Airgas)diffusiongascontaining0.3%CO.Thesubjectwillbreatheinthisbreaththroughamouthpiececonnectedtoaflowmeterandholditforapproximately10secondsbeforeexhalingthegas.Thismayberepeatedamaximumof3to5times.ThisisaroutineclinicaltestperformedinpulmonaryfunctionlabsintheUnitedStates.

• WholeBodyPlethysmography(Days1&4aOR5bExercise;Days1&3aOR4bNON-Exercise):

Subjectsperformastandardnon-invasiveproceduretomeasurefunctionalresidualcapacity(FRC),whichistheamountofairwithinthelungsattheendofapassiveexpiration.Subjectsalsoperformastandardnon-invasiveslowvitalcapacity(SVC)maneuvertodeterminethevitalcapacity(usablecapacity)ofthelungs.Theseprocedureswillrequirethesubjecttositinsideaclearplexiglassboxcalledawholebodyplethysmograph(MedGraphicsElite)andbreatheroomairthroughamouthpiece(pneumotachometer)connectedtoaflowmeter.UsingthevalueobtainedforFRCandthevalueobtainedforSVCtotallungcapacity(TLC)canbedetermined.ThisisaroutineclinicaltestperformedinpulmonaryfunctionlabsintheUnitedStates.

• NitrogenWashout(Days1&4aOR5bExercise;Days1&3aOR4bNON-Exercise):

Subjectsmayperformastandardnon-invasiveproceduretomeasureresidualvolumeforcalculationoftotallungcapacity.Thisprocedurewillrequiresubjectstobreathe100%oxygenthroughamouthpiecefor7-10minuteswhilewemonitornitrogenwashoutofthelungs.ThiswillbedonefollowingATS/ERSstandardcriteria.ThisisaroutineclinicaltestperformedinpulmonaryfunctionlabsintheUnitedStates.Thiswillonlybeperformediftheplethysmographisnotfunctioningproperly,i.e.itisacontingenttest.Ofnotewehaveneverneededtoperformthistest.

• TransthoracicSalineContrastEchocardiography(TTSCE)(Days1,3,4aOR5b&6aOR7bExercise;Days1-3aOR4bNON-Exercise):

EchocardiographyrequiresamedicalsonographerfromPeaceHealthtoplaceasmallprobeagainstthesubject'sribcage,whichtransmitsandreceivessoundwavestoproduceimagesthatarecapturedandstoredonacomputer.Salinecontrastismadebymanuallyagitating(mixing)3-5mlofsterilesalineand1mlofairtocreateasuspension(mixtureofliquidandgas)ofverysmallbubblescalledmicrobubbles.ThissuspensionisinjectedthroughanIV,whichallowsustodetectthetranspulmonarypassageofmicrobubbles.

• IntravenousCatheter(IV)(Days1,3,4aOR4b,5b,6a,7aOR7bExercise;Days1-3a,4aOR4bNON-Exercise):

Wewillplacea20-22gauge(smalldiameter)IVintoaveininthesubject’sarmthatwillbeusedfortherapidinjectionoftheagitatedsterilesalineforTTSCEduringDays1,3,4aOR4b,5b,6a,and7aOR7bExercise;Days1-4NON-Exercise.Thiscatheterwillalsobeusedtomeasureplasmainflammatorymediators.Bloodwillbecentrifugedandde-identifiedplasmastoredat-80°CuntilassayedbyELISAkit.TotalIVblooddrawisapproximately63mLforexerciseornon-exerciseparticipants.

• Hypercapnicventilatoryresponse(Days2&4aOR5bExercise;Days2-3aOR4bNON-Exercise):

Wewilluseapublished,well-establishedmethod(Duffinmethod)forassessingchemosensitivitytocarbondioxide(MacKayetal.,AdvPhysiolEducation,2016).Subjectswillbefittedwithanose-clipandbreatheroomairthroughatwo-wayrebreathingvalvethatcanbedirectedbetweenafiltered6Lnon-diffusingbagfilledwith7%CO2and93%O2(medicalgrade)androomair.Ventilation,endtidalCO2(PETCO2),endtidalO2(PETO2)andsaturationwillbemeasuredcontinuouslythroughoutthistesting(Medgraphics).Toestablishabaselinebeforehypercapnictestingusingthemodifiedrebreathingprotocol,subjectswillbreatheroomairfor5min.Subjectswillthenbecoachedtohyperventilatebyincreasingthelungvolumeandfrequencyofbreathingfor5minutestoreachatargetPETCO2of~20-25mmHg(~40-45mmHgisnormal);thispartofthetestisrequiredtoreduceCO2storesinthebody.At5minutesthesubjectwillbeaskedtotakeafullbreathinandoutthentheywillbeswitchedtothebagfilledwith7%CO2and93%O2andwillbecoachedtotake3largebreathsthenresumenormalbreathinguntil:1)theirbreathingincreasessomuchthatitbecomesintolerableandtheysignaltoquit;2)thePETCO2=55mmHgor3)therebreathingbagbecomesdeflated.Subjectswillbeinformedofwhattoexpectwiththistestpriortoperformingit,i.etheywillbetoldthatwewillcoachthemthroughitandthatwhentheystarttobreatheoutofthebagtheywillinitiallyhaveverylittleurgetobreathebutastherebreathingprogressestheywillhaveaverystrongurgetobreathe.

• Actigraphy(Days2&4aOR5bExercise;Days2-3aOR4bNON-Exercise):

AllsubjectswillwearanActiGraph(Pensacola,FL)GT3Xaccelerometerdailyforapproximately1weekPrePFO/ASDclosure(baseline)and1weekPostPFO/ASDclosure.Subjectswillbeinstructedtowearthedeviceatalltimesaroundtheirwaistexceptwhenshowering,bathing,swimming,orsleeping.AccelerometrydatawillbedownloadedtoacomputerusingActiLifev.6software.Totaldailyenergyexpenditure(TDEE;kcal/day)willbeestimated,andphysicalactivitylevels(PALs;TDEE/basalmetabolicrate[BMR])calculatedtoadjustforbodysize.Activityenergyexpenditure(AEE;kcal/day),calculatedasTDEE-BMR,willbeusedtodescribethecaloriccostsofphysicalactivity.Inaddition,timespentinstandardcategoriesofactivity(sedentary,moderate,vigorous)willbeassessed.MembersoftheLoveringlabareresponsibleforuploadingandanalyzingde-identifieddatafromtheActiGraphseveryweek.

• VO2MAXtestand6minutewalktest(Days2&4aOR5b;ExercisesubjectsOnly):

ThesixminutewalktestwillbeperformedonthesecondflooroftheCenterforMedicalEducationandResearch.ThisisthesamespaceusedtoperformthesetestsinDr.Dreyer’ssubjects.

TheVO2maxtestwillbeanincrementaltesttovolitionalexhaustiononacycleergometer.Subjectswillbreathethroughamouthpieceandwillbegincyclingataverylowresistance(25to75Wdependingonfitnesslevel),withtheresistanceincreasingeveryminuteby25W.ThetestwillcontinueuntilthesubjectreachesvolitionalexhaustionoraplateauinVO2asmeasuredbyourmetaboliccartisreached.Duringtheentireprotocol,subjectswillbreatheroomairthrougha2-waynon-rebreathingsmallsamplingflowmeter

(pneumotachometer),whichwillallowustomeasureventilation(VE),VO2,andbreath-by-breathmetabolicdata.Subjectswillbeinstrumentedwith12leadEKG.

• ArterialBloodGasMeasurement(Days3,6aOR7bExercisesubjects;Days2-3aOR4bNON-Exercisesubjects):

PriortocatheterplacementthephysicianwillperformamodifiedAllen’sTesttoconfirmadequacyofcollateralcirculationofthehand.Aphysician(JeroldHawn,MD)willperformcatheterizationoftheradialartery.Usingastandard,sterileprocedureDr.Hawnwillplaceasmallcatheterintotheradialartery(arterialcatheterization).Dr.Hawnwillinitiallynumbthewristwithlidocaine/nitroglycerinsolution.ThenDr.Hawnwillplaceaneedleintotheradialartery.Dr.Hawnwillthenplaceasmallguidewirethroughtheneedleintothevessel.Thenhewillplaceaflexiblecatheterintothevesselusingtheguidewirefordirection.Thiscatheterwillbeusedtocollectbloodtotaling<100mL(<7Tablespoons)intheexercisingsubjectsand<25ml(<2Tablespoons)inrestingsubjects.Blooddrawswillbeaccompaniedbyaheparinizedsalineflush(1unitheparin/ml)toreducechancesofcatheterclotting.12leadECG,heartrate,metabolic,ventilationdatawillbecontinuouslycollectedandarterialbloodoxygensaturationwillbecontinuouslymeasuredviaanon-invasivetranscutaneousforeheadsensor.

*Note:

TOTALblooddrawforExercisesubjects(i.e.,IV+ArterialLine)willbelessthan250mL.TOTALblooddrawforNon-Exercisesubjects(i.e.,IV+ArterialLine)willbelessthan125mL.

However,ifitisdeemedat6monthsbythereferringphysicianthatthePFO/ASDhasnotbeenphysicallyclosed/endothelialized,subjectswillnotpartakeinthescheduled6-monthpostPFO/ASDclosureprocedurevisits.Thus,theamountofblooddrawnfromthesesubjectswouldbesignificantlyreduced.Specifically:

Exercisesubjectswithout6monthvisits(i.e.,totalblooddrawn):<125mLNon-exercisesubjectswithout6monthvisits(i.e.,totalblooddrawn):<75mL

RisksandinterventionstomitigatesuchareincludedinSectionG.

• Exercisewitharterialline(Days3,6aOR7bExercisesubjectsonly):

Afterarteriallineplacement(seeabove)thesubjectswillperformtwoboutsofgradedsubmaximalexercisetestsonthecycleergometerat25%,50%,75%and90%oftheirVO2maxwitheachstagelasting4minuteswithupto15minutebreaksbetweenstages.Duringonebout,subjectswillbreathenormaloxygenlevels(21%oxygen),duringtheotherbout,subjectswillbreathehighoxygenlevels(40%oxygen).Boutswillberandomizedandseparatedby30minutesofrestbreathingroomair.

• Intrapulmonary&intracardiacShuntingwitharteriallineplacement(Days3,6aOR7bExercisesubjects;Days2-3aOR4bNON-Exercisesubjects):

Salinecontrastechocardiographywillbeperformedduringthethirdminuteofeachexercisestagetoassessintrapulmonaryandintracardiacshunting.SalinecontrastechocardiographywillalsobeperformedinNON-exercisesubjectsatrest.

• Measurementofcorebodytemperature(Days3,6aOR7bExercisesubjects;Days2-3aOR4bNON-Exercisesubjects):

Anesophagealtemperatureprobe(NelcorusedwithMon-a-ThermSystem)willbeplaced.Wewillbeusingesophagealtemperaturemonitoringbecausecoretemperatureisaprimaryoutcomevariableofthisstudyandesophagealtemperatureisconsideredtobethegoldstandardtechniqueformeasuringcoretemperatureduringshortdurationexercisetesting.Wealsousethistemperaturetocorrectourbloodgasvalues.Inordertoplacetheesophagealprobe,subjectswillbegivenlidocaineJelly(2%lidocaine,1mlintranasaladministration).AfteradministrationofthelidocaineJelly,researcherswillplacetheesophagealprobethroughoneofthenostrils,andadvancetheprobeuntilitisvisibleinthebackofthethroat.Oncetheprobeisvisible,thesubjectwillthenbegintosipwaterthroughastrawwhiletheresearcheradvancestheprobetotheappropriatedepth.Theswallowingofthewaterhelpstoinsurethattheprobegoesdowntheesophagusandnotthetrachea.Researcherswillmakenomorethan2attemptspernostriltoplacetheesophagealprobe.Intheeventsubjectscannottoleratetheesophagealtemperatureprobe,subjectswillswallowaningestiblepill,aboutthesizeofamulti-vitamin,thatisdesignedforhumanuse(FDAapproved)andisaccurateto0.1ºC(CoreTemp,HQITechnologies,Inc.).Thispillwillbeusedtomeasurecorebodytemperatureatrestandduringcycleergometerexercise.Priortoingestionthetemperaturepillwillbecalibratedwithanexternalwirelessrecordingdevice.Thiswillallowustowirelesslyacquirethesubjectscoretemperaturewhennecessaryasthetemperaturepilltransmitsasignaltotheexternaldevicethatwillthendisplaytheappropriatetemperature.Thispillwillharmlesslypassthroughthesubject’sintestinaltract.Thepillisnotrecovered,isdisposable,andeverysubjectreceivesanewpillforeachstudyday.

Table1–Exercise

Group-Exercise

Visits: 1 2 3 4a

4b

5a

5b 6a 6

b7a 7b

Pre-PFO/ASDClose x x x Post-PFO/ASDClose x x x x x x x xStudyProcedures: IC&HealthHx,HIPAAform x ModifiedAllenTest x x x xComprehensiveScreening x x x PulmonaryFunction x x x DiffusingCapacity x x x Plethysmography x x x NitrogenWashout* x x x TransthoracicSalineContrastEcho(TTSCE) x x x x x x

Intravenouscatheter(IV) x x x x x x x xHypercapnicVentilatoryResponse x x x

Actigraphy** x x x VO2Max&6minwalk x x x ArterialBloodGasMeasurement x x xExercisew/arterialline x x xIntrapulmonary/intracardiacshuntw/artline x x x

CoreBodyTemp x x xCompensation: IC&HealthHx 5

Echoscreen/blooddraw10

15

15

BloodDraw 10 1

0

PFT,diffcapacity,plethysmography10

15

15

Hypercapnicbreathingchallenge 10 1

5 15

activitymonitortraining 5 sixminwalk 5 5 5

vo2max 15 1

5 15

arterialline 100 13

0 130

exercisetests 75 100 10

0blooddraws/breathingroomair

Totalforcompletedstudyvisit25

35

175

30

10

35

30

230

35

10

230

Totalforallaspectsofthestudy 540

Table2–Non-Exercise

Group–Non-ExerciseVisits: 1 2 3a 3b 4a 4b

Pre-PFO/ASDClose x x Post-PFO/ASDClose x x x xStudyProcedures:

IC&HealthHx,HIPAAform x ModifiedAllenTest x x x xComprehensiveScreening x x xPulmonaryFunction x x xDiffusingCapacity x x x

Plethysmography x x xNitrogenWashout* x x xTransthoracicSalineContrastEcho(TTSCE) x x x xIntravenouscatheter(IV) x x x x xHypercapnicVentilatoryResponse x x xActigraphy** x x xVO2Max&6minwalk ArterialBloodGasMeasurement x x xExercisew/arterialline Intrapulmonary/intracardiacshuntw/artline x x xCoreBodyTemp x x xCompensation:

IC&HealthHx 5

Echoscreen/blooddraw1

0 Blooddraw 10 10

PFT,diffcapacity,plethysmography1

0 Hypercapnicbreathingchallenge 10 15 15activitymonitortraining 5 sixminwalk vo2max arterialline 100 130 130exercisetests blooddraws/breathingroomair 15 20 20Totalforcompletedstudyvisit 25 130 165 10 10 165Totalforallaspectsofthestudy 330

D. ResearchPopulation&RecruitmentMethods&Compensation

1-2.Samplesize,PopulationandRecruitmentMethods:

SampleSizeandDataAnalyses:

Necessarysamplesizewasdeterminedwithourprimaryoutcomevariables(AaDO2,VO2MAX,salinecontrastbubblescores,TNFalevels)usingourpreliminarydata,previouslypublishedworkandaprioripoweranalysis.UsingG-Powerandinformationaboutaphysiologically-meaningfuleffectfrompublishedstudies(i.e.reductionofAaDO2by50%,VO2MAXincreasingby10%and6minwalktestincreasingby50meters(15,34,41)�(24,40)(24,40)�,TNF-alevelsdecreasingby50%,adesiredpowerof0.80,andalpha(0.05),wedeterminedthatn=8-10individualswouldbesufficienttotestourhypotheses,usingarepeatedmeasuresdesign.Thus,weareaskingtorecruit20subjects(anycombinationofmaleandfemale)intheevent

ouractualpre-to-postchangesarelessthanexpectedand/orthereisgreatervariabilitythanourpreliminarydatasuggest.

MeandifferencesinAaDO2andcorebodytemperaturebetweenpre-andpost-PFO/ASDclosurewillbeanalyzedusingarepeatedmeasuresANOVAwithTukeyposttest.MeandifferencesinVO2MAX,6minutewalktest,activity,inflammatorymarkersandhypercapnicventilatorresponse,betweenpreandpostPFO/ASDclosurewillbeanalyzedusingapairedt-test.Differencesinbubblescorespre-andpost-closurewillbeanalyzedusingaMann-WhitneyUtest.

ThepopulationofsubjectswillincludepatientswhoareundergoingPFO/ASDclosureateitherPeaceHealthorMcKenzie-WillametteHospitals.SubjectswillbeidentifiedbyRickPadgett,MD(PeaceHealth/OregonHeart&VascularInstitute)andSamLau,MD(McKenzie-Willamette).ThesetwocardiologistswillonlyrefersubjectstocontacttheLoveringLabforinformedconsentandenrollmentintothestudy.Drs.LauandPadgettwillidentifypotentialsubjectsas“clearedforexercise”or“notclearedforexercise.”(SeestatementofPHIabove).Drs.LauandPadgettwillnotbeformallyengagedintheresearch(i.e.theywillnotconsentsubjects,haveaccesstoidentifiabledata,etc).Noresearchactivitieswilltakeplaceateitherhospital.Subjectfliers,initialphonescriptandemailscriptareattached.

3.DetailedRecruitmentinformation:

A)PatientsundergoingPFO/ASDclosurewillbeidentifiedbyDr.LauandPadgett.ThePIhasverballydiscussedthedetailsofthisstudyoverthephonewithDrs.LauandPadgett.Therealityisthatthethreeofushavebeendiscussingthepotentialtodothesestudiesforyearsandweonlyrecentlyreceivedthefundingtodothem.ThePIwillsendthecardiologistthecriterialistedbelowinTable3sothattheycanrefertothembeforemakingthedecisiontorecommendthemforthestudy.BecauseDrs.LauandPadgettunderstandthatthisstudyhasanexercisearmandanon-exercisearm,theywillusetheirbestjudgmentalongwithavailablemedicalrecordstodeterminewhetherornotasubjectwouldbeclearedforexerciseornotclearedforexercise.Forexample,asubjectwithahistoryofchestpainuponexertionandaclinicalexercisestudyrevealinganelevatedSTsegment(EKGabnormality)wouldnotqualifyfortheexercisestudywhereasasubjectswithhistoryofrunningmarathonswouldqualifyfortheexercisestudy.

B)Ifthecardiologistbelievesthattheirpatientmeetsthequalificationsforthisstudy,theywillsimplyhandthemaflier(eithertheexerciseornon-exerciseflierbasedoncardiologistrecommendation)anddirectthemtocontactus(Loveringandcolleagues)forquestions.

C)Onceasubjectcontactsusandagreestocomeinforconsent(afterreceivingaflierfromtheirphysician),wewillcontactthecardiologistsviaemail/phonetoVERIFYwhichgrouptheyqualifyfor(exercise/non-exercise).

D)Screeningateachstudyvisit:Femalesubjectswillberequiredtotakeaurinepregnancytestbeforeeachvisitbegins.Apositivetestatanytimewillresultinexclusion.AModifiedAllen’stestwillbeperformedonDay1forallsubjectsandduringeachdaywhenanarteriallineisplaced.FailingtheModifiedAllen’stestatanytimewillresultinexclusion.

Table3

Inclusion Exclusion

Menandwomenaged18-80recruitedfrompatientsinthesurroundingcommunityundergoingPFO/ASDclosure.Subject’sphysicianwilldetermineinclusionineitherexerciseornon-exercisegroup,basedonavailablemedicalinformation.

Previoushistoryofcoronaryarterydisease(ischemicheartdiseasesuchasangina,heartattack,myocardialinfarction).FailureofModifiedAllen’sTestinbothhands.Currentlytakingmedicationsorherbalsupplementsforanyheartorrespiratorydiseasethattheycannotstoptakingfor48hrspriortotesting(seasonalallergymedicationnotincludedinexclusionmedications).Lidocaine,nitroglycerineorheparinallergy.Womenwhoarepregnantortryingtobecomepregnant.Previoushistoryofanyconditionthatwouldpreventthesubjectfromperformingcycleergometerexercise(forexercisestudyonly).Physiciandetermination.PFO/ASDdeemedbyreferringphysicianasnotfullyclosed/endothelializedat6monthspost-PFO/ASDclosureprocedure.

4.Compensation:

SubjectCompensation(maximumof$540forexercisesubjectsand$330forNON-exercisesubjects;paidviacheckattheendofthestudy):

Visit#1(ExerciseSubjects):$25.00:Completingtheinformedconsentandhealthhistoryquestionnaire($5.00)andechocardiographicscreeningandblooddraw($10.00)willpay$15.00.Thepulmonaryfunctiontests,thediffusioncapacitytest,andthewholebodyplethysmographyornitrogenwashoutwillpay$10.00.Subjectswhochoosenottoparticipateuponreviewoftheinformedconsentorareexcludedbasedonanyfindingsduringthisvisitwillbepaidfortheirdegreeofvisitcompletion,thatis$5.00ifthesubjectdecidesnottoparticipateafterreviewingtheinformedconsent;$10.00forparticipationinthescreeningprocedures;totalcompensationforreviewingtheinformedconsentandparticipatinginscreeningis$15.00.

Visit#2(ExerciseSubjects):$35.00:Completingthehypercapnicbreathingchallenge($10),completingtheactivitymonitortraining($5),completingthesixminutewalktest($5)completingtheVO2maxtest($15).

Visit#3(ExerciseSubjects):$175:Completingthearterialbloodline($100)andexercisetests($75).

Visit#4a(ExerciseSubjects):$30.00:Completingtheechocardiographicscreeningandblooddraw($15.00)willpay$15.00.Thepulmonaryfunctiontests,thediffusioncapacitytest,andthewholebodyplethysmographyornitrogenwashoutwillpay$15.00.ReimbursementforDay4ismorethanDay1despitefewerprocedures.Thisistoencouragesubjectstoreturn3monthslater.

Visit#4b(ExerciseSubjects):$10.00:CompletingtheIVblooddraw.

Visit#5a(ExerciseSubjects):$35.00:Completingthehypercapnicbreathingchallenge($15)andcompletingthesixminutewalktest($5)completingtheVO2maxtest($15).

Visit#5b(ExerciseSubjects):$30.00:Completingtheechocardiographicscreeningandblooddraw($15.00)willpay$15.00.Thepulmonaryfunctiontests,thediffusioncapacitytest,andthewhole-bodyplethysmographyornitrogenwashoutwillpay$15.00.ReimbursementforVisit4ismorethanVisit1despitefewerprocedures.Thisistoencouragesubjectstoreturn6monthslater.

Visit#6a(ExerciseSubjects):$230:Completingthearterialbloodline($130)andexercisetests($100)

Visit#6b(ExerciseSubjects):$35.00:Completingthehypercapnicbreathingchallenge($15)andcompletingthesix-minutewalktest($5)completingtheVO2maxtest($15).

Visit#7a(ExerciseSubjects):$10.00:CompletingtheIVblooddraw.

Visit#7b(ExerciseSubjects):$230.00:Completingthearterialbloodline($130)andexercisetests($100)

NOTE:ReimbursementforVisits4-7ismorethanVisits1-3despitefewerprocedures.Thisistoencouragesubjectstoreturn3or6monthslaterforthestudy.

Visit#1(NON-ExerciseSubjects):$25.00:Completingtheinformedconsentandhealthhistoryquestionnaire($5.00)andechocardiographicscreeningandblooddraw($10.00)willpay$15.00.Thepulmonaryfunctiontests,thediffusioncapacitytest,andthewholebodyplethysmographyornitrogenwashoutwillpay$10.00.Subjectswhochoosenottoparticipateuponreviewoftheinformedconsentorareexcludedbasedonanyfindingsduringthisvisitwillbepaidfortheirdegreeofvisitcompletion,thatis$5.00ifthesubjectdecidesnottoparticipateafterreviewingtheinformedconsent;$10.00forparticipationinthescreeningprocedures;totalcompensationforreviewingtheinformedconsentandparticipatinginscreeningis$15.00.

Visit#2(NON-ExerciseSubjects):$130.00:Completingthehypercapnicbreathingchallenge($10),completingtheactivitymonitortraining($5),completingarterialline($100)andarterialblooddrawsbreathingroomairand100%O2($15).

Visit#3a(NON-ExerciseSubjects):$165.00:Completingthehypercapnicbreathingchallenge($15),completingarterialline($130)andarterialblooddrawsbreathingroomairand100%O2($20).

Visit#3b(NON-ExerciseSubjects):$10.00:CompletingtheIVblooddraw.

Visit#4a(NON-ExerciseSubjects):$10.00:CompletingtheIVblooddraw.

Visit#4b(NON-ExerciseSubjects):$165.00:Completingthehypercapnicbreathingchallenge($15),completingarterialline($130)andarterialblooddrawsbreathingroomairand100%O2($20).

NOTE:ReimbursementforDay3/4ismorethanDay2despitefewerprocedures.Thisistoencouragesubjectstoreturn3monthslater.

Anysubjectthatwithdraws(oriswithdrawn)beforetheendofthestudywillreceiveproratedpaymentuptothepointofcompletion.

E. InformedConsentProcess

Informedconsentwillbeadministeredtoeachsubjectbytheprimaryinvestigatorandcolleagues.

Theprimaryinvestigatoriswellversedintheprocessofinformedconsentandhastrainedhisco-investigatorsthoroughlyonhowtobestperformthisprocedure.ThePIwillensurethatallinvestigatorsobtainingconsenthaveexperienceintheinformedconsentprocedureandarecapableofadequatelydiscussingtherelatedphysiology,studyprocedureandpotentialrisks.

Theresearcherwillfirstverballyexplainthestudyinitsentiretyandindoingsowalkthroughtheinformedconsentinperson.Subjectswillthenbegivenasufficientlengthoftimetoreadthroughtheinformedconsentformprivatelyandinstructed/encouragedtowritedownorrememberanyquestions/concernstheymayhave.Afterward,theresearcherwillrejointhesubjectandaddressanyquestionorconcerntheymayhavewhilesubsequentlygoingbackthroughtheinformedconsentformwiththesubjectandobtaininganyneededinitialsandsignatureattheendofthedocument.Furthermore,theinvestigatorwillverballyaddressanyquestionsthesubjectmayhaveregardingtheseriousnessand/orlikelihoodfortheoccurrenceoftherisksdescribedintheInformedConsentForm.TheresearchteamwilladdressprobabilityandseverityofanyadversereactionswiththesubjectbycarefullyexplainingthestatementsregardingprobabilityandseveritycontainedwithintheInformedConsent.Theinvestigatorwillalsoprovideappropriatestatistics(whereavailable)regardingtheprobabilityofadversereactions.Theinvestigatoralsoadvisesthesubjectofwhathe/shecanexpecttofeelduringaparticularprocedure,forexample,duringcontrastinjection.Investigatorfurtherexplainsanyquestionsregardingphysiologyorreasonforaparticularprocedureinplainlanguage.

OnthedaybeforeALLvisits,thesubjectwillbetelephonedore-mailed(dependingonpreference)toconfirmparticipationandasareminderto1)notdrinkcaffeinefor12hoursbeforeeachstudyday,2)notexerciseordrinkalcoholfor24hoursbeforeeachstudydayand3)noteatfor2hoursbeforearrivingforeachstudyday.Malesubjectswillberequiredtogoshirtlessforallstudiesinvolvingechocardiography.Femalesubjectswillneedtowearasportsbraforallstudiesinvolvingechocardiography.Tominimizeanyriskofembarrassmentbothmaleandfemalesubjectswillbeallowedtowearaloosefittingshirt(providedbytheresearchers)thatallowstheupperbodytobecoveredbutalsoallowsforimagingoftheheartandtheplacementofsmallelectrodesthatrecordheartrate.

F. ProvisionsforParticipantPrivacyandDataConfidentiality

EachsubjectfolderwillbestoredinalockingfilecabinetinsidetheprimaryinvestigatorslockingofficelocatedintheUniversityofOregonCardiopulmonaryandRespiratoryPhysiologyLab.Thislabislocatedonthe2ndflooroftheCenterforMedicalEducationandResearchBuildingat722E.11thSt.,Eugene,OR97403.AllothercomputerfilesassociatedwiththesubjectwillbeidentifiedonlythroughtheiruniquesubjectIDandstoredonapasswordprotectedlabcomputers.Thede-identifieddatawillbekeptforatleast7yearsafterpublication,perNIHguidelines.Intheunlikelyeventthedataarenotpublished,theywillbekeptforatleast10yearsaftercollection.Thiswillensuresufficienttimeforpublicationafterdatahavebeencollectedconsideringsometraineestakeupto6yearstograduate,andoftenpublicationdoesnotoccuruntilmanyyearsaftergraduation.

EachsubjectwillbeassignedanIDusingarandomnumbercodesystemconsistingofthreetofivelettersdescribingthestudy(e.g.,CLOSE)andarandom,non-repeatingnumber(1-1000).ThisIDwillbeassociatedwiththeiruniquefolder,whichwillcontainallstudydocumentsanddatacollectedincludingallassociatedforms(i.e.informedconsentdocument).

TheprimaryinvestigatorwillmaintainasubjectIDkeycapableofidentifyingsubjectIDstosubjectnamesandcontactinformationtoprovideuswiththeabilitytoidentifysubjectsasadditionalquestionsorresearchfindingsarise.ThisIDkeywillbekeptinalockedfilingcabinetalsowithintheofficeoftheprimaryinvestigator.Nocontactinformationwillbestoredwithsubjectdata.

De-identifieddatamaypotentiallybesharedwithotherinvestigatorsforresearchpurposes.

G. PotentialResearchRisksorDiscomfortstoParticipants

Confidentiality:

Ifdataislostorstolen,subjectscouldexperienceinvasionofprivacy.Tominimizethepotentialinvasionofprivacy,wearenotcollectingsocialsecuritynumberssothatthepotentialeconomicimpactisgreatlyminimized.Allofourfileswillbekeptinalockedfilingcabinettopreventtheftanddatawillbede-identified.Dataacquiredoncomputerswillbepasswordprotected.Assuch,theprobabilityoftheadverseoutcomesdiscussedaboveislow,andtheseverityisminimal.

Psychological:

Malesubjectswillberequiredtogoshirtlessforallechocardiographyandexercisestudies.Femalesubjectswillneedtowearasportsbraforallechocardiographyandexercisestudies.Femalesubjectswillbeallowedtowearaloosefittingscrubtop(providedbytheresearchers)overtheirsportsbrathatallowsforechocardiographicimagingandEKGelectrodeplacement.Accordingly,bothmaleandfemalesubjectscouldpotentiallyfeelembarrassedorhavemodestyissuesbybeingshirtless(males)orwhenonlywearingasportsbra(females).Tominimizetheriskofembarrassmentormodestyissues,bothmaleandfemalesubjectswillbeallowedtowearaloosefittingscrubtop(providedbytheresearchers)thatallowsforconcealmentofupperbodybutalsoallowsforechocardiographicimagingandEKGelectrodeplacement.Femalesubjectswillstillbe

allowedtowearthesportsbrawiththescrubtopwhichwillallowforrequiredinstrumentation,butwillalsoallowthesubjecttocoverupasmuchaspossibleforthestudy.Bothmalesandfemalesmaywearsweatpantsorshorts,i.e.whatevermakesthesubjectcomfortable.Assuch,theprobabilityoftheadverseoutcomesdiscussedaboveislow,andtheseverityisminimal.

Physiological:

PulmonaryFunctionTests:Risksassociatedwithpulmonaryfunctiontestingincludeshortnessofbreath,cough,dizziness,andpossiblelossofconsciousness.Tominimizerisks,theco-investigatorswilladministerallpulmonaryfunctiontestsandallowsubjectstorestbetweenmeasurements.LungfunctiontestingperformedinourlabisaroutineassessmentperformedinpulmonaryfunctionlabsallovertheworldaccordingtoAmericanThoracicSocietyandEuropeanRespiratorySocietystandards.Youcanstopthetestatanytimeifyoufeelanyoftheabovesymptoms.Theprobabilityandseverityoftheserisksisverylow.

WholeBodyPlethysmography:Risksassociatedwithwholebodyplethysmographyincludeshortnessofbreath,dizziness,andcough.Tominimizerisks,theco-investigatorswilladministerallwholebodyplethysmographytestsandallowsubjectstorestbetweenmeasurements.Aswithpulmonaryfunctiontesting,theprobabilityoftheadversereactionsdiscussedaboveislow,andtheseverityisminimal.

NitrogenWashout:Therearenorisksassociatedwithbreathing100%oxygenfor7-10minutes.

DiffusionCapacity(DLco):Risksassociatedwiththediffusioncapacitytestingincludeexposuretocarbonmonoxide(CO),shortnessofbreath,dizziness,andcough.ThepercentageofCOinthegasbeingbreathedwillbe0.3%.Cigarettesmokecontains3%COortentimestheamountofCOthatwillbebreathed.Performingthetest5timeswillincreasethelevelofCOboundtohemoglobininthesubject’sbloodby3.5%.NormalrestinglevelsofCOboundtohemoglobinarelessthan3%asanon-smoker.Thismeansthatifasubjectperforms5tests,theirbloodlevelsofCOwillincreasefrom3to3.1%,maximally.Thehalf-lifeofCOinbloodisbetween5and6hr,meaningthatbloodwith3.1%COcontenttostartwith,wouldhavelessthan1%carbonmonoxide15to18hourslater.Assuch,theprobabilityoftheadversereactionsdiscussedaboveislow,andtheseverityisminimal.ThediffusingcapacitytestperformedinourlabisaroutineassessmentperformedinpulmonaryfunctionlabsallovertheworldaccordingtoAmericanThoracicSocietyandEuropeanRespiratorySocietystandards.Aswiththelungfunctiontesting,theprobabilityandseverityoftheserisksislow.TominimizerisksassociatedwithtestingdiffusioncapacityofthelungusingCO,testswillbeperformedusingacommerciallyavailablediffusiongasmixturewith0.3%COandeachsubjectwillbelimitedto3to5singlebreathtestsseparatedbyaminimumof4minaccordingtoATS/ERSrecommendationstominimizeexposuretoCO.Theco-investigatorswilladministeralldiffusioncapacitytests.

VO2MAXandexercisetesting:SubjectswillperformaVO2maxtestwheretheyexercisetovolitionalexhaustion.CriteriaforterminatingaVO2maxincludeachieving:1)heartrate>85%ofage-predictedmax(220-age),2)aplateauinoxygenconsumptionand/orarespiratoryexchangeratio>1.15;allofthesecriteriaarecontinuouslymonitoredonourmetabolicsystemand12leadEKG.Thiscarriestherareriskofdizziness,confusion,nausea,

fatigue,difficultybreathing,abnormalheartrhythms,stroke,heartattack,andsuddendeath.Insubjectslessthan35yearsold,theriskofsuddendeathofallcausesisestimatedtobe1in133,000formen(VanCampetalMSSE1995).Inthisstudyonly100of136deathswithidentifiablecauseswerecausedbycardiacevents,sothisestimateofriskmayoverestimateincidenceofcardiacevents.Theoverallriskofsuddendeathcausedbyaheartproblemforallagesandsexesisestimatedtobe1in15,000to18,000.(Source:AmericanCollegeofSportsMedicine-ACSM).Assuch,theprobabilityoftheadversereactionsdiscussedaboveislow,andtheseverityisverylow(e.g.dizziness)toveryhigh(e.g.suddendeath).

Hypercapniaduringrebreathingtests:Risksassociatedwithbreathinghypercapnia(highcarbondioxide)atrestincludefeelinglight-headed,headache,fatigue,dizziness,shortnessofbreath. Subjectswillbemonitoredwithaperipheralestimateofarterialoxygensaturationusingaforeheadmonitortoensureyouarewelloxygenatedandwewillcontinuouslymonitorinspiredandexpiredoxygenandcarbondioxidelevels.Assuch,theprobabilityoftheadversereactionsdiscussedaboveismoderate,andtheseverityisminimal.

Esophagealtemperatureprobe:Risksassociatedwithplacingtheesophagealtemperatureprobeincludenoseandthroatirritation,gaggingsensationandanextremelyremotetheoreticalriskofesophagealpuncture.Assuch,theprobabilityoftheadversereactionsdiscussedaboveislow,andtheseverityisminimal.Intheeventsubjectscannottoleratetheesophagealtemperatureprobe,subjectswillswallowaningestiblepill,aboutthesizeofamulti-vitamin,thatisdesignedforhumanuse(FDAapproved)andisaccurateto0.1ºC(CoreTemp,HQITechnologies,Inc.).Thispillwillbeusedtomeasurecorebodytemperatureatrestandduringcycleergometerexercise.Priortoingestionthetemperaturepillwillbecalibratedwithanexternalwirelessrecordingdevice.Thiswillallowustowirelesslyacquirethesubjectscoretemperaturewhennecessaryasthetemperaturepilltransmitsasignaltotheexternaldevicethatwillthendisplaytheappropriatetemperature.Thispillwillharmlesslypassthroughthesubject’sintestinaltract.Thepillisnotrecovered,isdisposable,andeverysubjectreceivesanewpillforeachstudyday.Theprobabilityandseverityofrisksassociatedwiththetemperaturepillisveryminimal.

Arterialcatheterization:Risksassociatedwiththeradialarterycatheterincludepainand/orbleedingduringinsertion,vasovagalsyncope,andhematoma(collectionofbloodundertheskinatthepuncturesite).Extremelyrarerisksusuallyassociatedwithlong-terminsertion(manydays)ofanarterialcatheterincludeinfectionandbloodvesselblockage.Ifabloodvesselblockageweretooccur,immediatesurgicaltreatmentmayberequired.Arterialcatheterizationwillbeperformedbyaboard-certifiedcardiologist(Dr.JeroldHawn)whilethesubjectiscomfortablyandsafelypositionedonagurneytomitigatethepotentialrisksassociatedwithvasovagalsyncope.Assuch,theprobabilityoftheadversereactionsdiscussedaboveislow,andtheseverityismoderate.ThePrincipalInvestigatorhasextensiveexperienceusingthistechniqueinaresearchsetting.

Intravenouscatheter:RisksassociatedwithplacementofanIVincludepainand/orbleedingduringplacement,vasovagalsyncope,hematoma(poolingofbloodundertheskin),infection,andvesselblockage.TheplacementoftheIVmaycausesomediscomfortwithrarebleedingorbruisingatthepuncturesite.Italsocarriestheriskofinfection.Tomitigaterisksassociatedwithvasovagalsyncope,thesubjectwillbesafelypositioneduprightand

sittinginanIVchair,andthesubjectwillbecontinuallymonitoredbyDr.Loveringand/oragraduatestudent.Assuch,theprobabilityoftheadversereactionsdiscussedaboveislow,andtheseverityisminimal.Dr.LoveringoragraduatestudentwillplaceIVs.

BloodRemoval:Risksassociatedwiththeremovalofbloodincludeanaversiontoseeingbloodthatcouldresultinnausea,vasovagalsyncope,increasedstress,and/orfeelingfaint.Tomitigatethesepotentialrisks,thesubjectiscontinuallymonitoredbyDr.JerryHawn(arteriallineplacement)andAndrewLoveringPhD(IVplacement)andcolleagues.Inaddition,thesubjectissafelyandcomfortablypositionedoneitheragurneyorIVchair.Inthisway,thepotentialriskofvasovagalsyncope(i.e.,fainting)ismitigated.Assuch,theprobabilityoftheadversereactionsdiscussedaboveislow,andtheseverityisminimal.

SalineContrastEchocardiography:ThePIhasbeenusingsalinecontrastechocardiographysince2003todetectbloodflowthroughintracardiacandintrapulmonaryshunts.Risks:transientdizzinessassociatedwithagitatedsterilesalineinjectioninpatientswithcardiacshunting.Withrespecttoexercise,thePrincipalInvestigatorhas>10yearsofexperienceusingTTSCEinaresearchsetting.In4years(2003-2007)attheUniversityofWisconsinMadison,approximately60human(maleandfemale)subjects(including8subjectswithapatentforamenovale)weretestedwithoutasingleadverseeventrelatedtoTTSCE.Additionally,researchdoneattheUniversityorOregonbetween2008and2016hasinvolved>100subjectsusingTTSCEatrestandduringexercisewithoutincidentrelatedtotheTTSCE.Wewilluseagitatedsterilesalinewithoutpreservatives.Furthermore,wewilluseaminimalvolume(3-5mL)ofsterilesaline.Dr.Loveringoragraduatestudentwillperformsalinecontrastinjections,whileRandyGoodmanorEbenFutralfromPeaceHealthwillperformechocardiography.Mixedsaline(saltwater),eitheraloneorwith5%sugarinwaterhasbeenusedtohelpseetheultrasoundpictures(echocardiogram)foroverthirtyyears.Salinecontrastbubbleinjectionsareroutinelyusedtoscreenforthepresenceofapatentforamenovaleintheclinic.TheAmericanSocietyofEchocardiographyGuidelines(2014)statethat“…lifethreateningreactionsarerare(<1in10,000)”whenusingcontrastinjections(includingbubbleswithproteinshells)andTheEuropeanAssociationofEchocardiography(2009)hasstatedthat“…theevidenceshowsthatcontrastechocardiographyisverysafeinclinicalpractice.”Andthisincludesusingstabilizedbubbleswithproteinshellsandweonlyusenon-stabilizedsalinecontrastbubblesinourlab.Weonlyuseasmallamountofairmixedwithsaline,thustheprobabilityofanysevereadversereactionisverylow.Giventheevidencepresentedabove,theprobabilityoftheadversereactionsdiscussedaboveislow.Althoughtheseverityofarterialgasemboliishigh,giventheamountofairusedandtheshortlifespanofintravascularbubblesofthissize,thelikelihoodoftheconstellationofunfortunateeventsrequiredforaseriousadversereactiontooccurisverysmall.

Heparinandlidocaineallergy:Bothcarrythepotentialriskofelicitinganallergicreaction.Theriskofdevelopinganallergicreactiontoeachoftheseindividuallyorcumulativelyisverysmall.Somesymptomsofanallergicreactionincludeitching,tingling,chesttightness,difficultybreathing,nausea,orvomiting.Subjectswillbecontinuouslymonitoredforeachofthesesymptoms.Theprobabilityofthisriskisverylowandseverityoftheserisksismoderate.

RisksforsubjectsundergoingPFO/ASDclosure:PotentialrisksforsubjectsundergoingPFO/ASDclosureareatleastequaltothegeneralpopulationasoutlinedabove.Because

thesesubjectshaveaholeintheirheart,whichallowsforbloodtoflowacrosstheheartwithoutbeingfilteredbypulmonarycapillaries,thereisanelevatedriskforstroke,TIAand/orarterialhypoxemia(thesearelikelythereasonsthesubjectsisgettingthePFO/ASDclosed).Indeed,thesubjectswhohavebeenselectedforPFO/ASDclosureinthisstudywillincludethosewithprevioushistoryofstroke,TIAand/orexercise-inducedarterialhypoxemia.ThegoalofthePFO/ASDclosureistoreducesubsequentcerebrovascularaccidents(stroke&TIA)and/orprevent/minimizeexercise-inducedarterialhypoxemia.Thus,postPFO/ASDclosuresubjectswouldhaveareducedriskprofilethatwouldlikelyresemblethosewithoutaPFO/ASD.

SafetyEquipmentavailableintheCardiopulmonaryandRespiratoryPhysiologyLaboratory(wherealltestingandscreeningwillbeperformed):PhillipsFRxAED,aspareAEDbattery,andspareAEDpads,bottledoxygenandfacemasks,allnecessaryequipmenttorunACLSalgorithms(suction,masks,breathingbag,etc.)andACLSdrugssuchaschewableaspirin,andoxygenwillbeadministeredasrequiredbyAHAandACLSguidelines.Additionally,astandardfirstaidkitisalsoavailable.

EmergencyProcedures:AccordingtoAmericanHeartguidelines,intheeventofanadversecardiopulmonaryevent,wewillbeginCPR,call911(asdirectedbyUofOEH&S),andwillcontinueCPRasrequireduntilemergencymedicalpersonnelarrive.

SafetyMonitoring:Subjectswillbegivenclearinstructionsthattheyshouldnotifytheinvestigatorsimmediatelyiftheyexperienceanyoftheabove-mentionedrisksymptoms.Duringallexerciseandrecoveryprocedures,allsubjectswillbenon-invasivelyandcontinuouslymonitoredforvitalsignsusing:1)a12leadEKGtomonitorelectricalactivityoftheheart,and2)aforeheadprobetomonitorarterialoxygensaturationandheartrate.Duringallotherproceduressubjectswillbevisuallymonitoredforanysignsofdiscomfort,distressorproblems.Duringbothexerciseandrestingprocedures,theinvestigatorswillcontinuouslyaskthesubjectshowtheyarefeelingandhowtheyaredoing.

H. PotentialBenefitsoftheResearch

Thisstudywillnotimprovethehealthofsubjectsandisonlybeingdonetogatherinformation.Thisstudywillnotimprovethehealthofthegeneralsubjectpopulation.Completingtheaimsofthisstudywillhavethebenefitofcontributingtogeneralizableknowledge.

I. InvestigatorExperience

ThePIandcolleagueshavebeenperformingcardiopulmonaryandrespiratoryphysiologyinvestigationsatrestandduringexerciseinhealthyanddiseasedpopulationsattheUniversityofOregonfor~10years.Dr.Lovering’sCVisonfile.

ThePItrainsallgraduateandundergraduatepersonnelonalllaboratoryproceduresandprotocols.Co-investigatorJerryHawn,MDisaboardcertifiedcardiologistwhohasworkedwithDr.Lovering’sgroupforalmost10yearsplacingradialarterycatheters,interpretingechoesandprovidingsignificantintellectualinputtothelaboratorygroup.

Ultrasoundtechnicians,RandyGoodman,RDCSandEbenFutral,RDCShaveworkedwithDr.Lovering’sgroupforyearsaswell(Goodman~10years;Futral~5years).Thesetwo

registereddiagnosticcardiacsonographers(RDCS)haveperformedthousandsofrestingandstressechoesinpatientsandresearchsubjects.

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