PFO: Button me up, but wait... Comprehensive evaluation of the patient

Review

PFO:

Button

me

up,

but

wait

.

.

.

Comprehensive

evaluation

of

the

patient

Fausto

Pizzino

(MD)

,

Bijoy

Khandheria

(MD)

,

Scipione

Carerj

(MD)

,

Giuseppe

Oreto

(MD)

,

Maurizio

Cusma`-Piccione

(MD)

,

Maria

Chiara

Todaro

(MD)

,

Lilia

Oreto

(MD)

_,

_Giampiero

_Vizzari

_(MD)

_,

_Gianluca

_Di

_Bella

_(MD,

_PhD)

_,

Concetta

Zito

(MD,

PhD)

*

a_{CardiologyUnit,DepartmentofClinicalandExperimentalMedicine,UniversityofMessina,AziendaOspedalieraUniversitaria‘‘PoliclinicoG.Martino’’and}

Universita’degliStudidiMessina,Messina,Italy

b_{AuroraCardiovascularServices,AuroraSinai/AuroraSt.Luke’sMedicalCenters,UniversityofWisconsinSchoolofMedicineandPublicHealth,Milwaukee,}

WI,USA

Contents

Introduction... 486

CryptogenicstrokeandPFO ... 486

Transcatheterclosure:thefailureofthetrials... 486

Tocloseornottoclose?Thatisthequestion... 487

Clinicalfeaturesassociatedwithincreasedriskofparadoxicalembolism... 487

Age ... 487

Deep venous thrombosis . . . 488

Exclusionoflacunarbraininfarctionandneuroimagingpatternlesionevaluation ... 488

ARTICLE INFO Articlehistory:

Received6November2015

Receivedinrevisedform6January2016 Accepted18January2016

Availableonline23February2016 Keywords:

Patentforamenovale Cryptogenicstroke Transcatheterclosure Device

ABSTRACT

Patentforamenovale(PFO)isaslitortunnel-likecommunicationintheatrialseptumoccurringin

approximately 25% of the population. A wide number of pathological conditions have been linked to its

presence,mostnotably,cryptogenicstroke(CS)andmigraine.However,inthesettingofaneurological

event,itisnotoftenclearwhetherthePFOispathogenicallyrelatedtotheindexeventoranincidental

finding. Therefore, a detailed analysis of several clues is needed for understanding PFO’s clinical

significance,withafrequentcase-by-casedecisionaboutdestinationtherapy.Indeed,thecontroversy

aboutPFO’spathogenicitypromptedaparadigmshiftofresearchinterestfrommedicaltherapywith

antiplatelets or anticoagulants to percutaneous transcatheter closure, in secondary prevention.

Observationaldata andmeta-analysis of observational studieshad previously suggested that PFO

closurewithadevicewasasafeprocedurewithalowrecurrencerateofstroke.Todate,however,recent

randomizedcontrolledtrialshavenotshownthesuperiorityofPFOclosureovermedicaltherapy.Thus,

theoptimalstrategyforsecondarypreventionofparadoxicalembolisminpatientswithaPFOremains

unclear.Moreover,thelatest guidelinesfortheprevention onstrokerestrictedindicationsforPFO

closuretopatientswithdeepveinthrombosisandhigh-riskofitsrecurrence.Giventheserecentdata,in

the present review, we critically discuss current treatment options, pointing out the role of a

comprehensive patient evaluation in overcoming PFO closure restrictions and planning the best

managementforeachpatient.

!2016JapaneseCollegeofCardiology.PublishedbyElsevierLtd.Allrightsreserved.

* Correspondingauthorat:c/oAuroraCardiovascularServices,AuroraSt.Luke’sMedicalCenter,2801W.KinnickinnicRiverParkway,Ste.840,Milwaukee,WI53215, USA.Tel.:+14146493909;fax:+14146493578.

E-mailaddress:publishing160@aurora.org(C.Zito).

ContentslistsavailableatScienceDirect

Journal

of

Cardiology

j our na l ho me pa g e : w ww . e l se v i e r . com / l oca t e / j j cc

http://dx.doi.org/10.1016/j.jjcc.2016.01.013

Prothromboticstatus ... 488

The RoPE score . . . 488

Cluesfromcardiacimaging:howtocarefullystudythePFOforplanningoptimaltreatments... 488

PFOsize,shuntseverity,andshuntatrest... 489

Atrial septal aneurysm . . . 489

TunneledPFO... 489

Fossaovalerims... 490

Hybriddefect... 491

Eustachianvalve/Chiari’snetworkandEustachianridge... 491

Conclusiveremarks... 491 Funding ... 491 Conflictofinterest... 491 Acknowledgements... 491 References... 491 Introduction

Patentforamenovale(PFO)hasbeenrelatedtoincreasedriskof cryptogenic stroke (CS) in young patients [1], encouraging the developmentoftranscatheterpercutaneousclosure,whichproved tobesafeandhashadahighrateofsuccess.However,randomized controlledtrials(RCT)inthepastfewyearsfailedtodemonstrate

the superiority of closure in comparison to medical therapy

[2–4].Asaresult,thelatestguidelinesforthepreventionofstroke significantlyrestrictedtheindications forPFO closure (Table1)

[5].However,clinical,anatomicaland hemodynamicfeaturesin thehuge scenarioofpatients withCSand PFOcouldidentifya subgroupthatmaypotentiallybenefitfromPFOclosure.Weaimto

show the pivotal role of echocardiography for a detailed

reconstruction of PFO anatomy and shunt quantification thus

encouragingitsextensiveapplication.Thisapproachmightleadto potentiallyovercomingtherestrictionsarisingfromthecurrent guidelinesandchoosingtheoptimaltherapeuticstrategyinevery case.

CryptogenicstrokeandPFO

About 35% of ischemic cerebral events are defined as

‘‘cryptogenic’’becauseitisimpossibletoidentifyaclearetiology

[6]. Retrospective studies described high prevalence of PFO in

young patients with CS in comparison to healthy controls

[7,8]. However, recent large prospective studies demonstrated that PFO is not a predictor of stroke or silent cerebrovascular events(CVE)[9].TheseresultsindicatethatsimplyfindingPFOin

patients with CS does not increase the risk of stroke and

consequently does not support closure. Therefore, identifying

thesubsetofpatientswithCSduetoPFOisofcentralimportance. Themostacceptedmechanismtoexplaintherelationshipbetween

CSand PFO is paradoxicalembolism.The main supportof this

hypothesisisthatyoungadultswithCSaremorelikely tohave bothPFOandpelvicdeepveinthrombosis(DVT)thanyoungadults withischemicstrokeofknowncause[10],togetherwithfewcase reportsshowingclotstrappedinaPFOinpatientswithcentralor systemicembolization[11,12].

Transcatheterclosure:thefailureofthetrials

In2012,alargemeta-analysisofobservationalstudiesreported asignificantreductionofrecurrentCVEof3.5(95%CI:2.1–5.0)/100 patientsperyearinpatientsthatundergoclosureincomparisonto medicaltreatment[13].Nonetheless,threefollowingRCTsfailedto confirmthis preliminaryresult in their intention-to-treat (ITT) analysis,whichdidnotdemonstratethatclosurewassuperiorto medicaltreatment(Table2),eventhoughtherewasatrendinall

threestudiesthatclosuresweremorebeneficial[2–4].However, several inconsistenciesinthemethodologyofthestudiescould haveinfluencedthenegativeresults,including:

!Statisticalpowerofthestudies:Alowerthaninitiallyestimated numberofpatientsrecruitedaffectedthestatisticalsignificance ofthethreeRCTs(particularlyforCLOSUREI).

!Deviceused:DifferentclosuredeviceswereusedintheRCTs,in twoofthem(PCandRESPECT)theAmplatzerPFOOccluder(St. JudeMedical,SaintPaul,MN,USA)wasused;whileinthethird,

theSTARflexdevice(NMTMedical,Boston,MA,USA)wasused

(CLOSUREI).TheuseoftheAmplatzerappearedtobesuperiorto

the other devices, although rates of thrombosis and atrial

fibrillationweresimilar[14].

!Inclusioncriteriaandbaselinefeaturesofpopulation:Onlythe RESPECTstudyrestrictedtheinclusiontopatientswithstroke only,excludingsubjectswithtransientischemicattack(TIA)and lacunarbraininfarction[14].Asaresult,RESPECTsuggested,but didnotprove,thathighlyselectedpatientswithfeaturesclearly suggestiveofparadoxicalembolismshouldbethemostlikelyto benefitfromPFOclosure,andthiscouldbethefocusoffuture investigation[14].

!Medical therapy: Only one prospective study compared

out-comes in patients withPFO and strokerandomizedto either

aspirin or warfarin, reporting a not statistically significant difference in 2-year event ratebetween thewarfarin-treated groupandtheaspirin-treatedgroup(hazardratio,0.5;95%CI, 0.2–1.7,p=0.28) [15].Asa consequence,thethreeRCTsused eitherantiplateletoranticoagulanttherapyatthediscretionof theinvestigators.

!Follow-up:ThestrokerateswerelowinallthreeRCTs;alonger follow-upwasprobablyrequired.

Accordingtotheseconcepts,therecentlypresentedresultsof theextendedfollow-upoftheRESPECT(morethan10years)study revealedthat,althoughtherewerenosignificantbetween-group differencesforall-causestrokesintheoverallITTanalysis,which includedbothCSthoseclassifiedas‘‘other,’’onthecontrarythere wasa significantreductionforPFOclosurevs.medical

manage-ment when researchers looked specifically at incidence of CS

(10 strokes vs 19, respectively; hazard ratio 0.46, p=0.04). Moreover,authorsfoundthat20%ofthepatientpopulationaged

past the original cut-off point of 60 years, making the older

patientsmoresusceptibletonon-CS,whichcannotbeprevented byPFOclosure.Indeed,whenlimitingITTanalysistothoseunder theageof60,therelativeriskreductionforall-causestrokewas 52%forthePFOclosurevscontrolgroup(p=0.035).Inaddition, therewasa75%relativeriskreductionforCSforthePFO-closure patientswhohadatrialseptalaneurysmor‘‘substantialshunts’’ (p=0.007)[16].

Tocloseornottoclose?Thatisthequestion

ThenegativeresultsoftheRCTshaveledtoarestrictionofthe guidelinesinregardtotrans-catheterPFOclosurethat‘‘mightbe considered’’onlyinpatients withanassociationofPFO,CS,and DVT(ClassIIb;LevelofEvidenceC);whileindifferentconditions closureisfirmlycontraindicated[5].

ThestrictinterpretationoftheresultsofRCTsaimstoprotect patientsfromtherisksinherenttotheclosureintheabsenceofa

clear advantage of the procedure over medical treatment;

however,a consistentnumber ofpatients who maypotentially

benefit from the closure are going to be eliminated from

consideration of the procedure. A sub-analysis of the RESPECT

studyreportedthatpatientswithoutvascularriskfactors,witha corticalinfarctonbaselinemagneticresonanceimaging(MRI),and

asubstantialPFOshuntmaybenefitfromtheAmplatzerdevice

during a multiple-year period [2]. In addition, other studies

reported that specific clinical, anatomical, and hemodynamic

features are associated with increased risk of paradoxical

embolismand recurrentCVE.Therefore, a carefulevaluation of advantagesandrisksperformedineverysinglepatient,takingin account datacollected by both clinical evaluation and imaging methods,maybe thekeytoidentifyinga subset ofpatients in whomtheriskofrecurrentCVEishighandclosurecanrepresenta concreteadvantageovermedicaltherapy[17,18].

The information provided by imaging techniques is also

importantinassessingthefeasibilityofthepercutaneousclosure,

toestimatetheprobabilityofproceduralsuccessandtoselectthe mostappropriateclosuredevice[19–21].

Regarding the effects of closure on migraine, the recent

PREMIUM study, a randomized, sham-controlled, double-blind

study of percutaneousclosure of PFO with the Amplatzer-PFO

Occluderinsubjectswithmedicallyintractablemigrainewithor withoutaura,demonstrated asignificantreductionin headache days(3.4vs2.0days,p=0.03)intheclosuregroup;however,the studyfailedtheprimaryendpointofdemonstratingthedevice’s

superiority in reducing migraine attacks of more than 50% in

comparison to medical therapy [22]. Also in this case, specific

patient characteristics may help for accurately identifying

responders.Indeed,subgroupanalysisofPREMIUMsuggeststhat individualswithauraoccurringduringthemajorityoftheirattacks mayrespondmorefavorablytoPFOclosure(p=0.015),andthata smallbutsignificant(p=0.02)percentageofmigrainewithaura patientsmayexperiencecompleteremissionofmigraine[22]. Clinicalfeaturesassociatedwithincreasedriskofparadoxical embolism

Age

In patients with CS, PFO prevalence is greater in younger

patientsincomparisontoolderones[23].Ameta-analysisshowed thattheoddsratioforCSinPFOpatientswas2.0(95%CI1–3.7)in patients >55years ofagewhiletheoddsratiofor patients<55

Table1

Guidelinesonthemanagementofpatientswithstrokeassociatedwithpatentforamenovale.

Thereareinsufficientdatatoestablishwhetheranticoagulationisequivalentorsuperiortoaspirinforsecondarystroke preventioninpatientswithPFO

ClassIIb;levelofevidenceB ForpatientswithanischemicstrokeorTIAandaPFOwhoarenotundergoinganticoagulationtherapy,antiplatelettherapyis

recommended

ClassI;levelofevidenceB ForpatientswithanischemicstrokeorTIAandbothaPFOandavenoussourceofembolism,anticoagulationisindicated,

dependingonstrokecharacteristics

ClassI;levelofevidenceA ForpatientswithanischemicstrokeorTIAandbothaPFOandavenoussourceofembolism,whenanticoagulationis

contraindicated,aninferiorvenacavafilterisreasonable

ClassIIa;levelofevidenceC ForpatientswithacryptogenicischemicstrokeorTIAandaPFOwithoutevidenceforDVT,availabledatadonotsupportabenefit

forPFOclosure

ClassIII;levelofevidenceA InthesettingofPFOandDVT,PFOclosurebyatranscatheterdevicemightbeconsidered,dependingontheriskofrecurrentDVT ClassIIb;levelofevidenceC Source:AmericanHeartAssociation,Inc./AmericanStrokeAssociation,Inc.[5].

DVT,deepveinthrombosis;PFO,patentforamenovale;TIA,transientischemicattack.

Table2

Mainfeaturesofthethreerandomizedcontrolledtrialscomparingpatentforamenovaleclosuretomedicaltherapy.

CLOSURE1 RESPECT PC

Deviceused Starflexseptaloccluder Amplatzerseptaloccluder Amplatzerseptaloccluder

Randomizedpatients 909 980 414

Inclusioncriteria TIAandstroke Stroke TIA,stroke,andPE Exclusioncriteria >60yearsofage

Otheridentifiablecausesofstroke

Lacunarinfarction >60yearsofage

Otheridentifiablecausesofstroke

>60yearsofage

OtheridentifiablecausesofstrokeorPE Medicaltherapy Acetylsalicylicacid

Warfarin Acetylsalicylicacid Clopidogrel Warfarin Acetylsalicylicacid Ticlopidine Clopidogrel Warfarin End-point Stroke

Deathwithin30days Deathfromanycausebetween 31daysand2years

Stroke

Deathwithin30–45days

Death,stroke,TIA,PE

Follow-up 2years 2.75years(closure) 2.46years(medical)

4.1years Primaryend-pointrate C=23/447(5.1%)

M=29/462(6.2%)

C=9/499(1.8%) M=16/481(3.3%)

C=7/204(3.4%) M=11/210(5.2%) Hazardratioforclosure

vs.medicaltherapy

0.78;95%CI,0.45–1.35;p=0.37 0.49;95%CI,0.22–1.11;p=0.08 0.63;95%CI,0.24–1.62;p=0.34

years was5.1 (95% CI 3.3–7.8); theprobabilities that a PFO in patientswithCSisincidentalwere33%(28–39%)inage-inclusive studies,20%(16–25%)inyoungerpatients,and48%(34–66%)in olderpatients[24].Thiscanbeexplainedbytheassumptionthatin olderpatients,theprevalenceofotherriskfactorsforCSisrelevant andPFOismorefrequentlyfoundbycoincidence.

Deepvenousthrombosis

ThehypothesisoftheparadoxicalembolismthroughthePFO

presupposes the presence of DVT; consequently, a Doppler

evaluation in patients with PFO and CS should be performed.

ThelatestAmericanHeartAssociation/AmericanStroke Associa-tionguidelinesindicatethat percutaneousclosure isreasonable onlyinpatientswithevidenceofDVTassociatedwithCSorTIAand PFO(Table1)[5].

Exclusionoflacunarbraininfarctionandneuroimagingpatternlesion evaluation

Lacunar brain infarction is usually associated with intrinsic

pathology of small cerebral perforating vessels rather than

embolism [25]. Only the RESPECT study excluded patients

presentingwithlacunarinfarction;anundefinednumberofpatients

could have been included in the other two RCTs despite their

cerebrovasculareventthatwasnotcompatiblewithparadoxical embolism.AccurateneuroradiologicevaluationbyMRIshouldbe

performed before considering proceeding with percutaneous

intervention. Moreover, the neuroimaging lesions’ pattern may

helptodistinguishatrialfibrillationfromPFO-relatedstrokes[26]. Prothromboticstatus

Hypercoagulabilitymayfacilitatetheformationofthrombiin thevenoussystemandhasbeenrelatedtoparadoxicalembolism.

Geneticmutation offactorV Leidenandprothrombinmutation

wereassociatedwithincreasedriskforstrokeinPFOpatients[27], whilethecombinationofPFOandantiphospholipidantibodiesdid notsignificantlyincreasetheriskforstrokeinamulticenterstudy

[28].

TheRoPEscore

Kentetal.,analyzingdatafrom12studies,deriveda

clinically-determined score called Risk of Paradoxical Embolism (RoPE),

aimingtoprovideauser-friendlyandreliableinstrumenttoassess

theprobabilityoffindingaPFOinapatientwithCSandtheriskof

recurrent CS related to paradoxical embolism [29]. Variables

increasingthelikelihoodoffindingaPFOinCSpatientsincluded: youngerage,thepresenceofacorticalstrokeonneuroimaging,and theabsenceofdiabetes,hypertension,smoking,andpriorstrokeor TIA.Thescoreconsistsofa10-pointsystemderivedfromthese variables.PatientswithaRoPEscoreof0–3haveaPFO-attributable riskof0%(95%CI0–4)anda2-yearstroke/TIArecurrenceriskof 20%;whilepatientswithascoreof9–10haveaPFO-attributable fractionof88%(95%CI83–91)anda2-yearstroke/TIArecurrence riskof2%.Theadvantageofthisscoreistheeasyapplicationin clinicalpractice;however,itisbasedonlyonclinicalvariables,not takingintoaccounttheimportanceofanatomicalevaluationofthe

PFOandthehemodynamicfeaturesoftheshunt.

Cluesfromcardiacimaging:howtocarefullystudythePFOfor

planningoptimaltreatments

Contrast-enhancedechocardiographyhasbecomethemethod

of choicetodiagnose and evaluatethe PFO (Table 3). Contrast

transesophageal echocardiography (c-TEE) appears the

gold-standard technique allowing direct visualization of the shunt

andPFOanatomy.Moreover,itcanalsoincreasethesuspicionfor othersourcesofcardiacembolism,rulingoutthediagnosisofCS. Themain limitationis therelative invasivenessof themethod.

Three-dimensional TEE is reproducible and accurate with the

exceptionofsmallPFO(<2mm).Thistechniqueenablesaclearer understanding ofPFOmorphologyand isparticularlyhelpfulin

delineating the relationship of the PFO with surrounding

structuresandassistanceduringtheclosureprocedure[30]. Con-trastenhancedtransthoracicechocardiography(c-TTE)isaccurate andeasytoperform,butitshowslowsensitivity,particularlyin smallshunts.Moreover,TTEcandetectothersourcesofcardiac embolism, excluding the diagnosis of CS. Contrast transcranial Doppler(c-TCD)isasensitive,feasible,andaccuratetool;themain limitation is its low specificity because of the difficulty in differentiating intrapulmonary shunts from intracardiac shunts

[31].Accordingly,c-TCDandc-TTEcanbeconsidered complemen-taryandbothincludedasstandardexaminationsduringCS

work-up. Thus, an empiric approach could take into account an

integration of c-TTEand c-TCD, as first-linetools; while c-TEE and,ifavailable,three-dimensionalTEE,shouldbelimitedtothe followingselectedcategoriesofsubjects:(1)patientsscheduledfor transcatheter PFOclosure;(2) patientsin whomeither thePFO diagnosis is uncertainor an alternative emboliccardiac source mustbeconsidered;(3)patientswithhigh-riskPFO,particularly

Table3

Advantagesandlimitationsofthemainechocardiographicmethodsusedtodiagnoseandevaluatethepatentforamenovale.

Sensitivity Specificity Advantages Limitations Definitionofsevereshunt TTE Low High !Directvisualization

!Feasibility !Lowinvasiveness

!Potentialidentificationofother cardioembolicsources

!Badacousticwindow !SmallPFO

>25bubbles

TCD High Low !Feasibility !Lowinvasiveness !Detectionofsmallshunts

!Intrapulmonaryshunts !Highcalcificationofthecranium

(oldage)

>10MESCurtaineffect

TTE+TCD High High !Directvisualization !Detectionofsmallshunts

!Badacousticwindow

!Highcalcificationofthecranium

Curtaineffect TEE High High !Directvisualization

!Assessmentoftheanatomiccomplexity

!Invasiveness

!DifficultyinVMperformance

>25bubbles "4mm 3DTEE High High !Directvisualization

!Assessmentoftheanatomiccomplexity !Accurateevaluationofsurroundingstructures

!Invasiveness !SmallPFO

>25bubbles "4mm

MES, microembolic signals; TCD, transcranialDoppler; TEE,two-dimensional transesophageal echocardiography; 3D TEE, three-dimensionaltransesophageal echocardiography;TTE,two-dimensionaltransthoracicechocardiography;VM,valsalvamaneuver;PFO,patentforamenovale.

those experiencing recurrent CVE; and (4) patients with atrial septalaneurysm(ASA)and/orfindingofalargeparadoxicalshunt onc-TCD.

OncethePFOisidentified,severalechocardiographicfeatures thatareassociatedwithanincreasedriskofembolismneedtobe evaluated.A comprehensive inspectionof overall atrialseptum regionisalsorequiredinordertoobtainasuccessfulPFOclosure,

whenadvised.Themostimportantelementstobeaddressedare

thefollowing.

PFOsize,shuntseverity,andshuntatrest

Usually,theevaluationoftheanatomicalareaofPFOisnoteasy, becauseoftheirregularshapeoftheopeningandforthedynamic changesduringthecardiaccycle.TEEallowsadirectvisualization

of the atrial septum and is the criterion standard for the

measurement of the PFO size [1]. The measurement of the

maximumopeningbetweenseptumprimumandseptum

secun-dumintheleftatriumisthemostusedparametertoevaluatePFO

sizeincurrentpractice.Themeasurementshouldbeperformed

immediatelyafterthereleaseoftheValsalvamaneuver,duringthe maximumincreaseoftherightatrialpressureovertheleftatrium

one. The PFO consists of a valve-like structure, allowing a

unidirectionalflowfromtheright totheleftatrium; therefore, onlyatemporaryinversionofthepressuregradientinducedbya provocativemaneuvercanunmasktheshunt.Accordingly,thePFO canbeclassifiedaslarge("4mm),medium(3.9–2mm),andsmall (<2mm).AsizeofPFO"3mmhasbeendemonstratedtobethe mostpowerfulpredictivefactorofstrokerecurrencewithin3years (95%confidenceinterval2.1–3.7mm,areaunderthecurve0.889, p<0.001;sensitivityandspecificityof90.0%and79.4%, respec-tively) [32]. Similar results were revealed in other studies, reportingthatthepresenceof alarge sized PFOwasrelated to increasedrecurrenceofischemicstroke[20,33].

Theseverityoftheshuntisindirectlymeasuredbycountingthe numberofbubblesgoingthroughthePFOintotheleftatriumafter endovenousinjectionofcontrastvisualizedbyTEEorTTE.Onthis basis,theshuntcanbedefinedassmall(#5bubbles),moderate(6–

25 bubbles), or severe (>25 bubbles); however, there is no

commonagreementonthesevalues.Theevaluationofshuntsize

byTCDalsodemonstratedagoodcorrelationwithdataderived

from TEE; a severe shunt is defined by the detection of >10 microembolicsignalsoftenassociatedwithanalmosttotaloverlap ontheDopplerspectrumdefinedas‘‘curtaineffect’’[34].Alarger PFOisusuallyassociatedwithamoresevereshunt[35].Komar etal.demonstratedthatsymptomaticpatientsshowedlargePFO andsevereshuntmorefrequentlythanpatientswithsilentPFO

[19].ResultsoftheRESPECTstudysuggestedthatpatientswitha

large shunt and ASA benefited more from closure rather than

medicaltreatment[2].Goeletal.showedatrendtowardahigher prevalenceofsevereshuntinpatientspresentingwithrecurrent CVEwithoutstatisticalsignificance,however,theauthorsuseda cut-offof>30bubblestodefinesevereshunt[20],whichmayhave influencedthelackofstatisticalsignificance.Inourexperience,the useofprovocativemaneuvers,particularlyValsalvamaneuver,is crucialtoaccuratelyassessthesizeandtheseverityofshunt,and thepatientshouldbeproperlyinstructedtoperformanadequate

strain and a prompt release. Moreover, the operator should

carefullysearchforthesignssuggestiveofaneffectiveValsalva maneuversuchastheatrialseptumshifttowardtheleft,during TEEand/orTTE,andthedecreaseofmidcerebralarteryvelocity,by pulsedwaveDoppler,duringTCD.

Thepresenceofasignificantshuntatrest,withoutresortingto provocativemaneuvers,hasbeenrelatedtoanincreasedriskof recurrentCVE.Astudycomparing180patientswithright-to-left

shunt (RLS) at rest with 140 patients with RLS only after

provocativemaneuversrevealedthatthepresenceofrestingRLS wasassociatedwiththehighestriskofrecurrentstroke(oddsratio 5.9,95%,CI2.0–12,p<0.001);patientspresentingwithrestingRLS hadincreasedfrequencyofmultipleischemicbrainlesionsonMRI, previousrecurrentstroke,previousperipheralarterialembolism,

migrainewithaura,and—morefrequently—ASAandprominent

Eustachianvalve[36]. Atrialseptalaneurysm

ASAisdefinedas‘‘alocalizedsacculardeformity,generallyat thelevelofthefossaovalis,whichprotrudestotherightortheleft atriumorboth’’[37].Olivares-Reyesetal.classifiedASAbasedon

the major excursion direction in five types and reported an

incidence of 1.9% with a female/male ratio of 2:1. Criteria to diagnoseASAincludeanexcursionof"10mmintotherightorleft atriumoratotalsumofbilateralexcursion>10mmandabase amplitude "15mm [37]. Patients presenting withASAshowed higherprevalenceofPFO(about60%)incomparisontopatients withoutASA[38].Moreover,ASAisassociatedwithlarge-sizedPFO

[39]andsomeauthorsconsideritasahallmarkofapotentially severeshunt.InpatientspresentingwithCSandPFO,thepresence ofASAisanindependentpredictorofrecurrentneurologicalevents

[32,40].Meissneretal.reporteda riskofCVEnearlyfourtimes higherinpatientswithASAindependentlyfromdiagnosisofPFO (hazardratio3.72,95%CI0.88–15.71,p=0.074)[41].Presenceof ASAhasalsobeenassociatedwithlowerratesofsuccessfulclosure

and higher finding of residual shunting at follow-up probably

becauseoftherelativeinstabilityoftheimplanteddevice[35]. TunneledPFO

The length of the overlapping region interposed between

septumprimumandseptumsecundumiswidelyvariable,ranging

from a virtual channel (difficult to differentiate from ostium

secundum atrial septal defect) to long-tunneled PFO. PFOs

presenting with a tunnel "8mm have been associated with

increased risk of recurrent CVE with higher prevalence of

incomplete closureandresidualshuntafterpercutaneous inter-vention [19,20]. Percutaneous closure of long-tunneled PFO is oftenchallengingbecausedeviceswitharelativelyshortwaistdo

not sit appropriately in the defect and can remain partially

unfolded[21,30,35](Fig.1).Someauthorsstatethehypothesisthat

Fig.1.Pictureshowingtheanatomyofthefossaovalisandsurroundingstructures. AO, aorta; AR, aortic rim; CS, coronary sinus; CSR,coronary sinus rim; ER, Eustachianridge;EV,Eustachianvalve;FO,fossaovalis;IR,inferiorrim;PFO,patent foramenovalis;PR,posteriorrim;RAA,rightatriumappendage;RLPV,rightlower pulmonaryvein;RPA,rightpulmonaryartery;RUPV,rightupperpulmonaryvein; SR,superiorrim;SVC,superiorvenacava;TV,tricuspidvalve.

turbulentbloodflowthroughthelong-tunneledtractofthePFO couldpromoteclotting;theseclotscouldembolizeinperipheral arterialterritories increasingtheriskofCVE[20],however,this suggestionhasneverbeenclearlyproved.

Fossaovalerims

Theatrialseptumconsistsofthethincentralportionoriginating

from the septum primum (representing the floor of the fossa

ovalis) and of a thicker border originating from the septum

secundumforming themostpartoftheright sideof theatrial septum.Thethicknessoftherimsurroundingthefossaovalisisan

importantdeterminantinthemanagementofthetreatment.An

excessivelythickfossaovalisridgeisariskfactorforsuboptimal deviceaccommodationandstability[21].Ranaetal.reportthata thickness"10mmcanrepresentapotentialobstacletoacomplete devicedeliveryintheirexperience[21,30].Thewidthoftherimsis alsoimportantand shouldbecarefullyevaluated before telling

patients aboutpercutaneousclosures. Therim surrounding the

fossaovaleisdividedintofiveareas(Fig.2):themostimportantis

Fig. 2. Transesophageal echocardiography (90-degree bicaval view). Superior portionofthefossaovalis,whichisthemostcommonlocalizationofthetunnel patentforamenovale.

Fig.3.ProposedalgorithminpatientswithPFOandcryptogenicstroke.ThiscomprehensiveevaluationofthepatientspresentingwithPFOassociatedwithCScouldhelpthe cliniciansinthedecision-makingprocess.ASA,atrialseptalaneurysm;CS,cryptogenicstroke;CVE,cerebrovascularevents;DVT,deepveinthrombosis;PFO,patentforamen ovale;RLS,right-to-leftshunt;RoPE,RiskofParadoxicalEmbolism;TCD,transcranialDoppler;TEE,transesophagealechocardiography;TIA,transientischemicattack;TTE, transthoracicechocardiography.

theinferiorone,whichseparatesthefossaovalefromtheinferior venacava:ifitis<5mmtheimplantationofadeviceshouldbe avoided[42].

Hybriddefect

Theso-calledhybriddefectconsistsofaPFOassociatedwith otherdefectsoftheatrialseptum.Theymaypresenteitherasa discreteadditionalopeningorasmultiplefenestrationssitedin

theseptumprimum(fenestratedseptum)atavariabledistance

fromthePFOopeningintheleftatrium.Thereisawidevariability inthenumberandentityofthedefects[30].Themostrelevant issueinpresenceofahybriddefect,consistsoftheneedtoclose allthedefectsduringthepercutaneousinterventioninorderto

avoid a significant residual shunt. Reaching this goal can be

challengingparticularlywhenthedistancebetweenthedefectsis wide.

Eustachianvalve/Chiari’snetworkandEustachianridge

Eustachian valve (EV) is an embryological residual of the

inferiorvena cavavalve;duringfetal life, this structure directs thebloodflowcomingfromtheinferiorvenoussystemthroughthe foramenovaleinordertoshuntthepulmonarycircle.TheChiari networkhasthesameoriginandissimilartoEVbutitismore extensiveandfilamentous.Inastudyincluding800highlyselected patientsthatfocusedonPFOclosure,theonlypredictivefactorof recurrentCVEwasthefindingofaprominentEV[43].Thepresence

of either EV or Chiari network may interfere with the device

placement, hindering the passage of wires and reducing the

availablespaceintherightatrium.Accurateevaluationofthese structuresisvitalinordertoplanthemostappropriatetreatment strategy[30].

The Eustachian ridge, also known as ‘‘sinus septum’’ is

prominentlylocated betweenthefossaovalis and thecoronary

sinusostium;themedialportionoftheEVtakesinsertiononthis structureandcontinuesinthetendonofTodaro,whichrunsonthe

Eustachian ridge toward the central fibrous body [44]. An

excessively prominent Eustachian ridge can hinderthe correct

deploymentandpositioningofthedevice;moreover,ifthedisc

rests on this structure, the tension on the device and on the

primary septum can cause the opening of the PFO and the

persistenceoftheshunt.

Conclusiveremarks

Notwithstandingtheeffortsof thescientificcommunity, the

therapeutic management of CS associated with PFO remains

controversial.OneofthemainlimitationsoftheRCTswasthatthe

three studies allowed patients with a low probability of

paradoxicalembolismtobeincluded,affectingthefailureofthe primaryend-point.Theevaluationofdefinedclinicalfeatures,in

additiontoanatomicalandhemodynamicinformationderivedby

echocardiography, can add a significant incremental value in

estimatingtheprobabilityofparadoxicalembolism.Thiscanhelp

to identify a subgroup of patients who can benefit from

percutaneous closure. It is worth noting that some conditions

areassociatedwithbothincreasedriskofrecurrentCVEandhigh incidenceofproceduralfailure(ASA,hybriddefect,longtunnel; shuntatrest);thisfurtherunderlinestheimportanceofacareful estimationoftherisk/benefitratioinpointingpatientstodifferent therapeuticindications.Finally,weproposeasimpleflowchartfor

a comprehensive evaluation of patients presenting with PFO

associatedwithCS(Fig.3)that couldhelpthecliniciansin the decision-makingprocess.

Funding

Thisresearchreceivednograntfromanyfundingagencyinthe public,commercial,ornot-for-profitsectors.

Conflictofinterest

Theauthorsdeclarethatthereisnoconflictofinterest. Acknowledgments

Theauthorsgratefullyacknowledge SusanNordandJennifer PfaffofAuroraCardiovascularServicesforeditorialpreparationof

the manuscript, and Brian Miller and Brian Schurrer of Aurora

ResearchInstitutefortheirhelpinpreparingfigures. References

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