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ACCME/Disclosure:Dr.SchoenisaconsultantforMedtronicandThoratec,Inc.,but
hasnotconflictofinterestwithhispresentation.
Schoen‐Case2
Diagnosis‐Pumpthrombosis
DISCUSSION‐CARDIACASSISTANDREPLACEMENT:PATHOLOGICCONSIDERATIONS
Heartfailure(HF)continuestobeasignificanthealthcareproblemintheUS
(incidenceover5.8million)andglobally(incidenceover23million).1,2Theannual
economiccostintheUSisover$39billion.Despiteadvancedmedicaltherapy,HFstill
carriesasignificanthumancost:amortalityof50%atfiveyears,rivalingmanydiagnoses
ofcancer.IntheUSannually,HFistheprincipalcauseofdeathin>65,000individuals,a
contributingfactorinover300,000deaths,andover900,000personshaveanewdiagnosis
ofHF.Ithasbeenestimatedthatatleast60,000ofthesepersonscouldbenefitfromheart
transplantationorlong‐termmechanicalsupport.Projectionsshowthattheprevalenceof
HFwillincrease46%from2012to2030,resultingin>8millionpeople≥18yearsofage
withHF.However,asonlyapproximately4000donorheartsareavailableworldwide
annually,ventricularassistdevices(VADs)andtotalartificialhearts(TAHs)arethemost
promisingalternativetohuman‐to‐humancardiactransplantation.
CardiacAssistandReplacementTechnology
WithaVADthenaturalheartremainsinplaceandthedeviceisconnectedvia
cannulastotheatriumorventricle(pumpinflow)andtotheaorta(foranLVAD)or
pulmonaryartery(foranRVAD)(pumpoutflow).3,4,5Thepumpingchamberiseither
implantedinternally(intracorporeal),positionedimmediatelyontopoftheskin
(paracorporeal),orsupportedexternally(extracorporeal);thiscontrastswithaTAH
(analogoustoatypicalcardiactransplant),inwhichthenaturalheartisexcisedand
replaced.6,7VADshavebeenusedprimarilyin3settings:1)Asabridgetotransplantation
(BTT)‐‐End‐stageHFnotlikelytorecoverandwheremechanicalsupportwillpermita
patienttosurviveuntilasuitabledonorheartisfound.Indeednearlyhalfofpatientsdie
whileawaitingahearttransplant.Mosttransplantcandidateswhorequiresomeformof
mechanicalcardiacsupporteventuallyundergotransplantationwithresultsnot
substantiallydifferentfortransplantrecipientswhodonotreceivesupportbyaVAD.2)
Asdestinationtherapy(DT)‐‐Tosupportthecirculationlong‐terminpatientswithend‐
stageheartdiseasewhoeithercannotberemovedfromcardiacsupport,orarenot
candidatesfororotherwisecannotreceivetimelytransplantation‐‐andforwhomdevice
implantationwouldimprovequalityoflife.3)Asabridgetorecovery‐‐Potentially
recoverableheartfailure,inwhichcardiacfunctionislikelytoimprovesufficientlyto
permitweaningfromcardiacassist,shouldcardiacrest(whichresultsinventricular
unloading,decreasedmyocardialwork,andincreasedsubendocardialperfusion)be
facilitated,whilesystemicorganperfusionismaintained.Cardiacrecoveryismostlikelyto
occurinvarioussettingswherehealing/remodelingareactive,e.g.,post‐cardiotomy,
1 myocarditis,acutemyocardialinfarctionorotherevolvingprocess,andinsomecasesof
cardiomyopathy.
Forintracorporeal(implanted)LVsupport(asshownintheFigure),theLVapexis
coredandcannulatedattheapexusingtheinflowcannulatotheleft‐sidedVAD(i.e.,LVAD).
Theoutflowcannula(fromthepump)istypicallyanastomosedtotheproximalascending
aorta.Representativeoffirst‐generationclinicalLVADs,pulsatileflowpumpshaveablood‐
containingchamberwithanelastomericmovingbladder/membranewhichdisplacesblood
insidearigidhousing,mechanicalorbioprostheticvalvestoensureunidirectionalflow,
fabricandmetalconduits.Clinicalbenefitwasdemonstratedinpatientsassistedshort‐
termfollowingacuteHF,followingcardiotomyormyocardialinfarction.8DuringLVAD
therapytheailingventricleactsmainlyasaconduitforbloodflowinpatientswith
irreversibledamage.Theprospective,multicenterREMATCHtrialwasthefirstclinicaltrial
todemonstratethatLVADsusedasDTsignificantlyimprovedsurvivalandthequalityof
lifeofpatients,whencomparedtooptimalmedicalmanagement.9FollowingREMATCH,
theHeartMateXVE,apulsatilebloodpumpandthefirstimplantableVADforbridge‐to‐
transplantation(BTT),wasapprovedbytheFDAforDTin2001.Thestudiesdescribedin
Refs.3,4,5followedforBTTandDT.Pulsatiledevicessignificantlyadvancedheartfailure
therapyoverallandbenefittedsomepatients,buthadseverallimitations:1)largesize,
necessitatingimplantationintotheabdominalcavity;2)noise,owingtopulsatile
pneumaticactuation;3)mechanicalfailuresowingtocomponentwearandbioprosthetic
valvedeterioration.Theselimitationsstimulatedthedevelopmentof(nowFDA‐approved)
smallerandmoredurablecontinuousflow(CF)LVADs(secondandthirdgeneration
devices),inwhichcirculationisachievedbyacontinuouslyspinningmotorresultingin
nonpulsatileflow.TheHeartMateII(usingaxialflowviaaspinningapropeller)wasthe
firstsuchdeviceandtheHeartWareHVAD(whichgeneratescentrifugalflowusing
blades/impellers)followed.10,11,12ThemostrecentlydevelopedVADsutilizemagneticor
hydrauliclevitationsystemstosuspendthemovingimpellerinthebloodstream.This
designeliminatestheneedforbearingsbetweentheimpelleranditshousing,henceonly
theimpellerisamovingpart.Thecurrent1‐yearsurvivalofnearly75%withCFDT
providesanimpressivebenchmarkfortheapplicationofthistherapy.
ComplicationsofandPathologicConsiderationswithVADs
AdverseclinicaloutcomessuchafterimplantationwithCFLVAD(summarizedinthe
Table)include,mostprominently,thrombosisandthromboembolism,bleeding,infection,
exacerbationofrightheartfailureandaorticvalvedeformationandinsufficiency.13,14
Therelativeadvantages/disadvantagesofpulsatilevscontinuousfloware
controversial.ThereducedsizeofCFdevices,owingtotheeliminationofthepumping
chamberandvalves,reducestheriskofsurgicalsitebleedingandinfection.However,
severalcomplicationshavebeennotedsuchasdenovoaorticinsufficiency(presumably
duetotheprogressivefusionoftheaorticcommissures)andGIbleeding(possiblydueto
lossofvonWillebrandmultimersorarteriovenousmalformations).
2 Aswithvirtuallyallcomplexcardiovascularprostheticdevicesandtheiruse,
thrombosisandhemorrhagearekeycomplicationswithVADsupport.15Neurologic
complicationsincludingembolicandhemorrhagicstrokeoftenoccurinVAD‐supported
patients,duetoinadequate/excessiveanticoagulationtherapy,thrombogenicsurfaces,and
thromboticstagnationwithinthedeviceortheheart.16Foryetunexplainedreasons,the
incidenceofthrombosisassociatedwithinternalpumpcomponents,everarisk,has
increasedoverthepastseveralyears.17Potentialfactorscontributingtothiscomplication
havebeencategorizedaspump‐related(i.e.,interactionsattheinterfacebetweenblood
andpumpcomponents),patient‐related(e.g.,atrialfibrillationandhypercoagulability)and
management‐related(e.g.,sub‐therapeuticanticoagulationand/orantiplatelettherapy,
tendencytorunatlowpumpspeedstominimizegastrointestinal(GI)bleeding,von
WillebrandFactor(vWF)deficiencyandaorticvalveabnormalities[seebelow]).
Postoperativebleedingandcardiactamponadeareamongthemostcommon
complicationsrequiringreexplorationafterVADimplantation.Recently,theprevalenceof
acquiredvonWillebranddisease(i.e.,vWFdeficiency)hasbeenrecognizedinCFLVAD
patientsandsuggestedasanimportantcausalmechanismforbleeding.18,19Indeed,
patientswhoundergoBTTwithCFdevicesoftenhavedecreasedtoabsentlevelsofvon
WillebrandFactormultimers,owingtothehighshearstressrelatedtotherotating
impeller,whichaltersthe3‐dimensionalstructureofvWF,andenhancesproteolysisofthe
multimerswhicharecriticaltoitshemostaticfunctions;thisdefectnormalizesafterheart
transplant.20GIbleedingoccursinperhapsathirdofpatientsimplantedwithaCFdevice.
Althoughtheexactmechanismsareunclear,itappearsthatpharmacologicanticoagulation
andthedevelopmentofGIarteriovenousmalformationsaremajorcontributors;21and
possiblyvWFdeficiencyiscontributory,similarlytopatientswithsevereaorticstenosis.22
PlateletaggregationisimpairedfollowingimplantationofCFLVADsandisanareafor
furtherinvestigation,sincepulsatileflowmaybebeneficialtovascularvasoresponsesand
remodelling,microcirculation,andend‐organperfusion,CFdeviceswithsuperimposed
pulsatilitymayalleviatethisissuebyprovidingsomeshearstressinherentinapulsatile
system,totheintestinalvasculature.
InfectionsremainamajormortalityriskfactorinVADsupportedpatients.
Percutaneousdrivelineinfectionsarethemostcommonformofinfection.Althoughthe
newerCFLVADsshowsignificantlyloweredriskfordrivelineinfections,theycontinueto
beobservedinapproximately20%ofpatients.
Rightventricularfailure(RVF)occursinasmanyas50%ofpatientstreatedwith
LVADs.AdequateRVfunctionisessentialforLVADfunction,sinceelevatedvenous
pressurecausedbyRVFdecreasesLVADloadingandejection.Significantpreexisting
tricuspidregurgitation,presentinabout50%ofLVADrecipients,hindersdevicefunction
similarlytoRVF.Currently,noneoftheimplantableaxialorcentrifugalpumpshaveyet
beenapprovedbytheFDAforbiventricularorisolatedrightventricularsupport,although
off‐labelusemayoccur.
Sinceaorticvalvecuspalmobilityisdependentonantegradeflowacrossthevalve,
theaorticvalveremainsclosedduringtheunloadingoftheLVduringCFLVADsupport.23
ThiscreatesstasisintheLVoutflowtract,leadingtothrombusformationattheventricular
3 sideoftheaorticvalve.Organizationofthrombuscanthenleadtoaorticcuspfibrosis,
thickeningandstenosisorregurgitation,whichmaybemaskedbytheLVADfunction,
necessitatingAVrepairorreplacementsurgeryinpatientsundergoingBTR,orwhose
LVADsfail.Thus,theaorticvalvecuspsremainsstaticandsomeAVcommissuralfusionis
commonfollowingLVAD.24,25AorticinsufficiencyassociatedwithCFLVADscanresultin
inefficientflow,increasedriskofthromboembolism,andreducedabilityformyocardial
recovery.
PathologicalAnalysisofaRemovedVAD
Pathologistshaveanimportantregulatoryroleinrecognizingclinical
prosthesis‐associatedcomplicationsintheirpractices.Thisresponsibilityisakeyelement
oftheUSAFederalSafeMedicalDevicesActof1990(PL101‐629);thefirstmajor
amendmenttotheFederalFood,DrugandCosmeticActsincetheMedicalDevice
Amendmentsof1976.26,27Underthe"userreporting"requirementsofthislegislation,
healthcarepersonnelandhospitalsmustreportalldevice‐relateddeaths,seriousillnesses
andinjuriestotheFDA,themanufacturerortoboth.Thus,apathologistwhoinitially
discoversharmordeathduetoamalfunctioningcardiovasculardeviceisrequiredto
initiatethereportingprocess(throughhis/herinstitution).InCanadathisresponsibilityis
mandatedbythehealthprotectionbranchoftheFederalMinistryofHealthandintheUK
bytheequivalentsectionattheMinistryofHealth.
Schemaandresultshavebeenpublishedfortheanalysisofretrievedcardiacassist
devicesandtotalartificialheartsinthecontextoftheentirepatient,withemphasisonthe
localpump‐patientinterface,remotecardiovascularandend‐organeffectsandtheimpact
ofcirculatorysupportonthenativeheart,28,29,30,31,32,33includingrecommendationsofthe
SocietyforCardiovascularPathologyandtheAssociationforEuropeanCardiovascular
Pathology.34
Thespecificobjectivesareto1)characterizethebloodpump,especiallyblood‐
contactingsurfaces,valves(ifpresent),conduitsandothercomponents(includingenergy
sources),and2)otherrelevantpathology(especiallycardiopulmonaryandlocaland
distantpatient‐prosthesisinteractions).Thesegoalsarebestmetbyapproachingand
dissectingtheimplant(andtherecipientifatautopsy)appropriately,inordertoensure
adequateretentionofinformationwhichmaybelostwhentheimplantisremovedfromits
anatomiccontext,andsubsequentphotographicdocumentation,microscopicexamination,
microbiologicandbiochemicalassaysandcompliancewithregulatoryandmanufacturer
requirements.
Theanalysisbeginsbyobtaininginformationdescribingtheindicationforthe
procedure/device,thetypeofVADused,implantationprocedureandtheclinicalcourse
followingdeviceimplantation.IfacardiacexplantissubmittedwiththeVAD,photographs
shouldbetakentodocumenttheVAD'sanatomicalposition,externalpathologicfeatures
anddevice‐hosttissueinteractions.TheLVshouldbedissectedwiththeinflowcannulain
place,inordertoassessanypathologyatthepumpinflow,includingdamagetothe
ventricularandseptalmyocardium.Cardiacexaminationisotherwiseasdoneroutinely
4 whenthereiscomplexcardiacpathology.Apieceoftissueforculture(microbiology)
shouldbetakenfromanyareaofpurulentexudateortissuenecrotictissue.Mural
thrombus,especiallythrombusaroundthebaseoftheinflowcannula(intraventricular
portion),shouldbenoted,asshouldhosttissuegrowthontheinflowcannula,especiallyon
itsinnersurface.Transmuralsectionsshouldbeobtainedfromthecannulationsiteto
assessfibrosis,calcification,andischemicdamage.Theleft‐sidevalves,especiallytheaortic
valve,shouldbeexaminedforVAD‐relatedpathologies,includingfibrosis,stenosis,and
commissural/cuspalfusion.Thecannulasanddrivelinesofmostdevicescanbedetached
fromthepumptocheckforintra‐devicepathology.Thecannulaeshouldbeevaluatedfor
thrombosis,vegetation,kinking,structuralfailure,andpatencyofanastomosis.Pulsatile
devicescontainmechanicalorbioprostheticvalves,whichshouldbecheckedforfunctional
integrity,degradation,thrombosis,orvegetations.Thepumpitselfmaynotbeamenableto
opening,thougheffortsshouldbemadetoassessin‐pumpthrombosisbyinspectingeither
visuallyorwithanendoscopicinstrument.Thepumpcanbesenttospecialistlaboratories
ortothemanufacturerfordisassemblyandtesting.Specialattentionshouldbedirected
towardsamplingandculturingfragmentsoftissueintheimplantbedandadjacentto
percutaneouselectricalandhydrauliclines,allofwhicharepotentialsitesforinfection.
Disclosure
In the course of consultations on developmental preclinical and/or clinical research over
approximately the past 5 years, the author has received or may receive something of value from
the following organizations that may be impacted by the work reviewed in this manuscript:
Direct Flow Medical, Inc, Celxcel; Edwards LifeSciences; Medtronic, Inc.; Sorin Medical, Inc.;
Sadra/Boston Scientific, Inc; St. Jude Medical, Inc.; Symetis; Xeltis; Thoratec, inc..
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Table
Complicationsof/PathologicFindingsAssociatedwith
ContemporaryVentricularAssistDevices
_____________________________________________________________________________
Thrombosisandthromboembolism
Hemorrhage
Infection
Devicemalfunction
Ventriculararrhythmia
Rightventricularfailure
Tricuspidregurgitation
Leftatrialcollapse
Mitralvalveregurgitation
Aorticvalvecuspfibrosis/regurgitation/stenosis
Endocardialfibrosis/thrombusatinflowcannula
Drivelinethrombosis,infection,kinking,structuralfailure,
anastomoticpatency
7 Figure‐Pulsatileandcontinuousflowleftventricularassistdevices.
SlaughterMS,etal‐NewEnglJ.Med2009;361:2241.
FrederickJ.Schoen,M.D.,Ph.D.
BrighamandWomen'sHospital
HarvardMedicalSchool
75FrancisStreet
Boston,MA02115
[email protected]
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