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an acute PE that is not due to another cause. Some guidelines also suggest pulseless or persistent
bradycardia (<40 beats per minute) as alternative inclusionary criteria.14 Hypotension is generally
defined as asystolic blood pressure <90 mmHg,a systolic drop ≥40 mm Hgfor>15 minutes or the
requirementforvasopressorsupport.
2,11,14,15
Evidenceoftissuehypoperfusion,suchasalacticacidosis,
suggestsaprogressiontoshock.
Low(nonsubmassive)andintermediate(submassive)riskPEsarehemodynamicallystable.Theseclasses
are separatedbyRV dysfunctionand/ormyocardial injury—one ortwoofthesefeaturesarepresentin
intermediatedisease,butbotharelackinginlow-riskPEs.RVdysfunctionisdefinedbythepresenceof
RV dilation, elevated NT-proBNP or BNP, or ECGchanges (represented bynew right bundle branch
block;anteroseptalSTelevationordepression;oranteroseptalT-waveinversion).14Myocardialinjury
isreflectedaselevatedtroponinIorT.
14
E.Presentation
PEcanmanifestwith awidevariety ofsymptoms—ranging from none to suddendeath—depending on
disease severity and patient comorbidities. Symptoms are usually nonspecific, including dyspnea,
pleuritic chest pain, cough, and/or lower extremity swelling.16 Physical examination may reveal
tachypnea, tachycardia, decreased breath sounds, decreased arterial oxygen saturation, and/or
hypotension.
16
F.Diagnosis
Riskcategorydictatesworkupandtreatment.Patientswithsuspectedhigh-risk(massive)PEsshouldbe
immediatelystabilized,including with vasopressors ifnecessary. Earlydiagnosis iscrucial, astime to
treatment affects the risk of mortality. If patients become stable enough for transport to radiology,
immediate CT pulmonary angiogram (CTPA) should be done. Bedside echocardiography should be
performed,particularlyifpatientsareunabletoundergoCTPA.FindingsofsevereRVdilation,decreased
systolicfunction,septalbowing,RVwallhypokinesisorMcConnellsign(RVmid-freewallakinesiawith
normalapicalmotion),visualizedright-heartthrombi,and/orinspiratorylackofinferiorvenacava(IVC)
collapsesuggesthigh-riskPE.17Whenstable,patientsshouldundergoconfirmatoryCTPA.
Hemodynamically stable patients with suspected low- or intermediate-risk PE should undergo further
workup. D-dimer may be high, although this occurs in many other conditions including infection,
pregnancy, and cancer. Arterial blood gas may reveal hypoxemia, alveolar-arterial gradient, or
respiratoryalkalosis.Otherfindingsmaybeelevatedleukocytosis,BNP,ortroponin.ECGusuallyshows
sinus tachycardia and nonspecific ST- and T-wave changes; less common findings include new
arrhythmia,rightbundlebranchblock,RVstrain,rightaxisdeviation,orinferiorQ-waves,amongothers.
ChestX-rayrarelyshowsHamptonhumporWestermarksign.
Afterassessment,thepretestprobabilityofPEshouldbeevaluatedinhemodynamicallystable patients.
Thiscanbe donebyeitherclinical suspicionor predictive calculators, such asthe modifiedWells or
Genevascores.
11,18,19
If PE is likely, CTPA is theinitial stepindiagnosticworkup. Ifit revealsclots,
treatmentshouldbegin;ifitisnegative,otherdiagnosesshouldbeconsidered.IfscoringsuggeststhatPE
isunlikely,D-dimertestingmaybedone,followedbyCTPAifthelevelishigh.Inpatientswithacontrast
allergy,renalfailure, or pregnancy, theinitial imagingtestshould beventilation/perfusion (V/Q) scan.
EchocardiographymaybeusefulinsomehemodynamicallystablepatientstoevaluateforRVstrain,butit
isnotrequired.
G.Treatment
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TreatmentdependsonPErisk.Hemodynamicallyunstablepatientswithhigh-risk(massive)diseaseareat
increased risk for early death. Supportive measures should be initiated while a treatment decision is
made; these include vasopressors and oxygenas necessary.11 Definitive reperfusion treatmentcan be
performedwithsystemicthrombolysis,catheter-directedinterventions,orsurgicalembolectomy.
1.High-Risk(massive)PE
a.Thrombolysis
Thrombolysisrapidlybreaksdownclotstoimproveperfusionandoff-loadtheRV.Inhigh-riskPE,itis
associatedwithdecreasedmortalityandimprovedhemodynamicscomparedwithanticoagulationalone.
20,21
The most commonly used thrombolytics are recombinant tissue-type plasminogen activation (tPA,
alteplase),streptokinase,andurokinase.14Ofthese,tPAisusuallychosenforitsshortinfusiontime(the
general standarddoseis100mgtPAover2h).14Ifanticoagulationwasstarted,itmaybetemporarily
stoppedduringthrombolyticinfusion.
The major sideeffect ofthrombolysisisincreased bleedingrisk,andsoitshouldnotbe usedinmany
patients. Absolute contraindications include active bleed; known intracranial malignancy or vascular
lesion; any prior intracranial hemorrhage; suspected aortic dissection; and recent (ie, within the past
3mo)ischemicstroke,brainorspinesurgery,orsignificantclosed-headand/orfacialtrauma.14Relative
contraindicationsvarybetweenguidelinesbut generallyincludehistoryofand/orcurrentsevere poorly
controlledhypertension,prolonged CPR(>10min)ormajorsurgeryintheprevious3weeks,ischemic
stroke >3 months ago, internal bleeding within the past 2-4 weeks, active peptic ulcer, dementia,
noncompressible vascular puncture, pregnancy, current anticoagulant use, age >75 years, infective
endocarditis, advanced liver disease, or diabetic retinopathy.
11,14
Based on these contraindications,
approximately50%-60%ofpatientsdonotreceivesystemicthrombolysis.
22
b.Catheter-DirectedManagement
1.Catheter-DirectedEmbolectomy
Catheter-basedPEtreatmentmayconsistofmechanical,thrombolytic,orcombinedinterventionstooffload the RV and improve perfusion.23 For patientswith absolutecontraindications to thrombolysis, a
mechanicalprocedure,suchasthrombusfragmentation,rheolyticthrombectomy,suctionthrombectomy,or
rotationalthrombectomy,maybeused.11Thesemethodsaregenerallyrecommendedonlyforclotsinthe
main or lobar PAs.14 Evidence for some ofthem is limited, and there are little datacomparing their
effectivenessandoutcomes.A2007systematicreviewdemonstratedapproximatelyequalsuccessrates
forthefirstthreetechniques(fragmentation82%,rheolytic75%,andsuction[aspiration]81%);however,
technology has significantly improved since this time.24 Given the required technical skill, these
interventionsshouldbeperformedonlyatexpertcenters.
i.ThrombusFragmentation
Thrombus fragmentation mechanically breaks the thrombus into smaller fragments. This immediately
reducesmainPAPbydisplacingthesesmallfragmentstothedistalbranches.23Inthisprocedure,asheath
isplacedandarotatablepigtailcatheterisintroducedoveraguidewire.Thecatheterismanuallyrotated
tobreakupthethrombus.Itmayalsobeperformedwithballoonangioplastycathetersorotherdevices.
14
Given that it is inexpensive, this is the most common technique; it can also be combined with other
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mechanicalmethodstoimproveoutcomes.
25
ii.RheolyticThrombectomy
RheolyticthrombectomyemploystheBernoulliprinciplethroughtheuseofhigh-pressuresalinejets.26In
thistechnique,asheathisplaced,aguidewireisintroduced,andthedeviceisinsertedoverit.Salinejets
areusedtocreatealow-pressurezonearoundthecatheter,whichmaceratesthethrombusandpullsthe
fragmentsbackforremovalviaasuctionport.Localthrombolyticscanalsobeinjectedandremovedvia
this system. Of note, at least one of the rheolytic thrombectomy systems has been associated with
intraprocedurebradycardiathatmay necessitateshorttreatmenttimes,temporarybreaks,ortransvenous
pacing.26Othersideeffectsmayincludehemoptysis,hemoglobinuria,andrenalinsufficiency.
iii.SuctionEmbolectomy
Suctionembolectomyuses suctiontoremovethrombusandcan be donealone or in combination with
other techniques. In this procedure, a specific aspiration sheath with a special hemostatic valve is
advancedintothethrombus.23Asyringeisusedtoapplysuctionwhilethecatheterismovedgentlyovera
shortdistanceinthepulmonaryartery.Clotisclearedwhenbloodentersthesyringe,andthisprocedure
may require multiple advancements of the suction catheter over the guidewire. Alternatively, suction
embolectomycanbeperformedwithnewerdevicesthatincorporateaspirationandfiltrationwithdualvenousaccess.Thisextracorporealcirculationbypasssystemaspiratesblood,clearsitofclot,andthen
reintroducesit.
26
iv.RotationalThrombectomy
RotationalthrombectomyusesrotatingcoilstotreatPEs.Ahigh-speedrotatingmetalliccoilinacatheter
lumencreatesanegativepressurethatdisruptsthethrombus,maceratesit,andthenaspiratesit.Asmall
studyhassuggestedthismethodiseffectiveinclearingthrombusandimprovingPAP.
27
2.Catheter-DirectedThrombolysis
Catheter-directedthrombolysis (CDT)denotesthelocal infusion ofthrombolytics, either aloneorwith
mechanicalinterventions.23Inthisprocedure,asimplecatheterwithmultiplesideholesisplacedintothe
pulmonaryarteryandthedrugispassivelyinfused.ThethrombolyticdoseusedinCDTisonlyasmall
amountofthatusedforsystemictreatment,andsobleedingriskisdecreased.
26
The combination of local thrombolysis with mechanical interventions is referred to as
pharmacomechanicalthrombolysis(PMT).StudiessuggestthatthebestoutcomescomefromPMT—one
analysis demonstrateda 95% success rate when fragmentation,suction, or rheolytic therapy was used
withlocalthrombolysis,comparedwith81%whenamechanicalinterventionwasusedwithoutCDT.
14,24
UltrasoundhasalsobeensuccessfullycombinedwithCDT.Inthismethod,aspecificdeviceisusedthat
consistsofacatheterwithmultiplesideholesandacentralultrasoniccorewire.Thecatheterisplaced
intothethrombusandthentheultrasoniccoreisinsertedandlockedintoplace.Thehigh-frequencywaves
disruptthethrombusandpromotebetterthrombolyticpenetration.
c.SurgicalEmbolectomy
Surgical embolectomyis recommended incentrally located, high-risk(massive) PE with thrombolytic
contraindicationsorfailure.28Italsoisusefulinpatientswithrightatrial(RA)andRVclotsoralarge
patentforamenovale.28Mortalitywashistoricallyaround30%;however,ithasdecreasedtoaslowas
4%-6%inmorerecentyears.
11,14
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PEembolectomyisavariationofthemodifiedTredenlenburgoperation.
28,29
Mediansternotomyismade
andnormothermiccardiopulmonarybypass(CPB)isestablished.Intravenous(IV)unfractionatedheparin
isthepreferredanticoagulationforbettercontrolandeasierreversal.Arteriotomyismadeintothemain
PAbetweenthepulmonicvalveandPAbifurcation.28ThisallowsforsaddleandleftPEaccess;clotis
extractedbyforcepswholeifpossibleorwithsuctionifnecessary.30IfclotisintherightPA,anincision
canbemadeinthisvesselbetweentheaortaandsuperiorvenacava.28Incisionscanbeextendeddistally
as necessary. Certain centers use lung massage for clot extraction and others do not because of an
increasedriskofpulmonarydamage.AllmainPAbranchesshouldbeinspectedbydirectvisualizationor
flexible surgicalangioscopy. TheRAandRVshould also be exploredandcleared;anypatentforamen
ovaleshouldbeclosed.Ofnote,aninferiorvenacavafiltermaybeinsertedpreoperativelyorwithinthe
first24hourspostoperativelytopreventreembolization.
29
2.Intermediate-Risk(submassive)andLow-Risk(nonsubmassive)
PulmonaryEmbolus
Hemodynamically stable patients should receive supportive care as needed duringdiagnostic workup.
Patients with intermediate-risk (submassive) PE should start anticoagulation with IV unfractionated
heparinor subcutaneous low-molecular-weight (LMW) heparin.Whenfullyanticoagulated,theycanbe
transitioned to an oral agent, namely either a direct factor Xa inhibitor, direct thrombin inhibitor, or
warfarin.
11,31
For the majority of patients with their first provoked PE, anticoagulation should be
continued for 3 months.14 Those with unprovoked clots may benefit from a longer treatment course,
dependingon their risk factors.
11,14
Patients withcancer or pregnancyare considered tobe a special
population;LMWheparinispreferredoveranoralagent.
11
Thrombolysisis generallynot recommendedinhemodynamicallystable patients with intermediate-risk
(submassive) PE.31 Thrombolysis improves hemodynamics in this population (compared with
anticoagulationalone),butmajorbleedingismorefrequent,anditisgenerallyconsideredthattherisks
outweighthebenefits.
11,31
Patientswithintermediate-riskdisease—particularlythosewithsignificantRV
dysfunction on echocardiography or borderline blood pressure—should be monitored carefully for
decompensation,intheeventthatthrombolysisbecomesnecessary.
14
Thrombolysis should not be used in low-risk (nonsubmassive) disease. Hospitalization may not be
requiredinthispopulation,butanticoagulationshouldbeinitiated.
III.PulmonaryHypertension
A.Definition
PHrefers to an elevated PA pressure, defined as a mean PA pressure (mPAP) ≥25 mm Hg at rest as
measuredbyarightheartcatheterization(RHC).32Basedontheetiology,theWorldHealthOrganization
(WHO) divides PHintofive major groups. The first is pulmonary arterial hypertension (WHO group
1PH).TheotherfourincludePHduetoleftheartdisease(group2),chroniclungdiseaseorhypoxemia
(group 3), chronic thromboemoli (group 4), andmiscellaneous conditions (group5). PH may also be
namedbased on the site of elevated pressure—if onlyarterial, itis “precapillary”but if“venous” as
defined by a high mean pulmonary arterial wedge pressure (PAWP), then it may be referred to as
“postcapillary.” Asthese terms are theendsofa wide spectrum of vasculopathic changes that can be
presentinPH,thediseasemaynotalwaysbeeasilyclassifiableintooneofthesetwodistinctentities.
33
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B.Epidemiology
BecauseofthemanycausesofPH,itsprevalenceisdifficulttodetermine.Estimatessuggestthatitaffects
1% of the global population,althoughthis increases to 10%inthose older than 65 years.34 The most
commoncauseisleftheartdisease(WHOPHgroup2).35Prognosisandtreatmentdiffervastlybetween
theWHOPHgroups,andsoitisessentialthatdiseaseiscorrectlyclassified,particularlyinpatientswith
multipleriskfactors.
35
C.PulmonaryArterialHypertension(WHOPHGroup1)
1.Introduction
PAH(WHO group1 PH)encompasses PH that is idiopathic (IPAH), heritable (HPAH),drug or toxin
related,orassociatedwithcertainconditions(connectivetissuedisease[CTD],congenitalheartdisease
[CHD], portal hypertension, human immunodeficiency virus-1 [HIV-1], or schistosomiasis). The
prevalenceofPAHisunknownbutisbelievedthattheremaybe15casesper1millionpeople.35IPAHis
most common (approximately 40%-60%), followed by PAH associated with CTD, CHD, and portal
hypertension.
36,37
Historically,PAHwasmostfrequentinyoungfemales.Recentdatastillrevealafemale
predominance(60%-80%),butthemeanageatdiagnosishasincreasedtothemid-50s.
38
2.Presentation
PAHpresentswithnonspecificsymptomsincludingdyspnea,fatigue,andexerciseintolerance; initially,
theseareonlywithexertionbutoccuratrestasthediseaseprogresses.35Latersymptomsincludeangina,
syncope, peripheral edema, and palpitations.Becauseofthe vaguepresentation, the mediantime from
symptomonsettoRHCis1.1yearsintheUnitedStates.38Twentypercentofpatientsreportsymptomsfor
>2yearsbeforediagnosis.
39
PHsymptomseverityisgradedwiththeWHOfunctionalassessment,whichisamodificationoftheNew
YorkHeartAssociationsystemforheartfailure.WHOfunctional class (WHO-FC)Icorresponds tono
limitationofphysicalactivity. ClassII denotesa slightactivity limitation (dyspnea,fatigue,chestpain,
nearsyncopewithordinaryactivity)butnosymptomsatrest.ClassIIIindicatessymptomswithlessthan
ordinaryphysicalactivity.ClassIVindicatessymptomsatrest,andthesepatientsmayhaveevidenceof
rightheartfailure.
3.Diagnosis
Giventhenonspecificpresentation,PAHshouldbeconsideredinanypatientwithdyspneathatcannotbe
fully explained by any present heart or lung disease. The bestscreeningtest for any suspected PH is
transthoracicDopplerechocardiography.ThereisnodefinedPHcutoff,butindividualguidelinessuggest
thatasystolicpulmonaryarterypressure(sPAP)of≥40or≥50mmHgrequiresfurtherworkup.
40,41
Other
suspiciousfindingsonechocardiographyincludeRAorRAenlargement,PAdilation,orseptalflattening.
Additional evaluation should be done to identify any underlying cause of PH.35 History may suggest
familial inheritance, drugs/toxins, or left heart disease.35 Laboratory testing should include HIV-1,
rheumatologic studies (eg, antinuclear antibody), liver and thyroid function, coagulation studies, and
complete blood count. Chest X-ray should be performed; in advanced disease, this may reveal an
enlarged RA or RV, dilated pulmonary arteries, or prunedperipheral pulmonaryvessels.42 Pulmonary
functiontestsandsleepstudiesshouldbedoneinallpatientstoevaluateforWHOgroup3PH,withthe
additionofhigh-resolutionchestCTifclinicalhistorysuggestsinterstitiallungdisease.PHworkupfor
CHD,portalhypertension,andchronicthromboemboliarediscussedinthefollowingsections.
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RHC is required for definitive PH diagnosis and classification. PAH is characterized by an mPAP
≥25mm Hgwith PAWP ≤15mmHg and PVR >3 Woodunits.32Of note,heartfailurewith preserved
ejectionfraction(HFpEF)mayinfrequentlypresentwithasimilarhemodynamicprofiletoPAHwithlow
PAWP.Inthisinstance,clinicalcontextincludingcomorbiditiesandleftheartfunctionshouldbeassessed;
leftheartcatheterizationmaybe useful. Volume challengeduring RHC to assess forPAWP increase is
controversialandisnotrecommendedbythemostrecentguidelinesbecauseoflackofstandardization.
32,43
During RHC and unless contraindicated (eg, because of systemic hypotension or cardiac shock),
vasoreactivityshouldbetestedinallPAHpatientstodeterminecandidacyforhigh-dosecalciumchannel
blocker(CCB)treatment.42ThistestisparticularlyimportantinpatientswithIPAH,HPAH,anddrug-
related PAH; those with other associated PAH forms are extremely unlikely to be vasoreactive. It is
performed withinhaled nitric oxide, IV epoprostenol,or IVadenosine.Vasoreactivity is presentif the
meanpulmonaryarterypressure(mPAP)decreases≥10mmHgandto<40mmHgwithoutdecreasein
cardiacoutputorsystolicbloodpressure.
44
4.Treatment
PAHisaprogressiveandcomplexdisease.45Treatmenthasmultiplegoals:decreasesymptomstoWHO-
FCI/II, increasesix-minutewalk distance (6MWD), decreaseBNP, normalizeRV sizeandfunctionon
echocardiography, and normalize hemodynamics.46 Notably, many of these factors—WHO-FC, BNP,
6MWD, and certain hemodynamic parameters, among others—correlate with survival, which has
increasedoverrecentyears.Noneofthecurrentdrugs,however,areapprovedforthespecificindication
ofdecreasingmortality.
47,48
Atdiagnosis,PAHpatientsshouldbecounseledongeneralmeasuresincludingdirectedphysicalactivity,
pregnancyavoidance,psychosocialsupport,medicationadherence,andvaccinations.
42,49
Areferraltoan
expert center should be made. Supportive therapy should include oxygen for low arterial oxygen
saturationsanddiureticsfordecompensatedrightheartfailure.
42,49
Warfarinissometimesrecommended
inIPAH,aswellaspatientsonIVprostanoidanalogues,althoughtheevidencesupportingitsroutineuse
isnotrobust.
40,42
Digoxinmaybeusefultocontroltachyarrythmias.
40
Disease riskdictatesthe needforPAHtherapy. Riskis basedonsignsofRVfailure,time tosymptom
progression, syncope, WHO-FC, 6MWD, cardiopulmonary exercise test (if done), NT-proBNP,
echocardiography,andhemodynamics.
40,50
WHO-FCIpatientsdonotrequiretherapy,buttheyshouldbe
closelymonitoredfordiseaseprogression.
51
WHO-FCIIandIIIpatientsshouldstarttreatment.InIPAH,HPAH,ordrug-relatedPAH,initialtherapy
dependsonthevasoreactivitytest.ThesmallvasoreactivesubsetshouldbestartedonaCCB,provided
thattheydonothaverightheartfailureorothercontraindications.51Nifedipine,diltiazem,oramlodipine
canbeused.40Long-termresponders—evenamongvasoreactivepatients—areinfrequentandhigh-dose
CCBs may have significant side effects, so this population should be reassessed for response
approximately3monthsafterstartingtherapy.
44,52
ThefoundationofPAHtreatmentisadvancedtherapy.Threecontributingpathwayscanbetargetedbyone
of five drug classes: endothelin receptor antagonists (ERAs), guanylate cyclase stimulators,
phosphodiesterase-5 inhibitors (PDE5), prostacyclin analogues, and receptor agonists. Initial
monotherapyhashistoricallybeenfavored, althoughinteresthasincreased in upfronttreatmentwith≥2
drugs. Recently, the Ambrisentan and Tadalafil in Patients with Pulmonary Arterial Hypertension
(AMBITION)trialexamined theuseofinitialcombinationtherapyinthetreatment-naïvepopulation.
53
PatientstreatedwithambrisentanandtadalafilhaddecreasedPAH-relatedclinicalfailures(acomposite
of measures including death, disease progression, unsatisfactory long-term response), compared with
thosetreatedwitheitherdrugalone.Patientswhoreceivedcombinationtherapyalsohadbetter6MWDs,
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NT pro-BNP reductions, and clinical responses.53 Currently, the European Society of Cardiology
(ESC)/EuropeanRespiratorySocietyrecommendinitialcombinationtherapyasanoptioninWHO-FCII
toIVdisease.42Ofnote,intreatment-naïvepatientswithWHO-FCIVorrapidlyprogressiveWHO-FC
III, continuously infused prostacyclin analogues should be started (in addition to another drug, if
combinationtherapyistobeutilized).
46,51
Patientsshouldbe monitoredcloselywithrepeatechocardiographyand6MWT.
42,48,54
Double or triple
sequentialcombinationtherapyisusedinpatientswhohaveinadequateresponsetomonotherapyordualdrugtreatment.
46
In WHO-FCIVpatients withinadequate clinical responseorseveresyncope despitemaximalmedical
therapy,balloonatrialseptostomy(BAS)maybeconsidered.42Theinteratrialseptumispuncturedwitha
guidewireandthensuccessivedilationsareperformedwithgradedballooncathetersofincreasingsizes.
42,55
This creates a right-to-left shunt that off-loads the RV; despite the decreased oxygen saturation,
systemicflowisincreasedandsooveralloxygenationisimproved.
56,57
Thisisapalliativeprocedure—
potentiallyusefulinbridgingtolungtransplant—butsmallstudiesdemonstrateimprovedhemodynamics
and6MWD.42Thismethodcanbeassociatedwithsignificantmortalityandsoshouldnotbeperformedin
end-stagepatients,asitmayworsentheirdisease.
56,57
ThePottsshunt—ananastomosisbetweentheleft
PAanddescendingaorta—maybeusefulinchildrenwithsevererefractoryWHO-FCIVPAH.
D.AtrialSeptalDefects
1.Epidemiology
WHOgroup1PHmayalsodevelopfromcongenitalheartdisease(CHD)includingatrialseptaldefects
(ASDs).Worldwide,ASDsoccurin1.6per1000livebirthsandaccountfor13%ofCHD.
58,59
Basedon
the defect site, there are different types: secundum (70%), primum (15%), sinus venous (15%), and
coronarysinus(1%).SecundumASDsaremorecommoninwomen.
2.Presentation
Most smallASDs(≤4mm)spontaneously close orshrink, butlargerdefects≥8-12 mm areatriskfor
enlarging.60 Most patients are asymptomatic until adulthood but develop symptoms after their 40s
includingfatigue,dyspnea,palpitations,andexerciseintolerance.61AsPAHdevelops,patientsmayhave
cyanosis,syncope,hemoptysis,atrialarrhythmias,orRVfailure.62Exammayrevealfixedsplittingofthe
secondheartsoundorasystolicflowmurmur.
61
3.Pathogenesis
EstimatessuggestthatPAH(withor withoutEisenmengersyndrome) occurs in 5%-10% ofadultswith
untreatedASDs.60Small defects haveminimal left-to-rightshunting,but itmay besignificant inlarger
ASDs (>10mm).60This causes progressive vessel remodeling, increased PVR, and ultimately PH.
63
Eisenmengersyndrome(ES)occurswhenPHforcesshuntreversaltoright-to-leftflow,causingcyanosis
at rest.35 Patients with ES have worse outcomes than ASD-PAH alone, and they were historically
consideredtobebetterthanthoseinIPAH.Recentdata,however,suggestthatsurvivalbetweenIPAHand
ES cohorts is similar, although it is not clear if this perceived better prognosis is due to improved
medicaltherapyortosurvivorbias.
64
4.Diagnosis
In suspected PAH-CHD, transthoracic Doppler echocardiography should be used to assess the atrial
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septum. Agitatedsaline may reveal right-to-leftflow,but it should notbe used in known large shunts
becauseofairembolusrisk.Iftransthoracicimagingisnotrevealing,transesophagealechocardiography
(TEE) shouldbe done.62Cardiac MRI may be useful if echocardiography is inconclusive.62 Cardiac
catheterizationisrequiredforASD-PAHdiagnosis.
5.Treatment
After ASD-PAH diagnosis is made, patients should be referred to an expert PAH center. General
supportive measures should be initiated, with the addition of dehydration and strenuous exercise
avoidance.42Anti-arrhythmicsandanticoagulationshouldbeusedforatrialarrhythmiasasappropriate;
however, anticoagulation without arrhythmia is not indicated because of bleeding risk, especially
hemoptysis.
63
ASD treatment dependsonthe defect sizeandassociatedPAHseverity. Patients with smallshuntsand
normal RV size should be monitored for RV enlargement and/or PAH with routine ECG and
echocardiography.62EarlyclosureisessentialtopreventPAH.Guidelinesrecommendthatitshouldbe
done inpatients withRVoverload—despite symptoms—whohave not progressed to severe PAH.
61,62
The ESC guidelines recommend that PVR be <5 Wood units to undergo closure, although it can be
considered in patients witha left-to-right shunt and PVR <2/3 of systemic vascular resistance or PAP
<2/3systemicpressure(baselineorpostvasodilator).
61,62
Closureshouldalsobeconsideredinpatients
withparadoxicalembolismororthodeoxia-platypnea.
61,62
Ofnote,outcomesarebestwhenageatrepair
is<25years;however,closurecanbeperformedatanyageanditisthoughttobetheoptimalmanagement
eveninadults(vs.medicaltherapy).
61,65
It should notbedoneinES—pulmonaryremodeling islikely
extensiveandrepairmayworsenPAH,leadingtoRVfailureanddeath.
62,63,66
a.AtrialSeptalDefectClosureMethods
ClosureofanASDcanbedonesurgicallyor percutaneously.Percutaneoustranscatheterinterventionis
recommended for secundum defects that are <36-40 mm diameter and that have adequate margins off
valves (except the aorta).
60-62
Outcomes are excellent with closure rates of 93%-99% and a major
complicationrateof1%.60ThisprocedureisperformedunderTEEandfluoroscopicguidance.Briefly,
the left atrium is catheterized and a guidewire is inserted. ASDsizecanbe estimated witha balloon
catheter and the“stop-flow” technique, inwhich theballoonis placed across the defect, inflated with
contrast until theshuntdisappearsbyechocardiography, deflated, andthenreinflated.AnASDclosure
devicethatisofequalsizeoronesizelargerthanthedefectisselectedandsoakedinsalinetopreventair
embolus.Thedeliverysystemisadvancedintoanupperpulmonaryvein(usuallytheleft),andthewire
anddilatorareremovedwhileallowingfreebloodflowfromthesheathtodecreaseairembolusrisk.The
device isinserted,the left atrial discisdeployed, and thisis checkedwithfluoroscopy andTEE.The
sheathis pulled back and then the right atrial disc is thendeployed.Its positionis verified; the discs
shouldbeparallelandseparatedbytheatrialseptum.Ifthedevicepositioniscorrect,thedeliverycable
isreleased.TEEshouldrevealnoorminimalresidualshunt.
Surgery was the preferred intervention but now is used for nonclosable or nonsecundum ASDs.
62
Pericardial patchclosureispreferred, although direct suturing is possible for small defects.It can be
done by open or minimally invasive approaches. Success rates are similar to percutaneous repair,
althoughcomplicationsarehigherandhospitalizationstendtobelonger.
60
Patientswithresidualshunt,PAH,arrhythmias,orage>40yearsshouldbefollowedafterclosurewith
echocardiography and ECG.61 Antiplatelet therapy and endocarditis prophylaxis are advised after
percutaneousintervention.
61
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b.MedicalTherapy
Patients with ESshould notundergoASDclosure. InWHO-FC III and IV disease, guidelines suggest
advancedpharmacologic therapy. Europeanguidelinesrecommendbosentan;small studies suggestthat
otheragentsmayalsoimproveoutcomesbutthesearenotrecommended.61Combinationtherapycanbe
considered,butitsefficacyisunknown.
E.OtherFormsofPAH-CHD
InadditiontoASD,otherformsofCHDmayresultinPAH.Someofthemmaybeaddressedbypalliative
atrialseptostomy.ThePottsshuntproceduremayalsobeusedfortranspositionofthegreatarteries,and
althoughbeyondthescopeofthischapter,theGlennorFontanshuntcreationcanaddresshypoplasticleft
heartsyndromeand/ortricuspidatresia.
F.PortopulmonaryHypertension
Portopulmonaryhypertension(PoPH)isWHOgroup1PAHassociatedwithportalhypertension,withor
without underlying liver disease. Estimates of PoPH vary widely, but it appears to account for
approximately10%ofallPAHdiagnoses.
67,68
Riskisincreasedinfemalesandautoimmunehepatitis.
67
The pathogenesis of PoPHis notwellunderstood.Multiple mechanisms havebeenproposed including
volume overload causing shear stress, systemic inflammatory changes, and portosystemic shunts
circulating nonmetabolized circulating toxins.69 PVR increases and ultimately leads to pulmonary
vascular remodeling. No correlationhas been identified between the severityof liver disease and of
PoPH.
35
Like IPAH,PoPH presents with nonspecific symptoms, andpatients are usuallyintheir 40s or 50s at
diagnosis.70 TTE is the best screening test, but the gold standard for diagnosis, like all other PAH
subgroups,isRHC.AllpatientsundergoinglivertransplantevaluationshouldreceiveatleastTTE,with
RHCifneededbasedontheTTEfindings.
Treatment options for PoPH are limited. Diuretics should be initiated. Anticoagulation is not
recommended, giventhat this populationis already at increased risk ofbleeding duetocoagulopathy.
CCBsshouldalsobeavoided,astheycouldworsenportalhypertension.Ifadvancedtherapyisrequired,
IV epoprostenol or sildenafil can be used, although there may be a role for other PAH-specific
medications.
70,71
Of note, transjugular intrahepatic portosystemic shunt (TIPS) placement increases
preload,CO,andmPAPandisthereforecontraindicatedinPoPH.
72
Livertransplantation(LT)isacurativeoptionforcertainPoPHpatients.Guidelinessuggestitisindicated
incandidateswithmPAP<35mmHgandPVR<5Woodunits.73Patientswithworsehemodynamicswho
undergo LT have higher mortality. In this group, a trial of advanced vasodilator therapy should be
attempted,andpatientsshouldbelistedforLTifmPAPandPVRfallto<35mmHgand<5Woodunits,
respectively. In the United States, this well-controlled PoPH group is granted an exception from the
traditionalModel forEnd-StageLiverDisease(MELD)system, thus raisingtheirscoresandhopefully
decreasing time to transplant.74 Of note, not all PoPH patients who undergo liver transplant have
resolutionofPoPH—somemaycontinuetorequirevasodilatortherapy,althoughthereasonsforthisare
notclear.
G.ChronicThromboembolicPulmonaryHypertension
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1.Introduction
Chronic thromboembolic PH (CTEPH) results from chronic obstruction of pulmonary arteries and
arterioles.ItisaformofprecapillaryPHdefinedas mPAP≥25mmHgwithPAWP≤15mmHginthe
settingofchronicflow-limitingpulmonaryarterythrombiafter≥3monthsofeffectiveanticoagulation.
75,76
CTEPH develops in 1%-4% of acute PE patients, although this is likely an underestimate.
75,77,78
Interestingly, it appears that approximately 25%-63% of CTEPH patients have never had a known or
documented acute PE, although these events may have simply not been detected.
79,80
CTEPH risk is
particularlyhigh inthose acutePEpatientswhoareyoungor whohave anidiopathicpresentation.
79,81
OtherriskfactorsaresimilartothoseforPEs,withoftheadditionofsplenectomy,hypothyroidism,or
ventriculoatrialshunt.
2.Diagnosis
CTEPH should beconsidered inacutePE patients whosesymptoms (ie, dyspnea, etc.) donot resolve
after3-6months.78TTEshouldbeperformed;ifitissuggestiveofPH,aV/Qscanisdonenext.75Ifthis
imaging demonstrates a high probability of PE, both RHC and pulmonary angiography are needed to
confirmCTEPH,determineseverity,andevaluatesurgicalcandidacy.75IftheV/Qscanisindeterminate
butthesuspicionforCTEPHisstillhigh,guidelinessuggesteitherpulmonaryangiographyand/orRHC.
75,82
CTEPH is unlikely with a normal V/Q scan. CTPA may be useful before surgery, but it is less
sensitivethanV/Qandisnotrecommendedfordiagnosis.
83
Certain patterns on angiography are associated with CTEPH: pouch defects; intimal irregularities;
pulmonary artery bands or webs; abrupt or angular narrowing of the major pulmonary arteries; and
obstructedmain, lobar,orsegmentalvesselsattheirpointoforiginwith absentdownstreamflow.
84-86
TwoormoreofthesepatternstendtobepresentinCTEPH.
84
3.Treatment
At diagnosis, CTEPH patients should be referred to an expert center. The only curative option is
pulmonary endarterectomy(PEA), and the majority ofpatients are candidatesfor this procedure.78 In
nonsurgicalcandidates(owingtocomorbiditiesand/orclotaccessibility),balloonpulmonaryangioplasty
(BPA)ormedicaltherapymaybeconsidered.Atdiagnosis,lifelonganticoagulationshouldbestartedto
preventpulmonaryclotpropagationandDVT.ItcanbeinitiatedwitheitherIVunfractionatedheparinor
subcutaneous low-molecular-weightheparin.After fulltherapeutic anticoagulationisachieved, patients
canbe transitioned towarfarinwithaninternational normalizedratio goal of 2.0-3.0.87 Inferior vena
cava(IVC)filterplacementiscontroversial,anditsusevariesbetweencenters.
a.PulmonaryEndarterectomy
PEAistheonlydefinitivetreatmentforCTEPH.82Mortalityis<5%atexpertfacilities,andmostpatients
experience significant symptom and hemodynamic improvement.87 Mortality increases with PVR;
residual/recurrentPHaftersurgeryisthemajorpredictorofdeath.
87
ToundergoPEA,thethromboembolimustbeaccessible,symptomsorhemodynamicabnormalitiesshould
besevere,andpatientsmustbesurgicalcandidates.88TheroleofPEAinearlyCTEPHisnotdefined—
some recommend immediate intervention to prevent hemodynamic abnormalities and others suggest
routinemonitoring.
87
Before PEA, pulmonary angiography is essential to determine thrombi location. PEA is used for
thromboemboli inthemain, lobar,segmental,andsomesubsegmental pulmonaryarteries.89It may not
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