Alcohol Septal Ablation in Obstructive Hypertrophic Cardiomyopathy: Four Years of Experience at a Reference Center

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Revista

Portuguesa

de

Cardiologia

Portuguese

Journal

of

Cardiology

www.revportcardiol.org

ORIGINAL

ARTICLE

Alcohol

septal

ablation

in

obstructive

hypertrophic

cardiomyopathy:

Four

years

of

experience

at

a

reference

center

夽

António

Fiarresga

∗

,

Duarte

Cacela,

Ana

Galrinho,

Ruben

Ramos,

Lídia

de

Sousa,

Luís

Bernardes,

Lino

Patrício,

Rui

Cruz

Ferreira

Servic¸odeCardiologia,HospitaldeSantaMarta,CentroHospitalardeLisboaCentral,EPE,Lisboa,Portugal

Received13March2013;accepted25April2013 Availableonline11February2014

KEYWORDS Obstructive hypertrophic cardiomyopathy; Percutaneous treatment; Alcoholseptal ablation Abstract

Introduction:We describeourcenter’sinitial experiencewith alcoholseptalablation(ASA) forthetreatmentofobstructivehypertrophiccardiomyopathy.Theprocedure,itsindications, resultsandclinicaloutcomeswillbeaddressed,aswillitscurrentpositioncomparedtosurgical myectomy.

Objective: ToassesstheresultsofASAinallpatientstreatedintheﬁrstfouryearsofactivity atourcenter.

Methods:WeretrospectivelystudiedallconsecutiveandunselectedpatientstreatedbyASA betweenJanuary2009andFebruary2013.

Results:Intheﬁrstfouryearsofexperience40patientsweretreatedinourcenter.Inthree patients(7.5%)theinterventionwasrepeated.Proceduralsuccesswas84%.Minorcomplications occurredin7.5%.Twopatientsreceivedapermanentpacemakerforatrioventricularblock(6% ofthosewithoutpreviouspacemaker).Themajorcomplicationratewas5%.Therewere no in-hospitaldeaths;duringclinicalfollow-up(22±14months)cardiovascularmortalitywas2.5% andoverallmortalitywas5%.

DiscussionandConclusion: Theresultspresentedreﬂecttheinitialexperienceofourcenter with ASA. The success rate was high and inline with published results,but with room to improve with betterpatient selection.ASA was shownto besafe, withalow complication rateandnoprocedure-relatedmortality.OurexperienceconﬁrmsASAasapercutaneous alter-nativetomyectomyforthetreatmentofsymptomaticpatientswithobstructivehypertrophic cardiomyopathyrefractorytomedicaltreatment.

夽 _Please_cite_this_article_as:_Fiarresga_A,_Cacela_D,_Galrinho_A,_et_al._Ablac_¸ão_septal_alcoólica_no_tratamento_da_{cardiomiopatia}_{hipertróﬁca} obstrutivaexperiênciadequatroanosdeumcentro.RevPortCardiol.2014;33:1---10.

∗_{Corresponding}_author.

E-mailaddresses:antoniojoseﬁ[email protected],a.ﬁ[email protected](A.Fiarresga).

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PALAVRAS-CHAVE Cardiomiopatia hipertróﬁca obstrutiva; Tratamento percutâneo; Ablac¸ãoseptal alcoólica

Ablac¸ãoseptalalcoólicanotratamentodacardiomiopatiahipertróﬁcaobstrutiva

experiênciadequatroanosdeumcentro

Resumo

Introdução:Aablaçãoseptalalcoólica(ASA)éaformapercutâneadetratamentoinvasivoda cardiomiopatiahipertróficaobstrutiva(CMHO).Apropósitodadescriçãodaexperiêncianonosso centro,procurar-se-áreverasindicações,osaspetostécnicosepráticoseosresultadosdaASA, assimcomoasuaposiçãoatualemcomparaçãocomamiectomiacirúrgica.

Objetivo:Avaliar os resultados da ASA numa série de doentes consecutivos tratados nos primeirosquatroanosdeatividade.

Métodos: Estudoretrospetivodetodososdoentes,consecutivosenãoselecionados,comCMHO, tratadosporASA,entrejaneirode2009efevereirode2013.

Resultados: Durante o período de quatro anos foram tratados com ASA 40 doentes. Em três doentes (7,5%) repetiu-se o procedimento. A taxa de sucesso foi de 84%. A taxa de complicaçõesminorfoide7,5%.Foinecessárioimplantarpacemakerdefinitivopor bloqueio-auriculoventricular em dois doentes (6%, do subgrupo sem pacemaker prévio). A taxa de complicaçõesmajorfoide5%.Nãohouvemortalidadeintra-hospitalarnestapopulação.Durante oseguimentoclínico(22±14meses)amortalidadecardiovascularfoide2,5%.Amortalidade totalfoide5%.

Discussãoeconclusão:Osresultadosapresentadosrefletemaexperiênciainicialdotratamento comASAnonossocentro.Oprocedimentofoibem-sucedidonamaioriadosdoentes,sendo ataxade sucesso semelhanteàdescritaem outras séries,mas ainda compossibilidadede beneficiardeumamelhorseleçãodosdoentes.Aintervençãotambémserevelousegura,com umabaixaocorrênciadecomplicaçõesesemmortalidadeassociada.AASAéumaalternativa percutâneanotratamentoinvasivodosdoentescomCMHOrefratáriaàterapêuticamédica. © 2013 SociedadePortuguesa de Cardiologia. Publicado por Elsevier España, S.L.Todos os direitosreservados.

Introduction

Hypertrophiccardiomyopathy(HCM)wasﬁrstdescribedover 50yearsago,1_and_it_was_soon_clear_that_one_of_its_most

char-acteristicfeatureswasthepresence ofdynamic subaortic obstructioninasigniﬁcantnumberofpatients.2

Thegeneticandphenotypicheterogeneityofthisprimary cardiomyopathycomplicatesclinicalassessmentand treat-ment,andhasgivenrisetoconsiderabledebate.3_One_of_the

morerecent controversies concernsinvasive treatment of obstructivehypertrophiccardiomyopathy(OHCM);the intro-ductionofpercutaneousalcoholseptalablation(ASA)asan alternativetotheestablishedsurgical techniqueof septal myectomyled tomuch discussionconcerning the relative meritsofthetwotreatmentsthatcontinuestothisday.

MostpatientswithHCMpresentsigniﬁcant intraventric-ular obstruction at rest or with provocation, usually the Valsalvamaneuver(or,strictlyspeaking,theeffortrequired forthemaneuver).4_This _obstruction_is _caused_by _the

sys-tolic anteriormotion (SAM) of the anterior leaflet of the mitralvalve, which results from the force of left ventri-cular (LV) ejection and the narrowing of the LV outflow tract (LVOT); elongation of the mitral valve leaflets may alsocontribute in some cases.5 _The _obstruction _increases

intracardiac pressure, oxygen consumption and cardiac work,andisalsooftenassociatedwithmitralregurgitation, coronaryﬂowabnormalitiesanddiastolicdysfunction.The degreeofobstructioncorrelateswithsymptomseverityand worsesurvival.6

Identiﬁcation of patients with OHCM is important, because the obstruction is itself a therapeutic target;

reducingitfrequentlyresultsinimprovementorcomplete resolution of symptoms. Medical therapy is effective in most cases and should therefore be the ﬁrst-line treat-ment, using inotropic depressors such as beta-blockers, non-dihydropyridine calciumchannel blockersor disopyra-mide(thelatterunavailableinPortugal).

However,in 5---10% ofpatients medicaltherapy is inef-fective,nottoleratedorcontraindicated.7_In_such_cases,_an

invasiveapproachisanalternativeforsymptomaticpatients withimpairedqualityoflife.Theaimistoreducethe thick-nessofthebasalportionoftheinterventricularseptumand hencetheobstruction.Theﬁrsttechniqueusedwassurgical myectomy,inwhichapartoftheseptalmuscleisexcised; thiswasthe onlyoption for decades.Inexperienced cen-ters,mortalityis≤2%inyoungpatientswithoutsigniﬁcant comorbidities.8_It_is_not_considered_an_easy_procedure,_since

thesurgeonfacesconsiderablevariationinthemorphology of the LVOT with limited transaortic access. However, in centerswithdecadesofexperiencethathavetreated hun-dredsofcasestheprocedureishighlyeffective,signiﬁcantly reducinggradientsandsymptomsin90---95%ofpatients.7

The need for another therapeutic option for patients withcontraindicationorhighriskforsurgerypromptedthe developmentofapercutaneousalternative.ASAconsistsof injectionofalcoholintoacoronaryarteryinordertocause limitedmyocardialnecrosisinthebasalseptum,whichwhen healed reduces septal thickness and hence the subaortic gradient. The technique has been the subject of contro-versysinceitsintroduction,butitsresultsaresuchthatit has become a viable alternative to surgical treatment of patientswithOHCM.

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Objective

The aimof thisstudyis toassessthe resultsofASA in all patientstreatedintheﬁrstfouryearsofactivityatasingle cardiologicalreferencecenter.

Methods

Weperformedaretrospectivestudybasedondatacollected prospectively of all consecutive and unselected patients withOHCMandindicationforaninvasiveapproach,treated byASA between thebeginningof activityin January2009 andFebruary2013.

Demographic variables, clinical indications, minor and majorcomplications,proceduralsuccessandlong-term out-come wereassessed.Success wasdeﬁnedassymptomatic improvement (reduction of at least one New York Heart Association[NYHA]orCanadianCardiacSociety[CCS]class) together witha reduction of over 50% in subaortic gradi-entsatrestorwithprovocation.3_Major_{complications}_were

consideredtobethosethatresultedindeathorsigniﬁcant morbidityorwerelife-threateningduringtheprocedureor follow-up.

Categorical variables arepresented ascounts and per-centages, and continuous variables as means ± standard deviation.ThestatisticalanalysiswasperformedusingSPSS version20.

Results

Duringthefour-yearstudyperiod,43patientswith indica-tionfor invasivetreatmentwere assessed,threeof whom wereexcludedbecauseatargetvesselwaslackingor per-fusedremotemyocardialsegments.Atotalof43procedures wereperformedin40patients.Themaincharacteristicsof thestudypopulationarepresentedinTable1.

The most frequent indication was exertional dyspnea; onepatient(2.5%)wasinNYHAclassIVandinanother(2.5%) thesoleindicationwasexertionalangina.Sixpatients(15%) hadapreviouslyimplantedpacemaker,onewithaDDD pace-makerimplantedprior totheintervention duetoexisting left bundle branch block, which put her at high risk for completeatrioventricularblock(AVB)followingthe proce-dure.

Mean subaortic gradient at rest was 90±34mmHg and mean septal thickness was 21.6±4 mm. Three patients (7.5%) had a resting gradient of <50 mmHg and in these casestheindicationwasduetothegradientobtainedwith provocation.Tenpatients(30%)wereconsidered notideal formyectomyduetoage,obesityorcomorbidities,andtwo (5%)wereformallyrejectedforsurgery.

Data on the intervention and in-hospital course are presented in Table 2. Alcohol was injected into a single target vessel, which was changed after intramyocardial contrast injection in four cases (10%). Two patients (6% of those without previous pacemaker) received a perma-nent pacemaker for AVB, one late, on the seventh day aftertheprocedureandafterreintroductionofbeta-blocker therapy. In four patients (10%) with AVB after 24 hours the initial approachwas conservative based on their risk score,waitingfor resolutionoftheedemaassociatedwith

Table1 Baselinecharacteristicsofthe studypopulation (n=40).

Age(years) 61.5±12.7

Age_≥75years 6(15)

Female 27(70)

NYHAclassIII/IV 39(97.5)

CCSclassII/III 10(25) Syncope 1(2.5) Previoushistory Hypertension 26(65) Diabetes 3(7.5) Coronarydisease 4(10) Atrialﬁbrillation 7(17.5) LBBB 2(5)

Previouspermanentpacemaker 3(7.5)

PreviousICD 1(2.5)

Echocardiogram

Maximumseptalthickness 21.6_±2.66

Gradientatrest 89.6±33.6

Gradientwithprovocation 109_±30 Mitralregurgitationgrade≥2 1(2.5) Ejectionfraction<50% 0(0) Therapy

Beta-blocker 29(72.5)

Calciumchannelblocker 27(67.5)

Dualtherapy 17(43)

DDDpacemaker 2(5)

Myectomy 0(0)

Values are counts (%) or means ± standard deviation. CCS: CanadianCardiacSociety;LLLB:leftbundlebranchblock;ICD: implantable cardioverter-deﬁbrillator; NYHA:New YorkHeart Association.

Table2 Interventionandhospitalization(n=40).

No.ofseptalarteries 43

Volumeofalcoholinjected(ml) 2.1±0.3

PeakCK(U/ml) 1130±438

AVBriskscore

Low 27(75a₎

Intermediate 7(19a₎

High 2(6a₎

Permanentpacemaker 2(6a₎

Sustainedventriculartachycardia 0(0)

Ventricularﬁbrillation 1(2.5)

Complicationsduringhospitalization

Major 2(2.5)

Minor 3(7.5)

In-hospitalmortality 0(0)

Valuesarecounts(%)ormeans_±standarddeviation.AVB: atrio-ventricularblock;CK:creatininekinase.

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Table3 Clinicalcourse(n=39).

Meanfollow-up(months) 22_±14

Symptomaticimprovement Dyspnea 31(86a₎ Angina 9(90a₎ Syncope 1(100a₎ Reductioningradient 33(89) SuccessfulASA 31(84) Permanentpacemaker 0(0) ICD 1(2.5) RepeatASA 3(7.5) Myectomy 1(2.5) Nocardiovascularevents 31(78)

Rehospitalizationforcardiaccause 5(12.5)

Mortality

Cardiovascular 1(2.5)

Suddendeath 0(0)

Total 2(5)

Valuesarecounts(%)ormeans_±standarddeviation.ASA: alco-holseptalablation;AVB:atrioventricularblock;ICD:implantable cardioverter-deﬁbrillator.

a_Percentage_for_patients_with_this_symptom.

thenecroticareaandre-establishmentof atrioventricular conduction,whichinsomecasesdidnotoccuruntiltheﬁfth day.

Therateofminorcomplicationswas7.5%.Intwopatients infectionswereresolvedby antibiotictherapy,andinone patient rapid atrial ﬁbrillation was controlled with phar-macologicaltherapy.Themajorcomplicationratewas5%, includingonepatientwithtamponadecausedbythe intro-ductionofthecatheterandresolvedbypericardiocentesis andpericardial drainage, andone withan inferior infarc-tioncausedbyrecruitmentofthecollateralsofthetarget vesseltothe posteriorinterventricular branch,leading to anepisodeofventricularﬁbrillationafew hoursafterthe intervention,resolvedbyshocktherapy.Allpatients under-wentHolterECG monitoringbeforedischarge;nocomplex ventriculararrhythmiasweredocumented.Therewere no in-hospitaldeaths.

Table 3 presents the data on clinical follow-up. Most patientsexperiencedsymptomaticimprovementassociated with a significant reduction in subaortic gradient. Pro-cedural success was 84%. Information on post-procedural gradient is unavailable for four patients, three because theprocedure wasperformed less than threemonthsago and one because of difficulty in repeating echocardiog-raphy due to severe neurological sequelae of a stroke. Twopatients(5%)sufferedstroke,bothmorethan30days after the intervention; four (10%) were readmitted due toparoxysmal atrial fibrillation, one of whom underwent successfulablation. Onepatient(2.5%)wasrehospitalized forimplantationofanimplantablecardioverter-defibrillator duetofaintingandnon-sustained ventriculartachycardia, both documented before ASA. Overall mortality was 5%: one patient died from probable pulmonary embolism 13 monthsafter theintervention andone diedof colon can-cer.

Discussion

SincetheﬁrstprocedureperformedbyUlrichSigwartin1994 anddescribed,withtwoothercases,in1995,9_ASA_has_been

reﬁnedandisnowmoreeffectiveandsafe,tothepointthat itsresultsarenowcomparabletosurgicalmyectomy.Itisno longerseen asapioneeringandpoorly-deﬁned technique, buthasbecomeanestablishedprocedureoverthecourseof nearlytwodecades,duringwhichithasbeenusedtotreat morepatientsthansurgery.10

Patient

selection

Theindications forASAarethesameasforsurgical myec-tomy,although itisimportant tostress thatpatientswith no or mild symptoms are not indicated for any invasive treatment.7 _The _presence _of _obstruction _is _an

indepen-dentprognosticmarkerofprogressiontoheartfailureand mortality,6_but_there_is_currently_{insufﬁcient}_evidence_that

interventionaltersprognosisinthesepatients;itsroleisto treatsymptomsthatsigniﬁcantlyaffectpatients’qualityof life.

Selectedpatientsshouldhaveexertionaldyspnea(NYHA class III or IV), exertional angina (CCS class II or III) or exertionalsyncopeforwhichanarrhythmiccausehasbeen excluded. There should be dynamic obstruction of ≥50 mmHgatrestand/or≥70mmHgwithprovocation,although thecurrenttrendistoconsiderpatientswithlowervalues ---≥30 mmHgatrest and/or ≥50mmHgwithprovocation. In our study population, which reﬂects our initial experi-ence and hence a learning curve, we opted for a more conservative selection process using the higher values. It shouldbestressedagainthatinvasivetreatmentisonly indi-cated when medical therapy is ineffective, not tolerated or contraindicated. In reference centers, optimization of medicaltherapyinpatientsreferredforinvasivetreatment canimproveclinicalstatusinaconsiderableproportionand removetheinitialindicationforASAormyectomy.11

Giventhe riskof causing an iatrogenicinterventricular communication, basalseptalthicknessshould be≥16mm for both ASA and myectomy. Mitral regurgitation,even if signiﬁcant, is not a contraindicationfor ASA solong as it isfunctionalandduetoSAM,sincethelatterwillimprove withreductionoftheobstruction.However,primarymitral regurgitation, or another indication for cardiac surgery, is reason to perform myectomy. In patients with severe hypertrophy (>30mm) or inwhom thepapillarymuscle is implanted directly intotheanterior mitralleaﬂetcausing LVOTobstruction,ASAislesslikelytosucceedandsurgery ispreferable.ForASAtobefeasibleitisalsoessentialthat theobstructionshouldbeintheregionofthebasalseptum andthatthereshouldbeoneor moreseptalarteriesthat canbeselectivelycatheterizedandthatirrigateonlythat partoftheseptum.ASAcanbeperformedafterunsuccessful myectomy.12

Althoughcases of ASA inchildren have been reported, manyoperators,includingtheauthors,considerthatthelow surgical risk at pediatric ages and the lack of knowledge ofthelong-termconsequencesofmyocardialnecrosisina young andstill developingheart mean thatsurgery is the preferredoption.

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Procedure

Theprocedurebeginswithcoronaryangiographyinorderto identifythetargetvessel,usuallytheﬁrstseptalbranchto thebasal septum,in which systolicmilking isvisible. The target septal branch may arise from a diagonal, the cir-cumﬂex, or even the right coronary artery, although the latterwasnotobservedinourpopulation.Following assess-mentofthecoronaryanatomy,includingeaseofaccessto and caliberof the target vessel, the material tobe used in the procedure can be selected. In our center we gen-erallyuse 6FJudkinsandEBUguiding catheters,BMW® _or

Pilot50®_guidewires_(Abbott_Vascular,_Santa_Clara,_CA,_USA)

and Apex Flex® _{over-the-wire} _balloon _catheters _(Boston

Scientific, Natick, MA, USA). A femoral approach is pre-ferredforgreaterstabilityduringcoronarycatheterization. When significant coronary lesionsare detected with indi-cation for revascularization, we consider that this should be performed first and ASA postponed pending reassess-mentofsymptoms.Inoneofourpatientstheoriginofthe target septalbranch wasclosetoa lesion inthe anterior descending artery and stenting would have compromised subsequentaccess,and soit wasdecidedtoperformASA first and then to treat the lesion in the same procedure (Figures1and2).

All patients shouldundergo priorDoppler echocardiog-raphytoconﬁrmthediagnosisandtoaccuratelylocateand quantifytheobstruction(Figure3).Whendoubtsremain con-cerningthelatter,hemodynamicassessmentisperformedto recordaorticandintraventricularpressuressimultaneously and to quantify the gradient at rest, with the Valsalva maneuver,andafteraventricularprematurebeat.

During the procedure, transthoracic echocardiographic studyisfirstperformedtoassesstheechogenicityofthe car-diacstructuresfor subsequent comparisonandtoexclude pericardialeffusion. Afterthetarget vesselis identifieda temporarypacingcatheteris placedin theright ventricle via a transvenous femoral or jugular approach. Follow-ingconfirmation that thisis stable andeffective, heparin 70---100U/kgisadministered,thenthetargetseptalartery is approached with a guidewire previously inserted into the balloon catheter. The latter is then introduced over theguidewireintothetargetvessel andpositionedat the desiredlocation,whichisselectedaccordingtothe diame-terofthevesselandtheexistenceofbifurcationsthatmay or maynot besubjectto alcohol injection,depending on theirsizeandcourse.Thediameteroftheballoonshouldbe 0.5mmgreaterthanthatofthetargetvesselatthepoint whereinflationwilltakeplace;asmallerdiametermaynot completelyoccludethevessel,allowingalcoholtoflowback totheanteriordescendingartery,whileanoversizedballoon maybedisplacedduringalcoholinjection.

Following balloon inflation at low pressure (4---6 atm), the guidewire is withdrawn and angiographic contrast is injectedinordertovisualizethedistalcirculationofthe tar-getvessel,excludetheexistenceofcollateralsandconfirm totalocclusionofthevesselwithnobackflowofcontrastto theanteriordescendingartery.Then1---2ccofmyocardial contrastisinjected;initiallyLevovist® _(Bayer_AG,_Schering

AG, Germany)wasused,and afterthis wasdiscontinued, SonoVue®_(Bracco,_Milan,_Italy)._{Transthoracic}

echocardiog-raphyisusedtoassessthehyperechogenicityofthetarget

region,thebasal septumwhereSAMoccurs, andﬂow tur-bulence,andtoexcludetheinvolvementofremoteregions suchastheLVfreewall,therightventricleandthepapillary muscles.

Once the decision is made to go ahead with alcohol ablation,analgesiais administeredwithmorphine (4---6cc intravenously, which is well tolerated in most patients) andthecorrectfunctioningofthetemporarypacemakeris checked.Thisstepisextremelyimportant,sincetransient AVBis common.Slowinjection(1 cc/min)of 1cc alcohol percm thicknessof thetarget septaltissue follows, con-stantlymonitoringthat theballoon iscorrectly positioned andwellinflated.Followingalcoholadministrationandafter a10-minwait,theguidewireisreinsertedintothelumenof theballoon catheter,which isdeflatedandthewhole sys-temisremoved.Afinalangiogramisperformedtoexclude coronarydissectionorimpairedcoronaryflow.

Patientsremain in the coronary care unit for the ﬁrst 24---48hours,undercontinuousECGsurveillance.The creat-ininekinasecurveismonitoredatfour-hourintervalsuntil itspeak,thetimeofwhichisoneoftheparametersinthe AVBriskscoreusedinourpopulation.13_In_low-risk_patients

thepacingcatheterisremoved24---48hoursafterthe inter-ventionandthepatientreturnstothewardundertelemetric ECG monitoring and restarts his or her previous medica-tion(beta-blockersand/orcalciumchannelblockers),which areusually suspended beforethe procedure. If there are nocomplications,thepatientisdischargedonthesixthor seventhday.

The procedure described aboveundoubtedly differs in smalldetailsfromthatusedbyothercentersandoperators, butthebasicstepswillbecommontoallforwhomsafety isa priority.We highlight threechangesthathave helped improve safety and outcomes compared to the ﬁrst pub-lishedseries.Firstly,weuseasmallerquantityofalcohol, reducingtheareaofnecrosisandhencetheriskofaffecting atrioventricularconductiontissue.Similarly,theimmediate objectiveofreducingthesubaorticgradient,withrepeated alcoholinjectionsifnecessary,hasbeenabandonedinfavor ofassessingtheresultafterseptalhealingandremodeling. Thesecondchange,introducedbyFaberetal.in1998,was theuseofintraproceduralmyocardialcontrastinjectionand transthoracicechocardiographytodeterminethetarget ves-selandpreventnecrosisinremotemyocardialregions.14_This

isnowanimportantstepintheprocedure;inourseriesthe targetvessel waschangedin 10%of cases,and the inter-ventionwasabandoned in threepatients(not included in thestudy)becauseechocardiographicassessmentfailedto identifyasuitablevessel. Thirdly,the introductionof risk scoresfor high-degreeAVB hasmade itpossible to distin-guishpatientsinwhomitisbettertoawaitresolutionofthe acutephaseofseptaledema,afterwhichconduction distur-bancesresolveinthemajorityofcases,fromthoseinwhom apermanentpacemakershouldbeimplantedimmediately.13

Efﬁcacy

Immediate gradient reduction is no longer considered essential for the efﬁcacy of the procedure. Follow-ing ASA, the gradient goes through three stages: immediately after alcohol administration it falls due

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Figure1 Procedure:(a)angiography,rightobliquecranialviewoftheleftcoronaryartery,showingthetargetvessel;(b)selective catheterizationofthetargetvessel andplacementofballooncatheter;(c)selectiveangiographyofthetargetvessel,showing injectionofcontrastthroughthelumen oftheballooncatheter; (d) transthoracicechocardiography, 4-chamberview,showing hyperechogenicbasalseptumafterinjectionofcontrast.

tomyocardial stunning; it then rebounds over 5---10 days due to edema in the necrosed area; and ﬁnally scarring andremodeling occur after aroundthree months,usually leadingtoimprovementinthegradient uptoayearafter theintervention.15

In 2006, Alam et al. published a meta-analysis of 42 studies on outcomes after ASA in 2959 patients.16 _At ₁₂

months,therewasasustaineddecreaseinrestingand pro-vokedLVOTgradient(65.3to15.8mmHgand125.4to31.5 mmHg,respectively)accompaniedbyreductioninbasal sep-talthickness(20.9to13.9mm),improvementinNYHAclass (2.9 to 1.2), and increase in exercise capacity (325.3 to 437.5seconds).ASA isassociated withsustained improve-mentsin symptoms and gradient in >85% of patients.17,18

RepeatASAduetopersistenceorrecurrenceofsymptoms is necessary in around 7% of cases, a similar ﬁgure to myectomy.16

ASA results in increased LVOT area and reduced gradient19,20_;_besides_symptomatic_improvement,_its

bene-ﬁtsincludeincreasedcoronaryﬂowreserve21_and_LV_size_and

reducedLVmass,22_{end-diastolic}_pressure,14_left_atrial_size14

andmitralregurgitation.23_The_clinical_effects_observed_are

alsoduetoimprovedLVdiastolicfunction,whichis compa-rabletothatobtainedbymyectomy.24,25

Iftheprocedure isunsuccessful, myectomyremains an option,albeitwithagreaterriskofneedforpermanent pac-ing,duetothe combination ofthe completeright bundle

branchblockthat oftenresultsfromalcoholinjectionand theleftbundlebranchblockcausedbythesurgicalincision intheleftsideoftheseptum.

Safety

and

complications

The most common complication in ASA is irreversible high-degree AVB, but the improvements in the technique describedabovehavereducedthefrequencyofthis compli-cation to <10%, far lowerthan the initial results of some centers.17,18 _In _some _cases_persistence _of _AVB _beyond_the

first 24 hoursis due tothe effect of perinecrotic inflam-mation on adjacent conduction tissue, rather than its permanent destruction; our experience confirms that in intermediate-risk patients with persistent AVB it is worth waiting a few days for the inflammation to subside and for intraventricular conduction to be re-established, in which case therewill be no need for a permanent pace-maker.

Other possible complications are related to vascular accessandintravascularcathetermanipulation,similarto percutaneous coronaryintervention, but they are uncom-monifcareistakenwithtechnicalaspectsoftheprocedure. Alametal.describeddissectionoftheanteriordescending arteryin1.8%ofpatients,16_while_cardiac_tamponade_caused

byinsertionofthetemporarypacingcatheterhasareported incidenceof0.6%.16

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Alcoholleakagetotheanteriordescendingarteryorvia collateralstoremotetissuesisaseriouscomplicationthat

canleadtoanunconﬁnedinfarctionoutsidethetargetarea. Leakagecan beavoided by takinggreat careto keepthe

Figure2 Changeinthe targetvessel aftercontrast injection:(a) selectivecatheterization ofthesecond septalbranch;(b) selectivecatheterizationofthefirstseptalbranch;(c)opacificationoftherightsideoftheseptumafterinjectionofcontrastin thesecondseptalbranch;(d)opacificationoftheappropriateregionoftheseptum(belowtheanteriorleafletofthemitralvalve), followingcontrastinjectioninthefirstseptalbranch.

Figure3 Echocardiographicimages:(a)transthoracicechocardiography,4-chamberview,beforetheintervention;(b)continuous Dopplerstudyshowingsubaorticgradientbeforetheintervention;(c)transthoracicechocardiography,4-chamberview,threemonths afterthe intervention,showing decreasedthickness ofthe basalseptum; (d)continuous Doppler studythreemonths afterthe intervention,showingreductioninthesubaorticgradient.

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balloon fullyinﬂated andto maintain thestability of the entiresystemtopreventreﬂuxofalcohol.Therecruitment ofcollateralsisanunpredictablecomplication,sinceasin ourexperience,they maynot be visualized at the begin-ning of the intervention, but this is rare. In one of the fewpublishedcases,Chowdharyetal.suggestthat recruit-mentofcollaterals maybefacilitatedbylonger occlusion ofthetargetvesselbeforealcoholadministration,26 _which

was in fact the case in our patient due to the need to replacetheechocardiographic probe.Sincethen,wehave paidparticularattentiontotheneedtominimizeocclusion time.

Another possible cause for concern is the creation of an intramyocardial septalscar, due toits arrhythmogenic potentialinadiseaseinwhichthereisalreadyasubstrate for arrhythmias. However, after nearly 20 years of expe-rienceand thousands of procedures, this fearhas proved groundless(seefollowingsection).Carefulstratiﬁcationof arrhythmicriskis essential,asalways inthetreatment of HCM.

In-hospital mortality associated with ASA is 0---4%,27

lower in centers with greater experience with ASA and percutaneous interventions generally, reﬂecting the need for a learning period. Kwon et al. reported no intrapro-cedural mortality in patients at high surgical risk.28 _In

the review by Alam et al., early (30-day) mortality was 1.5% (0.0---5.0%) and late mortality (>30 days) was 0.5% (0.0---9.3%).16

Comparison

with

myectomy

Aswithotherconditionsforwhichthereareboth percuta-neousandsurgicaltreatmentoptions,eitherasalternatives orcomplementary,therehasbeenconsiderabledebate con-cerningthebestapproach.Itisgenerallyagreedthatthere isunlikelytobealargerandomizedmulticentertrial com-paringthetwostrategies that couldhelpclarify which of thetwoshouldbepreferred.29_The_low_prevalence_of_OHCM

andthelackofﬁnancialincentive(nospecialized technol-ogyor intellectual propertyis involved) would makesuch atrial difﬁcult toimplement.We arethus leftwith com-paringthelimitationsofeachtechniqueandtheresultsof observationalstudiesinmeta-analyses.

Proponents of surgery frequently point to the greater long-term experiencewith myectomy, although this argu-ment is becomingweaker asthe years pass; there arein factnowmorepatientstreatedpercutaneouslythan surgi-cally.Surgical treatmentcandealwithcertainanatomical featuresthat ASA cannot,suchasmitral valverepairand casesrequiringalargerquantityofhypertrophiedmuscleto beresected,thusachievingagreaterandmorerapid reduc-tioninintraventriculargradient, butthis doesnot appear toaffectclinicaloutcomes.CompletesustainedAVBisless frequentwithmyectomy(5%asopposedto10%withASA); thisisprobablythemaindifferenceintheresultsofthetwo techniques.16

ASA has the advantages of other percutaneous treat-ments:it is less invasive,does notrequire sternotomy,is associatedwithshorterrecoverytime,andcanbeusedto treatpatientswithrelativeorabsolutecontraindicationsfor surgery,suchaselderlyorobeseindividualsandthosewith

signiﬁcant comorbidities. Clinical outcomesare similarto thoseofmyectomy,asshownintworecentmeta-analyses, in which theonly differencewastheneed for permanent pacing.30,31_These_results_reﬂect_the_learning_curve_required

forASA,aswasinitiallyseenformyectomy,althoughnotin recentpublications.

Two of the main limitations of ASA are the need for favorable anatomical conditions and more unpredictable outcomes,althoughthesecanbereducedbycarefulpatient selection.

Thegreatestcontroversyconcernstheriskofventricular arrhythmiaswithASA.Suchfearswereheightenedbysome smallobservationalstudies,32,33_but_these_were_contradicted

by other similarstudies that indicated the techniquewas safe.34,35_These_conﬂicting_results,_and_the_lack_of_sufﬁcient

evidence,havecreatedconfusionthatcanonlyberesolved bylargestudiesofpatientstreatedbyASAwithlong-term outcomesandbymeta-analysescomparingtheresultsofthe twotechniques. In 2008 Kuhn etal. publishedthe results of644consecutive patientstreatedbyASAovera 10-year period.36_Annual_cardiac_mortality_after_discharge_was_0.7%,

a similar percentage to the untreated population, which doesnotsupporttheideathatthesepatientsareatgreater riskofsuddendeath.37_The_latest_and_largest_{meta-analysis}

ofthetwotechniquesanalyzed2207patientstreatedbyASA and1887patients treatedbymyectomyandfound no dif-ferencesinoverallmortalityorsuddendeath,eventhough thepopulationtreatedsurgicallywereyounger.38

Conclusion

Theresultsfromtheinitialexperienceofourcenterconﬁrm the efﬁcacy andsafety of ASA for the invasivetreatment ofpatients withOHCM refractorytomedicaltherapy.This percutaneous approach is a valid alternative for invasive treatmenttoreducesubaorticobstructioninthesepatients.

Ethical

disclosures

Protection of human and animal subjects.The authors declare that theprocedures followed werein accordance withtheregulationsoftherelevantclinicalresearchethics committeeandwiththoseoftheCodeofEthicsoftheWorld MedicalAssociation(DeclarationofHelsinki).

Conﬁdentialityofdata.Theauthorsdeclarethattheyhave followedtheprotocolsoftheirworkcenteronthe publica-tionofpatientdataandthatallthepatientsincludedinthe studyreceivedsufﬁcientinformationandgavetheirwritten informedconsenttoparticipateinthestudy.

Righttoprivacyandinformedconsent.Theauthorshave obtained the written informedconsent of thepatients or subjectsmentionedinthearticle.Thecorrespondingauthor isinpossessionofthisdocument.

Conﬂicts

of

interest

(9)

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