Background:Acuteleftventricular(LV)apicalballooningwithnormalcoronaryangi-ographyoccursrarelyinobstructivehypertrophiccardiomyopathy(OHCM);itmaybe associated with severe hemodynamic instability.Methods, Results:WesearchedforacuteLVballooningwithapicalhypokinesia/aki-nesiaindatabasesoftwoHCMtreatmentprograms.DiagnosisofOHCMwasmadebyconventionalcriteriaofLVhypertrophyintheabsenceofaclinicalcauseforhy-pertrophyandmitral-septalcontact.Among1519patients,weobservedacuteLVballooningin13(0.9%),associatedwithdynamicleftventricularoutflowtract(LVOT)obstructionandhighgradients,92±37mmHg,10female(77%),age64±7years,LVEF31.6±10%.SeptalhypertrophywasmildcomparedtothatoftherestofourHCMcohort,15vs20mm(P<0.00001).Anelongatedanteriormitralleafletoran-teriorlydisplacedpapillarymusclesoccurredin77%.Coursewascomplicatedbycar-diogenic shockandheart failure in5, and refractoryheart failure in1.High-dosebeta-blockadewasthemainstayoftherapy.ThreepatientsrequiredurgentsurgicalreliefofLVOTobstruction,2forrefractorycardiogenicshock,andoneforrefractoryheartfailure.Inthethreepatients,surgeryimmediatelynormalizedrefractorysevereLVdysfunction, and immediately reversedcardiogenic shockandheart failure.AllhavenormalLVsystolicfunctionat45-monthfollow-up,andallhavesurvived.Conclusions:AcuteLVapicalballooning,associatedwithhighdynamicLVOTgradi-ents,maypunctuatethecourseofobstructiveHCM.Thesyndromeisimportanttorecognizeonechocardiographybecauseitmaybeassociatedwithprofoundreversi-bleLVdecompensation.
Dynamic variation of gradient severity is characteristic of left ventric-ularoutflowtract(LVOT)obstructioninhypertrophiccardiomyopa-thy (HCM).1,2Obstructionmaybe spontaneously labile.Gradientsmaybeprovocablebyactivitiesofdailylifesuchasstanding,eating,orexerciseandareanimportantcauseofsymptomsanddisability.2 The systolic pressure gradients across the LVOT cause symptomsdue to increased LV pressure and work, coronary hypoperfusion,supplydemandischemia,3aninstantaneousdropinejectionveloc-ities and flow caused by obstruction, mitral regurgitation, tension- mediateddiastolicdysfunction, inabilityto increasecardiacoutputwith exercise, and occasionally frank hypotension. Moreover, thecardiomyocytes of HCM patients often demonstrate geneticallydeterminedinefficientenergyutilization,andconsequentdepletionof high-energy phosphate moieties.4,5 Cardiomyocyte energy de-pletion, shownbyphosphorus-31 cardiacmagnetic resonance im-aging,occursinHCMpatientsirrespectiveofobstructionandisalsopresent in genotype-positive, phenotype-negative patients beforethedevelopmentofhypertrophy.6ObstructioninHCMadditionallyexacerbatesenergydepletionbydintoftheincreasedwork.Similarreversibleenergydepletionoccursinaorticstenosisthatcanleadtosystolic dysfunction.7 In lightof theadversepathophysiology, it isnotsurprisingthatcontractileimpairmentofvaryingseverityoccursin someHCMpatientswith LVOTobstruction, evenwhen the LVejectionfraction isnormalorhigh.Thissystolic impairment ispar-adoxicalbecauseHCMisunderstoodasahyperdynamiccondition,bothofglobalLVfunctionandatthegranularsarcomericlevel.
We have termed this phenomenon “dynamic systolic dysfunc-tiondue toLVOTobstruction.”4,8–13 It ismost commonlymanifestasareversiblemid-systolicdropinpulsedDopplermid-LVejectionvelocitiesandflowinpatientswithLVOTgradients>60mmHg;itscharacteristic spectral Doppler appearance has fostered the termthe“lobsterclaw”abnormality.8,9ThisflowabnormalityiscausedbyaprematureterminationoflongitudinalLVcontraction.10,11
WecaredfortwoHCMpatientswithknownlatentobstructionwhosuddenlydevelopedpersistentsystolicanteriormotion(SAM)atrestwithunrelentinghighrestinggradients.Thesetwopatientsdeveloped apical and mid-ventricular ballooning, refractory car-diogenicshock,andheart failure.They improved intra-operativelyimmediatelyaftersurgicalreliefofLVoutflowobstruction.12Theirdramaticclinicalcourseledustosearchourdatabasesforotherpa-tientswithapicalballooninginobstructiveHCM.
2 | METHODS
This is a retrospective study of patients under our care who de-veloped apical ballooning in the presence of obstructive HCM.We searched the comprehensive research databases of theHCMProgramsofNewYorkUniversityLangoneHealthandMountSinaiWestHospital(formerlyRooseveltHospital)inNewYorkforallpa-tientswithanepisodeofacuteLVapicalballooning.Thedatabases
comprisepatientswhoprovidedconsenttousetheirclinicalinforma-tionforresearchpurposesbeginningin1999.Follow-upisacquiredyearly,eitherintheclinicorbyscriptedtelephoneinterview.TheselongitudinalregistrieshavebeenapprovedbytherespectiveIRBsoftheinstitutions.Thetwopreviouslyreportedcases12 are included in thepresentcaseseries.
2.1 | Diagnoses of obstructive HCM and apical ballooning
ChronicHCM-related symptoms of exercise intolerance, dyspnea,angina, or syncope were tabulated as well as medications beforetheindexadmission.Detailsoftheapicalballooningadmissionwererecorded,includingacutesymptoms,initialECG,laboratoryvalues,echocardiogram, catheterization results, pharmacologic and othertreatments,andoutcome.Cardiogenicshockwasdiagnosedwhentherewasprolongedhypotensionsystolic<80mmHg,coolextremi-ties,andoliguriaintheabsenceofanyothercauseofshock.
2.3 | Echocardiography
Echocardiogramswere reviewedbyoneof twoexperiencedHCMphysicians (MS or BK). Detailed measurements were made fromechocardiograms,duringtheballooningepisode,andbeforeoraftertheepisode,atatimewhenLVfunctionwasnormal.Ifthepatienthadmultipleechocardiogramsperformedon theballooningadmission,weselectedthestudywiththehighestCWDopplerLVOTgradientformeasurement.WemeasuredsegmentalLVwallthicknessesfrom2Dechocardiographyaspreviouslyreported.14 We measured mitral valveleafletlengthaspreviouslydescribedandassessedabnormali-tiesofthepapillarymusclesandchordaetendineae,bothknownas-sociationswithLVOTobstruction.15–22 Mitral anterior leaflets were measuredfromthetipoftheleaflettotheaorticannulus,includingthe intervalvular fibrosa.Baseduponpreviouswork,anterior leaf-letsmeasuring>30mm(>16mm/m2)werecharacterizedasabnor-mally long.23–25PapillarymuscleandchordalabnormalitiespositionthemitralvalveanteriorlyintheLVcavity,subjectingittothedragof ejection flow.21,22,26 Exercise echocardiography with standingandsupinepostexercisegradientacquisitionswasperformedwhen
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indicatedclinicallyaspreviouslydescribed.1,2Postprandialexerciseechocardiography(SPEPP)wasperformedintwopatientsbecausethe conventional treadmill stress echo showed postexercise SAMbutgradientswerenothighenoughtoexplainthepatient’ssymp-toms.27Mitral regurgitationwasqualitativelyassessed fromgrade0–4. LV ejection fractionwas calculated using Simpson’smethod.Coronary angiographywasperformed inevery caseoneither thedayoforthedayafteradmission.LVejectionfractionwasqualita-tivelyestimated.Cine-angiographicmitralregurgitationwasqualita-tively assessed from grade 0 to 4.
Therewere13HCMpatientswithanacuteepisodeofapicalbal-looning,0.9%ofthe1519HCMpatientsenrolledinourdatabasesfrom1999toJuly2017.All13patientshadhighCWDopplerLVOTgradients during their ballooning admission 92±37mmHg; thesewere due to SAM, mitral-septal contact, and asymmetric septalhypertrophy.
3.1 | Clinical features of HCM
Table1 summarizes the demographic, clinical, and HCM echocar-diographicvariablesatatimewhenLVsystolicfunctionwasnormal.Patients were aged 62.8±7years when HCMwas diagnosed. Ten(77%)werefemale.Elevenofthepatientswerewhite,onewasblack,andoneAsian.EightpatientswerediagnosedwithHCMand latentobstructionamedianof24.5(range4–122months)before their bal-looningadmission.Sixpatientshadcardiacsymptoms:dyspneain6,chestpainin2,syncopein2,andparoxysmalatrialfibrillationin1;theremainingtwopatientswerediagnosedbecauseofaheartmurmur.Infiveotherpatients,obstructiveHCMwasfirstdiagnosedat the time of theirballooningeventbecauseofASHandSAM.Inthesefivepatients,duringrecoveryafterward,gradientssubsidedto<30mmHgandLVfunctionnormalized.But,5monthslaterseverelatentLVOTobstruc-tionwasdefinitivelydemonstratedbyprovocationofLVoutflowgra-dientsaveraging92mmHg(range50–144)afterValsalvaorexercise.
3.2 | Clinical presentation of apical ballooning event
Table2 summarizes the clinical, echocardiographic, angiographic,and treatmentvariablesof theballooningadmission.Thepatientswere 64.3±7years when the ballooning event occurred. Ten
patients(77%)hadprecipitantsthatappearedtoprovoketheirbal-looningepisodes:overexertionin3,adiarrhealillnessin2,dehydra-tionin3,andafuneralin2.Symptomsthatpromptedtheemergencyroomvisitweredyspneaandtypicalchestpainin5,dyspneain2,chestpainin2,andsyncopein4.ECGsdemonstratedSTsegmentelevationsin5,STandTwavedepressionsin2,Twaveinversionsin2,andacuteQTprolongationin1.ThreepatientshadLVH.Peaktro-poninIwas1.78±0.97ng/mL(normal<0.04).Thus,clinicalpresen-tationsinallcasesmetcriteriaforanacutecoronarysyndrome.Onthisbasis, all patientsunderwentemergent coronary angiographyshortlyafterpresentation;nopatienthadsignificantnarrowing.
3.3 | Treatment of the ballooning episode
Acutely,twelvepatientsweretreatedwithbeta-blockade,8intrave-nously,inanattempttoreduceLVOTobstruction.Theclinicalcoursewas complicated in seven patients (54%)who had persistent highdegreeobstruction.Fivesufferedbothcardiogenicshockandheartfailure,onehadhypotension,andonehadrefractoryheartfailure.FivepatientsrequiredIVphenylephrineforbloodpressuresupport,and2were treatedwithan intra-aorticballoonpump (IABP).Twopatientswithacute refractory cardiogenic shockandheart failureunderwentemergentsurgerytoabolishLVOTobstruction.Inthese2patients,arterialpHwas7.23and7.18,respectively,frommeta-bolicacidosisimmediatelybeforetheyweretakentosurgery.Athirdpatient had acute and persistent refractory heart failure and un-derwent urgent surgery to relieve her unrelenting outflow obstruc-tion.Theindividualclinicalcoursesofthe13patientsareshowninFigure1.RepresentativesequentialechocardiogramsfrompatientsareshowninFigures2–6.
aDyspnea6,angina2,syncope2,paroxysmalatrialfibrillation1.bElongatedleaflets5,anteriorlydisplacedpapillarymuscles5andthick-ened shortened chordae in one. cBeta-blockade2;beta-blockadeanddisopyramide3; calciumchannelblockade2.
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3.3.1 | Echocardiography
Atthetimeoftheirballooningadmission,thebasalanteriorseptalLVsegmentwasthickenedinthe13patients,average15.2±2mm.WhenLVcavitysizeandfunctionwerenormal,itwas15.4±2.Theanteriorseptalthickeningwaslessthanthatobservedinthe1506patientsinourregistrieswhodidnothaveballooning,19.9±6mm,P<0.00001.Wallthickeningwasabsentormodest intheremain-ing segments. During the ballooning hospitalization, SAM withmitral-septalcontactandrestingLVOTgradientswerenotedall13patients,averaging92±37mmHg. In10of13patients,the initialechocardiogram, often obtained in the emergency department,showed the highest gradient of the ballooning admission. However, in threepatients,higher restinggradientsweredocumented later,associatedwithpartialrecoveryofLVsystolicfunction.LVejectionfractionwas32±10%withapicaldilation,andapicalandmid-LVhy-pokinesia/akinesia.ThebasalLVsegmentswerespared,evidencingnormal,orhyperkineticcontraction.Mitralregurgitationgradewas3.3±0.8,moderatelysevereonaverage.
3.4 | Low or absent gradients when LV function was normal
resting gradients<30mmHg. In thewhole group, dynamic gradi-entsprovokedeitherbeforeorafter theballooningepisodebyei-therValsalvaorexercisewere115±52mmHg.Ineightcases,stressechocardiographyusingtreadmillexercisewasperformedatatimewhenLVsystolicfunctionwasnormal;for2ofthesecases,testingfollowedamoderately sizedmeal.Nopatient evidenced a restingsystolic LVOT gradient≥30mmHg. After stress, the peak LVOTgradientsaveraged118±44mmHg.
Therewereabnormalitiesof themitralapparatus thatcontrib-utedtoSAMin10 (77%)patientsobservedduringballooningepi-sodesandalsowhentheLVsystolicfunctionnormalized.Findingsincluded an elongated anterior leaflet in 5, and anterior displace-mentofthepapillarymusclesin5andthickenedshortenedchordaethatanteriorlydisplaced themitralvalve inone.Themitral leafletelongationobservedin4HCMpatientswithlatentobstructionandsevere ballooning is shown in Figures7–8. The obstructive HCMpatient inFigure7developedcardiogenic shock10yearsafterhisinitialobstructiveHCMdiagnosis.Hisanterior leafletwasparticu-larlylong,38mm(1.9mm/m2).Thispatient’spre-andpostoperativeechocardiogramsareshowninMoviesS1–S3.Anothersurgicalcaseis shown inMoviesS4–S5. This patient had refractory congestiveheartfailure;hersevereLVdysfunctionreversedtonormalcomingoffcardiopulmonarybypassafterseptalmyectomy.Figure9showstheballooningepisodeofanotherpatient.AfternormalizationofLVfunction subsequentexerciseechocardiogramshowedahighpro-vokedgradient.Thispatientalsohadanelongatedanteriorleaflet.
F IGURE 1 Theindividualclinicalcoursesofthe13patients.BB=betablocker;CP=chestpain;Dx=diagnosis;Refract=refractory;trop=troponin;Uncomp=uncomplicated
F IGURE 2 Sixty-seven-year-oldmalewithhypertrophiccardiomyopathy(HCM)andprovocableobstruction.ExerciseechoattimeofHCMdiagnosis.LVfunctionwasnormalatrestandhyperkineticwithexercise.Leftframe:Parasternallong-axisviewinenddiastole.Mildbasalanteroseptalhypertrophy,17mm(redarrow).Middleframe:Systolicpostexerciseapical3-chamberviewwithsystolicanteriormotionandmitral-septalcontact(orangearrow).Rightframe:PostexerciseCWDoppler:systolicleftventricularoutflowtractgradientwas125mmHg
F IGURE 3 SamepatientasFigure2.Fouryearslaterafterexercisingvigorouslyonahotsummerday,hewasadmittedwithseverechestpainanddyspnea.Leftframe:Diastolic2-Dapical4-chamberviewperformedonadmission.Redarrowindicatesthemildseptalbulge.Middleframe:Systolicframeshowssystolicanteriormotion(SAM)ofthemitralvalve(orangearrow)andapicalakinesis(whitearrowheads).Rightframe:CWDopplerwithrestingleftventricularoutflowtractgradientof85mmHg.Thus,thispatientwithknownhypertrophiccardiomyopathyandlatentobstructionandnormalLVsystolicfunction(figure1)presented4ylaterwithapicalballooning(Figure2).Thispaperproposesthattheballooningisduetothesuddenobstructionatrest,andunrelentinghighLVOTgradients
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3.4.1 | Cardiac catheterization
Coronary angiograms were either completely normal or showedmildluminalirregularities.Nopatienthadacoronarystenosis>50%.The peak-to-peak catheter LV intraventricular pressure gradientwas measured in 10 patients and was 47±26mmHg. LV cine-angiographywasperformed in6patients; visually estimatedejec-tion fraction averaged 27±5%, andmitral regurgitation averagedgrade2.8±1.7.
3.4.2 | Cardiac magnetic resonance imaging
Cardiac magnetic resonance imaging was performed as clinicallyindicatedon8of 13patients. In two itwasperformedbefore LVsegmental systolic functionhadnormalized.Thickeningwas local-izedtotheanteriorseptumandaveraged15.1±2.1mm.SixpatientshadmildSAMwithaccelerationof flow in theoutflow tract.TwopatientshadLGEencompassing4and5%oftheLVmass.
3.4.3 | Follow- up
Patientswerefollowed-upforamedianof45monthsafterthediag-nosisofHCM.Ninepatientsweretreatedwithoralbeta-blockade,twowithbeta-blockadeanddisopyramide,and2withwarfarin.Nopatientwhohad not received surgerywas treatedwith an angio-tensin converting enzyme inhibitor or angiotensin receptor block-ade. The one patient who could not take beta-blockade becauseof a drug-related rash had a second episode of severe chest pain11monthslater,associatedwitha100mmHgLVOTgradientduetoSAM,andatroponinriseto2.3ng/mL.LVwallmotionwasnormalatthattime.ShewastreatedwithIVmetoprololwithresolutionofsymptomsandgradient,butthebetablockerwasagaindiscontinuedduetodrugrash.Sheremainslimited.Inthe13patientsatfollow-up,NYHAclasswas1.9±0.7.AllhadnormalLVsystolicfunction,andnopatientevidencedarestingLVOTgradient≥30mmHg.Threepa-tientscontinuetohavemoderatedyspneaaftermildexertionduetolatentobstruction.Nopatientexpired.
4 | DISCUSSION
Anepisodeof LVapical ballooningpromptedurgent admission andcoronary angiography in 13 HCM patients with dynamic obstruc-tion.TheballooningeventwasassociatedwithhighLVOTgradients,92±37mmHg. HCM was diagnosed by conventional criteria: (a)asymmetrichypertrophy intheabsenceofclinicalcauseforthehy-pertrophy;and(b)LVOTobstructionduetoSAM,withmitral-septalcontact provoked by Valsalva’s maneuver or exercise. All patientsdemonstratedsevereLVOTobstructionduringtheacuteepisodeofapicalballooningwithgradientsaveraging92mmHg.Eightpatientshadlatentobstructiondiagnosedmedian25monthsbeforetheirbal-looningepisodes,whilefivehadtheirobstructiveHCMdiagnosismadeduring the course of their acute ballooning admission, and definitively
Three-quarters of these patients were elderly women.Presentationmimickedanacute coronary syndromewith sudden-onsetcardiac symptoms, ischemicECGabnormalities, andmodesttroponinelevationsforthedegreeofwallmotionabnormality.Theirechocardiograms showed only a modest degree of isolated basal an-teriorseptalthickeningaveraging15.2mm.EchocardiographicLVEFaveraged32%withapicaldilatation,andapicalandmid-LVakinesiaorhypokinesiawithnormalorincreasedbasilarcontraction.LVcine-angiogramscorroboratedtheechocardiographicLVfindings;coro-nary angiograms showed no significant coronary stenosis.
Of note, despite treatmentwith IV beta blockade and fluids, 5patientsdevelopedcardiogenicshock,andonedevelopedrefractoryheartfailureandonepatientdevelopedhypotensionduringthebal-looninghospitalization;5requiredIVphenylephrineforbloodpres-suresupportandtwopatientsunderwentIABP.Twootherpatients,previously reported, are included in this series12; they developedrefractorycardiogenic shockandprofoundheart failuredespite in-travenousbetablockade, litersof intravenousfluidandintravenousphenylephrine.TheyweretakentotheoperatingroominextremisforreliefoftheirLVoutflowobstruction;within2hoursofabolitionoftheirLVgradientssystolicfunctionhaddramaticallyimproved.Athirdpatientwithrefractoryheartfailurehadurgentsurgeryforreliefofobstruction;herLVseveresystolicdysfunctionreversedimmediatelyaftersurgicalreliefofobstructionatterminationofcardiopulmonarybypass.
4.1 | Dynamic systolic dysfunction in obstructive HCM
A spectrumof dynamic systolic dysfunctionwith varying sever-ityhasbeendemonstrated inobstructiveHCMpatientseven inpatients with normal or high ejection fractions.4,8–13 In patientswith LVOT gradients ≥60mmHg, there is a ubiquitous mid-systolic drop in Doppler velocities and flow of LV ejection thatcanbedemonstratedwithpulsedDopplerinterrogationoftheLVcavitybeforeentry into theLVOT.8–11,13Othersdemonstratedamid-systolic drop in descending aortic velocities.28 The drop inLVejectionvelocitiesexplainssomeofthewell-recognizedclini-cal features of HCM, including the biphasic carotid pulse andmid-systolic closure of the aortic valve. Conklin and colleaguesshowed an exacerbation of the reduction in forward flow after administration of dobutamine.9 The mid-systolic drop in veloci-tiesanditsspectralappearancemayvaryfrompatienttopatientandfromhourtohourdependingontheseverityoftheoutflow
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gradient,andthecapabilityoftheLVtoovercometheobstruction.However,thetimingofthenadiralwaysmovesinpreciselockstepwiththepeakvelocityoftheCWDoppleracrosstheoutflowtractandhencecoincideswithpeakLVafterload.8,11TissueDopplerim-agingrecordsamid-systolicdropinsystolicmyocardialvelocitiesduetoobstructionandprematureterminationofseptalcontrac-tion.Boththemid-systolicdropinejectionvelocitiesandthedropintissueDopplercontractionvelocitiesarereversedandnormal-izeduponabolitionofobstruction.10,11Thisdemonstratesthatthemid-systolic drop is notmerely a flowphenomenon; rather, it isduetomyocardialdysfunction.Itisaninstantaneousfailureoftheventricle to overcome obstruction.
Narrowing of the intramyocardial penetrating arterioles is afrequentobservation inHCMpatients,as isprovocable ischemiainwatershedareas.Ischemiamaybeworsenedbyafterload,exer-cise,orcatecholaminesurgessuchasthatseenintakotsubosyn-drome.3Amid-systolicdropinejectionvelocitiescanalsobeseenwhenchronicmid-LVobstructioncausesapicalaneurysmsduetocompletemid-LVobstructionofejectionflow.13,29,30Suchpatientsoften have characteristic Doppler echocardiographic findings
includingamid-systolicdrop inapicalPWejectionvelocities (al-most to zero), a LVmid-systolic Doppler signal void on the CWDopplerspectraltracingduetocompletecessationofflowoutofthe apex, andparadoxical diastolic flowof trappedbloodout oftheLVapex.30Astepwisepathologiccascadetoapicalaneurysmhas been described; the etiology is chronic afterload- mismatch and supplydemandischemiafromobstruction.30,31Intimalandmedialhyperplasiacausingnarrowingoftheintramuralpenetratingarter-iesandjeopardizingflowreserveisanimportantco-contributor.32 Afterload mismatch is caused by the extremely high impedancetoflowfromthemid-LVobstruction,andinherentinefficiencyofsarcomeric energy utilization due to the cardiomyopathy of themutated cardiomyocytes.4 The same pathophysiologic factorsare acting inmid-LVobstruction as in acuteballooning, albeit inballooningtheprocessisacuteandduetoLVOTobstruction.Theslowdevelopmentofapicalaneurysmsaddstotheplausibilityofthe acute development of ballooning; they are both part of thespectrum of dynamic systolic dysfunction due to afterload andischemiainHCM,differingintheirrateofdeteriorationandcapac-ity for resolution.
F IGURE 4 Ballooningeventof66-year-oldfemalewithknownhypertrophiccardiomyopathyandsystolicanteriormotion(SAM)butnotpreviouslyknowntoobstructpresentedacutelywithchestpressure,shortnessofbreathandsyncope.FrameAandB:Parasternallong-axisviewindiastole(A)andsystole(B).Theframesdemonstratetheseptalbulge(redarrow),SAMwithmitral-septalcontact(orangearrow),andakineticanteroseptum(whitearrowheads).PanelC,CWDopplerwithrestingleftventricular outflow tract gradient of 88mmHg.PanelD,SystolicLVcine-angiographicframeonadmissionwithapicalandmid-LVballooning
(A) (B)
(D)(C)
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Previouslywe have reported two patientswith latent LVOTobstruction in whom apical and mid-LV dilatation and severehypokinesia developed after LVOT obstruction became severeand unrelenting.12Theirdownwardspiralandcardiogenicshockwasnot relieveduntil theyhadsurgical reliefof theirLVOTob-struction.MoviesS1–S3showthepre-andpostoperativeecho-cardiogram on one of these patients. MoviesS4–S5 show thenormalizationofLV function in theoperating roomofapatientaftersurgicalseptalmyectomyperformedforrefractoryconges-tive heart failure.
4.1.1 | Previous reports
LeftventricularballooninghasbeenreportedpreviouslyinisolatedcasesinHCMpatients33–37buthasnotbeenmentionedasapossiblecomplica-tionofHCMinpublishedreviews.38,39Toourknowledge,the13patientsreported here represent the largest case series of patientswith theseassociatedproblems.Thepaucityofprior reportscouldstemfromtheuncommonoccurrence,mildASH,orbecauseHCMpublicationstendtooriginatefromcentralizedoutpatientHCMclinics.Ballooningadmissionsmayfirstbeseenintheemergencydepartmentsofcommunityhospitals.
F IGURE 5 SamepatientasFigure4.AftertheballooninghospitalizationLVfunctionnormalizedandtherewasnoleftventricularoutflowtract(LVOT)gradient.Elevenmonthsaftertheballooninghospitalization,shewasreadmittedwithseverechestpainanddyspneaafterwalkingupsubwaystairs.Onthisoccasion,therewasnormalLVsystolicwallmotion.Leftframe:Twodimensionalsystolicapical3-chamberviewonadmission,LVEFwas65%withnormalwallmotion.Thereissystolicanteriormotionwithmitral-septalcontact(orangearrow).Rightframe:CWDopplerwithrestingLVOTgradientof100mmHg
F IGURE 6 SamepatientasFigures4,5.Afterdischarge,intermittentexercise-relatedchestpainanddyspnearecurred.LVfunctionatrestwasnormalandhyperkineticafterexercise.Therewasnoobstructionatrest.Stresstreadmillechocardiogramaftereating(SPEPP)wasperformedtoprovokegradient.Leftframe:parasternallong-axisviewindiastole.Middleframe:systolicanteriormotion(SAM)ofthemitralvalvewithmitral-septalcontact.Rightframe:Three-chamberviewCWDopplerwithapeakpostexercisesystolicgradientof120mmHg.SPEPP=standingpostexercisepostprandialechocardiogram.Thus,thispatientwithknownhypertrophiccardiomyopathyandSAMpresentedsuddenlywithanepisodeofapicalballooningandsevereobstruction(Figure4);subsequently,afterLVfunctionhadrecovered,shehadanotherepisodeofseveresymptomsassociatedwithsevereobstructionatrest,butnormalLVfunction(Figure5).Afterrecoveryfromthisepisode,anexerciseechocardiogramreproducedseverelatentobstruction(Figure6)
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4.2 | Variation in gradient during the ballooning admission
TemporalvariationintheseverityofLVOTobstructionischaracteris-tic,asitdependsupondynamicchangesinloadingconditionsandLVcontractility.AnabruptdropinLVcontractilitydecreasesthehydro-dynamic force on the mitral valve, decreasing the tendency for SAM
and thereby reducing LVOT obstruction and gradient. This is themechanismwhereby negative inotropes decrease obstruction.40,41 Thus,itwouldbeanticipatedthatasevereinsulttoLVsystolicfunc-tionwoulddecreasetheoriginallyhighLVOTgradient.Conversely,recoveryofLVsystolic functionwouldbeexpectedtoresult inanincreaseingradient.AnincreaseinLVOTgradientobservedinthreeofourpatientsduringtheirballooningepisodefollowedthispattern.
F IGURE 7 Mitralelongationinmalepatientwithhypertrophiccardiomyopathy(HCM)andlatentobstruction.Hepresented10yearsafterhisobstructiveHCMdiagnosis,atage70withapicalballooningandcardiogenicshock.Theseframeswereacquiredduringhisballooningadmission.Left:Diastolicframeshowingtheveryelongatedmitralanteriorleaflet,38mm(19mm/m2).Theorangearrowpointstotheanteriormitralleaflet.Middle:Momentofsystoliccoaptationshowing“nightcap”mitralvalvethatprotrudesintotheLVcavity.16 Right:mitral-septalcontact(orangearrow).Leftventricularoutflowtractgradientwas90mmHg.Akineticanteriorseptalandposteriorwallsareseen(whitearrowheads).MoviesS1–S3showpreoperativeandpostoperativeechocardiogramsofthisindividual.WallmotionabnormalitiesnormalizedimmediatelyafterreliefofLVOTobstructionaftercompletionofcardiopulmonarybypass
F IGURE 8 Threepatientswithmitralvalveelongationmildseptalhypertrophyandanepisodeofapicalballooning.Top3frames(A–C)showdiastolicandsystolic3-chamberframesfromthesamepatientatatimewhenLVsystolicfunctionwasnormal.A,Diastolicframeshowinganteriormitralvalveleafletelongation34mm,20mm/m2(elongated>16mm/m2).23–25B,Momentofcoaptation.Protrudingmitralanteriorleafletisshownbyorangearrow.Thispatternhasbeentermeda“nightcap”mitralvalvebecauseofitscharacteristicappearance.16,46C,Earlysystoleshowingsystolicanteriormotion(SAM)ofthemitralvalvewiththeresidualleaflet.Therewasnomitral-septalcontactandnoleftventricularoutflowtract(LVOT)gradient.SuchSAMcanbeacluethatLVOTobstructionisthecauseofapicalballooning.Gradientwasprovokedbyexerciseechocardiography.Bottom,D–E,showsystolicframesinanotherpatientatthetimeofapicalballooning.D,“Nightcap,”protrudingmitralleafletatthemomentofcoaptation(orangearrow).Elongatedanteriorleafletlengthinthispatientwas34mm,19.5mm/m2.E,Laterinsystole.SAMofthemitralvalveandmitral-septalcontact.ThewhitearrowsinframesDandEshowtheballooningakineticapicalseptum.F:Apical4-chamberviewinanotherpatient.Protrudingmitralvalveatthemomentofcoaptation
(A)
(D) (E) (F)
(B) (C)
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4.3 | Is apical ballooning caused by HCM and sudden unrelenting obstruction, or caused by coincident Takotsubo syndrome?
Couldthepatientshavetwoconditions,bycoincidence?Takotsubosyndrome (TTS) is an acute, reversible LV systolic dysfunction ofunknowncause,oftentimestriggeredbyastressfuleventoccurringmostofteninpostmenopausalwomen.WenoticethatourpatientshaveasimilardemographicandclinicalpresentationasdopatientswithTTS.Patientspresentwithsymptomssimilartoanacutecor-onary syndromebut there is no significant angiographic coronaryarterydisease.ThemechanismofLVsystolicdysfunctioninTTSisa subject of active investigation.42,43AlthoughSAMandLVOTob-structionhavebeenobservedinTTS,ithasnotbeenconsideredofpathogenicsignificance.Instead,SAMinTTSisconsideredtoresultfrom narrowing of the LV base and the resultant development ofVenturiforcesintheLVOT.
Wethinkitisunlikelythatourpatientshavetwocoincidentcon-ditions,HCMandTTS,toexplainboththeirchronicHCMillnessandtheir acute ballooning for the following reasons:
1. For our 13 patients, high provocable gradients due to SAM,and the morphologic predispositions to SAM of HCM werepresent temporally remote from the ballooning episode, at atimewhentheLVsystolicfunctionwasnormal.AllthepatientshadasymmetricseptalhypertrophyandlatentLVOTobstructiondue to SAM before and/or after the acute episode. In thisregard, in 10 of 13 our patients, we found abnormalities ofthe mitral valve that previously have been associated withobstructive HCM. It has increasingly been appreciated thatmitralabnormalitiespredisposetoobstructioninHCMpatientswith only mild degrees of hypertrophy, as in the present se-ries.15–20,24,26 Thus, mitral-septal contact was shown by prov-ocation to be inherent to their HCM with latent obstruction, and not from their ballooning, per se.
2. TwopatientswithknownpreviousHCMandlatentobstructionsuddenly developed unrelenting high resting LVOT gradientsandapicalballooning,refractorycardiogenicshock,andheartfailureanddidnotrespondtofluids,highdoseIVbetablock-ers, or phenylephrine.However, their severe LVdysfunction,shock,andheartfailurenormalizedwithin2hoursofsurgically
F IGURE 9 Anotherpatientwithmitralvalveelongation,mildseptalhypertrophy,andanepisodeofapicalballooning;therewassubsequentprovocationof high left ventricular outflow tract (LVOT)gradientafterexercise.Toppair:Apical4-chamberviewsduringtheapicalballooningadmission.Protrudingelongated mitral valve leaflets are shown with orange arrows. Mitral anterior leaflet indiastolemeasured37mm,19mm/m2. Thearrowheadsindicatetheseverelyhypokineticapex.Bottompanels:Apical4-chamberviewsandCWDopplerafterpeakexercise,atatimelaterwhenrestingLVfunctionwasnormal.Elongatedprotrudingmitralleafletsareshownwithorangearrows.NotethatLVsystolicfunctionafterstressishyperkineticandsubstantially better than in the frame above. Systolic anterior motion is shown andpeakDopplerLVOTgradientwas144 mm Hg
3. IthasbeenhypothesizedthattheSAMobservedinTTSmightbeduetocompensatoryhyperkinesiaofthebasalLV,leadingtonar-rowingofthebase,highLVOTvelocitiesatthatlocus,andSAMbyaVenturimechanism.Thus,ithasbeenhypothesizedthattheSAMofTTSisduetotheTTSitself.However,currentthinkingandthepreponderanceofevidenceaboutSAMinHCMisthatitiscausedbyflowdrag,thepushingforceofflow.21,25,44 As ejec-tionflowsweepsaroundthebulgingseptum,itcatchesthemitralvalve from behind and pushes it into the septum, rather thanpulledbyaVenturimechanism.LVOTvelocities are low inob-structiveHCMwhenSAMbegins,precludingVenturiforcesasamechanism.21,44Thus,inour13patients,theSAMisinherenttotheirwell-documentedHCMwithlatentobstructionandnotat-tributabletocoincidentTTS.
4. As summarized here, obstruction in HCM patients causes dy-namicsystoliccontractiledysfunctioneveninpatientswithnor-mal or high ejection fraction; this is reversible upon relief ofSAM.8–13Thereisnocompellingneedtopositanotherneurohu-moralmechanism.Thus,ourprincipalhypothesis is that the re-versible apical ballooning was caused by LVOT obstruction,afterload-mismatchandsupplydemandischemia,notasaresultofaseparateprocess.HCMhasbeendescribedasthe“greatmas-querader” in cardiology.45 In the13casesdescribedherein,weposit thatobstructiveHCMhastakenonanotherguise, thatoftheperpetratorofacutedilatationandseveresystolicdysfunc-tionoftheapicalandmid-LVmyocardialsegments.
4.4 | Why these HCM patients? Why ballooning now?
Thesuddendevelopmentofpersistentrestingobstructionintheelderlyhasbeenrepeatedlyreportedeveninpatientswithisolatedseptalthickening38,39bydintofadropinpreloadorafterload,orincreasedcontractility,orconceivablyadditionalslackintheirmi-tralvalvesoradditionalseptalthickening.Latentobstructioncanexplosively escalate into persistent obstruction because of theamplifying nature of obstruction. Themitral valve is swept fur-ther intotheseptumbythepressuregradient itself;obstructionbreeds more obstruction.44 Any drop in stroke volume causes areflexenhancementincontractilityandgradient.Our13patientshadaparticularphenotypeofHCM;except for the septalbulgeseeninall,wallthickeningwasabsentormodestintheremainingsegments.ThemodesthypertrophythroughouttheremainderoftheLVmaylimititsabilitytocompensateforthesuddenincreaseinwallstressassociatedwithhighLVsystolicpressures,andnotaswellasiftherewereawiderdistributionofhypertrophy.More
widespreadLVhypertrophy,asisoftenpresentinthevastmajor-ity of youngerHCMpatients,might havenormalizedwall stressand mitigated the apical ballooning. Thus, the sudden develop-ment of persistent high gradientsmay be particularly detrimen-tal to the systolic function of these ventricles with only modest hypertrophy,andthereforeunpreparedtoperforminthefaceofanabrupt increase inafterload.Supportingthisconceptwastheimmediate restoration of normal systolic function after the surgi-cal removal of obstruction.
4.5 | When is surgical intervention indicated?
We have considered disopyramide in these patients but havenot administered it out of concern that it might reduce already severelycompromisedLVfunction.However,itmightbeconsid-ered in apatientwith severeobstructionandheart failurewhocouldnot beoperatedbecauseof comorbidity. Intra-aortic bal-loon pumping might improve tissue perfusion, but it decreasesafterload which might increase obstruction; thus, we have gener-ally avoided this modality. Emergent surgical relief of obstruction shouldbeconsideredwhenshockwithpoor tissueperfusionorpulmonarycongestionpersistdespitehigh-doseintravenousbetablockade, copious intravenous fluids, and intravenous phenyle-phrine. Surgery should especially be considered when there isprogressivemetabolicacidosis,oliguria,orrequirementforcon-tinued intubation and respiratory support. The specific surgicalstrategy for relief of left ventricular outflow obstruction should dependonlocalexpertiseandpractice.12,20,26,46 We believe that theparamountconsideration isavoidingasecondpumprunbe-cause of incomplete abolition of obstruction; one should avoidimposing additional ischemia on an already compromised leftventricle.12
4.6 | Previously reported subsets of takotsubo patients
Thiswasnotastudyofthecauseofballooningintakotsubosyn-drome.Intheliterature,therearetakotsubocasereportsthatbearon this case series and its discussion,47–51 including that 25%oftakotsubopatientsmayhaveseptalhypertrophyandLVOTgradi-ents,andtheobservationthatLVOTgradientsmayonlyemergeintherecoverystagewhenLVfunctionisrecovering.However,thepatientsinthecurrentreporthadmuchhigherrestingLVOTgra-dients,mean 92mmHg, comparedwith the previous takotsuboreportwhere gradientsweremean34mmHg, occurring only inthe25%withobstruction.47 In thepresent report,mitral abnor-malitieswerecommon in theHCMpatientswithballooning,butthishasnotbeennotedpreviously.Whilethepatientswithgradi-entsreportedbyElMahmoudetalhadagreaterNYHAfunctionalclassatadmission,none requiredsurgery forprofoundhemody-namiccompromise.Consequently,noneinthatreportcouldshowthe immediate recovery of systolic function we observed after surgical relief of the LVOT obstruction.We present, from prior
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publications, a plausible mechanism whereby LVOT obstructioninHCMcouldleadtoapicalballooning.Itispossiblethatthepa-tients reportedhereare similar to those reported ina subsetofpatientswithtakotsubosyndrome.Buttoexplorethispossibility,aconsecutiveseriesoftakotsubopatientswouldhavetobeevalu-atedfortheanatomicanddynamicfeaturesofHCMpatientsre-portedhere,includingabnormalitiesofthemitralapparatus.Thiswouldalsorepresentadeparturefromthewidelyexceptedpro-posedneurohumoralmechanism for takotsubosyndrome.52Thiswasoutsidethescopeofthepresentresearch.Anotherlimitationis the following: since this is a retrospective database study re-quiringconsent,itispossiblethatnotallHCMpatientstreatedatourinstitutionswereenrolled.Thismayimpacttheestimatedfre-quencyofapicalballooninginHCM,anditsapparentlyfavorableprognosiswithtreatmenttargetingobstruction.
5 | CONCLUSIONS
The clinical course of patients with hypertrophic cardiomyopathyand latent LVOTobstruction can rarely be complicatedby LV api-cal ballooning when obstruction becomes severe and unrelenting withhighgradients,92±37mmHg.ThiscomplicationofHCM,oc-curringin0.9%ofHCMpatientsfromtwolargereferralcenters, isassociatedwithamorphologicphenotypeofmodestlocalizedbasalanteriorseptalthickeningandfrequently,mitralvalvestructuralab-normalities thatpredispose toSAMandLVOTobstruction.Severehemodynamic instability is a common clinical complication duringthe acute ballooning episode andoccurred in half of our patients.Beta-blockadeisthemainstayofpharmacologictreatment,butthreepatientsrequiredurgentsurgerytorelieveobstructionforrefractorycardiogenicshockintwo,andrefractoryheartfailureinone.
Asreviewed inthismanuscript,dynamicsystolicdysfunctiontoa lesserdegree iscommoninobstructiveHCMpatients,evenwhentheejectionfractionisnormalorhigh.Weproposeasahy-pothesisthatthepatientsdescribedhereinsufferfromthesamephenomenon, albeitmuchmore severely.Wepropose that theirparadoxical apical ballooning is caused by suddenworsening oflatentLVOTobstruction,afterload-mismatch,andsupplydemandischemia. Since obstruction is latent both before and after the bal-looning event,when LV systolic function is normal, provocationwithValsalva’smaneuver, standing, and exercise echocardiogra-phyisessentialforafullappreciationofthedynamicobstructivenatureofthepathology.
DISCLOSURE
There are no financial disclosures or conflicts related to thismanuscript.
ORCID
Mark V. Sherrid https://orcid.org/0000-0003-4972-7780
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SUPPORTING INFORMATION
Additional supporting information may be found online in theSupportingInformationsectionattheendofthearticle.
Movie S1. A 70 year old patient with HCM and latent LVOT ob-struction presented 10 years after his initial diagnosis with near
14 | SHERRID Et al.
syncope,heart failureandhypotensionevolving to refractorycar-diogenic shock. The first 2movies are soon after admissionwiththe ballooning event. The 3rd movie was done postoperatively.Parasternal long-axisechocardiogramshowingamildseptalbulge,SAM,andmitral-septalcontact.Thereisballooningoftheapicalandmid-LV segmentswith akinesia there. Systolic LVOT gradientwas90mmHg.OrangearrowshowstheSAM.Whitearrowheadsindi-catetheakineticseptumandposteriorwall.
Movie S2.Apical3-chamberviewinthesamepatient.Thereisaverylonganteriormitralvalveleaflet39mmlong,19.5mm/m2(elongated >16mm/m2).Thereisballooningoftheapicalandmid-LVsegments.Theanteriorseptalandposteriorwallareakineticwhiletheapexwasseverelyhypokinetic.Thevideodemonstratestheverylonganteriormitralvalveleaflet(orangearrow),theakineticseptumandposteriorwall(smallwhitearrowheads),andtheseptalbulge(redarrow).
Movie S3. Postoperative long-axis echocardiogramperformed4daysafter surgery to relieve LVOT obstruction with a mitral valve re-placement and limitedmyectomy.Yellowarrowpoints to thebio-prostheticmitralvalve.ParadoxicalseptalmotionispresentduetotheLBBBfromthemyectomy.NineyearsaftersurgerytorelievehissevereLVOTobstructionandshockheiswell,andNYHAI.Hehasparoxysmal atrial fibrillation.Mitral valve replacementwas explic-itlyselected in the twocardiogenicshockpatientsbecauseof theonlymodestseptalthickeningandtoassurethatonlyonepumprunwould be necessary.
Movie S4.A73-year-oldfemalewasdiagnosedwithHCMandlatentLVOTgradientswithsymptomsofdizzinessandepisodicdyspnea.Threeandahalfyearslatershedevelopedsevereorthostatichypo-tensionandheartfailuresymptomswithmildexercise.Whenacutedyspneaatrestoccurred,shewasfoundtohaveapicalballooningonTTE.VideoloopsfromherTEEintheoperatingroomareshown,performed before cannulation, before surgical septal myectomy.Yellowarrowheadsinlowerloopspointtotheapicalballooning.Redarrowpointstomitral-septalcontact.Notethepoormid-LVsystolicfunctionontheshortaxisloop.
Movie S5. Samepatient asMovieS4.TEEvideo loopsperformedimmediately after myectomy and completion of cardiopulmonarybypassshowingresolutionofthesevereLVsystolicdysfunction.
How to cite this article:SherridMV,RiedyK,RosenzweigB,etal.Hypertrophiccardiomyopathywithdynamicobstruction and high left ventricular outflow gradients associatedwithparadoxicalapicalballooning.Echocardiography. 2018;00:1–14. https://doi.org/10.1111/echo.14212
