PostgraduateMedicalJournalFurthersupportfortheviewthattheobstructioncausesthemitralincompetenceisthatpharmacologicalabolitionofthestenosisalsoabolishesthemitralincompetenceWigleetal1967FIG1Hy ID: 960959
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FestschriftforSirJohnMcMichaelThesystolicmurmurinhypertrophicobstructivecardiomyopathyandthenatureoftheobstructionM.NELLENM.S.GOTSMANCardiacClinic,DepartmentofMedicine,GrooteSchuurHospital,andCouncilforScientificandIndustrialResearchCardiovascular-PulmonaryResearchGroup,DepartmentofMedicine,UniversityofCapeTownPATIENTSwithhypertrophicobstructivecardio-myopathypresentwithdyspnoea,anginapec-toris,palpitations,fatigueorsyncope,butthesystolicmurmurshoulddrawattentiontothecondition.Themurmurbeginsafterthefirstheartsound,hasacrescendo-decrescendocon-figurationandhasitsmaximumintensitytotherightofthemid-systolicpoint.Itisbestheardinthefourthleftintercostalspace,radiatestotheapexandbaseoftheheartandhasaharsh,low-pitchedquality.Itvariesinintensityfrommomenttomoment-occasionallyitisloud,atothertimesitmaybesoftorabsent.Othernotablefeaturesonauscultationarethestrikingfourthheartsound,asofterthirdheartsound,leftandright-sidedmid-diastolicflowmurmursduetoinflowobstructionandoccasionallypara-doxicalorpartialparadoxicalsplittingofthesecondheartsoundduetoprolongedleftven-tricularejection.Anaorticearlydiastolicmur-murisoccasionallyheardandmaybeduetodistortionoftheaorticvalveringbyasymmetri-calhypertrophy(Braunwaldetal.,1954a,b;Tuckeretal.,1966;Goodwin,1967).Wedonotknowwhetherthehypertrophyorgradientinthecaseswhererightventricularinvolvementhasbeendescribedeitheraloneorwithleftventriculardiseaseissufficienttocauseasystolicmurmurwithintherightventricularsystem,butthisisprobable.Inarecentlydes-cribedcaseofapparentlypurelyrightventricularinvolvement,aharshloudejectionsystolicmur-murwasheardbestattheleftsternalborderandapex(Falcone,Moore&Lambert,1967).However,eventhoughnoleftventriculargradientwasfoundtheremayhavealsobeeninvolvementoftheleftventriclewhichmaybe-comemoreapparentinthefuture.Theapicalsiteofthemurmurwould,however,suggestaleftventricularoriginofthemurmureveninthiscase.Whilethesystolicmurmurmayoccuratatimewhenthereisnopressuregradientasshownbyintraventricularphonocardiogram(Goodwin,1967),theintensityofthemurmurappearsfromourstudiestovarywiththegradient.Thattheincreaseingradientisassociatedwithincreaseinsystolicmurmurintensitydoesnotexcludemitralincompetenceasthecauseofthemurmurbecausethehypertrophyoftheseptumandpapillarymusclecauseboththegradientandmitralincompetence.Mitralinsufficiencyalmostinvariablyaccompanieshypertrophicobstructivecardiomyopathy(Wigle,Marquis&Auger,1967)However,weagreewithGoodwin(1967,1968)thatthereareprobablyseveralreasonsforthesystolicmurmurinhypertrophicobstructivecar-diomyopathy.Thusobstructionwithintheleftventricle,mitralincompetenceandprobablyturbulencewithinthestronglyandrapidlycon-tractingventriclemayallplayapartinitsproduction.Wehaveshownthatamylnitritemarkedlydiminishestheregurgitantmurmurofrheumaticvalvarmitralincompetenceandthatphenyl-ephrineintensifiesthemurmur(Vogelpoeletal.,1959;Becketal.,1961).Amylnitriteintensifiesthesystolicmurmurinhypertrophicobstructivecardiomyopathy(Nellenetal.,1965)andincreasesthegradient(Wigleetal.,1964)andphenylephrineabolishesormarkedlyreducesthemurmurandgradient;isoproterenolincreasesthegradientandmurmur(Nellenetal.,1965).Thesefindingsdonotruleoutincompetenceofthemitralvalve(Fig.1)asafactorintheproductionofthesystolicmurmur.Thecauseofthemitralin-competenceinhypertrophicobstructivecardio-myopathyispapillarydysfunctionduetopapillaryandseptalhypertrophyandnotapurevalvemechanism.Thesedrugsbyalteringtheinternaldiameterandmechanicsoftheobstruc-tivehypertrophyintheleftventricularchamberaffectthemurmurinoppositedirectionstotheireffectinpurevalvarmitralincompetence.89 PostgraduateMedicalJournalFurthersupportfortheviewthattheobstruc-tioncausesthemitralincompetenceisthatphar-macologicalab
olitionofthestenosisalsoabolishesthemitralincompetence(Wigleetal.,1967).FIG.1.Hypertrophicobstructivecardiomyopathy.Thesystolicmurmurreflectsthehaemodynamicsituationwith(a)amylnitrite,(b)phenylephrineand(c)iso-prenaline.Pressuremeasurementsinleftventricleandfemoralartery.Simultaneousexternalphonocardiogramshowninlowerchannel.Incontrasttothemarkedlesseninginintensityordisappearanceofthesystolicmurmurinhypertrophicobstructivecardiomyopathywithintravenousphenylephrinewehaveshownthatthemurmurofaorticstenosisishardlyaffected.Itusuallylessensonlyslightlybutmayactuallyintensify-thismaybeausefulbedsidetestasthetwoconditionsmaymimiceachother(Nellenetal.,1965)(Fig.2).ThestudiesofMarcus,Perloff&DeLeon(1964)andHancock&Fowkes(1966)showthatinhalationofamylnitriteismoreusefulthanisoproterenolasaprovocativetestforhyper-trophicobstructivecardiomyopathy.Inhalationofamylnitritehasagreatereffectthanintra-venousinjectionof2mgofisoproterenol,ismorereadilyadministered,hasabrieferactionandislesslikelytoinduceadverseeffectssuchasventriculararrhythmias.TheeffectofpromptsquattingonthesystolicmurmurPromptsquattingprovidesasimplebedsidemethodofacutelyincreasingvenousreturn,effectivefillingpressureoftheheart,strokeout-putandsystemicarterialpressureandresistance(Sharpey-Shafer,1955).Wehavethereforestudiedtheeffectofthismanoeuvreonthesystolicmurmurintwelvepatientswithhypertrophicobstructivecardio-myopathy(Nellenetal.,1967),andwehavecomparedtheeffectofthismanoeuvreineightpatientswitlhfixedvalvaraorticstenosisandinfivepatientswithmitralvalvarincompetenceasthesystolicmurmursinthesecasesmayresemblethatofhypertrophicobstructivecardiomyopathy.Inhypertrophicobstructivecardiomyopathywefoundthatthismanoeuvreabolishedthemurmurinthree,andsofteneditmarkedlyinseven.Inone,themurmursoftenedslightlyandinonetheeffectwasvariable(Figs.3and4).Innocasedidthemurmurintensify.Inallthecasesofvalvaraorticstenosisandmitralin-competencethesystolicmurmurincreasedinloudness.Tohelpintheassessmentofthemech-anismofsquattingwestudiedtheeffectofthisprocedureonthemurmurofpulmonarysteno-sis.Thesystolicmurmurinthisconditionalsoquicklyintensifiedonsquatting.Inthisconditiontheincreaseinmeanarterialpressureandinperipheralarterialresistancewouldnotbeex-pectedtoincreasethemurmur,whereasin-creaseinvenousreturnandeffectivecardiacFSystolicmurmurControlIPhenylephrineHypertrophicobstructivecordiomyopothyAorticstenosisFIG.2.Phenylephrinevirtuallyabolishesthesystolicmurmurinhypertrophicobstructivecardiomyopathy,andonlyslightlyaffectsthemurmuranaorticvalvarstenosis.90 FestschriftforSirJohnMcMichaelFIG.3.Hypertrophicobstructivecardiomyopathy:(a)standing,and(b)squatting.Phonocardiogram(MF=mediumfrequency)takenmedialtotheapex.Thesystolicmurmurisvirtuallyabolishedonsquatting.(LeadVIoftheelectrocardiogramisindicatedinthetoptracing.Eachlargesquareontherecordindicates0-05sec.)fillingpressurewoulddoso.Thesamemech-anismwouldapplytotheincreaseofsystolicmurmurinvalvaraorticstenosisandmitralvalvarincompetence.Inthelatter,increasedperipheralresistancecouldbeanaddedfactor.Theincreaseinintensityofthesystolicmur-murinhypertrophicobstructivecardiomyopathycanbeexplainedbyincreasedvenousreturnleadingtoincreasedleftventricularfillingandincreaseinend-diastolicvolume-aneffectsimi-lartoarapidinfusionofbloodortiltingthepatientintoahead-downposition(Braunwaldetal.,1964a,b;Shahetal.,1965;Mason,Braunwald&Ross,1966).Withlargerintra-3Murmurabolished7MurmursoftensmarkedlyFIG.4.Effectofsquattingonthemurmurofhyper-trophicobstructivecardiomyopathyintwelvepatients.ventricularvolume,thegradientlessensduetotheincreaseinventriculardimensionwhichreducesthedegreeofobstruction.Additionallytheraisedarterialpressureandperipheralresist-ance,thebradyca
rdiaandreductionofleftventricularcontractilitywouldreducethegradientandthustheintensityofthemurmur.ThenatureoftheobstructionBraunwaldetal.(1964a,b)attributedthehaemodynamicfindingsandthemurmurtoob-structionofleftventricularoutflow;Goodwin(1964)broadenedtheconceptandaddedim-pedancetoinflowintherightandleftventricleasacauseofthediastolicmurmurs.Crileyetal.(1965)questionedobstructiontotheoutflowregionandsuggestedthatthehourglasssilhouetteobservedatangiocardiographyisadiastoliceventduetoinflowofnon-opaquebloodfromtheleftatrium.Theyproposedthatthehighventricularpressuregradientsresultedfromsus-tainedcontractionandabsenceofflowinobliteratedportionsoftheleftventricularcavity.Thehypertrophiedventricleemptiesmorecom-pletelyandfasterthantheunobstructednormalventricle,withmarkedapicalobliteration.Theyalsosuggestedthatthesystolicmurmurisduetomitralincompetencefromabnormalalign-mentofthepapillarymusclesinthegreatlyhypertrophiedleftventricle.Rossetal.(1966)showedthepresenceofdefiniteoutflow-tractobstructionduringsystole,70%ofthesystolicbloodvolumeisejectedduringaperiodwhenagradientispresent,whilst30%oftheforwardstrokevolumeisejectedearlywhennosignificantpressuregradientispresent.Theseworkersshowedthatisometricpressuredevelopmentandearlyventricularejec-tionproceedmorerapidlythannormally,thisearlysystolicperiodbeingresponsibleforthesharpupstrokeofthearterialpulse.Theseworkershavethuspreparedastrongbriefinsupportofthepostulatethatanobstructivefac-torexistsinthehaemodynamichypertrophicleftventriclesyndrome.ThestudiesofWigleetal.(1967)supporttheviewsofRossetal.(1966).Theseauthorsstresstheimportanceoftheoutflowtractasbeingthesiteofobstructioninhypertrophicobstructivecardiomyopathyandshowbyretrogradeandtrans-septalcatheterizationthattheobstructioniscausedbysystolicappositionoftheventricularseptumandanteriorleafletofthemitralvalve.Theyshowhowanabnormallyhighpressureattheapexoftheventricularchambercanbeob-tainedby'imbedding'or'catheterentrapment'invariousconditionsincludinghypertrophicob-MurmursoftensslightlyonpropranololVariableresponse91 92PostgraduateMedicalJournalstructivecardiomyopathy(Wigleetal.,1967;Cross&Salisbury,1963;Martin,Hackel&Sieker,1963;DeBono,Proctor&Brock,1965;Martinetal.,1965;White,Lewis&Criley,1965;Morrowetal.,1965;Tobinetal.,1965;Wilsonetal.,1967).Intheselatterconditions(exceptforhypertrophicobstructivecardiomyopathy)theinflowtractpressurewillequaltheaorticpressurewhereasinhypertrophicobstructivecardiomyo-pathythepressureishigherintheinflowtractthanintheoutflowtractandaorta.ConclusionsThereareprobablyseveralreasonsforthesystolicmurmurinhypertrophicobstructivecardiomyopathy.Obstructionwithintheleftven-tricle,mitralincompetenceandturbulencewithinthestronglyandrapidlycontractingventriclemayallplayapart.Thesystolicmurmur(andgradient)isabolishedorlessensmarkedlyinintensitywithintravenousphenylephrine,incontrasttothein-creaseinloudnessofthemurmurofvalvarmitralincompetenceandlittlesignificantchangeinfixedvalvaraorticstenosis.Inhypertrophicob-structivecardiomyopathyamylnitriteinhalationandintravenousisoproterenolintensifythemur-murandthegradient.Amylnitriteisprobablythebestprovocativetestforthediagnosisofthecon-dition-beingsaferandeasiertoadministerthanisoproterenolandhavingagreatereffectthantheusual20,ugdoseofthelatter8-stimulatingcatecholamine.Promptsquattinghasprovedtobeanexcellentbedsidetestinthiscondition-thesystolicmur-murneverincreasesbutiseitherabolishedordecreasesmarkedlyinintensityinmostcases,incontrasttotheintensificationofthesystolicmurmurofvalvarmitralincompetenceandfixedvalvaraorticstenosis.Theobstructioncausesatruegradientwithintheoutflowtractoftheleftventricleandinter-feresalsowithpapillarymusclefunction,caus-inginmostcas
essomemitralincompetenceTheproblemof'entrapment'or'imbedding'ofthecatheterintheapexhasbeenreferredto.Wewouldagreethatalthoughthereisatre-mendousamountofinformationonthecondi-tionofhypertrophicobstructivecardiomyopathy'Thecitadelholdingtheultimatetruthofthesyndrome,isstilltobetaken'(Burchell,1966).AcknowledgmentsWewishtothankProfessorV.SchriveandourcolleaguesintheCardiacClinic,andourlaboratorystaffforassistancewiththecatherizationprocedures,andDrJ.G.Burger,SuperintendentofGrooteSchuurHospital,forpermissiontopublish.WeacknowledgewiththanksthecontinuedfinancialsupportoftheCouncilforScientificandIndustrialResearchandtheCityCouncilofCapeTown.Figs.Iand3aretakenfromNellenetal.(1967)Brit.med.J.ii,340,withpermissionoftheEditor.ReferencesBECK,W.,SCHRIRE,V.,VOGELPOEL,L.,NELLEN,M.&SWANEPOEL,A.(1961)Haemodynamiceffectsofamylnitriteandphenylephrineonthenormalhumancircula-tionandtheirrelationtochangesincardiacmurmurs.Amer.J.Cardiol.8,341.BRAUNWALD,E.,LAMBREW,C.T.,ROCKOFF,S.D.,Ross,J.&MORROW,A.G.(1964a)Idiopathichypertrophicsub-aorticstenosis1.Adescriptionofthediseasebaseduponananalysisof64patients.Circulation,30,3(Suppl.No.4).BRAUNWALD,E.,OLDHAM,H.N.,JR,Ross,J.,JR,LINBART,J.W.,MASON,D.T.&FORT,L.(1964b)Circulatoryresponseofpatientswithidiopathichypertrophicsub-aorticstenosistoNitroglycerinandtothevalsalvamanoevre.III.Circulation,29,422.BURCHELL,H.B.(1966)Pressuredifferencesandobstructionofleftventricularoutflow.(Editorial).Circulation,34,556.CRILEY,J.M.,LEWIS,K.B.,WHITE,R.I.&Ross,R.S.(1965)Pressuregradientswithoutobstruction-anewconceptof'hypertrophicsubaorticstenosis'.Circulation,32,881.CROSS,C.E.&SALISBURY,P.F.(1963)Functionalsubaorticstenosisproducedinanimals.Amer.J.Cardiol.12,394.DEBONO,A.H.,PROCTOR,E.&BROCK,R.(1965)Dynamicobstructionoftheleftventricle.Itsproductionandabolitionbydrugsinnormalanimals.Guy'sHosp.Rep.114,4.FALCONE,D.M.,MOORE,D.&LAMBERT,E.C.(1967)Idio-pathichypertrophiccardiomyopathyinvolvingtherightventricle.Amer.J.Cardiol.19,735.GOODWIN,J.F.(1964)Hypertrophicobstructivecardio-myopathy.Brit.med.J.i,1527.GOODWIN,J.F.(1967)Disordersoftheoutflowtractoftheleftventricle.Brit.med.J.ii,461.GOODWIN,J.F.(1968)Mitralregurgitationincongestivecardiomyopathy.Postgrad.med.J.44,62.HANCOCK,E.W.&FOWKES,W.C.(1966)Effectsofamylnitriteinaorticvalvularandmuscularsubaorticstenosis.Circulation,33,383.MARCUS,F.I.,PERLOFF,J.K.&DELEON,A.C.(1964)Useofamylnitriteinthehemodynamicassessmentofaorticvalvularandmuscularsubaorticstenosis.Amer.HeartJ.68,468.MARTIN,A.M.,HACKEL,D.B.&SIEKER,H.O.(1963)Intra-ventricularpressurechangesindogsduringhemorrhagicshock.Fed.Proc.22,259.MARTIN,A.M.,JR,HACKEL,D.B.,SPOCH,M.S.,CAPP,M.P.&MIKAT,E.(1965)Cineangiocardiographyinhemorr-hagicshock.Amer.HeartJ.69,283.MASON,D.T.,BRAUNWALD,E.&Ross,J.,JR(1966)Effectofchangesinbodypositiononthesecurityofobstruc-tiontoleftventricularoutflowinidiopathichypertrophicsubaorticstenosis.Circulation,33,374.MORROW,A.G.,VASKO,J.S.,HENNEY,R.P.&BRAWLEY,R.K.(1965)Canoutflowobstructionbeinducedwithinthenormalleftventricle.Amer.J.Cardiol.16,540.NELLEN,M.,BECK,W.,VOGELPOEL,L.,SWANEPOEL,A.&SCHRIRE,V.(1965)Theeffectofamylnitrite,phenylephrineandisoproterenolonthesystolicmurmurinhypertrophicobstructivecardiomyopathy.S.Afr.med.J.39,304.NELLEN,M.,GOTSMAN,M.S.,VOGELPOEL,L.,BECK,W.&SCHRIRE,V.(1967)Effectsofpromptsquattingonthesystolicmurmurinidiopathichypertrophicobstructivecardiomyopathy.Brit.med.J.ii,340.RosS,J.,JR,BRAUNWALD,E.,GAULT,J.H.,MASON,D.T.&MORROW,A.G.(1966)Themechanismoftheintra-ventricularpressuregradientinidiopathichypertrophicsubaorticstenosis.Circulation,34,558. FestschriftforSirJohnMcMichael93SHAH,P.M.,AMARASINGHAM,R.&OAKLEY,C.M.(1965)Haemodynamiceffectsofchangesinbloodvolumeinhypertrophicobstru
ctivecardiomyopathy.Brit.HeartJ.27,83.SHARPEY-SCHAFER,E.P.(1955)Effectsofsquattingonthenormalandfailingcirculation.Brit.med.J.i,693.TOBIN,J.R.,BLUNDELL,P.E.,GOODRICH,R.G.&SWAN,H.J.C.(1965)Inducedpressuregradientsacrossinfundi-bularzoneofrightventricleinnormaldogs.Circulat.Res.16,162.TUCKER,R.B.K.,BARLOW,J.B.,ZION,M.M.&GALE,G.E.(1966)HypertrophicobstructivecardiomyopathyinJohannesburg.Proceedings,FifthWorldCongressonCardiology,1966,p.197.VOGELPOEL,L.,NELLEN,M.,SWANEPOEL,A.&SCHRIRE,V.(1959)Theuseofamylnitriteinthediagnosisofsystolicmurmurs.Lancet,ii,810.WHITE,R.I.,LEWIS,K.B.&CRILEY,J.M.(1965)Non-obstructivenatureofisoproterenol-inducedleftventri-cularpressuregradientsindogs.(Abstract).Circulation,32,suppl.11,11.WIGLE,D.E.,CHRYSOHOU,A.&LENKEI,S.C.M.(1964)Theeffectofperipheralvasodilatationinmuscularsubaorticstenosis.(Abstract).Amer.J.Cardiol.13,144.WIGLE,D.E.,MARQUIS,Y.&AUGER,P.(1967)Muscularsubaorticstenosis.Initialleftventricularinflowtractpressureintheassessmentofintraventricularpressuredifferencesinman.Circulation,35,1100.WILSON,W.S.,CRILEY,J.M.&Ross,R.S.(1967)Dynamicsofleftventricularemptyinginhypertrophicsubaorticstenosis.Amer.HeartJ.73,4.AmodifiedindexofphosphateexcretionB.E.C.NORDINL.BULUSUMedicalResearchCouncilMineralMetabolismResearchUnit,GeneralInfirmary,LeedsTHEREareseveralwaysoflookingattheexcre-tionofphosphorus,orforthatmatterofanyelementintheurine.Forcertainpurposes,itismostappropriatetoconsiderthetotaldailyorweeklyexcretionandrelateittothedietaryintakeandfaecaloutputaspartofabalancestudy,theobjectofwhichistoestablishwhetherthesubjectisinnegativeorpositivebalanceonaparticulardietaryintake.Inthestudyofkid-neystonedisease,theimportantcriterionisprobablytheconcentrationofthedifferentphos-phateionspeciesintheurineandthesecanbecalculatedfromaknowledgeofurinarypHandtotalphosphorusconcentration(theorganicphosphoruscontentoftheurinebeingneglig-ible).Inrelationtomanyotheraspectsofcal-ciumandphosphorusmetabolism,however,thephysiologicalparameterofparticularinterestisthetubularreabsorptionofphosphorus,bothbe-causeitisalargefactorintheregulationoftheplasmaphosphoruslevelandbecauseitisunderthecontroloftheparathyroidglands.Therearevariouswaysofassessingtubularreabsorptionofphosphorus,thesimplestbeingthemeasurementofphosphateclearance(whichIsinverselyrelatedtotubularreabsorption)(Kyle,Schaaf&Canary,1958)andthemostsophisticatedthemeasurementofthemaximumtubularreabsorptivecapacity(Anderson&Par--sons,1963).Betweentheseextremesisthephosphate/creatinineclearanceratiowhichin-dicatestheproportionoffilteredphosphatethatisnotreabsorbedbythetubules;ittendstoberaisedinhyperparathyroidismandreducedinhypoparathyroidism(Milne,Stanbury&Thomp-son,1952;Nordin&Fraser,1954).Unfortunately,thephosphate/creatinineclear-anceratioisitselfgovernednotonlybytubularfunctionbutalsobythefilteredloadofphos-phorusitselfsincethereisaveryhighcorrela-tionbetweentheplasmaphosphoruslevelandthephosphate/creatinineclearanceratioinnor-malsubjects(Lambert,vanKessel&Leplat,1947).Forthisreason,Nordin&Fraser(1960)suggestedthatanyparticularvalueofCpI/C,rshouldalwaysberelatedtotheplasmaphos-phoruslevelandthattheextenttowhichtheobservedvaluedifferedfromthepredictedvaluecouldbeusedasameasureoftubularre-absorptionofphosphorus.Theycalledthisvaluethephosphateexcretionindex,establishedthelimits+0-09andshowedthathighervalueswereassociatedwithstatesofhyperparathyro-idismandlowvalueswithstatesofparathyroidinsufficiency.Thegeneralvalidityofthephosphateexcre-tionindexhassincebeenconfirmed.Itisgenerallyraisedinprimaryhyperparathyroidism(Nordin&Smith,1965)andfrequentlyalsointhesecondaryhyperparathyroidismofosteo-malacia(Nordin&Fraser,1960),renalfailureandhighphosphatefeeding(Smith&Nordin,