CoronaryArtery.docx

CoronaryArtery.docx

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CoronaryArtery

NEJM，Volume328:

608-613,March4,1993,Number9

RelationbetweenActivatedSmooth-MuscleCellsinCoronary-ArteryLesionsandRestenosisafterAtherectomy

MichaelSimons,GuyLeclerc,RobertD.Safian,JeffreyM.Isner,LawrenceWeir,andDonaldS.Baim

ABSTRACT

BackgroundNeointimalproliferationleadingtorestenosisfrequentlydevelopsaftercoronaryangioplasty.Thisprocessisassociatedwithachangeinvascularsmooth-musclecellsfromacontractile（quiescent）phenotypetoasyntheticorproliferating（activated）one.Weinvestigatedwhetherthepresenceofactivatedsmooth-musclecellsincoronarylesionsatthetimeofcoronaryatherectomypredisposespatientstosubsequentrestenosis.

MethodsWeusedinsituhybridizationtostudytheexpressionofmessengerRNAincoronary-atherectomyspecimensfrom20patients.PlaquematerialwashybridizedwithaprobefortheBisoformofhumannonmusclemyosinheavychain,amajornonmusclemyosinisoforminactivated,butnotquiescent,smooth-musclecells.Angiographicfollow-updatawereobtainedamean（±SD）of174±54daysafteratherectomyin16ofthe20patients,andtheextentofrecurrentluminalnarrowingwasanalyzedquantitatively.Thepresenceofrestenosiswasassessedbyexercisethalliumscintigraphyintheotherfourpatients.

ResultsAtherectomyspecimensfrom10ofthe20patientsshowedhybridizationwiththeprobe,definedastheclusteringofmorethan20silvergrainspercellnucleusinmorethan10nucleiinfivehigh-powerfields（x250）;specimensfromtheother10patientsshowednosuchhybridization.Atfollow-up,restenosishaddevelopedin8ofthe10patientswithpositivehybridizationresults,butwasabsentin9ofthe10patientswithnegativeresults（P=0.007）.Thedegreeoflatelossinluminaldiameterwassignificantlyhigherinpatientswithpositivehybridizationresultsthaninthosewithnegativeresults（ratiooflatelosstoimmediategainafteratherectomy,0.76±0.3vs.0.36±0.3;P<0.001）.

ConclusionsWeconcludethattheexpressionoftheBisoformofnonmusclemyosinheavychainisincreasedinsomecoronaryatheroscleroticplaquesandthatthisincreaseinexpressionidentifiesagroupoflesionsathighriskforrestenosisafteratherectomy.

Restenosisaftercoronaryangioplastyisamajorclinicalproblem.Withinsixmonths,clinicallyimportantstenosisrecursatthesiteofangioplastyin35to45percentofpatientswhohaveundergoneasingle-vesselprocedure,andin50to60percentofthosewhohaveundergonemultivesselangioplasty1.Althoughavarietyofclinical,anatomical,andtechnicalfactors2havebeenassociatedwiththesubsequentdevelopmentofrestenosis,accuratepredictionsforindividualpatientsandlesionsarenotpossible.

Anumberofstudieshavedemonstratedthatthehallmarkofrestenosisistheabundantproliferationofneointimalsmooth-musclecells3,4.Similarpathologicalfindingshavebeendescribedincoronary-arterybypassgrafts5andinsmallarteriesinpatientswithlongstandinghypertension6.Althoughthereissomedegreeofsmooth-muscleproliferationaftervirtuallyanyinjury（suchasangioplasty）,lessthanhalfofpatientshavesufficientproliferationtocreatetheclinicallyimportantnarrowingofthevesselknownasrestenosis.Anumberoffactorsmaythusbeoperatingsimultaneouslytoexplaintheapparentlyrandomvariabilitybetweenpatients.Onesuchfactorcouldbethattheproliferativepotentialofvariousatheroscleroticplaquesdiffersandthatclinicallyinapparentdifferencesinplaquecompositionatthetimeofangioplasty（orothercoronaryintervention）mayinfluencethesubsequentclinicalcourse.

Smooth-musclecellshavetwodifferentphenotypes7.Thecontractile,orquiescent,phenotypeischaracterizedbythepresenceoftypicalsmooth-musclecontractileproteins（suchasalpha-actinandsmooth-musclemyosin）,well-developedthickfilaments,contractioninresponsetochemicalandmechanicalstimuli,andtheinabilitytoundergocytokinesis.Thesynthetic,oractivated,phenotype,ontheotherhand,ischaracterizedbyalossofcontractilefunction,declineinlevelsofcontractileproteins,andgreatlyincreasedsyntheticandproliferativecapacity.Smooth-musclecellsfoundinrestenoticlesionsappeartohavethesyntheticphenotype8.Wereasonedthatthepresenceoftheseactivatedsmooth-musclecellsinatheroscleroticlesionsatthetimeofatherectomymightpredisposepatientstohigherratesofsubsequentgrowthandproliferationandhencetothemorelikelydevelopmentofrestenosis.

Theadventofdirectionalatherectomy9hasforthefirsttimealloweddirectaccesstopathologicintravascularmaterialinvivo.Earlierresultsofhistologicanalysisofatherectomytissues10demonstratedthepresenceofsheetsofproliferatingsmooth-musclecellsinonethirdofcoronaryplaques.Thehistologicappearanceofthesecellsissimilartothatofproliferativesmooth-musclecellsfoundinrestenoticlesions.Usinginsituhybridizationanalysisofatherectomyspecimens,wepreviouslydemonstratedthatproliferatingsmooth-musclecellsinrestenoticvascularlesionsexpressanisoformofnonmusclemyosinheavychainthatdoesnotappeartobepresentinnormalvascularsmoothmuscle11.Inanumberofanimalmodels,thesameBisoformisexpressedintheneointimaafterarterialinjury8,12,13.ThesefindingssuggestthattheBisoformofnonmusclemyosinmaybeintimatelyinvolvedintheprocessofsmooth-muscleproliferationandrestenosis.WethereforeundertookthepresentstudytocharacterizefurtherthecellsinprimaryatheroscleroticplaqueswithregardtotheirexpressionofthemessengerRNA（mRNA）fortheBisoformofnonmusclemyosin,andtocorrelateitsappearancewiththesubsequentdevelopmentofrestenosisafteratherectomy.

Methods

CoronaryAtherectomy

Coronary-atherectomyspecimenswereobtainedinaprospectivemannerfrom20patients（chosenwithoutanysystematicselectioncriteriafromallpatientsundergoingcoronaryatherectomyatBethIsraelHospitalbetweenFebruary16,1990,andDecember9,1991）withtheSimpsonAtheroCath（DevicesforVascularInterventions,Redwood,Calif.）,aspreviouslydescribed10.Thedecisiontoperformatherectomywasbasedstrictlyonanatomicalandtechnicalfactorsandwasnotinfluencedbythestudy.Ofthe20atherectomysamplesobtainedinthisstudy,17werefromleftanteriordescendingcoronaryarteriesand3fromsaphenous-veingrafts.Seventeenlesionswereprimary（notpreviouslytreated;15fromleftanteriordescendingcoronaryarteriesand2fromsaphenous-veingrafts）,and3wererestenotic（2fromleftanteriordescendingarteriesand1fromasaphenous-veingraft）.Asinglelesionfromeachpatientwasusedforthisstudy.Approximately20mgoftissuewasremovedwitheachprocedure;10mgwasusedforinsituhybridization,and10mgforlightmicroscopy.ThestudyprotocolwasapprovedbytheClinicalStudiesReviewBoardofBethIsraelHospital,andinformedconsentwasobtainedfromallthepatients.

InSituHybridization

Thetissuesandprobeswerepreparedaspreviouslydescribed11.Allslideswerereviewedbytwoobserverswhowereunawareoftheresultsofclinicalandangiographicfollow-upandthenatureofthespecimens（primaryorrestenotic）.Anaverageoftwoslidesofeachtissuespecimenwerehybridizedwithantisenseprobes（whicharecomplementarytothemRNA）,andtwoslideswithsenseprobes（whicharenotcomplementarytothemRNA）.Therelationofsilvergrainstothecellnucleuswasusedtojudgethestrengthofthesignal.Aslidewassaidtoshowhybridizationifmorethan10nucleihadoverlyingclustersofsilvergrains（morethan20grainspernucleus）infivehigh-powerfields（x250）11.Thiscriterionwasestablishedprospectively,beforetheresultsofclinicalandangiographicfollow-upbecameavailable.Ameasureofhybridizationwasalsoobtainedbycountingthenumberofpositivenucleiperfivehigh-powerfieldsoneachslideandaveragingthisnumberforthetwoslidesthatwerepreparedforeachpatient.Anydisagreementbetweentheobserverswasresolvedbyajointreviewofslides.

LightMicroscopy

Aportionofeveryspecimenwasfixedin10percentformalinforlight-microscopicalexamination.Thepresenceorabsenceofintimalhyperplasia,definedasincreasedcellularity,wasassessedforeachparaformaldehyde-fixedspecimen.

AngiographicAnalysis

Coronaryangiographywasperformedimmediatelybeforeandafteratherectomy.Toassesstheirseverity,lesionsweremeasuredwithelectroniccalipers（DigitalCaliperSystem,SandhillScientific,Littleton,Colo.）onopticallymagnifiedimagesoftheviewshowingthegreatestdegreeofstenosis,witha9-Frenchguidingcatheterasareference.Suchelectronicmeasurementsarereproducibleandcorrelatewellwiththeresultsofcomputerizeddigitalanalysis14.Afollow-upangiographicstudywasperformedin16ofthe20patientsandwasanalyzedinasimilarmanner.Theremainingfourpatientsdeclinedfollow-upangiographyandwereevaluatedwithserialexercisethalliumtests.Forallthepatientsthediameterofthelesionandthatofthereferencesegmentwererecordedbeforeandafteratherectomyandatafollow-upstudy.Restenosiswasdefinedasstenosisofmorethan50percentattheatherectomysiteatthetimeoffollow-upangiography.Theamountofimmediategainwasdefinedasthedifferenceinthediameterofthelesionbeforeandafteratherectomy.Theamountoflatelosswasdefinedastheabsolutechangeinluminaldiameterbetweenthemeasurementafteratherectomyandthefollow-upstudy.TheamountoflatelosswasadjustedfortheimmediategainaccordingtothemethodofKuntzetal15.

ClinicalData

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