PulmonaryhypertensionfamilyandenvironmentAMGonzalezASmithCEmeryandTHigenbottamRespiratoryMedicineDivisionofClinicalScienceFFloorMedicalSchoolUniversityofShefeldShefeldUKpatientswhohavetakentheanorect ID: 896196
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1 JournalofHumanHypertension(1997)11,559±5
JournalofHumanHypertension(1997)11,559±561Ó1997StocktonPress.Allrightsreserved0950-9240/97$12.00 Pulmonaryhypertension,familyandenvironmentA-MGonzalez,ASmith,CEmeryandTHigenbottamRespiratoryMedicine,DivisionofClinicalScience,FFloor,MedicalSchool,UniversityofShef®eld,Shef®eld,UK patientswhohavetakentheanorecticdexfen¯ura-minewhodevelopedPPH.15ResultingfromthisCorrespondence:DrA-MGonzalez Pulmonaryhypertension,familyandenvironment A-MGonzalezetal 560observation,aninternationalprospectivecase-con-recentexamplehasbeenseenintheHanpeoplewhoinvadedTibet.UnlikenativeTibetanstheytrolstudywasundertakeninfourcountries;France,Belgium,UKandtheNetherlands.16developPHmorecommonly.26AlsotheinfantshaveahighincidenceofinfantilePHandpolycythae-Therewere220cardiothoraciccentreswhichcon-tributedtothestudy.Atotalof95indexcasesweremia.27Ageneticsensitivitytohypoxiaisalikelyexplanation.accepted,allhadbeenvettedbyanindependentreviewertoexcludesecondarycausesofPH.Foreachtwoorthreecasecontrols,ageandgenderThefawnhoodedrat(FHR)matchedwererecruitedfromthepatients'owngen-eralpractitioner.QuestionnaireswereadministeredTheFHRoffersamodelforthesusceptibilitytoPHwithmildhypoxiaasinman.Theirvalueisfurtherbyprofessionalbutun-informedworkersineachcountry.enhancedbytherecentdescriptionofanextensivegeneticmapwith130markers.TheFHRofinterestTheprinciple®ndingwasanincreasedriskofPPHinthosepeoplewithahistoryoftakinganorec-hasaplateletpoolstoragedisorderencodedbyasin-glegenewhichmapstoaregionofchromosome-1ticagents.Thirtycases(31.6%)ofindexcaseshadtakentheseagentscomparedwith26(7.3%)ofthecontainingthered-eyedilutiongene(r).Thisisoneofthreerecessivecoatcolourmarkersforwhichthecontrols,oddsratioof7.1(95%CIof3.7to13.9).Theoddsratiorosesharplyinthosewhohadtakenstrainishomozygous.Thispoolstoragedefectispartofawidespreadstoragedisorderwhichofinter-thedrugforalongerperiodthan3months,risingto23.1.Anincidencestudygaveanannualvalueofestalsoincludes5-HT(andotherbiogenicamines).Parallelswiththeeffectofdexfentreatmenthave1per500000ofthepopulationforPPH.Anumberofmechanismstoaccountforthesebeendrawn,whereplatelet5-HTlevelsarealsoreducedandcirculatinglevelsarethoughttobe®ndingshavebeenproposed.Incommonwithami-norex,dexfen¯uraminehasaphenylethylaminehigherthannormal.GeneticstudiesoftheFHRhaveindicatedlinkagestructure.Whilstitcanbedemonstratedthatpul-monaryvasoconstrictioncanbeproducedbybetweenrandthegenesresponsibleforaminestor-age,systemichypertensionandrenalimpairmentdexfen,17possiblythroughanactiononacalciumdependentpotassiumchannelonthesmoothmusclewhichcandevelopinthestrain.TheRf-1andRf-2genesareresponsibleforabouthalfofthegeneticcells,18thisisseenatconcentrationsinexcessofthoseseenduringtreatmentwiththeagent.variationinkeyindicesofrenalfailure.TheBpfh-1isresponsiblefor26%ofthevariationonsystemicItalsocaninhibituptakeof5-HTbyendothelialandneuralcellstogetherwithplatelets,throughhypertension;allarelocalisedtothechromosome1closetor.28inhibitionoftheserotonintransporter.19Thismayleadtoelevatedcirculatinglevelsof5-HT,itselfaUnlikeotherstrainsofrat,PHoccursintheFHRduringperinatalexposuretomildhypoxia.ThisPHvasoconstrictor.20However,wehaveshownthatchronictreatmentwithdexfenactuallyreducestheshowsthecharacteristicremodellingofpulmo
2 naryhypertensionandincreasedexpressionof
naryhypertensionandincreasedexpressionofthepre-pulmonaryvascularresponsesto5-HT.Thisindi-catesapossiblein¯uenceofdexfenontheproET-1mRNA.29,30RestorationofnormoxiainhibitsthedevelopmentofPHintheFHR.expressionof5-HTreceptors.21FinallydexfencanalterthebalanceoftheproductionofthevasoactivePerinatalhypoxia,aswithotheradverseinuteroconditionswhichreducebirthweightareknowntothromboxaneandprostacyclin.Asyetnoclearexplanationisavailablefortherelationshipbetweenenhancetheprevalenceandmortalityfromcoronaryarterydisease.31,32IthasbeenarguedthatitmightdexfenandPPH.alsocauseadultPH.33WhilstinWistarratswehavenotbeenabletoshowevidenceofPHinadultratsHypoxiaandPHwhohadbeenexposedtoperinatalhypoxia,markedchangeswereobserved.WefoundincreasedAmorecommonenvironmentalfactorleadingtoPHishypoxia.About10%ofpatientswithsevereair-expressionofmRNAforpre-proET-1andreducedexpressionofNOSIIImRNA,togetherwithalteredwaysobstructionfromchronicobstructivebron-chitisdevelopsecondaryPH.Theworsethehypoxiacomplianceofthepulmonaryvasculature.34Itsug-geststhatdevelopmentofthepulmonarycirculationthegreatertherisk.ThesameocclusivevascularlesionsareseenintheconditionasinPPH,how-canbealteredbyperinatalhypoxiaandthiseffectpersistsuntiladultlife.IntheFHRwesuspectthatever,thereisevidencethatreversaloccurswithlong-termoxygentherapy(LTOT).22Notonlyissur-thisadaptationisexaggerated.vivalimprovedbyLTOTbuttheelevatedpulmon-aryvascularresistancecanbereduced.23ConclusionNotonlyislungdiseaseacauseofhypoxicPHbutthesamealsoappearstrueofcongenitalheartHerewehavedescribedhowenvironmentandinheritanceappeartointeracttocontributetothedisease.AstudyofLTOTinEisenmengersSyn-dromeshowsthatagainsurvivalisimproved.24ItdevelopmentofPHinmanandanimalmodels.LocationofthegenesforfamilialPPHandsuscepti-hasbeenrecognisedthatsusceptibilitytohypoxiaoccursinanumberofanimals,forinstanceincattle,bilitytohypoxiaseemlikelytobeidenti®edinthenearfuture.Aninterestinglinkbetweentheanorec-sheepandtheYak,strainsappearsensitivetohypoxiaindevelopingseverePH.25ticagentswhichdisturbbiogenicaminemetabolismandsusceptibilitytohypoxiaintheFHRpotentiallyThesamemayalsobetrueinman.Themost Pulmonaryhypertension,familyandenvironmentA-MGonzalezetal 56118MichelakisEDetal:AnorexicagentsinhibitpotassiumindicatearoleforsuchaminesinPH.Thecomplexcurrentsinpulmonaryarterysmoothmusclecells.AmandpoorlyunderstooddisordercouldsoonbeJRespCritCareMed1995;151(SupplA):725explained.(abstract).19GellerE,RitscoER,FreemanBJ,YurlevA.PreliminaryReferencesobservationsontheeffectoffen¯uramineonbloodserotoninandsymptomsofthreeautisticboys.NEngl1PenkethARL,HigenbottamTW,HakimM,WallworkJMed1980;307:165±169.J.Heartandlungtransplantationinpatientswithend20HervePetal.Increasedplasmaserotonininprimarystagelungdisease.BrMedJ1987;295:311±314.pulmonaryhypertension..AmJMed1995;99:249±2BarstRJetal.Acomparisonofcontinuousepopros-254.terol(prostacyclin)withconventionaltherapyforpri-21RattrayMetal.Chronicd-fen¯uraminedecreasessero-marypulmonaryhypertension.NEnglJMed1996;tonintransportermessengerRNAexpressionindorsal334:296±301.raphenucleus.EurJPharmacol1994;268:439±442.3DresdaleDT,SchultzM,MichtomRJ.Primarypul-22MRCWorkingParty.Longtermdomiciliaryoxygenmonaryhypertension:IClinicalandhaemodynamismtherapyinchr
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