Andersons pediatric cardiology 205
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FetalHemodynamicsandBrainGrowth
andDevelopment
Inkeepingwiththefindingsofpriorinvestigations,thebrainsofnewbornswith
CHDinourstudiesweresmallerandhadabnormalwhitematteranddeepgray
mattermicrostructurebydiffusiontensorimagingcomparedwithnormal
controls.27,28Thesefindingshavebeeninterpretedasevidenceofdelayedbrain
development,aconceptthatissupportedbytheimmaturecerebral
electrophysiologyoftermnewbornswithCHDandinfantbehaviorthatismore
characteristicofnewbornswithnormalheartsborninthelatepreterm
period.29,30Limperopoulosetal.usedMRItomeasurebraingrowthand
metabolisminfetuseswithCHDandfoundaslowingofbraingrowthand
metabolism,particularlyduringthethirdtrimester.31Weandothershave
speculatedthatthiscouldhaveresultedfrominuterocerebralhypoxia.The
principleof“oxygenconformance”ordelivery-dependentconsumptionhasbeen
establishedatacellularlevelinvitrowherebyevensmallreductionsincellular
oxygendeliveryresultinaseriesofmetabolicadaptions,whichserveto
downregulatecellularrequirementsforoxygen,thusprotectingthecellagainst
energeticcollapse.32Thecellularmechanismsinvolvedinoxygenconformance
includehypoxic-induciblefactor-mediatedchangesingeneexpression,the
switchfromaerobictoanaerobicrespiration,thereductionofcellularrespiration
andslowingoftheelectrontransferchain,aswellasdownregulationofthecell's
requirementforATP.Modificationofthesepathwaysresultsindownstream
effectsonproteinsynthesisandcellcycling.Similarly,infetalanimalmodels,
chronichypoxiahasbeenassociatedwithaslowingofneuronalmetabolismand
reductionsinsynaptogenesisandmyelination.33,34Thesewouldbeinkeeping
withtheapparentmatchingofsubstratedeliveryandbraingrowthand
metabolismindicatedbytheresultsshowninTables7.5and7.6.However,a
causalrelationshipbetweendiminishedcerebraloxygendeliveryandbrain
growthandmaturationhasyettobeestablishedinhumanfetuseswithCHD.
RecentwholegenomesequencingevidenceobtainedfromchildrenwithCHD
revealsahighrateofdenovomutations,particularlyinthosechildrenwith
neurodevelopmentaldelay.35Interestingly,someofthesemutationsalsohave
beenassociatedwithneurodevelopmentaldelayinchildrenwithnormalhearts
andithasbeensuggestedthatintrinsicgeneticfactorsmaybemoreimportant
thancerebralhemodynamicsforbraindevelopmentinchildrenwithCHD.Thus,
thereducedcerebraloxygendeliveryweobservedinfetuseswithCHDcould
reflectinnatedifferencesintherateofbraingrowtharisingfromgenesor
epigeneticfactorsthatinfluencebraindevelopment.Oneapproachto
investigatingtherelationshipbetweenCDO2andbraindevelopmentisto
attempttoaugmentCDO2.Wehaveshownincreasesinumbilicalveinoxygen
saturationinfetuseswithCHDduringacuteadministrationofsupplemental
maternalinhaledoxygen.36Aclinicaltrialthataimstotestthehypothesisthat
chronicmaternalhyperoxygenationenhancesfetalbraindevelopmentinthe
settingofsingleventricleCHDiscurrentlyunderway.However,thebenefitof
acceleratingfetalbrainmaturationinCHDpatientsthroughfetalinterventionis
alsouncertain.Indeed,theetiologyoftheneurodevelopmentaldeficitsreported
inchildrenwithCHDislikelytobemultifactorial.OurserialpostnatalMRI
studiesofchildrenundergoingneonatalcardiacsurgerysuggestthatpostnatal
derangementsincardiovascularphysiologyandperioperativeinjuryare
potentiallymoreimportantthanthesubtledelaysofbraingrowthand
developmenttypicalofthefetalperiod.37
FetalHemodynamicsandLung
Development
Theclinicalsignificanceoftheobstructionofpulmonaryvenousreturninutero
hasbeenknownformanyyears.Lungpathologycaseseriesinnewbornsdying
fromhypoplasticleftheartwithahighlyrestrictiveorintactatrialseptumand
obstructedtotallyanomalouspulmonaryvenousconnectionhaverevealed
widespreadchangesinthepulmonarycirculationincludingmuscularizationof
thepulmonaryveins,hypoplasiaofthesmallpulmonaryarteries,andthickening
ofthearteriolarsmoothmuscle.38,39Pulmonarylymphangiectasiawasobserved
in50%to75%ofthesecasesofpulmonaryvenoushypertension,inkeeping
withfailureofthenormalregressionofthepulmonarylymphaticsinutero.
DilatedpulmonarylymphaticshavebeendemonstratedonconventionalT2weightedfastspinechoinpatientswithpulmonaryvenousobstructionand
correlatedwithpostnatallungbiopsyfindingsofpulmonarylymphangiectasia
andpulmonaryhypertension.40–42Thesepatientshavehighperioperative
mortality,andwhentheysurvivetheymayhavepersistentlyelevatedpulmonary
vascularresistance—insomecasesprecludingbidirectionalcavopulmonary
shunting.TheappearancesofpulmonarylymphangiectasiaonfetalMRIare
showninFig.7.14.Fetuseswithobstructedpulmonaryvenousdrainagealways
haveverylowpulmonarybloodflow,whichcorrelateswithanobstructed
pulmonaryvenousDopplerpattern.Reliefofthepulmonaryvenousobstruction
inuterobyballoonatrialseptostomyorstentingresultsinanincreasein
pulmonarybloodflowandmorestableclinicalpresentationatbirth,althoughthe
impactonlong-termsurvivalisnotyetcertain.43
