BiophysicalPropertiesofFetal
Myocardium
Thebiophysicalcharacteristicsoffetal,neonatal,andadultmyocardiumhave
beeninvestigatedinanumberofmammalianspecies,butstudiesinthesheep
andrabbithaveprovidedthemajorityofinformation11,12(seealsoChapter4).
Thesestudieshaveconsistentlydemonstratedthatactivedevelopmentoftension
islowerinfetalthanadultmyocardiumatalllengths,includingtheoptimal
length.11Inaddition,intheovinefetus,restingtensionisgreaterthanthatinthe
adultanimal.
Thedifferenceindevelopedtensioncannotbeaccountedforentirelybythe
greaterproportionofnoncontractileproteinperunitcross-sectionalareaoffetal
myocardium.Itmaybeexplainedinpartbythedifferentsensitivityofthefetal
contractileproteinstroponinandmyosintocytosoliccalcium.12
Intheearlyhumanfetus,handlingofcalciumdependsondiffusionalgradients
throughthesarcolemmaintheabsenceofadevelopedsarcoplasmicreticulum.
Sarcoplasmiccalciumadenosinetriphosphatase(ATPase)isexpressedina
downstreamgradientalongtheprimitivehearttube,resultinginincreased
contractiondurationintheoutletportionsoftheheart.Bythe38thdayof
gestation,theearlyhumanmyocardiummaybedividedintoprimaryand
workingfunctionalcomponents.Theprimarycomponentsarecharacterizedby
slowconductionofthecardiacimpulse,owingtothelowdensityofgap
junctionsandthepresenceofslowvoltage-gatedcalciumionchannels.The
workingcomponents,foundintheatriumsandventricles,permitfastconduction
throughthedevelopmentofgapjunctionsandoffastvoltage-gatedsodium
channels.Thesarcoplasmicreticulumlaterregulatescalciumreleaseinthecell
andisknowntoplayanimportantroleinthefrequency-dependentfacilitationof
theL-typecalciumcurrentintheratventricularmyocyte.13
Thethreemajorconnexins,40,43,and45,arepresentincardiacmyocytes
andaredevelopmentallyregulated.Immunoconofocalmicroscopyhasbeenused
tocomparethedistributionofthesewithinthedevelopingmouseandhuman
heart.Inthehuman,connexin45ismostprominentintheconductiontissues,
connexin40isalsoabundantinconductiontissues,particularlyinthePurkinje
fibersandintheatrialratherthanintheventricularmuscle,whereasconnexin43
isdistributedintheventricularmyocardiumandplaysanimportantrolein
conductionacrossgapjunctions.14Knock-outmicemodelshaveincreasedour
understandingofthepathophysiologicroleofconnexindiversityintheheart.15
Thismaypermitthedevelopmentofconnexin-specifictreatmentstrategiesto
treatheritablearrhythmiasaffectingthefetus.Chronicexposuretoanadverse
intrauterineenvironment,suchaschronichypoxemiaassociatedwithrestriction
ofgrowth,orinconditionswithabnormalvolumeloadingmayresultinaltered
patternsofcalciumionicfluxesandofabnormalβ-adrenoceptorstimulation
similartothatidentifiedindiseasedadultmyocardium.16
ProteinComponents
Troponin
Thedifferencesbetweenfetalandadultmyocardialcontractilefunctionare,in
largepart,relatedtotheirregulatoryandstructuralproteincomponents.Different
isoformsoftroponinandmyosinheavychainhavebeenidentifiedinfetaland
adultmyocardiumfromanumberofmammalianspecies,includinghumans.
Thesearegeneticallyprogrammedduringearlyembryonicdevelopmentandare
modulatedbyspecificneurohormones,includingthyroidhormone.TroponinT
hasbeenstudiedextensivelyandcloned.Itregulatescontractioninresponseto
theconcentrationofioniccalcium.17Multipleisoformshavebeenrecognized,
thegeneTNNT2beingidentifiedonchromosome1q23.Slowskeletalmuscle
troponinTisthepredominantisoformthroughoutfetallife,anditsswitchtothe
cardiacformappearstodefinemyofilamentcalciumsensitivity.18Inthehuman,
thistransitionoccursbetween20and33gestationalweeks,19withonlythe
cardiacisoformoftroponinIdetectableby9monthsofpostnatallife.20The
genescodingforthesetwoisoformslieincloseappositionbutshowindependent
tissue-specificexpression,althoughthisclosearrangementmaycomplicate
investigationofmutationsimplicatedincardiomyopathy.21Aknock-outmodel
ofmyocardialtroponinIshowedthat,althoughaffectedmicearebornhealthy,
theybegintodevelopheartfailureby15days.Theyhaveanisoformoftroponin
IthatisidenticaltoslowskeletaltroponinI,permittingsurvival,butthisisoform
disappearsafterbirthdespitethelackofcompensatorymyocardialtroponinI.
Consequently,theventricularmyocyteshaveshortenedsarcomeresandelevated
restingtension,andtheyshowreducedsensitivityoftheirmyofilamentsto
calciumunderactivatingconditions.22
β-Myosin
Theβ-myosinheavychainisoformpredominatesinallfetalmammalsthusfar
examined,includinghumans.Thisisoformisadvantageousinthefetusbecause
ituseslessoxygenandATPthantheadultα-isoformtogeneratethesame
amountofforce.Recentinvestigationshaveshownrepressionoffetalgenesthat
downregulateadult,butnotfetal,isoformsinresponsetoincreasedcardiacwork
andsubsequentmechanicalunloading.Thisresponseappearstoresultin