Hypertrophyassociatedwithbothhypertensionandobstructiontoventricularoutflowleadstopathologiccardiacgrowthanditisassociatedwithincreasemorbidityandmortality.Symptomaticventriculardiseasetakesagrowingtollonthehealthofnations.Asothercardiovasculardiseasessuchasstrokeandmyocardialinfractionareindeclineascausesofmortality,theheartfailureproblembecomesincreasinglyurgent.Congenitalheartdefectsoccurin1%oflivebirthsandfetalheartmalformationsareimplicatedinmanypregnanciesthatendinstill-birthorspontaneousabortion.ThecurrentparADIgmsuggeststhattheheartadaptstoexcessofhemodynamicloadingbycompensatoryhypertrophy,whichunderconditionofpersistentstress,overtimeevolvesintodysfunctionandmyocardialfailure.Thereisconsiderableevidencethatdirecteffectsofincreasedmechanicalstressaresensedwithintheventricularwallandthatsignalscriticalforthegenerationofgrowthresponses.Despitecompellingstatisticswestilldonotunderstandbiochemicallywhyheartdefectsaresoprevalent.AsingletranscriptionalregulatorinitiallyassociatedwiththeactivationoftheT-cells(NFATc4)hasbeenshowntolinkgeneticandenvironmentalcausesofoneclassofcongenitalheartdisorders–birthdefectsinvolvingvalveandseptumformation.Withintheendocardium,specificinductiveeventsappeartoactivateNF-ATc:itislocalizedtothenucleusonlyinendocardialcellsthatareadjacenttotheinterfacewiththecardiacjellyandmyocardium,whicharethoughttogivetheinductivestimulustothevalveprimordia.TreatmentwithFK506,aspecificcalcineurininhibitor,preventsnuclearlocalizationofNF-ATc4.ActivatedCaMKstimulatescalcineurin,whichthanactsthroughNF-ATc4inassociationwithGATA4,toinducehypertrophy.AmodelfortheproposedroleofcalreticulinintheregulationofcardiacdevelopmentrequiresamyogenicsignalfromextracellularspacetoactivatetheproductionofIP3thatresultsinthereleaseofCa2+fromERundertheregulationofcalreticulin(CRT).IncreasedintracellularCa2+bindstocalmodulin(CaM)andactivatescalcineurin(CaN).CaNdephosphorylatesNF-ATc4thattranslocatestothenucleus.InthenucleusNF-ATformscomplexeswiththeGATA-4andothertranscriptionfactorsleadingtoactivationoftranscriptionofgenes(ANF,a-actin,b-mysin,TNFa,ET-1,Adss1etc)essentialforcardiacdevelopment.ForacomprehensivelistofmyocytegenesregulatedattranscriptionallevelseeMolecularandCellularBIOLOGyofCardiacHypertrophyandFailurebyHunteretal.,inMolecularBasisofCardiovascularDiseaseedbyChienKR,pp211-250)

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