Circulation.2017;136:743–746.DOI:10.1161/CIRCULATIONAHA.117.029566August22,2017743EDITORIALDulguunAmgalan,MSYunChen,PhDRichardN.Kitsis,MDEDITORIALArticle,seep729Researchoverthepast3decadeshasestablishedthatlossofcardiomyocytesthroughregulatedcellsuicidemechanismscontributescriticallytothepatho-genesisofmyocardialinfarction,heartfailure,andothercardiacsyndromes.1Twoofthemostimportantcelldeathprogramsinthecontextofheartdiseaseareapoptosisandnecrosis.Theseformsofcelldeathdifferprimarilywithrespecttothemagnitudeofcollateraldamageinflictedonsurroundingtissue.Inapoptosis,theplas-mamembraneremainsintactuntilthedyingcellundergoesphagocytosis,whereasinnecrosisnotonlydoesthemembranebecomeleaky,butthecellactivelysecretespro-inflammatorymolecules.Apoptosishasalwaysbeenrecognizedasagene-directedandregulatedprocess.Incontrast,necrosiswasthoughttobeanuncontrolledformofcelldeathresultingfromoverwhelmingphysicalandchemicaltraumatoacell.Abigsurpriseoverthepast15years,however,hasbeentherealizationthatasignificantproportionofnecroticcelldeathsoccursthroughhighlyregulatedmechanisms.Bothapoptosisandnecrosiscanbeinitiatedthrough2majorpathways:1in-volvingmitochondriaandtheothercellsurfacedeathreceptors(Figure,A).InthisissueofCirculation,Guoetal2utilizemultiplemousegeneticmodelstodissectthedeathreceptorpathwayintheheart.Themostimportantfindinginthisstudyisthatknockoutofthegeneencodingtumornecrosisfactorreceptor-associatedfac-tor2(TRAF2),aproteininthispathway,resultsindilatedcardiomyopathythroughunleashingapoptoticandnecroticcardiomyocytedeath.Thedeathreceptorpathwayisinitiatedbyvariousligandsofthetumornecrosisfactor(TNF)family.3ThepresentstudyfocusesonbindingofTNF-αtoTNFreceptor1.Dependingonothersignalsandconditionsinthecell,thismaypromotecellsur-vival,apoptosis,oraregulatedformofnecrosis,whichinthispathwayisreferredtoasnecroptosis(Figure,B).CellsurvivalisstimulatedbyTNF-α-inducedrecruit-mentofproteinsintocomplexIattheplasmamembrane.ComplexI,however,canmorphintoseveralcytoplasmicprote...
