心衰中的炎症,, .ppt

1,Inflammationinheartfailure,LiaoYu-HuaInstituteofCardiologyUnionHospitalHuazhongUniversityofScienceandTechnology,WuhanChina,2,Cognitiveprocessofpathophysiologyandtherapyinhaertfailure,3,InflammationandHeartfailure,Interactionbetweenneuroendocrineandcytokinesinheartfailuretherapybetweeninflammationandheartfailure,4,-adrenergicstimulationinducesproinflammatorycytokineexpressioninmyocardium,mRNAexpressionbyNorthernblotting,proteinlevelsbyWesternblotting,*P0.01,*P0.0001vssaline-treatedanimals.,Murrayetal.Circulation.2000;101:2338-2341.,Incontrolmyocardium,TNF-a,IL-1bandIL-6werenotdetected.Isoproterenolinfusionsignificantlyincreasedexpressionofall3cytokines,indicatingthatchronic-adrenergicstimulationwasassociatedwithproinflammatorycytokineexpression.,5,CausalrelationshipbetweenAngIIandTGF-1incardiachypertrophy,SchultzJEJ,etal.JClinInvest2019;109:78796,ThelackoftheTGF1genefullypreventedthedevelopmentofcardiachypertrophyinducedbysubpressordosesofAngIIthatwasobservedinwildtypemice,AngII-inducedcardiachypertrophyismediatedbyTGF-1,6,EvidenceforaconnectionbetweenAngIIandTGF-1incardiactissue,StephanRosenkranz.CardiovascularResearch2019;63:423432,SomestudiesindicatethatAngIIandTGF-1actinanauto-/paracrinemanner,andsuggestcross-talkbetweenthevariousmyocardialcelltypesandcompartments,7,AngiotensinII-inducedmyocardialTNFbiosynthesisintheadultheart,TNFmRNAexpression,KalraD,etal.Circulation2019;105:2198205.,TreatmentwithAngIIresultedinarapidincreaseinTNFmRNAsynthesisinisolatedbufferperfusedhearts,8,AngiotensinIIinducedactivationofNF-B,KalraD,etal.Circulation2019;105:2198205.,StimulationwithAngIIleadtoarapidincreaseinNF-Bbindingactivityinisolatedbufferperfusedhearts,thefindingsuggestapossiblepathwayinAngIImediatedTNFbiosynthesis,9,Cross-regulationbetweentherenin-angiotensinsystemandinflammatorymediators,K.Sekiguchietal.CardiovascularResearch2019；63：433442,Thereisacomplicatednetworkinheartfailurebetweenneuroendocrinesystemandimmunesystem,AngIIprovokesinflammatoryresponsesintheheartthroughanNF-Bdependentpathway,whereasTNFprovokeactivationoftheRASintheheartthroughincreasedACEactivity.BothofthesepathwaysconvergeonoverlappingMAPKsignaltransductionpathways,10,InflammationandHeartfailure,Interactionbetweenneuroendocrineandcytokinesinheartfailuretherapybetweeninflammationandheartfailure,11,AutoimmuneresponseafterAMI,LiaoYH.Autoimmunityinmyocardialinfarction.IntJCardiol,2019;112:21-26,12,Newfieldoftherapyininflammationandheartfailure,ProblemofImmunosuppresiontherapyProblemofanti-cytokinetherapyImmuoregulatoryeffectof-blockersoninflammationafterAMIImmuoregulatoryeffectofstatinsoninflammationafterAMI,LiaoYH.Autoimmunityinmyocardialinfarction.IntJCardiol,2019;112:21-26,13,MyocardialinflammationshouldbesuppressedorregulatedafterAMI?,AclinicalstudyusingmethylprednisoloneinpatientswithAMI,whichresultedincatastrophicresults,increasedtheincidenceofventriculararrhythmiasandextendinginfarctsizeSubsequentinvestigationssuggestedthatcorticosteriodsinhibittheinflammatoryprocessdecreasingthenumberofinfiltratingleukocytes,butalsodelayhealingandcollagendeposition,RobertsR,DeMelloV,SobelBE.Circulation.1976;204-206.KlonerRA,FishbeinMC,LewH,etal.Circulation.1978;1:56-63.,14,Newfieldoftherapyininflammationandheartfailure,ProblemofImmunosuppresiontherapyProblemofanti-cytokinetherapyImmuoregulatoryeffectof-blockersoninflammationafterAMIImmuoregulatoryeffectofstatinsoninflammationafterAMI,Targetedanticytokinetherapyhasbeengivengreatexpectation,buttheresultsfromlargescaleclinicaltrialswerenotsatisfying,LiaoYH.Autoimmunityinmyocardialinfarction.IntJCardiol,2019;112:21-26,15,RENEWALtrial,MannDL,etal.Circulation2019;109:1594-1602,EtanerceptisasolubleTNFantagonist,whichcanlowertheserumlevelofTNFinpatientswithheartfailure,buttheresultsofRENEWALruleoutaclinicallyrelevantbenefitontherateofdeathorhospitalizationduetochronicheartfailure,16,Explanationsbydesigner,ProinflammationcytokinesdonotplayadeleteriousroleinthepathophysiologyofchronicheartfailureThedosesofetanerceptwerenotsufficienttoneutralizeTNF-ThetargetedapproachthatwastakenwasnotsufficienttodisruptthenetworkofinflammatorymediatorsthatareactivatedinheartfailureEtanerceptalsohasintrinsicbiologicalactivityandcanactasagonistsforthecytokinethattheybind,MannDL,etal.Circulation2019;109:1594-1602,17,ATTACHtrial,InfliximabisarecombinantTNF-monoclonalantibodythatspecificallyandpotentlybindstoTNF-AlthoughitcanlowerthelevelsofcirculatoryCRPandIL-6,theshort-terminfliximabtreatmentcannotimproveandhighdoses(10mg/kg)adverselyaffecttheclinicalconditionofpatientswithchronicheartfailure,ChungES,etal.Circulation2019;107:313340,18,ATTACHtrialresults,ChungES,etal.Circulation2019;107:313340,DeathorCHFHospitalization,*P=0.043vsplacebo,19,TheactivationofTNF-maynotplayadeleteriousroleinheartfailureThetoxicityofTNF-mightbealsoenhancediftreatmentwithinfliximabcausedcirculatinglevelsofTNF-toreboundWhenexposedtocellsexpressingtransmembraneTNF-,infliximabcancausecelllysisinthepresenceofcomplement,Explanationsbydesigner,ChungES,etal.Circulation2019;107:313340,20,ExpressionofcytokinesinmyocardiumafterAMI,ZhangJY,ChengX,LiaoYH,etal.CardiovascDrugTher.2019;19:13-21,OurstudyshowthecytokinesmightbesecretedbymeansofanautocrineandparacrineinmyocardiumafterAMI,21,RENEWALtrial:ThedosesofetanerceptmaybesufficienttoneutralizecirculatingTNF-,butnotsufficienttoneutralizemyocardialTNF-ATTACHtrial:InfliximabisdirectlycytotoxictocellsexpressingTNF-onthemyocardium.Sohighdosesofinfliximab(10mg/kg)adverselyaffectedtheclinicalconditionofpatientswithchronicheartfailure.Theanti-cytokinetherapyisabortedbecausethecytokinesmightbesecretedbymeansofanautocrineandparacrineinmyocardium,Explanationsbyourexperiment,22,Newfieldoftherapyininflammationandheartfailure,ProblemofImmunosuppresiontherapyProblemofanti-cytokinetherapyImmuoregulatoryeffectof-blockersoninflammationafterAMIImmuoregulatoryeffectofstatinsoninflammationafterAMI,LiaoYH.Autoimmunityinmyocardialinfarction.IntJCardiol,2019;112:21-26,23,CarvedilolreducedcardiaccytokineproteinexpressioninAMIratsaftertherapy4w,LiB,LiaoYH,etal.NatlMedJChina,2019,85(6):416-418LiB,LiaoYH,etal.ChinHospPharmJ,2019;24(11):659-661,*Comparedwithsham-operatedgroup,P0.01;ComparedwithMIgroup,P0.01,24,CarvediloldecreasedmyocardialMMP-2andMMP-9expressioninAMIrats,*Comparedwithsham-operatedgroup,P0.01;ComparedwithMIgroup,P0.01,LiB,LiaoYH,etal.NatlMedJChina,2019,85(6):416-418LiB,LiaoYH,etal.ChinHospPharmJ,2019;24(11):659-661,25,CarvediloldecreasedmyocardialtypeandcollagensexpressioninAMIrats(200),LiB,LiaoYH,etal.NatlMedJChina,2019,85(6):416-418LiB,LiaoYH,etal.ChinHospPharmJ,2019;24(11):659-661,26,MetoprololregulatescytokinesproteinproductionofLVmyocardiumpost-MI,*P0.01vs.Shamgroup.#P0.05vs.MIgroup,A,ChengX,LiaoYH,etal.ChinJCardiol,2019;33(5):448-452,B,27,Localizationofcytokinesimmunoreactivityinmyocardium,SH:Sgroup,I:infarctedzoneofMIgroup,B-I:infarctedzoneofMI-Bgroup,N:noninfarctedzoneofMIgroup,B-N:noninfarctedzoneofMI-Bgroup(400),ChengX,LiaoYH,etal.ChinJCardiol,2019;33(5):448-452,28,Newfieldoftherapyininflammationandheartfailure,ProblemofImmunosuppresiontherapyProblemofanti-cytokinetherapyImmuoregulatoryeffectof-blockersoninflammationafterAMIImmuoregulatoryeffectofstatinsoninflammationafterAMI,LiaoYH.Autoimmunityinmyocardialinfarction.IntJCardiol,2019;112:21-26,29,AtorvastatininhibitsTh1responseinAMIpatients,ChengX,LiaoYH,etal.Circulation.2019;110(17)SupplementIII:696-697,butatorvastatinhasnoeffectonTh2responseinpatientswithAMI,whichmaybeoneofthemechanismsthatatorvastatinpreventsheartfailureafterAMI.,30,AtorvastatininhibitsTh1responseinvitrotheeffectcanbereversedbyMevalonate,A,B,*P0.05vs.culturedwithoutatorvastatingroup#P0.05vs.culturedwithatorvastatin(3mol/L)group,ChengX,LiaoYH,etal.Circulation.2019;110(17)SupplementIII:696-697,31,SimvastatinreducesTNF-expressioninmyocardium,ZhangJY,ChengX,LiaoYH,etal.CardiovascDrugTher.2019;19:13-21,32,*P0.01vsSham#P0.01vsMI-C,SimvastatinmodulatecytokinesproteinexpressionafterAMI,ZhangJY,ChengX,LiaoYH,etal.CardiovascDrugTher.2019;19(1):13-21,33,HeartfunctionimprovedinAMIratsaftersimvastatintreatment,Comparedwithshamgroup,*p0.01ComparedwithMI-C,#p0.05,SimvastatinanimaltrialafterAMI,ZhangJY,ChengX,LiaoYH,etal.CardiovascDrugTher.2019