兴奋收缩耦联和心力衰竭的治疗.ppt

田野教授哈医大二院心内科,兴奋收缩耦联和心力衰竭的治疗,TOPICS,Excitation-contraction(EC)couplingExcitationCalciumCyclingContractionAlterationsofE-CcouplinginHFInotropicagentsforHF,Excitation-contractioncoupling,Thepoweroflocomotionisthatwhichcontractsandrelaxesthemuscleswherebythemembersandjointsaremoved,extendedorflexed.Thispowerreachesthelimbsbywayofthenervesandthereareasmanyformsofpowerasthereareofmovement.Eachmusclehasitsownpeculiarpurposeanditobeysthedecreeofthecompositesense.,Avicenna(11671248),WilliamHarvey(15781657),HewasanEnglishmedicaldoctor/physician,whoiscreditedwithbeingthefirsttocorrectlydescribe,inexactdetail,thesystemiccirculationandpropertiesofbloodbeingpumpedaroundthebodybytheheart.,Weshalldesignatetheentireseque-nceofreactions:excitation,inwardactinglink,andactivationofcontra-ctionbythetermexcitation-contractioncoupling.,ALEXANDERSANDOW,1952(NewYorkUniversity),SandowA.YaleJBiolMed.1952.25(3):176201,Cardiacexcitationcontractioncouplingistheprocessfromelectricalexcitationofthemyocytetocontractionoftheheart(whichpropelsbloodout).TheubiquitoussecondmessengerCa2+isessentialincardiacelectricalactivityandisthedirectactivatorofthemyofilaments,whichcausecontraction.,BersDM.Nature,2019,415(6868):198-205.,Excitation,Thecardiacactionpotential,AnotabledifferencebetweenskeletalandcardiacmyocytesishoweachelevatesthemyoplasmicCa2+toinducecontraction.Incardiacmyocytes,thereleaseofCa2+fromthesarcoplasmicreticulumisinducedbyCa2+influxintothecellthroughvoltage-gatedcalciumchannels.,CalciumCycling,PictorialOFCalciumCycling,Ca+,Ca+,Ca+,Ca+,Plb,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Ca+,Na+,Na+,Na+,Ca+,SERCA,SR,RyR,L-TypeCa+Channel,Na+/Ca+Exchanger,Ca+,Sarcolemma,Ca+,Cardiactissueandcells,ConductelectricalwavesContractinresponsetoanelectricalstimulus,(Guinea-pigventricularcell),Cardiactissue,Function,B,SarcoplasmicReticulum(SR),PLNandSERCA,thesitesofinteractionbetweenPLNandSERCA,Sodium-calciumexchanger(NCX),Two-waytransporter“forward”mode“reverse”modeNa:Ca=3:1,CareleaseCoincideswithactivationofthecontractilemachinery,Contraction,SlidingFilamentTheory,A.F.Huxley1954,EMevidenceforslidingfilamenttheory,Themicrographshowsmyosinboundtoactin,Themolecularbasisformyocardialcontraction,Thinfilament(Actin,Tropom-yosin,Troponin)Thickfilament(Myosin)Otherproteins,Chien,K.R.,2019,Z,Z,Titin,28,000aminoacids(3MDa)thelargestproteinknowninmammals.,MYOSINMW480kDaFormsthickfilamentsHydrolysesATPInteractswithF-actin300-400myosinmoleculesper1filament,S1,150nm,ThickFilamentProteins,RLC,ELC,ATPBindingSite,ActinBindingSite,ATP（Myosin）ADP+Pi+Energy,MyosinHead(S1)molecularmotorofmusclecontraction,G-ActinF-Actin,GtoFactinMW42kDaTheblueandgreymoleculesareactinmonomers(MW42.000),KenC.Holmes:Max-Planck-Institute,Takeda,S.etal.Nature424,3541,2019,CrystalStructureofHumanCardiacTroponin,Gordonetal.2019,Regulationofthinfilamentincontraction,MuscleContraction,AlterationsinE-CcouplinginHF,RyR2channelleak,HeartFailure,PDE4DlevelslossofFKBP12.6,RyR2channelleak,Arrhythmiaandprogressionofheartfailure.,JefferyDMolkentin.NatureMedicine11,1284-1285(2019),PLNSERCA2ainteractionsinphysiologicalanddiseasedcardiacfunction,StevenR.Houser.JMolCellCardiol32,15951607(2000),InotropicAgentsforHF,InotropicAgentsand-blocker,DigitalisPhosphodiesteraseinhibitor-adrenoceptorblocker,Digitalis(200years),DigilispurpureaPurplefoxglove,WilliamWithering(17411799),MechanismofAction,Digitalis,Otherstudy,Someevidencesuggeststhatthebenefitsofdigitalismayberelatedinparttoenzymeinhibitioninnoncardiactissues.InhibitionofNa-KATPaseinvagalafferentfibersactstosensitizecardiacbaroreceptors,whichinturnreducessympatheticoutflowfromthecentralnervoussystem.Inaddition,byinhibitingNa-KATPaseinthekidney,digitalisreducestherenaltubularreabsorptionofsodium;theresultingincreaseinthedeliveryofsodiumtothedistaltubulesleadstothesuppressionofreninsecretionfromthekidneys.,ThamesMD.CircRes.1979;44:815.FergusonDWetal.Circulation.1989;80:6577.TorrettiJetal.AmJPhysiol.1972;222:1398405.,Placebon=3403,Digoxinn=3397,48,0,12,24,36,Mortality%,NEnglJMed2019;336:525,Months,p=0.8,N=6800NYHAII-III,DIGtrail(2019),ACC/AHAHFguideline2009,Long-termuseofaninfusionofapositiveinotropicdrugmaybeharmfulandisnotrecommendedforpatientswithcurrentorpriorsymptomsofHFandreducedLVEF,exceptaspalliationforpatientswithend-stagediseasewhocannotbestabilizedwithstandardmedicaltreatment(StageD).(ClassIII,LevelofEvidence:C),Continuousintravenousinfusionofapositiveinotropicagentmaybeconsideredforpalliationofsymptomsinpatientswithrefractoryend-stageHF(StageD).(ClassIIb,LevelofEvidence:C),Phosphodiesteraseinhibitor,ThedifferentformsorsubtypesofphosphodiesterasewereinitiallyisolatedfromratbrainsbyUzunovandWeissin1972andweresoonafterwardsshowntobeselectivelyinhibitedinthebrainandinothertissuesbyavarietyofdrugsThepotentialforselectivephosphodisteraseinhibitorsastherapeuticagentswaspredictedasearlyas1977byWeissandHait.Thispredictionmeanwhilehasprovedtobetrueinavarietyoffields.,Uzunov,P.andWeiss,BBiochim.Biophys.Acta284:220-226,1972,Weiss,B.andHait,W.N.:Ann.Rev.Pharmacol.Toxicol.17:441-477,1977.,Phosphodiesterase-3inhibitor,PDEI,cAMP,AMP,PDE3,YuanJamesRao,(2009),Mechanismofaction,Asaresultofitshighexpressioninboththevasculatureandtheairways,PDE3wasidentifiedasapotentialtherapeutictargetincardiovasculardiseaseandasthma.AugmentmyocardialcontractilityRelaxvascularandairwaysmoothmuscleInhibitplateletaggregationInducelipolysis,BARNESP.J.etal.Pharmacol.Rev.1988;40:4984.MANGANIELLOV.C.,etal.CellSignal.2019;7:445455.,“IwishIhadmybeta-blockershandy,Hislandmarkinventionofpropranololin1964andtheH2-receptorantagonist,cimetidine,in1972earnedhimtheNobelPrizeinMedicinein1988.,JamesW.Black,-adrenoceptorReceptorBlockers,Mechanismofaction,Densityof1receptorsInhibitcardiotoxicityofcatecholaminesNeurohormonalactivationHRAntiischemicAntihypertensiveAntiarrhythmicAntioxidant,Antiproliferative,100,90,80,60,70,50,24,0,20,16,12,8,4,28,Placebo,Carvedilol,Months,N=2289III-IVNYHA,NEJM2019;344:1651,Survival%,p=0.0001435%RR,COPERNICUSStudy(2019),ACC/AHAHFguideline2009,Useof1ofthe3betablockersproventoreducemortality(i.e.,bisoprolol,carvedilol,andsustainedreleasemetoprololsuccinate)isrecommendedforallstablepatientswithcurrentorpriorsymptomsofHFandreducedLVEF,unlesscontraindicated.(ClassI,LevelofEvidence:A),Whentostart?,PatientstableNophysicalevidenceoffluidretentionNoneedforI.V.inotropicdrugsStartACE-I/diureticfirstStartLow,IncreaseSlowlyIncreasethedoseevery2-4weeks,Risksoftreatment,FluidRetentionAndWorseningHF(intensificationofconventionaltherapy)FatigureBradycardiaAndHeartBlockHypotension(blockalpha-1receptors),Reviewtreatment(+/-diuretics,otherdrugs)ReducedoseConsidercardiacpacingDiscontinuebetablockeronlyinseverecases,Howshouldclinicaldeteriorationbemanagedinpatientswhohavebeentakingabetablockerforlongperiodsoftime(morethan3months)?ifpatientsdevelopfluidretention,withorwithoutmildsymptoms,itisreasonabletocontinuethebetablockerwhilethedoseofdiureticisincreased.Ifthedeteriorationinclinicalstatusischaracterizedbyhypoperfusionorrequ