田野田野 教授教授哈医大二院心内科兴奋收缩耦联和心力衰竭的治疗兴奋收缩耦联和心力衰竭的治疗TOPICSpExcitation-contraction(EC)couplingExcitationCalciumCyclingContractionpAlterationsofE-CcouplinginHFpInotropicagentsforHFExcitation-contractioncoupling兴奋收缩耦联和心力衰竭的治疗Thepoweroflocomotionisthatwhichcontractsandrelaxesthemuscleswherebythemembersandjointsaremoved,extendedorflexed.Thispowerreachesthelimbsbywayofthenervesandthereareasmanyformsofpowerasthereareofmovement.Eachmusclehasitsownpeculiarpurposeanditobeysthedecreeofthecompositesense.Avicenna(11671248)WilliamHarvey(15781657)HewasanEnglishmedicaldoctor/physician,whoiscreditedwithbeingthefirsttocorrectlydescribe,inexactdetail,thesystemiccirculationandpropertiesofbloodbeingpumpedaroundthebodybytheheart.Weshalldesignatetheentireseque-nceofreactions:excitation,inwardactinglink,andactivationofcontra-ctionbythetermexcitation-contractioncoupling.ALEXANDER SANDOW,1952(New York University)Sandow A.YaleJBiolMed . 1952.25 (3): 176201 Cardiacexcitationcontractioncouplingistheprocessfromelectricalexcitationofthemyocytetocontractionoftheheart(whichpropelsbloodout).TheubiquitoussecondmessengerCa2+isessentialincardiacelectricalactivityandisthedirectactivatorofthemyofilaments,whichcausecontraction.BersDM.Nature,2002,415(6868):198-205.Excitation兴奋收缩耦联和心力衰竭的治疗ThecardiacactionpotentialAnotabledifferencebetweenskeletalandcardiacmyocytesishoweachelevatesthemyoplasmicCa2+toinducecontraction.Incardiacmyocytes,thereleaseofCa2+fromthesarcoplasmicreticulumisinducedbyCa2+influxintothecellthroughvoltage-gatedcalciumchannels.CalciumCycling兴奋收缩耦联和心力衰竭的治疗PictorialOFCalciumCyclingCa+Ca+Ca+Ca+PlbCa+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+SERCASRRyRL-Type Ca+ChannelNa+/Ca+ ExchangerCa+SarcolemmaCa+CardiactissueandcellsConductelectricalwavesContractinresponsetoanelectricalstimulus(Guinea-pig ventricular cell)Cardiac tissueFunctionBSarcoplasmicReticulum(SR)PLNandSERCAthesitesofinteractionbetweenPLNandSERCASodium-calciumexchanger(NCX)Two-waytransporter“forward”mode“reverse”modeNa:Ca=3:1Ca release Coincides with activation of the contractile machinery Contraction兴奋收缩耦联和心力衰竭的治疗SlidingFilamentTheoryA.F.Huxley1954EMevidenceforslidingfilamenttheoryThemicrographshowsmyosinboundtoactinThemolecularbasisformyocardialcontractionThin filament (Actin ,Tropom-yosin, Troponin) Thick filament (Myosin)Other proteinsChien,K.R.,1999ZZTitin28,000 amino acids (3MDa) the largest protein known in mammals.Titin MYOSIN MW 480 kDaForms thick filamentsHydrolyses ATPInteracts with F-actin 300-400 myosin molecules per 1 filamentS1S1150 nmThickFilamentProteinsRLCELCATP Binding SiteActin Binding SiteATP （Myosin） ADP + Pi + EnergyMyosinHead(S1)molecularmotorofmusclecontractionG-ActinF-ActinG to F actin MW 42 kDaThe blue and grey molecules are actin monomers (MW 42.000)Ken C. Holmes: Max-Planck-Institute Takeda, S. et al. Nature 424, 35 41, 2003 HCTnCHCTnIHCTnTTropomyosinTropomyosinbinding regionHypervariable regionCrystalStructureofHumanCardiacTroponinGordonetal.2001RegulationofthinfilamentincontractionMuscleContractionAlterationsinE-CcouplinginHF兴奋收缩耦联和心力衰竭的治疗RyR2channelleakHeart FailurePDE4D levelsloss of FKBP12.6RyR2 channel leakArrhythmia and progression of heart failure.JefferyDMolkentin.NatureMedicine11,1284-1285(2005)PLNSERCA2ainteractionsinphysiologicalanddiseasedcardiacfunctionStevenR.Houser.JMolCellCardiol32,15951607(2000)InotropicAgentsforHF兴奋收缩耦联和心力衰竭的治疗InotropicAgentsand-blockerDigitalisPhosphodiesteraseinhibitor-adrenoceptorblockerDigitalis(200years)DigilispurpureaPurplefoxgloveWilliamWithering(17411799)MechanismofActionDigitalisOtherstudySome evidence suggests that the benefits of digitalis may be related in part to enzyme inhibition in noncardiac tissues. Inhibition of Na-KATPaseinvagalafferentfibers acts to sensitize cardiac baroreceptors, which in turn reducessympatheticoutflow from the central nervous system.In addition, by inhibitingNa-KATPaseinthekidney, digitalis reduces the renal tubular reabsorption of sodium; the resulting increase in the delivery of sodium to the distal tubules leads to the suppressionofreninsecretion from the kidneys.ThamesMD.CircRes.1979;44:815.FergusonDWetal.Circulation.1989;80:6577.TorrettiJetal.AmJPhysiol.1972;222:1398405.50403020100Placebon=3403Digoxinn=3397480122436Mortality %NEnglJMed1997;336:525Monthsp=0.8N=6800NYHA II-IIIDIGtrail(1997)ACC/AHAHFguideline2009Long-termuseofaninfusionofapositiveinotropicdrugmaybeharmfulandisnotrecommendedforpatientswithcurrentorpriorsymptomsofHFandreducedLVEF,exceptaspalliationforpatientswithend-stagediseasewhocannotbestabilizedwithstandardmedicaltreatment(StageD).(ClassIII,Level of Evidence: C)Continuousintravenousinfusionofapositiveinotropicagentmaybeconsideredforpalliationofsymptomsinpatientswithrefractoryend-stageHF(StageD).(Class IIb, Level of Evidence: C)PhosphodiesteraseinhibitorThedifferentformsorsubtypesofphosphodiesterasewereinitiallyisolatedfromratbrainsbyUzunovandWeissin1972andweresoonafterwardsshowntobeselectivelyinhibitedinthebrainandinothertissuesbyavarietyofdrugsThepotentialforselectivephosphodisteraseinhibitorsastherapeuticagentswaspredictedasearlyas1977byWeissandHait.Thispredictionmeanwhilehasprovedtobetrueinavarietyoffields.Uzunov,P.andWeiss,BBiochim.Biophys.Acta284:220-226,1972Weiss,B.andHait,W.N.:Ann.Rev.Pharmacol.Toxicol.17:441-477,1977.Phosphodiesterase-3inhibitorPDEI cAMPAMPPDE3YuanJamesRao,(2009)MechanismofactionAs a result of its high expression in both the vasculature and the airways, PDE3 was identified as a potential therapeutic target in cardiovascular disease and asthma.-Augment myocardial contractility -Relax vascular and airway smooth muscle-Inhibit platelet aggregation -Induce lipolysisBARNESP.J.etal.Pharmacol.Rev.1988;40:4984.MANGANIELLOV.C.,etal.CellSignal.1995;7:445455.“IwishIhadmybeta-blockershandyHislandmarkinventionofpropranololin1964andtheH2-receptorantagonist,cimetidine,in1972earnedhimtheNobelPrizeinMedicinein1988.James W. Black -adrenoceptorReceptorBlockersMechanismofactionDensityof1receptorsInhibitcardiotoxicityofcatecholaminesNeurohormonalactivationHRAntiischemicAntihypertensiveAntiarrhythmicAntioxidant,Antiproliferative1001009090808060607070505024240 02020161612128 84 42828PlaceboPlaceboCarvedilolCarvedilolMonthsMonthsN=2289III-IVNYHANEJM 2001;344:1651NEJM 2001;344:1651Survival%Survival%p p=0.00014=0.0001435% RR 35% RR COPERNICUSStudy(2001)ACC/AHAHFguideline2009Useof1ofthe3betablockersproventoreducemortality(i.e.,bisoprolol,carvedilol,andsustainedreleasemetoprololsuccinate)isrecommendedforallstablepatientswithcurrentorpriorsymptomsofHFandreducedLVEF,unlesscontraindicated. (Class I, Level of Evidence: A)Whentostart?PatientstableNophysicalevidenceoffluidretentionNoneedforI.V.inotropicdrugsStartACE-I/diureticfirstStartLow,IncreaseSlowlyIncreasethedoseevery2-4weeksRisksoftreatmentFluidRetentionAndWorseningHF(intensification of conventional therapy)FatigureBradycardiaAndHeartBlockHypotension(block alpha-1receptors)Reviewtreatment(+/-diuretics,otherdrugs)ReducedoseConsidercardiacpacingDiscontinuebetablockeronlyinseverecasesHowshouldclinicaldeteriorationbemanagedinpatientswhohavebeentakingabetablockerforlongperiodsoftime(morethan3months)?ifpatientsdevelopfluidretention,withorwithoutmildsymptoms,itisreasonabletocontinuethebetablockerwhilethedoseofdiureticisincreased.Ifthedeteriorationinclinicalstatusischaracterizedbyhypoperfusionorrequirestheuseofintravenouspositiveinotropicdrugs,itmaybeprudenttohaltorsignificantlyreducetreatmentwithbetablockerstemporarilyuntilthestatusofthepatientstabilizes.Insuchpatients,positiveinotropicagentswhoseeffectsaremediatedindependentlyofthebetareceptor(e.g.,aphosphodiesteraseinhibitorsuchasmilrinone)maybepreferred.AdamsKF,Lindenfeld J,etal.HFSA2006HeartFailureGuideline.JCardFail2006;12:e1Usewithcautioninpatientswith:-Diabeteswithrecurrenthypoglycemia-Asthmaorrestinglimbischemia.lUsewithconsiderablecautioninpatientswithmarkedbradycardia(55bpm)ormarkedhypotension(SBP80mmHg).lNotrecommendedinpatientswithasthmawithactivebronchospasm.CONCLUSIONpVIEW1:LongtermpVIEW2:ComprehensivepVIEW3:FromBasictoClinicTHANKS FOR YOUR ATTENTION!