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1、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TOPICSpExcitation-contraction(EC)couplingExcitationCalciumCyclingContractionpAlterationsofE-CcouplinginHFpInotropicagentsforHFExcitation-contractioncouplingThepoweroflocomotionisthatwhichcontractsandrelaxesthemuscleswherebythemembersandjointsaremoved,extendedorflexed.T
2、hispowerreachesthelimbsbywayofthenervesandthereareasmanyformsofpowerasthereareofmovement.Eachmusclehasitsownpeculiarpurposeanditobeysthedecreeofthecompositesense.Avicenna(11671248)WilliamHarvey(15781657)HewasanEnglishmedicaldoctor/physician,whoiscreditedwithbeingthefirsttocorrectlydescribe,inexactde
3、tail,thesystemiccirculationandpropertiesofbloodbeingpumpedaroundthebodybytheheart.Weshalldesignatetheentireseque-nceofreactions:excitation,inwardactinglink,andactivationofcontra-ctionbythetermexcitation-contractioncoupling.ALEXANDER SANDOW,1952(New York University)Sandow A.YaleJBiolMed . 1952.25 (3)
4、: 176201 Cardiacexcitationcontractioncouplingistheprocessfromelectricalexcitationofthemyocytetocontractionoftheheart(whichpropelsbloodout).TheubiquitoussecondmessengerCa2+isessentialincardiacelectricalactivityandisthedirectactivatorofthemyofilaments,whichcausecontraction.BersDM.Nature,2002,415(6868)
5、:198-205.ExcitationThecardiacactionpotentialAnotabledifferencebetweenskeletalandcardiacmyocytesishoweachelevatesthemyoplasmicCa2+toinducecontraction.Incardiacmyocytes,thereleaseofCa2+fromthesarcoplasmicreticulumisinducedbyCa2+influxintothecellthroughvoltage-gatedcalciumchannels.CalciumCyclingPictori
6、alOFCalciumCyclingCa+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+CardiactissueandcellsConductelectricalwavesContr
7、actinresponsetoanelectricalstimulus(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 m
8、achinery ContractionSlidingFilamentTheoryA.F.Huxley1954EMevidenceforslidingfilamenttheoryThemicrographshowsmyosinboundtoactinThemolecularbasisformyocardialcontractionThin filament (Actin ,Tropom-yosin, Troponin) Thick filament (Myosin)Other proteinsChien,K.R.,1999ZZTitin28,000 amino acids (3MDa) the
9、 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)molecularmotorofmusclecontracti
10、onG-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.etal.Nature424,3541,2003 HCTnCHCTnIHCTnTTropomyosinTropomyosinbinding regionHypervariable regionCrystalStructureofHumanCardiacTroponinGordonetal.2001Regulation
11、ofthinfilamentincontractionMuscleContractionAlterationsinE-CcouplinginHFRyR2channelleakHeart FailurePDE4D levelsloss of FKBP12.6RyR2 channel leakArrhythmia and progression of heart failure.JefferyDMolkentin.NatureMedicine11,1284-1285(2005)PLNSERCA2ainteractionsinphysiologicalanddiseasedcardiacfuncti
12、onStevenR.Houser.JMolCellCardiol32,15951607(2000)InotropicAgentsforHFInotropicAgentsand-blockerDigitalisPhosphodiesteraseinhibitor-adrenoceptorblockerDigitalis(200years)DigilispurpureaPurplefoxgloveWilliamWithering(17411799)MechanismofActionDigitalisOtherstudySome evidence suggests that the benefits
13、 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 r
14、educes 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;222:1398405.50403020100
15、Placebon=3403Digoxinn=3397480122436Mortality %NEnglJMed1997;336:525Monthsp=0.8N=6800NYHA II-IIIDIGtrail(1997)ACC/AHAHFguideline2009Long-termuseofaninfusionofapositiveinotropicdrugmaybeharmfulandisnotrecommendedforpatientswithcurrentorpriorsymptomsofHFandreducedLVEF,exceptaspalliationforpatientswithe
16、nd-stagediseasewhocannotbestabilizedwithstandardmedicaltreatment(StageD).(ClassIII,Level of Evidence: C)Continuousintravenousinfusionofapositiveinotropicagentmaybeconsideredforpalliationofsymptomsinpatientswithrefractoryend-stageHF(StageD).(Class IIb, Level of Evidence: C)PhosphodiesteraseinhibitorT
17、hedifferentformsorsubtypesofphosphodiesterasewereinitiallyisolatedfromratbrainsbyUzunovandWeissin1972andweresoonafterwardsshowntobeselectivelyinhibitedinthebrainandinothertissuesbyavarietyofdrugsThepotentialforselectivephosphodisteraseinhibitorsastherapeuticagentswaspredictedasearlyas1977byWeissandH
18、ait.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 b
19、oth 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.MANGANIEL
20、LOV.C.,etal.CellSignal.1995;7:445455.“IwishIhadmybeta-blockershandyHislandmarkinventionofpropranololin1964andtheH2-receptorantagonist,cimetidine,in1972earnedhimtheNobelPrizeinMedicinein1988.James W. Black -adrenoceptorReceptorBlockersMechanismofactionDensityof1receptorsInhibitcardiotoxicityofcatecho
21、laminesNeurohormonalactivationHRAntiischemicAntihypertensiveAntiarrhythmicAntioxidant,Antiproliferative1001009090808060607070505024240 02020161612128 84 42828PlaceboPlaceboCarvedilolCarvedilolMonthsMonthsN=2289III-IVNYHANEJM 2001;344:1651NEJM 2001;344:1651Survival%Survival%p p=0.00014=0.0001435% RR
22、35% RR COPERNICUSStudy(2001)ACC/AHAHFguideline2009Useof1ofthe3betablockersproventoreducemortality(i.e.,bisoprolol,carvedilol,andsustainedreleasemetoprololsuccinate)isrecommendedforallstablepatientswithcurrentorpriorsymptomsofHFandreducedLVEF,unlesscontraindicated. (Class I, Level of Evidence: A)When
23、tostart?PatientstableNophysicalevidenceoffluidretentionNoneedforI.V.inotropicdrugsStartACE-I/diureticfirstStartLow,IncreaseSlowlyIncreasethedoseevery2-4weeksRisksoftreatmentFluidRetentionAndWorseningHF(intensification of conventional therapy)FatigureBradycardiaAndHeartBlockHypotension(block alpha-1r
24、eceptors)Reviewtreatment(+/-diuretics,otherdrugs)ReducedoseConsidercardiacpacingDiscontinuebetablockeronlyinseverecasesHowshouldclinicaldeteriorationbemanagedinpatientswhohavebeentakingabetablockerforlongperiodsoftime(morethan3months)?ifpatientsdevelopfluidretention,withorwithoutmildsymptoms,itisrea
25、sonabletocontinuethebetablockerwhilethedoseofdiureticisincreased.Ifthedeteriorationinclinicalstatusischaracterizedbyhypoperfusionorrequirestheuseofintravenouspositiveinotropicdrugs,itmaybeprudenttohaltorsignificantlyreducetreatmentwithbetablockerstemporarilyuntilthestatusofthepatientstabilizes.Insuc
26、hpatients,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!
