抗心律失常ppt课件

抗心律失常药抗心律失常药Anti-Arrhythmic Drug抗心律失常课件抗心律失常课件1正常心脏电生理正常心脏电生理抗心律失常课件正常心脏电生理抗心律失常课件2Cardiac electrical activity and ECG抗心律失常课件Cardiac electrical activity an3 Cardiac electrical activity抗心律失常课件 Cardiac electrical activity抗心4Heterogeneous APs in heart抗心律失常课件Heterogeneous APs in heart抗心律失5Ion channels and AP01234INaICa.LIKrIKsIK1IK1ITo1INa-Ca抗心律失常课件Ion channels and AP01234INaICa6Ion currents underlying AP in ventricleInward currentsINaICaINa/CaOutward currentsIK1Ito1IKrIKsIto2ITOSCN5ADHP receptorNCX1Kir2.xKv4.x?HERG/MiRP1KvLQT1/minKPossible cloneTTX,STX,lidocaineDHP,Cd2+,Co2+Ni+,NCX1-antibodyBa2+4-APDIDS,9-ACDofetilide,sotalolChromanol 293BBlockers抗心律失常课件Ion currents underlying AP in7窦房结细胞动作电位时程中的参与电流窦房结细胞动作电位时程中的参与电流（Currents underlying depolarization in SA nodal cells）抗心律失常课件窦房结细胞动作电位时程中的参与电流（Currents und8心律失常发生机制心律失常发生机制折返折返自律性升高自律性升高后除极后除极 早后除极早后除极 迟后除极迟后除极基因缺陷基因缺陷抗心律失常课件心律失常发生机制折返抗心律失常课件9折返形成机制折返形成机制(Unidirectional block and reentry)抗心律失常课件折返形成机制(Unidirectional block an10预激综合症中房室预激综合症中房室折返环路的形成折返环路的形成Atrioventricular reentry in the Wolff-Parkinson-White syndrome抗心律失常课件预激综合症中房室折返环路的形成Atrioventricula11心肌细胞的早后除心肌细胞的早后除极和迟后除极极和迟后除极(Two forms of abnormal activity,early and delayed afterdepolarizations)抗心律失常课件心肌细胞的早后除极和迟后除极(Two forms of ab12抗心律失常药物作用抗心律失常药物作用降低自律性降低自律性减少后除极减少后除极消除折返消除折返抗心律失常课件抗心律失常药物作用降低自律性抗心律失常课件13降低自律性的降低自律性的四种方式四种方式(Four ways to reduce the rate of spontaneous discharge in automatic tissues)抗心律失常课件降低自律性的四种方式(Four ways to reduc14心律失常类型心律失常类型抗心律失常课件心律失常类型抗心律失常课件15Atrial flutter 抗心律失常课件Atrial flutter 抗心律失常课件16Atrial fibrillation抗心律失常课件Atrial fibrillation抗心律失常课件17Atrial fibrillation抗心律失常课件Atrial fibrillation抗心律失常课件18Ventricular beat抗心律失常课件Ventricular beat抗心律失常课件19Ventricular fibrillation抗心律失常课件Ventricular fibrillation抗心律失常课20Cardiac arrhythmias Tachy-cardiac arrhythmias-Atrial-premature beats-Atrial flutter-Atrial fibrillation(AF)-Ventricular-premature beats(contractions)-Ventricular-tachycardia(VT)-Ventricular fibrillation(VF)Brady-cardiac arrhythmias-Bundle branch blocks-Sinus bradycardia(Sick Sinus Syndrome)抗心律失常课件Cardiac arrhythmias Tachy-card21抗心律失常药物分类抗心律失常药物分类抗心律失常课件抗心律失常药物分类抗心律失常课件22Summary of antiarrhythmic drugsClassDrug exampleActions UsesIaIbIcQuinidine,ProcainamideLidocaine,MexiletineFlecainide,EncainideBlock of INa,IK,and ICa,ADP,ERP,Velocity,ContractilityBlock of INa(fast dissociation),APD,ERPBlock of INa(slow dissociation),Velocity,ContractilityVT,AFVP VTIIPropranolol,MetoprololBlock of-adrenoceptor ContractilityAT,VTIIIDofetilide,IbutilideAmiodaroneBlock of IKr,ADPBlock of INa(Inac),IKr,ADPAF,ATIVVerapamil,Diltiazem Block of Ca2+channelsAPD,A-V velocityAFflutter抗心律失常课件Summary of antiarrhythmic drug23End!抗心律失常课件End!抗心律失常课件24Problems to be solvedPro-arrhythmias of antiarrhythmic drugsi.e.lack of selectivity when they are used to treat atrial fibrillation.No effective drugs for arrhythmias in patients with heart failure.No drugs available for Sick Sinus Syndrome.抗心律失常课件Problems to be solvedPro-arrhy25Pro-arrhythmia of antiarrhythmic drugs抗心律失常课件Pro-arrhythmia of antiarrhyth26Arrhythmogenic action in rabbit heartQuinidine(5 M)E-4031(0.5 M)Asono et al.(1997)JMCC,29:831 抗心律失常课件Arrhythmogenic action in rabbi27Lack of IKur in human ventricleAtrial cellVentricular cellA ControlD ControlB 4-AP 50 MC 4-AP-sensitiveE 4-AP 50 MF 4-AP-sensitive+50 50 mV200pA30 ms Li et al(1996):Circ Res 78:689抗心律失常课件Lack of IKur in human ventricl28Ion currents in human atrium&ventricleInward currentsOutward currentsINaICaINa/CaIK1Ito1IKurIKrIKsAtriumVentricle抗心律失常课件Ion currents in human atrium&29Human atrial IKur-A target for developing selective anti-atrial fibrillation drug抗心律失常课件Human atrial IKur-A target fo30Atrial Fibrillation(AF)AF is the most common arrhythmia in elderly personsAF is a potent risk factor for ischemic stroke,increasing the risk of stroke 5-fold and accounting for about 15%of all strokes in USA.Symptomatic AF may also reduce quality of life,functional status,and cardiac performance.It is associated with higher medical costs as well as an increased risk of death.抗心律失常课件Atrial Fibrillation(AF)AF is 31Go,A.S.et al.JAMA 2001;285:2370-2375.Projected Number of Adults With Atrial Fibrillation in the United States Between 1995 and 2050抗心律失常课件Go,A.S.et al.JAMA 2001;28532A population-based study of the long-term risks associated with atrial fibrillation 20-year follow-up of the Renfrew/Paisley study Stewart et al.Am J Med.2002;113:359-64抗心律失常课件A population-based study of th33It is important to develop selective anti-atrial fibrillation drugs抗心律失常课件It is important to develop sel34Life-threatening VF in heart failure抗心律失常课件Life-threatening VF in heart 35Heart failure-mortality15%Within 1 year after diagnosisKannel,et al.Br Heart J 1994;72:S3-S9抗心律失常课件Heart failure-mortality15%With3680%In 6 years after diagnosisHeart failure-mortalityKannel,et al.Br Heart J 1994;72:S3-S9抗心律失常课件80%In 6 years after diagnosisH37Of deaths,up to 50%are sudden or unexpected50%Heart failure-mortalityTendera&Ochala Curr Opin Cardiol 2001;16:180 抗心律失常课件Of deaths,up to 50%are sudde38Lethal arrhythmias:VT or VFVFVT抗心律失常课件Lethal arrhythmias:VT or VFVF39Prolongation of ECG Q-T interval in HF patients Choy et al.Am Heart J,1998;136:664-71抗心律失常课件Prolongation of ECG Q-T interv40Cellular mechanisms of arrhythmias in HFVTVFEADsControlHFDADsHF抗心律失常课件Cellular mechanisms of arrhyth41APs and Ito,IKs in dog ventricleLiu et al.Circ.Res.1993;72:671,1995;76:351抗心律失常课件APs and Ito,IKs in dog ventri42Question How the heterogeneous electrophysiology of the transmural ventricular wall is remodeled in heart failure?抗心律失常课件Question抗心律失常课件43Dog HF model and human HFHuman explanted heart抗心律失常课件Dog HF model and human HFHuman44Regional ventricular cells抗心律失常课件Regional ventricular cells抗心律失45EndoM cellEpiEADsEADsEADsEADs in regional cells from dog HF抗心律失常课件EndoM cellEpiEADsEADsEADsEADs 46No change of ICa in cells from dog HF AControlHeart failure-50 mV0 mV500 pA100 msTP(mV)-3003060ICa(pA/pF)-9-6-30EndoMEpimV-40-200204060ICa(pA/pF)-9-6-30EndoMEpiBCControlHeart failure抗心律失常课件No change of ICa in cells from47IK1 reduction in dog HFControlHeart failure 2 nA 100 ms-40-110 mVAB抗心律失常课件IK1 reduction in dog HFControl48Reduction of regional IK1 in dog HFControlTP(mV)-80-70-60-50-40-30Current(pA/pF)02468*HF-110-90-70-50-30-30-20-10010HFControl*TP(mV)Current(pA/pF)AB抗心律失常课件Reduction of regional IK1 in d49Reduction of regional Ito1 in dog HFTP(mV)-3003060246810Epi M Endo ATP(mV)-3003060246810EpiMEndoControlHeart FailureB抗心律失常课件Reduction of regional Ito1 in 50Down-regulation of IKs in dog HFEpiMEndoIKs.tail(+30mV)BCurrent(pA/pF)02468AControlEpiMEndoDEpiMEndo 400 pA 2 sec-60+50mV-30IKs.tail(+30 mV)Current(pA/pF)02468EpiMEndoHeart failureC 400 pA 2 sec抗心律失常课件Down-regulation of IKs in dog 51No change of IKr in dog HF+40 mVControlE-4031E-4031-sensitive+20 mV0 mV*I=0A170 pA 1.3 sec+40 mV-60-30 TP(mV)-20-10010203040IKr(pA/pF)0.00.20.40.60.81.0Epi M EndoEpi MEndoBControl:HF:抗心律失常课件No change of IKr in dog HF+40 52抗心律失常课件抗心律失常课件53No change of ICa in human HFTP(mV)-40-200204060Current(pA/pF)-12-10-8-6-4-20ControlHFABControlHF抗心律失常课件No change of ICa in human HFTP54IK1 reduction in human HFControlHeart failureCurrent(pA/pF)BTP(mV)-100-80-60-40-20-18-15-12-9-6-303Control FH*ATP(mV)-80-60-40-200.00.51.01.52.02.5*抗心律失常课件IK1 reduction in human HFContr55Reduction of Ito1 in human HFATP(mV)-3003060pA/pF246810ControlFH*ControlHFB抗心律失常课件Reduction of Ito1 in human HFA56AControlHF250 pA1.2 sec-50+50-30BTP(mV)-30-20-10 010 20 30 40 500.00.20.40.60.8ControlHF*Down-regulation of IKs in human HF抗心律失常课件AControlHF250 pA1.2 sec-50+50-57SummaryIKsIK1Ito1抗心律失常课件SummaryIKsIK1Ito1抗心律失常课件58SummaryFibrillationVT0EADs抗心律失常课件SummaryFibrillationVT0EADs抗心律59IK1,IKs activatorsFuture perspectiveEADs抗心律失常课件IK1,IKs activatorsFuture pers60Sick Sinus Syndrome抗心律失常课件Sick Sinus Syndrome抗心律失常课件61 Cardiac electrical activity抗心律失常课件 Cardiac electrical activity抗心62ECGSick Sinus SyndromeBradycardiac and tachycardia are seen in Sick Sinus Syndrome抗心律失常课件ECGSick Sinus SyndromeBradyca63Atriaficial pacemaker抗心律失常课件Atriaficial pacemaker抗心律失常课件64 Threshold potential Diastolic potential(60 mV)034Pacemaker cell action potentials ICaIKIf Pacemaker potentialSinoatrial node(SA node)抗心律失常课件 Threshold potential Diastolic65Pacemaker potential and If 35 mV85 mV5 mVFrom Difrancesco:Cardiovasc Res 1995;29:449-456抗心律失常课件Pacemaker potential and If 66Modulation of IfACBFrom Difrancesco:Cardiovasc Res 1995;29:449-456抗心律失常课件Modulation of IfACBFrom Difran67If and cloned HCN channelsFrom Ludwig et al.:Nature 1998;393:587-591HCN:Hyperpolarization-activated,cyclic nucleotide-gated channels,the HCN family includes the members HCN1-HCN4.抗心律失常课件If and cloned HCN channelsFrom68