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1、抗心律失常药Anti-Arrhythmic Drug,抗心律失常课件,抗心律失常课件,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,Cardiac electrical activity and ECG,抗心律失常课件,Cardiac electrical activity an,Cardiac electrical activity,抗心律失常课件,Cardiac electrical activity抗心,Heterogeneous APs in heart,抗心律失常课件,Heterogeneous APs in heart抗心律失,Ion channels and AP
2、,0,1,2,3,4,INa,ICa.L,ITo1,INa-Ca,抗心律失常课件,Ion channels and AP01234INaICa,Ion currents underlying AP in ventricle,抗心律失常课件,Ion currents underlying AP in,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 und,心律失常发生机制,折返自律性升高后除极 早后除极 迟后除极基因缺陷,抗心律失常
3、课件,心律失常发生机制折返抗心律失常课件,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 an,预激综合症中房室折返环路的形成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Atrioventricula,心肌细胞的早后除极和迟后除极(Two forms of abnormal activity,early and delayed afterdepolarizatio
4、ns),抗心律失常课件,心肌细胞的早后除极和迟后除极(Two forms of ab,抗心律失常药物作用,降低自律性减少后除极消除折返,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,降低自律性的四种方式(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 reduc,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,Atrial flutter,抗心律失常课件,Atrial flutter 抗心律失常课件,At
5、rial fibrillation,抗心律失常课件,Atrial fibrillation抗心律失常课件,Atrial fibrillation,抗心律失常课件,Atrial fibrillation抗心律失常课件,Ventricular beat,抗心律失常课件,Ventricular beat抗心律失常课件,Ventricular fibrillation,抗心律失常课件,Ventricular fibrillation抗心律失常课,Cardiac arrhythmias,Tachy-cardiac arrhythmias-Atrial-premature beats-Atrial flu
6、tter-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-card,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,Summary of an
7、tiarrhythmic drugs,抗心律失常课件,Summary of antiarrhythmic drug,End!,抗心律失常课件,End!抗心律失常课件,Problems to be solved,Pro-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
8、 for Sick Sinus Syndrome.,抗心律失常课件,Problems to be solvedPro-arrhy,Pro-arrhythmia of antiarrhythmic drugs,抗心律失常课件,Pro-arrhythmia of antiarrhyth,Arrhythmogenic action in rabbit heart,Quinidine(5 M),E-4031(0.5 M),Asono et al.(1997)JMCC,29:831,抗心律失常课件,Arrhythmogenic action in rabbi,Lack of IKur in human
9、ventricle,Atrial cell,Ventricular cell,A Control,D Control,B 4-AP 50 M,C 4-AP-sensitive,E 4-AP 50 M,F 4-AP-sensitive,+50,50 mV,200pA,30 ms,Li et al(1996):Circ Res 78:689,抗心律失常课件,Lack of IKur in human ventricl,Ion currents in human atrium&ventricle,Atrium,Ventricle,抗心律失常课件,Ion currents in human atriu
10、m&,Human atrial IKur-A target for developing selective anti-atrial fibrillation drug,抗心律失常课件,Human atrial IKur-A target fo,Atrial Fibrillation(AF),AF is the most common arrhythmia in elderly persons,AF is a potent risk factor for ischemic stroke,increasing the risk of stroke 5-fold and accounting fo
11、r 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,Go,A.S.et al.JAMA 2001;285:2370-2375.,Projected Number of
12、 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;285,A 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 populatio
13、n-based study of th,It is important to develop selective anti-atrial fibrillation drugs,抗心律失常课件,It is important to develop sel,Life-threatening VF in heart failure,抗心律失常课件,Life-threatening VF in heart,Heart failure-mortality,15%,Within 1 year after diagnosis,Kannel,et al.Br Heart J 1994;72:S3-S9,抗心律
14、失常课件,Heart failure-mortality15%With,80%,In 6 years after diagnosis,Heart failure-mortality,Kannel,et al.Br Heart J 1994;72:S3-S9,抗心律失常课件,80%In 6 years after diagnosisH,Of deaths,up to 50%are sudden or unexpected,50%,Heart failure-mortality,Tendera 16:180,抗心律失常课件,Of deaths,up to 50%are sudde,Lethal a
15、rrhythmias:VT or VF,VF,VT,抗心律失常课件,Lethal arrhythmias:VT or VFVF,Prolongation 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 interv,Cellular mechanisms of arrhythmias in HF,EADs,Control,HF,抗心律失常课件,Cellular mechanisms of arrhyth,APs and Ito,IKs
16、 in dog ventricle,Liu et al.Circ.Res.1993;72:671,1995;76:351,抗心律失常课件,APs and Ito,IKs in dog ventri,Question 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,Dog HF model and human HF,Human explanted heart,抗心律失常课件,Dog HF
17、 model and human HFHuman,Regional ventricular cells,抗心律失常课件,Regional ventricular cells抗心律失,Endo,M cell,Epi,EADs,EADs,EADs,EADs in regional cells from dog HF,抗心律失常课件,EndoM cellEpiEADsEADsEADsEADs,No change of ICa in cells from dog HF,A,Control,Heart failure,-50 mV,0 mV,500 pA,100 ms,抗心律失常课件,No change
18、 of ICa in cells from,IK1 reduction in dog HF,Control,Heart failure,2 nA,100 ms,-40,A,B,抗心律失常课件,IK1 reduction in dog HFControl,Reduction of regional IK1 in dog HF,Control,TP(mV),-80,-70,-60,-50,-40,-30,Current(pA/pF),0,2,4,6,8,*,*,*,*,*,HF,-110,-90,-70,-50,-30,-30,-20,-10,0,10,HF,Control,*,*,*,*,*,*
19、,*,TP(mV),Current(pA/pF),A,B,抗心律失常课件,Reduction of regional IK1 in d,Reduction of regional Ito1 in dog HF,TP(mV),-30,0,30,60,2,4,6,8,10,Epi,M,Endo,A,TP(mV),-30,0,30,60,2,4,6,8,10,Epi,M,Endo,Control,Heart Failure,B,抗心律失常课件,Reduction of regional Ito1 in,Down-regulation of IKs in dog HF,Epi,M,Endo,IKs.t
20、ail(+30mV),B,Current(pA/pF),0,2,4,6,8,A,Control,Epi,M,Endo,400 pA,2 sec,抗心律失常课件,Down-regulation of IKs in dog,No change of IKr in dog HF,+40 mV,Control,E-4031,E-4031-sensitive,+20 mV,0 mV,*,*,*,*,*,I=0,A,170 pA,1.3 sec,+40 mV,-60,-,30,抗心律失常课件,No change of IKr in dog HF+40,抗心律失常课件,抗心律失常课件,No change o
21、f ICa in human HF,A,B,Control,HF,抗心律失常课件,No change of ICa in human HFTP,IK1 reduction in human HF,Control,Heart failure,Current(pA/pF),B,TP(mV),-100,-80,-60,-40,-20,-18,-15,-12,-9,-6,-3,0,3,Control,FH,*,*,A,TP(mV),-80,-60,-40,-20,0.0,0.5,1.0,1.5,2.0,2.5,*,*,*,*,*,抗心律失常课件,IK1 reduction in human HFCon
22、tr,Reduction of Ito1 in human HF,A,TP(mV),-30,0,30,60,pA/pF,2,4,6,8,10,Control,FH,*,*,*,*,*,*,*,Control,HF,B,抗心律失常课件,Reduction of Ito1 in human HFA,A,Control,HF,250 pA,1.2 sec,-50,+50,-30,B,Down-regulation of IKs in human HF,抗心律失常课件,AControlHF250 pA1.2 sec-50+50-,Summary,IKs,IK1,Ito1,抗心律失常课件,Summary
23、IKsIK1Ito1抗心律失常课件,Summary,0,EADs,抗心律失常课件,SummaryFibrillationVT0EADs抗心律,IK1,IKs activators,Future perspective,抗心律失常课件,IK1,IKs activatorsFuture pers,Sick Sinus Syndrome,抗心律失常课件,Sick Sinus Syndrome抗心律失常课件,Cardiac electrical activity,抗心律失常课件,Cardiac electrical activity抗心,ECGSick Sinus Syndrome,Bradycard
24、iac and tachycardia are seen in Sick Sinus Syndrome,抗心律失常课件,ECGSick Sinus SyndromeBradyca,Atriaficial pacemaker,抗心律失常课件,Atriaficial pacemaker抗心律失常课件,Threshold potential,Diastolic potential(60 mV),0,3,4,Pacemaker cell action potentials,ICa,IK,If,Pacemaker potential,Sinoatrial node(SA node),抗心律失常课件,Th
25、reshold potential Diastolic,Pacemaker potential and If,5 mV,From Difrancesco:Cardiovasc Res 1995;29:449-456,抗心律失常课件,Pacemaker potential and If,Modulation of If,A,C,B,From Difrancesco:Cardiovasc Res 1995;29:449-456,抗心律失常课件,Modulation of IfACBFrom Difran,If and cloned HCN channels,From Ludwig et al.:Nature 1998;393:587-591,HCN: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 channelsFrom,
