心衰中的分子医学系列(英文)-课件.ppt
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1、Series on Molecular Medicine in Heart Failure Ion Channel Remodeling in Heart Failure,Professor and Dean College of Life Science and Technology Huazhong University of Science and Technology And Professor, Director, Staff Center for Cardiovascular Genetics Cleveland Clinic Lerner College of Medicine
2、of Case Western Reserve University and Cleveland Clinic Cleveland, Ohio, USA,王擎(Qing K. Wang),Ion Channel Remodeling and Heart Failure,Heart failure is a major cause of sudden death About 50% of heart failure deaths are due to ventricular tachycardia (VT) Prolongation of the action potential duratio
3、n is a consistent finding in heart failure,Michael, G. et al. Cardiovasc Res 2009 81:491-499; doi:10.1093/cvr/cvn266,(A) Schematic cardiac action potential (AP) with phases and principal corresponding ion currents indicated,Na-Ch,Ca-Ch,SERCA,Na/Ca exchanger,VENTRICULAR MYOCYTE,SR,RyR2,NTG cell,Ca-me
4、diated excitation-contraction coupling,Copyright restrictions may apply.,Michael, G. et al. Cardiovasc Res 2009 81:491-499; doi:10.1093/cvr/cvn266,A schematic diagram showing the changes in Ca2+ handling and contractility and the potential compensatory function of ion-channel remodelling that causes
5、 action potential (AP) duration (APD) prolongation in congestive heart failure,Cardiac Sodium Channel,Cardiac Action Potential,in,out,phase 1,Cardiac Sodium Channel Nav1.5 and Heart Failure,Encoded by SCN5A gene On chromosome 3p21 220 kDa Highly expressed in heart Generate and propagate AP,Gain-of-F
6、unction Mutations in SCN5A Cause Long QT Syndrome (LQTS),Incomplete channel inactivation,OPEN,INACTIVE,CLOSED,N1325S,Late INa,Increased APD,Prolonged QTc,VT Sudden Death,N1325S,Not1,BstEII,BstEII,Not1,a-mMHCp,TG-LQT3 (SCN5A),hGH plA,Probe A,Probe B,Generation of Transgenic TG-WT and TG-LQT3 Mice,a-m
7、MHCp,TG-WT (SCN5A),hGH plA,Southern blot,Western blot,N1325S,1. TG-LQT3 (MTG): generated by transgenic overexpression of mutant SCN5A mutation N1325S in the mouse heart 2. TG-WT (WTG): generated by transgenic overexpression of wild type SCN5A in the mouse heart,-100 mV,-20 mV,60 ms,Only TG-LQT3 myoc
8、ytes generate late sodium current INa, L,Prolonged QTc High incidence of cardiac arrhythmias and sudden death Late INa current,Phenotypes of TG-LQT3 Mice,Telemetry Recordings,(Tian et al., 2004 Cardiovas Res),TG-LQT3 mice manifest the clinical features of the LQTS,sinus,PVCs (premature of ventricula
9、r contractions),VT (monomorphic) - VT (polymorphic) -,VF (polymorphic) or Torsades des Pointes (TdP) -,VF (fine or low “activity” frequency - cardiac arrest,(Tian et al., 2004),Tachycardia in TG-LQT3 Mice,Seizure in TG-LQT3 Mice,(Zhang T et al al. Unpublished Data),Optical Mapping Repeated multiple
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