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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
10、ventricular extrasystoles,Tian X et al 2007 BBRC,Optical Mapping Initiation of spontaneous VT/VF episode in TGM,Tian X et al 2007 BBRC,Optical Mapping Reentry mechanism is responsible for maintaining VT/VF episode,Tian X et al 2007 BBRC,Na+,ventricular action potential,Long QT Syndrome and Ventricul
11、ar Tachyarrhythmias (VT),Net increase in Na+i,Long QT,QT,Ventricle,Electrocardiogram (ECG),Identification of Dilated Cardiomyopathy and Heart Failure in TG-LQT3 Mice,Zhang T et al Unpublished Data,TG-LQT3,TG-WT,NTG,Gross morphology of whole hearts and LV transverse sections,Systole,Diastole,NTG,M-mo
12、de,Short axis image view,Echocardiographic Assessment,Systole,Diastole,TG-WT,M-mode,Short axis image view,Echocardiographic Assessment,Systole,Diastole,Echocardiographic Assessment,TG-LQT3,M-mode,Short axis image view,systolic dysfunction,TG-LQT3,NTG,TG-WT,Echocardiographic Assessment,LQTS and DCM/H
13、eart Failure in Humans,One patient with SCN5A mutation N1325S developed DCM, atrial fibirllation, and 1-degree AV block (Yong et al. BBRC 2007;352:378-383) Proband in a family with SCN5A mutation E1784K developed DCM at the age of 31 years (unpublished data) 60% of heart failure patients have prolon
14、ged QTc (Davey PP et al 2000 Clin Sci 98:603) Two mutation carriers in an LQT3 family with mutation delQKP 1507-1509 in SCN5A showed features of DCM (Shi R et al 2008 Europace 10:1329-35),LQTS and Heart Failure in Humans,*P 0.05, significant difference from control group P 0.05 , Significant differe
15、nce from hypertrophy group,Davey PP et al (2000) Clinical Science 98:603-610,Potential Causes of Dilated Cardiomyopathy and Heart Failure in TG-LQT3 Mice,Zhang T et al Unpublished Data,a,d,c,A,b,e,D,C,B,*,*,P=0.0015,P=0.0045,P=0.15,Detection of Cardiomyocyte Apoptosis in TG-LQT3,Caspase 3,P=0.040907
16、,P=0.034885,P=0.772707,Caspase 8 and 9 Activity Assays,*,Caspase 8,Caspase 9,Massons Trichrome Staining for Myocardial Fibrosis,NTG(x20),TG-WT(x20),TG-LQT3(x20),TG-LQT3(x40),collagen,nuclei,Cytoplasm muscle,Potential Causes of Cardiomyopathy Apoptosis in TG-LQT3 Mice,Yong S et al Unpublished Data,Na
17、-Ch,Ca-Ch,SERCA,Na/Ca exchanger,VENTRICULAR MYOCYTE,SR,RyR2,NTG cell,Na-Ch N1325S,Ca-Ch,SERCA,Na/Ca exchanger,VENTRICULAR MYOCYTE,SR,RyR2,TG-LQT3 cell,Intracellular Sodium Overload in TG-LQT3 Cardiomyocytes,10 ms,10 ms,10 ms,10 ms,10 ms,10 ms,10 ms,10 ms,10 ms,10 ms,10 ms,10 ms,10 ms,10 ms,10 ms,10
18、ms,10 ms,10 ms,0.1,0.1,0.1,0.1,0.1,0.1,0.1,0.1,0.1,NTG,TG-WT,TG-LQT3,+ Caff,Intracellular Calcium Abnormalities in TG-LQT3 Cardiomyocytes,Sodium Channel Blocker TTX Attenuates Intracellular Calcium Abnormalities in TG-LQT3 Cardiomyocytes,0 Extracellular Calcium Attenuates Intracellular Calcium Abnor
19、malities in TG-LQT3 Cardiomyocytes,No NCX Current in TG-LQT3 Cardiomyocytes,Conclusion,Cardiomyocyte Apoptosis,Progressive Loss of Cardiomyocytes,Replacement of Myocardial Fibrosis,Impaired Heart Structure (DCM),Defective Heart Function (HF),SCN5A N1325S mutation,Intracellular Calcium Overload,Late Sodium Current,LQTS VT Sudden Death,Intracellular Sodium Overload,NCX,?,