心衰中的分子医学系列（英文）-课件.ppt

Series on Molecular Medicine in Heart FailureIon 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 of Case Western Reserve University and Cleveland Clinic Cleveland, Ohio, USA 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 duration is a consistent finding in heart failure Phenotypes of TG-LQT3 Mice Prolonged QTc High incidence of cardiac arrhythmias and sudden death Late INa current Optical MappingRepeated multiple ventricular extrasystoles Optical Mapping Initiation of spontaneous VT/VF episode in TGM Optical Mapping Reentry mechanism is responsible for maintaining VT/VF episode Identification of Dilated Cardiomyopathy and Heart Failure in TG-LQT3 Mice LQTS and DCM/Heart 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 BBRC 2007;352:378-383) Proband in a family with SCN5A mutation E1784K developed DCM at the age of 31 years (unpublished data) 60% of heart failure patients have prolonged QTc (Davey PP et al 2000 Clin Sci 98:603) Two mutation carriers in an LQT3 family with mutation delQKP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 Potential Causes of Dilated Cardiomyopathy and Heart Failure in TG-LQT3 Mice Masson’s Trichrome Staining for Myocardial Fibrosis Potential Causes of Cardiomyopathy Apoptosis in TG-LQT3 Mice 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 ms 10 ms 10 m