心衰中分子醫(yī)學系列英文

1、心衰中分子醫(yī)學系列英文Ion Channel Remodeling and Heart FailureHeart failure is a major cause of sudden deathAbout 50% of heart failure deaths are due to ventricular tachycardia (VT)Prolongation of the action potential duration is a consistent finding in heart failureMichael, G. et al. Cardiovasc Res 2009 81:49

2、1-499; doi:10.1093/cvr/cvn266(A) Schematic cardiac action potential (AP) with phases and principal corresponding ion currents indicatedNa-ChCa-ChSERCANa/CaexchangerVENTRICULARMYOCYTESRRyR2NTG cellCa-mediated excitation-contraction couplingCopyright restrictions may apply.Michael, G. et al. Cardiovas

3、c Res 2009 81:491-499; doi:10.1093/cvr/cvn266A schematic diagram showing the changes in Ca2+ handling and contractility and the potential compensatory function of ion-channel remodelling that causes action potential (AP) duration (APD) prolongation in congestive heart failureCardiac Sodium ChannelCa

4、rdiac Action Potentialinoutphase 1Cardiac Sodium Channel Nav1.5 and Heart FailureEncoded by SCN5A geneOn chromosome 3p21220 kDaHighly expressed in heartGenerate and propagate APIIIIVIIIN1325SGain-of-Function Mutations in SCN5A Cause Long QT Syndrome (LQTS)Incomplete channel inactivationOPENINACTIVEC

5、LOSEDN1325SLate INaIncreased APDProlonged QTcVTSudden DeathN1325SNot1BstEIIBstEIINot1a-mMHCpTG-LQT3 (SCN5A)hGH plAProbe AProbe BGeneration of Transgenic TG-WT and TG-LQT3 Micea-mMHCpTG-WT (SCN5A)hGH plASouthern blotWestern blotN1325S1. TG-LQT3 (MTG): generated by transgenic overexpression of mutant

6、SCN5A mutation N1325S in the mouse heart2. TG-WT (WTG): generated by transgenic overexpression of wild type SCN5A in the mouse heart -100 mV-20 mV60 msOnly TG-LQT3 myocytes generate late sodium current INa, LProlonged QTcHigh incidence of cardiac arrhythmias and sudden deathLate INa currentNTGTGLQT3

7、0 pAinward sodium current-2000 pATG-WTLate sodium currentQTTGPhenotypes of TG-LQT3 MiceTelemetry Recordings(Tian et al., 2004 Cardiovas Res)QTc= RR/QTTG-LQT3 mice manifest the clinical features of the LQTSsinusPVCs (premature of ventricular contractions)VT (monomorphic) - VT (polymorphic) -VF (polym

8、orphic) or Torsades des Pointes (TdP) -VF (fine or low “activity” frequency - cardiac arrest(Tian et al., 2004)Tachycardia in TG-LQT3 MiceSeizure in TG-LQT3 Mice(Zhang T et al al. Unpublished Data)Optical MappingRepeated multiple ventricular extrasystoles Tian X et al 2007 BBRCOptical Mapping Initia

9、tion of spontaneous VT/VF episode in TGM Tian X et al 2007 BBRCOptical Mapping Reentry mechanism is responsible for maintaining VT/VF episode Tian X et al 2007 BBRCNa+ventricular action potentialLong QT Syndrome and Ventricular Tachyarrhythmias (VT)Net increase in Na+iLong QTQTVentricleElectrocardio

10、gram (ECG)Identification of Dilated Cardiomyopathy and Heart Failure in TG-LQT3 MiceZhang T et al Unpublished DataTG-LQT3TG-WTNTGGross morphology of whole hearts and LV transverse sectionsSystoleDiastoleNTGM-modeShort axis image viewEchocardiographic AssessmentSystoleDiastoleTG-WTM-modeShort axis im

11、age viewEchocardiographic AssessmentSystoleDiastoleEchocardiographic AssessmentTG-LQT3M-modeShort axis image viewsystolic dysfunctionTG-LQT3NTGTG-WTEchocardiographic AssessmentLQTS and DCM/Heart Failure in HumansOne patient with SCN5A mutation N1325S developed DCM, atrial fibirllation, and 1-degree

12、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 1507-15

13、09 in SCN5A showed features of DCM (Shi R et al 2008 Europace 10:1329-35)LQTS and Heart Failure in HumansECG ParametersControl(n = 16)Hypertrophy(n = 16)HF(n = 34)Heart rate at rest (beats/min)743684863*Mean QT (ms)3766393103799Mean QTc (ms)410740384357*Lead II QT at rest (ms)3816399940011Lead II QT

14、c at rest (ms)4216420647110*P 0.05, significant difference from control groupP 0.05 , Significant difference from hypertrophy groupDavey PP et al (2000) Clinical Science 98:603-610Potential Causes of Dilated Cardiomyopathy and Heart Failure in TG-LQT3 MiceZhang T et al Unpublished DataadcAbeDCBP=0.7

15、35P=1.80088E-10*P=0.0015P=0.0045P=0.15P=3.90744E-07P=0.417Detection of Cardiomyocyte Apoptosis in TG-LQT3Caspase 3Caspase3 Activity AssayTG-LQT3TG-WTNTG0153045607590105Cleavage of pNA umol/mg protein 1 hrP=0.040907P=0.034885P=0.772707Caspase 8 and 9 Activity Assays*Caspase 8Caspase 9Massons Trichrom

16、e Staining for Myocardial FibrosisNTG(x20)TG-WT(x20)TG-LQT3(x20)TG-LQT3(x40)collagennucleiCytoplasmmusclePotential Causes of Cardiomyopathy Apoptosis in TG-LQT3 MiceYong S et al Unpublished DataNa-ChCa-ChSERCANa/CaexchangerVENTRICULARMYOCYTESRRyR2NTG cellNa-Ch N1325SCa-ChSERCANa/CaexchangerVENTRICUL

17、ARMYOCYTESRRyR2TG-LQT3 cellIntracellular SodiumOverloadin TG-LQT3 Cardiomyocytes10 ms10 ms10 ms10 ms10 ms10 ms10 ms10 ms10 ms10 ms10 ms10 ms10 ms10 ms10 ms10 ms10 ms10 ms0.10.10.10.10.10.10.10.10.1NTGTG-WTTG-LQT3+ Caff0.00.10.20.30.40.50.00.10.20.30.40.5012345152025012345152025Transient Amplitude (F

18、O/F)Time to 90% Recovery (T90r ms)*TG-LQT3NTGTG-WT- Caff- Caff+ Caff+ Caff*Intracellular Calcium Abnormalities in TG-LQT3 CardiomyocytesSodium Channel Blocker TTX Attenuates Intracellular Calcium Abnormalities in TG-LQT3 Cardiomyocytes0 Extracellular Calcium Attenuates Intracellular Calcium Abnormalities in TG-LQT3 CardiomyocytesNo NCX Current in TG-LQT3 Cardiom