1 QT (long QT syndrome LQTS) QT (short QT syndrome, SQTS) VF. CAST (cardiac arrhythmias suppressing trial) SWORD( survival with oral d-sotalol) Na +

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1 Chinese Bulletin of Life Sciences Vol. 20, No.1 Feb, (2008) ( ) Na + K + Ca 2+ K Ca 2+ : FKBP12.6 R542.2 A CAST (cardiac arrhythmias suppressing trial) SWORD( survival with oral d-sotalol) Na + Ikr d- (d-sotalol) Na + K + Ca 2+ (sodium-calcium exchanger, NCX) (sarcoplasmic reticulum) Ca 2+ ( ryanodine receptor type RyR 2 RyR2) Ca 2+ (sarco/endoplasmic reticulum ATPase 2a SERCA2a 2a ) ( calcium handling proteins) (gap proteins) connexin 43 (CX43) (VF) 1 QT (long QT syndrome LQTS) QT (short QT syndrome, SQTS) VF LQTS [1] LQTS KCNQ1 (LQT1- KvLQT1 IKs α ) KCNH2 (LQT2 HERG IKr) KCNE1(LQT5 HMINK IKs β ) KCNE2 (LQT6) SCN5A (LQT3 INa) LQT1 LQT2 (IKr IKs) APD( ) (delayed after depolarization, DAD) (torsades de piontes Tdp) VF ( non-reentrant mechanism) LQT2 [2] HERG QT 520ms [3] HERG HMINK LQTS QTc( QT ) ms 460ms LQTS QT ms (repolarization reservoir) ( ) * dezaidai@vip.sina.com

2 70 I Kr (KCNH2) I Ks (KCNQ1) I K1 (KCNJ2) (gain of function mutation) [4,5] K + APD SQTS VF Brugada [4] KCNH2 QTc (QTc< ms) SQTS IKr IKr d-sotalol K588D IKr Asp LQT2 SQTS 2 RyR2 [6] ICa.L RyR2 (FKBP12.6 calstabin 2) β- camp PKA RyR2 FKBP12.6 RyR2 RyR2 (calcium leak) [6] ( ) DAD( ) Tdp VF ( triggered activity) FKBP12.6 RyR2 [7] FKBP12.6 RyR2 RyR2 [8] JTV519 [9] FKBP12.6 RyR2 RyR2 RyR2 FKBP12.6 [10] [11,12] CPVT RyR % [11] (arrhythmic right ventricular cardiomyopathy/dysplasia, ARVC/D) [13,14] RyR2 3 L- ( ) [15] 10min VF / VF APD( ) ICa.L [16,17] IKr [18] IKs [19] IKr IKs SQTS [4] SQTS ICa.L Cav1.2 ICa.L APD LQTS LQTS APD APD ( / ) VF CPU86017 VF III [20] [21] RyR2 FKBP12.6 [6,11] L- RyR2 FKBP12.6 SERCA2a PLB(phospholamban ) [22]

3 71 [23] [24] RyR2 FKBP12.6 Ry R 2 FKBP126 SERCA2a PLB [25] ( ) RyR2 FKBP12.6 RyR2 FKBP12.6 β- [26] 4 [2] HERG 10% 20% RyR2 10% 20% [27] LQTS (marker) LQTS APD [28] [22,26] Tomaselli Zipes [29] [2,26] (1) (2) VF 49 DNA [30] 1/3 7 RyR2 10 LQTS( LQT1 5 LQT2 3 LQT3 2 ) 8:2 2/3 LQTS (arousal) (mrna ) VF PKA RyR2 (gating protein)fkbp12.6 (IKr IKs) (ICa.L) PKC (calmodulin) 5 (ET-1 ET) prepro-et-1( ) ECE( ) ETAR ETBR [31] big-et-1 ECE 31 ET- 1 ET ET A R ET B R ET A R ET B R bosentan ET A R CPU0213 bosentan [32] ET ET bosentan ET [33] BQ610 (ventricular tachycardia VT) VF FR139317(ET A ) SB209670(ET A /ET B ) (33.3mM) QT (Ito IKr IKs) APD bosentan K + APD [34] ET IK1 Kir2.0x [35] ET A /ET B

4 72 [36] ET-1 [37] ET A BQ123 PD ET ET-1 VT VF ET A BQ123 24h VT/VF [38] ET-1 [39] VT/VF big ET-1 ET-1 [40] ET A ET A/B ET A CPU0213 CPU0213 VF [41] ET A darusentan VF [42] ET (reactive oxygen species ROS) ET ROS ET-ROS [43] NF-κB( nuclear factor κ B) TNFα ET TGFβ NF-κB TNFα TGFβ ET inos [42] ET β- PKA PKA (RyR2 F KBP12.6 SERCA2a PLB) FKBP12.6 PLB [41] (calcium transients) CPU (dispersion of reperfusion) [43] APD [44] QTc(QTc=QT/(R-R) 1/2 ) ( d-sotalol) QTc Tdp [45] [46] VF [47] 9 QTc [48] QTc QTc CPU86017( III ) QTc [49] 15d (ISO) Langendorff ( )/ VF RyR2 SERCA2a mrna ISO NCX1( 1) mrna CPU86017 VF ( RyR2 SERCA2) NCX1 [49] PKA / VF ICa.L ISO ICa.L ( ) III CPU86017 ICa.L ICa.L RyR2 ICa.L RyR2 (dofetilide) Tdp [50]

5 73 7 VF [51] (VF) 10min 1 3min VF 9 (mrna ) 10min 1 3min VF 9 VF FKBP12.6 ECE( ) PKA [25] CPU86017 VF PKA FKBP12.6 VF FKBP12.6 LQTS SQTS VF VF ET 8 MicroRNA RNA mir-133 Langendorff mir-133 HERG(IKr) LQTS [54] mir-1 GJA1 ( CX43) KCNJ2( Kir2.1 ) [55] mirna HCN2 HCN4 [56] LQTS LQTS Brugada LQTS SQTS [57] LQTS QT LQTS 78% [58] QT (SQTS) [59,60] QT QT APD(QT) III ibutilide ( ) Ia [57,59] QTc 20% Ito IKr IKs 60% 70% 40% ICaL APD IKr [60] β- IKs APD ET [61] calcineurin (RyR2 ) [62] [1] Schwartz P J. Management of long QT syndrome. Nat Clin Pract Cardiovasc Med, 2005, 2: [2] Dai D Z, Zhang G Q, Yang P, et al. Two patterns of ion channelopathies relating to arrhythmias and direct and indirect blockade of ion channels by antiarrrhythmic agents. Drug Dev Res, 2003, 58: [3], Armstrong M,,. PCR-SSCP MINK.,1999, 21(5): 14-6 [4] Brugada R, Hong K, Cordeiro J M, et al. Short QT syndrome. CMAJ, 2005, 173:

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