20 1 2008 2 Chinese Bulletin of Life Sciences Vol. 20, No.1 Feb, 2008 1004-0374(2008)01-0069-07 ( 210009) 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 ) 320 460ms 460ms LQTS QT 360 460ms (repolarization reservoir) 2007-07-05 2007-10-22 (30230170) * Email: dezaidai@vip.sina.com
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<300 320ms) 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 RyR2 10 40% [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]
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 10 5 2 1 2 (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
72 [36] ET-1 [37] ET A BQ123 PD142893 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) CPU0213 6 (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]
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 31 21 [61] calcineurin (RyR2 ) [62] [1] Schwartz P J. Management of long QT syndrome. Nat Clin Pract Cardiovasc Med, 2005, 2: 346-51 [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: 42-50 [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: 1349-54
74 [5] Schimpf R, Wolpert C, Gaita F, et al. Short QT syndrome. Cardiovasc Res, 2005, 67: 357-66 [6] Wehrens X H, Lehnart S E, Huang F, et al. FKBP12.6 deficiency and defective calcium release channel (ryanodine receptor) function linked to exercise-induced sudden cardiac death. Cell, 2003, 113: 829-40 [7] Doggrell S A. Stabilisation of calstabin2--a new approach in sudden cardiac death. Expe Opin Ther Targets, 2005, 9(5): 955-62 [8] Yano M, Kobayashi S, Kohno M, et al. FKBP12.6-mediated stabilization of calcium-release channel (ryanodinereceptor) as a novel therapeutic strategy against heart failure. Circulation, 2003, 107(3): 477-84 [9] Nakaya H, Furusawa Y, Ogura T, et al. Inhibitory effects of JTV-519, a novel cardioprotective drug, on potassium currents and experimental atrial fibrillation in guinea-pig hearts. Br J Pharmacol, 2000, 131: 1363-72 [10] Wehrens XH, Marks AR. Sudden unexplained death caused by cardiac ryanodine receptor (RyR2) mutations. Mayo Clin Proc, 2004, 79: 1367-71 [11] Sumitomo N, Harada K, Nagashima M, et al. Catecholaminergic polymorphic ventricular tachycardia: electrocardiographic characteristics and optimal therapeutic strategies to prevent sudden death. Heart, 2003, 89(1): 66-70 [12] George CH, Higgs GV, Lai FA. Ryanodine receptor mutations associated with stress-induced ventricular tachycardia mediate increased calcium release in stimulated cardiomyocytes. Circ Res, 2003, 93(6): 531-40 [13] Matolweni LO, Bardien S, Rebello G, et al. Arrhythmogenic right ventricular cardiomyopathy type 6 (ARVC6): support for the locus assignment, narrowing of the critical region and mutation screening of three candidate genes. BMC Med Genet, 2006, 28(7): 29 [14] Haverkamp W, Rolf S, Osterziel KJ, et al. Arrhythmogenic right ventricular cardiomyopathy. Herz, 2005, 30(6): 565-70 [15] Yu F, Dai DZ, An LF, et al. Heart hypertrophy induced by levothyroxine aggravates ischemic lesions and reperfusion arrhythmias in rats. Acta Pharmacol Sin, 1997, 18: 71-4 [16] Dai DZ, Hu HJ, Yang DM, et al. Chronic levothyroxin treatment is associated with ion channel abnormalities in cardiac and neuronal cells. Clin Exp Pharmacol Physiol, 1999, 26: 819-21 [17] Wang HL, Li SB, Dai DZ. Change on L type calcium current in single guinea pig hypertrophic ventricular myocytes induced by levothyroxine. J Chn Pharmaceut Univ, 2000, 31: 130-4 [18] Zhang GQ, Ma YP, Hao XM, et al. Rapidly activating delayed rectifier K + current and inward rectifier K + current in cardiomyocytes from hypertrophied guinea pig hearts induced by thyroxine. J Chn Pharmaceut Univ,2000,31: 451-4 [19] Zhang GQ, Hao XM, Ma YP, et al. Characteristics of the delayed rectifier K + current in guinea pig hypertrophied ventricular myocytes induced by thyroxin. Chn Pharmacol Bull, 2001. 17: 174-7 [20] Dai DZ. CPU86017: a novel class III antiarrhythmic agent with multiple actions at ion channels. Cardiovasc Drug Rev, 2006, 24: 100-114 [21],,. L- CPU86017., 2005, 29(9): 417-21 [22] Na T, Huang ZJ, Dai DZ, et al. Abrupt changes in expression of FKBP12.6 & SERCA2a contribute to sudden occurrence of ventricular fibrillation on reperfusion and are prevented by CPU86017. Acta Pharmacol Sin, 2007, 28: 773-82 [23] Wang YQ, Shi YP, Dai DZ. Therapeutic Effects of CPU86017 on acute and chronic congestive cardiac failure mediated by reducing ET-1, NOS and oxidative stress in rats. Drug Dev Res, 2004, 63: 22-32 [24] He HB, Dai DZ, Dai Y. Over-activated endothelin system involved in abnormal altered expression of calcium handling system in Isoproterenol stimulated rat heart failure model. J Pharmacol Pharm, 2007, 59(7): 977-84 [25] Qi MY, Xia HJ, Dai DZ, et al. A novel endothelin receptor antagonist CPU0213 improves diabetic cardiac insufficiency attributed to up-regulation of the expression of FKBP12.6, SERCA2a and PLB in rats. J Cardiovas Pharmacol, 2006, 47: 729-35 [26] Dai D Z. Two patterns of ion channelopathy in the myocardium: perspectives for development of anti-arrhythmic agents. Curr Opin Investig Drugs, 2005, 6: 289-97 [27] Gollob MH. Genetic profiling as a marker for risk of sudden cardiac death. Curr Opin Cardiol, 2006, 21: 42-6 [28] Chow BJ, Gollob M, Birnie D. Brugada syndrome precipitated by a tricyclic antidepressant. Heart, 2005, 91: 651 [29] Tomaselli GF, Zipes DP. What causes sudden death in heart failure? Circ Res, 2004, 95: 754-63 [30] Tester DJ, Spoon DB, Valdivia HH, et al. Targeted mutational analysis of the RyR2-encoded cardiac ryanodine receptor in sudden unexplained death: a molecular autopsy of 49 medical examiner/coroner, s cases. Mayo Clin Proc, 2004, 79(11):1380-4 [31] Miyauchi T, Masaki T. Pathophysiology of endothelin in the cardiovascular system. Annu Rev Physiol, 1999, 61: 391-415 [32] Dai DZ, Huang M, Ji M, et al. Endothelin receptor antagonist activity and selective blocking the ET A and ET B of compound 0213. J Chn Pharm Univ, 2004, 35(6): 552-7 [33] Horkay F, Geller L, Kiss O, et al. Bosentan the mixed endothelin-a-and-b-receptor antagonist suppresses intrapericardial endothelin-1-induced ventricular arrhythmias. J Cardiovasc Pharmacol, 2000, 36(5 Suppl 1): S320-2 [34] Ding Y, Zou R, Judd RL, et al. Endothelin-1 receptor blockade prevented the electrophysiological dysfunction in cardiac myocytes of streptozotocin-induced diabetic rats. Endocrine, 2006, 30(1): 121-7 [35] Kiesecker C, Zitron E, Scherer D, et al. Regulation of cardiac inwardly rectifying potassium current IK1 and Kir2.x channels by endothelin-1. J Mol Med, 2006, 84(1): 46-56 [36] Isaka M. Effects of endogenous endothelin 1 on norepinephrine release and arrhythmia in cardiac ischemia and reperfusion--a study by Langendorff perfusion system using
75 the heart excised from a guinea pig. Hokkaido Igaku Zasshi, 2005, 80(6): 605-10 [37] Isaka M, Kudo A, Imamura M, et al. Endothelin receptors, localized in sympathetic nerve terminals of the heart, modulate norepinephrine release and reperfusion arrhythmias. Basic Res Cardiol, 2007, 102(2): 154-62 [38] Baltogiannis GG, Tsalikakis DG, Mitsi AC, et al. Endothelin receptor--a blockade decreases ventricular arrhythmias after myocardial infarction in rats. Cardiovasc Res, 2005, 67(4): 647-54 [39] Kozak M, Izakovicova Holla L, Krivan L, et al. Endothelin- 1 gene polymorphism in patients with malignant arrhythmias. J Cardiovasc Pharmacol, 2004, 44: S92-S95 [40] Szucs A, Roka A, Soos P, et al. Effect of incessant ventricular tachyarrhythmias on serum endothelin and big-endothelin levels. J Cardiovasc Pharmacol, 2004, 44: S402-S406 [41] Feng Y, Tang XY, Dai DZ, et al. Reveral of isoproterenolinduced down regulation of phospholamban and FKBP 12. 6 by CPU02B-mediated antagonistn of endothelin recepors. Acta Pharmacol Sin, 2007, 28(11): 1746-54 [42] Xia HJ, Dai DZ, Dai Y. Up-regulated inflammatory factors endothelin, NFκB, TNF-α and inos involved in exaggerated cardiac arrhythmias in L-thyroxin induced cardiomyopathy are suppressed by Darusentan in rats. Life Sci, 2006, 79: 1812-9 [43] Xu FP, Chen MS, Wang YZ, et al. Leptin induces hypertrophy via endothelin-1-reactive oxygen species pathway in cultured neonatal rat cardiomyocytes. Circulation, 2004, 110 (10): 1269-75 [44] Piccirillo G, Magri D, Matera S, et al. QT variability strongly predicts sudden cardiac death in asymptomatic subjects with mild or moderate left ventricular systolic dysfunction: a prospective study. Eur Heart J, 2007, 28(11): 134-50 [45] Thomsen MB, Verduyn SC, Stengl M, et al. Increased shortterm variability of repolarization predicts d-sotalol-induced torsades de pointes in dogs. Circulation, 2004, 110: 2453-9 [46] Zabel M, Malik M. Predictive value of T-wave morphology variables and QT dispersion for postmyocardial infarction risk assessment. J Electrocardiol, 2001, 34 Suppl: 27-35 [47] Wang CL, Lee WL, Wu MJ, et al. Increased QTc dispersion and mortality in uremic patients with acute myocardial infarction. Am J Kidney Dis, 2002, 39(3): 539-48 [48] Ueda H, Nakayama Y, Tsumura K, et al. Intravenous nicorandil can reduce the occurrence of ventricular fibrillation and QT dispersion in patients with successful coronary angioplasty in acute myocardial infarction. Can J Cardiol, 2004, 20(6): 625-9 [49] Lopes NH, Grupi C, Dina CH, et al. QT interval dispersion analysis in acute myocardial infarction patients: coronary reperfusion effect. Arq Bras Cardiol, 2006, 87(2): 91-8 [50] Cui YJ, Yang P, Dai DZ, et al. CPU86017 suppresses tachyarrhythmias induced by ouabain and myocardial infarction: concentrations in plasma and different areas of the heart in dogs. Drug Dev Res, 2003, 58(1): 131-7 [51] Wang HL, Dai DZ, Gao F, et al. Dispersion of ventricular mrna of RyR2 and SERCA2 associated with arrhythmogenesis in rats. Acta Pharmacol Sin, 2004, 25(6): 738-43 [52] Huang ZJ, Dai DZ, Li Nret al. Calcium antagonist property of cpu228, a dofetilide derivative, contributes to its low incidence of torsades de pointes in rabbits. Clin Exp Pharmacol Physiol, 2007, 34(4): 310-7 [53] Rubart M, Zipes D P. Mechanisms of sudden cardiac death. J Clin Invest, 2005, 115: 2305-15 [54] Xiao JN, Luo XB, Lin HX, et al. MicroRNA mir-133 represses HERG K + channel expression contributing to QT. prolongation in diabetic hearts. J Biol Chem, 2007, 282(17): 12363-7 [55] Yang BF, Lin HX, Xiao JN, et al. The muscle-specific microrna mir-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med, 2007, 13(4): 486-91 [56] Xiao JN, Yang BF, Lin HX, et al. Novel approaches for genespecific interference via manipulating actions of micrornas: examination on the pacemaker channel genes HCN2 and HCN4. J Cell Physiol, 2007, 212(2): 285-92 [57] Brugada J, Brugada R, Brugada P. Channelopathies: a new category of diseases causing sudden death. Herz, 2007, 32(3): 185-91 [58] Taggart NW, Haglund CM, Tester DJ, et al. Diagnostic miscues in congenital long-qt syndrome. Circulation, 2007,115 (20):2613-20 [59] Wolpert C, Schimpf R, Veltmann C, et al. Short QT syndrome. Herz, 2007, 32(3): 206-10 [60] Borchert B, Lawrenz T, Stellbrink C. Long and short QT syndrome. Herzschrittmacherther Elektrophysiol, 2006, 17 (4): 205-10 [61] Zhang Y, Xiao J, Lin H,et al. Ionic mechanisms underlying abnormal QT prolongation and the associated arrhythmias in diabetic rabbits: a role of rapid delayed rectifier K + current. Cell Physiol Biochem, 2007, 19(5-6): 225-38 [62] Ren AJ, Yuan X, Lin L, et al. Arrhythmogenic action of endothelin-1(1-31) through conversion to endothelin-1(1-21). Exp Biol Med (Maywood), 2006 ; 231(6): 937-41 [63] Khoo MS, Li J, Singh MV, et al. Death, cardiac dysfunction, and arrhythmias are increased by calmodulin kinase II in calcineurin cardiomyopathy. Circulation, 2006, 114(11352-9)