進階搜尋


 
系統識別號 U0026-0812200911565936
論文名稱(中文) 探討安德森氏症所引發心律不整之細胞機制的模擬研究
論文名稱(英文) Simulation studies of cellular arrhythmogenic mechanisms in patients with Andersen-Tawil syndrome
校院名稱 成功大學
系所名稱(中) 生理學研究所
系所名稱(英) Department of Physiology
學年度 94
學期 2
出版年 95
研究生(中文) 吳俊賢
研究生(英文) Jiun-Shain Wu
學號 s3692104
學位類別 碩士
語文別 英文
論文頁數 67頁
口試委員 召集委員-潘偉豐
口試委員-羅錦興
指導教授-吳勝男
中文關鍵字 安德森氏症  心律不整 
英文關鍵字 Andersen’s syndrome  Long QT  Simulation  Ventricular arrhythmias 
學科別分類
中文摘要 目前已知安德森氏症是由於染色體的基因(KCNJ2)多處突變,導致向內修正鉀離子通道(Kir2.1)失去功能所致。在診斷上已知的徵兆包含生長畸形、週期性麻痺、和心律不整等。為了探討安德森氏症的生理機制以及致病機轉,我們使用了修正後的心臟動態模型(LRD Model)來進行電腦的模擬。在此模型中,我們為了更精確地計算實際上所面臨的問題,加入了動態模擬的鉀離子電流運算公式。為了進一步了解KCNJ2基因突變對於心臟動作電位的影響,我們採用了馬可夫的機率方程來模擬鉀離子通道的分子行為以及電流變化。實驗中我們發現,若逐步地抑制Kir2.1的導電性將換導致心臟動作電位興奮後復極化所需的時間增長,並且使得靜止模電位產生去極化的現象。當抑制的情形到達百分之九十的時候,會在心臟動作電位上產生早期再極化(Early afterdepolarization),靜止膜電位則去極化至-55毫伏特(對照組:-90毫伏特),並進一步造成自發性的動作電位產生(Spontaneous action potential),進而造成心律不整。此時若是細胞外的鉀離子升高,會加速上述的現象產生;反之若是細胞外鉀離子濃度下降,則可減緩或避免心律不整的情形。腎上腺素刺激除了加速造成心律不整的情形之外,還會進一步造成晚期再極化(Delayed afterdepolarization)。根據這些實驗模擬的結果我們可以推論安德森氏症所引發的心律不整可能藉由下列因素造成:(1)早期或晚期再極化的發生,(2)不正常的自發性動作電位。此外鉀離子濃度的下降以及腎上腺素刺激的作用對心律不整有加成的作用,是故安德森氏症的病人若同時患有低鉀型週期性麻痺,運動時很可能會造成心律不整的發生。
英文摘要 Patients with Andersen-Tawil syndrome (ATS) mostly have different mutations on the KCNJ2 genes producing loss of function or dominant-negative suppression of the inward rectifier K+ channel Kir2.1. However, clinical manifestations of ATS including dysmorphic features, periodic paralysis (hypo-, hyper-, or normokalemic), long QT, and ventricular arrhythmias (VA) are considerably variable. Using a modified dynamic Luo-Rudy simulation model of cardiac ventricular myocyte, we elucidated the mechanisms of VA in ATS. We adopted a kinetic model of KCNJ2 in which channel block by Mg+2 and spermine was incorporated. In this study, we attempted to examine the effects of KCNJ2 mutations on the ventricular action potential (AP), single-channel Markovian models were reformulated and incorporated into the dynamic Luo-Rudy model for rapidly and slowly delayed rectifying K+ currents and KCNJ2 channel. During pacing at 1.0 Hz with [K+]o at 5.4 mM, a stepwise 10% reduction of Kir2.1 channel conductance progressively prolonged the terminal repolarization phase of AP along with gradual depolarization of the resting membrane potential (RMP). At 90% reduction, early after-depolarizations (EADs) became inducible and RMP was depolarized to -55.0 mV (control: -90.1 mV) followed by emergence of spontaneous action potentials (SAP). Both EADs and SAP were facilitated by a decrease in [K+]o and suppressed by increase in [K+]o. -adrenergic stimulation enhanced delayed after-depolarizations (DADs) and could also facilitate EADs as well as SAP in the setting of low [K+]o and reduced Kir2.1 channel conductance. In conclusion, the spectrum of VA in ATS includes (a) triggered activity mediated by EADs and/or DADs, and (b) abnormal automaticity manifested as SAP. These VA can be aggravated by a decrease in [K+]o and -adrenergic stimulation, and cause sudden death. In patients with ATS, the hypokalemic form of periodic paralysis should have the highest propensity to VA especially during physical activities.
論文目次 Acknowledgement 2
Abstract 4
中文摘要 6
Introduction 7
Material and Methods 9
Results 11
Effects of reduction of Kir2.1 channel conductance on APD and RMP 11
Effects of Kir2.1 channel conductance on IK1, ICa,L, and INCX 12
Effects of reduction of Kir2.1 conductance on [Ca+2]i, Irel, [Ca+2]JSR, and [Ca+2]NSR 13
Effects of changes in [K+]o with reduction of Kir2.1 channel conductance 13
Influences of -adrenergic stimulation 15
Discussion 17
Limitations of the study 26
Clinical Implications 27
References 28
Tables 34
Figures 37
Appendix: LRD model c++ code 50
參考文獻 Ai T, Fujiwara Y, Tsuji K, Otani H, Nakono S, Kubo Y, Horie M. Novel KCJN2 mutation in familial periodic paralysis with ventricular dysrhythmia. Circulation 105: 2592-2594, 2002.
Andelfinger G, Tapper AR, Welch RC, Vanoye CG, George AL Jr, Benson DW. KCJN2 mutation results in Anderson syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Gene 71: 663-668, 2002.
Andersen ED, Krasilnikoff PA, Overvad H. Intermittent muscular weakness, extrasystoles and multiple developmental abnormalities: a new syndrome? Acta Paediat Scand 60: 559-564, 1971.
Antzelevitch C, Sicouri S. Clinical relevance of cardiac arrhythmias generated by afterdepolarizations: role of M cells in the generation of U waves, triggered activity and torsade de pointes. J Am Coll Cardiol 23: 259-277, 1994.
Bendahhou S, Donaldson MR, Plaster NM, Tristani-Firouzi M, Fu YH, Ptacek LJ. Defective potassium channel Kir2.1 trafficking underlies Andersen-Tawil syndrome. J Biol Chem 278: 51779-51785, 2003.
Bendahhou S, Fournier E, Sternberg D, Bassez G, Furby A, Sereni C, Donaldson MR, Larroque MM, Fontaine B, Baehanin J. In vivo and in vitro functional characterization of Andersen's syndrome mutations. J Physiol 565: 731-741, 2005.
Canun S, Perez N, Beirana LG. Andersen syndrome: autosomal dominant in three generations. Am J Med Genet 85: 147-156, 1999.
Choi BR, Burton F, Salama G. Cytosolic Ca+2 triggers early afterdeplarizations and torsade de pointes in rabbit hearts with type 2 long QT syndrome. J Physiol 543: 615-631, 2002.
Chun TU, Epstein MR, Dick M II, Andelfinger G, Ballester L, Vanoye CG, George AL Jr, Benson DW. Polymorphic ventricular tachycardia and KCNJ2 mutations. Heart Rhythm 1: 235-241, 2004.
Clancy CE, Rudy Y. Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death. Cariovasc Res 50: 301-313, 2001.
Donaldson MR, Jensen JL, Tristani-Firouzi M, Tawil R, Bendahhou S, Suarez WA, Cobo AM, Poza JJ, Behr E, Wagstaff J, Szepetowski P, Pereira S, Mozaffar T, Escolar DM, Fu YH, Ptacek LJ. PIP2 binding residues of Kir2.1 are common targets of mutations causing Andersen syndrome. Neurology 60: 1811-1816, 2003.
Doupnik CA, Davidson N, Lester HA. The inward rectifier potassium channel family. Curr Opin Neurobiol 5: 268-277, 1995.
Faber GM, Rudy Y. Action potential and contractility changes in [Na]i overload cardiac myocytes: a simulation study. Biophys J 78: 2392-2404, 2000.
Hosaka Y, Hanawa H, Washizuka T, Chiunshi M, Yamashita F, Yoshita T, Komura S, Watanabe H, Aizawa Y. Function, subcellular localization and assembly of a novel mutation of KCNJ2 in Andersen’s syndrome. J Mol Cell Cardiol 35: 409-415, 2003.
Jongsma HJ, Wilders R. Channelopathies: Kir2.1 mutations jeopardize many cell functions. Cur Biol 11: R747-R750, 2001.
Kannankeril PJ, Roden DM, Fish FA. Suppression of bidirectional ventricular tachycardia and unmasking of prolong QT interval with verapamil in Andersen’s syndrome. J Cardiovasc Electrophysiol 15: 119, 2004.
Katra RP, Laurita KR. Cellular mechanism of calcium-mediated triggered activity in the heart. Circ Res 96: 535-542, 2005.
Koumi SI, Backer CL, Arentzen CE, Sato R. -adrenergic modulation of the inwardly rectifying potassium channel in isolated human ventricular myocytes. Alteration in channel response to -adrenergic stimulation in failing human hearts. J Clin Invest 96: 2870-2881, 1995.
Kubo Y, Baldwin TJ, Jan YN, Jan LN. Primary structure and functional expression of a mouse inward rectifier potassium channel (see comments). Nature 362: 127-133, 1993.
Lange PS, Er F, Gassanov N, Hoppe UC. Andersen mutations of KCNJ2 suppress the native inward rectifier current IK1 in a dominant-negative fashion. Cardiovasc Res 59: 321-327, 2003.
Liu GX, Derst C, Schlichthorl G, Heinen S, Seebohm G, Bruggermann A, Kummer W, Veh RW, Daut J, Preisig-Muller R. Comparison of cloned Kir2 channels with native inward rectifier K+ channels from guinea-pig cardiomyocytes. J Physiol 532: 115-126, 2001.
Lopatin AN, Nicholis CG. Inward rectifiers in the heart: an update on IK1. J Mol Cell Cardiol 33: 625-638, 2001.
Lopatin AN, Nichols CG. Inward rectification of outward rectifying DRK1 (Kv2.1) potassium channels. J Gen Physiol 103: 203-216, 1994.
Luo CH, Rudy Y. A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. Circ Res 74: 1071-1096, 1994.
Marban E, Robinson SW, Wier WG. Mechanisms of arrhythmogenic delayed and early afterdepolarizations in ferret ventricular muscle. J Clin Invest 78: 1185-1192, 1986.
Matsuda H. Effects of external and internal K+ ions on magnesium block of inwardly rectifying K+ channels in guinea-pig heart cells. J Physiol 435: 83-99, 1991.
Matsuoka S, Sarai N, Jo H, Noma A. Simulation of ATP metabolism in cardiac excitation-contraction coupling. Prog Biophys Mol Biol 85: 279-299, 2004.
Mazzanti M, DiFrancesco J. Intracellular Ca modulates K-inward rectifier in cardiac myocytes. Pflugers Archiv 413: 322-324, 1990.
McLerie M, Lopatin A. Dominant-negative suppression of Ik1 in the mouse heart leads to altered cardiac excitability. J Mol Cell Cardiol 35: 367-378, 2003.
Miake M, Marban E, Nuss HB. Biological pacemaker created by gene transfer. Nature 419: 132-133, 2002.
Miake M, Marban E, Nuss HB. Functional role of inward rectifier current in heart probed by Kir2.1 overexpression and dominant-negative suppression. J Clin Invest 111: 1529-1536, 2003.
Nichols CG, Makhina EN, Pearson WL, Sha Q, Lopatin AN. Inward rectification and implications for cardiac excitability. Circ Res 78: 1-7, 1996.
Noble D. Ionic mechanisms in cardiac electrical activity. In: Cardiovascular Electrophysiology, edited by Zipes DP and Jalife J. Philadelphia, PA: Saunders, 1995.
Nuss HB, Kabb S, Kass DA, Tomaselli GF, Marban E. Cellular basis of ventricular arrhythmias and abnormal automaticity in heart failure. Am J Physiol 277: H80-H91, 1999.
Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL Jr, Fish A, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu YH, Ptacek LJ. Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen’s syndrome. Cell 105: 511-519, 2001.
Preisig-muller R, Schlichthorl G, George T, Heinen S, Bruggemann A, Rajan S, Derst C, Veh RW, Daut J. Heteromerization of Kir2.x potassium channels contribute to the phenotype of Andersen’s syndrome. Proc Natl Acad Sci USA 99: 7774-7779, 2002.
Ptacek LJ, George AL Jr, Griggs RC, Tawil R, Kallen RG, Bardi RL, Robertson M, Leppert MF. Identification of a mutation in the gene causing hyperkalemic periodic paralysis. Cell 67: 1021-1027, 1991.
Ptacek LJ, Tawil R, Griggs RC, Engel AG, Layzer RB, Kwiecinski H, McManis PG, Santiago L, Moore M, Fouad G, Bradley P, Leppert MF. Dihydropyriline receptor mutations cause hypokalemic periodic paralysis. Cell 77: 863-868, 1994.
Sanguinetti MC, Jurkiewicz K. Role of external Ca2+ and K+ in gating of cardiac delayed rectifier currents. Pflugers Archiv 420: 180-186, 1992.
Sansone V, Griggs RC, Meola G, Ptacek LJ, Barohn R, Innaccone S, Bryan W, Baker N, Janas SJ, Scott W, Ririe D, Tawil R. Andersen’s syndrome: a distinct periodic paralysis. Ann Neurol 42: 305-312, 1997.
Schwartz PJ, Moss AJ, Vincent GM, Crampton RS. Diagnostic criteria for the long QT syndrome: an update. Circulation 88: 782-784, 1993.
el-Sherif N, Caref EB, Yin H, Restivo M. The electrophysiological mechanism of ventricular arrhythmias in the long QT syndrome: tridimensional mapping of activation and recovery patterns. Circ Res 79: 474-492, 1996.
Shimizu W, Antzelevitch C. Cellular basis for the electrocardiographic features of the LQT1 form of the long QT syndrome: effects of -adrenergic agonists, antagonists and sodium channel blockers on transmural dispersion of repolarization and torsade de pointes Circulation 98: 2314-2322, 1998.
Silva J, Rudy Y. Subunit interaction determines IKs participation in cardiac repolarization and repolarization reserve. Circulation 112: 1384-1391, 2005.
Surawicz B. Electrolytes, hormones, temperature, and miscellaneous factors. In: Electrophysioloic Basis of ECG and Cardiac Arrhythmias. New York: Williams & Wilkins, 1995, p. 426-453.
Tawil R, Ptacek LJ, Pavlakis SG, DeVivo DC, Penn AS, Ozdemir C, Griggs RC. Andersen’s syndrome: potassium-sensitive periodic paralysis, ventricular ectopy, and dysmorphic features. Ann Neurol 35: 326-330, 1994.
Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, Ptacek LJ, Tawil R. Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest 11: 381-388, 2002.
Tsuboi M, Antzelevitch C. Cellular basis for electrocardiographic and arrhythmic manifestations of Andersen-Tawil syndrome (LQT7). Heart Ryhthm 3: 328-335, 2006.
Tsuji Y, Zicha S, Qi XY, Kodama I, Nattel S. Potassium channel subunit remodeling in rabbits exposed to long term bradycardia or tachycardia. Discrete arrhythmogenic consequences related to differential delayed-rectifier changes. Circulation 113: 345-355, 2006.
Viswanathan P, Shaw R, Rudy Y. Effects of IKr and IKs heterogeneity on action potential duration and its rate dependence: a simulation study. Circulation 99: 2466-2474, 1999.
Volders PGA, Vos MA, Szabo B, Sipido KR, de Groot M, Gorgels APM, Wellens HJJ, Lazarra R. Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts. Cardiovasc Res 46: 376-392, 2000.
Yamada M, Kurachi Y. Spermine gates inward-rectifying muscarinic but not ATP-sensitive K+ channels in rabbit atrial myocytes: intracellular substance-mediated mechanism of inward rectification. J Biol Chem 270: 9289-9294, 1995.
Yang J, Jan YN, Jan LY. Control of rectification and permeation by residues in two distinct domains in an inward rectifier K+ channel. Neuron 14: 1047-1054, 1995a.
Yang J, Jan YN, Jan LY. Determination of the subunit stoichiometry of an inwardly rectifying potassium channel. Neuron 15: 1441-1447, 1995b.
Zaritsky JJ, Eckman DM, Wellman GC, Nelson MT, Schwarz TL. Targeted disruption of Kir2.1 and Kir2.2 genes reveals the essential role of the inwardly rectifying K+ current in K+-mediated vasodilation. Circ Res 87: 160-166, 2000.
Zaritsky JJ, Redell JB, Tempel BL, Schwarz TL. The consequences of disrupting cardiac inwardly rectifying K+ current (IK1) as revealed by the targeted deletion of murine Kir2.1 and Kir2.2 genes. J Physiol 533: 697-710, 2001.
Zeng J, Laurita KR, Rosenbaum DS, Rudy Y. Two components of the delayed rectifier K+ currents in ventricular myocytes of the guinea pig type. Therorectical formulation and their role in repolarization. Circ Res 77: 140-152, 1995.
Zhang L, Benson W, Tristani-Firouzi M, Ptacek LJ,Tawil R, Schwartz P, George AL, Horie M, Andelfinger G, Snow GL, Fu YH, Ackerman MJ, Vincent M. Electrcardiographic features in Andersen-Tawil syndrome patients with KCNJ2 mutations. Characteristic T-U-wave patterns predict the KCJN2 genotype. Circulation 111: 2720-2726, 2005.
Zoble C, Cho HC, Nguyen TT, Pekhletski R, Diaz RJ, Wilson GJ, Backx PH. Molecular dissection of the inward rectifier potassium current (IK1) in rabbit cardiomyocytes: evidence for heteromeric co-assembly of Kir2.1 and Kir2.2. J Physiol 550: 365-372, 2003.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2007-07-13起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2007-07-13起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw