針對因 L 型鈣離子通道突變而造成的 QT 間期縮短與 Brugada 症候群之模擬

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蕭弼尹(Pi-Yin Hsiao) 查詢紙本館藏

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生命科學系

論文名稱

針對因 L 型鈣離子通道突變而造成的 QT 間期縮短與 Brugada 症候群之模擬
(Simulation of L-type Calcium Channel Mutation-induced Short QT and Brugada Syndrome)

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摘要(中)

近年來的研究發現，因為基因變異性而產生的 QT 間期縮短具有可能造成心律不整及心源性猝死的特性。經由前人的發現我們可知再極化電流功能的提高，如：快速後期鉀離子通道 (IKr)，緩慢後期鉀離子通道 (IKs) 及一號鉀離子通道 (IK1) (第一到三型 QT 間期縮短症候群)，或是去極化電流功能的喪失，如：L 型鈣離子通道 (ICa,L) (第四型 QT 間期縮短症候群)，均會導致 QT 間期的縮短。有趣的是，L 型鈣離子通道突變造成的功能喪失，不僅會造成 QT 間期縮短，在 ajmaline 的測試後也發現其具有 ST 段提高的現象，這是另一種心律不整疾病 Brugada 症候群的症狀之一。在本專題中，我們嘗試模擬產生 G490R 突變的 L 型鈣離子通道。以觀察其造成心律不整的原因。在本論文中首先將 ten Tusscher 等人所發表的人類心臟細胞模型，其中包含了對於 L 型鈣離子通道活性以及細胞內鈣循環的描述，針對前人電生理資料進行調試，同時對其進行突變的模擬，觀察其所組成的左心室二維組織是否會因突變而提高弱點再進入間期 (vulnerability window, VW) 的長度。接著我們將對其進行右心室環境的調整，來觀察 L 型鈣離子通道突變與 Brugada 症候群之間的關係。在本專題中，我們成功的找出能夠產生第四型 QT 間期縮短與 Brugada 症候群的條件，此條件也能和前人的研究現象吻合。

摘要(英)

Idiopathic short QT syndrome (SQTS) is a recently identified, genetically heterogeneous condition characterized by abbreviated QT interval and an increased susceptibility to cardiac arrhythmias and sudden cardiac death. Molecular genetic studies have shown that gain–in-function of any repolarizing currents such as IKr, IKs, and IK1 (SQT1-3) or loss-of-function of depolarizing Ica,L (SQT4) could contribute to shortening of the action potential (AP), thereby abbreviation of QT interval. Interestingly, this entity caused by Ica,L mutation not only consists of short QT, but also an ST-segment elevation in the right precordial ECG leads that implies Brugada syndrome after ajmaline challenge. In this project, we intend to apply the method of modeling to simulate the G490R mutation of the Ica,L channel. The goals were (1) to unveil electrophysiological mechanisms responsible for arrhythmogenesis. We will first use a modified dynamic ten Tusscher model which has incorporated detailed kinetics of the Ica,L channel and intracellular Ca2+ cycling along with a multi-cellular 2D model to measure vulnerability window in left ventricle condition. Then we will simulate the same mutation with a multi-cellular strand model incorporate right ventricle condition to figure out relationship between Ica,L channel mutation and Brugada syndrome. Finally, we find out the condition that could generate SQT4 and Brugada syndrome.

關鍵字(中)

★ 心臟
★ 間期縮短
★ 模擬

關鍵字(英)

★ simulation
★ BrS3
★ Brugada
★ SQT4

論文目次

摘要 iii
ABSTRACT iv
目錄 vi
圖目錄 vii
1 緒論 1
1-1 心臟 1
1-2 心電圖 1
1-3 ten Tusscher 心肌細胞模型 2
1-4 心肌細胞與其產生之動作電位 2
1-5 QT 間期縮短症候群第四型 (SQT4) 和 Brugada 症候群 4
1-6 弱點再進入間期 (vulnerable window, VW) 5
2 材料與方法 6
2-1 ten Tusscher 心肌細胞模型 6
2-2 左心室心肌組織之模擬 6
2-3 緩慢後期鉀離子通道電流 (IKs) 之調整 7
2-4 電流最大值與電壓關係圖 (I-V curve) 7
2-5 L 型鈣離子通道電流及其突變之模擬 7
2-6 弱點再進入間期的測量 8
2-7 右心室心肌組織之模擬 8
2-8 右心室外流孔道 (Right ventricle outflow tract, RVOT) 之模擬 9
3 研究結果 10
3-1 中層外層間組織阻力之模擬 10
3-2 緩慢後期鉀離子通道之調整 10
3-3 L 型鈣離子通道之及其突變之模擬 11
3-4 左心室弱點再進入間期的測量 11
3-5 右心室心肌組織之模擬 12
3-6 右心室外流孔道處仿心電圖之模擬 12
3-7 右心室外流孔道處弱點再進入間期的測量 13
4 討論 15
4-1 結果討論 15
4-2 限制 16
4-3 貢獻 17
5 參考文獻 42
6 附錄 47

參考文獻

Antzelevitch C. 2006. Brugada syndrome. Pacing Clin Electrophysiol 29(10):1130-1159.
Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, Guerchicoff A, Pfeiffer R, Oliva A, Wollnik B et al. . 2007. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 115(4):442-449.
Antzelevitch C, Shimizu W, Yan GX, Sicouri S, Weissenburger J, Nesterenko VV, Burashnikov A, Di Diego J, Saffitz J, and Thomas GP. 1999. The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart. J Cardiovasc Electrophysiol 10(8):1124-1152.
Bebarova M, Matejovic P, Pasek M, Simurdova M, and Simurda J. 2005a. Effect of ajmaline on action potential and ionic currents in rat ventricular myocytes. Gen Physiol Biophys 24(3):311-325.
Bebarova M, Matejovic P, Pasek M, Simurdova M, and Simurda J. 2005b. Effect of ajmaline on transient outward current in rat ventricular myocytes. Gen Physiol Biophys 24(1):27-45.
Bellocq C, van Ginneken AC, Bezzina CR, Alders M, Escande D, Mannens MM, Baro I, and Wilde AA. 2004. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 109(20):2394-2397.
Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M, Menendez TM, Brugada J, Pollevick GD, Wolpert C et al. . 2004. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 109(1):30-35.
Drouin E, Charpentier F, Gauthier C, Laurent K, and Le Marec H. 1995. Electrophysiologic characteristics of cells spanning the left ventricular wall of human heart: evidence for presence of M cells. J Am Coll Cardiol 26(1):185-192.
Dumaine R, Towbin JA, Brugada P, Vatta M, Nesterenko DV, Nesterenko VV, Brugada J, Brugada R, and Antzelevitch C. 1999. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res 85(9):803-809.
Enomoto K, Imoto M, Nagashima R, Kaneko T, Maruyama T, Kaji Y, Tsuda Y, Kanaya S, Fujino T, and Niho Y. 1995. Effects of ajmaline on non-sodium ionic currents in guinea pig ventricular myocytes. Jpn Heart J 36(4):465-476.
Faber GM, Silva J, Livshitz L, and Rudy Y. 2007. Kinetic properties of the cardiac L-type Ca2+ channel and its role in myocyte electrophysiology: a theoretical investigation. Biophys J 92(5):1522-1543.
His W, Jr. 1949. The story of the atrioventricular bundle with remarks concerning embryonic heart activity. J Hist Med Allied Sci 4(3):319-333.
Hong K, Piper DR, Diaz-Valdecantos A, Brugada J, Oliva A, Burashnikov E, Santos-de-Soto J, Grueso-Montero J, Diaz-Enfante E, Brugada P et al. . 2005. De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero. Cardiovasc Res 68(3):433-440.
Keith A, and Flack M. 1907. The Form and Nature of the Muscular Connections between the Primary Divisions of the Vertebrate Heart. J Anat Physiol 41(Pt 3):172-189.
Kiesecker C, Zitron E, Luck S, Bloehs R, Scholz EP, Kathofer S, Thomas D, Kreye VA, Katus HA, Schoels W et al. . 2004. Class Ia anti-arrhythmic drug ajmaline blocks HERG potassium channels: mode of action. Naunyn Schmiedebergs Arch Pharmacol 370(6):423-435.
Luo CH, and Rudy Y. 1994. A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. Circ Res 74(6):1071-1096.
Miyoshi S, Mitamura H, Fujikura K, Fukuda Y, Tanimoto K, Hagiwara Y, Ita M, and Ogawa S. 2003. A mathematical model of phase 2 reentry: role of L-type Ca current. Am J Physiol Heart Circ Physiol 284(4):H1285-1294.
Poelzing S, and Veeraraghavan R. 2007. Heterogeneous ventricular chamber response to hypokalemia and inward rectifier potassium channel blockade underlies bifurcated T wave in guinea pig. Am J Physiol Heart Circ Physiol 292(6):H3043-3051.
Priori SG, Pandit SV, Rivolta I, Berenfeld O, Ronchetti E, Dhamoon A, Napolitano C, Anumonwo J, di Barletta MR, Gudapakkam S et al. . 2005. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res 96(7):800-807.
Sangwatanaroj S, Prechawat S, Sunsaneewitayakul B, Sitthisook S, Tosukhowong P, and Tungsanga K. 2001. New electrocardiographic leads and the procainamide test for the detection of the Brugada sign in sudden unexplained death syndrome survivors and their relatives. Eur Heart J 22(24):2290-2296.
Starmer CF, Biktashev VN, Romashko DN, Stepanov MR, Makarova ON, and Krinsky VI. 1993. Vulnerability in an excitable medium: analytical and numerical studies of initiating unidirectional propagation. Biophys J 65(5):1775-1787.
ten Tusscher KH, Noble D, Noble PJ, and Panfilov AV. 2004. A model for human ventricular tissue. Am J Physiol Heart Circ Physiol 286(4):H1573-1589.
ten Tusscher KH, and Panfilov AV. 2006. Alternans and spiral breakup in a human ventricular tissue model. Am J Physiol Heart Circ Physiol 291(3):H1088-1100.
Volders PG, Sipido KR, Carmeliet E, Spatjens RL, Wellens HJ, and Vos MA. 1999. Repolarizing K+ currents ITO1 and IKs are larger in right than left canine ventricular midmyocardium. Circulation 99(2):206-210.
Weiss DL, Seemann G, Sachse FB, and Dossel O. 2005. Modelling of short QT syndrome in a heterogeneous model of the human ventricular wall. Europace 7 Suppl 2:105-117.
Yan GX, and Antzelevitch C. 1999. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation 100(15):1660-1666.
Zhang H, and Hancox JC. 2004. In silico study of action potential and QT interval shortening due to loss of inactivation of the cardiac rapid delayed rectifier potassium current. Biochem Biophys Res Commun 322(2):693-699.
Zhang H, Kharche S, Holden AV, and Hancox JC. 2008. Repolarisation and vulnerability to re-entry in the human heart with short QT syndrome arising from KCNQ1 mutation--a simulation study. Prog Biophys Mol Biol 96(1-3):112-131.
Antzelevitch C. 2006. Brugada syndrome. Pacing Clin Electrophysiol 29(10):1130-1159.
Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC, Aizawa Y, Guerchicoff A, Pfeiffer R, Oliva A, Wollnik B et al. . 2007. Loss-of-function mutations in the cardiac calcium channel underlie a new clinical entity characterized by ST-segment elevation, short QT intervals, and sudden cardiac death. Circulation 115(4):442-449.
Antzelevitch C, Shimizu W, Yan GX, Sicouri S, Weissenburger J, Nesterenko VV, Burashnikov A, Di Diego J, Saffitz J, and Thomas GP. 1999. The M cell: its contribution to the ECG and to normal and abnormal electrical function of the heart. J Cardiovasc Electrophysiol 10(8):1124-1152.
Bebarova M, Matejovic P, Pasek M, Simurdova M, and Simurda J. 2005a. Effect of ajmaline on action potential and ionic currents in rat ventricular myocytes. Gen Physiol Biophys 24(3):311-325.
Bebarova M, Matejovic P, Pasek M, Simurdova M, and Simurda J. 2005b. Effect of ajmaline on transient outward current in rat ventricular myocytes. Gen Physiol Biophys 24(1):27-45.
Bellocq C, van Ginneken AC, Bezzina CR, Alders M, Escande D, Mannens MM, Baro I, and Wilde AA. 2004. Mutation in the KCNQ1 gene leading to the short QT-interval syndrome. Circulation 109(20):2394-2397.
Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M, Menendez TM, Brugada J, Pollevick GD, Wolpert C et al. . 2004. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation 109(1):30-35.
Drouin E, Charpentier F, Gauthier C, Laurent K, and Le Marec H. 1995. Electrophysiologic characteristics of cells spanning the left ventricular wall of human heart: evidence for presence of M cells. J Am Coll Cardiol 26(1):185-192.
Dumaine R, Towbin JA, Brugada P, Vatta M, Nesterenko DV, Nesterenko VV, Brugada J, Brugada R, and Antzelevitch C. 1999. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res 85(9):803-809.
Enomoto K, Imoto M, Nagashima R, Kaneko T, Maruyama T, Kaji Y, Tsuda Y, Kanaya S, Fujino T, and Niho Y. 1995. Effects of ajmaline on non-sodium ionic currents in guinea pig ventricular myocytes. Jpn Heart J 36(4):465-476.
Faber GM, Silva J, Livshitz L, and Rudy Y. 2007. Kinetic properties of the cardiac L-type Ca2+ channel and its role in myocyte electrophysiology: a theoretical investigation. Biophys J 92(5):1522-1543.
His W, Jr. 1949. The story of the atrioventricular bundle with remarks concerning embryonic heart activity. J Hist Med Allied Sci 4(3):319-333.
Hong K, Piper DR, Diaz-Valdecantos A, Brugada J, Oliva A, Burashnikov E, Santos-de-Soto J, Grueso-Montero J, Diaz-Enfante E, Brugada P et al. . 2005. De novo KCNQ1 mutation responsible for atrial fibrillation and short QT syndrome in utero. Cardiovasc Res 68(3):433-440.
Keith A, and Flack M. 1907. The Form and Nature of the Muscular Connections between the Primary Divisions of the Vertebrate Heart. J Anat Physiol 41(Pt 3):172-189.
Kiesecker C, Zitron E, Luck S, Bloehs R, Scholz EP, Kathofer S, Thomas D, Kreye VA, Katus HA, Schoels W et al. . 2004. Class Ia anti-arrhythmic drug ajmaline blocks HERG potassium channels: mode of action. Naunyn Schmiedebergs Arch Pharmacol 370(6):423-435.
Luo CH, and Rudy Y. 1994. A dynamic model of the cardiac ventricular action potential. I. Simulations of ionic currents and concentration changes. Circ Res 74(6):1071-1096.
Miyoshi S, Mitamura H, Fujikura K, Fukuda Y, Tanimoto K, Hagiwara Y, Ita M, and Ogawa S. 2003. A mathematical model of phase 2 reentry: role of L-type Ca current. Am J Physiol Heart Circ Physiol 284(4):H1285-1294.
Poelzing S, and Veeraraghavan R. 2007. Heterogeneous ventricular chamber response to hypokalemia and inward rectifier potassium channel blockade underlies bifurcated T wave in guinea pig. Am J Physiol Heart Circ Physiol 292(6):H3043-3051.
Priori SG, Pandit SV, Rivolta I, Berenfeld O, Ronchetti E, Dhamoon A, Napolitano C, Anumonwo J, di Barletta MR, Gudapakkam S et al. . 2005. A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. Circ Res 96(7):800-807.
Sangwatanaroj S, Prechawat S, Sunsaneewitayakul B, Sitthisook S, Tosukhowong P, and Tungsanga K. 2001. New electrocardiographic leads and the procainamide test for the detection of the Brugada sign in sudden unexplained death syndrome survivors and their relatives. Eur Heart J 22(24):2290-2296.
Starmer CF, Biktashev VN, Romashko DN, Stepanov MR, Makarova ON, and Krinsky VI. 1993. Vulnerability in an excitable medium: analytical and numerical studies of initiating unidirectional propagation. Biophys J 65(5):1775-1787.
ten Tusscher KH, Noble D, Noble PJ, and Panfilov AV. 2004. A model for human ventricular tissue. Am J Physiol Heart Circ Physiol 286(4):H1573-1589.
ten Tusscher KH, and Panfilov AV. 2006. Alternans and spiral breakup in a human ventricular tissue model. Am J Physiol Heart Circ Physiol 291(3):H1088-1100.
Volders PG, Sipido KR, Carmeliet E, Spatjens RL, Wellens HJ, and Vos MA. 1999. Repolarizing K+ currents ITO1 and IKs are larger in right than left canine ventricular midmyocardium. Circulation 99(2):206-210.
Weiss DL, Seemann G, Sachse FB, and Dossel O. 2005. Modelling of short QT syndrome in a heterogeneous model of the human ventricular wall. Europace 7 Suppl 2:105-117.
Yan GX, and Antzelevitch C. 1999. Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation. Circulation 100(15):1660-1666.
Zhang H, and Hancox JC. 2004. In silico study of action potential and QT interval shortening due to loss of inactivation of the cardiac rapid delayed rectifier potassium current. Biochem Biophys Res Commun 322(2):693-699.
Zhang H, Kharche S, Holden AV, and Hancox JC. 2008. Repolarisation and vulnerability to re-entry in the human heart with short QT syndrome arising from KCNQ1 mutation--a simulation study. Prog Biophys Mol Biol 96(1-3):112-131.

指導教授

宋瑞珍(Ruey J. Sung)

審核日期

2011-6-10

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