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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Title:	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
Authors:	蕭弼尹;Pi-Yin Hsiao
Contributors:	生命科學研究所
Keywords:	心臟;間期縮短;模擬;simulation;BrS3;Brugada;SQT4
Date:	2011-06-10
Issue Date:	2012-01-05 14:28:06 (UTC+8)
Abstract:	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。 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.
Appears in Collections:	[Graduate Institute of Life Science] Electronic Thesis & Dissertation

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