長QT症候群(Long QT syndrome,LQTS)在心電圖上的特徵就是QT 間期延長(QT interval prolongation)，同時伴隨著臨床上的徵狀有暈厥(syncope)，心跳停止(cardiac arrest)或猝死(sudden death)。長QT症候群有很多種類型，其中第I型長QT症候群(LQT I)肇因於KCNQ1基因所編碼出的緩慢延遲整流型鉀離子通道(the slow delayed rectifier K+ current, IKs)失去了功能。臨床上的LQT1病人傾向於在運動時發生心律不整(arrhythmia)，特別在游泳時發生的機率更高，而目前的第一線用藥貝塔阻斷劑(beta-blocker)只能提供不完整的保護作用。在本研究中，我們想要藉由電腦模擬來定義出β-腎上腺素刺激(Beta-adrenergic stimulation, BAS)所促成的心律不整之途徑，更重要的是找到有效的治療方式來避免心律不整的發生。我們應用了Luo-Rudy(LRd)心室心肌細胞模型來模擬LQT1及其中的細胞內鈣離子循環(Intracellular Ca2+ cycling)的情形。心臟不正常跳動的機轉有自主性跳動(automaticity)，迴旋性(reentry)和促發自主性(triggered activity)，而在治療策略中我們主要聚焦在BAS作用的五個通道：ICa,L、IKs、IK1、INaK和Iup，於BAS刺激下會使這些標靶通道增強或抑制其表現。我們期望能看到LQT1在BAS促進運作下所誘導的延遲去極化(delayed afterdepolarization, DAD)生成，並從中看到ICa,L和Iup會增強其電流，之後同時或單獨處理ICa,L和Iup抑制劑來找出有效濃度，未來也許可依此來對BAS受體阻斷劑的治療做調整，以期能得到最完整的保護作用。

Long QT syndrome (LQTS) is referred to as a clinical constellation in which patients manifest episodic syncope, cardiac arrest or sudden death due to torsades de pointes associated with electrocardiographic QT prolongation and otherwise normal hearts. Of the ten types of LQTS, LQT1 is caused by mutations in the gene encoding KCNQ1 leading to “loss of function” of the IKs channel. Of note, clinically LQT1 patients tend to develop cardiac events during physical exertion (esp. swimming)[1] and beta-adrenergic receptor blocking agents provide only incomplete protection. In the proposed study, we sought to define mechanisms by which beta-adrenergic stimulation (BAS) provoke cardiac arrhythmias and more importantly to search for an alternative or adjunctive regimen for more effectively to prevent cardiac arrhythmias from occurrence. We plan to apply the Luo-Rudy ventricular myocyte model which has incorporated a relatively detailed dynamics of intracellular Ca2+ cycling to simulate LQT1. Mechanisms to be defined include abnormal automaticity, reentry, and triggered activity whereas potential targeted sites of therapy will be focused on components enhanced by BAS, ICa,L, IKs, IK1, INaK and Iup. We anticipate that LQT1 will have inducible delayed afterdepolarizations that are aggravated by BAS-induced enhancement of ICa,L and Iup, and an inhibitor capable of blocking both ICa,L and Iup should be an useful adjunctive to beta-adrenergic receptor blocking agents.
Keywords：Long QT syndrome; Torsades de pointes; Beta-adrenergic stimulation (BAS); Intracellular Ca2+ cycling

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