Timothy Syndrome 是一種由於Cav1.2離子通道基因突變而產生「功能增益」情況所造成的致死性心臟疾病。我們希望由其電生理機制上的特性來探討出Timothy Syndrome和致死性心律不整的相關性。在我們的研究中，我們採用的模擬模組是Luo-Rudy的細胞模組和一維的線性細胞排列模組。在模擬Cav1.2離子通道的突變當中，我們將調控Cav1.2離子通道打開時間的時間常數由兩倍開始逐步增加。這樣的操作顯示，動作電位的長度和心電圖中的QT波的間距會隨之增長。這樣的處理方式會使心肌中層細胞(mid-myocardium cells)先出現Delayed afterdepolarizations (DADs)並引發其細胞活性，接下來我們還觀察到動作電位中DADs和early afterdepolarizations (EADs)的交替(APD alternans)。此外，隨著時間常數的倍增，我們還觀察到穿越肌層的再極化分佈(transmural dispersion of repolarization, TDR)也隨之增加，這種情況也伴隨著動作電位回復曲線(APD restitution curves)陡峭的趨勢。在觀察到以上的情況之後，我們也嘗試去了解beta-adrenergic刺激所造成的影響，這樣的刺激除了會使得TDR增大和動作電位回復曲線的陡峭外，更重要的是，不斷促進DADs誘發之活性的結果，最後會導致一種“flutter- or fibrillatory-like”的動作電位節奏，這種情形是由短暫往細胞內流動的電流所造成，這樣的電流是由Na+-Ca2+ 交換電流(INCX)、非特異性鈣離子活化電流(nonspecific Ca2+-activated currents, INS(Ca))、鈣離子誘發的肌漿膜鈣離子自動釋放(evoked by spontaneous Ca2+ release from the sarcoplasmic reticulum (Irel,overload) related to “Ca2+ overload.”)等電流所組成。然而，在心跳減速的時候，動作電位的延長和其他類似前心律不整的情況也會產生。在此研究當中，我們得到了以下的結論，Cav1.2這個離子通道的突變導致其原有的功能有所改變之後，會引發致死性的心室性心律不整，疾病的狀況更有可能因為交感神經的影響和心跳減慢而加重。

Timothy syndrome (TS) is a malignant form of congenital long QT syndrome caused by genetic mutations that result in “nearly complete failure” of voltage-dependent inactivation (VDI) of the Cav1.2 channel leading to "gain of function”. We set out to explore electrophysiological mechanisms underlying the propensity to develop lethal ventricular arrhythmias associated with TS. We adopted a modified Luo-Rudy cell model of ventricular myocyte along with 1-dimensional multicellular strand model. To simulate mutant-induced reduction of VDI of the Cav1.2 channel, the time constant of VDI was multiplied by 2-fold to 20-fold. This resulted in progressive prolongation of action potential duration (APD) and QT interval without eliciting abnormal automaticity. Delayed afterdepolarizations (DADs) and DAD-mediated trigger activity first appeared in the mid-myocardial cell, and intermittently, and we also observed APD alternans with early afterdepolarizations (EADs). Additionally, there was a progressive increase in transmural dispersion of repolarization (TDR) alongside steepening of APD restitution. Beta-adrenergic stimulation further amplified TDR and steepened APD restitution, and importantly, facilitated induction of DAD-mediated triggered activity culminating in its transformation into a “flutter- or fibrillatory-like” rhythm driven by a transient inward current (ITi) generated by forward mode Na+-Ca2+ (INCX) and nonspecific Ca2+-activated currents (INS(Ca)) evoked by spontaneous Ca2+ release from the sarcoplasmic reticulum (Irel,overload) related to “Ca2+ overload.” Of note, bradycardia further prolonged APD and exerted similar proarrhythmic effects. In patients with TS, significant reduction of VDI of the Cav1.2 channel may provide not only a trigger but also a substrate for the propensity to develop lethal ventricular arrhythmia aggravated by enhanced sympathetic tone and bradycardia.

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