| Summary: | 碩士 === 國立成功大學 === 生理學研究所 === 96 === 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.
|
|---|
