Pause induced early afterdepolarizations in the long QT syndrome: a simulation study

Objective: The long QT syndrome (LQTS) is characterized by prolonged repolarization and propensity to syncope and sudden death due to polymorphic ventricular tachycardias such as torsade de pointes (TdP). The exact mechanism of TdP is unclear, but pause-induced early afterdepolarizations (EADs) have been implicated in its initiation. In this study we investigate the mechanism of pause-induced EADs following pacing at clinically relevant rates and characterize the sensitivity of different cell types (epicardial, midmyocardial, and endocardial) to EAD development. Methods: Simulations were conducted using the Luo-Rudy (LRd) model of the mammalian ventricular action potential (AP). Three cell types - epicardial, midmyocardial (M), and endocardial - are represented by altering the channel density of the slow delayed rectifier current, I-Ks. LQTS is modelled by enhanced late sodium current (LQTS), or reduced density of functional channels that conduct I-Kr (LQT2) and I-Ks (LQT1). The cell is paced 40 times at a constant Basic Cycle Length (BCL) of 500 ms. Following a 1500 ms pause, an additional single stimulus is applied. Results: Our results demonstrate that pause-induced EADs develop preferentially in M cells under conditions of prolonged repolarization. These EADs develop at plateau potentials ('plateau EADs'). Mechanistic investigation shows that prolongation of the plateau phase of the post-pause AP due to a smaller delayed rectifier potassium current, I-Ks, and enhancement of the sodium-calcium exchange current, I-NaCl, allows for the reactivation of the L-type calcium current, I-Ca(L), which depolarizes the membrane to generate the EAD. Conclusions: APD is a very important determinant of arrhythmogenesis and its prolongation, either due to acquired or congenital LOTS, can result in the appearance of EADs. The formation of pause-induced EADs preferentially in M cells suggests a possible role for these cells in the generation of arrhythmias that are associated with abnormalities of repolarization (e.g., TdP). The ionic mechanism of pause-induced EADs involves reactivation of the L-type calcium current during the prolonged plateau of the post-pause AP. (C) 1999 Elsevier Science B.V. All rights reserved.