Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts.

Abstract

Time for primary review 19 days. Afterdepolarizations are oscillations of the transmembrane potential that depend on the preceding action potential (AP) for their generation and can give rise to new APs when they reach a critical threshold for activation of a depolarizing current. This form of abnormal impulse generation is called ‘triggered activity’ [1]. Two types of afterdepolarizations have been distinguished: delayed (DADs) and early afterdepolarizations (EADs). DADs have been defined as “oscillations in membrane potential that occur after repolarization of an action potential” [2]. EADs are generated during the AP and have been defined as “oscillations at the plateau level of membrane potential or later during phase 3 of repolarization” [2]. Depending on the level of the membrane potential at which they are generated, EADs can trigger new APs that may appear as ectopic beats on the ECG. EADs can also augment electrical heterogeneity in regions of neighboring myocardium, which can lead to the formation of new APs via electrotonic interaction between areas that are still inexcitable and those that have already recovered from refractoriness [3]. Although the latter mechanism is reentrant rather than triggered activity, the occurrence of EADs is of pivotal importance for arrhythmogenesis under these circumstances. The clinical significance of EADs lies in their capacity to provide both the trigger (premature ectopic beats) and the substrate (electrical heterogeneity with nonuniform repolarization and refractoriness) for the initiation and perpetuation of torsades de pointes. In this article, we discuss the evidence for a new concept of EAD formation, which includes an important role for cytoplasmic-[Ca2+]-dependent mechanisms, as schematically illustrated in Fig. 1. As a background, we will first review the recent literature on cellular Ca2+ homeostasis. Then, we introduce the classical view on EAD formation with a discussion of the … * Corresponding author. Tel.: +31-43-3875093; fax: +31-43-3875104 p.volders{at}cardio.azm.nl