Cardiac biexcitability: Two ways to catch a wave

Abstract

i a b t b n u w s E s i b s s c Early afterdepolarizations (EADs) are abnormal oscillations of the membrane potential that occur during action potential repolarization. EADs occurring at potentials near the plateau of the action potential are due to reactivation of the L-type Ca-channel current (ICaL) often in the context of educed repolarizing K currents. Mathematical models ave revealed common ionic mechanisms underlying EADs nd have explained how ICaL reactivation interacts with K currents to dictate EAD rate dependence. Modeling and in vitro experimental studies have recently demonstrated that the highly irregular occurrence of EADs can be explained by dynamical chaos and is highly sensitive to random fluctuations in ionic currents. EADs play a key role in the genesis of polymorphic ventricular tachycardia (PVT) in long QT syndrome (LQTS), particularly the undulating PVT known as torsades de pointes (TdP). Two main hypotheses have been proposed to explain how EADs contribute to TdP. Dessertenne initially proposed that TdP arises from repeated firing from multiple interacting foci (caused by EADs.) Numerous studies have supported this hypothesis either by stimulating the ventricles at multiple locations or by directly imaging multifocal activity using optical mapping. An alternative hypothesis is that TdP is initiated by EADs at a single focus, which because of the enhanced dispersion of repolarization induces reentrant arrhythmia. In this case, meandering or hifting reentrant arrhythmias would be responsible for the ndulating axis characteristic of TdP. Multiscale mathematical models have mechanistically linked molecular defects underlying congenital LQTS to irregular EADs, enhanced dispersion of repolarization, and arrhythmia. But one of the important unanswered questions is why clinically observed TdP exhibits considerably slower rotation and often self-terminates compared with typical Na current (INa)-mediated reentrant arrhythmias. In this issue of HeartRhythm, Chang et al propose an intriguing new hypothesis of how EADs initiate and sustain arrhythmia. The authors began by modifying a previously validated computational model of the rabbit ventricular