Biexcitability and Early Afterdepolarization-Mediated Cardiac Arrhythmias

Abstract

Under normal conditions in ventricular tissue, both planar wave propagation and spiral wave reentry are mediated by Na current (INa)-mediated depolarization. Under diseased conditions in which repolarization reserve is reduced, however, secondary depolarizations can occur in the plateau or repolarizing phase of the action potential (AP) due to reactivation of the L-type calcium current (ICa,L), known as early afterdepolarizations (EADs). Under these conditions, we observed a novel behavior in which both INa-mediated spiral wave reentry and ICa,L-mediated spiral wave reentry coexisted in the same homogeneous tissue. INa-mediated spiral waves were similar to those observed under normal condition, with high rotation frequency (∼10 Hz) and nearly full repolarization between beats. ICa,L-mediated spiral waves, however, rotated much slower (2-3 Hz) with membrane voltage remaining above −40 mV, at which INa is inactivated. We call this novel property of an excitable medium biexcitability. In heterogeneous tissue with transmural AP gradients, pause-induced EADs initiated ICa,L-mediated rotors from the M-cell region. The resulting arrhythmia was characterized by co-existing ICa,L- and INa-mediated wavefronts, with a frequency and electrocardiographic appearance resembling Torsades de Pointes. The arrhythmia either terminated spontaneously or degenerated to ventricular fibrillation. We propose biexcitability as a novel mechanism of Torsades de Pointes in long QT syndromes.