title: Synchronization of chaotic early afterdepolarizations in the genesis of cardiac arrhythmias.
abstract: The synchronization of coupled oscillators plays an important role in many biological systems, including the heart. In heart diseases, cardiac myocytes can exhibit abnormal electrical oscillations, such as early afterdepolarizations (EADs), which are associated with lethal arrhythmias. A key unanswered question is how cellular EADs partially synchronize in tissue, as is required for them to propagate. Here, we present evidence, from computational simulations and experiments in isolated myocytes, that irregular EAD behavior is dynamical chaos. We then show in electrically homogeneous tissue models that chaotic EADs synchronize globally when the tissue is smaller than a critical size. However, when the tissue exceeds the critical size, electrotonic coupling can no longer globally synchronize EADs, resulting in regions of partial synchronization that shift in time and space. These regional partially synchronized EADs then form premature ventricular complexes that propagate into recovered tissue without EADs. This process creates multiple premature ventricular complexes that propagate as [corrected] "shifting" foci resembling polymorphic ventricular tachycardia. Shifting foci encountering shifting repolarization gradients can also develop localized wave breaks leading to reentry and fibrillation. As predicted by the theory, rabbit hearts exposed to oxidative stress (H(2)O(2)) exhibited multiple shifting foci causing polymorphic tachycardia and fibrillation. This mechanism explains how collective cellular behavior integrates at the tissue scale to generate lethal cardiac arrhythmias over a wide range of heart rates.
authors.affiliation: Cardiovascular Research Laboratory, Department of Medicine (Cardiology), David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sato
authors.forename: Lai-Hua
authors.initials: LH
authors.lastname: Xie
authors.forename: Ali A
authors.initials: AA
authors.lastname: Sovari
authors.forename: Diana X
authors.initials: DX
authors.lastname: Tran
authors.forename: Norishige
authors.initials: N
authors.lastname: Morita
authors.forename: Fagen
authors.initials: F
authors.lastname: Xie
authors.forename: Hrayr
authors.initials: H
authors.lastname: Karagueuzian
authors.forename: Alan
authors.initials: A
authors.lastname: Garfinkel
authors.forename: James N
authors.initials: JN
authors.lastname: Weiss
authors.forename: Zhilin
authors.initials: Z
authors.lastname: Qu
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced / Q000503:physiopathology*; D004594:Electrophysiology; D005260:Female; D006861:Hydrogen Peroxide / Q000494:pharmacology; D008954:Models, Biological; D018408:Patch-Clamp Techniques; D011817:Rabbits; D013997:Time Factors
chemical_list: D006861:Hydrogen Peroxide