title: Chaos and the transition to ventricular fibrillation: a new approach to antiarrhythmic drug evaluation.
abstract: Sudden cardiac death resulting from ventricular fibrillation can be separated into 2 components: initiation of tachycardia and degeneration of tachycardia to fibrillation. Clinical drug studies such as CAST and SWORD demonstrated that focusing exclusively on the first component is inadequate as a therapeutic modality. The hope for developing effective pharmacological therapy rests on a comprehensive understanding of the second component, the transition from tachycardia to fibrillation. We summarize evidence that the transition from tachycardia to fibrillation is a transition to spatiotemporal chaos, with similarities to the quasiperiodic transition to chaos seen in fluid turbulence. In this scenario, chaos results from the interaction of multiple causally independent oscillatory motions. Simulations in 2-dimensional cardiac tissue suggest that the destabilizing oscillatory motions during spiral-wave reentry arise from restitution properties of action potential duration and conduction velocity. The process of spiral-wave breakup in simulated cardiac tissue predicts remarkably well the sequence by which tachycardia degenerates to fibrillation in real cardiac tissue. Modifying action potential duration and conduction velocity restitution characteristics can prevent spiral-wave breakup in simulated cardiac tissue, suggesting that drugs with similar effects in real cardiac tissue may have antifibrillatory efficacy (the Restitution Hypothesis). If valid for the real heart, the Restitution Hypothesis will support a new paradigm for antiarrhythmic drug classification, incorporating an antifibrillatory profile based on effects on cardiac restitution and the traditional antitachycardia profile (classes 1 through 4).
authors.affiliation: Department of Medicine, UCLA Cardiovascular Research Laboratory, UCLA School of Medicine and Cedars-Sinai Medical Center, Los Angeles, CA, USA. jweiss@mednet.ucla.edu
authors.forename: J N
authors.initials: JN
authors.lastname: Weiss
authors.forename: A
authors.initials: A
authors.lastname: Garfinkel
authors.forename: H S
authors.initials: HS
authors.lastname: Karagueuzian
authors.forename: Z
authors.initials: Z
authors.lastname: Qu
authors.forename: P S
authors.initials: PS
authors.lastname: Chen
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000627:therapeutic use*; D018849:Controlled Clinical Trials as Topic; D016757:Death, Sudden, Cardiac / Q000517:prevention & control*; D004562:Electrocardiography; D005069:Evaluation Studies as Topic; D006801:Humans; D017711:Nonlinear Dynamics; D017180:Tachycardia, Ventricular / Q000150:complications / Q000188:drug therapy*; D014693:Ventricular Fibrillation / Q000150:complications / Q000188:drug therapy*
chemical_list: D000889:Anti-Arrhythmia Agents