doi: 10.1161/01.RES.0000224540.97431.f0
© 2006 American Heart Association, Inc.
Review |
From Pulsus to Pulseless
The Saga of Cardiac Alternans
From the Departments of Medicine (Cardiology) (J.N.W., Y.S., A.G., Z.Q.) and Physiology (J.N.W.), David Geffen School of Medicine at UCLA, and Department of Physiological Science (A.G.), UCLA, Los Angeles, Calif; Division of Cardiology (P.-S.C.), Cedars-Sinai Medical Center, Los Angeles, Calif; Department of Physics and the Center for Interdisciplinary Research on Complex Systems (A.K.), Northeastern University, Boston, Mass.
Correspondence to James N. Weiss, MD, Division of Cardiology, 3645 MRL Building, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095. E-mail jweiss{at}mednet.ucla.edu
This Review is part of a thematic series on the Biology of Cardiac Arrhythmias, which includes the following articles:
Antiarrhythmic Drug Target Choices and Screening
Inherited Arrhythmogenic Diseases: The Complexity Beyond Monogenic Disorders
Genomics in Sudden Cardiac Death
Regulation of Ion Channel Expression
Biology of Cardiac Arrhythmias: Ion Channel Protein Trafficking
From Pulsus to Pulseless: The Saga of Cardiac Alternans
This series is in honor of Harry A. Fozzard, 8th Editor of Circulation Research
Eduardo Marbán and Gordon Tomaselli Editors
Computer simulations and nonlinear dynamics have provided invaluable tools for illuminating the underlying mechanisms of cardiac arrhythmias. Here, we review how this approach has led to major insights into the mechanisms of spatially discordant alternans, a key arrhythmogenic factor predisposing the heart to re-entry and lethal arrhythmias. During spatially discordant alternans, the action potential duration (APD) alternates out of phase in different regions of the heart, markedly enhancing dispersion of refractoriness so that ectopic beats have a high probability of inducing reentry. We show how, at the cellular level, instabilities in membrane voltage (ie, steep APD restitution slope) and intracellular Ca (Cai) cycling dynamics cause APD and the Cai transient to alternate and how the characteristics of alternans are affected by different "modes" of the bidirectional coupling between voltage and Cai. We illustrate how, at the tissue level, additional factors, such as conduction velocity restitution and ectopic beats, promote spatially discordant alternans. These insights have illuminated the mechanistic basis underlying the clinical association of cardiac alternans (eg, T wave alternans) with arrhythmia risk, which may lead to novel therapeutic approaches to avert sudden cardiac death.
Key Words: arrhythmias • alternans • heart failure • intracellular Ca cycling • electrical restitution
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