From pulsus to pulseless: the saga of cardiac alternans.

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.