Calcium alternans in cardiac myocytes: order from disorder

Abstract

Calcium alternans is associated with T-wave alternans and pulsus alternans, harbingers of increased mortality in the setting of heart disease. Recent experimental, computational, and theoretical studies have led to new insights into the mechanisms of Ca alternans, specifically how disordered behaviors dominated by stochastic processes at the subcellular level become organized into ordered periodic behaviors. In this article, we summarize the recent progress in this area, outlining a holistic theoretical framework in which the complex effects of Ca cycling proteins on Ca alternans are linked to three key properties of the cardiac Ca cycling network: randomness, refractoriness, and recruitment. We also illustrate how this '3R theory' can reconcile many seemingly contradictory experimental observations.