A unified theory of calcium alternans in ventricular myocytes

Intracellular calcium (Ca²⁺) alternans is a dynamical phenomenon in ventricular myocytes, which is linked to the genesis of lethal arrhythmias. Iterated map models of intracellular Ca²⁺ cycling dynamics in ventricular myocytes under periodic pacing have been developed to study the mechanisms of Ca²⁺ alternans. Two mechanisms of Ca²⁺ alternans have been demonstrated in these models: one relies mainly on fractional sarcoplasmic reticulum Ca²⁺ release and uptake, and the other on refractoriness and other properties of Ca²⁺ sparks. Each of the two mechanisms can partially explain the experimental observations, but both have their inconsistencies with the experimental results. Here we developed an iterated map model that is composed of two coupled iterated maps, which unifies the two mechanisms into a single cohesive mathematical framework. The unified theory can consistently explain the seemingly contradictory experimental observations and shows that the two mechanisms work synergistically to promote Ca²⁺ alternans. Predictions of the theory were examined in a physiologically-detailed spatial Ca²⁺ cycling model of ventricular myocytes.