Mechanisms of Subcellular Spatially Discordant Calcium Alternans in Cardiac Myocytes

Abstract

Subcellular spatially discordant calcium alternans (SDCA) is a behavior in which calcium transient alternates with the opposite phase in different regions of a cell. Experimentally, SDCA has been observed in both atrial and ventricular myocytes in various experimental conditions. Previous studies suggested that SDCA could be resulted from a Turing instability under the condition of negative calcium-to-voltage coupling. However, this theory cannot explain the SDCA observed in voltage clamp experiments and those noted when the calcium-to-voltage coupling is positive. Here we use computer simulations and theoretical treatments to investigate the dynamical mechanisms of SDCA. We first carried out simulations with a physiologically detailed ventricular myocyte model. Under the action potential clamped condition, the spatial calcium release patterns can be either concordant or discordant, and the discordant patterns are random, which depends on the initial conditions. Under the free-running action potential condition, the spatial calcium release pattern depends not only on the properties of calcium-to-voltage coupling but also on the pacing rates. At fast pacing rates, the release pattern changes from concordant to discordant when the calcium-to-voltage coupling changes from positive to negative. When the pacing rate decreases to a certain value, the effect of calcium-to-voltage coupling on the transition from concordant to discordant is reversed. We then proposed a FitzHugh-Nagumo model with a global delayed feedback loop, which well captures the key dynamics of the ventricular cell model. Finally, we extracted a coupled iterated map model to perform nonlinear dynamics analysis. This map model reveals the bifurcations leading to the patterns observed in the detailed ventricular cell model and the simplified FitzHugh-Nagumo model.