Synchronization of spatially discordant voltage and calcium alternans in cardiac tissue.

Abstract

The heart is an excitable medium which is excited by membrane potential depolarization and propagation. Membrane potential depolarization brings in calcium (Ca) through the Ca channels to trigger intracellular Ca release for contraction of the heart. Ca also affects voltage via Ca-dependent ionic currents, and thus, voltage and Ca are bidirectionally coupled. It has been shown that the voltage subsystem or the Ca subsystem can generate its own dynamical instabilities which are affected by their bidirectional couplings, leading to complex dynamics of action potential and Ca cycling. Moreover, the dynamics become spatiotemporal in tissue in which cells are diffusively coupled through voltage. A widely investigated spatiotemporal dynamics is spatially discordant alternans (SDA) in which action potential duration (APD) or Ca amplitude exhibits temporally period-2 and spatially out-of-phase patterns, i.e., APD-SDA and Ca-SDA patterns, respectively. However, the mechanisms of formation, stability, and synchronization of APD-SDA and Ca-SDA patterns remain incompletely understood. In this paper, we use cardiac tissue models described by an amplitude equation, coupled iterated maps, and reaction-diffusion equations with detailed physiology (the ionic model) to perform analytical and computational investigations. We show that, when the Ca subsystem is stable, the Ca-SDA pattern always follows the APD-SDA pattern, and thus, they are always synchronized. When the Ca subsystem is unstable, synchronization of APD-SDA and Ca-SDA patterns depends on the stabilities of both subsystems, their coupling strengths, and the spatial scales of the initial Ca-SDA patterns. Spontaneous (initial condition-independent) synchronization is promoted by enhancing APD instability and reducing Ca instability as well as stronger Ca-to-APD and APD-to-Ca coupling, a pattern formation caused by dynamical instabilities. When Ca is more unstable and APD is less unstable or APD-to-Ca coupling is weak, synchronization of APD-SDA and Ca-SDA patterns is promoted by larger initially synchronized Ca-SDA clusters, i.e., initial condition-dependent synchronization. The synchronized APD-SDA and Ca-SDA patterns can be locked in-phase, antiphase, or quasiperiodic depending on the coupling relationship between APD and Ca. These theoretical and simulation results provide mechanistic insights into the APD-SDA and Ca-SDA dynamics observed in experimental studies.