Buffering and total calcium levels determine the presence of oscillatory regimes in cardiac cells

Abstract

Calcium oscillations and waves induce depolarization in cardiac cells which are believed to cause life-threathening arrhythimas. In this work, we study the conditions for the appearance of calcium oscillations in both a detailed subcellular model of calcium dynamics and a minimal model that takes into account just the minimal ingredients of the calcium toolkit. To avoid the effects of homeostatic changes and the interaction with the action potential we consider the somewhat artificial condition of a cell without pacing and with no calcium exchange with the extracellular medium. Both the full subcellular model and the minimal model present the same scenarios depending on the calcium load: two stationary states, one with closed ryanodine receptors (RyR) and most calcium in the cell stored in the sarcoplasmic reticulum (SR), and another, with open RyRs and a depleted SR. In between, calcium oscillations may appear. The robustness of these oscillations is determined by the amount of calsequestrin (CSQ). The lack of this buffer in the SR enhances the appearance of oscillations. The minimal model allows us to relate the stability of the oscillating state to the nullcline structure of the system, and find that its range of existence is bounded by a homoclinic and a Hopf bifurcation, resulting in a sudden transition to the oscillatory regime as the cell calcium load is increased. Adding a small amount of noise to the RyR behavior increases the parameter region where oscillations appear and provides a gradual transition from the resting state to the oscillatory regime, as observed in the subcellular model and experimentally.

Author summary

In cardiac cells, calcium plays a very important role. An increase in calcium levels is the trigger used by the cell to initiate contraction. Besides, calcium modulates several transmembrane currents, affecting the cell transmembrane potential. Thus, dysregulations in calcium handling have been associated with the appearance of arrhythmias. Often, this dysregulation results in the appearance of periodic calcium waves or global oscillations, providing a pro-arrhythmic substrate. In this paper, we study the onset of calcium oscillations in cardiac cells using both a detailed subcellular model of calcium dynamics and a minimal model that takes into account the essential ingredients of the calcium toolkit. Both reproduce the main experimental results and link this behavior with the presence of different steady-state solutions and bifurcations that depend on the total amount of calcium in the cell and in the level of buffering present. We expect that this work will help to clarify the conditions under which calcium oscillations appear in cardiac myocytes and, therefore, will represent a step further in the understanding of the origin of cardiac arrhythmias.