Dependency of Calcium Alternans on Ryanodine Receptor Refractoriness

Alvarez-Lacalle

Chaos: An Interdisciplinary Journal of Nonlinear Science

et al. 2017

Self Cite

In the heart, rapid pacing rates may induce alternations in the strength of cardiac contraction, termed pulsus alternans. Often, this is due to an instability in the dynamics of intracellular calcium concentration, whose transients become larger and smaller at consecutive beats. This alternation has been linked experimentally and theoretically to two different mechanisms: an instability due to 1) a strong dependence of calcium release with sarcoplasmic reticulum (SR) load, together with a slow calcium reuptake into the SR or 2) to SR release refractoriness, due to a slow recovery of the ryanodine receptors (RyR2) from inactivation. The relationship between calcium alternans and refractoriness of the RyR2 has been more elusive than the corresponding SR Ca load mechanism. To study the former, we reduce a general calcium model, which mimics the deterministic evolution of a calcium release unit, to its most basic elements. We show that calcium alternans can be understood using a simple nonlinear equation for calcium concentration at the dyadic space, coupled to a relaxation equation for the number of recovered RyR2s. Depending on the number of RyR2s that are recovered at the beginning of a stimulation, the increase in calcium concentration may pass, or not, over an excitability threshold that limits the occurrence of a large calcium transient. When the recovery of the RyR2 is slow, this produces naturally a period doubling bifurcation, resulting in calcium alternans. We then study the effects of inactivation, calcium diffusion and release conductance for the onset of alternans.We find that the onset of alternans requires a well-defined value of diffusion while it is less sensitive to the values of inactivation or release conductance.PACS numbers: 47.55. 47.20.Ma, 68.03.Cd ionic models; ventricular arrhythmias; calcium alternans 1 Cardiac alternans is a dysfunction that has been identified as a risk factor for cardiac arrhythmias. During alternans, beat-to-beat alternations in action potential duration (APD) appear alongside alternations in cytosolic calcium concentration. Despite been tightly coupled, voltage clamp experiments have shown that, often, the originating mechanism for alternans stems from an instability in calcium handling. Two alternative scenarios may explain this instability, either a slow reuptake of calcium after a release, or a long refractory period in release. In this paper we study the conditions for alternans due to refractoriness in calcium release, by reducing the dynamics of calcium to a simple two-variable model. The model includes a nonlinear dependence of release with calcium concentration and a slow recovery from refractoriness. This simple model presents excitability with a threshold that depends on the state of the ryanodine receptors (RyRs), i.e., calcium sensitive channels through which calcium is released to the cytosol. Calcium alternans appears as a bifurcation in which only one out of every two pulses is able to cross this excitability limit.

Section: Role Of Diffusion and Release Strength In The Appearance mentioning

confidence: 90%

Section: Introductionmentioning

confidence: 99%

Minimal model for calcium alternans due to SR release refractoriness

Alvarez-Lacalle

Chaos: An Interdisciplinary Journal of Nonlinear Science

et al. 2017

Self Cite

“…In particular, its long latency period (4,5) gives rise to SR refractoriness, which has been related to the onset of alternans (1,31,32,38,42). This mechanism is particularly relevant in situations when the SERCA pump is able to rapidly eliminate calcium from the cytoplasm and fully recover the same enddiastolic SR calcium concentration at every beat.…”

mentioning

confidence: 99%

Are SR Ca content fluctuations or SR refractoriness the key to atrial cardiac alternans?: insights from a human atrial model

Lugo

American Journal of Physiology-Heart and Circulatory Physiology

et al. 2014

Self Cite

Despite the important role of electromechanical alternans in cardiac arrhythmogenesis, its molecular origin is not well understood. The appearance of calcium alternans has often been associated to fluctuations in the sarcoplasmic reticulum (SR) Ca loading. However, cytosolic calcium alternans observed without concurrent oscillations in the SR Ca content suggests an alternative mechanism related to a dysfunction in the dynamics of the ryanodine receptor (RyR2). We have investigated the effect of SR release refractoriness in the appearance of alternans, using a mathematical model of a single human atrial cell, based on the model by Nygren et al. (30), where we modified the dynamics of the RyR2 and of SR Ca release. The genesis of calcium alternans was studied stimulating the cell for different periods and values of the RyR2 recovery time from inactivation. At fast rates cytosolic calcium alternans were obtained without concurrent SR Ca content fluctuations. A transition from regular response to alternans was also observed, changing the recovery time from inactivation of the RyR2. This transition was found to be hysteretic, so for a given set of parameters different responses were observed. We then studied the relevance of RyR2 refractoriness for the generation of alternans, reproducing the same protocols as in recent experiments. In particular, restitution of Ca release during alternans was studied with a S1S2 protocol, obtaining a different response if the S2 stimulation was given after a long or a short release. We show that the experimental results can be explained by RyR2 refractoriness, arising from a slow RyR2 recovery from inactivation, stressing the role of the RyR2 in the genesis of alternans.

“…Some authors have suggested (see [8] and references therein) that the RyR has a rather slow recovery from inactivation. Equilibration time between inactivated and closed states is comparable with the heart pacing rate.…”

Section: +Xmentioning

confidence: 99%

“…While an average (or mean field) description of intracellular calcium alternans leads naturally to a period doubling bifurcation when the pacing period is decreased, the underlying stochasticity of its multiple subcellular domains suggests a more complex behavior close to the transition point. An approach based on an average description focuses on the effects and causes of the nonlinear release, either by strong dependency of calcium release on SR load, or RyR recovery from inactivation [8]. On the contrary, an analysis of the local stochastic Ca dynamics focuses on the combination of stochasticity of Ca signaling and nearest neighbor interactions as sources of calcium alternans [7,9].…”

Section: Introductionmentioning

confidence: 99%

Calcium alternans is a global order-disorder phase transition. Robustness on Ryanodine Receptor release dynamics

Alvarez-Lacalle

2015 Computing in Cardiology Conference (CinC)

et al. 2015

Self Cite

Electromechanical alternans is a beat-to-beat alternation in the strength of contraction of a cardiac cell which appears often due to an instability of calcium cycling. The global calcium signal in cardiomyocytes is the result of the combined effect of several thousand micron scale domains called Calcium Release Units (CaRU), coupled through diffusion, where the flow of calcium among different cell compartments is regulated by stochastic signaling involving the ryanodine receptor (RyR). Recently, numerical simulations have suggested that the transition from regular Ca cycling to alternans is an order-disorder phase transition consistent with the Ising universality class. Inside the cell, groups of CaRU form transient areas within the cell where alternans appear. However, global alternans appears only as a result of the synchronization of the oscillation phase among different subunits. We show here that this transition is indeed robust and universal upon changes in the behavior of the RyR. Using three different set of parameters for the transition rates among open, closed and inactivated states in the RyR, we show that different RyR behavior leads to the same type of order-disorder transition.