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

Abstract

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.

Alternans in atria: Mechanisms and clinical relevance

“…The study of Shkryl et al [54] demonstrated that in rabbit atrial myocytes a large amplitude CaT indeed prolongs RyR refractoriness and that the kinetics of RyR recovery from inactivation is a key factor in the generation of Ca 2+ alternans. This hypothesis also found support from in silico simulations [68]. …”

“…4B) [72]. Computer simulations using cell models with and without t-tubules have predicted significant differences in possible alternans mechanisms [23,68,73]. The cardiac cell models lacking t-tubules exhibited higher likelihood to develop Ca 2+ alternans and pointed towards the role of Ca 2 + diffusion, inhomogeneity in [Ca 2+ ] i [73] and RyR refractoriness [68] in the process.…”

“…Computer simulations using cell models with and without t-tubules have predicted significant differences in possible alternans mechanisms [23,68,73]. The cardiac cell models lacking t-tubules exhibited higher likelihood to develop Ca 2+ alternans and pointed towards the role of Ca 2 + diffusion, inhomogeneity in [Ca 2+ ] i [73] and RyR refractoriness [68] in the process. This is consistent with experimental observations of intracellular gradients of the degree of Ca 2+ alternans and that Ca 2+ alternans can be spatially and temporally inhomogeneous even at the level of a single atrial myocyte and, in the extreme cases, subcellular regions can even alternate out-of-phase (Fig.…”

Minimal model for calcium alternans due to SR release refractoriness

“…In order to reduce Eqs. (14), (15) to an autonomous problem that can be analyzed by AUTO, we rewrite the forcing in terms of the periodic solutions of an auxiliary autonomous ordinary differential equations (ODE) system 27,32 . We represent the calcium current I CaL as a pulse of duration ∆t = 10ms, that starts with a delay t c1 after each T period and with a halftime steep value, m, to its maximum value I CaLmax (Fig.…”

Ca2+-activated chloride channel activity during Ca2+alternans in ventricular myocytes

“…It is generally agreed that bi-directional coupling between these parameters underlies the development of cardiac alternans, 18,19 however it has remained a matter of debate which one of the 2 parameters, when its regulation becomes disturbed, is the primary cause of cardiac alternans. While computational studies have generated arguments in favor of both parameters ([Ca 2C ] i or V m ), 9,[24][25][26] experimental studies have provided growing evidence that alternans are initiated by disturbances of intracellular Ca 2C handling. [15][16][17]27,28 Major support for this hypothesis came from the demonstration that CaT alternans can be elicited in voltage-clamped ventricular myocytes even when beat-to-beat changes of V m were kept constant.…”