Abstract
BackgroundRapid pacing rates induce alternations in the cytosolic calcium concentration caused by fluctuations in calcium released from the sarcoplasmic reticulum (SR). However, the relationship between calcium alternans and refractoriness of the SR calcium release channel (RyR2) remains elusive.Methodology/Principal FindingsTo investigate how ryanodine receptor (RyR2) refractoriness modulates calcium handling on a beat-to-beat basis using a numerical rabbit cardiomyocyte model. We used a mathematical rabbit cardiomyocyte model to study the beat-to-beat calcium response as a function of RyR2 activation and inactivation. Bi-dimensional maps were constructed depicting the beat-to-beat response. When alternans was observed, a novel numerical clamping protocol was used to determine whether alternans was caused by oscillations in SR calcium loading or by RyR2 refractoriness. Using this protocol, we identified regions of RyR2 gating parameters where SR calcium loading or RyR2 refractoriness underlie the induction of calcium alternans, and we found that at the onset of alternans both mechanisms contribute. At low inactivation rates of the RyR2, calcium alternans was caused by alternation in SR calcium loading, while at low activation rates it was caused by alternation in the level of available RyR2s.Conclusions/SignificanceWe have mapped cardiomyocyte beat-to-beat responses as a function of RyR2 activation and inactivation, identifying domains where SR calcium load or RyR2 refractoriness underlie the induction of calcium alternans. A corollary of this work is that RyR2 refractoriness due to slow recovery from inactivation can be the cause of calcium alternans even when alternation in SR calcium load is present.
Highlights
Despite the important role of electro-mechanical alternans in cardiac arrhythmogenesis [1], [2], its molecular origin is not well understood
We first verified that changes in RyR2 activation and inactivation rates could produce alternans at fast pacing rates
Alternans was associated with oscillations in the sarcoplasmic reticulum (SR) calcium loading, and with alternations in the level of recovered RyR2s ready to open on each stimulation
Summary
Despite the important role of electro-mechanical alternans in cardiac arrhythmogenesis [1], [2], its molecular origin is not well understood This phenomenon has been associated with alternation in both ionic currents and in the cytosolic calcium transient. Shkryl et al [11] have confirmed the presence of alternans without SR calcium fluctuations and related it to incomplete recovery in refractoriness of SR calcium release This suggests that, besides calcium loading, other properties of the SR, such as activation of the ryanodine receptor (RyR2) [5], [6], inactivation of the RyR2 [12], [13], recovery of the RyR2 from inactivation [12], [14], and termination of calcium release through the RyR2 [15], [16], may all intervene in the regulation of the beat-to-beat stability of the cytosolic calcium transient. The relationship between calcium alternans and refractoriness of the SR calcium release channel (RyR2) remains elusive
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