Refractoriness of sarcoplasmic reticulum Ca<sup>2+</sup> release determines Ca<sup>2+</sup> alternans in atrial myocytes

Shkryl, Vyacheslav M.; Maxwell, Joshua T.; Domeier, Timothy L.; Blatter, Lothar A.

doi:10.1152/ajpheart.00079.2012

Cited by 83 publications

(153 citation statements)

References 68 publications

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“…In fact, we find that the onset of alternans is dependent on the recovery time of the RyR2s, which we propose as the origin of refractoriness, as has been discussed recently with the use of a model for rabbit ventricular cells (1). This relation has been further investigated showing that a slow recovery of the RyR2s can explain all the experimental results in Shkryl et al (38).…”

mentioning

confidence: 79%

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

Lugo

Cantalapiedra

Peñaranda

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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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.

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mentioning

confidence: 79%

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

Lugo

Cantalapiedra

Peñaranda

et al. 2014

American Journal of Physiology-Heart and Circulatory Physiology

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“…For example, for long pacing cycle lengths in the swine left ventricle, CaD measured at a 50% level of recovery was almost 81% longer with high-affinity probes (fluo 4 and fluo 2MA) than with low-affinity probes (fluo 4FF and fluo 2LA) (43). Very-low-affinity probes with extremely high K d (ϳ22-90 M), such as fluo 5N (75,84,87) and ratiometric mag-fura 2 (33), have been used to study SR Ca 2ϩ in isolated cardiac myocytes. SR Ca 2ϩ has also been optically mapped in myocardial tissue using mag-fluo 4 (45,104) and fluo 5N (111).…”

Section: Ca I 2ϩ Fluorescence Probesmentioning

confidence: 99%

A technical review of optical mapping of intracellular calcium within myocardial tissue

Jaimes

Walton

Pasdois

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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“…This mechanism requires that Ca DSRL alternate concomitantly with SR Ca release, but the refractoriness of SR Ca release is not explicitly required. Subsequent mathematical analyses and simulation studies either potentiated this theory (30,45,57,64,69,71) (41), and the importance of refractoriness in Ca alternans has been demonstrated in later studies (32,58). Therefore, the above experimental studies raise the issue of the roles of SR Ca and refractoriness of SR Ca release in the genesis of Ca alternans.…”

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confidence: 96%

“…In other words, the SR Ca concentration ([Ca] SR ) reaches the same level every beat even though the myoplasmic Ca transient amplitude (and thus the SR Ca depletion amplitude) undergoes alternans. Since Ca DSRL is the same in each beat, the refractoriness of SR Ca release is considered as the primary mechanism of alternans (41), and the importance of refractoriness in Ca alternans has been demonstrated in later studies (32,58). Therefore, the above experimental studies raise the issue of the roles of SR Ca and refractoriness of SR Ca release in the genesis of Ca alternans.…”

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confidence: 97%

Calcium alternans in a couplon network model of ventricular myocytes: role of sarcoplasmic reticulum load

Nivala

2012

American Journal of Physiology-Heart and Circulatory Physiology

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Nivala M, Qu Z. Calcium alternans in a couplon network model of ventricular myocytes: role of sarcoplasmic reticulum load. Am J Physiol Heart Circ Physiol 303: H341-H352, 2012. First published June 1, 2012; doi:10.1152/ajpheart.00302.2012.-Intracellular calcium (Ca) alternans in cardiac myocytes have been shown in many experimental studies, and the mechanisms remain incompletely understood. We recently developed a "3R theory" that links Ca sparks to whole cell Ca alternans through three critical properties: randomness of Ca sparks; recruitment of a Ca spark by neighboring Ca sparks; and refractoriness of Ca release units. In this study, we used computer simulation of a physiologically detailed mathematical model of a ventricular myocyte couplon network to study how sarcoplasmic reticulum (SR) Ca load and other physiological parameters, such as ryanodine receptor sensitivity, SR uptake rate, Na-Ca exchange strength, and Ca buffer levels affect Ca alternans in the context of 3R theory. We developed a method to calculate the parameters used in the 3R theory (i.e., the primary spark rate and the recruitment rate) from the physiologically detailed Ca cycling model and paced the model periodically to elicit Ca alternans. We show that alternans only occurs for an intermediate range of the SR Ca load, and the underlying mechanism can be explained via its effects on the 3Rs. Furthermore, we show that altering the physiological parameters not only directly changes the 3Rs but also alters the SR Ca load, having an indirect effect on the 3Rs as well. Therefore, our present study links the SR Ca load and other physiological parameters to whole cell Ca alternans through the framework of the 3R theory, providing a general mechanistic understanding of Ca alternans in ventricular myocytes. calcium cycling; calcium spark; modeling T-WAVE ALTERNANS HAVE BEEN closely associated with cardiac arrhythmias and sudden cardiac death (3,50,51,66,69). Intracellular calcium (Ca) alternans, as a potential cause of T-wave alternans (15,46), have been shown in many experimental studies (2, 5, 7, 16 -19, 25, 35, 41, 68, 71). However, the underlying mechanism of Ca alternans remains incompletely understood. Adler et al. (1) proposed a theoretical mechanism linking a nonlinear sarcoplasmic reticulum (SR) Ca release function to mechanical alternans. Evidence from experimental studies (17)(18)(19)71) shows that Ca alternans could be explained by a steep nonlinear dependence of SR Ca release upon the diastolic SR Ca load (Ca DSRL ) immediately preceding the release (a steep fractional release-load relationship). This mechanism requires that Ca DSRL alternate concomitantly with SR Ca release, but the refractoriness of SR Ca release is not explicitly required. Subsequent mathematical analyses and simulation studies either potentiated this theory (30,45,57,64,69,71) (41), and the importance of refractoriness in Ca alternans has been demonstrated in later studies (32,58). Therefore, the above experimental studies raise the issue of the roles of SR Ca an...

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Refractoriness of sarcoplasmic reticulum Ca²⁺ release determines Ca²⁺ alternans in atrial myocytes

Abstract: Shkryl VM, Maxwell JT, Domeier TL, Blatter LA. Refractoriness of sarcoplasmic reticulum Ca 2ϩ release determines Ca 2ϩ alternans in atrial myocytes.

Cited by 83 publications

References 68 publications

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

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

A technical review of optical mapping of intracellular calcium within myocardial tissue

Calcium alternans in a couplon network model of ventricular myocytes: role of sarcoplasmic reticulum load

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Refractoriness of sarcoplasmic reticulum Ca2+ release determines Ca2+ alternans in atrial myocytes

Abstract: Shkryl VM, Maxwell JT, Domeier TL, Blatter LA. Refractoriness of sarcoplasmic reticulum Ca 2ϩ release determines Ca 2ϩ alternans in atrial myocytes.

Cited by 83 publications

References 68 publications

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

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

A technical review of optical mapping of intracellular calcium within myocardial tissue

Calcium alternans in a couplon network model of ventricular myocytes: role of sarcoplasmic reticulum load

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Refractoriness of sarcoplasmic reticulum Ca²⁺ release determines Ca²⁺ alternans in atrial myocytes