Decoding myocardial Ca2+ signals across multiple spatial scales: A role for sensitivity analysis

Abstract

Numerous studies have employed mathematical modeling to quantitatively understand release of Ca2+ from the sarcoplasmic reticulum (SR) in heart. Models have been used to investigate physiologically important phenomena such as triggering of SR Ca2+ release by Ca2+ entry across the cell membrane and spontaneous leak of Ca2+ from the SR in quiescent heart cells. In this review we summarize studies that have modeled myocardial Ca2+ at different spatial scales: the sub-cellular level, the cellular level, and the multicellular level. We discuss each category of models from the standpoint of parameter sensitivity analysis, a common simulation procedure that can generate quantitative, comprehensive predictions about how changes in conditions influence model output. We propose that this is a useful perspective for conceptualizing models, in part because a sensitivity analysis requires the investigator to define the relevant parameters and model outputs. This procedure therefore helps to illustrate the capabilities and limitations of each model. We further suggest that in future studies, sensitivity analyses will aid in simplifying complex models and in suggesting experiments to differentiate between competing models built with different assumptions. We conclude with a discussion of unresolved questions that are likely to be addressed over the next several years.

In silico study of the effects of anti-arrhythmic drug treatment on sinoatrial node function for patients with atrial fibrillation

“…Thirdly, the uncertainty analysis is important for a more precise evaluation of the safety of antiarrhythmic drugs 25,78 . Therefore, our models and methodology should be improved, and statistics and treatment of uncertainties should be considered [78][79][80] and further investigated. Fourthly, the block effects of amiodarone on beta-adrenergic receptors were modelled with the same percentage decrease in the effects of (2020) 10:305 | https://doi.org/10.1038/s41598-019-57246-5 www.nature.com/scientificreports www.nature.com/scientificreports/ beta-adrenergic receptor stimulation on targets.…”

There and back again: Iterating between population-based modeling and experiments reveals surprising regulation of calcium transients in rat cardiac myocytes

“…Additionally, the phenomenological calcium release mechanism does not simulate realistic local depletion of SR [Ca 2+ ], an effect that is known to be important for proper termination of Ca 2+ release [60, 61]. However, as the experimental results demonstrate, phenomenological models that lack mechanistic details of Ca 2+ release can still be useful for addressing questions that depend primarily on the balance of fluxes across the cellular and SR membranes [21]. …”

Alterations in T-tubule and dyad structure in heart disease: challenges and opportunities for computational analyses

“…At the cellular level, however, different categories of models must be used to understand the cellular-level consequences of the structural changes. 50 For instance, a few recent cellular models can simulate both stochastic triggering of sparks and Ca 2+ flux balance between the cytosol and the SR. 17,18,47 These new models can consider not only some of the structural changes observed in HF such as RyR orphaning, but also changes to cell-wide Ca 2+ fluxes, such as increased NCX activity and decreased activity of the SR Ca 2+ ATPase (SERCA). Although these whole-cell models have been used to understand SR Ca 2+ leak in quiescent cells from diseased myocytes, most simulations performed to date have focussed on changes in RyR gating or SERCA function rather than on structural changes.…”

“…To understand the functional consequences of altered sub-cellular structures, it seems clear that stochastic models of local SR Ca 2+ release, 18,41,47 which usually assume idealized geometries, will need to be combined with models that simulate Ca 2+ movements in complex and realistic geometries. 60,69,70 As discussed in more detail elsewhere, 50 these two categories of models have generally been developed separately, but the strengths of the two approaches must be combined to address how alterations to T-tubules and dyads, Computational analysis of cardiac dyads which can sometimes be subtle, might affect EC coupling. Along these lines, an interesting question that has not yet been addressed through simulations concerns the functional consequences of irregularities in the structure of RyR clusters.…”