Decoding myocardial Ca2Â + signals across multiple spatial scales: A role for sensitivity analysis

Numerous studies have employed mathematical modeling to quantitatively understand release of Ca2 + from the sarcoplasmic reticulum (SR) in the 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. This article is part of a Special Issue entitled “Calcium Signaling in Heart”.