Identification of Cardiomyocytes' Inner Workings Responsible for Dynamical Changes in Calcium Profile in Response to Mechanical Load

Abstract

Background: We embedded cardiomyocytes in a cross-linked hydrogel to study the effect of increased afterload on in the heart. We observed that mechanically-loaded cardiomyocytes undergo changes in their Ca2+ dynamics that can compensate for the increase in load. We have shown that these changes are mediated by the upregulation of nitric oxide (NO) signalling, which in turns affects Ca2+ handling. Because many different Ca2+ pathways could be affected we used an agnostic approach based on mathematical modelling to tease out changes in cell characteristics responsible for the differences in calcium and contraction profiles between load-free and after-load environment. Mathematical Method: We coupled the Shannon-Bers ventricular action potential model to a viscoelastic model to simulate the myocyte contracting in either a load-free condition (Tyrode solution) or under load (in the gel matrix). The mathematical model establishes a closed feedback loop between the calcium system and the extracellular environment that gives rise to the self-regulation we observed. We ran extensive simulations where parameters associated with the influx and efflux of Ca2+ were modulated such that they are either up-regulated or down-regulated by NO. In silico results are filtered out to qualitatively match cell-in-gel in vitro results. The filtering process is based on measures that capture multiple properties of calcium profiles. Conclusion: Our approach of identification hints that the upregulation of NO has the effect of simultaneously modulating multiple parameters of the Ca2+ handling pathway. Of the modulated parameters, the L-type current amplitude has to be consistently increased. Coupled with the increase in L-type current, parameters associated with release and uptake of calcium by the SR have to be modulated in opposite directions.