Cardiac systems biology and parameter sensitivity analysis: Intracellular Ca²⁺ regulatory mechanisms in mouse ventricular myocytes

Intracellular Ca²⁺ dynamics of cardiac myocytes are regulated by complex mechanisms of a variety of ion channels, transporters, and exchangers. Alterations of these Ca²⁺ regulatory components might lead to development of cardiac diseases. To investigate the regulatory mechanisms and hidden Ca²⁺ dynamics we use integrative systems analysis. Herein, we briefly summarize cardiac systems biology and, within the context of cardiac systems biology, identify the functional role of key Ca²⁺ regulatory proteins and their influence on intracellular Ca²⁺ dynamics (i.e., Ca²⁺ transient, SR Ca²⁺ content, CICR gain, half-decay time) using parameter sensitivity analysis based on an experimentally validated mathematical model of mouse ventricular myocytes. In addition, we analyze the influence of the pacing period (frequency) of a stimulus current since most of the Ca²⁺ regulatory proteins react with different timescales. Throughout the parameter sensitivity analysis, we found that alteration of SERCA or LTCC has a more significant effect on the Ca²⁺ dynamics than that of RyR or NCX. In particular, for the 70% down-regulation of LTCC, the Ca ²⁺ influx through LTCC failed to initialize the SR Ca²⁺ release and thereby the intracellular Ca²⁺ dynamics was dramatically changed. We also found that the pacing period has a significant effect on the half-decay time of the Ca²⁺ transients. These findings provide us with new insights into the pathophysiology of cardiac failure as well as the development of new therapeutic strategies.