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

Intracellular Ca(2+) dynamics of cardiac myocytes are regulated by complex mechanisms of a variety of ion channels, transporters, and exchangers. Alterations of these Ca(2+) regulatory components might lead to development of cardiac diseases. To investigate the regulatory mechanisms and hidden Ca(2+) 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 Ca(2+) regulatory proteins and their influence on intracellular Ca(2+) dynamics (i.e., Ca(2+) transient, SR Ca(2+) 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 Ca(2+) 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 Ca(2+) 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 Ca(2+) release and thereby the intracellular Ca(2+) dynamics was dramatically changed. We also found that the pacing period has a significant effect on the half-decay time of the Ca(2+) transients. These findings provide us with new insights into the pathophysiology of cardiac failure as well as the development of new therapeutic strategies.