Depolarization of Cardiac Membrane Potential Synchronizes Calcium Sparks and Waves in Tissue

The diastolic membrane potential (V-m) can be hyperpolarized or depolarized by various factors such as hyperkalemia or hypokalemia in the long term, or by delayed after depolarizations in the short term. In this study, we investigate how V-m affects Ca sparks and waves. We use a physiologically detailed mathematical model to investigate individual factors that affect Ca spark generation and wave propagation. We focus on the voltage range of -90 similar to -70 mV, which is just below the V-m for sodium channel activation. We find that V-m depolarization promotes Ca wave propagation and hyperpolarization prevents it. This finding is directly validated in voltage clamp experiments with Ca waves using isolated rat ventricular myocytes. Ca transport by the sodium-calcium exchanger (NCX) is determined by V-m as well as Na and Ca concentrations. Depolarized V-m reduces NCX-mediated efflux, elevating [Ca](i), and thus promoting Ca wave propagation. Moreover, depolarized Vm promotes spontaneous Ca releases that can cause initiation of multiple Ca waves. This indicates that during delayed after depolarizations, Ca release units (CRUs) interact with not just the immediately adjacent CRUs via Ca diffusion, but also further CRUs via fast (similar to 0.1 ms) changes in V-m mediated by the voltage and Ca-sensitive NCX. This may contribute significantly to synchronization of Ca waves among multiple cells in tissue.