Investigation of the Extracellular Calcium Effects on Action Potential Using the Most Recent Human Ventricular Cell Models

Which are the quantitative contributions of the mechanisms involved in the relationship between extracellular calcium concentration [Ca²⁺]o and the action potential (AP)? The present work aims to answer this question using human-based modeling and simulations since they could provide useful support to investigate this phenomenon. However, [Ca²⁺]o dependence on AP duration is not reproduced correctly by most of the commonly used human AP models. Four of the most recent human ventricular AP models have been tested by simulating different extracellular calcium concentrations during the AP-clamp protocol. From earlier studies, it is well known that the L-type Ca²⁺ current (ICaL) is the ionic current mainly affected by [Ca²⁺]o changes. In particular, calcium-dependent inactivation (CDI) seems to play the most significant role. For this reason, we simulated two different conditions: with the basal models and with the models in which the CDI has been turned off. The results pointed out from the models' comparison is that not only ICaL CDI contributes to the APD-[Ca²⁺]orelationship but also the sodium-calcium Exchanger (INaCa) played an important role.