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

Chiara Bartolucci1, Michelangelo Paci2, Stefano Severi1
1University of Bologna, 2Tampere University


The present work aims to answer the following question: what are the quantitative contributions of the mechanisms involved in the relationship between extracellular calcium concentration [Ca2+]o and the action potential (AP)? In this context, human-based modeling and simulations could provide useful support to investigate this phenomenon. However, [Ca2+]o dependence on AP duration, which is opposite, is not reproduced correctly by most of the commonly used human AP models. Four of the most recent human ventricular AP models (Grandi-Bers (GB), O’Hara-Rudy (ORd), Tomek et al. (TorORd), and Bartolucci et al. (BPS)) have been tested by simulating different extracellular calcium concentrations during an 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 during AP-clamp simulations. The result of our analysis was three ventricular models (ORd, GB, and TorORd) responded with APD prolongation to [Ca2+]o increase, a behavior which is in contrast to the APD shortening observed in vitro and in vivo when extracellular, or plasma calcium concentration, is increased. Instead, the BPS model correctly reproduced this dependence. The effects of CDI on ICaL in the ORd, and TorORd models are underestimating; in the GB model, this behavior is less evident, but still, the APD-[Ca2+]o dependence was not correctly simulated. Therefore in the BPS model strong CDI, enables simulating APD prolongation at decreasing [Ca2+]o. To better understand the GB behaviour we analyzed the other currents affected by [Ca2+]o variations and this investigation pointed out the contribution of INaCa.