title: Limitations in electrophysiological model development and validation caused by differences between simulations and experimental protocols.
abstract: Models of ion channel dynamics are usually built by fitting isolated cell experimental values of individual parameters while neglecting the interaction between them. Another shortcoming regards the estimation of ionic current conductances, which is often based on quantification of Action Potential (AP)-derived markers. Although this procedure reduces the uncertainty in the calculation of conductances, many studies evaluate electrophysiological AP-derived markers from single cell simulations, whereas experimental measurements are obtained from tissue preparations. In this work, we explore the limitations of these approaches to estimate ion channel dynamics and maximum current conductances and how they could be overcome by using multiscale simulations of experimental protocols. Four human ventricular cell models, namely ten Tusscher and Panfilov (2006), Grandi et al. (2010), O'Hara et al. (2011), and Carro et al. (2011), were used. Two problems involving scales from ion channels to tissue were investigated: 1) characterization of L-type calcium voltage-dependent inactivation ICa,L; 2) identification of major ionic conductance contributors to steady-state AP markers, including APD90, APD75, APD50, APD25, Triangulation and maximal and minimal values of V and dV/dt during the AP (Vmax, Vmin, dV/dtmax, dV/dtmin). Our results show that: 1) ICa,Linactivation characteristics differed significantly when calculated from model equations and from simulations reproducing the experimental protocols. 2) Large differences were found in the ionic currents contributors to APD25, Triangulation, Vmax, dV/dtmaxand dV/dtminbetween single cells and 1D-tissue. When proposing any new model formulation, or evaluating an existing model, consistency between simulated and experimental data should be verified considering all involved effects and scales.
authors.affiliation: Universidad San Jorge, Campus Universitario, Autov A23 Km 299, 50830, Villanueva de Gállego, Zaragoza, Spain; Aragon Institute for Engineering Research, Universidad de Zaragoza, Spain; CIBER in Bioengineering, Biomaterials & Nanomedicine (CIBER-BBN), Spain. Electronic address: jcarro@usj.es.
authors.forename: Jesús
authors.initials: J
authors.lastname: Carro
authors.affiliation: Aragon Institute for Engineering Research, Universidad de Zaragoza, Spain; LaBS, Department of Chemistry, Materials and Chemical Engineering "Giulio Natta", Politecnico di Milano, Italy. Electronic address: josefelix.rodriguezmatas@polimi.it.
authors.forename: José F
authors.initials: JF
authors.lastname: Rodríguez-Matas
authors.affiliation: Universidad San Jorge, Campus Universitario, Autov A23 Km 299, 50830, Villanueva de Gállego, Zaragoza, Spain. Electronic address: vmonasterio@usj.es.
authors.forename: Violeta
authors.initials: V
authors.lastname: Monasterio
authors.affiliation: Aragon Institute for Engineering Research, Universidad de Zaragoza, Spain; CIBER in Bioengineering, Biomaterials & Nanomedicine (CIBER-BBN), Spain. Electronic address: epueyo@unizar.es.
authors.forename: Esther
authors.initials: E
authors.lastname: Pueyo
mesh_terms: D000200:Action Potentials; D015415:Biomarkers / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D020746:Calcium Channels, L-Type / Q000378:metabolism; D055724:Electrophysiological Phenomena; D006352:Heart Ventricles / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008955:Models, Cardiovascular
chemical_list: D015415:Biomarkers; D020746:Calcium Channels, L-Type; D002118:Calcium
keywords: Action potential; Cardiac modeling; Electrophysiology; Ionic currents; Model validation