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305 - Multiscale Methods for Definition of Ionic Variables in ElectrophysiologicalModelsJ. Carro1,2,3,*, J.F. Rodríguez Matas4,2 and E. Pueyo2,31Universidad San Jorge, Villanueva de Gállego, Spain
2Aragon Institute for Engineering Research, IIS Aragón, Universidad de Zaragoza, Spain
3CIBER in Bioengineering, Biomaterials & Nanomedicine (CIBER-BBN), Spain
4LaBS, Department of Chemistry, Materials and Chemical Engineering “Giulio Natta”, Politécnico di Milano, Milano, Italy*jcarro@usj.esI. INTRODUCTION
Models of gating currents are usually built by fitting the expression of individual gating variables to experimental data,thus considering each gate as independent of others. In thiswork, we present a methodology to fit ionic currents while considering the interaction with other elements defining the current
as well as the effects at cell and tissue levels.

II. METHODSThe Carro-Rodríguez-Laguna-Pueyo (CRLP) human ventricular action potential (AP) model [1] was used as the basis
for this study. In silico simulations of experimental protocols
were run to optimally define voltage-dependent L-type calcium(ICaL) current inactivation gates (f, f2). The parameters describing steady-state gating inactivation were identified by solving
an optimization problem using a response surface methodology[2]. A number of constraints were considered, and each result
validated, at the ionic level, based on experimental evidence:steady-state voltage-dependent ICaL inactivation was required todecrease monotonically for negative voltage values and have
only one inflection point. The effects of introducing thosechanges in the model were evaluated at cell and tissue level. In
this regard, a set of arrhythmic risk markers, including systolicand diastolic intracellular calcium concentration ([Ca2+] i), AP
duration (APD), AP triangulation and the slow time constant of
APD adaptation to abrupt cycle length changes ( slow) were required to lie within experimental ranges.

being 20% lower than for the original CRLP model. At cell andtissue levels, APD, Triangulation and slow lay within physiological ranges, and systolic and diastolic [Ca2+] i values were of
the same order than for the original CRLP model.

IV. CONCLUSIONS
The methodology proposed in this study can greatly help to define ionic current models in good concordance with experimental results. To avoid model overfitting, validation at all involved scales is advised.

ACKNOWLEDGMENT
This work was supported by Ministerio de Economía yCompetitividad and FEDER (EU), under projects DPI201675458-R, by CIBER in Bioengineering, Biomaterials & Nanomedicne (CIBER-BBN) through Instituto de Salud Carlos III,and by Grupo Consolidado BSICoS (T96) and Grupo Consolidado AMB (T88), from DGA and European Social Fund.

CONFLICT OF INTEREST
The authors declare that they have no conflict of interest.

REFERENCES
1.

2.

III. RESULTS
The redefined ICaL current satisfactorily reproduced experimental observations, with mean square errors between simulated and experimental steady-state inactivation current values

J. Carro, J. F. Rodríguez, P. Laguna, and E. Pueyo, “A human ventricular cell model for investigation of cardiac arrhythmias under
hyperkalaemic conditions”, Phil Trans A, vol. 369, iss. 1954, pp.
4205-4232, 2011.
J.F. Rodríguez, J.E. Renaud and L.T. Watson, “Trust region augmented lagrangian methods for sequential response surface approximation and optimization”, J Mech Design, vol 120(1), pp. 5866, 1998.