Novel Computational Model of Human Ventricular Action Potential for Investigate the Extracellular Calcium Effects

Chiara Bartolucci

Univ. of Bologna, Dept. of Electrical, Electronic and Information Engineering "Guglielmo Marconi"

Friday 5th March 2021

11:00:00

Online seminar: https://mox.polimi.it/elenco-seminari/?id_evento=2027&t=763721

The importance of electrolyte concentrations for the cardiac function is well established. Electrolyte variations can lead to arrhythmias onset, due to their important role in the action potential (AP) genesis and in maintaining cell homeostasis. However, most of the human AP computer models available in the literature were developed with constant electrolyte concentrations, and fail to simulate physiological changes induced by electrolyte variations. This is especially true for Ca2+, even in the most widely used models in cardiac electrophysiology. The new human ventricular model (BPS2020, [1]), based on O’Hara-Rudy (ORd, [2]) model, aims to correct simulate changes due to electrolytes and answer the question: "which are the quantitative contributions of the mechanisms involved in the relationship between extracellular calcium concentration [Ca2+]o and the AP?"[3], using human-based modeling and simulations since they could provide useful support to investigate this phenomenon. 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, the main changes needed with respect to ORd are: (i) increased sensitivity of ICaL current inactivation to [Ca2+]o; (ii) a single compartment description of the sarcoplasmic reticulum; iii) the replacement of Ca2+ release. BPS2020 can simulate the physiological APD-[Ca2+]o relationship, while also retaining the well-reproduced properties of ORd (APD rate dependence at [K+]o=4mM, restitution, accommodation, and current block effects). We also used BPS2020 to generate an experimentally-calibrated population of models to investigate: (i) the occurrence of repolarization abnormalities in response to hERG current block; (ii) the rate adaptation variability; (iii) the occurrence of alternans and delayed after-depolarizations at fast pacing. Our results indicate that we successfully developed an improved version of ORd, which can be used to investigate electrophysiological changes and pro-arrhythmic abnormalities induced by electrolyte variations and current block at multiple rates and at population level. [1] Bartolucci C, Passini E, Hyttinen J, Paci M, Roth BJ. Simulation of the Effects of Extracellular Calcium Changes Leads to a Novel Computational Model of Human Ventricular Action Potential With a Revised Calcium Handling 2020;11:1-20. doi:10.3389/fphys.2020.00314. [2] O’Hara T, Virág L, Varró A, Rudy Y. Simulation of the undiseased human cardiac ventricular action potential: Model formulation and experimental validation. PLoS Comput Biol 2011;7. [3] Bartolucci C, Paci M, Severi S. Investigation of the Extracellular Calcium Effects on Action Potential using the Most Recent Human Ventricular Cell Models. 2020 Comput Cardiol Conf 2020;47:7-10. doi:10.22489/cinc.2020.296. Contatto: francesco.regazzoni@polimi.it