Simulation of the Effects of Extracellular Calcium Changes Leads to a Novel Computational Model of Human Ventricular Action Potential With a Revised Calcium Handling.

Chiara Bartolucci,Michelangelo Paci,Elisa Passini,Jari Hyttinen,Stefano Severi

doi:10.3389/fphys.2020.00314

Abstract

The importance of electrolyte concentrations for 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 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 O’Hara-Rudy model (ORd), one of the most widely used models in cardiac electrophysiology. Therefore, the present work develops a new human ventricular model (BPS2020), based on ORd, able to simulate the inverse dependence of AP duration (APD) on extracellular Ca2+ concentration ([Ca2+]o), and APD rate dependence at 4 mM extracellular K+. The main changes needed with respect to ORd are: (i) an increased sensitivity of L-type Ca2+ current inactivation to [Ca2+]o; (ii) a single compartment description of the sarcoplasmic reticulum; iii) the replacement of Ca2+ release. BPS2020 is able to simulate the physiological APD-[Ca2+]o relationship, while also retaining the well-reproduced properties of ORd (APD rate dependence, 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 the population level.

Highlights

In the last few decades, computational models have been increasingly used to study biological systems, due to the productive synergy between the in silico approach and the collection of experimental data, as well as to the improvement in computational resources
Most of the published models respond with action potential (AP) prolongation to increases in [Ca2+]o, i.e., opposite of what observed in vitro and in vivo (Leitch, 1996; Severi et al, 2009; Nagy et al, 2013; Supplementary Figure S1), including ORd
An additional quantitative analysis of AP biomarkers dependence on extracellular electrolytes ([K+]o and [Na+]o) was performed

Summary

Introduction

In the last few decades, computational models have been increasingly used to study biological systems, due to the productive synergy between the in silico approach and the collection of experimental data, as well as to the improvement in computational resources. One of the most productive fields of application is cardiac physiology: modeling has provided physiological insights through the prediction of phenomena and mechanisms, later confirmed or disproved experimentally (e.g., Denis and Yoram, 2001; Carusi et al, 2012; Severi et al, 2014; Krogh-Madsen et al, 2016; Ni et al, 2018; Niederer et al, 2019). The “gold standard” for in silico human ventricular cellular electrophysiology is the O’Hara-Rudy (ORd) model (O’Hara et al, 2011). Since mathematical models are reduced representations of the real biological systems, there is always room for improvements. The present work aims to propose a new and improved model of the human cardiac ventricular AP, starting from the ORd model

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