In-silico human electro-mechanical ventricular modelling and simulation for drug-induced pro-arrhythmia and inotropic risk assessment

Francesca Margara,Zhinuo J Wang,Francesc Levrero-Florencio,Alfonso Santiago,Mariano Vázquez,Alfonso Bueno-Orovio,Blanca Rodriguez

doi:10.1016/j.pbiomolbio.2020.06.007

Abstract

Human-based computational modelling and simulation are powerful tools to accelerate the mechanistic understanding of cardiac patho-physiology, and to develop and evaluate therapeutic interventions. The aim of this study is to calibrate and evaluate human ventricular electro-mechanical models for investigations on the effect of the electro-mechanical coupling and pharmacological action on human ventricular electrophysiology, calcium dynamics, and active contraction.The most recent models of human ventricular electrophysiology, excitation-contraction coupling, and active contraction were integrated, and the coupled models were calibrated using human experimental data. Simulations were then conducted using the coupled models to quantify the effects of electro-mechanical coupling and drug exposure on electrophysiology and force generation in virtual human ventricular cardiomyocytes and tissue. The resulting calibrated human electro-mechanical models yielded active tension, action potential, and calcium transient metrics that are in agreement with experiments for endocardial, epicardial, and mid-myocardial human samples. Simulation results correctly predicted the inotropic response of different multichannel action reference compounds and demonstrated that the electro-mechanical coupling improves the robustness of repolarisation under drug exposure compared to electrophysiology-only models. They also generated additional evidence to explain the partial mismatch between in-silico and in-vitro experiments on drug-induced electrophysiology changes.The human calibrated and evaluated modelling and simulation framework constructed in this study opens new avenues for future investigations into the complex interplay between the electrical and mechanical cardiac substrates, its modulation by pharmacological action, and its translation to tissue and organ models of cardiac patho-physiology.

Highlights

IntroductionHuman-based computational approaches have builtmomentum beyond academia, reaching clinical, industrial, and regulatory environments
Human-based computational approaches have builtAbbreviations: AP, action potential; APD, action potential duration; CaT, calcium transient; EAD, early afterdepolarisation.momentum beyond academia, reaching clinical, industrial, and regulatory environments
The aim of this study is to investigate the effects of electromechanical coupling in human ventricular electrophysiology, calcium dynamics and active contraction, and their modulation by pharmacological action using multiscale modelling and simulation

Summary

Introduction

Human-based computational approaches have builtmomentum beyond academia, reaching clinical, industrial, and regulatory environments. Technical advancement and availability of human tissue have fostered the collection of human-specific datasets, characterising different aspects of ventricular electro-mechanics These include excitation-contraction coupling and calcium dynamics (Lou et al, 2011; O’Hara et al, 2011; Coppini et al, 2013), as well as contractile (Mulieri et al, 1992; Pieske et al, 1996; Rossman, 2004; Land et al, 2017; Coppini et al, 2019) and passive material properties (Demer and Yin, 1983; Yin et al, 1987; Holzapfel and Ogden, 2009). Experimental data at different scales from subcellular to whole-organ dynamics have been integrated into multiscale computer models of human physiology (Augustin et al, 2016; Land et al, 2017; Prakosa et al, 2018; Levrero-Florencio et al, 2020)

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