Elisa Passini

National Centre for the Replacement, Refinement and Reduction of Animals in Research | NC3Rs

With many advancements in in silico biology in recent years, the paramount challenge is to translate the accumulated knowledge into exciting industry partnerships and clinical applications. Achieving models that characterize the link of molecular interactions to the activity and structure of a whole organ are termed multiscale biophysics. Historica...

Levetiracetam (LEV), a well-established anti-seizure medication (ASM), was launched before the original ICH S7B nonclinical guidance assessing QT prolongation potential and the introduction of the Comprehensive In Vitro Proarrhythmia Assay (CiPA) paradigm. No information was available on its effects on cardiac channels. The goal of this work was to...

The preclinical identification of drug-induced cardiotoxicity and its translation into human risk are still major challenges in pharmaceutical drug discovery. The ICH S7B Guideline and Q&A on Clinical and Nonclinical Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential promotes human in silico drug trials as a novel tool for proar...

Background and Purpose Preclinical identification and understanding of drug-induced cardiotoxicity is still a major challenge. The ICH S7B Q&A promote human in silico drug trials for proarrhythmia risk assessment. However, additional evidence is needed to support further regulatory impact and for their integration in the current preclinical assessm...

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NC3Rs Infrastructure for Impart Award (NC/P001076/1) Wellcome Trust Senior Research Fellowship in Basic Biomedical Sciences (214290/Z/18/Z) Background Human-based computer modelling and simulations have been widely used in cardiac elec...

We applied a set of in silico and in vitro assays, compliant with the CiPA (Comprehensive In Vitro Proarrhythmia Assay) paradigm, to assess the risk of chloroquine or hydroxychloroquine‐mediated QT prolongation and Torsades de Pointes (TdP), alone and combined with erythromycin and azithromycin, drugs repurposed during the first wave of COVID‐19. E...

Objectives: Improvements in human stem cell-derived cardiomyocyte (hSC-CM) technology have promoted their use for drug testing and disease investigations. Several in silico hSC-CM models have been proposed to augment interpretation of experimental findings through simulations. This work aims to assess the response of three hSC-CM in silico models (...

Prediction of drug effects on the heart still represents a challenge in drug development, given potential adverse outcomes. Computer modelling and simulations of the human heart offer a powerful technology to augment existing animal and clinical methodologies. Here we describe the translation process that led to the development and uptake of Virtua...

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 electrol...

Cardiac Purkinje cells (PCs) are implicated in lethal arrhythmias caused by cardiac diseases, mutations, and drug action. However, the pro-arrhythmic mechanisms in PCs are not entirely understood, particularly in humans, as most investigations are conducted in animals. The aims of this study are to present a novel human PCs electrophysiology biophy...

High-throughput in vitro drug assays have been impacted by recent advances in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) technology and by contact-free all-optical systems simultaneously measuring action potential (AP) and Ca²⁺ transient (CaTr). Parallel computational advances have shown that in silico simulations can pr...

Torsades de Pointes (TdP) is a type of ventricular arrhythmia which could be observed as an unwanted drug-induced cardiac side effect, and it is associated with repolarization abnormalities in single cells. The pharmacological evaluations of TdP risk in previous years mainly focused on the hERG channel due to its vital role in the repolarization of...

Human-based in silico models are emerging as important tools to study the effects of integrating inward and outward ion channel currents to predict clinical proarrhythmic risk. The aims of this study were 2-fold: 1) Evaluate the capacity of an in silico model to predict QTc interval prolongation in the in vivo anesthetized cardiovascular guinea pig...

Human-based modelling and simulations are becoming ubiquitous in biomedical science due to their ability to augment experimental and clinical investigations. Cardiac electrophysiology is one of the most advanced areas, with cardiac modelling and simulation being considered for virtual testing of pharmacological therapies and medical devices. Curren...

This white paper presents principles for validating proarrhythmia risk prediction models for regulatory use as discussed at the In Silico Breakout Session of a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/US Food and Drug Administration–sponsored Think Tank Meeting on May 22, 2018. The meeting was convened to evalu...

High-throughput in vitro drug assays have been impacted by recent advances in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs) technology and by contact-free all-optical systems simultaneously measuring action potential (AP) and Ca ²⁺ transient (CaTr). Parallel computational advances have shown that in silico models can predict...

Background and purpose: Early identification of drug-induced cardiac adverse events is key in drug development. Human-based computer models are emerging as an effective approach, complementary to in vitro and animal models. Drug-induced shortening of the electromechanical window has been associated with increased risk of arrhythmias. This study in...

Background: Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to h...

Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human. Key ch...

Background: Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are in vitro models with the clear advantage of their human origin and suitability for human disease investigations. Limitations however include an incomplete characterization and variability reported in different cell lines and laboratories. Objective: We aim to...

Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are characterized by an extreme variability, which cannot be reproduced by a single in silico model. Here we present a population of hiPSC-CM models, calibrated using six different experimental datasets. By sampling the maximum conductances of 11 ionic currents, 10000 parameter...

Both biomedical research and clinical practice rely on complex datasets for the physiological and genetic characterization of human hearts in health and disease. Given the complexity and variety of approaches and recordings, there is now growing recognition of the need to embed computational methods in cardiovascular medicine and science for analys...

Supplementary material

Physiological variability manifests itself via differences in physiological function between individuals of the same species, and has crucial implications in disease progression and treatment. Despite its importance, physiological variability has traditionally been ignored in experimental and computational investigations due to averaging over sampl...

Both biomedical research and clinical practice rely on complex datasets for the physiological and genetic characterization of human hearts in health and disease. Given the complexity and variety of approaches and recordings, there is now growing recognition of the need to embed computational methods in cardiovascular medicine and science for analys...

Introduction: Hypertrophic cardiomyopathy (HCM) is a cause of sudden arrhythmic death, but the understanding of its pro-arrhythmic mechanisms and an effective pharmacological treatment are lacking. HCM electrophysiological remodelling includes both increased inward and reduced outward currents, but their role in promoting repolarisation abnormalit...

During haemodialysis (HD) sessions, patients undergo alterations in the extracellular environment, mostly concerning plasma electrolyte concentrations, pH, and volume, together with a modification of sympathovagal balance. All these changes affect cardiac electrophysiology, possibly leading to an increased arrhythmic risk. Computational modeling ma...

Hypertrophic cardiomyopathy (HCM) is a genetic disorder characterised by increased arrhythmic risk. The causes are still unclear, but potential pro-arrhythmic mechanisms may include increased temporal and spatial variability in action potential duration (APD) as well as repolarisation abnormalities, such as early after-depolarisations (EADs) and AP...

Atrial fibrillation (AF) incidence is high in end-stage renal disease (ESRD) patients, and haemodialysis (HD) session may induce paroxysmal AF episodes. Structural atrium remodelling is common in ESRD patients, moreover, HD session induces rapid plasma electrolytes and blood volume changes, possibly favouring arrhythmia onset. Therefore, HD session...

It is well known that extracellular calcium concentration ([Ca2+]o) affects cardiac action potential duration (APD): their inverse relationship has been experimentally observed in vivo and in vitro. Both shortening and prolongation of AP are associated with an increased risk of arrhythmias and extracellular calcium variations may occur in many clin...

Extracellular calcium concentration ([Ca2+]o) affects cardiac action potential (AP): their inverse dependence has already been assessed in vivo and in vitro. Both shortening and prolongation of AP are associated with an increased risk of arrhythmias and Ca2+ variations may occur in many different contexts (e.g. pathological hypo/hypercalcemia, haem...

Several episodes of ventricular arrhythmias have been reported during spaceflights, and cardiovascular deconditioning induced by microgravity exposure has already been assessed. Strict Head-Down Bed Rest (HDBR) can be used to simulate microgravity effects on the cardiovascular system. Therefore, it represents an invaluable opportunity to study and...

Purpose: Atrial fibrillation (AF) is the most common cardiac rhythm disorder. Pharmacological treatment of AF is hampered by ventricular pro-arrhythmia. Modulation of atrium-specific Kir3.x channels, which generate a constitutively active current (IK,ACh-c) after atrial remodeling, could possibly circumvent this problem. However, it is not yet know...

A decrease in extracellular calcium concentration ([Ca2+]o) prolongs the action potential (AP) in ventricular cardiomyocytes, and vice versa. Although this phenomenon can be relevant to arrhythmogenesis in clinical settings, it is not included in most of the commonly used computational models of ventricular AP. Therefore, the aim of this study has...