PUBLICATIONS

Ion Channel Expression & Electrophysiology of Singular Human (Primary & Induced Pluripotent Stem Cell-Derived) Cardiomyocytes

Single-cell patch-clamp reverse transcriptase-quantitative polymerase chain reactions were used to clarify the composition of the iCell cardiomyocyte population to compare with atrial and ventricular cardiomyocytes. This comparison provided evidence that may hamper the interpretation of drug effects parameters depending on a combination of ionic currents, such as beat rate, and supports the evaluation of drug effects in a more realistic cardiomyocyte environment. 

PUBLICATION: Cells (2021)

AUTHORS: Christina Schmid, Najah Abi-Gerges, Michael Georg Leitner, Dietmar Zellner and Georg Rast

Cardiotoxic Potential of Hydroxychloroquine, Chloroquine and Azithromycin in Adult Human Primary Cardiomyocytes

This paper evaluates the pro-arrhythmia risk and inotropic effects of Hydroxychloroquine, Chloroquine and Azithromycin in the cardiomyocyte contractility-based model of the human heart due to their proposed repurposed use to treat COVID-19. The study conclusion has the potential to inform clinical studies evaluating repurposed therapies and demonstrates the translational value of human cardiomyocyte contractility-based model for novel COVID-19 therapies.

PUBLICATION: Society of Toxicology (2021)

AUTHORS: Pierre Jordaan, Berenge`re Dumotier, Martin Traebert, Paul E. Miller, Andre Ghetti, Laszlo Urban and Najah Abi-Gerges

Multiparametric Mechanistic Profling of Inotropic Drugs in Adult Human Primary Cardiomyocytes

To combat challenges in assessing drug effects on cardiac contractility, the development of an adult primary cardiomyocyte contractility model that has the potential to provide a predictive preclinical approach for simultaneously predicting drug-induced inotropic effect is needed. The contractility model used in this paper could accurately facilitate informed mechanistic-based decision making, risk management and discovery of molecules with the most desirable pharmacological profile for heart failure correction.

PUBLICATION: Scientific Reports (2020)

AUTHORS: Najah Abi-Gerges, Tim Indersmitten, KyTruong, William Nguyen, Phachareeya Ratchada, Nathalie Nguyen, Guy Page, Paul E. Miller & Andre Ghetti

Discovery and characterization of the NCX inhibitor ORM-11372

The lack of selective sodium-calcium exchanger (NCX) inhibitors has hampered the exploration of physiological and pathophysiological roles of cardiac NCX 1.1. This paper aimed to discover more potent and selective drug like NCX 1.1 inhibitor. ORM-11372 was found to be a positive inotropic compound and potent inhibitor of human and rat NCX 1.1.

PUBLICATION: British Journal of Pharmacology (2020)

AUTHORS: Leena Otsomaa, Jouko Levijoki, Gerd Wohlfahrt, Hugh Chapman, Ari-Pekka Koivisto, Kaisa Syrjänen, Tuula Koskelainen, Saara-Elisa Peltokorpi, Piet Finckenberg, Aira Heikkilä, Najah AbiGerges, Andre Ghetti, Paul E. Miller, Guy Page, Eero Mervaala, Norbert Nagy, Zsófia Kohajda, Norbert Jost, László Virág, András Varró and Julius Gy. Papp

Computational cardiology and risk stratification for sudden cardiac death: one of the grand challenges for cardiology in the 21st century

Computational cardiology currently stands at the threshold of clinical utility regarding risk stratification and treatment of patients at risk of sudden cardiac death. This white paper outlines a roadmap of what needs to be done to make a translational step using the relatively well-developed case of acquired or drug-induced long QT syndrome as an exemplar case.

PUBLICATION: Journal of Physiology (2016)

AUTHORS: Adam P. Hill, Matthew D. Perry, Najah Abi-Gerges, Jean-Philippe Couderc, Bernard Fermini, Jules C. Hancox, Bjorn C. Knollmann, Gary R. Mirams, Jon Skinner, Wojciech Zareba and Jamie I. Vandenberg

Human-based approaches to pharmacology & cardiology: an interdisciplinary and intersectorial workshop

This paper describes the next steps for a human-based approach to disease supported by computational methodologies as described at a Workshop on Computational Cardiovascular Science. The main ideas outlined show a shift towards human-based methodologies spurred by advances in computational approaches to complement in vitro, in vivo and ex vivo experimental and clinical data as an integral part of pharmacology and medicine.

PUBLICATION: European Society of Cardiology (2017)

AUTHORS: Blanca Rodriguez, Annamaria Carusi, Najah Abi-Gerges, Rina Ariga, Oliver Britton, Gil Bub, Alfonso Bueno-Orovio, Rebecca A.B. Burton, Valentina Carapella, Louie Cardone-Noott, Matthew J. Daniels, Mark R. Davies, Sara Dutta, Andre Ghetti, Vicente Grau, Stephen Harmer, Ivan Kopljar, Pier Lambiase, Hua Rong Lu, Aurore Lyon, Ana Minchole, Anna Muszkiewicz, Julien Oster, Michelangelo Paci, Elisa Passini1, Stefano Severi, Peter Taggart, Andy Tinker, Jean-Pierre Valentin, Andras Varro, Mikael Wallman and Xin Zhou

Quantitative Comparison of Effects of Dofetilide, Sotalol, Quinidine & Verapamil between Human Ex vivo Trabeculae and In silico Ventricular Models Incorporating Inter-Individual Action Potential Variability

A lack of human-specific data and appropriate model techniques have previously prevented quantitative comparison of drug effects between in silico models and recordings from human cardiac preparations. This paper compares changes in repolarization biomarkers caused by dofetilide, dl-sotalol, quinidine, and verapamil, between in silico populations of human ventricular cell models and ex vivo human ventricular trabeculae.

PUBLICATION: Frontiers in Physiology (2017)

AUTHORS: Oliver J. Britton, Najah Abi-Gerges, Guy Page, Andre Ghetti, Paul E. Miller and Blanca Rodriguez

Human ex-vivo action potential model for pro-arrhythmia risk assessment

This paper investigates if a human ex-vivo AP-based model could provide a more predictive approach for assessing pro-arrhythmic risk. The effects of dofetilide, dl-sotalol, quinidine, paracetamol, and verapamil on action potential (AP) duration and recognized pro-arrhythmia predictors, triangulation, and incidence of early afterdepolarizations were evaluated. The model provided an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach.

PUBLICATION: Journal of Pharmacological and Toxicological Methods (2016)

AUTHORS: Guy Page, Phachareeya Ratchada, Yannick Miron, Guido Steiner, Andre Ghetti, Paul E. Miller, Jack A. Reynolds, Ken Wang, Andrea Greiter-Wilke, Liudmila Polonchuk, Martin Traebert, Gary A. Gintant, Najah Abi-Gerges

Adult Human Primary Cardiomyocyte-Based Model for the Simultaneous Prediction of Drug-Induced Inotropic and Pro-arrhythmia Risk

Cardiac safety remains the leading cause of drug development discontinuation. AnaBios has developed a human cardiomyocyte-based model that has the potential to provide a predictive preclinical approach for simultaneously predicting drug-induced inotropic and pro-arrhythmia risk.

PUBLICATION: Frontiers in Physiology (2017)

AUTHORS: Nathalie Nguyen, William Nguyen, Brynna Nguyenton, Phachareeya Ratchada, Guy Page, Paul E. Miller, Andre Ghetti and Najah Abi-Gerges

FDA Workshop on Improving Cardiotoxicity Assessment With Human-Relevant Platforms

The National Center for Toxicological Research of the US Food and Drug Administration (FDA) hosted a workshop to discuss current gaps and challenges in translating preclinical cardiovascular safety data to humans. This white paper summarizes the topics presented by speakers from academia, industry, and government intended to address the theme of improving cardiotoxicity assessment in drug development.

PUBLICATION: Circulation Research (2019)

AUTHORS: Li Pang, Philip Sager, Xi Yang, Hong Shi, Frederick Sannajust, Mathew Brock, Joseph C. Wu, Najah Abi-Gerges, Beverly Lyn-Cook, Brian R. Berridge, Norman Stockbridge

Human Purkinje in silico model enables mechanistic investigations into automaticity and pro-arrhythmic abnormalities

Cardiac Purkinje cells (PCs) are implicated in lethal arrhythmias caused by cardiac diseases, mutations, and drug action and are not entirely understood in humans. The aims of this study were to present novel human PCs electrophysiology biophysically detailed computational model, and to disentangle ionic mechanisms of human Purkinje-related electrophysiology, pacemaker activity and arrhythmogenicity. The model used unlocked further investigations into the role of cardiac Purkinje in ventricular arrhythmias through computer modelling and multiscale simulations.

PUBLICATION: Journal of Molecular and Cellular Cardiology (2020)

AUTHORS: Cristian Trovato, Elisa Passini, Norbert Nagy, Andras Varro, Najah Abi-Gerges, Stefano Severi and Blanca Rodriguez

Adult Human Primary Cardiomyocytes: An Integrative Translational Model for Preclinical Drug Testing

AnaBios has established methodologies that consistently allow the procurement and experimental interrogation of human heart tissue preparations to provide a much-needed integrative preclinical model to reliably assess the toxicity risk of new drugs. These novel methodologies include scalable ex-vivo heart models from the isolation of adult human primary cardiomyocytes.

PUBLICATION: Journal of Pharmacological and Toxicological Methods (2017)

AUTHORS: Nathalie NguyenYannick MironPhachareeya RatchadaGuy PagePaul E. MillerAndre Ghetti and Najah Abi-Gerges

Label-Free Imaging Of Atherosclerotic Plaques Using Third-Harmonic Generation Microscopy​

Third harmonic generation (THG) from atherosclerotic plaques revealed morphological details of cellular and extracellular lipid deposits. The THG signal adds an endogenous contrast mechanism with a practical degree of specificity for atherosclerotic plaques that complements current nonlinear optical methods for the investigation of cardiovascular disease. The use of the whole-mount tissue and backward scattered epi-detection suggests THG could potentially be used in the future as a clinical tool.

PUBLICATION: Biomedical Optics Express (2014)

AUTHORS: David M. Small, Jason S. Jones, Irwin I. Tendler, Paul E. Miller, Andre Ghetti and Nozomi Nishimurav

Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabecula

To assess drug-induced pro-arrhythmic risk, new models such as in-silico modeling of ventricular action potential (AP) and stem cell-derived cardiomyocytes (SC-CMs) have been proposed. The findings indicated that SC-CMs exhibited immature phenotype and had the propensity to generate false positives in predicting Torsades de Pointe (TdP) risk. Human ventricular trabeculae (hVT) were used to evaluate drugs to expand the knowledge base. The hVT AP-based model combined with the integrated analysis of pro-arrhythmic score was found to have a greater predictive performance when compared to human SC-CM models.

PUBLICATION: Frontiers in Physiology (2018)

AUTHORS: Yusheng Qu, Guy Page, Najah Abi-Gerges, Paul E. Miller, Andre Ghetti and Hugo M. Vargas

RESEARCH POSTERS

Action Potential Recording and Pro-arrhythmia Risk Analysis in Human Ventricular Trabeculae

To assess drug-induced pro-arrhythmic risk, new models such as in-silico modeling of ventricular action potential (AP) and stem cell-derived cardiomyocytes (SC-CMs) have been proposed. The findings indicated that SC-CMs exhibited immature phenotype and had the propensity to generate false positives in predicting Torsades de Pointe (TdP) risk. Human ventricular trabeculae (hVT) were used to evaluate drugs to expand the knowledge base. The hVT AP-based model combined with the integrated analysis of pro-arrhythmic score was found to have a greater predictive performance when compared to human SC-CM models.

AUTHORS: Yusheng Qu, Guy Page, Najah Abi-Gerges, Paul E Miller, Andre Ghetti and Hugo M. Vargas

Effect of Ozanimod (RPC1063) on Action Potential Parameters in Adult Human Purkinje Fibres

Isolated human Purkinje fibres (PFs) in combination with electrophysiology are a unique tool that can be used to understand subtle differences between drugs on cardiac conduction. Ozanimod is an oral once-daily immunomodulator that has shown therapeutic benefit in clinical trials of relapsing multiple sclerosis and ulcerative colitis. The goal was to determine whether the higher selectivity of Ozanimod explains its improved clinical profile. The data agreed that Ozanimod has no effect on the measured conduction parameters.

AUTHORS: Najah Abi-Gerges, Paul E. Miller, Andre Ghetti, Fiona L. Scott, Kristen R. Taylor Meadows, Bryan Clemons, Paul Frohna, Guy Page, Gregory J. Opiteck

A human ex-vivo contractility-based assay for the simultaneous prediction of drug-induced inotropic and pro-arrhythmia risk

Cardiac safety remains the leading cause of drug development discontinuation. AnaBios has developed a human cardiomyocyte-based model that has the potential to provide a predictive preclinical approach for simultaneously predicting drug-induced inotropic and pro-arrhythmia risk. The human ventricular trabeculae-based model can clearly differentiate between pro-arrhythmia and non-proarrhythmic drugs and has the potential to enable a generation of reliable and predictive human-based cardiotoxicity data at the pre-clinical stage.

AUTHORS: Najah Abi-Gerges, Ashley Alamillo, Phachareeya Ratchada, Guy Page, Yannick Miron, Nathalie Nguyen, Paul E Miller and Andre Ghetti

Adult human primary cardiomyocyte-based platform for the profiling of positive inotropes with potential to treat heart failure

Heart failure remains a major unmet medical need. To facilitate the identification of molecules with the most desirable efficacy profile, AnaBios developed a human cardiomyocyte contractility assay for the identification of positive inotropes with the potential to correct contractility deficits in heart failure. This adult human primary cardiomyocyte-based platform will facilitate the identification of molecules with the most desirable pharmacological correction of specific forms of contractility deficit.

AUTHORS: Najah Abi-Gerges, Tim Indersmitten, Ky Truong, William Nguyen, Ismael Tapia, Nathalie Nguyen, Guy Page, Paul E Miller and Andre Ghetti

A Human Cardiomyocyte-Based Platform for the Profiling of Drug-Induced Effects on Cardiac Contractility: Predicting Inotropic Mechanisms of Action

Drug-induced effects on cardiac contractility can lead to serious adverse events including heart failure and limit the utility of innovative treatments. AnaBios sought to develop a human cardiomyocyte contractility assay that has the potential to simultaneously predict drug-induced inotropic risk and generate multi-parameter data to profile different inotropic mechanisms of action. The created adult human primary cardiomyocyte-based platform is scalable, efficient, and predictive for preclinical risk management.

AUTHORS: Najah Abi-Gerges, Tim Indersmitten, Ky Truong, William Nguyen, Nathalie Nguyen, Guy Page, Paul E Miller and Andre Ghetti