ArticleJournal of pharmacological and toxicological methods
Human ex-vivo action potential model for pro-arrhythmia risk assessment.
Article in Journal of pharmacological and toxicological methods. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 42 citations in OpenAlex.
- Functional hydrogels in cardiovascular therapy: Design, applications and clinical challenges (Review).International journal of molecular medicine · 2026Review
- Short-term electrical stimulation promotes partial functional and morphological maturation of human-induced pluripotent stem cell-derived cardiomyocytes enabling cardiotoxicity risk mitigation at early-stage drug discovery for cardiac contractility modulation.Toxicological sciences : an official journal of the Society of Toxicology · 2026Article
- Comparison of in silico predictions of action potential duration in response to inhibition of IKr and ICaL with new human ex vivo recordings.PLoS computational biology · 2025Article
- Unique pharmacological properties of etrasimod among S1P receptor modulators.FEBS open bio · 2025Article
- Integrating drug effects on individual cardiac ionic currents and cardiac action potentials to understand nonclinical translation to clinical ECG changes.Frontiers in pharmacology · 2025Article
- Oxa-Iboga alkaloids lack cardiac risk and disrupt opioid use in animal models.Nature communications · 2024Article
- Local Control Model of a Human Ventricular Myocyte: An Exploration of Frequency-Dependent Changes and Calcium Sparks.Biomolecules · 2023Article
- Generation of left ventricle-like cardiomyocytes with improved structural, functional, and metabolic maturity from human pluripotent stem cells.Cell reports methods · 2023Article
- The importance of mechanical conditions in the testing of excitation abnormalities in a population of electro-mechanical models of human ventricular cardiomyocytes.Frontiers in physiology · 2023Article
- Functional isolation, culture and cryopreservation of adult human primary cardiomyocytes.Signal transduction and targeted therapy · 2022Article
- Article
- Pathogenesis and drug response of iPSC-derived cardiomyocytes from two Brugada syndrome patients with different NaJournal of biomedical research · 2021Article
- Arrhythmogenic and antiarrhythmic actions of late sustained sodium current in the adult human heart.Scientific reports · 2021Article
- Cardiotoxic Potential of Hydroxychloroquine, Chloroquine and Azithromycin in Adult Human Primary Cardiomyocytes.Toxicological sciences : an official journal of the Society of Toxicology · 2021Article
- In-silico human electro-mechanical ventricular modelling and simulation for drug-induced pro-arrhythmia and inotropic risk assessment.Progress in biophysics and molecular biology · 2021Article
- Discovery and characterization of ORM-11372, a novel inhibitor of the sodium-calcium exchanger with positive inotropic activity.British journal of pharmacology · 2020Article
- hiPSC-Derived Cardiac Tissue for Disease Modeling and Drug Discovery.International journal of molecular sciences · 2020Review
- Multiparametric Mechanistic Profiling of Inotropic Drugs in Adult Human Primary Cardiomyocytes.Scientific reports · 2020Article
- Human Purkinje in silico model enables mechanistic investigations into automaticity and pro-arrhythmic abnormalities.Journal of molecular and cellular cardiology · 2020Article
- Workshop Report: FDA Workshop on Improving Cardiotoxicity Assessment With Human-Relevant Platforms.Circulation research · 2019Review
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
While current S7B/E14 guidelines have succeeded in protecting patients from QT-prolonging drugs, the absence of a predictive paradigm identifying pro-arrhythmic risks has limited the development of valuable drug programs. We investigated if a human ex-vivo action potential (AP)-based model could provide a more predictive approach for assessing pro-arrhythmic risk in man. Human ventricular trabeculae from ethically consented organ donors were used to evaluate the effects of dofetilide, d,l-sotalol, quinidine, paracetamol and verapamil on AP duration (APD) and recognized pro-arrhythmia predictors (short-term variability of APD at 90% repolarization (STV(APD90)), triangulation (ADP90-APD30) and incidence of early afterdepolarizations at 1 and 2Hz to quantitatively identify the pro-arrhythmic risk. Each drug was blinded and tested separately with 3 concentrations in triplicate trabeculae from 5 hearts, with one vehicle time control per heart. Electrophysiological stability of the model was not affected by sequential applications of vehicle (0.1% dimethyl sulfoxide). Paracetamol and verapamil did not significantly alter anyone of the AP parameters and were classified as devoid of pro-arrhythmic risk. Dofetilide, d,l-sotalol and quinidine exhibited an increase in the manifestation of pro-arrhythmia markers. The model provided quantitative and actionable activity flags and the relatively low total variability in tissue response allowed for the identification of pro-arrhythmic signals. Power analysis indicated that a total of 6 trabeculae derived from 2 hearts are sufficient to identify drug-induced pro-arrhythmia. Thus, the human ex-vivo AP-based model provides an integrative translational assay assisting in shaping clinical development plans that could be used in conjunction with the new CiPA-proposed approach.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.