Evidence map›Paper›PMID 40863351›Full record

ArticleJournal of cardiovascular development and disease2025

Nonclinical Human Cardiac New Approach Methodologies (NAMs) Predict Vanoxerine-Induced Proarrhythmic Potential.

M Iveth Garcia, Bhavya Bhardwaj, Keri Dame, Verena Charwat, Brian A Siemons, Ishan Goswami, Omnia A Ismaiel, Sabyasachy Mistry, Tromondae K Feaster, Kevin E Healy and 2 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Journal of cardiovascular development and disease, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.

0numbers the graph read from it
0cells of the map it votes in
5citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

5 citing papers in PubMed.

  1. Review of in vitro approaches for assessing the toxicity of chemical stressors across diverse physiological systems.Toxicological sciences : an official journal of the Society of Toxicology · 2026
    Review
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  5. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

12 authors.

M Iveth GarciaDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Bhavya BhardwajDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Keri DameDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.ORCID 0000-0002-1772-7076
Verena CharwatDepartment of Bioengineering, California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, CA 94720, USA.ORCID 0000-0002-2222-3702
Brian A SiemonsDepartment of Bioengineering, California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, CA 94720, USA.ORCID 0009-0009-6075-9653
Ishan GoswamiDepartment of Bioengineering, California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, CA 94720, USA.
Omnia A IsmaielDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Sabyasachy MistryDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Tromondae K FeasterDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Kevin E HealyDepartment of Bioengineering, California Institute for Quantitative Biosciences (QB3), University of California at Berkeley, Berkeley, CA 94720, USA.
Alexandre J S RibeiroDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.
Ksenia BlinovaDivision of Applied Regulatory Science, Office of Clinical Pharmacology, Office of Translational Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD 20993, USA.ORCID 0000-0003-1123-3152

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

New approach methodologies (NAMs), including microphysiological systems (MPSs), can recapitulate structural and functional complexities of organs. Vanoxerine was reported to induce cardiac adverse events, including torsade de points (TdP), in a Phase III clinical trial. Despite earlier nonclinical animal models and Phase I-II clinical trials, events of QT prolongation or proarrhythmia were not observed. Here, we utilized cardiac NAMs to evaluate the functional consequences of vanoxerine treatment on human cardiac excitation-contraction coupling. The cardiac MPS used in this study was a microfabricated fluidic culture platform with human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) capable of evaluating voltage, intracellular calcium handling, and contractility. Likewise, the hiPSC-CM comprehensive in vitro proarrhythmia assay (CiPA) was employed based on multielectrode array (MEA). Vanoxerine treatment delayed repolarization in a concentration-dependent manner and induced proarrhythmic events in both NAM platforms. The complex cardiac MPS displayed a frequency-dependent vanoxerine response such that EADs were eliminated at a faster pacing rate (1.5 Hz). Moreover, exposure analysis revealed a 99% vanoxerine loss in the cardiac MPS. TdP risk analysis demonstrated high to intermediate TdP risk at clinically relevant concentrations of vanoxerine and frequency-independent EAD events in the hiPSC-CM CiPA model. These findings demonstrate that nonclinical cardiac NAMs can recapitulate clinical outcomes, including detection of vanoxerine-induced delayed repolarization and proarrhythmic effects. Moreover, this work provides a foundation to evaluate the safety and efficacy of novel compounds to reduce the dependence on animal studies.

Indexed as

calcium handlingcardiomyocytescomplex in vitro modelcontractilityelectrophysiologyhiPSC-CMmicrophysiological systems (MPSs)new approach methodologies (NAMs)nonclinical study

Identifiers

PMID40863351
PMCPMC12387051

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Registered trials

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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.