ZeTox – Toxicology Services

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icon-cardio-tox CardioTox – Cardiotoxicology Services

Cardiotoxicity is among the most common causes for clinical and post-market drug attrition. Thus, an early (and predictive) assessment of drug-induced cardiotoxicity is essential during the drug development process. CardioTox takes advantage of the high similarity between zebrafish and human heart physiologies to assess drug-induced cardiotoxicity.

Figure 1. Conserved electrophysiology between zebrafish and humans.

Advantages

Predictability levels referred to clinical data above 85%.

Comparable predictability to that reported in dogs (gold-standard in vivo model for cardiotoxicity prediction).

Strong correlation with in vitro hERG models.

Automated platform to process high amounts of embryos.

Analysis based on our validated software ZeCardio.

Prediction of drug-induced cardiovascular liabilities in humans with only 4-hours drug incubation.

Simultaneous assessment of neurotoxicity and hepatotoxicity through the service ZeGlobalTox.

Method description

Transgenic zebrafish embryos expressing green fluorescent protein (GFP) in cardiomyocytes are incubated with the No Observable Effect Concentration (NOEC) of the molecule of interest during 4 hours. At end point every larvae heart is video imaged during 1 min and analyzed with ZeCardio™ unique software of analysis (ZeClinics-developed cardiovascular software). Videos are analyzed for the presence of heart dysfunctions.

Readouts

Determination of relevant parameters related to the cardiac function at 120 hpf:

  • Heartbeat frequency (ventricle and atrium)
  • Arrhythmias
  • Ejection fraction
  • QT prolongation
  • Fibrillation
  • Cardiac arrest
Figure 2. Heartbeat recordings of transgenic zebrafish expressing GFP in cardiomyocytes after treatment with negative control or a bradycardic compound. It allows a non-invasive analysis of real-time cardiac readouts.
Figure 3. Cardiac kymographs displayed by ZeCardioTM illustrate zebrafish heartbeat phenotypes after exposure to a negative control, a tachycardic and a bradycardic compound.

References

  1. Dyballa S, Miñana R, Rubio-Brotons M, Cornet C, Pederzani T, Escaramis G, Garcia-Serna R, Mestres J, Terriente J. Comparison of zebrafish larvae and hiPSC cardiomyocytes for predicting drug induced cardiotoxicity in humans. Toxicol Sci. 2019 Jul 30;171(2):283–95.
  2. Cornet C, Calzolari S, Miñana-Prieto R, Dyballa S, van Doornmalen E, Rutjes H, Savy T, D'Amico D, Terriente J. ZeGlobalTox: An Innovative Approach to Address Organ Drug Toxicity Using Zebrafish. Int J Mol Sci. 2017 Apr 19;18(4):864.