Optimisation of Embryonic and Larval ECG Measurement in Zebrafish for Quantifying the Effect of QT Prolonging Drugs

Research output: Contribution to journalArticle

Authors

  • Sundeep Singh Dhillon
  • Éva Dóró
  • István Magyary

External organisations

  • King's College London
  • Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, United States of America; Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, United States of America.
  • University of Birmingham
  • Department of Cell Biology and Immunology
  • Wageningen University and Research Centre
  • Department of Nature Protection
  • University of Kaposvar
  • University of Pecs

Abstract

Effective chemical compound toxicity screening is of paramount importance for safe cardiac drug development. Using mammals in preliminary screening for detection of cardiac dysfunction by electrocardiography (ECG) is costly and requires a large number of animals. Alternatively, zebrafish embryos can be used as the ECG waveform is similar to mammals, a minimal amount of chemical is necessary for drug testing, while embryos are abundant, inexpensive and represent replacement in animal research with reduced bioethical concerns. We demonstrate here the utility of pre-feeding stage zebrafish larvae in detection of cardiac dysfunction by electrocardiography. We have optimised an ECG recording system by addressing key parameters such as the form of immobilization, recording temperature, electrode positioning and developmental age. Furthermore, analysis of 3 days post fertilization (dpf) zebrafish embryos treated with known QT prolonging drugs such as terfenadine, verapamil and haloperidol led to reproducible detection of QT prolongation as previously shown for adult zebrafish. In addition, calculation of Z-factor scores revealed that the assay was sensitive and specific enough to detect large drug-induced changes in QTc intervals. Thus, the ECG recording system is a useful drug-screening tool to detect alteration to cardiac cycle components and secondary effects such as heart block and arrhythmias in zebrafish larvae before free feeding stage, and thus provides a suitable replacement for mammalian experimentation.

Details

Original languageEnglish
Article numbere60552
JournalPLoS ONE
Volume8
Issue number4
Publication statusPublished - 8 Apr 2013