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.
Highlights
Repolarisation abnormalities can lead to various conditions, such as cardiac arrhythmias and QT prolongation
Repolarisation in human ventricles occurs mainly via the voltage-gated potassium channel in phase 3 of the ventricular myocyte action potential [1]. Disruption to this ion channel can result in QT prolongation, which is often a predisposing factor to arrhythmias and can be monitored through electrophysiological recordings
Cardiac arrhythmias originate from abnormal electrical activity in the heart and may be life-threatening or merely irritating
Summary
Repolarisation abnormalities can lead to various conditions, such as cardiac arrhythmias and QT prolongation (where the duration of ventricular depolarisation and repolarisation is extended). Drug-induced QT prolongation is a growing problem and accounts for around 20% of failures in the drug development process, as it can be caused by many compounds that are often unrelated to each other in structure and function. It can occur by various mechanisms, such as blocking of cardiac ion channels such (e.g. hERG), either when they are inactive/active or open/closed [6]. Pharmaceutical companies and regulatory agencies addressed this problem by developing in silico models and by introducing new standards in the drug development program [8]
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