The Effect of Hypothermia and Osmotic Shock on the Electrocardiogram of Adult Zebrafish

SIMPLE SUMMARY: Assessing cardiac toxicity of new drugs is a requirement for their approval. One of the parameters which is carefully looked at is the QT interval, which is determined using an electrocardiogram (ECG). Before undertaking clinical trials using human patients, it is important to first perform pre-clinical tests using animal models. Zebrafish are widely used to study cardiac physiology and several reports suggest that although ECG measurement can be performed, the recording configuration appears to affect the results. Our research aimed to provide a comprehensive characterization of adult zebrafish ECG to determine the best practice for using this model during cardiac toxicity trials. We tested three recording configurations and determined that exposing the heart provided the most reliable and reproducible ECG recordings. We also determined the most accurate correction to apply to calculate the corrected QT, which makes the QT interval independent of the heart rate, a critical parameter when assessing drug cardiac toxicity. Overall, our study highlights the best conditions to record zebrafish ECG and demonstrates their utility for cardiac toxicity testing. ABSTRACT: The use of zebrafish to explore cardiac physiology has been widely adopted within the scientific community. Whether this animal model can be used to determine drug cardiac toxicity via electrocardiogram (ECG) analysis is still an ongoing question. Several reports indicate that the recording configuration severely affects the ECG waveforms and its derived-parameters, emphasizing the need for improved characterization. To address this problem, we recorded ECGs from adult zebrafish hearts in three different configurations (unexposed heart, exposed heart, and extracted heart) to identify the most reliable method to explore ECG recordings at baseline and in response to commonly used clinical therapies. We found that the exposed heart configuration provided the most reliable and reproducible ECG recordings of waveforms and intervals. We were unable to determine T wave morphology in unexposed hearts. In extracted hearts, ECG intervals were lengthened and P waves were unstable. However, in the exposed heart configuration, we were able to reliably record ECGs and subsequently establish the QT-RR relationship (Holzgrefe correction) in response to changes in heart rate.