Oxidative Stress Remodeling of Zebrafish Cardiac Electrical Gradients

Abstract

In mammalian hearts, electrical gradients ensure well-orchestrated electrical stability and mechanical efficiency under physiological baseline. Regional heterogeneities of ion channels and/or calcium handling proteins establish gradients of activation, action potential duration (APD), and repolarization that are protective at baseline, but susceptible to disruptive remodeling in myocardial injuries and failure. However, in zebrafish hearts, physiological electrical gradients are unexplored. Considering the important application of zebrafish hearts in high-throughput screening for drug-induced cardiotoxicities (such as QT prolongation) and the role of the apicobasal APD and repolarization gradients in the inscription of the T wave and the QT interval, this study investigates the apicobasal electrical gradients in normal adult zebrafish and the arrhythmogenic impact of acute H2O2-induced oxidative stress. Following epicardial optical mapping of intact zebrafish hearts, apicobasal gradients of activation, repolarization, and APD under normal baseline vs. oxidative stress (H2O2, 100 μmol/L) condition were determined. At baseline, an apicobasal APD90 gradient was evident with longer APD90 in the apex due to earlier activation and later repolarization compared to the base (apex 198 ± 23 > base 121 ± 13 ms, n=5; P<0.0004). Acute H2O2 challenge abolished or reversed the apicobasal APD gradient and prolonged both apical and basal APDs (apex 352 ± 86 < base 401 ± 37 ms, n=4; NS). However, H2O2 remodeling impact was regionally heterogeneous, affecting the base more than apex. H2O2 impaired repolarization and induced occasional early after depolarizations and trigger activity. Given that the apicobasal APD and repolarization gradients in normal zebrafish are reverse those in normal humans, one should exert caution when extrapolating drug-induced QT prolongation in zebrafish to humans. Nonetheless, based on the human-like arrhythmogenic response of the zebrafish heart to acute H2O2 challenge, zebrafish constitutes a relevant model to investigate repolarization disorders associated with oxidative stress.