Electrocardiogram Signals to Assess Zebrafih Heart Regeneration: Implication of Long QT Intervals

Abstract

Zebrafish is an emerging model system for cardiac conduction and regeneration. Zebrafish heart regenerates after 20% ventricular resection within 60 days. Whether cardiac conduction phenotype correlated with cardiomyocyte regeneration remained undefined. Longitudinal monitoring of the adult zebrafish heart (n = 12) was performed in terms of atrial contraction (PR intervals), ventricular depolarization (QRS complex) and repolarization (heart rated corrected QTc interval). Baseline electrocardiogram (ECG) signals were recorded one day prior to resection and twice per week over 59 days. Immunostaining for gap junctions with anti-Connexin-43 antibody was compared between the sham (n = 5) and ventricular resection at 60 days post-resection (dpr) (n = 7). Heart rate variability, QTc prolongation and J-point depression developed in the resected group but not in the sham. Despite a trend toward heart rate variability in response to ventricular resection, the differences between the resected and sham fish were, by and large, statistically insignificant. At 10 dpr, J-point depression was statistically significant (sham: −0.179 ± 0.061 mV vs. ventricular resection: −0.353 ± 0.105 mV, p < 0.01, n = 7). At 60 days, histology revealed either cardiomyocyte regeneration (n = 4) or scar tissues (n = 3). J-point depression was no longer statistically significant at 59 dpr (sham: −0.114 ± 0.085 mV; scar tissue: −0.268 ± 0.178 mV, p > 0.05, n = 3; regeneration: −0.209 ± 0.119 mV, p > 0.05, n = 4). Despite positive Connexin-43 staining in the regeneration group, QTc intervals remained prolonged (sham: 325 ± 42 ms, n = 5; scar tissues: 534 ± 51 ms, p < 0.01, n = 3; regeneration: 496 ± 31 ms, p < 0.01, n = 4). Thus, we observed delayed electric repolarization in either the regenerated hearts or scar tissues. Moreover, early regenerated cardiomyocytes lacked the conduction phenotypes of the sham fish.