Cardiotoxicity Studies in Zebrafish - Zebrafish: Methods for Assessing Drug Safety and Toxicity - page 58

Pfeufer et al., 2005; Newton-Cheh et al., 2007). Homozygous breakdance embryos
display striking increases in APD compared to wild-type siblings (Fig. 5.3a). There
was also evidence of action potential “triangulation,” a hallmark of arrhythmic risk
characterized by replacement of the plateau phase of the action potential with slow,
linear repolarization (Fig. 5.3a). We observed spontaneous early afterdepolarizations
(EADs), the triggers of TdP (Fig. 5.3b), in the bkd / zebrafish hearts (Nerbonne and
Kass, 2005). Optically measured action potential durations correlate well with
reported intracellular recordings from wild-type zebrafish ventricular myocytes
(Arnaout et al., 2007).
Figure 5.3 Parallels between zebrafish and human cardiac repolarization. (a) Ventricular action potential
durations (APD) in wild-type (wt) and breakdance heterozygotes (þ/) and homozygotes (/) at 6 days
post fertilization. denotes p < 0.05. (b) Typical ventricular action potentials are displayed for wild-type
(wt), breakdance heterozygote (þ/), and homozygote (/) embryos. The heterozygote action potential
is subtly prolonged, while the homozygote recording shows marked action potential prolongation. Vertical
calibration bar denotes 20%DF/F 0 and horizontal bar denotes 100 ms. (c) Upper panel: Simultaneous atrial
and ventricular voltage recordings from a breakdance (/) heart showing the mechanism of 2:1
atrioventricular block: action potentials are so prolonged in the ventricle that alternate atrial impulses
encroach on the refractory plateau of the previous ventricular repolarization. Lower panel: EADs (arrows)
observed in breakdance (/) embryos during ventricular pacing; the pacing train is shown below the
action potential recording. EADs appear as spontaneous depolarizations occurring before repolarization is
complete and prior to the subsequent paced beat. (d) Heterozygote breakdance embryos display increased
sensitivity to I Kr blockade (10 nM dofetilide). (Figure adapted from Milan et al., 2009.)