Zebrafish heart as a model for human cardiac electrophysiology

Abstract

The zebrafish (Danio rerio) has become a popular model for human cardiac diseases and pharmacology including cardiac arrhythmias and its electrophysiological basis. Notably, the phenotype of zebrafish cardiac action potential is similar to the human cardiac action potential in that both have a long plateau phase. Also the major inward and outward current systems are qualitatively similar in zebrafish and human hearts. However, there are also significant differences in ionic current composition between human and zebrafish hearts, and the molecular basis and pharmacological properties of human and zebrafish cardiac ionic currents differ in several ways. Cardiac ionic currents may be produced by non-orthologous genes in zebrafish and humans, and paralogous gene products of some ion channels are expressed in the zebrafish heart. More research on molecular basis of cardiac ion channels, and regulation and drug sensitivity of the cardiac ionic currents are needed to enable rational use of the zebrafish heart as an electrophysiological model for the human heart.

Keywords: calcium channels; cardiac action potential; cardiac ionic currents; potassium channels; sodium channels.

Figure 1.

Ventricular action potential of the zebrafish heart. (A) Typical action potential of the zebrafish ventricle shows fast upstroke (phase-0), long plateau (phase-2), rapid repolarization (phase-3) and stable resting membrane potential (phase-4), but lacks the fast phase-1 repolarization (arrow), which is typical for the human cardiac action potential (top right). As an ectotherm action potential duration and heart rate in the zebrafish is temperature-dependent within the thermal-tolerance range of the species. (B) Representative microelectrode recordings of ventricular AP at selected temperatures (36°C, 28°C and 19°C) and (C) within the whole range of temperatures between 10°C and 36°C.

Figure 2.

Comparison of human and zebrafish electrocardiograms (ECG). (Top) ECG of an adult zebrafish at 23°C (kindly provided by prof. Tzung Hsiai). (Bottom) ECG of a healthy 43-year old human male. For direct comparison of zebrafish and human ECGs both recordings are shown in the same time scale. Similar to the human electrocardiogram, P, QRS and T waves are clearly distinguishable in the zebrafish ECG.

Figure 3.

Transcript expression of the 4 K_v11 (erg) channel family members in the zebrafish heart. The bar graph shows abundances of KCNH transcripts in atrial and ventricular muscle of the zebrafish normalized to the expression of the housekeeping gene DnaJA2 (mean ± SEM; n = 6). The pie charts indicate relative proportions (%) of each KCNH transcript in the whole KCNH pool in atrium and ventricle. Statistically significant differences (Student's t-test; p < 0.05) between atrium and ventricle are indicated with an asterisk.