Modeling Human Cardiac Arrhythmias: Insights from Zebrafish

Abstract

Cardiac arrhythmia, or irregular heart rhythm, is associated with morbidity and mortality and is described as one of the most important future public health challenges. Therefore, developing new models of cardiac arrhythmia is critical for understanding disease mechanisms, determining genetic underpinnings, and developing new therapeutic strategies. In the last few decades, the zebrafish has emerged as an attractive model to reproduce in vivo human cardiac pathologies, including arrhythmias. Here, we highlight the contribution of zebrafish to the field and discuss the available cardiac arrhythmia models. Further, we outline techniques to assess potential heart rhythm defects in larval and adult zebrafish. As genetic tools in zebrafish continue to bloom, this model will be crucial for functional genomics studies and to develop personalized anti-arrhythmic therapies.

Keywords: atrial fibrillation; cardiac arrhythmia; cardiac rhythm phenotyping; cardiomyopathy; genetic models; heart development; imaging; in vivo screening; inherited arrhythmia; zebrafish.

Figure 1

Stages of heart development in zebrafish from 10 to 96 h post-fertilization (hpf). (A) Atrial and ventricular cardiac progenitors are located in the anterior lateral plate mesoderm by ~15 hpf. (B) The cardiac disc is visible by 22 hpf as cardiac progenitors surround endocardial cells at the midline. (C) At 24 hpf, the linear heart tube forms and jogs to the left in preparation for heart looping. (D) At 36 hpf, the heart tube undergoes rightward looping. The AV canal (orange) begins to develop between the cardiac chambers. (E) At 48 hpf, the cardiac chambers begin to balloon and expand outwards. The bulbus arteriosus (dark blue) and AV canal (orange) continue to develop and mature. (F) From 72 to 96 hpf, the cardiac chambers expand and align beside each other. (G) A cross-section of a 96 hpf heart showing the trabeculae, the finger-like muscular projections on the inner wall of the ventricle, and endocardial leaflets (orange) of the AV canal. (A–D) dorsal views; (E–G) ventral views.

Figure 2

Overview of molecular pathways in the mammalian cardiac conduction system. The sinoatrial node (SAN, green) develops from Tbx18⁺, Nkx2-5^low progenitor cells. Nkx2-5 represses expression of Tbx3 and Isl1 to establish the boundary between the SAN and atrial cardiomyocytes. SAN precursor cell differentiation is marked by expression of Tbx3, Isl1, Shox2, and Hcn4. Pitx2 represses SAN development on the left side of the sinus venosus by repressing this transcriptional network. The Tbx5 (activator) and Pitx2 (repressor) regulatory loop regulates atrial conduction genes. Relative Tbx3/Tbx5 dosage determines specification of the conduction system. The atrioventricular node (AVN, blue) acts as a secondary pacemaker, and is characterized by slow conduction that is patterned by low levels of Tbx5 and high levels of Tbx3. A fast conduction state in the ventricular conduction system (VCS, pink) is specified by higher levels of Tbx5 and low Tbx3.