The zebrafish as a tool to identify novel therapies for human cardiovascular disease

Abstract

Over the past decade, the zebrafish has become an increasingly popular animal model for the study of human cardiovascular disease. Because zebrafish embryos are transparent and their genetic manipulation is straightforward, the zebrafish has been used to recapitulate a number of cardiovascular disease processes ranging from congenital heart defects to arrhythmia to cardiomyopathy. The use of fluorescent reporters has been essential to identify two discrete phases of cardiomyocyte differentiation necessary for normal cardiac development in the zebrafish. These phases are analogous to the differentiation of the two progenitor heart cell populations in mammals, termed the first and second heart fields. The small size of zebrafish embryos has enabled high-throughput chemical screening to identify small-molecule suppressors of fundamental pathways in vasculogenesis, such as the BMP axis, as well as of common vascular defects, such as aortic coarctation. The optical clarity of zebrafish has facilitated studies of valvulogenesis as well as detailed electrophysiological mapping to characterize the early cardiac conduction system. One unique aspect of zebrafish larvae is their ability to oxygenate through diffusion alone, permitting the study of mutations that cause severe cardiomyopathy phenotypes such as silent heart and pickwick(m171), which mimic titin mutations observed in human dilated cardiomyopathy. Above all, the regenerative capacity of zebrafish presents a particularly exciting opportunity to discover new therapies for cardiac injury, including scar formation following myocardial infarction. This Review will summarize the current state of the field and describe future directions to advance our understanding of human cardiovascular disease.

Keywords: Cardiovascular; Drug discovery; Zebrafish.

Fig. 1.

The zebrafish as a model to study human cardiovascular disease. Middle panel shows the four-chambered human heart with associated cardiovascular pathologies. RA, right atrium; LA, left atrium; RV, right ventricle; LV, left ventricle. Side panels show examples of cardiac development and disease studied in the zebrafish. (A) In contrast to the human heart, the zebrafish heart is two-chambered with a single atrium and ventricle. Characterization of the second heart field in zebrafish has the potential to illuminate new therapies for human congenital heart defects such as right ventricular outflow tract obstruction. (B) Zebrafish expressing the gridlock mutation fail to develop circulation in the tail and trunk (wild-type fish on left; gridlock fish on right), similar to human aortic coarctation. (C) Calcium activation in the zebrafish heart mimics wave propagation in the human heart, enabling the study of arrhythmias. Isochronal mapping of the zebrafish ventricle using a fluorescent calcium indicator (color gradient) demonstrates calcium excitation over time, with red lines depicting areas of the ventricle depolarized simultaneously. (D) Zebrafish hearts regenerate following injury, a process that could be harnessed therapeutically to prevent scar formation following myocardial infarction. Red cells designate regrowth of cardiomyocytes in the zebrafish.