Functional genomics in zebrafish as a tool to identify novel antiarrhythmic targets

Abstract

In the face of an aging population and thereby an increasing number of patients suffering from heart rhythm diseases development of therapeutic agents is one of the major challenges in modern biomedical research. Antiarrhythmic drug discovery was mainly hindered by the limited knowledge of the molecular underpinnings of cardiac electrophysiology in health and disease. In recent years, the zebrafish has emerged as an effective model organism to dissect the pathology of human disorders in particular in the area of cardiovascular diseases. Especially, certain aspects of cardiac electrophysiology of the zebrafish such as action potential or heart rate are similar to that of humans. The zebrafish shares many features of human physiology and body plan but it develops extra-uterine and is initially transparent, allowing detailed and comprehensive characterization of cardiac development and function in vivo. Moreover, zebrafish are well amenable to large-scale forward and reverse functional genomics approaches, which has led to the identification of numerous novel genetic key-players and potential targets of cardiac disease. In this context, several zebrafish lines with mutations in defined ion channels have emerged as novel vertebrate models for human arrhythmia disorders such as long or short QT syndrome. In addition, due to its size and the high number of progeny, zebrafish are very suitable for rapid in vivo analysis of the bioactivity of small molecules and their therapeutic potential, especially in the context of cardiovascular diseases such as arrhythmias. In this review we highlight an assortment of established zebrafish models that enable the dissection of human heart rhythm disorders and the potential of this model system for the discovery of novel antiarrhythmic targets and drugs.