Assessment of Drug-Induced Cardiotoxicity in Zebrafish - Zebrafish: Methods for Assessing Drug Safety and Toxicity - page 43

Chapter 4

Assessment of Drug-Induced
Cardiotoxicity in Zebrafish

Louis D'Amico 1 , Wen Lin Seng 1 , Yi Yang 2 , and Willi Suter 2
1 Phylonix, Cambridge, MA, USA
2 Novartis Pharmaceuticals, East Hanover, NJ, USA

4.1 INTRODUCTION

Cardiotoxicity is a major problem for hundreds of pharmaceutical agents, industrial
chemicals, and naturally occurring products. In the pharmaceutical sector, several
compounds have been shown to lengthen cardiac repolarization, leading to QT
interval prolongation and torsades de pointes, which has the potential to cause sudden
death. Previous research has shown that compounds capable of inducing repolari-
zation abnormalities cause bradycardia in zebrafish (Chapter 5). In this chapter, we
describe methods for assessing compound-induced cardiotoxicity in zebrafish and
report results for 10 reference compounds.

4.2 ZEBRAFISH HEART

The zebrafish (Danio rerio) is a useful animal model system for studying cardio-
vascular development, genetics, and cardiotoxicity. Zebrafish transparency permits
visual assessment of circulation and morphology. Zebrafish use gills for respiration
and have a single-loop circulatory system. The heart consists of two chambers: an
atrium that receives blood and a ventricle that pumps blood to the body. Both the
mammalian and zebrafish heart share development of specialized chambers, outflow
tracts to an intricate vasculature, valves to ensure directionality, specialized endo-
thelial cells (endocardium) to drive a high-pressure system, and an electrical system to
regulate rhythm. There is inflow of blood from a major vein to an atrium; the blood
moves to a muscular ventricle for delivery to the aorta; valves are present to direct