In Vivo Recording of the Adult Zebrafish Electrocardiogram - Zebrafish: Methods for Assessing Drug Safety and Toxicity - page 62

Chapter 6

In Vivo Recording of the Adult
Zebrafish Electrocardiogram

David J. Milan 1 and Calum A. MacRae 2
1 Cardiovascular Research Center and Cardiology Division, Massachusetts General
Hospital, Boston, MA, USA
2 Cardiovascular Division, Brigham and Women's Hospital, Boston, MA, USA

6.1 INTRODUCTION

QT prolongation and the attendant risk of the malignant arrhythmia, torsades de
pointes, have led to the post marketing withdrawal of multiple medications from the
U.S. market. Since drug-induced cardiotoxicity is difficult to predict, it has become a
major focus for regulatory scrutiny, and is an area of intense pharmaceutical and
academic research (Roden, 2004; Camm, 2005). The cardiac toxicities of new drugs
are one of the most important areas of investigation in new drug development. Indeed,
more drugs were withdrawn from the US market due to concerns regarding QT
prolongation than for any other single cause (Roden, 2004; Camm, 2005).
Cardiac repolarization is the result of the integrated effects of channels, receptors,
and cytoskeletal proteins. Further complexity arises from substantial local differences in
repolarizationwithin the heart. Drug-induced cardiotoxicity is often difficult to predict as
many of the responsible agents perturb repolarization only in combination with other
drugs. These interactions may be pharmacokinetic or pharmacodynamic in nature.
Inherited variation is known to affect the diathesis toward drug-induced arrhythmias and
contributes to limited predictive utility of simple in vitro systems (Yang et al., 2002).
Other issues that make drug-induced cardiotoxicity so difficult to predict prior to
human use are the low frequency of arrhythmic events, the increasing complexity of
drug-drug interactions, the low specificity of cellular hERG assays, and the low
throughput of truly representative animal models. Multiple new assays have been
introduced to the field in the last few years, highlighting not only to the importance of
cardiotoxicity, but also the limited predictive utility current techniques (Bass et al., 2005).