Cardiotoxicity Studies in Zebrafish - Zebrafish: Methods for Assessing Drug Safety and Toxicity - page 53

Chapter 5

Cardiotoxicity Studies
in Zebrafish

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

5.1 INTRODUCTION

The major focus of regulatory attention in cardiotoxicity has been the risk of sudden
death due to QT interval prolongation and torsades de pointes (TdP). This form of
toxicity has led to the withdrawal of several agents from the U.S. market and has been
estimated to cost the pharmaceutical industry close to 1 billion dollars per year. Life-
threatening arrhythmia in the setting of QT prolongation occurs as a result of inherited
mutations in ion channel genes or, in the case of drug-induced repolarization toxicity,
as a consequence of drugs interacting with the function of these same channels (Camm
et al., 2000; Keating and Sanguinetti, 2001). Despite their medical importance, drug-
induced repolarization disorders and related arrhythmias remain difficult to predict.
Additional forms of cardiotoxicity including contractile dysfunction, other
arrhythmias, valvulopathy, or pulmonary hypertension exist, but have been associated
with agents targeting specific pathways that are more readily predicted. The mechan-
isms of many of these toxicities remain poorly understood, and range from on-target
receptor-mediated effects to idiosyncratic responses. As the pathways targeted by
pharmaceutical agents multiply, unpredicted toxicities will also become more
common. Conventional preclinical testing in rodents and large animals, including
nonhuman primates, can frequently detect common toxic effects. However, the total
number of animals screened prior to clinical testing is often only a few hundred, and as
a result, rarer toxic events, even if these are catastrophic, often will only be observed
after extensive clinical use. Similarly, traditional preclinical toxicology studies
usually focus on classic model organism strains where there is little genetic