A mouse model for juvenile doxorubicin-induced cardiac dysfunction

Wuqiang Zhu, Weinian Shou, R. Mark Payne, Randall Caldwell, Loren J. Field

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Doxorubicin (DOX) is a potent antitumor agent. DOX can also induce cardiotoxicity, and high cumulative doses are associated with recalcitrant heart failure. Children are particularly sensitive to DOX-induced heart failure. The ability to genetically modify mice makes them an ideal experimental system to study the molecular basis of DOX-induced cardiotoxicity. However, most mouse DOX studies rely on acute drug administration in adult animals, which typically are analyzed within 1 wk. Here, we describe a juvenile mouse model of chronic DOX-induced cardiac dysfunction. DOX treatment was initiated at 2 wk of age and continued for a period of 5 wk (25 mg/kg cumulative dose). This resulted in a decline in cardiac systolic function, which was accompanied by marked atrophy of the heart, low levels of cardiomyocyte apoptosis, and decreased growth velocity. Other animals were allowed to recover for 13 wk after the final DOX injection. Cardiac systolic function improved during this recovery period but remained depressed compared with the saline injected controls, despite the reversal of cardiac atrophy. Interestingly, increased levels of cardiomyocyte apoptosis and concomitant myocardial fibrosis were observed after DOX withdrawal. These data suggest that different mechanisms contribute to cardiac dysfunction during the treatment and recovery phases.

Original languageEnglish (US)
Pages (from-to)488-494
Number of pages7
JournalPediatric Research
Volume64
Issue number5
DOIs
StatePublished - Nov 2008

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health

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