Adriamycin-induced cardiotoxicity (cardiomyopathy and congestive heart failure) in rats.

Abstract

Summary The recent development of numerous analogs of the anthracycline class of oncolytic agents has resulted in an urgent need for a standardized, accurate, reproducible, and cost-effective system for cardiotoxicity testing. The present studies were designed to determine the feasibility of using the rat as a model for induction of the chronic type of cardiotoxicity (i.e., cardiomyopathy and congestive heart failure). Adriamycin (ADR) was administered to rats at doses of 1 to 2 mg/kg/week for 10 to 14 weeks. The majority of ADR-treated rats developed cardiomyopathy from 3 to 23 weeks after the last injection. Forty to 70% of those rats with cardiomyopathy had gross evidence of congestive heart failure (pleural effusions, ascites, hepatomegaly, cardiomegaly). Histological myocardial changes consisted of myocyte vacuolation and degeneration, interstitial edema, and mild fibroplasia. In addition, damage to atrial ganglion cells was evident in several rats. Ultrastructural alterations involved sarcoplasmic disruption with distentions of subcellular organelles and loss of myofilaments. Extracardiac toxic effects of ADR (nephrotoxicity, myelosuppression, enteropathy, arrested osteogenesis) were minor and were observed more frequently at higher cumulative doses. The results of the present study suggest that the rat model is an accurate, reproducible, and cost-effective system for large-scale cardiotoxicity testing of analogs of ADR and daunorubicin.