Short-term and long-term models of doxorubicin-induced cardiomyopathy in rats: A comparison of functional and histopathological changes

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O'Connell, Joao Lucas ; Dias Romano, Minna Moreira ; Campos Pulici, Erica C. ; Carvalho, Eduardo E. V. ; de Souza, Fernanda R. ; Tanaka, Denise M. ; Maciel, Benedito Carlos ; Salgado, Helio C. ; Fazan-Junior, Rubens ; Rossi, Marcos A. ; Simoes, Marcus V.

• Document type: Journal article
• Source: EXPERIMENTAL AND TOXICOLOGIC PATHOLOGY; v. 69, n. 4, p. 213-219, APR 2017.
• Web of Science Citations: 6

Abstract

Objectives: Doxorubicin (DXR), an anthracyclic antineoplastic agent, is one of the most commonly drug utilized to induce dilated cardiomyopathy (DCM) and heart failure (HF), but the well optimized protocol for cardiomyopathy induction leading to development of cardiac systolic dysfunction is unclear. This study aims to critically compare short-term and long-term DXR injection protocols for the induction of DCM in rats. Methods: Animals were allocated into 3 experimental groups: a ST (short-term DXR injection) group, in which animals received 6 intraperitoneal (i.p.) injections of DXR (2.5 mg/kg per dose) over a period of 2 weeks (cumulative dose of 15 mg/kg); a LT (long-term DXR injection) group in which animals received weekly i.p. injections of DXR (2 mg/kg per dose) over a period of 9 weeks (cumulative dose of 18 mg/kg); and a control group in which animals received an appropriate volume of 0.9% saline i.p. All animals were submitted to echocardiography analysis at baseline and after completion treatment. Afterwards, the hearts were collected for conventional light microscopy and collagen quantification. Results: Morphological myocardial analysis of both DXR-treated groups showed an identical pattern of swollen and vacuolated cardiomyocytes and disorganization of myofibrils. There was, pronounced interstitial fibrosis in both groups of DXR-treated hearts as compared to controls, as assessed by the interstitial collagen volume fraction. There was no difference in interstitial fibrosis between the ST and LT groups. The echocardiography analysis of the LT group showed structural and functional findings compatible with DCM, including increased left ventricular systolic (5.02 +/- 0.96 mm) and diastolic (7.68 +/- 0.96 mm) dimensions and reduction of ejection fraction (69.40 +/- 8.51%) as compared to the ST group (4.10 +/- 0.89 mm, 7.32 +/- 0.84, and 79.68 +/- 7.23%, respectively) and control group (4.07 +/- 0.72 mm, 7.17 +/- 0.68 mm and 80.08 +/- 4.71%, respectively), ANOVA p < 0.01. Conclusions: These results indicate that LT injection of DXR is more effective than ST injection in inducing left ventricular dysfunction and structural cardiac changes resembling those found in dilated cardiomyopathy. (C) 2017 Elsevier GmbH. All rights reserved. (AU)

• FAPESP's process: 10/13199-1 - Dystrophin and its associated proteins in the pathogenesis of doxorubicin-induced cardiomyopathy
• Grantee: Marcos Antonio Rossi
• Support Opportunities: Regular Research Grants