Short-term and long-term models of doxorubicin-induced cardiomyopathy in rats: A comparison of functional and histopathological changes.
OBJECTIVE
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 (2.5mg/kg per dose) over a period of 2 weeks (cumulative dose of 15mg/kg); a LT (long-term DXR injection) group in which animals received weekly i.p. injections of DXR (2mg/kg per dose) over a period of 9 weeks (cumulative dose of 18mg/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±0.96mm) and diastolic (7.68±0.96mm) dimensions and reduction of ejection fraction (69.40±8.51%) as compared to the ST group (4.10±0.89mm, 7.32±0.84, and 79.68±7.23%, respectively) and control group (4.07±0.72mm, 7.17±0.68mm 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.
Cardiology Division, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, 14048-900, Brazil; Faculty of Medicine, Federal University of Uberlândia, Uberlândia, Minas Gerais, 38400-902, Brazil. Electronic address: oconnelljl@uol.com.br.
João Lucas
JL
O'Connell
Cardiology Division, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, 14048-900, Brazil. Electronic address: minna@fmrp.usp.br.
Minna Moreira Dias
MM
Romano
Department of Phisiotherapy, Federal University of Uberlândia, Uberlândia, Minas Gerais, 38400-678, Brazil. Electronic address: ericacp@ufu.br.
Erica C
EC
Campos Pulici
Cardiology Division, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, 14048-900, Brazil. Electronic address: carvalhoeev@hotmail.com.
Eduardo E V
EE
Carvalho
Department of Phisiotherapy, Federal University of Uberlândia, Uberlândia, Minas Gerais, 38400-678, Brazil. Electronic address: nandaeduca@yahoo.com.br.
Fernanda R
FR
de Souza
Cardiology Division, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, 14048-900, Brazil. Electronic address: denisemt@usp.br.
Denise M
DM
Tanaka
Cardiology Division, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, 14048-900, Brazil. Electronic address: bcmaciel@fmrp.usp.br.
Benedito Carlos
BC
Maciel
Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, 14049-900, Brazil.
Hélio C
HC
Salgado
Department of Physiology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, 14049-900, Brazil.
Rubens
R
Fazan-Júnior
Department of Pathology, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirao Preto, São Paulo, 14049-900, Brazil.
Marcos A
MA
Rossi
Cardiology Division, Faculty of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, 14048-900, Brazil. Electronic address: msimoes@fmrp.usp.br.
Marcus V
MV
Simões
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000633:toxicity; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000473:pathology*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000633:toxicity; D006321:Heart / Q000187:drug effects; D008297:Male; D051381:Rats; D017208:Rats, Wistar
D000903:Antibiotics, Antineoplastic; D004317:Doxorubicin
Cardiotoxicity; Doxorubicin; Heart failure; Left ventricular dysfunction