Ultrastructural and Echocardiographic Assessment of Chronic Doxorubicin-Induced Cardiotoxicity in Rats

Document Type: Original Articles

Authors

1 Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

2 School of Pharmacy, Tabriz University of Medical Sciences, Tabriz, Iran

3 Department of Cellular and Molecular Biotechnology, Razi Vaccine and Research Institute, Agricultural Research, Education, and Extension Organization, Karaj, Iran

4 Department of Veterinary Clinical Sciences, Tabriz Branch, Islamic Azad University, Tabriz, Iran

5 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran

Abstract

Doxorubicin (DOX) is one of the secondary metabolites of Streptomyces peucetius var. caesius. It is a common and effective chemotherapeutic agent used for the treatment of different diseases, including lymphoma, leukemia, breast cancer, and solid tumors. However, this medicine causes cardiotoxic side effects, which limit its clinical application. The present study examined the cardiomyopathy induced by DOX via echocardiography and transmission electron microscopy (TEM). The main objective was to evaluate the capacity of echocardiography and TEM as diagnostic tools for DOX-induced cardiotoxicity. Moreover, the correlation between intracellular and functional changes due to cardiotoxicity was assessed in a rat model. Cardiomyopathy was induced in rats by two cumulative doses of DOX. Group I received DOX 12 [i.e., 12 mg/kg, intraperitoneal (IP)] and group II received DOX 15 (i.e., 15 mg/kg, IP) in six equal doses over two weeks. Group III as the control (Ctrl) group received normal saline as a vehicle. Mortality during the study was only observed in the DOX 15 group. The echocardiographic assessments revealed significant changes in ejection fraction, fractional shortening, and heart rate in the groups which received DOX. In addition, severe cardiac arrhythmia was evident in DOX-treated groups. Remarkable adverse effects, such as moderately degenerated cells and inflated mitochondria were observed in the TEM analysis of rat hearts in the DOX groups. The present study indicated that rat models are suitable for investigating DOX-induced cardiomyopathy, especially at the dose of 12 mg/kg. Furthermore, echocardiography and TEM examinations were found to be valuable methods for the determination of cardiotoxicity in rats due to DOX. 

Keywords


Article Title [French]

Étude Ultrastructurale et Échocardiographique de la Cardiotoxicité Chronique Induite par la Doxorubicine chez le Rat

Abstract [French]

La doxorubicine (DOX) est l'un des métabolites secondaires de Streptomyces peucetius var. caesius. La DOX est un agent chimiothérapeutique commun et efficace utilisé pour le traitement de différentes maladies, y compris le lymphome, la leucémie, le cancer du sein et les tumeurs solides. Cependant, ce médicament provoque des effets secondaires cardiotoxiques, ce qui limite son application clinique. La présente étude a examiné la cardiomyopathie induite par la DOX par échocardiographie et microscopie électronique à transmission (MET). L'objectif principal était d'évaluer la capacité de l'échocardiographie et de la MET comme outils de diagnostic de la cardiotoxicité induite par la DOX. De plus, la corrélation entre les changements intracellulaires et fonctionnels causés par la cardiotoxicité de cette substance a été évaluée dans un modèle de rat. La cardiomyopathie a été induite chez le rat par l’injection de deux doses cumulées de DOX. Le groupe I a reçu DOX 12 [12 mg/kg, intrapéritonéal (IP)] et le groupe II a reçu DOX 15 (15 mg/kg, IP) en six doses égales sur deux semaines. Le groupe III (groupe témoin, Ctrl) a reçu une solution saline normale comme véhicule. Au cours de cette étude, la mortalité n’a été observée que dans le groupe DOX 15. L'évaluation échocardiographique a révélé des changements significatifs dans la fraction d'éjection, le raccourcissement fractionnaire et la fréquence cardiaque dans les groupes traités avec la DOX. De plus, ces derniers montraient une arythmie cardiaque sévère évidente. L'analyse MET sur le cœur de rats traités avec la DOX a montré des effets indésirables remarquables comme des cellules modérément dégénérées et des mitochondries gonflées. Cetteeétude montraitque les modèles de rat conviennent pour étudier la cardiomyopathie induite par la DOX, en particulier à la dose de 12 mg/kg. De plus, l'échocardiographie et les examens MET se sont révélés être des méthodes précieuses pour la détermination de la cardiotoxicité de la DOX chez le rat.

Keywords [French]

  • Cardiomyopathie
  • Doxorubicine
  • Échocardiographie
  • Microscopie électronique
  • Cœur de rat
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