This Article Full Text Full Text (PDF) All Versions of this Article: 108/19/2423    most recent 01.CIR.0000093196.59829.DFv2 01.CIR.0000093196.59829.DFv1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lebrecht, D. Articles by Walker, U. A. Search for Related Content PubMed PubMed Citation Articles by Lebrecht, D. Articles by Walker, U. A. Related Collections Other heart failure Animal models of human disease

(Circulation. 2003;108:2423.)
© 2003 American Heart Association, Inc.

Basic Science Reports

Time-Dependent and Tissue-Specific Accumulation of mtDNA and Respiratory Chain Defects in Chronic Doxorubicin Cardiomyopathy

From the Medizinische Universitätsklinik, Departments of Rheumatology and Clinical Immunology (D.L., B.S., U.A.W.), Pediatrics (U.-P.K.), and Surgical Research (J.H.), Freiburg, Germany.

Correspondence to Dr Ulrich A. Walker, Medizinische Universitätsklinik, Hugstetterstraße 55, D-79106 Freiburg, Germany. E-mail walkerul{at}uni-freiburg.de

Received October 14, 2002; de novo received April 18, 2003; revision received July 9, 2003; accepted July 10, 2003.

Background— Doxorubicin causes a chronic cardiomyopathy of unknown pathogenesis. We investigated whether acquired defects in mitochondrial DNA (mtDNA) and interconnected respiratory chain dysfunction may represent a molecular mechanism for its late onset.

Methods and Results— Rats were treated weekly with intravenous doxorubicin (1 mg/kg) for 7 weeks, starting at 11 weeks of age (group B). Controls received saline. Group C received doxorubicin identically to group B, but the course was started at 41 weeks of age. All rats were killed at week 48. Doxorubicin was also injected once, either 6 days (group D) or 2 hours (group E) before euthanasia. Heart and skeletal muscle were examined. Only group B rats developed a significant clinical, macroscopic, histological, and ultrastructural cardiomyopathy. Group B hearts had the lowest cytochrome c oxidase (COX) activity (24% of controls; P=0.003), the highest citrate synthase activity (135% of controls; P=0.005), and the highest production of superoxide. In group B, the respiratory subunit COXI, which is encoded by mtDNA, was reduced (P<0.001), as was mtDNA (49% of controls, P<0.001). Group C hearts differed from group B in their lower cardiomyopathy score (P=0.006), higher COX activity (P=0.02), and higher mtDNA content (P=0.04). Group B and to a lesser extent group C hearts contained deleted mtDNA. There was no detectable mitochondrial toxicity in group D and E hearts or in skeletal muscle.

Conclusions— In doxorubicin cardiomyopathy, mtDNA alterations, superoxide, and respiratory chain dysfunction accumulate long-term in the absence of the drug and are associated with a late onset.

Key Words: cardiomyopathy • drugs • genetics • metabolism • pathology

This article has been cited by other articles:

				H. Tsutsui, S. Kinugawa, and S. Matsushima Mitochondrial oxidative stress and dysfunction in myocardial remodelling Cardiovasc Res, February 15, 2009; 81(3): 449 - 456. [Abstract] [Full Text] [PDF]

				L. Gianni, E. H. Herman, S. E. Lipshultz, G. Minotti, N. Sarvazyan, and D. B. Sawyer Anthracycline Cardiotoxicity: From Bench to Bedside J. Clin. Oncol., August 1, 2008; 26(22): 3777 - 3784. [Abstract] [Full Text] [PDF]

				L. W. Jones, M. J. Haykowsky, J. J. Swartz, P. S. Douglas, and J. R. Mackey Early Breast Cancer Therapy and Cardiovascular Injury J. Am. Coll. Cardiol., October 9, 2007; 50(15): 1435 - 1441. [Abstract] [Full Text] [PDF]

				Y. Chen, P. Jungsuwadee, M. Vore, D. A. Butterfield, and D. K. St. Clair Collateral Damage in Cancer Chemotherapy: Oxidative Stress in Nontargeted Tissues Mol. Interv., June 1, 2007; 7(3): 147 - 156. [Abstract] [Full Text] [PDF]

				P. G. Horan, M. F. McMullin, and P. P. McKeown Anthracycline cardiotoxicity Eur. Heart J., May 2, 2006; 27(10): 1137 - 1138. [Full Text] [PDF]

				X. Yi, R. Bekeredjian, N. J. DeFilippis, Z. Siddiquee, E. Fernandez, and R. V. Shohet Transcriptional analysis of doxorubicin-induced cardiotoxicity Am J Physiol Heart Circ Physiol, March 1, 2006; 290(3): H1098 - H1102. [Abstract] [Full Text] [PDF]

				M. Ikeuchi, H. Matsusaka, D. Kang, S. Matsushima, T. Ide, T. Kubota, T. Fujiwara, N. Hamasaki, A. Takeshita, K. Sunagawa, et al. Overexpression of Mitochondrial Transcription Factor A Ameliorates Mitochondrial Deficiencies and Cardiac Failure After Myocardial Infarction Circulation, August 2, 2005; 112(5): 683 - 690. [Abstract] [Full Text] [PDF]