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Evaluation of cardiac adrenergic neuronal damage in rats with doxorubicin-induced cardiomyopathy using iodine-131 MIBG autoradiography and PGP 9.5 immunohistochemistry

 Tae Joo Jeon  ;  Jong Doo Lee  ;  Jong-Won Ha  ;  Woo Ick Yang  ;  Sang Ho Cho 
 European Journal of Nuclear Medicine and Molecular Imaging, Vol.27(6) : 686-693, 2000 
Journal Title
 European Journal of Nuclear Medicine and Molecular Imaging 
Issue Date
3-Iodobenzylguanidine* ; Adrenergic Fibers/drug effects* ; Animals ; Antibiotics, Antineoplastic/toxicity* ; Cardiomyopathies/chemically induced* ; Cardiomyopathies/diagnostic imaging ; Doxorubicin/toxicity* ; Heart/diagnostic imaging ; Heart/innervation* ; Immunohistochemistry ; Norepinephrine/blood ; Radionuclide Imaging ; Rats ; Rats, Wistar ; Thiolester Hydrolases/analysis* ; Ubiquitin Thiolesterase ; Ventricular Function, Left/drug effects
Cardiomyopathy ; Doxorubicin ; Iodine-131 metaiodobenzylguanidine ; Immunohistochemistry ; Protein gene product 9.5
Doxorubicin is one of the most useful anticancer agents, but its repeated administration can induce irreversible cardiomyopathy as a major complication. The purpose of this study was to investigate doxorubicin toxicity on cardiac sympathetic neurons using iodine-131-metaiodobenzylguanidine (MIBG) and protein gene product (PGP) 9.5 immunohistochemistry, which is a marker of cardiac innervation. Wistar rats were treated with doxorubicin (2 mg/kg, i.v.) once a week for 4 (n=5), 6 (n=6) or 8 (n=7) weeks consecutively. Left ventricular ejection fraction (LVEF), calculated by M-mode echocardiography, was used as an indicator of cardiac function. Plasma noradrenaline (NA) concentration was measured by high-performance liquid chromatography (HPLC). 131I-MIBG uptake of the left ventricular wall (24 ROIs) was measured by autoradiography. 131I-MIBG uptake pattern was compared with histopathological results, the neuronal population on PGP 9.5 immunohistochemistry and the degree of myocyte damage assessed using a visual scoring system on haematoxylin and eosin and Masson's trichrome staining. LVEF was significantly decreased in the 8-week group (P<0.05). The serum NA level also showed no statistical difference until 4 weeks and was significantly increased in the 8-week group (P<0.05). MIBG uptake was decreased in the 6- and 8-week groups (P<0.05), and was closely correlated with the reduction in the number of nerve fibres on PGP 9.5 stain. Myocyte damage was seen only in the 8-week group. Neuronal population and the 131I-MIBG uptake ratio of subepicardium to subendocardium were significantly increased (P<0.05) in the 8-week group as compared with the control group. It may be concluded that radioiodinated MIBG is a reliable marker for the detection of cardiac adrenergic neuronal damage in doxorubicin-induced cardiomyopathy; it detects such damage earlier than do other clinical parameters and in this study showed a good correlation with the reduction in the neuronal population on PGP 9.5 stain. The subendocardial layer appeared to be more vulnerable to doxorubicin than the subepicardium.
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Nuclear Medicine (핵의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Yang, Woo Ick(양우익) ORCID logo https://orcid.org/0000-0002-6084-5019
Lee, Jong Doo(이종두)
Ha, Jong Won(하종원) ORCID logo https://orcid.org/0000-0002-8260-2958
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