Evaluation of cardiac adrenergic neuronal damage in rats with doxorubicin-induced cardiomyopathy using iodine-131 MIBG autoradiography and PGP 9.5 immunohistochemistry.
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.
Jeon
T J
TJ
Department of Diagnostic Radiology, Yonsei University Medical College, Seoul, Korea.
Lee
J D
JD
Ha
J W
JW
Yang
W I
WI
Cho
S H
SH
D019797:3-Iodobenzylguanidine; D000320:Adrenergic Fibers / Q000187:drug effects*; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity*; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000000981:diagnostic imaging; D004317:Doxorubicin / Q000633:toxicity*; D006321:Heart / Q000000981:diagnostic imaging / Q000294:innervation*; D007150:Immunohistochemistry; D009638:Norepinephrine / Q000097:blood; D011877:Radionuclide Imaging; D051381:Rats; D017208:Rats, Wistar; D013869:Thiolester Hydrolases / Q000032:analysis*; D043222:Ubiquitin Thiolesterase; D016277:Ventricular Function, Left / Q000187:drug effects
D000903:Antibiotics, Antineoplastic; D019797:3-Iodobenzylguanidine; D004317:Doxorubicin; D013869:Thiolester Hydrolases; D043222:Ubiquitin Thiolesterase; D009638:Norepinephrine