血清N末端脑钠肽前体早期诊断蒽环类药物心脏毒性的实验研究

Serum NT-proBNP as a Marker for Early Detection for Anthracycline-induced Cardiotoxicity in Rabbits

目的:探讨血清N末端脑钠肽前体(NT-proBNP)浓度是否可成为蒽环类药物心脏毒性的早期诊断指标。方法:新西兰雄性兔44只随机分为对照组和实验组,对照组新西兰兔静脉注射等体积的生理盐水,实验组分为4组,每次给予阿霉素2 mg/kg,每周1次,根据给药周数不同,分为1周组、2周组、4周组和8周组。经胸超声心动图测量左室射血分数(LVEF)和左室短轴缩短分数(FS)以及E峰和A峰比率,血清NT-proBNP浓度测量采用酶联免疫吸附测定法(ELISA),心肌光镜Billingham评分和电镜检查评价蒽环类药物心脏毒性。结果:8周组新西兰兔LVEF、FS以及E/A比率均下降(P<0.05),4周组新西兰兔心肌病评分高于对照组、1周组和2周组(P<0.05)。八周组新西兰兔心肌病评分高于其余各组新西兰兔(P<0.05)。心肌电镜检查结果证实二周组、四周组和八周组新西兰兔心肌损伤。与对照组血清NT-proBNP浓度相比,二周组、四周组和八周组新西兰兔血清NT-proBNP浓度均明显上升(P<0.05)。通过相关分析提示血清NT-proBNP浓度与阿霉素累积剂量及心肌损害的程度呈正相关。结论:血清NT-proBNP浓度可能是蒽环类药物心脏毒性较早期诊断指标。

Objective：To investigate serum NT-proBNP concentrations as an early biomarker for anthracycline-induced myocardial damage in rabbits. Methods： 44 male rabbits were randomly divided into control group or one of four doxorubicin groups. Rabbits in control group received saline, while rabbits in doxorubicin group received 2 mg/kg doxorubicin weekly for one （Group 1）, two （Group 2）, four （Group 3） and eight（Group 4）weeks. Echocardiography was performed to measure left ventricular ejection fraction （LVEF）, fractional shortening （FS）, and E/A ratio. Serum NT-proBNP concentrations were quantified by a rabbit-specific enzyme-linked immunosorbent assay （ELISA）. Cardiotoxicity scores were determined by light microscopy using Billingham＇s method and by electron microscopy. Results： Decreased LVEF, FS, and E/A ratio were detected in Group 4 （P 〈 0.05）. The Billingham cardiomyopathy scores of the rabbits in Group 3 were significantly higher （P 〈 0.05） than those of rabbits in control group or Groups 1 or 2. The Billingham cardiomyopathy scores in Group 4 were the highest of all five groups （P 〈 0.05）. Myocardial injury was verified by electron microscopy in rabbits from Groups 2, 3, and 4. Compared with control group, serum NT-proBNP concentrations increased in Groups 2, 3, and 4 （P 〈 0.05）. A positive correlation between the serum NT- proBNP concentrations and both the dose of doxorubicin and the cardiomyopathy score was found. Conclusion： Serum NT-proBNP concentrations may be a sensitive method for assessing early cardiotoxicity induced by anthracycline.