静脉化疗后血脑钠肽变化规律实验研究

Changes of blood brain natriuretic peptide after intravenous chemotherapy

目的脑钠肽(brain natriuretic peptide,BNP)早期诊断化疗相关心脏毒性的价值存在争议。本研究通过研究不同药物化疗后血BNP随时间变化的规律,探讨BNP早期诊断化疗相关心脏毒性的最佳采血时机和合适的化疗方案。方法选取健康成年新西兰兔24只,随机数字表法分4组,每组6只。单次耳缘静脉注射化疗药物建造心脏毒性模型,对照组(生理盐水8ml/kg)、表阿霉素低剂量组(表阿霉素4mg/kg)、表阿霉素高剂量组(表阿霉素8mg/kg)和多西他赛组(多西他赛6mg/kg)。ELISA法检测给药前和给药后1、4、8、12、24、48、96h静脉血BNP浓度。末次采血后将兔处死,取心室肌组织观察心肌损害情况。结果基线BNP浓度对照组(171.11±43.80)pg/mL、表阿霉素低剂量组(207.79±35.85)pg/mL、表阿霉素高剂量组(197.58±54.39)pg/mL、多西他赛组(188.35±42.13)pg/mL。用药后BNP均上升,1h达峰值,对照组(476.43±44.57)pg/mL、表阿霉素低剂量组(493.53±45.59)pg/mL、表阿霉素高剂量组(510.76±36.92)pg/mL、多西他赛组(464.33±42.97)pg/mL。此后BNP逐渐下降,96h后对照组(190.42±24.13)pg/mL、表阿霉素低剂量组(286.72±54.26)pg/mL、表阿霉素高剂量组(288.23±33.45)pg/mL、多西他赛组(231.96±8.92)pg/mL。两因素方差分析提示不同药物和采血时机均对BNP有影响,而药物和采血时机两者间无交互效应。4组均出现不同程度的心肌细胞肥大、凋亡、空泡变性、炎细胞浸润、细胞间隙增宽、间质内毛细血管扩张现象。对照组心肌细胞变性坏死和空泡所占比例的中位数为5%(5%,5%),表阿霉素低剂量组为20%(16%,35%),表阿霉素高剂量组为40%(9%,53%),多西他赛组为5%(5%,10%),各组心肌细胞变性坏死和空泡所占比例差异有统计学意义(H=13.015,P=0.005),两两比较提示对照组与表阿霉素高剂量组间比较差异有统计学意义(P=0.015),其余各组两两比较差异均无统计学意义,P>0.05。结论化疗后BNP变化是一个动态过程,与采血时机和化疗药物有关。化疗后96hBNP对早期诊断蒽环类药物引起的心脏毒性可能具有一定价值。

OBJECTIVE The value of BNP in early diagnosis of chemotherapy-related cardiotoxicity is controversial.This article aimed to explain the possible cause of controversy by studying the changes of blood BNP over time after intravenous different chemotherapy,and explore the optimal timing of blood sampling and appropriate chemotherapeutic drugs for early diagnosis of chemotherapy-related cardiotoxicity.METHODS Twenty-four healthy adult New Zealand rabbits were randomly divided into 4 groups,6 in each group:a single ear vein intravenous chemotherapy drug was taken to build a cardiotoxicity model:control group(normal saline 8 ml/kg),epirubicin low-dose group(epirubicin 4 mg/kg),epirubicin high-dose group(epirubicin 8 mg/kg),docetaxel group(docetaxel 6 mg/kg).BNP was measured before and after1,4,8,12,24,48 and 96 hafter administration(ELISA).Rabbits were sacrificed after the last blood collection,and myocardial damage was observed by ventricular muscle tissue.RESULTS Baseline BNP in the control group was(171.11±43.80)pg/ml,in the epirubicin low-dose group was(207.79±35.85)pg/ml,in the epirubicin high-dose group was(197.58±54.39)pg/ml,and in the docetaxel group was(188.35±42.13)pg/ml,respectively.After chemotherapy,the BNP increased and peaked at 1 h,which was(476.43±44.57)pg/ml in the control group,(493.53±45.59)pg/ml in the epirubicin low-dose group,(510.76±36.92)pg/ml in the epirubicin high-dose group,and(464.33±42.97)pg/ml in the docetaxel group,respectively.After that,the BNP gradually decreased,and after 96 h,it was(190.42±24.13)pg/ml in the control group,(286.72±54.26)pg/ml in the epirubicin low-dose group,(288.23±33.45)pg/ml in the epirubicin high-dose group and(231.96±8.92)pg/ml in the docetaxel group,respectively.Two-factor analysis of variance showed that different drugs and timing of blood collection had effects on BNP,but there was no interaction between drugs and timing.There were different degrees of myocardial hypertrophy,apoptosis,vacuolar degeneration,inflammatory cell infiltration,intercellular gap widening and interstitial capillary dilatation in four groups.The median proportion of degeneration,necrosis and vacuoles in the control group,epirubicin low-dose group,epirubicin high-dose group and docetaxel group were5%(5%,5%),20%(16%,35%),40%(9%,53%),5%(5%,10%),respectively.The proportion of degeneration,necrosis and vacuoles in different groups of cardiomyocytes was different(H=13.015,P=0.005).The comparison between the two groups indicated that there was a difference between the control group and the high dose group of epirubicin(P=0.015 after correction),while there was no difference between the other groups(P>0.05).CONCLUSIONS The change of BNP after chemotherapy is a dynamic process,which is related to the timing of blood collection and chemotherapeutic drugs.The 96 hBNP after chemotherapy may be valuable for early diagnosis of cardiotoxicity induced by anthracyclines.