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接受曲妥珠单抗与化疗的女性存在曲妥珠单抗相关心脏功能障碍（TRCD）的风险，因此临床亟需精准预测曲妥珠单抗心脏毒性的监测指标。 肌钙蛋白是由三种调节蛋白（C、I、T）组成的复合物，当肌肉损伤后，肌钙蛋白复合物释放到血液中，开始在血液中升高，并且保持很长时间。心肌和骨骼肌的肌钙蛋白C结构相同，故血液肌钙蛋白I和T可用于心脏毒性的实验室诊断。 脑钠肽（BNP）是利尿钠肽家族一员，主要由心室心肌细胞合成分泌，由32个氨基酸残基组成，因其首先在猪脑中发现而得名，能调节血压和血容量的自稳平衡，并有利尿作用。心肌细胞首先合成108个氨基酸的BNP激素原，又称BNP前体（proBNP）。在心肌细胞受到刺激后，proBNP在蛋白酶作用下分解为76个氨基酸组成的无活性线性多肽NT-proBNP（氨基末端-proBNP或N端-proBNP）和32个氨基酸组成的活性环形多肽BNP。BNP、NT-proBNP的半衰期分别约为20分钟、2小时，从临床检验的角度考虑，NT-proBNP相对较为稳定，给检测带来方便，其浓度可反映短暂时间内新合成的而不是贮存的BNP释放，血浆NT-proBNP水平随急性心衰程度加重而升高，NT-proBNP值正常可以排除心衰（阴性预测值接近100%）。 2016年10月26日，美国临床肿瘤学会官方期刊《临床肿瘤学杂志》在线发表国际乳腺研究组织（BIG）、比利时布鲁塞尔自由大学、瑞士伯尔尼大学、瑞士罗氏、荷兰格罗宁根大学的研究报告，探讨了心脏标志物（肌钙蛋白I和T、NT-proBNP）预测发生TRCD基线易感性的预后价值，检验了心脏终点事件或左室射血分数（LVEF）显著下降的发生是否与标志物增加有相关性。 该研究对同意参与本研究的533例赫赛汀辅助（HERA）研究患者，在不同时间点测定其心脏标志物并测量LVEF。排除缺失标志物测定的患者后，得到452例可评估患者。主要心脏终点事件定义为，经心脏科医师确诊的纽约心脏协会（NYHA）III或IV级症状性充血性心力衰竭，以及显著的LVEF下降、明确的或可能的心脏所致死亡。次要心脏终点事件定义为经确诊的无症状或有轻度症状的LVEF显著下降。 结果发现，基线肌钙蛋白升高（I＞40ng/L和T＞14ng/L）分别见于13.6%（56/412）和24.8%（101/407）的患者，单变量分析发现LVEF显著下降的风险分别增加4.52倍和3.57倍（P值均＜0.001）。少数患者在研究期间记录了肌钙蛋白I、T第一次升高值（分别有6例、25例）。分别有2例、31例发生主要、次要心脏终点事件，康复率为74%（23/31）。LVEF显著下降的患者可见NT-proBNP增加幅度较高。 因此，曲妥珠单抗用药前的肌钙蛋白I或T升高与TRCD风险增加有相关性。对于NT-proBNP无法得出类似结论，因为缺乏明确的升高阈值；然而，TRCD患者与无TRCD患者相比，NT-proBNP增加幅度较高。 J Clin Oncol. 2016 Oct 26. [Epub ahead of print] Role of Troponins I and T and N-Terminal Prohormone of Brain Natriuretic Peptide in Monitoring Cardiac Safety of Patients With Early-Stage Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer Receiving Trastuzumab: A Herceptin Adjuvant Study Cardiac Marker Substudy. Dimitrios Zardavas, Thomas M. Suter, Dirk J. Van Veldhuisen, Jutta Steinseifer, Johannes Noe, Sabine Lauer, Nedal Al-Sakaff, Martine J. Piccart-Gebhart, Evandro de Azambuja. Breast International Group; Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium; Bern University Hospital, Bern; F. Hoffmann-La Roche, Basel, Switzerland; University Medical Center Groningen, University of Groningen, The Netherlands. PURPOSE: Women receiving trastuzumab with chemotherapy are at risk for trastuzumab-related cardiac dysfunction (TRCD). We explored the prognostic value of cardiac markers (troponins I and T, N-terminal prohormone of brain natriuretic peptide [NT-proBNP]) to predict baseline susceptibility to develop TRCD. We examined whether development of cardiac end points or significant left ventricular ejection fraction (LVEF) drop was associated with markers' increases. PATIENTS AND METHODS: Cardiac marker assessments were coupled with LVEF measurements at different time points for 533 patients from the Herceptin Adjuvant (HERA) study who agreed to participate in this study. Patients with missing marker assessments were excluded, resulting in 452 evaluable patients. A primary cardiac end point was defined as symptomatic congestive heart failure of New York Heart Association class III or IV, confirmed by a cardiologist, and a significant LVEF drop, or death of definite or probable cardiac causes. A secondary cardiac end point was defined as a confirmed significant asymptomatic or mildly symptomatic LVEF drop. RESULTS: Elevated baseline troponin I (> 40 ng/L) and T (> 14 ng/L), occurring in 56 of 412 (13.6%) and 101 of 407 (24.8%) patients, respectively, were associated with an increased significant LVEF drop risk (univariate analysis: hazard ratio, 4.52; P < .001 and hazard ratio, 3.57; P < .001, respectively). Few patients had their first elevated troponin value recorded during the study (six patients for troponin I and 25 patients for troponin T). Two patients developed a primary and 31 patients a secondary cardiac end point (recovery rate of 74%, 23 of 31). For NT-proBNP, higher increases from baseline were seen in patients with significant LVEF drop. CONCLUSION: Elevated troponin I or T before trastuzumab is associated with increased risk for TRCD. A similar conclusion for NT-proBNP could not be drawn because of the lack of a well-established elevation threshold; however, higher increases from baseline were seen in patients with TRCD compared with patients without. DOI: 10.1200/JCO.2015.65.7916
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