Tu Yingxuan, Zhang Huaxing, Han Ruoling
Department of Ultrasound, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China.
Department of Ultrasound, Baoding No. 1 Central Hospital, Baoding, China.
J Ultrasound Med. 2025 Jun 28. doi: 10.1002/jum.16755.
To establish a mouse model of trastuzumab-induced cardiotoxicity that aligns with clinical standard treatment protocols, assess the extent of histological damage across various chambers of the mouse heart, and investigate whether 2-dimensional speckle tracking echocardiography (2D-STE) can detect early cardiac dysfunction, while comparing the diagnostic effectiveness of various parameters in cardiotoxicity.
Mice were randomly assigned to a trastuzumab group (Trz), a doxorubicin-sequential-trastuzumab group (Dox-Trz), and a control group (Con). A mouse model of cardiotoxicity was developed according to clinical standard treatment protocols. Echocardiographic assessments were conducted prior to the experiment, at the end of the first, third, and fourth weeks, and at the conclusion of the experiment to measure and document cardiac function in the mice. Following this, the hearts of the mice were collected for histological analysis, including histopathological evaluation using H&E staining, quantitative assessment of myocardial fibrosis using Masson staining, and evaluation of myocardial cell apoptosis using a TUNEL kit.
H&E staining revealed myocardial cell pathology in the hearts of mice in both the Trz and Dox-Trz groups, whereas no abnormalities were observed in the Con group. Masson staining demonstrated a significant increase in interstitial fibrosis in the hearts of mice in the Trz and Dox-Trz groups, with a higher proportion of collagen fibers in the atria compared to the ventricles, and a higher proportion in the right ventricle compared to the left ventricle, with statistical significance. TUNEL staining results indicated a statistically significant increase in myocardial cell apoptosis in the Trz and Dox-Trz groups compared to the Con group. 2D-STE showed significantly reduced left ventricular global longitudinal strain (GLS) and global radial strain (GRS) from baseline in both Trz and Dox-Trz groups at T2. At T3, GLS and GRS were significantly lower in these groups compared to the Con group. Both groups also exhibited significantly reduced global circumferential strain (GCS) from baseline at T3, with the Dox-Trz group showing significantly lower GCS than the Con group. All differences were statistically significant. However, left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS) parameter only exhibited intergroup differences at T4. Notably, GLS demonstrated the highest diagnostic efficacy for trastuzumab-induced cardiotoxicity.
This study confirms that GLS, GRS, and GCS can predict early cardiac dysfunction in a mouse model using 2D-STE. Additionally, histological analysis further validated the overall nature of cardiac damage.
建立一种符合临床标准治疗方案的曲妥珠单抗诱导的心脏毒性小鼠模型，评估小鼠心脏各腔室的组织学损伤程度，并研究二维斑点追踪超声心动图（2D-STE）能否检测早期心脏功能障碍，同时比较心脏毒性中各种参数的诊断效能。
将小鼠随机分为曲妥珠单抗组（Trz）、阿霉素序贯曲妥珠单抗组（Dox-Trz）和对照组（Con）。根据临床标准治疗方案建立心脏毒性小鼠模型。在实验前、第一周、第三周和第四周结束时以及实验结束时进行超声心动图评估，以测量和记录小鼠的心脏功能。在此之后，收集小鼠心脏进行组织学分析，包括使用苏木精-伊红（H&E）染色进行组织病理学评估、使用Masson染色对心肌纤维化进行定量评估以及使用TUNEL试剂盒评估心肌细胞凋亡。
H&E染色显示Trz组和Dox-Trz组小鼠心脏存在心肌细胞病变，而Con组未观察到异常。Masson染色显示Trz组和Dox-Trz组小鼠心脏间质纤维化显著增加，心房胶原纤维比例高于心室，右心室胶原纤维比例高于左心室，具有统计学意义。TUNEL染色结果表明，与Con组相比，Trz组和Dox-Trz组心肌细胞凋亡有统计学意义的增加。2D-STE显示，在T2时，Trz组和Dox-Trz组的左心室整体纵向应变（GLS）和整体径向应变（GRS）较基线显著降低。在T3时，与Con组相比，这些组的GLS和GRS显著降低。两组在T3时的整体周向应变（GCS）也较基线显著降低，Dox-Trz组的GCS显著低于Con组。所有差异均具有统计学意义。然而，左心室射血分数（LVEF）、左心室缩短分数（LVFS）参数仅在T4时表现出组间差异。值得注意的是，GLS对曲妥珠单抗诱导的心脏毒性具有最高的诊断效能。
本研究证实，GLS、GRS和GCS可通过2D-STE预测小鼠模型中的早期心脏功能障碍。此外，组织学分析进一步验证了心脏损伤的总体性质。
