Application of 2-Dimensional Speckle Tracking Technology for Trastuzumab-Induced Cardiotoxicity in a New Mouse Model.

Objectives: 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.

Methods: 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.

Results: 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.

Conclusions: 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.