曲妥珠单抗是第一种针对人表皮生长因子受体2（ERBB2/HER2）的人源化单克隆抗体，目前作为HER2(+)肿瘤的一线治疗药物。然而，曲妥珠单抗会增加心脏并发症的风险，但不影响心肌结构，提示一种不同的心脏毒性机制。我们使用曲妥珠单抗处理的人脐静脉内皮细胞的培养基，处理人类胚胎心脏组织源细胞株（CCC-HEH-2细胞）和人工诱导多能干细胞来源的心肌细胞（iPSC-CMs）来评估血管内皮细胞（VECs）与心肌细胞的相互作用。蛋白质质谱分析被用于鉴定VECs中调节心肌细胞功能的关键因子。我们应用RNA测序技术阐明PTX3导致心脏功能异常的机制。我们使用抗人/鼠HER2(neu)单克隆抗体制备大鼠模型，评估曲妥珠单抗对心脏结构和功能的影响以及拉帕替尼对曲妥珠单抗引起的心脏副作用的救助效应。曲妥珠单抗处理的脐静脉内皮细胞的培养基明显损害CCC-HEH-2细胞和iPSC-CMs的收缩能力。VECs中的PTX3导致小鼠心肌收缩能力缺陷和心脏功能障碍，表现为曲妥珠单抗处理的现象。PTX3影响心肌细胞的钙离子平衡，导致收缩性质缺陷。VECs中的EGFR/STAT3信号传导有助于PTX3的增加表达和释放。值得注意的是，拉帕替尼，一种EGFR/HER2的双重抑制剂，可通过阻止PTX3释放来预防曲妥珠单抗引起的心脏并发症。我们鉴定了一种独特的心脏毒性模式，其中曲妥珠单抗在VECs中促进PTX3的外排，从而导致心肌细胞功能受损并抑制细胞钙信号。我们证实了拉帕替尼可作为防止曲妥珠单抗引起心脏功能障碍的可行药物，并提供了联合应用拉帕替尼和曲妥珠单抗在癌症治疗中的机理学基础。我们鉴定PTX3作为曲妥珠单抗引起心脏并发症的潜在生物标志物和靶点，并证明拉帕替尼可以通过阻止VECs释放的EFGR/STAT3介导的PTX3来预防曲妥珠单抗引起的心脏功能障碍，为联合应用拉帕替尼和曲妥珠单抗提供了机理学基础。© 作者2023。由欧洲心脏病学会代表牛津大学出版发表。

Trastuzumab, the first humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (ERBB2/HER2), is currently used as a first-line treatment for HER2 (+) tumours. However, trastuzumab increases the risk of cardiac complications without affecting myocardial structure, suggesting a distinct mechanism of cardiotoxicity.We used medium from trastuzumab-treated human umbilical vein endothelial cells (HUVECs) to treat CCC-HEH-2 cells, the human embryonic cardiac tissue-derived cell lines, and human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to assess the crosstalk between vascular endothelial cells (VECs) and cardiomyocytes. Protein mass spectrometry analysis was used to identify the key factors from VECs that regulate the function of cardiomyocytes. We applied RNA-sequencing to clarify the mechanism, by which PTX3 causes cardiac dysfunction. We used an anti-human/rat HER2 (neu) monoclonal antibody to generate a rat model that was used to evaluate the effects of trastuzumab on cardiac structure and function and the rescue effects of lapatinib on trastuzumab-induced cardiac side effects. Medium from trastuzumab-treated HUVECs apparently impaired the contractility of CCC-HEH-2 cells and iPSC-CMs. PTX3 from VECs caused defective cardiomyocyte contractility and cardiac dysfunction in mice, phenocopying trastuzumab treatment. PTX3 affected calcium homeostasis in cardiomyocytes, which led to defective contractile properties. EGFR/STAT3 signalling in VECs contributed to the increased expression and release of PTX3. Notably, lapatinib, a dual inhibitor of EGFR/HER2, could rescue the cardiac complications caused by trastuzumab by blocking the release of PTX3.We identified a distinct mode of cardiotoxicity, wherein the activation of EGFR/STAT3 signalling by trastuzumab in VECs promotes PTX3 excretion, which contributes to the impaired contractility of cardiomyocytes by inhibiting cellular calcium signalling. We confirmed that lapatinib could be a feasible preventive agent against trastuzumab-induced cardiac complications and provided the rationale for the combined application of lapatinib and trastuzumab in cancer-therapy.We identified PTX3 as a potential biomarker and target for the treatment of trastuzumab-induced cardiac complications and demonstrated that lapatinib can prevent cardiac dysfunction caused by trastuzumab by blocking EFGR/STAT3-mediated PTX3 release from VECs, which provided a mechanistic rationale for the combined application of lapatinib and trastuzumab in cancer.© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.