Nishikawa Tatsuya, Shiba Mikio, Ikeda Yoshihiko, Ohta-Ogo Keiko, Kondo Takumi, Tabata Tomoka, Oka Toru, Shioyama Wataru, Yamamoto Hironori, Yasui Taku, Higuchi Yoshiharu, Ishibashi-Ueda Hatsue, Honma Keiichiro, Izumi Chisato, Higo Shuichiro, Hatakeyama Kinta, Sakata Yasushi, Fujita Masashi
Department of Onco-Cardiology, Osaka International Cancer Institute, 3-1-69, Otemae, Chuo-ku, Osaka City, Osaka 541-8567, Japan.
Department of Cardiovascular Medicine, Akashi Medical Center, Hyogo, Japan.
Eur Heart J Open. 2023 Oct 9;3(5):oead104. doi: 10.1093/ehjopen/oead104. eCollection 2023 Sep.
Doxorubicin is used in classical chemotherapy for several cancer types. Doxorubicin-induced cardiomyopathy (DOX-CM) is a critical issue among cancer patients. However, differentiating the diagnosis of DOX-CM from that of other cardiomyopathies is difficult. Therefore, in this study, we aimed to determine novel histopathological characteristics to diagnose DOX-CM.
Twelve consecutive patients with DOX-CM who underwent cardiac histopathological examination in two medical centres were included. Twelve patients with dilated cardiomyopathy, who were matched with DOX-CM patients in terms of age, sex, and left ventricular ejection fraction, formed the control group. Another control group comprised five consecutive patients with cancer therapy-related cardiac dysfunction induced by tyrosine kinase inhibitors or vascular endothelial growth factor inhibitors were the controls. The positive area of tenascin-C, number of infiltrating macrophages, and presence of p62- and ubiquitin-positive cardiomyocytes were evaluated. Human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used for investigation. The myocardium exhibited significantly greater tenascin-C-positive area and macrophage number in the DOX-CM group than in the control groups ( < 0.01). The tenascin-C-positive area correlated with the number of both CD68- and CD163-positive cells ( = 0.748 and = 0.656, respectively). Immunostaining for p62 was positive in 10 (83%) patients with DOX-CM. Furthermore, western blotting analysis revealed significant increase in tenascin-C levels in hiPSC-CMs upon doxorubicin treatment ( < 0.05).
The combined histopathological assessment for tenascin-C, macrophages, and p62/ubiquitin may serve as a novel tool for the diagnosis of DOX-CM. Doxorubicin may directly affect the expression of tenascin-C in the myocardium.
多柔比星用于多种癌症类型的经典化疗。多柔比星诱导的心肌病（DOX-CM）是癌症患者中的一个关键问题。然而，将DOX-CM的诊断与其他心肌病的诊断区分开来很困难。因此，在本研究中，我们旨在确定诊断DOX-CM的新组织病理学特征。
纳入了在两个医疗中心接受心脏组织病理学检查的12例连续的DOX-CM患者。12例扩张型心肌病患者，在年龄、性别和左心室射血分数方面与DOX-CM患者匹配，组成对照组。另一个对照组包括5例连续的由酪氨酸激酶抑制剂或血管内皮生长因子抑制剂引起的癌症治疗相关心脏功能障碍患者。评估了肌腱蛋白-C的阳性面积、浸润巨噬细胞数量以及p62和泛素阳性心肌细胞的存在情况。使用人诱导多能干细胞衍生的心肌细胞（hiPSC-CMs）进行研究。DOX-CM组心肌的肌腱蛋白-C阳性面积和巨噬细胞数量显著大于对照组（<0.01）。肌腱蛋白-C阳性面积与CD68和CD163阳性细胞数量均相关（分别为=0.748和=0.656）。10例（83%）DOX-CM患者的p62免疫染色呈阳性。此外，蛋白质印迹分析显示多柔比星处理后hiPSC-CMs中肌腱蛋白-C水平显著升高（<0.05）。
肌腱蛋白-C、巨噬细胞和p62/泛素的联合组织病理学评估可能作为诊断DOX-CM的新工具。多柔比星可能直接影响心肌中肌腱蛋白-C的表达。
