Tenascin-C as a potential marker for immunohistopathology of doxorubicin-induced cardiomyopathy

Tatsuya Nishikawa; Mikio Shiba; Yoshihiko Ikeda; Keiko Ohta-Ogo; Takumi Kondo; Tomoka Tabata; Toru Oka; Wataru Shioyama; Hironori Yamamoto; Taku Yasui; Yoshiharu Higuchi; Hatsue Ishibashi-Ueda; Keiichiro Honma; Chisato Izumi; Shuichiro Higo; Kinta Hatakeyama; Yasushi Sakata; Masashi Fujita

doi:10.1093/ehjopen/oead104

Tenascin-C as a potential marker for immunohistopathology of doxorubicin-induced cardiomyopathy

Eur Heart J Open. 2023 Oct 9;3(5):oead104. doi: 10.1093/ehjopen/oead104. eCollection 2023 Sep.

Authors

Tatsuya Nishikawa^{1

2}, Mikio Shiba^{3

4}, Yoshihiko Ikeda⁵, Keiko Ohta-Ogo⁵, Takumi Kondo³, Tomoka Tabata³, Toru Oka^{1

6}, Wataru Shioyama⁷, Hironori Yamamoto¹, Taku Yasui¹, Yoshiharu Higuchi⁴, Hatsue Ishibashi-Ueda^{5

8}, Keiichiro Honma⁹, Chisato Izumi¹⁰, Shuichiro Higo^{3

11}, Kinta Hatakeyama⁵, Yasushi Sakata³, Masashi Fujita¹

Affiliations

¹ Department of Onco-Cardiology, Osaka International Cancer Institute, 3-1-69, Otemae, Chuo-ku, Osaka City, Osaka 541-8567, Japan.
² Department of Cardiovascular Medicine, Akashi Medical Center, Hyogo, Japan.
³ Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
⁴ Cardiovascular Division, Osaka Police Hospital, Osaka, Japan.
⁵ Department of Pathology, National Cerebral and Cardiovascular Center, 6-1, Kishibeshinmachi, Suita, Osaka 564-8565, Japan.
⁶ Onco-Cardiology Unit, Department of Internal Medicine, Saitama Cancer Center, Saitama, Japan.
⁷ Department of Internal Medicine, Division of Cardiovascular Medicine, Shiga University of Medical Science, Shiga, Japan.
⁸ Department of Pathology, Hokusetsu General Hospital, Takatsuki, Osaka, Japan.
⁹ Department of Pathology, Osaka International Cancer Institute, Osaka, Japan.
¹⁰ Department of Heart Failure and Transplantation, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan.
¹¹ Department of Medical Therapeutics for Heart Failure, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Abstract

Aims: 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.

Methods and results: 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 in vitro investigation. The myocardium exhibited significantly greater tenascin-C-positive area and macrophage number in the DOX-CM group than in the control groups (P < 0.01). The tenascin-C-positive area correlated with the number of both CD68- and CD163-positive cells (r = 0.748 and r = 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 (P < 0.05).

Conclusion: 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.

Keywords: Cardiotoxicity; Doxorubicin; Tenascin-C.