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.
Tatsuya Nishikawa  1  2 ,  Mikio Shiba  3  4 ,  Yoshihiko Ikeda  5 ,  Keiko Ohta-Ogo  5 ,  Takumi Kondo  3 ,  Tomoka Tabata  3 ,  Toru Oka  1  6 ,  Wataru Shioyama  7 ,  Hironori Yamamoto  1 ,  Taku Yasui  1 ,  Yoshiharu Higuchi  4 ,  Hatsue Ishibashi-Ueda  5  8 ,  Keiichiro Honma  9 ,  Chisato Izumi  10 ,  Shuichiro Higo  3  11 ,  Kinta Hatakeyama  5 ,  Yasushi Sakata  3 ,  Masashi Fujita  1
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.
PMID: 37908440 DOI: 10.1093/ehjopen/oead104
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.
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