Alternative Titleがん治療に伴う心機能障害における心筋の病理組織学的およびエピジェネティックな変化
Note (General)type:Thesis
Aims：Cancer therapy-related cardiac dysfunction (CTRCD) is commonly reported, but its histopathology, mechanisms, and risk factors are not known. We aimed to clarify the histopathology and mechanisms of CTRCD to identify risk factors.Methods and results：We performed myocardial histopathological studies on 13 endomyocardial biopsies from CTRCD patients, 35 autopsied cancer cases with or without cardiac dysfunction, and controls without cancer (10 biopsies and 9 autopsies). Cardiotoxicity risk scores were calculated based on medication; and patient-related risk factors, fibrosis, and cardiomyocyte changes were scored; and p53 and H3K27ac histone modification were evaluated by histological score (H-score). In the biopsy cases, all histopathological changes and the p53 evaluation were significantly higher in the CTRCD group than in the controls [p53 H-score; 63 (9.109) vs. 33 (5.099), P < 0.05]. In patients with a short time between drug and disease onset (<4.2 years), fibrosis and p53 positively correlated (r = 0.76, P < 0.05), and in those with late onset disease (>4.2 years), cellular abnormalities and p53 trended to a positive correlation and cardiotoxicity risk scores and p53 positively correlated (r = 0.95, P < 0.05). A year after biopsy, the short-term group had significant recovery of ejection fraction compared with the long-term group (P < 0.05). The CTRCD group had a significantly worse overall survival prognosis than the control group [hazard ratio 7.61 (95% confidence interval 1.30–44.6), P < 0.05]. Autopsy cases with cancer treatment also had a high grade of histopathological changes, with even more severe changes in patients with cardiac dysfunction, and had increased p53 and H3K27ac expression levels, compared with controls. H-scores of p53 and H3K27ac showed a positive correlation in the CTRCD group in biopsy cases (r = 0.62, P < 0.05) and a positive correlation in autopsy cases.Conclusions：Our results indicate distinct morphological characteristics in myocardial histopathology associated with CTRCD. p53 and H3K27ac histone modification could be sensitive markers of CTRCD and suggest a mechanistic involvement of epigenetic changes.
権利情報：© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
identifier:ESC Heart Failure. 2022 Oct, vol.9, No.5, p.3031-3043
identifier:http://ginmu.naramed-u.ac.jp/dspace/handle/10564/4221
identifier:ESC Heart Failure, 9(5): 3031-3043
Collection (particular)国立国会図書館デジタルコレクション > デジタル化資料 > 博士論文
Date Accepted (W3CDTF)2023-12-05T21:41:05+09:00
Data Provider (Database)国立国会図書館 : 国立国会図書館デジタルコレクション