Department of Diagnostic Pathology, Nara Medical University, 840 Shijo, Kashihara, Nara, 643-8522, Japan.
Department of Cardiovascular Medicine, Nara Medical University, 840 Shijo, Kashihara, Nara, 634-8522, Japan.
ESC Heart Fail. 2022 Oct;9(5):3031-3043. doi: 10.1002/ehf2.14034. Epub 2022 Jun 23.
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.
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.
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.
癌症治疗相关的心脏功能障碍（CTRCD）较为常见，但对其组织病理学、机制和危险因素尚不清楚。本研究旨在阐明 CTRCD 的组织病理学和机制，以确定其危险因素。
我们对 13 例 CTRCD 患者的心肌活检组织、35 例有或无心脏功能障碍的尸检癌症病例和 10 例无癌症的活检组织（10 例活检和 9 例尸检）进行了心肌组织病理学研究。根据用药计算了心脏毒性风险评分，并对患者相关危险因素、纤维化和心肌细胞变化进行了评分，还通过组织学评分（H 评分）评估了 p53 和 H3K27ac 组蛋白修饰。在活检病例中，与对照组相比，CTRCD 组的所有组织病理学变化和 p53 评估均显著更高（p53 H 评分：63（9.109）vs. 33（5.099），P<0.05）。在药物与疾病发病时间间隔较短（<4.2 年）的患者中，纤维化和 p53 呈正相关（r=0.76，P<0.05），而在发病时间间隔较长（>4.2 年）的患者中，细胞异常和 p53 呈正相关趋势，且心脏毒性风险评分和 p53 呈正相关（r=0.95，P<0.05）。在活检后 1 年，短期组的射血分数明显高于长期组（P<0.05）。与对照组相比，CTRCD 组的总生存率明显较差[风险比 7.61（95%置信区间 1.30-44.6），P<0.05]。接受癌症治疗的尸检病例也具有较高的组织病理学变化程度，且有心律失常的患者变化更为严重，p53 和 H3K27ac 表达水平升高，与对照组相比。在活检病例中，CTRCD 组的 p53 和 H3K27ac 的 H 评分呈正相关（r=0.62，P<0.05），在尸检病例中也呈正相关。
我们的研究结果表明，心肌组织病理学与 CTRCD 相关的形态特征明显不同。p53 和 H3K27ac 组蛋白修饰可能是 CTRCD 的敏感标志物，并提示表观遗传变化的参与机制。
