Cove-Smith Laura, Woodhouse Neil, Hargreaves Adam, Kirk Jason, Smith Susan, Price Sally A, Galvin Melanie, Betts Catherine J, Brocklehurst Simon, Backen Alison, Radford John, Linton Kim, Roberts Ruth A, Schmitt Matthias, Dive Caroline, Tugwood Jonathan D, Hockings Paul D, Mellor Howard R
Clinical & Experimental Pharmacology, Cancer Research UK Manchester Institute, University of Manchester, Wilmslow Road, Manchester M20 4BX, UK Department of Medical Oncology, Christie Hospital NHS Trust, Wilmslow Road, Manchester M20 4BX, UK.
Personalised Healthcare & Biomarkers, AstraZeneca R&D, Alderley Park Macclesfield, Cheshire, SK10 4TF, UK.
Toxicol Sci. 2014 Jul;140(1):3-15. doi: 10.1093/toxsci/kfu057. Epub 2014 Mar 27.
Many efficacious cancer treatments cause significant cardiac morbidity, yet biomarkers or functional indices of early damage, which would allow monitoring and intervention, are lacking. In this study, we have utilized a rat model of progressive doxorubicin (DOX)-induced cardiomyopathy, applying multiple approaches, including cardiac magnetic resonance imaging (MRI), to provide the most comprehensive characterization to date of the timecourse of serological, pathological, and functional events underlying this toxicity. Hannover Wistar rats were dosed with 1.25 mg/kg DOX weekly for 8 weeks followed by a 4 week off-dosing "recovery" period. Electron microscopy of the myocardium revealed subcellular degeneration and marked mitochondrial changes after a single dose. Histopathological analysis revealed progressive cardiomyocyte degeneration, hypertrophy/cytomegaly, and extensive vacuolation after two doses. Extensive replacement fibrosis (quantified by Sirius red staining) developed during the off-dosing period. Functional indices assessed by cardiac MRI (including left ventricular ejection fraction (LVEF), cardiac output, and E/A ratio) declined progressively, reaching statistical significance after two doses and culminating in "clinical" LV dysfunction by 12 weeks. Significant increases in peak myocardial contrast enhancement and serological cardiac troponin I (cTnI) emerged after eight doses, importantly preceding the LVEF decline to <50%. Troponin I levels positively correlated with delayed and peak gadolinium contrast enhancement, histopathological grading, and diastolic dysfunction. In summary, subcellular cardiomyocyte degeneration was the earliest marker, followed by progressive functional decline and histopathological manifestations. Myocardial contrast enhancement and elevations in cTnI occurred later. However, all indices predated "clinical" LV dysfunction and thus warrant further evaluation as predictive biomarkers.
许多有效的癌症治疗方法会导致严重的心脏疾病，然而，目前缺乏能够用于监测和干预的早期损伤生物标志物或功能指标。在本研究中，我们利用了一种多柔比星（DOX）诱导的进行性大鼠心肌病模型，采用了多种方法，包括心脏磁共振成像（MRI），以提供迄今为止对这种毒性所涉及的血清学、病理学和功能事件的时间进程最全面的表征。汉诺威Wistar大鼠每周给予1.25mg/kg DOX，持续8周，随后有4周的停药“恢复”期。心肌的电子显微镜检查显示单次给药后亚细胞变性和明显的线粒体变化。组织病理学分析显示两次给药后心肌细胞进行性变性、肥大/细胞肿大和广泛的空泡化。在停药期出现广泛的替代性纤维化（通过天狼星红染色定量）。通过心脏MRI评估的功能指标（包括左心室射血分数（LVEF）、心输出量和E/A比值）逐渐下降，两次给药后达到统计学显著性，并在12周时达到“临床”左心室功能障碍的顶峰。八次给药后，心肌对比增强峰值和血清心肌肌钙蛋白I（cTnI）显著增加，重要的是在LVEF下降至<50%之前。肌钙蛋白I水平与钆延迟和峰值对比增强、组织病理学分级及舒张功能障碍呈正相关。总之，心肌细胞亚细胞变性是最早的标志物，随后是进行性功能下降和组织病理学表现。心肌对比增强和cTnI升高出现较晚。然而，所有指标均早于“临床”左心室功能障碍，因此有必要作为预测性生物标志物进行进一步评估。
