Department of Cardiology, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
Center for Medical Statistics, Informatics, and Intelligent Systems (CeMSIIS), and Department of Surgery, Medical University of Vienna, Währinger Gürtel 18-20, 1090 Vienna, Austria.
Cardiovasc Res. 2020 Apr 1;116(5):970-982. doi: 10.1093/cvr/cvz192.
The clinical application of doxorubicin (DOX) is severely compromised by its cardiotoxic effects, which limit the therapeutic index and the cumulative dose. Liposomal encapsulation of DOX (Myocet®) provides a certain protective effect against cardiotoxicity by reducing myocardial drug accumulation. We aimed to evaluate transcriptomic responses to anthracyclines with different cardiotoxicity profiles in a translational large animal model for identifying potential alleviation strategies.
We treated domestic pigs with either DOX, epirubicin (EPI), or liposomal DOX and compared the cardiac, laboratory, and haemodynamic effects with saline-treated animals. Cardiotoxicity was encountered in all groups, reflected by an increase of plasma markers N-terminal pro-brain-natriuretic peptide and Troponin I and an impact on body weight. High morbidity of EPI-treated animals impeded further evaluation. Cardiac magnetic resonance imaging with gadolinium late enhancement and transthoracic echocardiography showed stronger reduction of the left and right ventricular systolic function and stronger myocardial fibrosis in DOX-treated animals than in those treated with the liposomal formulation. Gene expression profiles of the left and right ventricles were analysed by RNA-sequencing and validated by qPCR. Interferon-stimulated genes (ISGs), linked to DNA damage repair and cell survival, were downregulated by DOX, but upregulated by liposomal DOX in both the left and right ventricle. The expression of cardioprotective translocator protein (TSPO) was inhibited by DOX, but not its liposomal formulation. Cardiac fibrosis with activation of collagen was found in all treatment groups.
All anthracycline-derivatives resulted in transcriptional activation of collagen synthesis and processing. Liposomal packaging of DOX-induced ISGs in association with lower cardiotoxicity, which is of high clinical importance in anticancer treatment. Our study identified potential mechanisms for rational development of strategies to mitigate anthracycline-induced cardiomyopathy.
阿霉素（DOX）的临床应用受到其心脏毒性的严重限制，这限制了治疗指数和累积剂量。DOX 的脂质体包封（Myocet®）通过减少心肌药物积累提供了一定的心脏毒性保护作用。我们旨在通过评估不同心脏毒性特征的蒽环类药物在翻译大型动物模型中的转录组反应，以确定潜在的缓解策略。
我们用 DOX、表阿霉素（EPI）或脂质体 DOX 治疗家猪，并将心脏、实验室和血液动力学效应与盐水处理的动物进行比较。所有组均发生心脏毒性，表现为血浆标志物 N 端脑钠肽前体和肌钙蛋白 I 的增加以及体重的影响。EPI 治疗动物的高发病率阻碍了进一步的评估。心脏磁共振成像（CMR）与钆延迟增强和经胸超声心动图显示，DOX 治疗的动物的左心室和右心室收缩功能以及心肌纤维化程度较脂质体制剂更强。通过 RNA-seq 分析左心室和右心室的基因表达谱，并通过 qPCR 进行验证。干扰素刺激基因（ISGs）与 DNA 损伤修复和细胞存活有关，DOX 下调了这些基因，但脂质体 DOX 在左心室和右心室中均上调了这些基因。DOX 抑制了心脏保护性转位蛋白（TSPO）的表达，但脂质体 DOX 没有。所有治疗组均发现心脏纤维化伴有胶原激活。
所有蒽环类药物衍生物均导致胶原合成和加工的转录激活。DOX 的脂质体包封与较低的心脏毒性相关，这在癌症治疗中具有重要的临床意义。我们的研究确定了减轻蒽环类药物诱导的心肌病的合理策略的潜在机制。
