Department of Clinical and Experimental Cardiology, Amsterdam University Medical Centers, University of Amsterdam, Meibergdreef 9, 1105, AZ, Amsterdam, The Netherlands.
Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands.
J Mol Med (Berl). 2021 Sep;99(9):1195-1207. doi: 10.1007/s00109-021-02098-8. Epub 2021 May 29.
As in other cardiomyopathies, extracellular matrix (ECM) remodeling plays an important role in anthracycline-induced cardiomyopathy. To understand the pattern and timing of ECM remodeling pathways, we conducted a systematic review in which we describe protein and mRNA markers for ECM remodeling that are differentially expressed in the hearts of animals with anthracycline-induced cardiomyopathy. We included 68 studies in mice, rats, rabbits, and pigs with follow-up of 0.1-8.2 human equivalent years after anthracycline administration. Using meta-analysis, we found 29 proteins and 11 mRNAs that were differentially expressed in anthracycline-induced cardiomyopathy compared to controls. Collagens, matrix metalloproteinases (MMPs), inflammation markers, transforming growth factor ß signaling markers, and markers for cardiac hypertrophy were upregulated, whereas the protein kinase B (AKT) pro-survival pathway was downregulated. Their expression patterns over time from single time point studies were studied with meta-regression using human equivalent years as the time scale. Connective tissue growth factor showed an early peak in expression but remained upregulated at all studied time points. Brain natriuretic peptide (BNP) and MMP9 protein levels increased in studies with longer follow-up. Significant associations were found for higher atrial natriuretic peptide with interstitial fibrosis and for higher BNP and MMP2 protein levels with left ventricular systolic function.
在其他心肌病中，细胞外基质（ECM）重塑在蒽环类药物诱导的心肌病中起着重要作用。为了了解 ECM 重塑途径的模式和时间，我们进行了系统评价，其中描述了在蒽环类药物诱导的心肌病动物心脏中差异表达的 ECM 重塑蛋白和 mRNA 标志物。我们纳入了 68 项关于小鼠、大鼠、兔子和猪的研究，在蒽环类药物给药后 0.1-8.2 个人类等效年进行随访。通过荟萃分析，我们发现 29 种蛋白质和 11 种 mRNA 在蒽环类药物诱导的心肌病与对照组相比存在差异表达。胶原蛋白、基质金属蛋白酶（MMPs）、炎症标志物、转化生长因子 β 信号标志物和心肌肥厚标志物上调，而蛋白激酶 B（AKT）促生存途径下调。使用荟萃回归分析，以人类等效年为时间尺度，研究了来自单次时间点研究的它们随时间的表达模式。结缔组织生长因子的表达水平早期达到峰值，但在所有研究时间点仍保持上调。在随访时间较长的研究中，脑钠肽（BNP）和 MMP9 蛋白水平增加。心房利钠肽与间质纤维化呈显著相关，而 BNP 和 MMP2 蛋白水平与左心室收缩功能呈显著相关。
