BACKGROUND Heart failure (HF) has been recognized as a global pandemic with a high rate of hospitalization, morbidity, and mortality. Although numerous advances have been made, its representative molecular signatures remain largely unknown, especially the role of genes in HF progression. The aim of the present prospective follow-up study was to reveal potential biomarkers associated with the progression of heart failure. METHODS We generated multi-level transcriptomic data from a cohort of left ventricular heart tissue collected from 21 HF patients and 9 healthy donors. By using Masson staining to calculate the fibrosis percentage for each sample, we applied lasso regression model to identify the genes associated with fibrosis as well as progression. The genes were further validated by immunohistochemistry (IHC) staining in the same cohort and qRT-PCR using another independent cohort (20 HF and 9 healthy donors). Enzyme-linked immunosorbent assay (ELISA) was used to measure the plasma level in a validation cohort (139 HF patients) for predicting HF progression. RESULTS Based on the multi-level transcriptomic data, we examined differentially expressed genes [mRNAs, microRNAs, and long non-coding RNAs (lncRNAs)] in the study cohort. The follow-up functional annotation and regulatory network analyses revealed their potential roles in regulating extracellular matrix. We further identified several genes that were associated with fibrosis. By using the survival time before transplantation, COL1A1 was identified as a potential biomarker for HF progression and its upregulation was confirmed by both IHC and qRT-PCR. Furthermore, COL1A1 content ≥ 256.5 ng/ml in plasma was found to be associated with poor survival within 1 year of heart transplantation from heart failure [hazard ratio (HR) 7.4, 95% confidence interval (CI) 3.5 to 15.8, Log-rank p value < 1.0 × 10- 4]. CONCLUSIONS Our results suggested that COL1A1 might be a plasma biomarker of HF and associated with HF progression, especially to predict the 1-year survival from HF onset to transplantation.

中文翻译：

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多级转录组测序确定COL1A1为人类心力衰竭进展中的候选标记。

背景技术心力衰竭（HF）已经被认为是全球性的大流行，其住院，发病率和死亡率很高。尽管已经取得了许多进步，但其代表性的分子特征仍然未知，尤其是基因在HF进展中的作用。本前瞻性随访研究的目的是揭示与心力衰竭进展相关的潜在生物标志物。方法我们从21名HF患者和9名健康供体中收集的一组左心室心脏组织生成了多级转录组数据。通过使用Masson染色计算每个样品的纤维化百分比，我们应用套索回归模型来鉴定与纤维化以及进展相关的基因。通过在同一队列中的免疫组织化学（IHC）染色和使用另一独立队列（20 HF和9名健康供体）的qRT-PCR进一步验证了基因。酶联免疫吸附测定（ELISA）用于测量验证队列（139名HF患者）中的血浆水平，以预测HF进展。结果基于多级转录组数据，我们研究了队列研究中差异表达的基因[mRNA，microRNA和长非编码RNA（lncRNA）]。后续功能注释和调节网络分析揭示了它们在调节细胞外基质中的潜在作用。我们进一步鉴定了与纤维化相关的几个基因。利用移植前的生存时间，COL1A1被确定为HF进展的潜在生物标志物，并通过IHC和qRT-PCR证实了其上调。此外，发现血浆中COL1A1含量≥256.5 ng / ml与心力衰竭导致的心脏移植术后一年内生存不良有关[危险比（HR）7.4，95％置信区间（CI）3.5至15.8，对数秩p值<1.0×10-4]。结论我们的研究结果提示，COL1A1可能是HF的血浆生物标志物，并与HF进展相关，尤其是预测从HF发作到移植的1年生存期。