BACKGROUND Plasma extracellular RNAs have recently garnered interest as biomarkers in heart failure (HF). Most studies in HF focus on single extracellular RNAs related to phenotypes and outcomes, and few describe their functional roles. We hypothesized that clusters of plasma microRNAs (miRNAs) associated with left ventricular (LV) remodeling in human HF would identify novel subsets of genes involved in HF in animal models. METHODS AND RESULTS We prospectively measured circulating miRNAs in 64 patients with systolic HF (mean age, 64.8 years; 91% men; median LV ejection fraction, 26%) with serial echocardiography (10 months apart) during medical therapy. We defined LV reverse remodeling as a 15% reduction in LV end-systolic volume index. Using principal components analysis, we identified a component associated with LV reverse remodeling (odds ratio=3.99; P=0.01) that provided risk discrimination for LV reverse remodeling superior to a clinical model (C statistic, 0.58 for a clinical model versus 0.71 for RNA-based model). Using network bioinformatics, we uncovered genes not previously widely described in HF regulated simultaneously by >2 miRNAs. We observed increased myocardial expression of these miRNAs during HF development in animals, with downregulation of target gene expression, suggesting coordinate miRNA-mRNA regulation. Target mRNAs were involved in autophagy, metabolism, and inflammation. CONCLUSIONS Plasma miRNAs associated with LV reverse remodeling in humans are dysregulated in animal HF and target clusters of genes involved in mechanisms implicated in HF. A translational approach integrating human HF, bioinformatics, and model systems may uncover novel pathways involved in HF. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT00351390.

中文翻译：

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与人类左心室逆向重构相关的MicroRNA识别心力衰竭进展的途径。

背景技术最近，血浆细胞外RNA作为心力衰竭（HF）中的生物标记物引起了人们的兴趣。HF的大多数研究关注与表型和结果相关的单个细胞外RNA，很少描述其功能作用。我们假设，与人类HF中左心室（LV）重塑相关的血浆microRNA（miRNA）簇将在动物模型中识别参与HF的基因的新子集。方法和结果我们采用连续超声心动图（相距10个月）在药物治疗期间对64例收缩期HF患者（平均年龄64.8岁；男性91％；左室射血分数中位数为26％）进行了前瞻性测量，测定了循环中的miRNA。我们将左室反向重构定义为左室收缩末期容积指数降低15％。使用主成分分析，我们确定了与LV逆向重塑相关的组件（比值比= 3.99； P = 0.01），该特征为LV逆向重塑提供了优于临床模型的风险鉴别能力（C统计量，临床模型为0.58，而基于RNA的模型为0.71）。使用网络生物信息学，我们发现了以前未被2多个miRNA同时调节的HF中未广泛描述的基因。我们观察到动物心衰期间这些miRNA的心肌表达增加，同时靶基因表达下调，这提示miRNA-mRNA的协调调控。靶mRNA参与自噬，代谢和炎症。结论与人类左心室反向重塑相关的血浆miRNA在动物HF和与HF相关的机制中涉及的基因的靶基因簇中失调。整合人类HF，生物信息学和模型系统的翻译方法可能会揭示涉及HF的新途径。临床试验注册网址：https：//www.clinicaltrials.gov。唯一标识符：NCT00351390。