From the Cardiology Division, Department of Medicine, Massachusetts General Hospital, Boston (R.S., O.Z., A.Y., X.L., D.R., C.Y.X., A.B., A.R., J.L.J., S.D.); University of Michigan at Ann Arbor (V.M.); Gladstone Institutes, University of California at San Francisco (K.H., A.R.P.); and Abcam Therapeutics, Cambridge, MA (M.T.).
Circ Heart Fail. 2018 Feb;11(2):e004278. doi: 10.1161/CIRCHEARTFAILURE.117.004278.
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.
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; =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.
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.
URL: https://www.clinicaltrials.gov. Unique identifier: NCT00351390.
血浆细胞外 RNA 最近作为心力衰竭 (HF) 的生物标志物引起了关注。大多数 HF 相关研究都集中在与表型和结局相关的单一细胞外 RNA 上，很少有研究描述其功能作用。我们假设与人类 HF 左心室 (LV) 重构相关的血浆 microRNAs (miRNAs) 簇将鉴定出在动物模型中涉及 HF 的新基因亚群。
我们前瞻性地测量了 64 例收缩性 HF 患者（平均年龄 64.8 岁；91%为男性；中位 LV 射血分数 26%）的循环 miRNAs，这些患者在药物治疗期间接受了连续超声心动图检查（间隔 10 个月）。我们将 LV 逆重构定义为 LV 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 逆重构相关的一个成分（比值比=3.99；=0.01），该成分对 LV 逆重构的风险预测优于临床模型（C 统计，临床模型为 0.58，RNA 模型为 0.71）。使用网络生物信息学，我们发现了以前在 HF 中未广泛描述的受>2 个 miRNAs 同时调控的基因。我们观察到这些 miRNA 在动物 HF 发展过程中心肌表达增加，靶基因表达下调，表明 miRNA-mRNA 调控的协调性。靶基因 mRNAs 参与自噬、代谢和炎症。
与人类 LV 逆重构相关的血浆 miRNAs 在动物 HF 中失调，并靶向涉及 HF 机制的基因簇。整合人类 HF、生物信息学和模型系统的转化方法可能会发现涉及 HF 的新途径。
