Aims Coronavirus disease 2019 (COVID-19) can lead to multiorgan damage. MicroRNAs (miRNAs) in blood reflect cell activation and tissue injury. We aimed to determine the association of circulating miRNAs with COVID-19 severity and 28 day intensive care unit (ICU) mortality. Methods and results We performed RNA-Seq in plasma of healthy controls (n = 11), non-severe (n = 18), and severe (n = 18) COVID-19 patients and selected 14 miRNAs according to cell- and tissue origin for measurement by reverse transcription quantitative polymerase chain reaction (RT–qPCR) in a separate cohort of mild (n = 6), moderate (n = 39), and severe (n = 16) patients. Candidates were then measured by RT–qPCR in longitudinal samples of ICU COVID-19 patients (n = 240 samples from n = 65 patients). A total of 60 miRNAs, including platelet-, endothelial-, hepatocyte-, and cardiomyocyte-derived miRNAs, were differentially expressed depending on severity, with increased miR-133a and reduced miR-122 also being associated with 28 day mortality. We leveraged mass spectrometry-based proteomics data for corresponding protein trajectories. Myocyte-derived (myomiR) miR-133a was inversely associated with neutrophil counts and positively with proteins related to neutrophil degranulation, such as myeloperoxidase. In contrast, levels of hepatocyte-derived miR-122 correlated to liver parameters and to liver-derived positive (inverse association) and negative acute phase proteins (positive association). Finally, we compared miRNAs to established markers of COVID-19 severity and outcome, i.e. SARS-CoV-2 RNAemia, age, BMI, D-dimer, and troponin. Whilst RNAemia, age and troponin were better predictors of mortality, miR-133a and miR-122 showed superior classification performance for severity. In binary and triplet combinations, miRNAs improved classification performance of established markers for severity and mortality. Conclusion Circulating miRNAs of different tissue origin, including several known cardiometabolic biomarkers, rise with COVID-19 severity. MyomiR miR-133a and liver-derived miR-122 also relate to 28 day mortality. MiR-133a reflects inflammation-induced myocyte damage, whilst miR-122 reflects the hepatic acute phase response.

中文翻译：

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心脏代谢 microRNA 与 COVID-19 严重程度和死亡率的关联


目标 2019 年冠状病毒病 (COVID-19) 可导致多器官损伤。血液中的 MicroRNA (miRNA) 反映细胞活化和组织损伤。我们的目的是确定循环 miRNA 与 COVID-19 严重程度和 28 天重症监护病房 (ICU) 死亡率的关联。方法和结果 我们对健康对照 (n = 11)、非重症 (n = 18) 和重症 (n = 18) COVID-19 患者的血浆进行了 RNA 测序，并根据细胞和组织来源选择了 14 种 miRNA通过逆转录定量聚合酶链反应 (RT–qPCR) 在轻度 (n = 6)、中度 (n = 39) 和重度 (n = 16) 患者的单独队列中进行测量。然后通过 RT-qPCR 对 ICU COVID-19 患者的纵向样本（n = 65 名患者的 240 个样本）进行测量。总共 60 种 miRNA，包括血小板、内皮细胞、肝细胞和心肌细胞来源的 miRNA，根据严重程度而表达差异，其中 miR-133a 增加和 miR-122 减少也与 28 天死亡率相关。我们利用基于质谱的蛋白质组学数据来确定相应的蛋白质轨迹。肌细胞来源的 (myomiR) miR-133a 与中性粒细胞计数呈负相关，与中性粒细胞脱颗粒相关的蛋白质（如髓过氧化物酶）呈正相关。相反，肝细胞来源的 miR-122 水平与肝脏参数以及肝脏来源的阳性（负相关）和阴性急性期蛋白（正相关）相关。最后，我们将 miRNA 与已确定的 COVID-19 严重程度和结果标记进行了比较，即 SARS-CoV-2 RNA 血症、年龄、BMI、D-二聚体和肌钙蛋白。虽然 RNA 血症、年龄和肌钙蛋白是死亡率的更好预测因子，但 miR-133a 和 miR-122 在严重程度方面表现出优异的分类性能。 在二元和三元组组合中，miRNA 提高了已建立的严重程度和死亡率标记物的分类性能。结论 不同组织来源的循环 miRNA，包括几种已知的心脏代谢生物标志物，随着 COVID-19 严重程度的增加而增加。 MyomiR miR-133a 和肝源性 miR-122 也与 28 天死亡率相关。 MiR-133a 反映炎症诱导的肌细胞损伤，而 miR-122 反映肝脏急性期反应。