Research Group Cardiovascular Diseases, GENCOR, University of Antwerp, Universiteitsplein 1, 2610 Wilrijk, Belgium.
Department of Cardiology, Antwerp University Hospital Drie Eikenstraat 655, 2650 Edegem, Belgium.
Eur J Prev Cardiol. 2021 Dec 29;28(15):1673-1681. doi: 10.1093/eurjpc/zwaa142.
Exercise training is a powerful adjunctive therapy in patients with heart failure with reduced ejection fraction (HFrEF), but ca. 55% of patients fail to improve VO2peak. We hypothesize that circulating microRNAs (miRNAs), as epigenetic determinants of VO2peak, can distinguish exercise responders (ER) from exercise non-responders (ENR).
We analysed 377 miRNAs in 18 male HFrEF patients (9 ER and 9 ENR) prior to 15 weeks of exercise training using a miRNA array. ER and ENR were defined as change in VO2peak of >20% or <6%, respectively. First, unsupervised clustering analysis of the miRNA pattern was performed. Second, differential expression of miRNA in ER and ENR was analysed and related to percent change in VO2peak. Third, a gene set enrichment analysis was conducted to detect targeted genes and pathways. Baseline characteristics and training volume were similar between ER and ENR. Unsupervised clustering analysis of miRNAs distinguished ER from ENR with 83% accuracy. A total of 57 miRNAs were differentially expressed in ENR vs. ER. A panel of seven miRNAs up-regulated in ENR (Let-7b, miR-23a, miR-140, miR-146a, miR-191, miR-210, and miR-339-5p) correlated with %changeVO2peak (all P < 0.05) and predicted ENR with area under the receiver operating characteristic curves ≥0.77. Multiple pathways involved in exercise adaptation processes were identified.
A fingerprint of seven miRNAs involved in exercise adaptation processes is highly correlated with VO2peak trainability in HFrEF, which holds promise for the prediction of training response and patient-targeted exercise prescription.
运动训练是射血分数降低的心力衰竭（HFrEF）患者的一种强大的辅助治疗方法，但约有 55%的患者未能提高 VO2peak。我们假设循环 microRNAs（miRNAs）作为 VO2peak 的表观遗传决定因素，可以区分运动应答者（ER）和运动无应答者（ENR）。
我们使用 miRNA 阵列分析了 18 名男性 HFrEF 患者（9 名 ER 和 9 名 ENR）在 15 周运动训练前的 377 个 miRNA。ER 和 ENR 的定义分别为 VO2peak 的变化>20%或<6%。首先，进行 miRNA 模式的无监督聚类分析。其次，分析 ER 和 ENR 中 miRNA 的差异表达，并与 VO2peak 的变化百分比相关。第三，进行基因集富集分析以检测靶向基因和途径。ER 和 ENR 的基线特征和训练量相似。miRNA 的无监督聚类分析以 83%的准确率区分 ER 和 ENR。ENR 与 ER 相比，共有 57 个 miRNA 表达差异。ENR 中上调的一组 7 个 miRNA（Let-7b、miR-23a、miR-140、miR-146a、miR-191、miR-210 和 miR-339-5p）与%changeVO2peak 相关（均 P<0.05），并预测 ENR 的受试者工作特征曲线下面积≥0.77。确定了多个涉及运动适应过程的途径。
参与运动适应过程的七个 miRNA 的特征与 HFrEF 中的 VO2peak 可训练性高度相关，这为训练反应的预测和针对患者的运动处方提供了希望。
