AimSevere functional tricuspid regurgitation (FTR) is associated with high risk of cardiovascular events, particularly heart failure (HF) and mortality. MicroRNAs (miRNAs) have been recently identified as novel biomarkers in different cardiovascular conditions, but no studies have focused on FTR. We sought to (1) to identify and validate circulating miRNAs as regulators of FTR and (2) to test association of miRNA with heart failure and mortality in FTR.Methods and resultsConsecutive patients with isolated severe FTR (n = 100) evaluated in the outpatient Heart Valve Clinic and age‐ and gender‐matched subjects with no TR (controls, n = 50) were prospectively recruited. The experimental design included (1) a screening phase to identify candidate miRNA differentially expressed in FTR (n = 8) compared with controls (n = 8) through miRNA array profiling of 192 miRNAs using quantitative reverse transcription PCR arrays [qRT‐PCR]) and (2) a validation phase in which candidate miRNAs identified in the initial screening were selected for further validation by qRT‐PCR in a prospectively recruited cohort of FTR (n = 92) and controls (n = 42). Bioinformatics analysis was used to predict their potential target genes and functional pathways elicited. A combined endpoint of hospital admission due to heart failure (HF) and all‐cause mortality was defined. Initial screening identified 16 differentially expressed miRNAs in FTR compared with controls, subsequently confirmed in the validation phase (n = 16 were excluded due to significant haemolysis). miR‐186‐5p, miR‐30e‐5p, and miR‐152‐3p identified FTR with high predictive value [AUC of 0.93 (0.88–0.97), 0.83 (0.75–0.91) and 0.84 (0.76–0.92), respectively]. During a median follow‐up of 20.4 months (IQR 8–35 months), 32% of FTR patients reached the combined endpoint. Patients with low relative expression of miR‐15a‐5p, miR‐92a‐3p, miR101‐3p, and miR‐363‐3p, miR‐324‐3p, and miR‐22‐3p showed significantly higher rates of events (log‐rank test for all P < 0.01). Both miR‐15a‐5p [hazard ratio: 0.21 (0.06–0.649, P = 0.007) and miR‐92a‐3p (0.27 (0.09–0.76), P = 0.01] were associated with outcomes after adjusting for age, gender, and New York Heart Association functional class.ConclusionsCirculating miRNAs are novel diagnostic and prognostic biomarkers in severe FTR. The quantification of miR‐186‐5p, miR‐30e‐5p, and miR‐152‐3p held strong diagnostic value, and the quantification of miR‐15a‐5p and miR‐92a‐3p are independently associated with outcomes. The recognition of specific miRNAs offers a novel perspective for TR evaluation.

中文翻译：

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功能性三尖瓣反流中的循环 miRNA。揭示与心力衰竭的新联系：一项试点研究

目的严重功能性三尖瓣反流 (FTR) 与心血管事件的高风险相关，特别是心力衰竭 (HF) 和死亡率。 MicroRNA (miRNA) 最近被确定为不同心血管疾病的新型生物标志物，但没有研究关注 FTR。我们试图 (1) 识别和验证循环 miRNA 作为 FTR 的调节因子，以及 (2) 测试 miRNA 与 FTR 心力衰竭和死亡率的关联。方法和结果连续患有孤立性严重 FTR 的患者（n= 100）在门诊心脏瓣膜诊所和没有 TR 的年龄和性别匹配受试者（对照、n= 50）是前瞻性招募的。实验设计包括 (1) 筛选阶段，以确定 FTR 中差异表达的候选 miRNA（n= 8) 与对照相比 (n= 8) 通过使用定量逆转录 PCR 阵列 [qRT-PCR] 对 192 个 miRNA 进行 miRNA 阵列分析）和 (2) 验证阶段，其中选择在初步筛选中确定的候选 miRNA 进行前瞻性 qRT-PCR 进一步验证招募的 FTR 队列（n= 92）和控制（n= 42）。生物信息学分析用于预测其潜在靶基因和引发的功能途径。定义了因心力衰竭（HF）住院和全因死亡率的联合终点。初步筛选确定了 FTR 中与对照相比有 16 个差异表达的 miRNA，随后在验证阶段得到证实（n= 16 因显着溶血而被排除）。 miR-186-5p、miR-30e-5p 和 miR-152-3p 鉴定出具有高预测价值的 FTR [AUC 分别为 0.93 (0.88–0.97)、0.83 (0.75–0.91) 和 0.84 (0.76–0.92)] 。在中位随访 20.4 个月（IQR 8-35 个月）期间，32% 的 FTR 患者达到了联合终点。 miR-15a-5p、miR-92a-3p、miR101-3p、miR-363-3p、miR-324-3p 和 miR-22-3p 相对表达较低的患者的事件发生率显着较高（log-所有人的排名测试磷< 0.01）。两种 miR-15a-5p [风险比：0.21（0.06-0.649，磷= 0.007) 和 miR-92a-3p (0.27 (0.09–0.76),磷= 0.01] 与调整年龄、性别和纽约心脏协会功能分级后的结果相关。结论循环 miRNA 是严重 FTR 的新型诊断和预后生物标志物。 miR-186-5p、miR-30e-5p 和 miR-152-3p 的定量具有很强的诊断价值，miR-15a-5p 和 miR-92a-3p 的定量与结果独立相关。特定 miRNA 的识别为 TR 评估提供了新的视角。