Circulating miR-19b-3p as a Novel Prognostic Biomarker for Acute Heart Failure

Yang Su, Yuxi Sun, Yansong Tang, Hao Li, Xiaoyu Wang, Xin Pan, Weijing Liu, Xianling Zhang, Fenglei Zhang, Yawei Xu, Chunxi Yan, Sang-Bing Ong, Dachun Xu, Yang Su, Yuxi Sun, Yansong Tang, Hao Li, Xiaoyu Wang, Xin Pan, Weijing Liu, Xianling Zhang, Fenglei Zhang, Yawei Xu, Chunxi Yan, Sang-Bing Ong, Dachun Xu

Abstract

Background Circulating microRNAs are emerging biomarkers for heart failure (HF). Our study aimed to assess the prognostic value of microRNA signature that is differentially expressed in patients with acute HF. Methods and Results Our study comprised a screening cohort of 15 patients with AHF and 5 controls, a PCR-discovery cohort of 50 patients with AHF and 26 controls and a validation cohort of 564 patients with AHF from registered study DRAGON-HF (Diagnostic, Risk Stratification and Prognostic Value of Novel Biomarkers in Patients With Heart Failure). Through screening by RNA-sequencing and verification by reverse-transcription quantitative polymerase chain reaction, 9 differentially expressed microRNAs were verified (miR-939-5p, miR-1908-5p, miR-7706, miR-101-3p, miR-144-3p, miR-4732-3p, miR-3615, miR-484 and miR-19b-3p). Among them, miR-19b-3p was identified as the microRNA signature with the highest fold-change of 8.4 and the strongest prognostic potential (area under curve with 95% CI, 0.791, 0.654-0.927). To further validate its prognostic value, in the validation cohort, the baseline level of miR-19b-3p was measured. During a follow-up period of 19.1 (17.7, 20.7) months, primary end point comprising of all-cause mortality or readmission due to HF occurred in 48.9% patients, while patients in the highest quartile of miR-19b-3p level presented the worst survival (Log-rank P<0.001). Multivariate Cox model showed that the level of miR-19b-3p could independently predict the occurrence of primary end point (adjusted hazard ratio,1.39; 95% CI, 1.18-1.64). In addition, miR-19b-3p positively correlated with soluble suppression of tumorigenicity 2 and echocardiographic indexes of left ventricular hypertrophy. Conclusions Circulating miR-19b-3p could be a valuable prognostic biomarker for AHF. In addition, a high level of circulating miR-19b-3p might indicate ventricular hypertrophy in AHF subjects. Registration URL: https://www.clinicaltrials.gov. Unique Identifier: NCT03727828.

Keywords: RNA‐sequencing; acute heart failure; biomarker; miR‐19b‐3p; prognosis.

Figures

Figure 1. Flow chart of the study.
Figure 1. Flow chart of the study.
AHF indicates acute heart failure; NYHA, New York Heart Association; ROC, receiver operating characteristics; and RT‐qPCR, Quantitative Real‐time Polymerase Chain Reaction.
Figure 2. Relative expression of 9 verified…
Figure 2. Relative expression of 9 verified miRNAs between patients with AHF and control.
miRNA candidates were verified in 50 AHFs and 26 controls by real‐time quantitative polymerase chain reaction. Out of 40 candidates, 9 were verified with significant differential expression and miR‐19b‐3p presented the highest relative expression fold‐change of 8.4. AHF indicates acute heart failure.
Figure 3. Receiver operating characteristic curves of…
Figure 3. Receiver operating characteristic curves of 9 validated miRNAs for diagnosis of AHF.
Receiver operating characteristic curves were performed to test the diagnostic value of 9 miRNA candidates for AHF in PCR‐discovery cohort. miR‐19b‐3p was found to have the highest discriminative potential for AHF (AUC=0.753). AHF denotes acute heart failure, AUC area under curve. Lower right annotation in each figure showed AUC with 95% CI and P value.
Figure 4. Prognostic power of 9 validated…
Figure 4. Prognostic power of 9 validated miRNAs by receiver operating characteristic curves.
Receiver operating characteristic curves were performed to test the diagnostic value of 9 miRNA candidates for AHF in PCR‐discovery cohort. miR‐19b‐3p was found to have the highest discriminative potential for AHF (AUC=0.753). AHF denotes acute heart failure, AUC area under curve. Lower right annotation in each figure showed AUC with 95% CI and P value.
Figure 5. Survival analysis of patients with…
Figure 5. Survival analysis of patients with AHF divided by baseline level of miR‐19b‐3p.
Survival analysis of miR‐19b‐3p for primary end point (all‐cause mortality or readmission due to HF) were performed and survival curves with 95% CI shown with dotted line in corresponding color. Through a follow‐up period of 19.1 [17.7, 20.7] months, survival curves showed group with higher level of miR‐19b‐3p presented worse event‐free survival, with Log‐Rank P value <0.001. Q1, Q2, Q3 and Q4 represent patients with AHF with relative expression of miR‐19b‐3p level lower than 1.63, 1.63‐2.15, 2.15‐3.41, and higher than 3.41, respectively.
Figure 6. The Forest plot of multivariate…
Figure 6. The Forest plot of multivariate Cox proportional hazard regression model for prognostic evaluation.
The level of miR‐19b‐3p, sST2, and NT‐proBNP was analyzed after logarithmic transformation.

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