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Background Clinicians need improved tools to better identify nonacute heart failure with preserved ejection fraction (HFpEF). Objectives The purpose of this study was to derive and validate circulating microRNA signatures for nonacute heart failure (HF). Methods Discovery and validation cohorts (N = 1,710), comprised 903 HF and 807 non-HF patients from Singapore and New Zealand (NZ). MicroRNA biomarker panel discovery in a Singapore cohort (n = 546) was independently validated in a second Singapore cohort (Validation 1; n = 448) and a NZ cohort (Validation 2; n = 716). Results In discovery, an 8-microRNA panel identified HF with an area under the curve (AUC) 0.96, specificity 0.88, and accuracy 0.89. Corresponding metrics were 0.88, 0.66, and 0.77 in Validation 1, and 0.87, 0.58, and 0.74 in Validation 2. Combining microRNA panels with N-terminal pro–B-type natriuretic peptide (NT-proBNP) clearly improved specificity and accuracy from AUC 0.96, specificity 0.91, and accuracy 0.90 for NT-proBNP alone to corresponding metrics of 0.99, 0.99, and 0.93 in the discovery and 0.97, 0.96, and 0.93 in Validation 1. The 8-microRNA discovery panel distinguished HFpEF from HF with reduced ejection fraction with AUC 0.81, specificity 0.66, and accuracy 0.72. Corresponding metrics were 0.65, 0.41, and 0.56 in Validation 1 and 0.65, 0.41, and 0.62 in Validation 2. For phenotype categorization, combined markers achieved AUC 0.87, specificity 0.75, and accuracy 0.77 in the discovery with corresponding metrics of 0.74, 0.59, and 0.67 in Validation 1 and 0.72, 0.52, and 0.68 in Validation 2, as compared with NT-proBNP alone of AUC 0.71, specificity 0.46, and accuracy 0.62 in the discovery; with corresponding metrics of 0.72, 0.44, and 0.57 in Validation 1 and 0.69, 0.48, and 0.66 in Validation 2. Accordingly, false negative (FN) (81% Singapore and all NZ FN cases were HFpEF) as classified by a guideline-endorsed NT-proBNP ruleout threshold, were correctly reclassified by the 8-microRNA panel in the majority (72% and 88% of FN in Singapore and NZ, respectively) of cases. Conclusions Multi-microRNA panels in combination with NT-proBNP are highly discriminatory and improved specificity and accuracy in identifying nonacute HF. These findings suggest potential utility in the identification of nonacute HF, where clinical assessment, imaging, and NT-proBNP may not be definitive, especially in HFpEF.

Aim The potential diagnostic utility of circulating microRNAs in heart failure (HF) or in distinguishing HF with reduced vs. preserved left ventricular ejection fraction (HFREF and HFPEF, respectively) is unclear. We sought to identify microRNAs suitable for diagnosis of HF and for distinguishing both HFREF and HFPEF from non-HF controls and HFREF from HFPEF. Methods and results MicroRNA profiling performed on whole blood and corresponding plasma samples of 28 controls, 39 HFREF and 19 HFPEF identified 344 microRNAs to be dysregulated among the three groups. Further analysis using an independent cohort of 30 controls, 30 HFREF and 30 HFPEF, presented 12 microRNAs with diagnostic potential for one or both HF phenotypes. Of these, miR-1233, -183-3p, -190a, -193b-3p, -193b-5p, -211-5p, -494, and -671-5p distinguished HF from controls. Altered levels of miR-125a-5p, -183-3p, -193b-3p, -211-5p, -494, -638, and -671-5p were found in HFREF while levels of miR-1233, -183-3p, -190a, -193b-3p, -193b-5p, and -545-5p distinguished HFPEF from controls. Four microRNAs (miR-125a-5p, -190a, -550a-5p, and -638) distinguished HFREF from HFPEF. Selective microRNA panels showed stronger discriminative power than N-terminal pro-brain natriuretic peptide (NT-proBNP). In addition, individual or multiple microRNAs used in combination with NT-proBNP increased NT-proBNP's discriminative performance, achieving perfect intergroup distinction. Pathway analysis revealed that the altered microRNAs expression was associated with several mechanisms of potential significance in HF. Conclusions We report specific microRNAs as potential biomarkers in distinguishing HF from non-HF controls and in differentiating between HFREF and HFPEF.

Natriuretic peptide receptor 3 (NPR3) is the clearance receptor for the cardiac natriuretic peptides (NPs). By modulating the level of NPs, NPR3 plays an important role in cardiovascular homeostasis. Although the physiological functions of NPR3 have been explored, little is known about its regulation in health or disease. MicroRNAs play an essential role in the post-transcriptional expression of many genes. Our aim was to investigate potential microRNA-based regulation of NPR3 in multiple models. Hypoxic challenge elevated levels of NPPB and ADM mRNA, as well as NT-proBNP and MR-proADM in human left ventricle derived cardiac cells (HCMa), and in the corresponding conditioned medium, as revealed by qRT-PCR and ELISA. NPR3 was decreased while NPR1 was increased by hypoxia at mRNA and protein levels in HCMa. Down-regulation of NPR3 mRNA was also observed in infarct and peri-infarct cardiac tissue from rats undergoing myocardial infarction. From microRNA microarray analyses and microRNA target predictive databases, miR-100 was selected as a candidate regulator of NPR3 expression. Further analyses confirmed up-regulation of miR-100 in hypoxic cells and associated conditioned media. Antagomir-based silencing of miR-100 enhanced NPR3 expression in HCMa. Furthermore, miR-100 levels were markedly up-regulated in rat hearts and in peripheral blood after myocardial infarction and in the blood from heart failure patients. Results from this study point to a role for miR-100 in the regulation of NPR3 expression, and suggest a possible therapeutic target for modulation of NP bioactivity in heart disease.