A NEW translational study identified a circulating exosomal microRNA closely linked to myocardial remodelling in patients with heart failure with reduced ejection fraction (HFrEF), supporting its potential role as a non-invasive biomarker and future therapeutic target.
HFrEF is characterised by impaired left ventricular contractile function and progressive structural remodelling. Despite advances in pharmacological and device-based therapies, prognosis remains poor for many patients, underscoring the need for biomarkers that reflect underlying disease mechanisms rather than late-stage clinical deterioration. Exosomal microRNAs, which are stable in circulation and mediate intercellular signalling, have emerged as promising candidates in cardiovascular disease.
Exosomal MicroRNA Heart Failure Signatures in Plasma
Researchers analysed plasma samples collected between March–December 2024 from 45 patients with HFrEF and 45 healthy controls at a single centre. Exosomes were isolated and subjected to high-throughput small RNA sequencing in a pilot cohort, followed by quantitative reverse transcription PCR validation in an expanded group.
A total of 27 differentially expressed exosomal microRNAs were identified, including 10 upregulated and 17 downregulated species. Validation confirmed significantly increased expression of hsa-miR-22-5p, hsa-miR-181b-5p, and hsa-miR-339-5p, alongside reduced levels of hsa-miR-192-5p and hsa-miR-1469. Among these, hsa-miR-339-5p showed the most consistent association with HFrEF and was selected for mechanistic investigation.
Heart Failure Mechanisms and Implications
Bioinformatic analyses suggested that hsa-miR-339-5p targeted NOD-like receptor family CARD domain-containing 5 (NLRC5), a regulator of immune and metabolic signalling pathways. In vitro experiments using human AC16 cardiomyocytes demonstrated active uptake of plasma-derived exosomes. Overexpression of hsa-miR-339-5p suppressed NLRC5, activated the PI3K/Akt signalling pathway, and significantly increased type 1 collagen and α-smooth muscle actin expression, indicating enhanced fibrotic remodelling. Conversely, inhibition of the microRNA attenuated these effects.
Myocardial remodelling is a central driver of disease progression in HFrEF, contributing to ventricular stiffness, reduced compliance, and worsening pump function. The identification of an exosomal microRNA heart failure pathway linking circulating biomarkers to intracellular remodelling signals is therefore clinically relevant.
Although limited by its modest sample size and single-centre design, the study integrated molecular profiling with functional validation. Larger prospective studies will be required to determine whether hsa-miR-339-5p can inform diagnosis, risk stratification, or treatment response.
Reference
Cheng D et al. Plasma exosomal hsa-miR-339-5p is associated with NOD-like receptor family CARD domain-containing 5 in heart failure with reduced ejection fraction. Sci Rep. 2026; DOI:10.1038/s41598-026-35519-0.
