miR-200c-3p: An Adjunct Chronic Heart Failure Risk Marker Modulating Cardiomyocyte Hypertrophic Transcription and Cardiac Fibroblast Fibrosis.

Abstract

This study evaluated circulating microRNA-200c-3p (miR-200c-3p) for diagnosis and prognosis in chronic heart failure (CHF) and its regulatory roles in cardiomyocyte hypertrophy and myocardial fibrosis in vitro. A single-center prospective cohort included 150 CHF patients and 80 healthy controls, with CHF stratified into heart failure with preserved ejection fraction (HFpEF), heart failure with mildly reduced ejection fraction (HFmrEF), and heart failure with reduced ejection fraction (HFrEF) subgroups. Serum miR‑200c‑3p was quantified by quantitative real‑time polymerase chain reaction (qRT‑PCR), N‑terminal pro‑B‑type natriuretic peptide (NT‑proBNP) and inflammatory markers were measured with a fully automated analyzer, and all subjects underwent a 1‑year follow‑up, with correlation, receiver operating characteristic (ROC), Kaplan-Meier, and multivariate Cox regression analyses evaluating its clinical associations and diagnostic and prognostic performance. Gain‑ and loss‑of‑function tests and cell counting kit‑8 (CCK‑8) assays were performed in primary neonatal rat ventricular myocytes (NRVMs) and primary-derived immortalized human cardiac fibroblasts (HCFs). Serum miR‑200c‑3p was significantly elevated in CHF and increased with higher New York Heart Association (NYHA) class, yielding a diagnostic area under the curve (AUC) of 0.86 that improved to 0.90 when combined with NT‑proBNP (DeLong test, p < 0.05); it showed numerically higher AUC and specificity but lower sensitivity than NT‑proBNP in the HFpEF subgroup, and correlated with heart failure and inflammatory markers rather than demographic factors. In NRVMs, angiotensin II (Ang II) upregulates miR‑200c‑3p and hypertrophic marker transcription with its overexpression enhancing the hypertrophic transcriptional program, while in HCFs, transforming growth factor‑β1 (TGF‑β1) upregulates miR‑200c‑3p and profibrotic marker transcription with its overexpression further boosting fibrotic transcription and cell proliferation, and miR‑200c‑3p inhibition attenuates all resulting transcriptional and proliferative abnormalities. miR‑200c‑3p is a potential adjunct biomarker for CHF, offering high‑specificity auxiliary value for HFpEF verification, predicting poor prognosis, and modulating transcriptional and cellular phenotypes linked to cardiac remodeling.