Medical Student University of British Columbia Vancouver, British Columbia, Canada
Background: Long non-coding RNAs (lncRNAs) are emerging as a promising RNA class with clinical relevance in heart failure (HF). lncRNAs are RNA transcripts over 200 nucleotides long that regulate gene expression at multiple levels, including transcription, RNA splicing, and translation. There is some evidence to suggest that lncRNAs may play key roles in the development and progression of HF. Despite increasing interest, there has been no in-depth analysis to determine the specific lncRNAs involved and their prognostic value in HF. This project aims to fill that gap by conducting a systematic review and meta-analysis to identify lncRNAs that are consistently upregulated or downregulated in HF and assess their potential prognostic value.
METHODS AND RESULTS: MEDLINE and EMBASE were systematically searched from database inception to March 2025. Studies that evaluated the diagnostic and/or prognostic value of at least one lncRNA in the peripheral blood of adult patients with HF were included for analysis. Exclusion criteria were non-human studies, non-HF studies, non-English studies, pediatric patients, editorials, letters to the editor, commentaries, abstracts, and reviews. After screening 955 titles, 34 studies were included in the analysis, encompassing 49 unique lncRNAs. Among these lncRNAs, 29 were significantly upregulated and 9 were significantly downregulated in HF patients while 5 showed no significant differences and 6 had incongruent or unclear findings. This analysis included different etiologies (ischemic and non-ischemic) and types of HF (reduced and preserved ejection fraction). We conducted a pooled analysis of eight studies reporting hazard ratios for all-cause mortality. Altered lncRNA expression was associated with significantly increased mortality risk (HR = 1.944, 95% CI: 1.547–2.444; p < 0.0001). The lncRNAs included were HEAT2, HEAT3, HEAT4, ZFAS1, LRRC75A-AS1, LIPCAR, NEAT1, and TUG1. Ten lncRNAs were significantly correlated with NT-proBNP. The correlation of each lncRNA with NT-proBNP was congruent with its expression pattern in HF versus non-HF patients. Twelve different lncRNAs were significantly associated with echocardiographic parameters of cardiac dysfunction.
Conclusion: This meta-analysis highlights the emerging role of lncRNAs as prognostic biomarkers in HF. Several upregulated lncRNAs were associated with increased all-cause mortality, with a pooled HR indicating an almost twofold elevated risk. These lncRNAs have been linked to inflammation, fibrosis, apoptosis, and mitochondrial function in the pathophysiology of HF. Given their detectability in blood-based assays, involvement in key pathophysiological processes, and association with mortality, lncRNAs represent promising candidates for clinical risk stratification.
