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    Whole blood transcriptomic profiling identifies molecular pathways related to cardiovascular mortality in heart failure

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    Author
    Romaine, Simon
    Samani, Nilesh
    Keyword
    chronic heart failure
    drug-repurposing
    fibroblast growth factor 23
    interleukins
    iron
    RNA
    T-cells
    Date
    2022-06
    
    Metadata
    Show full item record
    Publisher's URL
    https://onlinelibrary.wiley.com/doi/10.1002/ejhf.2540
    Abstract
    Aims: Chronic heart failure (CHF) is a systemic syndrome with a poor prognosis and a need for novel therapies. We investigated whether whole blood transcriptomic profiling can provide new mechanistic insights into cardiovascular (CV) mortality in CHF. Methods and results: Transcriptome profiles were generated at baseline from 944 CHF patients from the BIOSTAT-CHF study, of whom 626 survived and 318 died from a CV cause during a follow-up of 21 months. Multivariable analysis, including adjustment for cell count, identified 1153 genes (6.5%) that were differentially expressed between those that survived or died and strongly related to a validated clinical risk score for adverse prognosis. The differentially expressed genes mainly belonged to five non-redundant pathways: adaptive immune response, proteasome-mediated ubiquitin-dependent protein catabolic process, T-cell co-stimulation, positive regulation of T-cell proliferation, and erythrocyte development. These five pathways were selectively related (RV coefficients >0.20) with seven circulating protein biomarkers of CV mortality (fibroblast growth factor 23, soluble ST2, adrenomedullin, hepcidin, pentraxin-3, WAP 4-disulfide core domain 2, and interleukin-6) revealing an intricate relationship between immune and iron homeostasis. The pattern of survival-associated gene expression matched with 29 perturbagen-induced transcriptome signatures in the iLINCS drug-repurposing database, identifying drugs, approved for other clinical indications, that were able to reverse in vitro the molecular changes associated with adverse prognosis in CHF. Conclusion: Systematic modelling of the whole blood protein-coding transcriptome defined molecular pathways that provide a link between clinical risk factors and adverse CV prognosis in CHF, identifying both established and new potential therapeutic targets.
    Citation
    Nath, M., Romaine, S., Koekemoer, A., Hamby, S., Webb, T. R., Nelson, C. P., Castellanos-Uribe, M., Papakonstantinou, M., Anker, S. D., Lang, C. C., Metra, M., Zannad, F., Filippatos, G., van Veldhuisen, D. J., Cleland, J. G., Ng, L. L., May, S. T., Marelli-Berg, F., Voors, A. A., Timmons, J. A., … Samani, N. J. (2022). Whole blood transcriptomic profiling identifies molecular pathways related to cardiovascular mortality in heart failure. European journal of heart failure, 24(6), 1009–1019. https://doi.org/10.1002/ejhf.2540
    Type
    Article
    URI
    http://hdl.handle.net/20.500.12904/15653
    Collections
    Cardiology

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