Whole blood transcriptomic profiling identifies molecular pathways related to cardiovascular mortality in heart failure
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.
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Date
2022-06
Type
Article
Subject
chronic heart failure, drug-repurposing, fibroblast growth factor 23, interleukins, iron, RNA, T-cells
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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