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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.
Original language | English |
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Pages (from-to) | 1009-1019 |
Number of pages | 11 |
Journal | European Journal of Heart Failure |
Volume | 24 |
Issue number | 6 |
Early online date | 15 May 2022 |
DOIs | |
Publication status | Published - 3 Jun 2022 |
Keywords
- Chronic heart failure
- RNA
- T-cells
- Interleukins
- Fibroblast growth factor 23
- Iron
- Drug-repurposing
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- 1 Finished
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Aref#d: 21596. BIOSTAT-CHF: A Systems Biology Study to Tailored Treatment in Chronic Heart Failure
Doney, A. (Investigator), Guthrie, B. (Investigator), Lang, C. (Investigator), Morris, A. (Investigator), Palmer, C. (Investigator) & Struthers, A. (Investigator)
COMMISSION OF THE EUROPEAN COMMUNITIES
1/04/10 → 31/03/15
Project: Research