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

Mintu Nath, Simon P.R. Romaine, Andrea Koekemoer, Stephen Hamby, Thomas R. Webb, Christopher P. Nelson, Marcos Castellanos-Uribe, Manolo Papakonstantinou, Stefan D. Anker, Chim C. Lang, Marco Metra, Faiez Zannad, Gerasimos Filippatos, Dirk J. van Veldhuisen, Imperial london, Leong L. Ng, Sean T. May, Federica Marelli-Berg, Adriaan A. Voors, James A. TimmonsNilesh J. Samani* (Corresponding Author)

*Corresponding author for this work

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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 languageEnglish
Pages (from-to)1009-1019
Number of pages11
JournalEuropean Journal of Heart Failure
Volume24
Issue number6
Early online date3 Jun 2022
DOIs
Publication statusPublished - Jun 2022

Bibliographical note

Acknowledgement
We acknowledge the contribution of members of the BIOSTAT-CHF consortium.

Funding
The BIOSTAT-CHF project was funded by a grant from the European Commission (FP7-242209-BIOSTAT-CHF). Development of the gene-chip informatics methodologies were supported by the Medical Research Council UK (G1100015) to JAT. Dr Hamby is funded by the UK National Institute for Health Research and Drs Webb, Nelson, Timmons and Marelli-Berg by the British Heart Foundation.

Data Availability Statement

Additional supporting information may be found online in the Supporting Information section at the end of the article.

Keywords

  • Chronic heart failure
  • RNA
  • T-cells
  • Interleukins
  • Fibroblast growth factor 23
  • Iron
  • Drug-repurposing

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