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

Mintu Nath, Simon Pr 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, John G. Cleland, Leong L. Ng, Sean T. May, Federica Marelli-Berg, Adriaan A. Voors, James A. TimmonsNilesh J. Samani (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)
48 Downloads (Pure)


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
Issue number6
Early online date15 May 2022
Publication statusPublished - 3 Jun 2022


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


Dive into the research topics of 'Whole blood transcriptomic profiling identifies molecular pathways related to cardiovascular mortality in heart failure'. Together they form a unique fingerprint.

Cite this