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

Mintu Nath 1, 2, 3 Simon Romaine 1 Andrea Koekemoer 1 Stephen Hamby 1 Thomas Webb 1 Christopher Nelson 1 Marcos Castellanos‐uribe 3, 4 Manolo Papakonstantinou 1 Stefan Anker 5, 6 Chim Lang 7 Marco Metra 8 Faiez Zannad 9, 10, 11, 12 Gerasimos Filippatos 13, 14 Dirk van Veldhuisen 15 John Cleland 16, 17, 18 Leong Ng 1 Sean May 4 Federica Marelli‐berg 19, 20 Adriaan Voors 15 James Timmons 20, 21 Nilesh Samani 1 
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 1,153 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 5 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 (FGF23, sST2, adrenomedullin, hepcidin, pentraxin-3, WFDC2 and IL-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 modeling of the whole blood protein-coding transcriptome defined molecular pathways that provide a link between clinical risk factors and adverse cardiovascular prognosis in CHF, identifying both established and new potential therapeutic targets.
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Submitted on : Friday, May 20, 2022 - 1:40:41 PM
Last modification on : Thursday, June 2, 2022 - 9:27:25 AM




Mintu Nath, Simon Romaine, Andrea Koekemoer, Stephen Hamby, Thomas Webb, et al.. Whole blood transcriptomic profiling identifies molecular pathways related to cardiovascular mortality in heart failure. European Journal of Heart Failure, Oxford University Press (OUP), 2022, ⟨10.1002/ejhf.2540⟩. ⟨hal-03671387⟩



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