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

TY - JOUR

T1 - Whole blood transcriptomic profiling identifies molecular pathways related to cardiovascular mortality in heart failure

AU - Nath, Mintu

AU - Romaine, Simon Pr

AU - Koekemoer, Andrea

AU - Hamby, Stephen

AU - Webb, Thomas R.

AU - Nelson, Christopher P.

AU - Castellanos-Uribe, Marcos

AU - Papakonstantinou, Manolo

AU - Anker, Stefan D.

AU - Lang, Chim C.

AU - Metra, Marco

AU - Zannad, Faiez

AU - Filippatos, Gerasimos

AU - van Veldhuisen, Dirk J.

AU - Cleland, John G.

AU - Ng, Leong L.

AU - May, Sean T.

AU - Marelli-Berg, Federica

AU - Voors, Adriaan A.

AU - Timmons, James A.

AU - Samani, Nilesh J.

N1 - Funding Information: 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. © 2022 European Society of Cardiology.

PY - 2022/6/3

Y1 - 2022/6/3

N2 - 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.

AB - 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.

KW - Chronic heart failure

KW - RNA

KW - T-cells

KW - Interleukins

KW - Fibroblast growth factor 23

KW - Iron

KW - Drug-repurposing

UR - https://www.scopus.com/pages/publications/85131157422

U2 - 10.1002/ejhf.2540

DO - 10.1002/ejhf.2540

M3 - Article

C2 - 35570197

SN - 1388-9842

VL - 24

SP - 1009

EP - 1019

JO - European Journal of Heart Failure

JF - European Journal of Heart Failure

IS - 6

ER -