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Published on: September 20, 2024
Whole blood transcriptomic profiling identifies molecular pathways related to cardiovascular mortality in heart
Mintu Nath1,2, Simon P R Romaine1, Andrea Koekemoer1
1Department of Cardiovascular Sciences, University of Leicester and NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
Insights
Whole blood gene expression profiling in chronic heart failure (CHF) identified key pathways linked to cardiovascular mortality. This research reveals potential new therapeutic targets for improving outcomes in CHF patients.
Area of Science:
- Cardiovascular Medicine
- Genomics
- Translational Research
Background:
- Chronic heart failure (CHF) is a complex condition with significant mortality.
- Novel therapeutic strategies are urgently needed for CHF management.
- Understanding the molecular mechanisms of cardiovascular (CV) mortality in CHF is crucial.
Purpose of the Study:
- To investigate whole blood transcriptomic profiling for mechanistic insights into CV mortality in CHF.
- To identify molecular pathways associated with survival and mortality in CHF patients.
- To explore potential drug repurposing opportunities for CHF.
Main Methods:
- Transcriptome profiles generated from 944 CHF patients (BIOSTAT-CHF study).
- Multivariable analysis identified 1153 differentially expressed genes linked to CV mortality.
- Pathway analysis revealed associations with immune response, protein catabolism, T-cell regulation, and erythrocyte development.
- Correlation with seven circulating protein biomarkers and drug-repurposing database analysis.
Main Results:
- 1153 genes were differentially expressed between survivors and those dying from CV causes.
- Key pathways identified include adaptive immune response, proteasome-mediated protein catabolism, T-cell co-stimulation, T-cell proliferation, and erythrocyte development.
- These pathways showed selective relationships with seven CV mortality protein biomarkers, highlighting immune-iron homeostasis links.
- Drug-repurposing analysis identified potential therapies to reverse adverse molecular changes.
Conclusions:
- Systematic transcriptome modeling linked clinical risk factors to adverse CV prognosis in CHF.
- Identified established and novel molecular pathways and potential therapeutic targets.
- Whole blood transcriptomics offers mechanistic insights for CHF, guiding future therapeutic development.
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.
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