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Multiomics Analysis Provides Novel Pathways Related to Progression of Heart Failure

journal contribution
posted on 2024-01-15, 12:30 authored by W Ouwerkerk, JP Belo Pereira, T Maasland, JE Emmens, SM Figarska, J Tromp, AL Koekemoer, CP Nelson, M Nath, SPR Romaine, JGF Cleland, F Zannad, DJ van Veldhuisen, CC Lang, P Ponikowski, G Filippatos, S Anker, M Metra, K Dickstein, LL Ng, RA de Boer, N van Riel, M Nieuwdorp, AK Groen, E Stroes, AH Zwinderman, NJ Samani, CSP Lam, E Levin, AA Voors
Background: Despite major advances in pharmacological treatment for patients with heart failure, residual mortality remains high. This suggests that important pathways are not yet targeted by current heart failure therapies. Objectives: We sought integration of genetic, transcriptomic, and proteomic data in a large cohort of patients with heart failure to detect major pathways related to progression of heart failure leading to death. Methods: We used machine learning methodology based on stacked generalization framework and gradient boosting algorithms, using 54 clinical phenotypes, 403 circulating plasma proteins, 36,046 transcript expression levels in whole blood, and 6 million genomic markers to model all-cause mortality in 2,516 patients with heart failure from the BIOSTAT-CHF (Systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) study. Results were validated in an independent cohort of 1,738 patients. Results: The mean age of the patients was 70 years (Q1-Q3: 61-78 years), 27% were female, median N-terminal pro–B-type natriuretic peptide was 4,275 ng/L (Q1-Q3: 2,360-8,486 ng/L), and 7% had heart failure with preserved ejection fraction. During a median follow-up of 21 months, 657 (26%) of patients died. The 4 major pathways with a significant association to all-cause mortality were: 1) the PI3K/Akt pathway; 2) the MAPK pathway; 3) the Ras signaling pathway; and 4) epidermal growth factor receptor tyrosine kinase inhibitor resistance. Results were validated in an independent cohort of 1,738 patients. Conclusions: A systems biology approach integrating genomic, transcriptomic, and proteomic data identified 4 major pathways related to mortality. These pathways are related to decreased activation of the cardioprotective ERBB2 receptor, which can be modified by neuregulin.

History

Author affiliation

Department of Cardiovascular Sciences, University of Leicester

Version

  • AM (Accepted Manuscript)

Published in

Journal of the American College of Cardiology

Volume

82

Issue

20

Pagination

1921 - 1931

Publisher

Elsevier BV

issn

0735-1097

eissn

1558-3597

Copyright date

2023

Available date

2024-11-06

Spatial coverage

United States

Language

eng

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