Multiomics Analysis Provides Novel Pathways Related to Progression of Heart Failure

Wouter Ouwerkerk*, Joao P. Belo Pereira, Troy Maasland, Johanna E. Emmens, Sylwia M. Figarska, Jasper Tromp, Andrea L. Koekemoer, Christopher P. Nelson, Mintu Nath, Simon P.R. Romaine, John G.F. Cleland, Faiez Zannad, Dirk J. van Veldhuisen, Chim C. Lang, Piotr Ponikowski, Gerasimos Filippatos, Stefan Anker, Marco Metra, Kenneth Dickstein, Leong L. NgRudolf A. de Boer, Natal van Riel, Max Nieuwdorp, Albert K. Groen, Erik Stroes, Aeilko H. Zwinderman, Nilesh J. Samani, Carolyn S.P. Lam, Evgeni Levin, Adriaan A. Voors

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1921-1931
Number of pages11
JournalJournal of the American College of Cardiology
Volume82
Issue number20
DOIs
Publication statusPublished - 14 Nov 2023
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2023 American College of Cardiology Foundation

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