Multiomics Analysis Provides Novel Pathways Related to Progression of Heart Failure.

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.

Informations de copyright

Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Funding Support and Author Disclosures Dr Nieuwdorp is supported by a ZONMW VICI grant 2020 (09150182010020). Dr de Boer is supported by a grant from the European Research Council (ERC CoG 818715, SECRETE-HF). BIOSTAT-CHF was funded by a grant from the European Commission (FP7-242209-BIOSTAT-CHF; EudraCT 2010-020808-29). The University Medical Center Groningen, which employs several of the authors, has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Novo Nordisk, and Roche. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore. Dr Ponikowski has received research support from Coridea and Cibiem; and has served as a consultant to Cibiem. Dr Filippatos has received speaker fees and/or served as a committee member for registries and trials sponsored by Bayer, Medtronic, Vifor, Boehringer Ingelheim, Novartis, Servier, and Amgen. Dr Anker has received fees from Abbott, Bayer, Boehringer Ingelheim, Cardiac Dimension, Cordio, Impulse Dynamics, Novartis, Occlutech, Servier, and Vifor Pharma; and has received grant support from Abbott and Vifor Pharma. Dr Metra has received consulting honoraria from Bayer, Novartis, and Servier as a member of committees of clinical trials or advisory boards, unrelated to the current work. Dr de Boer has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche. Dr Nieuwdorp has received scientific advisory board fees from Caelus Health and Kaleido Biosciences (activities not related to the topic of this work). Dr Samani holds a chair funded by the British Heart Foundation and is a National Institute for Health and Care Research Senior Investigator. Dr Lam has received research support from Bayer and Roche Diagnostics; has served as a consultant or on the advisory board/steering committee/executive committee for Actelion, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, and Us2.ai; and has served as co-founder and nonexecutive director of Us2.ai. Dr Voors has received consultancy fees and/or research grants from Amgen, Bayer, Boehringer Ingelheim, Cytokinetics, Merck/MSD, Myokardia, Novartis, Novo Nordisk, and Roche Diagnostics. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.