Multiomics Analysis Provides Novel Pathways Related to Progression of Heart Failure

TY - JOUR

T1 - Multiomics Analysis Provides Novel Pathways Related to Progression of Heart Failure

AU - Ouwerkerk, Wouter

AU - Belo Pereira, Joao P.

AU - Maasland, Troy

AU - Emmens, Johanna E.

AU - Figarska, Sylwia

AU - Tromp, Jasper

AU - Koekemoer, Andrea

AU - Nelson, Christopher P.

AU - Nath, Mintu

AU - Romaine, Simon P. R.

AU - Cleland, John G. F.

AU - Zannad, Faiez

AU - van Veldhuisen, Dirk J.

AU - Lang, Chim C.

AU - Ponikowski, Piotr

AU - Filippatos, Gerasimos S.

AU - Anker, Stefan D.

AU - Metra, Marco

AU - Dickstein, Kenneth

AU - Ng, Leong L.

AU - de Boer, Rudolf A.

AU - van Riel, Natal

AU - Nieuwdorp, Max

AU - Groen, Albert K.

AU - Stroes, Erik S.

AU - Zwinderman, Aeilko H.

AU - Samani, Nilesh J.

AU - Lam, Carolyn S. P.

AU - Levin, Evgeni

AU - Voors, Adriaan A.

N1 - Copyright: © 2023 by the American College of Cardiology Foundation. Published by Elsevier.

PY - 2023/11/14

Y1 - 2023/11/14

N2 - 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.

AB - 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.

KW - Heart failure

KW - machine learning

KW - systems biology

KW - heart failure

KW - omics

U2 - 10.1016/j.jacc.2023.08.053

DO - 10.1016/j.jacc.2023.08.053

M3 - Article

C2 - 37940229

SN - 0735-1097

VL - 82

SP - 1921

EP - 1931

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 20

ER -