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 -