Differences in biomarkers and molecular pathways according to age for patients with HFrEF

João Pedro Ferreira; Wouter Ouwerkerk; Bernadet T. Santema; Dirk J. van Veldhuisen; Chim C. Lang; Leong L. Ng; Stefan D. Anker; Kenneth Dickstein; Marco Metra; John G. F. Cleland; Nilesh J. Samani; Gerasimos S. Filippatos; Joseph-Pierre Aboumallem; Rudolf A. de Boer; Sylwia Figarska; Iziah E. Sama; Adriaan A. Voors; Faiez Zannad

doi:10.1093/cvr/cvaa279

Differences in biomarkers and molecular pathways according to age for patients with HFrEF

João Pedro Ferreira (Lead / Corresponding author), Wouter Ouwerkerk, Bernadet T. Santema, Dirk J. van Veldhuisen, Chim C. Lang, Leong L. Ng, Stefan D. Anker, Kenneth Dickstein, Marco Metra, John G. F. Cleland, Nilesh J. Samani, Gerasimos S. Filippatos, Joseph-Pierre Aboumallem, Rudolf A. de Boer, Sylwia Figarska, Iziah E. Sama, Adriaan A. Voors, Faiez Zannad

Research output: Contribution to journal › Article › peer-review

9 Citations (Scopus)

100 Downloads (Pure)

Abstract

Aims: Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. We aim to better understand the underlying pathophysiological processes associated with aging in HFrEF potentially leading to targeted therapies in this vulnerable population.

Methods and Results: From a panel of 363 cardiovascular biomarkers available in 1,611 patients with HFrEF in the BIOSTAT-CHF index cohort and cross-validated in 823 patients in the BIOSTAT-CHF validation cohort, we tested which biomarkers were dysregulated in patients aged>75yr versus <65yr. Secondly, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in elderly versus younger patients. After adjustment, multiple test correction (FDR 1%), and cross-validation, 27/363 biomarkers were associated with older age, 22 positively, and 5 negatively. The biomarkers that were positively associated with older age were associated with tumor cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas biomarkers negatively associated with older age were associated with pathways that may point to cell proliferation and tumorigenesis. Among the 27 biomarkers, WFDC2 (WAP Four-Disulfide-Core-Domain-2) – that broadly functions as a protease inhibitor - was associated with older age and had the strongest association with all outcomes. No protein-by-sex interaction was observed.

Conclusions: In elderly HFrEF patients, pathways associated with extra-cellular matrix organization, inflammatory processes, and tumor cell regulation were activated, while pathways associated with tumor proliferation functions were down-regulated. These findings may help in a better understanding of the aging processes in HFrEF and identify potential therapeutic targets.

Original language	English
Pages (from-to)	2228-2236
Number of pages	9
Journal	Cardiovascular Research
Volume	117
Issue number	10
DOIs	https://doi.org/10.1093/cvr/cvaa279
Publication status	Published - 1 Oct 2020

Keywords

aging
chronological age
biological age
biomarkers
heart failure with reduced ejection fraction

Access to Document

10.1093/cvr/cvaa279

Author Accepted ManuscriptAccepted author manuscript, 395 KB
Figure 1Accepted author manuscript, 570 KB

Cite this

Ferreira, J. P., Ouwerkerk, W., Santema, B. T., van Veldhuisen, D. J., Lang, C. C., Ng, L. L., Anker, S. D., Dickstein, K., Metra, M., Cleland, J. G. F., Samani, N. J., Filippatos, G. S., Aboumallem, J.-P., de Boer, R. A., Figarska, S., Sama, I. E., Voors, A. A., & Zannad, F. (2020). Differences in biomarkers and molecular pathways according to age for patients with HFrEF. Cardiovascular Research, 117(10), 2228-2236. https://doi.org/10.1093/cvr/cvaa279

@article{b9c7553a81fa480593b095159a1d2c9e,

title = "Differences in biomarkers and molecular pathways according to age for patients with HFrEF",

abstract = "Aims: Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. We aim to better understand the underlying pathophysiological processes associated with aging in HFrEF potentially leading to targeted therapies in this vulnerable population.Methods and Results: From a panel of 363 cardiovascular biomarkers available in 1,611 patients with HFrEF in the BIOSTAT-CHF index cohort and cross-validated in 823 patients in the BIOSTAT-CHF validation cohort, we tested which biomarkers were dysregulated in patients aged>75yr versus <65yr. Secondly, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in elderly versus younger patients. After adjustment, multiple test correction (FDR 1%), and cross-validation, 27/363 biomarkers were associated with older age, 22 positively, and 5 negatively. The biomarkers that were positively associated with older age were associated with tumor cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas biomarkers negatively associated with older age were associated with pathways that may point to cell proliferation and tumorigenesis. Among the 27 biomarkers, WFDC2 (WAP Four-Disulfide-Core-Domain-2) – that broadly functions as a protease inhibitor - was associated with older age and had the strongest association with all outcomes. No protein-by-sex interaction was observed.Conclusions: In elderly HFrEF patients, pathways associated with extra-cellular matrix organization, inflammatory processes, and tumor cell regulation were activated, while pathways associated with tumor proliferation functions were down-regulated. These findings may help in a better understanding of the aging processes in HFrEF and identify potential therapeutic targets.",

keywords = "aging, chronological age, biological age, biomarkers, heart failure with reduced ejection fraction",

author = "Ferreira, {Jo{\~a}o Pedro} and Wouter Ouwerkerk and Santema, {Bernadet T.} and {van Veldhuisen}, {Dirk J.} and Lang, {Chim C.} and Ng, {Leong L.} and Anker, {Stefan D.} and Kenneth Dickstein and Marco Metra and Cleland, {John G. F.} and Samani, {Nilesh J.} and Filippatos, {Gerasimos S.} and Joseph-Pierre Aboumallem and {de Boer}, {Rudolf A.} and Sylwia Figarska and Sama, {Iziah E.} and Voors, {Adriaan A.} and Faiez Zannad",

year = "2020",

month = oct,

day = "1",

doi = "10.1093/cvr/cvaa279",

language = "English",

volume = "117",

pages = "2228--2236",

journal = "Cardiovascular Research",

issn = "0008-6363",

publisher = "Oxford University Press",

number = "10",

}

Ferreira, JP, Ouwerkerk, W, Santema, BT, van Veldhuisen, DJ, Lang, CC, Ng, LL, Anker, SD, Dickstein, K, Metra, M, Cleland, JGF, Samani, NJ, Filippatos, GS, Aboumallem, J-P, de Boer, RA, Figarska, S, Sama, IE, Voors, AA & Zannad, F 2020, 'Differences in biomarkers and molecular pathways according to age for patients with HFrEF', Cardiovascular Research, vol. 117, no. 10, pp. 2228-2236. https://doi.org/10.1093/cvr/cvaa279

TY - JOUR

T1 - Differences in biomarkers and molecular pathways according to age for patients with HFrEF

AU - Ferreira, João Pedro

AU - Ouwerkerk, Wouter

AU - Santema, Bernadet T.

AU - van Veldhuisen, Dirk J.

AU - Lang, Chim C.

AU - Ng, Leong L.

AU - Anker, Stefan D.

AU - Dickstein, Kenneth

AU - Metra, Marco

AU - Cleland, John G. F.

AU - Samani, Nilesh J.

AU - Filippatos, Gerasimos S.

AU - Aboumallem, Joseph-Pierre

AU - de Boer, Rudolf A.

AU - Figarska, Sylwia

AU - Sama, Iziah E.

AU - Voors, Adriaan A.

AU - Zannad, Faiez

PY - 2020/10/1

Y1 - 2020/10/1

N2 - Aims: Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. We aim to better understand the underlying pathophysiological processes associated with aging in HFrEF potentially leading to targeted therapies in this vulnerable population.Methods and Results: From a panel of 363 cardiovascular biomarkers available in 1,611 patients with HFrEF in the BIOSTAT-CHF index cohort and cross-validated in 823 patients in the BIOSTAT-CHF validation cohort, we tested which biomarkers were dysregulated in patients aged>75yr versus <65yr. Secondly, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in elderly versus younger patients. After adjustment, multiple test correction (FDR 1%), and cross-validation, 27/363 biomarkers were associated with older age, 22 positively, and 5 negatively. The biomarkers that were positively associated with older age were associated with tumor cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas biomarkers negatively associated with older age were associated with pathways that may point to cell proliferation and tumorigenesis. Among the 27 biomarkers, WFDC2 (WAP Four-Disulfide-Core-Domain-2) – that broadly functions as a protease inhibitor - was associated with older age and had the strongest association with all outcomes. No protein-by-sex interaction was observed.Conclusions: In elderly HFrEF patients, pathways associated with extra-cellular matrix organization, inflammatory processes, and tumor cell regulation were activated, while pathways associated with tumor proliferation functions were down-regulated. These findings may help in a better understanding of the aging processes in HFrEF and identify potential therapeutic targets.

AB - Aims: Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. We aim to better understand the underlying pathophysiological processes associated with aging in HFrEF potentially leading to targeted therapies in this vulnerable population.Methods and Results: From a panel of 363 cardiovascular biomarkers available in 1,611 patients with HFrEF in the BIOSTAT-CHF index cohort and cross-validated in 823 patients in the BIOSTAT-CHF validation cohort, we tested which biomarkers were dysregulated in patients aged>75yr versus <65yr. Secondly, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in elderly versus younger patients. After adjustment, multiple test correction (FDR 1%), and cross-validation, 27/363 biomarkers were associated with older age, 22 positively, and 5 negatively. The biomarkers that were positively associated with older age were associated with tumor cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas biomarkers negatively associated with older age were associated with pathways that may point to cell proliferation and tumorigenesis. Among the 27 biomarkers, WFDC2 (WAP Four-Disulfide-Core-Domain-2) – that broadly functions as a protease inhibitor - was associated with older age and had the strongest association with all outcomes. No protein-by-sex interaction was observed.Conclusions: In elderly HFrEF patients, pathways associated with extra-cellular matrix organization, inflammatory processes, and tumor cell regulation were activated, while pathways associated with tumor proliferation functions were down-regulated. These findings may help in a better understanding of the aging processes in HFrEF and identify potential therapeutic targets.

KW - aging

KW - chronological age

KW - biological age

KW - biomarkers

KW - heart failure with reduced ejection fraction

U2 - 10.1093/cvr/cvaa279

DO - 10.1093/cvr/cvaa279

M3 - Article

C2 - 33002110

SN - 0008-6363

VL - 117

SP - 2228

EP - 2236

JO - Cardiovascular Research

JF - Cardiovascular Research

IS - 10

ER -

Differences in biomarkers and molecular pathways according to age for patients with HFrEF

Abstract

Keywords

Access to Document

Fingerprint

Cite this