Insulin-like growth factor binding protein 7 (IGFBP7), a link between heart failure and senescence

Valentina Bracun; Bart van Essen; Adriaan A. Voors; Dirk J. van Veldhuisen; Kenneth Dickstein; Faiez Zannad; Marco Metra; Stefan Anker; Nilesh J. Samani; Piotr Ponikowski; Gerasimos Filippatos; John G.F. Cleland; Chim C. Lang; Leong L. Ng; Canxia Shi; Sanne de Wit; Joseph Pierre Aboumsallem; Wouter C. Meijers; IJsbrand T. Klip; Peter van der Meer; Rudolf A. de Boer

doi:10.1002/ehf2.14120

Insulin-like growth factor binding protein 7 (IGFBP7), a link between heart failure and senescence

Valentina Bracun, Bart van Essen, Adriaan A. Voors, Dirk J. van Veldhuisen, Kenneth Dickstein, Faiez Zannad, Marco Metra, Stefan Anker, Nilesh J. Samani, Piotr Ponikowski, Gerasimos Filippatos, John G.F. Cleland, Chim C. Lang, Leong L. Ng, Canxia Shi, Sanne de Wit, Joseph Pierre Aboumsallem, Wouter C. Meijers, IJsbrand T. Klip, Peter van der MeerRudolf A. de Boer^*

^*Corresponding author for this work

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

1 Citation (Scopus)

Abstract

Aims: Insulin like growth factor binding protein 7 (IGFBP7) is a marker of senescence secretome and a novel biomarker in patients with heart failure (HF). We evaluated the prognostic value of IGFBP7 in patients with heart failure and examined associations to uncover potential new pathophysiological pathways related to increased plasma IGFBP7 concentrations. Methods and results: We have measured plasma IGFBP7 concentrations in 2250 subjects with new-onset or worsening heart failure (BIOSTAT-CHF cohort). Higher IGFBP7 plasma concentrations were found in older subjects, those with worse kidney function, history of atrial fibrillation, and diabetes mellitus type 2, and in subjects with higher number of HF hospitalizations. Higher IGFBP7 levels also correlate with the levels of several circulating biomarkers, including higher NT-proBNP, hsTnT, and urea levels. Cox regression analyses showed that higher plasma IGFBP7 concentrations were strongly associated with increased risk of all three main endpoints (hospitalization, all-cause mortality, and combined hospitalization and mortality) (HR 1.75, 95% CI 1.25–2.46; HR 1.71, 95% CI 1.39–2.11; and HR 1.44, 95% CI 1.23–1.70, respectively). IGFBP7 remained a significant predictor of these endpoints in patients with both reduced and preserved ejection fraction. Likelihood ratio test showed significant improvement of all three risk prediction models, after adding IGFBP7 (P < 0.001). A biomarker network analysis showed that IGFBP7 levels activate different pathways involved in the regulation of the immune system. Results were externally validated in BIOSTAT-CHF validation cohort. Conclusions: IGFPB7 presents as an independent and robust prognostic biomarker in patients with HF, with both reduced and preserved ejection fraction. We validate the previously published data showing IGFBP7 has correlations with a number of echocardiographic markers. Lastly, IGFBP7 pathways are involved in different stages of immune system regulation, linking heart failure to senescence pathways.

Original language	English
Pages (from-to)	4167-4176
Number of pages	10
Journal	ESC heart failure
Volume	9
Issue number	6
DOIs	https://doi.org/10.1002/ehf2.14120
Publication status	Published - Dec 2022
Externally published	Yes

Bibliographical note

Funding Information:
This work was supported by a grant from the European Research Council (ERC CoG 818715, SECRETE‐HF). Furthermore, support was received from grants from the Netherlands Heart Foundation (CVON SHE‐PREDICTS‐HF, grant 2017‐21; CVON RED‐CVD, grant 2017‐11; CVON PREDICT2, grant 2018‐30; and CVON DOUBLE DOSE, grant 2020B005), and by a grant from the leDucq Foundation [Cure PhosphoLambaN induced Cardiomyopathy (Cure‐PLaN)].

Publisher Copyright:
© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

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10.1002/ehf2.14120

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Bracun, V., van Essen, B., Voors, A. A., van Veldhuisen, D. J., Dickstein, K., Zannad, F., Metra, M., Anker, S., Samani, N. J., Ponikowski, P., Filippatos, G., Cleland, J. G. F., Lang, C. C., Ng, L. L., Shi, C., de Wit, S., Aboumsallem, J. P., Meijers, W. C., Klip, IJ. T., ... de Boer, R. A. (2022). Insulin-like growth factor binding protein 7 (IGFBP7), a link between heart failure and senescence. ESC heart failure, 9(6), 4167-4176. https://doi.org/10.1002/ehf2.14120

@article{c67f1f79a11247849b0d91a866ba5a46,

title = "Insulin-like growth factor binding protein 7 (IGFBP7), a link between heart failure and senescence",

abstract = "Aims: Insulin like growth factor binding protein 7 (IGFBP7) is a marker of senescence secretome and a novel biomarker in patients with heart failure (HF). We evaluated the prognostic value of IGFBP7 in patients with heart failure and examined associations to uncover potential new pathophysiological pathways related to increased plasma IGFBP7 concentrations. Methods and results: We have measured plasma IGFBP7 concentrations in 2250 subjects with new-onset or worsening heart failure (BIOSTAT-CHF cohort). Higher IGFBP7 plasma concentrations were found in older subjects, those with worse kidney function, history of atrial fibrillation, and diabetes mellitus type 2, and in subjects with higher number of HF hospitalizations. Higher IGFBP7 levels also correlate with the levels of several circulating biomarkers, including higher NT-proBNP, hsTnT, and urea levels. Cox regression analyses showed that higher plasma IGFBP7 concentrations were strongly associated with increased risk of all three main endpoints (hospitalization, all-cause mortality, and combined hospitalization and mortality) (HR 1.75, 95% CI 1.25–2.46; HR 1.71, 95% CI 1.39–2.11; and HR 1.44, 95% CI 1.23–1.70, respectively). IGFBP7 remained a significant predictor of these endpoints in patients with both reduced and preserved ejection fraction. Likelihood ratio test showed significant improvement of all three risk prediction models, after adding IGFBP7 (P < 0.001). A biomarker network analysis showed that IGFBP7 levels activate different pathways involved in the regulation of the immune system. Results were externally validated in BIOSTAT-CHF validation cohort. Conclusions: IGFPB7 presents as an independent and robust prognostic biomarker in patients with HF, with both reduced and preserved ejection fraction. We validate the previously published data showing IGFBP7 has correlations with a number of echocardiographic markers. Lastly, IGFBP7 pathways are involved in different stages of immune system regulation, linking heart failure to senescence pathways.",

author = "Valentina Bracun and {van Essen}, Bart and Voors, {Adriaan A.} and {van Veldhuisen}, {Dirk J.} and Kenneth Dickstein and Faiez Zannad and Marco Metra and Stefan Anker and Samani, {Nilesh J.} and Piotr Ponikowski and Gerasimos Filippatos and Cleland, {John G.F.} and Lang, {Chim C.} and Ng, {Leong L.} and Canxia Shi and {de Wit}, Sanne and Aboumsallem, {Joseph Pierre} and Meijers, {Wouter C.} and Klip, {IJsbrand T.} and {van der Meer}, Peter and {de Boer}, {Rudolf A.}",

note = "Funding Information: This work was supported by a grant from the European Research Council (ERC CoG 818715, SECRETE‐HF). Furthermore, support was received from grants from the Netherlands Heart Foundation (CVON SHE‐PREDICTS‐HF, grant 2017‐21; CVON RED‐CVD, grant 2017‐11; CVON PREDICT2, grant 2018‐30; and CVON DOUBLE DOSE, grant 2020B005), and by a grant from the leDucq Foundation [Cure PhosphoLambaN induced Cardiomyopathy (Cure‐PLaN)]. Publisher Copyright: {\textcopyright} 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.",

year = "2022",

month = dec,

doi = "10.1002/ehf2.14120",

language = "English",

volume = "9",

pages = "4167--4176",

journal = "ESC heart failure",

issn = "2055-5822",

publisher = "The Heart Failure Association of the European Society of Cardiology",

number = "6",

}

Bracun, V, van Essen, B, Voors, AA, van Veldhuisen, DJ, Dickstein, K, Zannad, F, Metra, M, Anker, S, Samani, NJ, Ponikowski, P, Filippatos, G, Cleland, JGF, Lang, CC, Ng, LL, Shi, C, de Wit, S, Aboumsallem, JP, Meijers, WC, Klip, IJT, van der Meer, P & de Boer, RA 2022, 'Insulin-like growth factor binding protein 7 (IGFBP7), a link between heart failure and senescence', ESC heart failure, vol. 9, no. 6, pp. 4167-4176. https://doi.org/10.1002/ehf2.14120

TY - JOUR

T1 - Insulin-like growth factor binding protein 7 (IGFBP7), a link between heart failure and senescence

AU - Bracun, Valentina

AU - van Essen, Bart

AU - Voors, Adriaan A.

AU - van Veldhuisen, Dirk J.

AU - Dickstein, Kenneth

AU - Zannad, Faiez

AU - Metra, Marco

AU - Anker, Stefan

AU - Samani, Nilesh J.

AU - Ponikowski, Piotr

AU - Filippatos, Gerasimos

AU - Cleland, John G.F.

AU - Lang, Chim C.

AU - Ng, Leong L.

AU - Shi, Canxia

AU - de Wit, Sanne

AU - Aboumsallem, Joseph Pierre

AU - Meijers, Wouter C.

AU - Klip, IJsbrand T.

AU - van der Meer, Peter

AU - de Boer, Rudolf A.

N1 - Funding Information: This work was supported by a grant from the European Research Council (ERC CoG 818715, SECRETE‐HF). Furthermore, support was received from grants from the Netherlands Heart Foundation (CVON SHE‐PREDICTS‐HF, grant 2017‐21; CVON RED‐CVD, grant 2017‐11; CVON PREDICT2, grant 2018‐30; and CVON DOUBLE DOSE, grant 2020B005), and by a grant from the leDucq Foundation [Cure PhosphoLambaN induced Cardiomyopathy (Cure‐PLaN)]. Publisher Copyright: © 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.

PY - 2022/12

Y1 - 2022/12

N2 - Aims: Insulin like growth factor binding protein 7 (IGFBP7) is a marker of senescence secretome and a novel biomarker in patients with heart failure (HF). We evaluated the prognostic value of IGFBP7 in patients with heart failure and examined associations to uncover potential new pathophysiological pathways related to increased plasma IGFBP7 concentrations. Methods and results: We have measured plasma IGFBP7 concentrations in 2250 subjects with new-onset or worsening heart failure (BIOSTAT-CHF cohort). Higher IGFBP7 plasma concentrations were found in older subjects, those with worse kidney function, history of atrial fibrillation, and diabetes mellitus type 2, and in subjects with higher number of HF hospitalizations. Higher IGFBP7 levels also correlate with the levels of several circulating biomarkers, including higher NT-proBNP, hsTnT, and urea levels. Cox regression analyses showed that higher plasma IGFBP7 concentrations were strongly associated with increased risk of all three main endpoints (hospitalization, all-cause mortality, and combined hospitalization and mortality) (HR 1.75, 95% CI 1.25–2.46; HR 1.71, 95% CI 1.39–2.11; and HR 1.44, 95% CI 1.23–1.70, respectively). IGFBP7 remained a significant predictor of these endpoints in patients with both reduced and preserved ejection fraction. Likelihood ratio test showed significant improvement of all three risk prediction models, after adding IGFBP7 (P < 0.001). A biomarker network analysis showed that IGFBP7 levels activate different pathways involved in the regulation of the immune system. Results were externally validated in BIOSTAT-CHF validation cohort. Conclusions: IGFPB7 presents as an independent and robust prognostic biomarker in patients with HF, with both reduced and preserved ejection fraction. We validate the previously published data showing IGFBP7 has correlations with a number of echocardiographic markers. Lastly, IGFBP7 pathways are involved in different stages of immune system regulation, linking heart failure to senescence pathways.

AB - Aims: Insulin like growth factor binding protein 7 (IGFBP7) is a marker of senescence secretome and a novel biomarker in patients with heart failure (HF). We evaluated the prognostic value of IGFBP7 in patients with heart failure and examined associations to uncover potential new pathophysiological pathways related to increased plasma IGFBP7 concentrations. Methods and results: We have measured plasma IGFBP7 concentrations in 2250 subjects with new-onset or worsening heart failure (BIOSTAT-CHF cohort). Higher IGFBP7 plasma concentrations were found in older subjects, those with worse kidney function, history of atrial fibrillation, and diabetes mellitus type 2, and in subjects with higher number of HF hospitalizations. Higher IGFBP7 levels also correlate with the levels of several circulating biomarkers, including higher NT-proBNP, hsTnT, and urea levels. Cox regression analyses showed that higher plasma IGFBP7 concentrations were strongly associated with increased risk of all three main endpoints (hospitalization, all-cause mortality, and combined hospitalization and mortality) (HR 1.75, 95% CI 1.25–2.46; HR 1.71, 95% CI 1.39–2.11; and HR 1.44, 95% CI 1.23–1.70, respectively). IGFBP7 remained a significant predictor of these endpoints in patients with both reduced and preserved ejection fraction. Likelihood ratio test showed significant improvement of all three risk prediction models, after adding IGFBP7 (P < 0.001). A biomarker network analysis showed that IGFBP7 levels activate different pathways involved in the regulation of the immune system. Results were externally validated in BIOSTAT-CHF validation cohort. Conclusions: IGFPB7 presents as an independent and robust prognostic biomarker in patients with HF, with both reduced and preserved ejection fraction. We validate the previously published data showing IGFBP7 has correlations with a number of echocardiographic markers. Lastly, IGFBP7 pathways are involved in different stages of immune system regulation, linking heart failure to senescence pathways.

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U2 - 10.1002/ehf2.14120

DO - 10.1002/ehf2.14120

M3 - Article

C2 - 36088651

AN - SCOPUS:85137815850

SN - 2055-5822

VL - 9

SP - 4167

EP - 4176

JO - ESC heart failure

JF - ESC heart failure

IS - 6

ER -

Insulin-like growth factor binding protein 7 (IGFBP7), a link between heart failure and senescence

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