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

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posted on 2022-12-02, 17:05 authored by 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 GF Cleland, Chim C Lang, Leong L Ng, Canxia Shi, Sanne de Wit, Joseph P About Msallem, Wouter C Meijers, IJsbrand T Klip, Peter van der Meer, Rudolf A de Boer
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.

Funding

This work was supported by a grant from the European Re-search Council (ERC CoG 818715, SECRETE-HF). Furthermore,support was received from grants from the NetherlandsHeart Foundation (CVON SHE-PREDICTS-HF, grant 2017-21;CVON RED-CVD, grant 2017-11; CVON PREDICT2, grant2018-30; and CVON DOUBLE DOSE, grant 2020B005), and by a grant from the leDucq Foundation [CurePhosphoLambaN induced Cardiomyopathy (Cure-PLaN)].

History

Citation

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, I. J. T., van der Meer, P., and de Boer, R. A. (2022) Insulin-like growth factor binding protein 7 (IGFBP7), a link between heart failure and senescence. ESC Heart Failure, https://doi.org/10.1002/ehf2.14120.

Author affiliation

Department of Cardiovascular Sciences; NIHR Leicester Biomedical Research Centre

Version

  • VoR (Version of Record)

Published in

ESC HEART FAILURE

Publisher

WILEY PERIODICALS, INC

issn

2055-5822

eissn

2055-5822

Acceptance date

2022-08-15

Copyright date

2022

Available date

2022-12-02

Spatial coverage

England

Language

English

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