Association of C-Terminal Pro-Endothelin-1 with Mortality in the Population-Based KORA F4 Study

Abstract

Introduction

Endothelin-1 and its prohormone C-terminal pro-endothelin-1 (CT-proET-1) have been linked to metabolic alterations, inflammatory responses and cardiovascular events in selected study populations. We analyzed the association of CT-proET-1 with cardiovascular events and mortality, carotid intima-media-thickness as surrogate for early atherosclerotic lesions, biomarkers of subclinical inflammation and adipokines in a population-based study.

Methods

The cross-sectional and prospective analyses used data from the KORA F4 study with a median follow-up time of 9.1 (8.8–9.4) years. Data on CT-proET-1 and mortality were available for 1554 participants, data on the other outcomes in subgroups (n = 596–1554). The associations were estimated using multivariable linear regression and Cox proportional hazard models adjusted for sex, age, body mass index, estimated glomerular filtration rate, arterial hypertension, diabetes, low-density and high-density lipoprotein cholesterol, current and former smoking and physical activity. The Bonferroni method was used to correct for multiple testing.

Results

In the fully adjusted model, CT-proET-1 was associated with cardiovascular (hazard ratio (HR) per standard deviation increase: 1.66; 95% confidence interval (CI): 1.10–2.51; p = 0.017) and all-cause mortality (HR: 2.03; 95% CI 1.55–2.67; p < 0.001), but not with cardiovascular events, and was inversely associated with the intima-media thickness (β: −0.09 ± 0.03; p = 0.001). CT-proET-1 was positively associated with five out of ten biomarkers of subclinical inflammation and with two out of five adipokines after correction for multiple testing. After inclusion of biomarkers of subclinical inflammation in the Cox proportional hazard model, the association of CT-proET-1 with all-cause mortality persisted (p < 0.001).

Conclusion

These results emphasize the complexity of endothelin-1 actions and/or indicator functions of CT-proET-1. CT-proET-1 is a risk marker for all-cause mortality, which is likely independent of vascular endothelin-1 actions, cardiovascular disease and inflammation.

Keywords:

• endothelin
• CT-proET-1
• mortality
• cardiovascular events
• subclinical inflammation
• intima-media thickness

Abbreviations

CI, confidence interval; HR, hazard ratio; CT-proET-1, C-terminal pro-endothelin-1; CCA, common carotid artery; eGFR, estimated glomerular filtration rate; ET-1, endothelin-1; ETR, endothelin receptor(s); HDL, high density lipoprotein; hsCRP, high-sensitivity C-reactive protein; IMT, intima-media thickness; KORA, Cooperative Health Research in the Region of Augsburg; LDL, low density lipoprotein; LOD, limit of detection; MPO, myeloperoxidase; IL, interleukin; IL-1RA, interleukin-1 receptor antagonist; RBP-4, retinol-binding protein-4; sICAM-1, soluble intercellular adhesion molecule-1; SOD-3, superoxide dismutase-3; TNF-α, tumor necrosis factor-α.

Data Availability

The data are subject to national data protection laws and restrictions were imposed by the Ethics Committee of the Bavarian Chamber of Physicians to ensure data privacy of the study participants. Therefore, data cannot be made freely available in a public repository. However, data can be requested through an individual project agreement with KORA via the online portal KORA.passt (https://epi.helmholtz-muenchen.de/).

Acknowledgments

We gratefully acknowledge the contribution of all field staff members conducting the KORA F4 study and thank all study participants.

Disclosure

CH received a research grant from Sanofi-Aventis. MR reports consulting fees from Eli Lilly, Terra Firma, Fishawack Group, Target-RWE, Bristol-Myers Squibb and Inventiva, and honoraria for lectures from Boehringer-Ingelheim Pharma, Sanofi US, Novo Nordisk. WR reports the receipt of consulting fees for attending educational sessions or advisory boards run by AstraZeneca, Boehringer Ingelheim and NovoNordisk and institutional research grants from NovoNordisk. WK reports consulting fees from AstraZeneca, Novartis, Pfizer, The Medicines Company, DalCor, Kowa, Amgen, Corvidia, Daiichi-Sankyo, Genentech, Novo Nordisk, Esperion, OMEICOS, speaker honoraria from Amgen, Novartis, Berlin-Chemie, Sanofi, and Bristol-Myers Squibb, grants and non-financial support from Abbott, Roche Diagnostics, Beckmann, and Singulex. The reported disclosures are outside of the topic of the current work. The other authors declare that they have no conflict of interest associated with this manuscript.

Additional information

Funding

The study was supported by a research grant from the Virtual Diabetes Institute (Helmholtz Zentrum München) and the Clinical Cooperation Group Diabetes, Ludwig-Maximilians-University München and Helmholtz Zentrum München, and by the German Diabetes Center. The German Diabetes Center was supported by the Federal Ministry of Health (Berlin, Germany) and the Ministry of Culture and Science of the state North Rhine Westphalia (Düsseldorf, Germany). The KORA study was initiated and financed by the Helmholtz Zentrum München - German Research Center for Environmental Health, which is funded by the German Federal Ministry of Education and Research (BMBF) and by the State of Bavaria. This study was also supported by grants from the German Federal Ministry of Education and Research (BMBF) to the German Center for Diabetes Research e.V. (DZD). Further support was obtained from the Deutsche Diabetes Gesellschaft (DDG) and from the German Research Foundation (DFG, grant RA-45913/3-1). The funding sources had no role in in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.