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

Vasc Health Risk Manag. 2022 May 3:18:335-346. doi: 10.2147/VHRM.S363814. eCollection 2022.

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: CT-proET-1; cardiovascular events; endothelin; intima-media thickness; mortality; subclinical inflammation.

MeSH terms

  • Adipokines
  • Biomarkers
  • Cardiovascular Diseases* / diagnosis
  • Carotid Intima-Media Thickness
  • Cross-Sectional Studies
  • Endothelin-1*
  • Humans
  • Inflammation
  • Mortality*
  • Peptide Fragments
  • Prospective Studies

Substances

  • Adipokines
  • Biomarkers
  • Endothelin-1
  • Peptide Fragments

Grants and 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.