Vascular Health and Risk Management (May 2022)

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

  • Then C,
  • Sujana C,
  • Herder C,
  • Then H,
  • Heier M,
  • Meisinger C,
  • Peters A,
  • Koenig W,
  • Rathmann W,
  • Maalmi H,
  • Ritzel K,
  • Roden M,
  • Stumvoll M,
  • Thorand B,
  • Seissler J

Journal volume & issue
Vol. Volume 18
pp. 335 – 346

Abstract

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Cornelia Then,1,2 Chaterina Sujana,2– 4 Christian Herder,5– 7 Holger Then,8 Margit Heier,3,9 Christa Meisinger,10,11 Annette Peters,3,12 Wolfgang Koenig,12– 14 Wolfgang Rathmann,5,15 Haifa Maalmi,5,7 Katrin Ritzel,1 Michael Roden,5– 7 Michael Stumvoll,16 Barbara Thorand,2,3 Jochen Seissler1,2 1Department of Internal Medicine IV, University Hospital of Ludwigs-Maximilians-University Munich, Munich, Germany; 2German Center for Diabetes Research (DZD), Partner Munich-Neuherberg, Munich, Germany; 3Institute of Epidemiology, Helmholtz Zentrum Munich – German Research Center for Environmental Health (GmbH), Neuherberg, Germany; 4Institute for Medical Information Processing, Biometry, and Epidemiology, Pettenkofer School of Public Health, Ludwigs-Maximilians-University Munich, Munich, Germany; 5German Center for Diabetes Research (DZD), Munich, Germany; 6Department of Endocrinology and Diabetology, Medical Faculty and University Hospital of the Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; 7Institute of Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; 8Freie Waldorfschule Augsburg, Augsburg, Germany; 9KORA Study Centre, University Hospital Augsburg, Augsburg, Germany; 10Independent Research Group Clinical Epidemiology, Helmholtz Zentrum Munich – German Research Center for Environmental Health (GmbH), Neuherberg, Germany; 11Chair of Epidemiology, University Hospital Augsburg, Augsburg, Germany; 12DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany; 13Institute of Epidemiology and Medical Biometry, University of Ulm, Ulm, Germany; 14German Heart Center Munich, Technical University of Munich, Munich, Germany; 15Institute of Biometrics and Epidemiology, German Diabetes Center, Leibniz Institute at Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany; 16Department of Medicine, University of Leipzig, Leipzig, GermanyCorrespondence: Cornelia Then, Medizinische Klinik und Poliklinik IV - Klinikum der Ludwig-Maximilians-Universität, Ziemssenstraße 1, München, 80336, Germany, Tel +4989440052111, Fax +4989440054956, Email [email protected]: 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

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