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

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.