Elevated Plasma C-Terminal Endothelin-1 Precursor Fragment Concentrations Are Associated with Less Anxiety in Patients with Cardiovascular Risk Factors. Results from the Observational DIAST-CHF Study.

Thomas Meyer,Kathleen Nolte,Burkert Pieske,Maren Roggenthien,Christoph Herrrmann-Lingen,Rolf Wachter,Frank Edelmann,Mira-Lynn Chavanon

doi:10.1371/journal.pone.0136739

Abstract

BackgroundThe role of endothelin-1 (ET-1) in the neurobiology of anxiety is unknown, therefore, we assessed in the observational multicenter DIAST-CHF study whether the C-terminal ET-1 precursor fragment (CT-proET-1) is linked to anxiety.MethodsPlasma concentrations of CT-proET-1 were measured in a total of 1,410 patients presenting with cardiovascular risk factors (mean age 66.91±8.2 years, 49.3% males, mean left ventricular ejection fraction 60.0±8.2%) who had completed the Hospital Anxiety and Depression Scale (HADS) questionnaire.ResultsAmong the total study cohort (n = 1,410), there were 118 subjects (8.4%) with an HADS anxiety score above the cut-off level of 11 suggestive of clinically relevant anxiety. Plasma CT-proET-1 levels were significantly lower in the group of anxious patients as compared to non-anxious patients (p = 0.013). In regression models adjusted for sex, age, systolic blood pressure, and diameters of left atrium and ventricle, plasma CT-proET-1 was again linked to anxiety (Exp(β) = 0.247, 95%-confidence interval [95%-CI] = 0.067–0.914, p = 0.036). Given the high prevalence of depressive disorders in anxious patients, we additionally included the HADS depression score as an independent variable in the models and found that CT-proET-1 remained a significant predictor of anxiety, independent of comorbid depression (Exp(β) = 0.114, 95%-CI = 0.023–0.566, p = 0.008).ConclusionsOur data from a population-based study in outpatients with cardiovascular risk factors revealed that circulating CT-proET-1 levels are negatively associated with anxiety. Further investigations are required to clarify the putative anxiolytic effect of ET-1 or its precursor molecules in humans and to decipher its mechanistic pathways.

Highlights

Epidemiological evidence supports a pathological link between emotional distress and cardiovascular morbidity and mortality
In regression models adjusted for sex, age, systolic blood pressure, and diameters of left atrium and ventricle, plasma CT-proET-1 was again linked to anxiety (Exp(β) = 0.247, 95%-confidence interval [95%-confidence intervals (95%-CI)] = 0.067–0.914, p = 0.036)
The Framingham sum score was significantly higher in anxious patients as compared to non-anxious subjects (1.15±1.27 versus 0.71±1.12, p

Summary

Introduction

Epidemiological evidence supports a pathological link between emotional distress and cardiovascular morbidity and mortality. It was shown that ET-1 decreases the high-affinity uptake of the excitatory amino acid glutamate in primary cultured astrocytes from rat cerebral cortex, suggesting a direct effect on membrane depolarisation [5]. This is of special interest as a growing body of evidence suggests that glutamatergic neurotransmission may be involved in the biological mechanisms underlying stress response, panic/anxiety and anxiety-related disorders [6,7]. The role of endothelin-1 (ET-1) in the neurobiology of anxiety is unknown, we assessed in the observational multicenter DIAST-CHF study whether the C-terminal ET-1 precursor fragment (CT-proET-1) is linked to anxiety.

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