Elsevier

Psychoneuroendocrinology

Volume 62, December 2015, Pages 227-232
Psychoneuroendocrinology

Plasma mid-regional pro-adrenomedullin levels are inversely associated with anxiety but unrelated to depression: Results from the observational DIAST-CHF study in patients with cardiovascular risk factors

https://doi.org/10.1016/j.psyneuen.2015.08.007Get rights and content

Highlights

  • Data from the multicenter DIAST-CHF study in patients with cardiovascular risk factors (n = 1,410) demonstrated that elevated plasma mid-regional pro-adrenomedullin (MR-proADM) levels are linked to less severe anxiety symptoms.

  • The inverse association between MR-proADM and anxiety remained stable after adjustment for potential confounders, irrespective of whether continuous or dichotomized HADS (Hospital Anxiety and Depression Scale) anxiety scores above the clinically relevant cut-off level were used.

  • Our clinical findings in a human sample support data from a previous animal study showing over-anxious behavior in a conditional knock-out mouse line lacking brain-specific expression of ADM.

Abstract

Objectives

It has been postulated that patients with heart failure have a high risk of ventricular arrhythmias and sudden cardiac death resulting from anxiety-induced autonomic arousal. In the prospective and multicenter DIAST-CHF (Diagnostic Trial on Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure) study, we therefore, tested the hypothesis that adrenomedullin (ADM), a well-established predictor for cardiovascular outcome, is associated with self-rated anxiety symptoms in patients at risk of suffering from or actually with overt heart failure.

Participants and measures

Study participants with risk factors for diastolic dysfunction were requested to complete the Hospital Anxiety and Depression Scale (HADS), and plasma mid-regional pro-adrenomedullin (MR-proADM) concentrations were measured.

Results

In bivariate analysis, we found significantly lower plasma MR-proADM levels in patients with elevated HADS-anxiety scores above the clinically relevant cut-off level of ≥11 (n = 118, 536 pmol/l, interquartile range [IQR] 449–626) as compared to non-anxious study participants (n = 1,292, 573 pmol/l, IQR 486–702, p = 0.001). A set of multivariate models adjusted for potential confounders confirmed the negative association between self-rated anxiety symptoms and plasma MR-proADM. In similar models, no significant association was detected between HADS-depression scores and MR-proADM.

Conclusions

The inverse relationship between plasma MR-proADM and anxiety observed in patients with cardiovascular risk factors supports a previous experimental study using a mutant mouse line with a brain-specific loss of ADM expression which displayed hyperactive and over-anxious behavior. Further experimental and clinical studies are warranted to test the hypothesis that also in humans ADM acts as a neuromodulator with anxiolytic properties.

Introduction

Depression has long been shown to be a risk factor for adverse outcome in patients with cardiovascular diseases and, in addition, is associated with an increased incidence of heart failure after diagnosis of coronary heart disease (May et al., 2009). A growing body of evidence suggests that also anxiety is a clinically relevant predictor of adverse cardiovascular events, independent of comorbid depression (Olafiranye et al., 2011). The mechanisms underlying the observed linkage between anxiety and cardiovascular outcome are not entirely clear and may include activation of the hypothalamic–pituitary axis and the sympathetic nervous system, impaired vagal regulation, reduced heart rate variability, and unhealthy lifestyles. Peptides expressed both in the brain and vasculature may be involved in some pathophysiological pathways by which depression and/or anxiety affects outcome in patients with cardiovascular risk factors. However, our current knowledge on the role of neuroendocrine markers in anxious and/or depressed patients at cardiovascular risk is rather limited (Herrmann-Lingen et al., 2003).

In a recently published systematic review, the regulatory peptide adrenomedullin (ADM) was described as an independent predictor of death in patients with heart failure and of major adverse cardiac events (MACE) and all-cause mortality in patients who had suffered an acute myocardial infarction (Yuyun et al., 2015). Although ADM appears to contribute to risk stratification in the setting of ischemic heart disease, clinical studies on the impact of this multifunctional peptide on emotional and mood levels are currently rare. In a small sample of hypertensive patients (n = 112), Kong et al. (2014) reported that both plasma ADM and left ventricular mass index (LVMI) were higher in anxious patients compared with non-anxious patients. However, ADM and LVMI were significantly correlated, raising the possibility that elevated ADM was simply a proxy for left-ventricular hypertrophy. Unfortunately, analyses of ADM were not adjusted for LVMI or the degree of left ventricular dysfunction, although it has been well established that plasma ADM levels also increase in proportion to the severity of heart failure (Nishikimi et al., 2003). Therefore, we wondered whether, in patients with cardiovascular risk factors, there is any evidence of an association between self-rated anxiety and plasma ADM levels, independent of the severity of left ventricular dysfunction. The objective of the present prospective analysis was to test the hypothesis that ADM is linked to anxiety even after adjusting for known risk factors of heart failure.

Section snippets

Subjects

The Diagnostic Trial on Prevalence and Clinical Course of Diastolic Dysfunction and Heart Failure (DIAST-CHF) study recruited medical outpatients aged 50–85 years who presented with cardiovascular risk factors to their general practitioners or primary care physicians (Edelmann et al., 2011). Patients were asked to participate in this multicenter, population-based study when at least one risk factor for the development of diastolic dysfunction was assessed at the screening visit. Further

Patient characteristics

A total of 1937 patients were enrolled in the DIAST-CHF study, and complete cardiological, psychometric and MR-proADM data were available for 1410 subjects of them. Patients with missing data had a significantly lower mean Framingham sum (0.60 ± 1.17 vs 0.75 ± 1.14, p = 0.040) and a higher HADS-D score (4.8 ± 4.0 vs 4.2 ± 3.6, p = 0.029) than the participants with complete data, but they did not significantly differ with respect to sex, age, body-mass index (BMI), systolic blood pressure, dimensions of

Discussion

The present substudy of the DIAST-CHF trial demonstrated a link between plasma MR-proADM concentrations and self-rated anxiety symptoms. The results showed that plasma levels of MR-proADM were significantly lower in study participants with higher HADS anxiety scores. This negative association between MR-proADM and anxiety remained stable after adjustment for potential confounders, irrespective of whether continuous or dichotomized HADS-A scores above the clinically relevant cut-off level were

Conflict of interest

C.H.-L. receives royalties from Hans Huber Publishers, Berne, for the German version of the HADS. The other authors declare that they have no conflict of interest.

Funding

This work was supported by a grant from the German Federal Ministry of Education and Research (Competence Network Heart Failure, TP 7 [FKZ 01GI0205]).

Authors contributions

Conceived and designed the study: C.H.L., B.P., R.W., F.E., analyzed the data: M.L.C., T.M., wrote the paper: T.M.

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