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
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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Both authors contributed equally.