Anxiety as Predictor of the Cortisol Awakening Response in Patients with Coronary Heart Disease

Background

Anxiety is associated with worse outcomes in patients with coronary heart disease (CHD). A dysregulation of the HPA axis is a potential mechanism linking psychological factors and coronary disease. No study has yet investigated the relationship between anxiety and cortisol among patients with established CHD.

Purpose

The aim of this study was to assess the association between anxiety and the cortisol awakening response in patients with CHD.

Method

Four salivary cortisol samples were used to assess two measures of the cortisol awakening response (CAR) in 47 patients with established CHD. Anxiety was measured using the Hospital Anxiety and Depression Scale (HADS).

Results

Higher anxiety values were associated with a higher total output of cortisol in the first hour after awakening (AUCg, area under the curve with respect to ground) (p?=?0.04) and a nonsignificant trend towards a more pronounced increase (AUCi, area under the curve with respect to increase) (p?=?0.08). In patients who had a history of myocardial infarction (MI), the cortisol output was lower compared to patients who had no previous MI (p?=?0.02). In linear regression analyses, anxiety emerged as significant predictor of AUCg and AUCi after controlling for MI, ejection fraction (LVEF, left ventricular ejection fraction), and depression.

Conclusions

Our results provide further indications for an association between anxiety and a dysregulation of the HPA axis. History of MI emerged as second predictor of cortisol output in the morning.     

Elastic distortion determining conduction in BiFeO3 phase boundaries

It is now well-established that boundaries separating tetragonal-like (T) and rhombohedral-like (R) phases in BiFeO₃ thin films can show enhanced electrical conductivity. However, the origin of this conductivity remains elusive. Here, we study mixed-phase BiFeO₃ thin films, where local populations of T and R can be readily altered using stress and electric fields. We observe that phase boundary electrical conductivity in regions which have undergone stress-writing is significantly greater than in the virgin microstructure. We use high-end electron microscopy techniques to identify key differences between the R–T boundaries present in stress-written and as-grown microstructures, to gain a better understanding of the mechanism responsible for electrical conduction. We find that point defects (and associated mixed valence states) are present in both electrically conducting and non-conducting regions; crucially, in both cases, the spatial distribution of defects is relatively homogeneous: there is no evidence of phase boundary defect aggregation. Atomic resolution imaging reveals that the only significant difference between non-conducting and conducting boundaries is the elastic distortion evident – detailed analysis of localised crystallography shows that the strain accommodation across the R–T boundaries is much more extensive in stress-written than in as-grown microstructures; this has a substantial effect on the straightening of local bonds within regions seen to electrically conduct. This work therefore offers distinct evidence that the elastic distortion is more important than point defect accumulation in determining the phase boundary conduction properties in mixed-phase BiFeO₃.

The localized crystallography of conducting and non-conducting phase boundaries in mixed-phase BiFeO₃ is directly compared using scanning transmission electron microscopy techniques.

The complexity of electrical conductivity in domain walls in BiFeO₃ (and in ferroics in general) is as multifaceted as ever. Various influences such as point defect accumulation, octahedral rotations, magnetic interactions and electrostatic discontinuities are thought to be possible mechanisms at play,^1–8 either alone or in combination. The research area of domain wall conductivity is currently flourishing and the view that domain walls offer exciting prospects in terms of engineering systems in which the domain walls act as distinct identities to the domains which they separate is now widely accepted. We believe that it is pertinent timing to address a lack of experimental investigations providing meaningful direct comparison of the localised crystallography and defect structure responsible for observed enhanced electrical conductivity. This study is stimulated by the interesting discoveries of conductive phase boundaries, specifically, in mixed-phase BiFeO₃.^9,10 By tuning the local populations of the tetragonal-like (T) and rhombohedral-like (R) phases in BiFeO₃ thin films via electric and stress fields, we demonstrate that electrical conductivity along phase boundaries is significantly greater after stress-writing. We probe the key crystallographic differences between the R–T boundaries created via stress, compared to those already present in the as-grown microstructures, to disentangle the mechanism determining electrical conduction in mixed-phase BiFeO₃.The growth of BiFeO₃ on substrates enforcing a large in-plane compressive strain drives the formation of monoclinic phases that are approximately rhombohedral (R) and tetragonal (T). Similar to materials such as PbZr_0.53Ti_0.47O₃ that straddle a morphotropic phase boundary, highly strained BiFeO₃ can readily undergo phase transitions between the R and T phases (and vice versa). The high-strain T phase exhibits a tetragonal-like symmetry (almost P4mm) with a c/a ratio of ∼1.2; the Fe displacement towards one of the apical oxygens along [001]_pc results in fivefold oxygen coordinated Fe, and an enhanced polarisation roughly 1.5 times that of the bulk single crystal.^7,11 The R phase, on the other hand, resembles the rhombohedral bulk phase (almost R3c), where the Fe is octahedrally coordinated, with a ferroelectric distortion along the pseudocubic [111]_pc axis, and antiferrodistortive rotations of the FeO₆ octahedra around [111]_pc occur. The crystal structure and misfit strain associated with the native (as-grown) R and T phases is reported elsewhere, both theoretically^12–15 and experimentally,^6,7,16–21 making it well-known that the ferroelectric and the antiferrodistortive degrees of freedom in mixed-phase BiFeO₃ set it apart from other typical perovskites. Notably, despite the ample evidence provided on phase reversal and characterisation of the as-grown phases, most of the literature (especially regarding electric field cycling of the mixed-phase state) has been primarily concerned with X-ray diffraction (XRD) i.e. global measurements that will not necessarily pick up on the more subtle, atomic-scale aspects of structure local to the phase boundaries. The importance of the study described herein resides in the uniqueness of creating microstructures such that both the as-grown and stress-induced R–T phase boundaries can be included within one single cross-sectional transmission electron microscopy (TEM) lamella; this gives the best possible scenario to allow meaningful direct comparison of the localised crystallography and defect structure responsible for the observed enhanced electrical conductivity found at stress-induced phase boundaries.     

S6K1 controls pancreatic β cell size independently of intrauterine growth restriction

Type 2 diabetes mellitus (T2DM) is a worldwide heath problem that is characterized by insulin resistance and the eventual loss of β cell function. As recent studies have shown that loss of ribosomal protein (RP) S6 kinase 1 (S6K1) increases systemic insulin sensitivity, S6K1 inhibitors are being pursued as potential agents for improving insulin resistance. Here we found that S6K1 deficiency in mice also leads to decreased β cell growth, intrauterine growth restriction (IUGR), and impaired placental development. IUGR is a common complication of human pregnancy that limits the supply of oxygen and nutrients to the developing fetus, leading to diminished embryonic β cell growth and the onset of T2DM later in life. However, restoration of placental development and the rescue of IUGR by tetraploid embryo complementation did not restore β cell size or insulin levels in S6K1^–/– embryos, suggesting that loss of S6K1 leads to an intrinsic β cell lesion. Consistent with this hypothesis, reexpression of S6K1 in β cells of S6K1^–/– mice restored embryonic β cell size, insulin levels, glucose tolerance, and RPS6 phosphorylation, without rescuing IUGR. Together, these data suggest that a nutrient-mediated reduction in intrinsic β cell S6K1 signaling, rather than IUGR, during fetal development may underlie reduced β cell growth and eventual development of T2DM later in life.