Johnny Nijm

Inflammation and cortisol response in coronary artery disease

Atherosclerosis is characterized by chronic inflammation involving autoimmune components. The degree of inflammatory activity, as detectable both within the atherosclerotic plaque and in the circulation, is associated with plaque destabilization and atherothrombotic complications. Endogenous glucocorticoids are modulators of innate and acquired immune responses, and as such play a key role in the reciprocal interaction between neuroendocrine and immune systems. Abnormalities in hypothalamic-pituitary-adrenal axis (HPA) function have been described in several chronic inflammatory disorders, and evidence has emerged lately that HPA dysfunction may be implicated also in the pathogenesis of coronary artery disease. This review is an outline of knowledge gained so far by previous studies of glucocorticoids in coronary atherosclerosis and myocardial infarction. The results consistently point towards a dysregulated cortisol secretion that may involve a failure to contain inflammatory activity. A dysfunctional HPA axis and its possible implications for coronary artery disease progress, including the hypothetical link between stress and inflammation, are discussed.

Impaired cortisol response to acute stressors in patients with coronary disease. Implications for inflammatory activity

Objectives.  Inflammation is assumed to play a major role in the progress of atherosclerotic disease. We hypothesized that an altered hypothalamic‐pituitary adrenal (HPA) axis activity was linked to a disinhibited inflammatory activity in patients with coronary artery disease (CAD).

Denial in patients with a first-time myocardial infarction: relations to pre-hospital delay and attendance to a cardiac rehabilitation programme.

Background Survival of a myocardial infarction and subsequent prognosis are highly dependent on the time between onset of symptoms and medical intervention. Design This cross-sectional study examines whether patients who used the psychological defence mechanism of denial when faced with symptoms of a first-time myocardial infarction tended to also show a prolonged delay in going to the hospital and to be less willing to participate in a cardiac rehabilitation programme. Methods One hundred and seven patients, 78 men and 29 women, were enrolled in this study. The sample was divided into two groups depending on whether the patients sought medical help within 4h after they began experiencing myocardial infarction symptoms (non-delayers) or whether they waited longer (delayers). Denial was measured with the Hackett and Cassem semi-structured interview 3–5 days after the patients entered the hospital. Data on participation (attenders) or not (non-attenders) in the rehabilitation programme was also obtained. Results Forty-nine patients exhibited a prolonged delay and 76 patients did not attend the rehabilitation programme. Both prolonged delay and a lesser readiness to attend the rehabilitation programme that was offered were related to a greater use of denial. In addition, the great majority of the patients categorized as being high deniers were found to also be both delayers and non-attenders. Conclusions The results suggest denial to increase the health risks of persons potentially prone to myocardial infarction. If our knowledge about this psychological defence mechanism is increased, we might be able to reach more patients in alternative and individually based cardiac rehabilitation programmes.

Enhanced neutrophil expression of annexin-1 in coronary artery disease

The systemic inflammatory activity in patients with stable coronary artery disease (CAD) is associated with a dysregulated cortisol response. Moreover, an aberrant activation status of neutrophils in CAD has been discussed; and the question of glucocorticoid resistance has been raised. The anti-inflammatory actions of glucocorticoids are mediated by annexin-1 (ANXA1). We investigated the expression of glucocorticoid receptors (GR) and ANXA1, as well as the exogenous effects of ANXA1 on neutrophils in CAD patients and related the data to diurnal salivary cortisol. Salivary cortisol levels were measured in the morning and evening during 3 consecutive days in 30 CAD patients and 30 healthy individuals. The neutrophil expression of GR and ANXA1 was determined by flow cytometry. The effect of exogenous ANXA1 was determined in a neutrophil stimulation assay. The patients showed a flattened diurnal cortisol pattern compared with healthy subjects, involving higher levels in the evening. The neutrophil expression of GR-total and GR-alpha was decreased, whereas the GR-beta expression did not differ compared with controls. The neutrophil expression of ANXA1 was significantly increased in patients. Ex vivo, ANXA1 impaired the leukotriene B(4)-induced neutrophil production of reactive oxygen species in patients but not in controls. Our findings indicate a persistent overactivation of the hypothalamic-pituitary-adrenal axis in CAD patients but do not give any evidence for glucocorticoid resistance, as assessed by the neutrophil expression of GR and ANXA1. The altered neutrophil phenotype in CAD may thus represent a long-term response to disease-related activation.

Elevated levels of circulating matrix metalloproteinase-9 are associated with a dysregulated cortisol rhythm-A case-control study of coronary artery disease

A dysregulated cortisol pattern has been found to be associated with systemic inflammatory activity in patients with coronary artery disease (CAD). Matrix metalloproteinase (MMP)-9 is involved in both inflammation and matrix degradation and considered a main contributor to coronary plaque rupture. In this study, we hypothesized that a dysfunctional cortisol response also involved a failure to regulate systemic MMP-9 levels in CAD patients. Total MMP-9, active MMP-9 and the endogenous inhibitor TIMP-1 were measured in 30 CAD patients and 30 healthy controls. Morning and evening cortisol was measured in repeated saliva samples. Patients had higher levels of total and active MMP-9 (both p<0.01) and increased 24-h cortisol output (p<0.05) characterized by higher levels of evening cortisol (p=0.011). MMP-9 was associated with evening cortisol (p<0.001) independent of smoking and inflammatory markers. Compared with controls, patients also showed a blunted cortisol response to stress. After stress, the levels of MMP-9 became significantly reduced in controls whereas they remained unchanged in patients. The data indicate that MMP-9 is differently regulated in patients due to a dysfunctional hypothalamic-pituitary-adrenal (HPA) axis and emphasize the role of MMP-9 as a possible link between stress and cardiovascular disease.