title: Insufficient glucocorticoid signaling and elevated inflammation in coronary heart disease patients with comorbid depression.
abstract: Coronary heart disease (CHD) and depression are very common and often co-existing disorders. In addition to psychological and social morbidity, depression exacerbates adverse cardiac outcomes in CHD patients. Inflammation has been proposed as one of the mechanisms involved in the association between these two debilitating diseases. Therefore, the present study aimed to evaluate inflammatory responses as well as to investigate the pathophysiological mechanisms underlying the putative inflammatory activation in CHD patients with and without depression, by assessing the function of two important biological factors regulating inflammation, the hypothalamus-pituitary-adrenal (HPA) axis and the glucocorticoid receptor (GR). Eighty-three CHD patients with (n=28) and without (n=55) comorbid depression were recruited from primary care services in South London. Depression status was assessed by means of Clinical Interview Schedule Revised for diagnosis of depression, and Beck Depression Inventory for the presence of depressive symptoms. Serum C-reactive protein (CRP), plasma vascular endothelial growth factor (VEGF), and plasma and salivary cortisol were measured using commercially available ELISA kits. Gene expression of GR and interleukin-6 (IL-6) were conducted via qPCR. GR sensitivity was evaluated in vitro in isolated peripheral blood mononuclear cells using the dexamethasone inhibition of lipopolysaccharide-stimulated IL-6 levels. Serum levels of kynurenine pathway metabolites were measured using high performance liquid chromatography. Our results show that CHD patients with depression had higher levels of CRP, IL-6 gene expression, and VEGF compared with CHD non-depressed, as well as lower plasma and saliva cortisol levels. The CHD depressed group also exhibited a reduction in GR expression and sensitivity. Finally, tryptophan levels were significantly lower in patients with depression, who also showed an increased kynurenine/tryptophan ratio. In conclusion, CHD patients with depression had elevated levels of inflammation in the context of HPA axis hypoactivity, GR resistance, and increased activation of the kynurenine pathway. Reduced cortisol bioavailability and attenuated glucocorticoid responsiveness due to decreased expression and sensitivity of GR may lead to insufficient glucocorticoid signaling and thus elevation of inflammation in these patients.
authors: Department of Psychological Medicine, Institute of Psychiatry, King's College London, UK; Department of Life Sciences, University of Roehampton, London, UK.
authors: Naghmeh
authors: N
authors: Nikkheslat
authors: Department of Psychological Medicine, Institute of Psychiatry, King's College London, UK.
authors: Patricia A
authors: PA
authors: Zunszain
authors: Department of Psychological Medicine, Institute of Psychiatry, King's College London, UK.
authors: Mark A
authors: MA
authors: Horowitz
authors: Department of Psychological Medicine, Institute of Psychiatry, King's College London, UK.
authors: Izabela G
authors: IG
authors: Barbosa
authors: Department of Life Sciences, University of Roehampton, London, UK.
authors: Jennie A
authors: JA
authors: Parker
authors: Faculty of Medicine, Ludwig-Maximilian University, Munich, Germany.
authors: Aye-Mu
authors: AM
authors: Myint
authors: Faculty of Medicine, Ludwig-Maximilian University, Munich, Germany.
authors: Markus J
authors: MJ
authors: Schwarz
authors: Health Service and Population Research Department, Institute of Psychiatry, King's College London, UK.
authors: Andre T
authors: AT
authors: Tylee
authors: Department of Epidemiology and Public Health, University College London, UK.
authors: Livia A
authors: LA
authors: Carvalho
authors: Department of Psychological Medicine, Institute of Psychiatry, King's College London, UK. Electronic address: carmine.pariante@kcl.ac.uk.
authors: Carmine M
authors: CM
authors: Pariante
mesh_terms: D000367:Age Factors; D000368:Aged; D015415:Biomarkers / Q000097:blood; D002097:C-Reactive Protein / Q000378:metabolism; D003327:Coronary Disease / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D003866:Depressive Disorder / Q000150:complications / Q000378:metabolism* / Q000503:physiopathology; D005260:Female; D006801:Humans; D006854:Hydrocortisone / Q000097:blood; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism* / Q000503:physiopathology; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008297:Male; D010913:Pituitary-Adrenal System / Q000378:metabolism* / Q000503:physiopathology; D011569:Psychiatric Status Rating Scales; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D012737:Sex Factors; D015398:Signal Transduction / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
chemical_list: D015415:Biomarkers; D015850:Interleukin-6; D011965:Receptors, Glucocorticoid; D042461:Vascular Endothelial Growth Factor A; D002097:C-Reactive Protein; D006854:Hydrocortisone
keywords: Cardiovascular risk factors; Corticosteroid receptor; Cytokine; Kynurenine; Major depressive disorders; Neuroendocrine; Stress