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Title: Understanding the role of inflammation in coronary heart disease patients with and without depression
Author: Nikkheslat, Naghmeh
ISNI:       0000 0004 5346 0860
Awarding Body: University of Roehampton
Current Institution: University of Roehampton
Date of Award: 2014
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Coronary heart disease (CHD) and depression are very common and often co-existing disorders. The prevalence of depression among patients with CHD is considerably higher as compared to the general population. Depression exacerbates adverse cardiac outcomes in CHD patients increasing the risk of cardiovascular morbidity and mortality, besides worsening the psychological and social morbidity. Inflammation has been recognised to be involved in the association between these two debilitating disorders. Therefore, the present PhD thesis aimed to evaluate inflammatory responses and to investigate the pathophysiological mechanisms underlying the 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). Serum C-reactive protein (CRP), and plasma and salivary cortisol were measured using commercially available ELISA kits. Gene expression of GR and inflammatory biomarkers were analysed by means of quantitative real time PCR. GR function was assessed in vitro in isolated peripheral blood mononuclear cells using the dexamethasone inhibition of lipopolysaccharide-stimulated IL-6 production method. Serum levels of kynurenine pathway of tryptophan metabolism metabolites were measured using high performance liquid chromatography. CHD patients with depression showed higher CRP levels and IL-6 gene expression compared with CHD non-depressed. Both plasma cortisol levels and salivary cortisol awakening response were significantly lower in patients with depression when compared with CHD alone. The CHD depressed group exhibited a reduction in GR expression and function. Tryptophan levels were significantly lower in patients with depression who also showed an increased kynurenine/tryptophan ratio, which in turn was associated with an increased in 3-hydroxykynurenine level. 3 In CHD patients, depression was accompanied by 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 numbers and sensitivity of GR may lead to insufficient glucocorticoid signalling and thus elevation of inflammation in CHD patients with depression. An increased inflammatory response may in turn lead to a diversion of the kynurenine pathway towards the neurotoxic branch.
Supervisor: Opacka Juffry, Jolanta ; Pariante, Carmine ; Carvelho, Livia Sponsor: University of Roehampton ; British Council-Partek Partnership ; Biomedical Research Council ; King's College London (KCL) ; British Heart Foundation ; ECNP ; NARSAD
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available