Understanding the role of inflammation in coronary heart disease patients with and without depression

Hdl Handle:
http://hdl.handle.net/10142/332065
Title:
Understanding the role of inflammation in coronary heart disease patients with and without depression
Authors:
Nikkheslat, Naghmeh
Abstract:
ABSTRACT 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.
Issue Date:
2014
URI:
http://hdl.handle.net/10142/332065
Type:
Thesis
Language:
en
Sponsors:
University of Roehampton 2025 Sponsorhsip. EU-FP7-HEALTH-F2-2008-222963 "MOODINFLAME", by the British Council-Partek Partnership, by the Biomedical Research Council King's College London (KCL), by the British Heart Foundation and by the ECNP and NARSAD Young Investigator Awards to Dr Livia A Carvalho.
Appears in Collections:
PhD Theses

Full metadata record

DC FieldValue Language
dc.contributor.authorNikkheslat, Naghmehen
dc.date.accessioned2014-10-03T09:30:39Z-
dc.date.available2014-10-03T09:30:39Z-
dc.date.issued2014-
dc.identifier.urihttp://hdl.handle.net/10142/332065-
dc.description.abstractABSTRACT 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.en
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dc.description.provenanceApproved for entry into archive by Nancy Graham (nancy.graham@roehampton.ac.uk) on 2014-10-03T09:30:37Z (GMT) No. of bitstreams: 3 PhD Thesis Naghmeh Nikkheslat Finalv2.pdf: 2656944 bytes, checksum: e62be72db463e76f3f8ae51338fb0e9e (MD5) license_text: 22302 bytes, checksum: 1e0094e9d8adcf16b18effef4ce7ed83 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5)en
dc.description.provenanceMade available in DSpace on 2014-10-03T09:30:39Z (GMT). No. of bitstreams: 3 PhD Thesis Naghmeh Nikkheslat Finalv2.pdf: 2656944 bytes, checksum: e62be72db463e76f3f8ae51338fb0e9e (MD5) license_text: 22302 bytes, checksum: 1e0094e9d8adcf16b18effef4ce7ed83 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2014en
dc.description.sponsorshipUniversity of Roehampton 2025 Sponsorhsip. EU-FP7-HEALTH-F2-2008-222963 "MOODINFLAME", by the British Council-Partek Partnership, by the Biomedical Research Council King's College London (KCL), by the British Heart Foundation and by the ECNP and NARSAD Young Investigator Awards to Dr Livia A Carvalho.en
dc.language.isoenen
dc.titleUnderstanding the role of inflammation in coronary heart disease patients with and without depressionen
dc.typeThesisen
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