Cortisol and Depression coronary Heart Diseases

Low Cortisol and Glucocorticoid Signaling But High Levels of Inflammation: Risk Factors for Developing Depression in Patients with Coronary Heart Diseases

Cortisol – Glucocorticoid – Heart Diseases

A new Brain Behavior and Immunity study indicates that depression in coronary heart disease (CHD) is associated with high levels of inflammation in the context of low cortisol output and glucocorticoid receptor (GR) resistance.

Heart disease and depression are two very common and often co-existing disorders affecting the population worldwide. According to the World Health Organization Global Burden of Disease Survey, coronary heart disease (CHD) and major depressive disorder (MDD) are currently the first and second causes of disability in developed countries.

The prevalence of depression among patients with established CHD is considerably higher as compared to the general population. Depression exacerbates adverse cardiac outcomes in CHD patients, besides worsening the psychological and social morbidity. Indeed, depression has been recognized as a negative prognostic indicator and an independent factor greatly increasing the risk of cardiovascular related morbidity and mortality, regardless of etiology and other known cardiac risk factors.

There is a two-way relationship between heart disease and depression. People with depression develop heart disease at a higher rate than the general population. On the other hand, patients with established heart diseases have greater propensity to develop depression.

The mechanisms associated with the link between the two diseases are not completely understood and identifying the pathophysiological mechanisms underlying the increased incidence of depression in patients with CHD remains a big challenge. Inflammation has been recognized as a common link between these two mental and physical disorders

Thus, inflammation is regarded as an important pathogenic factor in both CHD and MDD. Inflammation plays a central role in pathogenesis of CHD and is involved in all stages of atherosclerosis including initiation, propagation, and activation of atherosclerotic plaque, ultimately leading to thrombogenesis. Indeed, CHD patients show higher circulating pro-inflammatory cytokines, higher clinical markers of inflammation like C-reactive protein (CRP), and association with higher expression of inflammatory genes.

Downregulation of the anti-inflammatory cytokine IL-10 and upregulation of the pro-inflammatory cytokines IL-6 and TNF-α have been reported in chronic heart failure patients with depressive symptoms, and patients with myocardial infarction have increased plasma IL-6 and CRP concentrations and altered response to the anti-inflammatory properties of glucocorticoids, which independently correlate with depressive symptoms.

Hypothalamus–pituitary–adrenal (HPA) axis also plays a fundamental role as a regulatory system in stress responses and inflammation. Alteration of the HPA axis is observed in a significant proportion of patients with major depression and seems to reflect an impaired ability of cortisol to exert its physiological effects including the negative feedback on the HPA axis itself as well as the anti-inflammatory effects at the peripheral level.

In the Brain Behavior and Immunity study, Naghmeh Nikkheslat and colleagues from the Institute of Psychiatry, King`s College London, UK evaluated 83 coronary heart disease patients, with or without diagnosed depression, and assessed whether depressive symptoms correlate with inflammatory markers and abnormal hypothalamus-pituitary-adrenal (HPA) axis activity.

The authors found that CHD patients with depression had higher levels of C-reactive protein (CRP) and interleukin (IL)-6 gene expression, but lower levels of cortisol and glucocorticoid receptor (GR) mRNA, and less functional ability of the GR to respond to glucocorticoids.

They also showed that depressed CHD patients had reduced plasma levels of tryptophan and increased plasma levels of kynurenines, suggesting over activation of the serotonin degradation pathway.

The authors propose a model where the level of the endogenous cortisol is insufficient to limit inflammation in CHD patients with depression, due to hypoactivity of the HPA axis and GR resistance. Thus, chronic inflammation in patients with CHD may contribute to the development of depression, which in turn leads to further activation of inflammatory processes as reflected in joint elevation in IL-6 expression and CRP.

This, however, is inadequately restrained by endogenous glucocorticoids that are both lower and less able to act on the GR, and which lead to further brain and metabolic dysfunction by activating the kynurenine pathway.

This results in higher level of inflammation in these patients, which further maintains the GR resistance. All this may contribute to additional brain and metabolic dysfunction by over activation of the tryptophan/serotonin degradation (kynurenine) pathway.

Source: Brain Behavior and Immunity, 2015. DOI: 10.1016/j.bbi.2015.02.002
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