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Inflammation and cortisol response i coronary artery disease
Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Atherosclerosis is characterized by a chronic inflammation, involving autoimmune components, in the arterial wall. An increase in proinflammatory activity relative to anti-inflammatory activity is considered to cause a progression of the disease towards plaque instability and risk of atherothrombotic events, such as acute coronary syndrome (ACS). Cortisol, the end product of the hypothalamus-pituitary-adrenal (HPA) axis, is a powerful endogenous anti-inflammatory mediator. Disturbances in the HPA axis have been reported in chronic inflammatory/autoimmune diseases, like rheumatoid arthritis. The aim of this thesis was to study various markers of systemic inflammation in patients with acute and stable conditions of coronary artery disease (CAD) and relate these findings to the cortisol response.

Both patients with ACS and patients with stable CAD had high levels of C-reactive protein (CRP), interleukin (IL)-6 and IL-1 receptor antagonist, compared with healthy controls. In addition, patients with stable CAD had significantly more neutrophil-platelet aggregates than controls, as a possible indicator of neutrophil activation.

The cortisol response was determined in two different cohorts of CAD patients; one consisting of patients with a first-time myocardial infarction and one consisting of patients with long-term stable CAD. From the acute phase to 3 months, the patients with a myocardial infarction showed a higher 24-h cortisol secretion and a flattened diurnal slope caused by higher cortisol levels in the evening, as compared with healthy controls. The patients with long-term stable CAD showed similarly high levels of cortisol in the evening. The levels of evening cortisol were strongly correlated with CRP and IL-6. When exposed to acute physical or acute psychological stress at 3 months, the ACS patients showed a markedly blunted cortisol response compared with healthy controls. Following the stress tests, a significant increase in CRP was observed in the patients but not in the controls, indicating a failure of the HPA axis to compensate for stress-induced inflammation in CAD.

In the ACS patients, the time course of matrix metalloproteinases (MMPs) and their tissue inhibitor TIMP-1 was determined during the 3 months follow-up. A major finding was that the MMP-9 and TIMP-1 levels remained significantly higher in the patients at all time points compared to the controls. MMP-9 and TIMP-1, but not MMP-2, MMP-3 or MMP-7, were related to inflammatory activity, as assessed by CRP and IL-6. MMP-9 and TIMP-1 showed significant correlation with evening cortisol, even after adjustment for CRP and IL-6, lending further support for a link between ´high´ flat cortisol rhythm and systemic inflammatory activity.

The activation status of neutrophils in stable CAD was further examined by measuring the expression, affinity state and signalling capacity of b2-integrins and the innate production of reactive oxygen species (ROS). However, the neutrophils in patients were not more activated in vivo than were cells in healthy controls, neither were they more prone to activation ex vivo. The data rather indicated an impaired function of neutrophils in stable CAD.

The neutrophils in CAD patients showed a significantly lower number of total glucocorticoid receptors (GRs) and a lower GRa:GRb ratio compared to healthy controls, indicating a chronic over activation of the HPA axis and, possibly, a state of glucocorticoid resistance. Moreover, the evening cortisol levels in patients were associated with an overexpression of annexin-1, the ´second messenger´ of glucocorticoid action. In contrast to neutrophils in controls, the neutrophils in patients also showed a hyper responsiveness to exogenous annexin-1 resulting in impaired neutrophil function.

To conclude, clinically stable CAD was associated with a systemic inflammatory activity, involving a high MMP-9:TIMP-1 ratio and an increased inflammatory response to acute stress but not any activation of neutrophils. This inflammatory activity was associated with a dysregulated cortisol secretion, defined by a flat diurnal rhythm and a blunted cortisol response to stress. Although the clinical relevance remains to be verified, an intriguing hypothesis is that a hyporesponsive HPA axis favours the development towards plaque instability.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2008. , 92 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1037
Keyword [en]
Coronary artery disease
National Category
Cardiac and Cardiovascular Systems Clinical Medicine
Identifiers
URN: urn:nbn:se:liu:diva-15978ISBN: 978-91-85895-00-7 (print)OAI: oai:DiVA.org:liu-15978DiVA: diva2:132574
Public defence
2008-02-01, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
Opponent
Supervisors
Note
On the day of the defence date the title of article III was: "A sustained elevation of serum matrix metalloproteinase-9 is associated with diurnal salivary cortisol in patients with acute myocardial infarction-a 3-month follow-up".Available from: 2009-03-12 Created: 2008-12-20 Last updated: 2010-01-12Bibliographically approved
List of papers
1. Circulating levels of proinflammatory cytokines and neutrophil-platelet aggregates in patients with coronary artery disease
Open this publication in new window or tab >>Circulating levels of proinflammatory cytokines and neutrophil-platelet aggregates in patients with coronary artery disease
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2005 (English)In: American Journal of Cardiology, ISSN 0002-9149, E-ISSN 1879-1913, Vol. 95, no 4, 452-456 p.Article in journal (Refereed) Published
Abstract [en]

Several lines of evidence indicate that increased inflammatory activity in peripheral blood is associated with the acute coronary syndrome. Systemic inflammation in clinically stable conditions of coronary artery disease has been less studied. We examined cytokine profiles in 20 patients who had acute coronary syndrome, 45 who had angiographically verified coronary artery disease and stable angina pectoris, and 45 healthy controls. Circulating levels of C-reactive protein, interleukin-1 receptor antagonist, interleukin-2 receptor, interleukin-6, interleukin-10, and interleukin-18 were determined. Subpopulations of peripheral immune cells, including neutrophil-platelet aggregates, were analyzed by 3-color flow cytometry using a panel of monoclonal antibodies. Patients who had acute coronary syndrome and stable angina pectoris had significantly higher levels of C-reactive protein, interleukin-6, and interleukin-1 receptor antagonist than did controls, whereas levels of interleukin-2 receptor, interleukin-10, and interleukin-18 were similar across groups. Patients had significantly more neutrophils, and the numbers of neutrophil-platelet aggregates were particularly large in patients who had stable angina pectoris. High levels of C-reactive protein, interleukin-6, and interleukin-1 receptor antagonist in patients were significantly related to numbers of neutrophils and neutrophil-platelet aggregates but not to other immune cell subpopulations. The data suggest that the interaction between neutrophils and platelets is an important component of proinflammatory activity seen in peripheral blood of stable and unstable forms of coronary artery disease.

Place, publisher, year, edition, pages
Elsevier, 2005
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17241 (URN)10.1016/j.amjcard.2004.10.009 (DOI)15695127 (PubMedID)
Available from: 2009-03-12 Created: 2009-03-12 Last updated: 2017-12-13Bibliographically approved
2. Impaired cortisol response to acute stressors in patients with coronary disease: Implications for inflammatory activity
Open this publication in new window or tab >>Impaired cortisol response to acute stressors in patients with coronary disease: Implications for inflammatory activity
2007 (English)In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 262, no 3, 375-384 p.Article in journal (Refereed) Published
Abstract [en]

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).

Methods: Thirty CAD patients were assessed 12-14 weeks after a first-time acute coronary syndrome. Serum samples were assayed for C-reactive protein (CRP) and interleukin-6. Free cortisol was measured in a 24-h urine sample and in repeated saliva samples 30 min after awakening and at bedtime. The levels of inflammatory markers and cortisol were also determined before and after standardized physical and psychological stress tests.

Results: The CAD patients had a higher 24-h cortisol secretion and a flattened diurnal slope, resulting from significantly higher cortisol levels at bedtime, compared to clinically healthy controls. The levels of evening cortisol were strongly related to inflammatory markers in serum. When exposed to acute physical and psychological stressors, the CAD patients showed a significantly blunted cortisol response compared to controls. In addition, a stress-induced increase in CRP was only observed in the patient group.

Conclusions: Patients with CAD exhibited a cortisol pattern that markedly differed from controls. The data indicate that a dysfunctional HPA axis response involves a failure to contain inflammatory activity in CAD patients, thus providing a possible link between stress and inflammation in disease.

Place, publisher, year, edition, pages
Blackwell Publishing Ltd, 2007
Keyword
Coronary artery disease, cortisol, inflammation, myocardial infarction, stress
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17242 (URN)10.1111/j.1365-2796.2007.01817.x (DOI)17697159 (PubMedID)
Available from: 2009-03-12 Created: 2009-03-12 Last updated: 2017-12-13
3. High serum matrix metalloproteinase-9 level is associated with diurnal salivary cortisol in patients with acute myocardial infarction - a 3-months follow-up
Open this publication in new window or tab >>High serum matrix metalloproteinase-9 level is associated with diurnal salivary cortisol in patients with acute myocardial infarction - a 3-months follow-up
(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are closely associated with inflammation and an increasing body of evidence suggests a role in coronary plaque rupture. We have recently shown that an impaired cortisol secretion is related to the enhanced inflammatory activity in patients with coronary disease. In the present paper, we studied the MMP profile in myocardial infarction (MI), its change over time and relation to diurnal salivary cortisol.

Methods: Thirty patients with a first-time MI were assessed at day 1-3, 2 weeks and 3 months. Serum samples were assayed for C-reactive protein (CRP), interleukin-6 (IL-6), MMP-9, MMP-2, MMP-3 and TIMP-1. Free cortisol was measured in a 24-h urine sample and in repeated saliva samples 30 minutes after awakening and in the evening.

Results: At 1-3 days, the patients showed increased levels of MMP-9, TIMP-1, IL-6 and CRP and decreased levels of MMP-2 compared to healthy controls. At 2 weeks and 3 months, the MMP-2, IL-6 and CRP levels in patients were similar to controls while the MMP-3 levels increased during follow-up. On the other hand, the levels of MMP-9 and TIMP-1 as well as the MMP-9/TIMP- ratio remained significantly increased in patients from the acute event to 3 months. At all time points, the MI patients showed a flat diurnal cortisol rhythm, as manifested by increased evening cortisol levels. At 2 weeks and 3 months, the evening salivary cortisol was an independent predictor of serum MMP-9 and TIMP-1, but not of MMP-2 or MMP-3.

Conclusion: In a 3-months follow-up of patients with acute MI, the serum MMP-9, TIMP-1 and MMP-9/TIMP- 1 ratio remined significantly elevated despite rapid normalizations of MMP-2, IL-6 and CRP. Moreover, MMP-9 and TIMP-1 showed a close association with a flat diurnal cortisol rhythm. The data indicate a link between imbalanced MMP pattern and dysfunctional cortisol response in coronary disease with potential implications for plaque progression.

Keyword
Myocardial infarction, coronary artery disease, cortisol, inflammation, matrix
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17245 (URN)
Available from: 2009-03-12 Created: 2009-03-12 Last updated: 2010-01-14
4. Neutrophil activation status in stable coronary artery disease.
Open this publication in new window or tab >>Neutrophil activation status in stable coronary artery disease.
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2007 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 2, no 10, e1056- p.Article in journal (Refereed) Published
Abstract [en]

Background: During the last years, neutrophils have emerged as important players in atherogenesis. They are highly activated in peripheral blood of patients with unstable angina. Moreover, a primed state of circulating neutrophils has been proposed in patients with stable angina. Our aim was to investigate the neutrophil activation status in patients with stable coronary artery disease (CAD) at conventional drug treatment.

Methodology and principal findings: Thirty patients with stable CAD and 30 healthy controls were included using a paired design. The neutrophil expression of CD18 and high-affinity state of CD11b was analysed by flow cytometry before and after stimulation with chemoattractants. Also, the production of reactive oxygen species (ROS) was determined by chemiluminescence. During basal conditions, the neutrophil expression of CD18 or high-affinity state of CD11b did not differ between patients and controls. Chemoattractants (Interleukin-8 and Leukotriene B(4)) did not increase either the expression or the amount of high-affinity CD11b/CD18-integrins in CAD patients compared to controls, and had no effect on the production of ROS. On the other hand, the ROS production in response to C3bi-opsonised yeast particles and the neutrophils' inherent capacity to produce ROS were both significantly decreased in patients.

Conclusion/Significance: We could not find any evidence that neutrophils in patients with stable CAD were primed, i.e. more prone to activation, compared to cells from healthy controls. According to our data, the circulating neutrophils in CAD patients rather showed an impaired activation status. It remains to be elucidated whether the neutrophil dysfunction in CAD is mainly a marker of chronic disease, an atherogenic factor or a consequence of the drug treatment.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17246 (URN)10.1371/journal.pone.0001056 (DOI)17957240 (PubMedID)
Available from: 2009-03-12 Created: 2009-03-12 Last updated: 2010-01-14
5. Enhanced Neutrophil Expression of Annexin-1 in Coronary Artery Disease
Open this publication in new window or tab >>Enhanced Neutrophil Expression of Annexin-1 in Coronary Artery Disease
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2010 (English)In: Metabolism: Clinical and Experimental, ISSN 0026-0495, E-ISSN 1532-8600, Vol. 59, no 3, 443-440 p.Article in journal (Refereed) Published
Abstract [en]

Background: A dysregulated cortisol response in patients with stable coronary artery disease (CAD) is related to systemic inflammatory activity. Moreover, a dysfunctional activation status of neutrophils in CAD has been discussed. The anti-inflammatory actions of glucocorticoids are mediated by annexin-1 (ANXA1), a protein mainly expressed by innate immune cells. An altered expression of glucocorticoid receptors (GR) and ANXA1 has been associated with glucocorticoid resistance.

Methods and Results: 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 neutrophil stimulation assays. The patients showed a flattened diurnal cortisol pattern compared to healthy subjects, involving higher levels in the evening. The neutrophil expression of GRtotal and GRα, as well as the ratio of GRα:GRβ expression was significantly decreased in patients, whereas the GRβ expression did not differ compared to controls. The neutrophil expression of ANXA1 was significantly increased in patients. Ex vivo, ANXA1 suppressed LTB4-induced ROS production in neutrophils from patients, but not from controls. On the other hand, ANXA1 impaired the LTB4-induced up-regulation of β2-integrins in both patients and controls.

Conclusion: CAD patients displayed a more flattened diurnal cortisol rhythm caused by higher cortisol levels in the evening compared to healthy subjects. Our findings indicate a chronic overactivation of the hypothalamic-pituitary-adrenal (HPA) axis but give no conclusive evidence for glucocorticoid resistance, as assessed by the neutrophil expression of GR and ANXA1. The data rather point towards an increased anti-inflammatory potential in neutrophils from patients with stable CAD.

Keyword
Coronary artery disease, cortisol, neutrophil, glucocorticoid receptor, annexin-1
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-17247 (URN)10.1016/j.metabol.2009.07.044 (DOI)000276761800021 ()
Note
Original Publication: Eva Särndahl, Ida Bergström, Johnny Nijm, Tony Forslund, Mauro Perretti and Lena Jonasson, Enhanced Neutrophil Expression of Annexin-1 in Coronary Artery Disease, 2010, Metabolism: Clinical and Experimental, (59), 3, 443-440. http://dx.doi.org/10.1016/j.metabol.2009.07.044 Copyright: Elsevier Science B.V., Amsterdam http://www.elsevier.com/ Available from: 2009-03-12 Created: 2009-03-12 Last updated: 2017-12-13

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