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High serum matrix metalloproteinase-9 level is associated with diurnal salivary cortisol in patients with acute myocardial infarction - a 3-months follow-up
Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
Östergötlands Läns Landsting, Heart Centre, Department of Cardiology. Linköping University, Department of Medicine and Health Sciences, Cardiology . Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart Centre, Department of Cardiology.
(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 [en]
Myocardial infarction, coronary artery disease, cortisol, inflammation, matrix
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-17245OAI: diva2:207754
Available from: 2009-03-12 Created: 2009-03-12 Last updated: 2010-01-14
In thesis
1. Inflammation and cortisol response i coronary artery disease
Open this publication in new window or tab >>Inflammation and cortisol response i coronary artery disease
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.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1037
Coronary artery disease
National Category
Cardiac and Cardiovascular Systems Clinical Medicine
urn:nbn:se:liu:diva-15978 (URN)978-91-85895-00-7 (ISBN)
Public defence
2008-02-01, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 13:00 (Swedish)
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

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