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Inflammatory response to acute mental stress is associated with altered cortisol reactivity and telomere shortening in patients with coronary artery disease
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Health Sciences.
Östergötlands Läns Landsting, Heart and Medicine Center, Department of Clinical Physiology in Linköping.
Linköping University, Department of Medical and Health Sciences, Division of Community Medicine. Linköping University, Faculty of Health Sciences.
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(English)Manuscript (preprint) (Other academic)
Abstract [en]

Background: Psychological stress and inflammation are both important risk factors for coronary artery disease (CAD). Susceptibility to mental stress-induced inflammation has been little explored in patients with CAD. Here, we investigated whether stress-induced inflammatory response, more precisely neutrophil activation, was associated with cortisol reactivity, leukocyte telomere length (TL) and carotid atherosclerotic burden in CAD.

Methods: Sixty-four patients with stable CAD underwent a laboratory stress test. Matrix metalloproteinase (MMP)-9, MMP-8, tissue inhibitors (TIMP)-1 and -2, myeloperoxidase (MPO) and salivary cortisol were measured before and 20 min after stress. Leukocyte TL was assessed as well as basal cortisol levels, background psychological factors and atherosclerosis in carotid arteries.

Results: The variation in stress-induced release of neutrophil markers was substantial. Patients were therefore divided into lower and upper tertiles depending on changes in serum MMP-9, T1: -12 %, T3: +27 %, with corresponding changes in MMP-8 and MPO. Clinical or psychological characteristics did not differ between groups, neither did basal levels of neutrophil markers or cortisol. Cardiovascular reactivity during stress was similar in T1 and T3, while cortisol declined after stress only in T3 (-30 %). Leukocyte TL was shorter in T3 than in T1, 0.78 vs 0.88, p = 0.006. Moreover, presence of plaques in right carotid artery differed between T1 and T3, 66 % vs 100 %, p = 0.004.

Conclusion: Stress-induced neutrophil activation in CAD patients was associated with altered cortisol reactivity, leukocyte telomere attrition and increased subclinical atherosclerosis. Data suggest that mental stress testing can identify high-risk patients in need of novel prevention and treatment strategies.

Keyword [en]
Stress, inflammation, matrix metalloproteinase, telomere length, cortisol, coronary artery disease
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-114326OAI: oai:DiVA.org:liu-114326DiVA: diva2:789275
Available from: 2015-02-18 Created: 2015-02-18 Last updated: 2015-02-18Bibliographically approved
In thesis
1. Leukocyte-derived matrix metalloproteinase-9 in patients with coronary artery disease: Associations with psychological stress and glucocorticoid sensitivity
Open this publication in new window or tab >>Leukocyte-derived matrix metalloproteinase-9 in patients with coronary artery disease: Associations with psychological stress and glucocorticoid sensitivity
2015 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Inflammation is closely associated with development of atherosclerosis. The proteolytic enzyme matrix metalloproteinase (MMP)-9 is considered to play a prominent role in this process. MMP-9 has also been introduced as a marker for plaque vulnerability. Still, the possible mechanisms behind altered levels of MMP-9 and its tissue inhibitors (TIMPs) in patients with atherosclerotic disease remain unclear. The general aim of this thesis was to compare leukocyte-derived MMP-9 and TIMPs in patients with coronary artery disease (CAD) and healthy controls and to further relate the findings to psychological stress and glucocorticoid sensitivity.

Levels of leukocyte-derived MMP-9 and TIMP-1 showed a significant difference between CAD patients and controls. Neutrophils in CAD patients were more prone to release MMP-9 and furthermore, PBMCs in patients expressed higher levels of MMP-9 and TIMP-1 and -2 mRNA than PBMCs in controls while there were no differences in plasma or serum levels. The increase in leukocyte-derived levels of MMP-9 and TIMPs indicate the presence of preactivated leukocytes in CAD.

Inflammation has been proposed as a mechanistic link between cardiovascular risk and depressive symptoms. We investigated whether the overexpression of leukocyte-derived MMP-9 and TIMPs in CAD patients was associated with psychological factors. Patients exhibited sustained elevations in depressive symptoms, however, these symptoms were not related to any MMP-9 or TIMP variables. The findings suggest that overexpression of leukocyte-derived MMP-9 and TIMPs and elevated depressive scores represent two parallel phenomena in CAD.

Chronic inflammation may be associated with reduced glucocorticoid sensitivity. We found that PBMCs in CAD patient expressed significantly increased levels of glucocorticoid receptor (GR)-α mRNA, whereas GR-β mRNA levels did not differ between patients and controls. Moreover, in ex vivo assays, dexamethasone efficiently suppressed MMP-9 and TIMPs equally or even more in patients compared to controls. The findings provide evidence for enhanced glucocorticoid sensitivity in CAD patients and also suggest that a state of relative hypocortisolism may contribute to the overexpression of leukocyte-derived MMP-9 and TIMPs.

Lastly, we explored the release of MMP-9, TIMPs and cortisol in response to acute mental stress in CAD patients. Patients who exhibited a significant stress-induced increase in serum MMP-9 also exhibited an altered cortisol response. Moreover, the susceptibility to stressinduced increase in serum MMP-9 was associated with shorter leukocyte telomere length and atherosclerotic plaque burden. The findings highlight the existence of a high-risk group which may be in need of improved diagnostic and therapeutic strategies.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2015. 72 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1438
National Category
Cardiac and Cardiovascular Systems Immunology in the medical area Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-114328 (URN)10.3384/diss.diva-114328 (DOI)978-91-7519-149-2 (ISBN)
Public defence
2015-03-20, Berzeliussalen, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Opponent
Supervisors
Available from: 2015-02-18 Created: 2015-02-18 Last updated: 2015-02-18Bibliographically approved

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Lundberg, Anna KJönsson, SimonZachrisson, HeleneKristenson, MargaretaJonasson, Lena

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Lundberg, Anna KJönsson, SimonZachrisson, HeleneKristenson, MargaretaJonasson, Lena
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Division of Cardiovascular MedicineFaculty of Health SciencesDepartment of Clinical Physiology in LinköpingDivision of Community MedicineDepartment of Cardiology in Linköping
Cell and Molecular Biology

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