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Plasma levels of matrix metalloproteinase‐9 in a normal population: a psychoneuroendocrinological approach
Linköping University, Department of Medicine and Health Sciences. Linköping University, Faculty of Health Sciences.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Several large‐scale epidemiological studies have demonstrated the prognostic significance of psychosocial factors and stress for coronary artery disease (CAD). Observations of sudden changes in CAD incidence have led to the proposal of mechanisms regarding atherosclerotic plaque vulnerability. The collagen‐degrading enzyme matrix metalloproteinase-9 (MMP-9) is increased in rupture‐prone plaques with high inflammatory activity, and circulating levels of MMP-9 are raised in patients with acute coronary syndrome. However, the distribution of MMP‐9 levels and its relations to psychosocial factors and the stress hormone cortisol have not been previously explored in a normal population.The aim of this dissertation was to examine in a normal population the association of circulating levels of MMP-9 with traditional cardiovascular risk factors including levels of C-reactive protein (CRP), with psychosocial factors, and with saliva levels of cortisol. In addition, the reliability of a new method of ambulatory saliva sampling for assessment of cortisol levels was evaluated. A sub‐sample of the Life conditions, Stress, and Health (LSH)-study, a population based study exploring psychoneuroendocrinological pathways mediating the differences in CAD incidence over socioeconomic status, was used. Plasma levels of MMP-9 were examined in a sample randomly drawn from the LSH‐study (n=400), aged 45 to 69 years at enrollment.The main findings were: 1) there was a positive association between plasma MMP-9 levels and total risk load of cardiovascular risk factors. The findings were persistent after adjusting for CRP and could not be attributed to a single risk factor. 2) After adjusting for traditional cardiovascular risk factors and CRP, MMP-9 levels were positively associated with psychosocial risk factors and negatively associated with psychosocial resources. 3) Pooling saliva samples prior to laboratory analysis were as reliable as arithmetic means for assessment of diurnal cortisol variation in a field research setting. 4) There was a positive association between circulating levels of MMP‐9 and saliva levels of cortisol, both diurnal peak level and evening level of cortisol. The observed associations between MMP‐9 and traditional cardiovascular risk factors, psychosocial factors, and saliva cortisol levels suggest a psychoneuroendocrinological pathway linking stress to plaque vulnerability and provide increased understanding of the association between psychosocial factors and CAD.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press , 2008. , 131 p.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1072
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-14929ISBN: 978‐91‐7393‐831‐0 OAI: oai:DiVA.org:liu-14929DiVA: diva2:25621
Public defence
2008-10-03, Berzeliussalen, ingång 63, Campus US, Linköpings universitet, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2008-09-30 Created: 2008-09-30 Last updated: 2009-08-21Bibliographically approved
List of papers
1. Circulating Matrix Metalloproteinase-9 Is Associated with Cardiovascular Risk Factors in a Middle-Aged Normal Population
Open this publication in new window or tab >>Circulating Matrix Metalloproteinase-9 Is Associated with Cardiovascular Risk Factors in a Middle-Aged Normal Population
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2008 (English)In: PLoS ONE, ISSN 1932-6203, Vol. 3, no 3, e1774- p.Article in journal (Refereed) Published
Abstract [en]

Background: Elevated levels of circulating matrix metalloproteinase-9 (MMP-9) have been demonstrated in patients with established coronary artery disease (CAD). The aim of this study was to analyse levels of MMP-9 in a population free from symptomatic CAD and investigate their associations with cardiovascular (CV) risk factors, including C-reactive protein (CRP).

 

Methods: A cross-sectional study was performed in a population based random sample aged 45–69 (n = 345, 50% women). MMP-9 levels were measured in EDTA-plasma using an ELISA-method. CV risk factors were measured using questionnaires and standard laboratory methods.

Results: Plasma MMP-9 was detectable in all participants, mean 38.9 ng/mL (SD 22.1 ng/mL). Among individuals without reported symptomatic CAD a positive association (p<0.001) was seen, for both men and women, of MMP-9 levels regarding total risk load of eight CV risk factors i.e. blood pressure, dyslipidemia, diabetes, obesity, smoking, alcohol intake, physical activity and fruit and vegetable intake. The association was significant also after adjustment for CRP, and was not driven by a single risk factor alone. In regression models adjusted for age, sex, smoking, alcohol intake and CRP, elevated MMP-9 levels were independently positively associated with systolic blood pressure (p = 0.037), smoking (p<0.001), alcohol intake (p = 0.003) and CRP (p<0.001). The correlation coefficient between MMP-9 and CRP was r = 0.24 (p<0.001).

 

Conclusions: In a population without reported symptomatic CAD, MMP-9 levels were associated with total CV risk load as well as with single risk factors. This was found also after adjustment for CRP

 

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14925 (URN)10.1371/journal.pone.0001774 (DOI)
Note

Original Publication: Peter Garvin, Lennart Nilsson, John Carstensen, Lena Jonasson and Margareta Kristenson, Circulating Matrix Metalloproteinase-9 Is Associated with Cardiovascular Risk Factors in a Middle-Aged Normal Population, 2008, PLoS ONE, (3), 3, e1774. http://dx.doi.org/10.1371/journal.pone.0001774 Licensee: Public Library of Science (PLoS) http://www.plos.org/

Available from: 2008-09-30 Created: 2008-09-30 Last updated: 2014-01-10
2. Plasma Levels of Matrix Metalloproteinase-9 are Independently Associated With Psychosocial Factors in a Middle-Aged Normal Population
Open this publication in new window or tab >>Plasma Levels of Matrix Metalloproteinase-9 are Independently Associated With Psychosocial Factors in a Middle-Aged Normal Population
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2009 (English)In: PSYCHOSOMATIC MEDICINE, ISSN 0033-3174, Vol. 71, no 3, 292-300 p.Article in journal (Refereed) Published
Abstract [en]

Objective: To test the association between psychosocial factors and circulating levels of matrix metalloproteinase-9 (MMP-9) in a normal population sample. Psychosocial factors have been associated with inflammatory markers and are of prognostic significance for coronary artery disease (CAD). The degrading enzyme MMP-9 is upregulated in inflammatory processes and hypothesized to play a role in the rupture of atherosclerotic plaques. Methods: A total of 402 participants (50% women), aged 45 to 69 years, were drawn randomly from a normal population. Psychosocial instruments covered depression (Center for Epidemiological Studies Depression Questionnaire, CES-D), vital exhaustion, hostile affect, cynicism, mastery, self-esteem, sense of coherence (SOC), emotional support, and social integration. Plasma MMP-9 was measured by an enzyme-linked immunosorbent assay method. Linear regression models were adjusted for age, sex, known CAD, rheumatoid arthritis, cancer, cardiovascular risk factors including C-reactive protein and ongoing medication. Results: After full adjustment, there were independent associations of elevated MMP-9 levels with CES-D (+2.9 ng/ml per SD, p=.02), hostile affect (+3.0 ng/ml per SD, p=.02), cynicism (+3.5 ng/ml per SD, p=.006), and SOC (-2.5 ng/ml per SD, p=.046). A principal component analysis extracted three components. The first was mainly extracted from CES-D, vital exhaustion, self-esteem, mastery, and SOC; the second was mainly extracted from hostile affect and cynicism. Both were independently associated with MMP-9 (p=.02, p=.04) when run in the same model. Conclusions: MMP-9 levels were associated with psychosocial factors in a middle-aged normal population sample, independently of traditional risk factors. The findings may constitute a possible link between psychosocial factors and cardiovascular risk.

Keyword
depression, hostile affect, cynicism, sense of coherence, metalloproteinases, cardiovascular
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-18140 (URN)10.1097/PSY.0b013e3181960e7f (DOI)
Note
This is a non-final version of an article published in final form: Peter Garvin, Lennart Nilsson, John Carstensen, Lena Jonasson and Margareta Kristenson , Plasma Levels of Matrix Metalloproteinase-9 are Independently Associated With Psychosocial Factors in a Middle-Aged Normal Population, 2009, PSYCHOSOMATIC MEDICINE, (71), 3, 292-300. http://dx.doi.org/10.1097/PSY.0b013e3181960e7f Copyright: Lippincott, Williams & Wilkins http://www.lww.com/ Available from: 2009-05-14 Created: 2009-05-08 Last updated: 2009-08-18Bibliographically approved
3. Pooling ambulatory saliva cortisol samples over consecutive days – as reliable as arithmetic means
Open this publication in new window or tab >>Pooling ambulatory saliva cortisol samples over consecutive days – as reliable as arithmetic means
2008 (English)In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 68, no 6, 508-512 p.Article in journal (Refereed) Published
Abstract [en]

Objective: When cortisol measurements are to be studied in large populations, cost-effective analyses are needed. This study aimed at testing whether one pooled cortisol value over three consecutive days is as reliable as using the arithmetic mean of the samples from the same measure points.

Material and methods: Thirty participants aged between 45 and 69 collected saliva in salivettes immediately after awakening (t1), 30 min after awakening (t2) and in the evening (t3) during 3 consecutive days. A fixed volume from each of the samples (t1, t2 and t3) was pooled prior to laboratory analysis. Mean levels over 3 days for t1, t2 and t3 were compared to corresponding levels of pooled vials. Cortisol levels were analysed using a radio immunoassay.

Results: All measures tested had high correlations between mean values and pooled samples, exemplified with diurnal deviation rdif t2–t350.974 (CI 0.946;0.987), and awakening response rdif t2–t150.982 (CI 0.963;0.991). There were no statistical differences between the pooled values and the arithmetic means.

Conclusion: Pooling samples gave as reliable results as arithmetic means did. Pooling samples prior to laboratory analysis is a cost-effective method for measuring general diurnal cortisol variation in field research projects.

Keyword
Cortisol, HPA-axis, measurements, methodology, saliva, stress
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14927 (URN)10.1080/00365510701832229 (DOI)
Note

Original publication: Peter Garvin, John Carstensen and Margareta Kristenson, Pooling ambulatory saliva cortisol samples over consecutive days – as reliable as arithmetic means, 2008, Scandinavian Journal of Clinical and Laboratory Investigation, (68), 6, 508-512. http://dx.doi.org/10.1080/00365510701832229. Copyright © Taylor & Francis Group, an informa business

Available from: 2008-09-30 Created: 2008-09-30 Last updated: 2017-12-13
4. Association between ambulatory saliva cortisol levels and plasma levels of matrix metalloproteinase-9 in a normal population
Open this publication in new window or tab >>Association between ambulatory saliva cortisol levels and plasma levels of matrix metalloproteinase-9 in a normal population
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(English)Manuscript (Other academic)
Abstract [en]

Background: Psychosocial strain has been demonstrated to be a risk factor for coronary artery disease (CAD) and also to be associated with a dysfunctional HPA-axis. Based on a proposal on cortisol resistance in maladaptive monocytes as a potential mechanism linking psychosocial strain with CAD, this study aimed at testing the association between levels of salivary cortisol and matrix metalloproteinase-9 (MMP-9) in a normal population.

Methods: 359 participants (50 % women) aged 45-69 were enrolled to this study, randomly drawn from a normal population in Sweden. Saliva samples were collected thrice per day (at awakening, 30 minutes after awakening, and just before going to bed) during three consecutive days. Cortisol levels at awakening and 30 minutes after awakening were used to estimate the diurnal peak. Cortisol was analyzed using a radioimmunoassay method. MMP-9 was measured in plasma using an ELISA-method.

Results: After adjustment for age and sex, significant trends regarding MMP-9 were found both for cortisol peak quintiles (beta +1.9 ng/mL per quintile, p=0.029) and cortisol evening values (beta +2.1 ng/ml per quintile, p=0.017). These findings were consistent in regressions either excluding participants with known diagnoses of myocardial infarction, angina pectoris, rheumatoid arthritis, diabetes, cancer with ongoing treatment, chronic obstructive lung disease, osteoporosis and hypothyroidism, or adjusting for these diseases, also after adjustment for cardiovascular risk factors.

Conclusions: The associations found between cortisol levels and MMP-9 in a normal population hint at a potential pathway linking prolonged psychosocial strain with cardiovascular events.

Keyword
Cardiovascular, cortisol, HPA‐axis, metalloproteinases, inflammation
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-14928 (URN)
Available from: 2008-09-30 Created: 2008-09-30 Last updated: 2010-01-14

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