Peter Garvin

Circulating Matrix Metalloproteinase-9 Is Associated with Cardiovascular Risk Factors in a Middle-Aged Normal Population

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.

Plasma Levels of Matrix Metalloproteinase-9 are Independently Associated With Psychosocial Factors in a Middle-Aged Normal Population

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. CAD = coronary artery disease; CES-D = Center for Epidemiological Studies Depression Questionnaire; CRP = C-reactive protein; HDL = high-density lipoprotein; IL = interleukin; IQR = interquartile range; LDL = low-density lipoprotein; LSH = Life conditions, Stress and Health; MMP-9 = matrix metalloproteinase-9; PHCC = Primary Health Care Centre; SOC = sense of coherence; SBP = systolic blood pressure; SD = standard deviation.

The role of saliva cortisol measurement in health and disease

This book is based on the wish to use saliva cortisol measurement because of its many advantages but frustrations over opposing results in the literature. Several discussions at different meetings led to the development of a network of researchers from Sweden, funded by the Swedish National Research Council. This network was soon expanded to also include colleagues from Norway and Denmark. The main aim of the group was to try to understand the results from different studies on saliva cortisol measurement and thereby better understand how and when saliva cortisol assessment best could be made. A hypothesis was that, seemingly, divergent findings could be effects of differences in the theoretic assumptions made and methods used. This led over to a decision to perform a literature review focusing on if the many different ways of evaluating the levels and dynamics of salivary cortisol especially with regard to time points of assessment and analyses of data affect the interpretation of cortisol measurement in various contexts.The aim of this book was to evaluate the usefulness of salivary cortisol as a biomarker in various settings. Our hypothesis was that observed diversities in results can be a function of different k ...The aim of the present chapter was to analyze whether measures of cortisol in saliva were associated with measures of sleep and to explore if divergent results were related to underlying differences in theoretic assumptions and methods. Measures of sleep quality included sleep duration, overall sleep quality, difficulty falling asleep, disturbed sleep, and sleep deprivation. Twenty-three papers were found to fulfil the inclusion criteria. Cortisol measures were grouped into single time points at different times during the day, deviations at different time periods during the day, reactivity and recovery after a standardized laboratory test, area under the curve and response to dexamethasone test. A large proportion of the studies included showed nonsignificant findings, which, in several cases, may be a result of low power. The most consistent results were a positive association between sleep duration and single measures of salivary cortisol at awakening, which was observed in 3 studies. In these studies, sleep duration was also associated with low evening cortisol levels, steep diurnal deviation of cortisol and/or high area under the curve. Together these findings suggest that longer sleep duration is related to a more dynamic cortisol secretion. Two of the 6 studies on disturbed or restless sleep showed relations to flat diurnal deviation and low laboratory stress test reactivity. This to some extent corroborates the findings on sleep duration. However, the many nonsignificant findings as well as the theoretical and methodological differences (e.g., heterogeneity in measures) complicate comparisons. Conflicting results may be at least partially due to differences in methods and underlying assumptions.

Provitamin A carotenoids are independently associated with matrix metalloproteinase-9 in plasma samples from a general population.

Abstract.  Rydén M, Garvin P, Kristenson M, Leanderson P, Ernerudh J, Jonasson L (Linköping University, Linköping, Sweden; Örebro University Hospital, Örebro, Sweden; University of British Colombia, Vancouver, BC, Canada). Provitamin A carotenoids are independently associated with matrix metalloproteinase‐9 in plasma samples from a general population. J Intern Med 2012; 272: 371–384.

Plasma Matrix Metalloproteinase-9 Levels Predict First-Time Coronary Heart Disease: An 8-Year Follow-Up of a Community-Based Middle Aged Population

Background The enzyme in matrix metalloproteinase (MMP)-9 has been suggested to be an important determinant of plaque degradation. While several studies have shown elevated levels in patients with coronary heart disease, results in prospective population based studies evaluating MMP-9 in relation to first time coronary events have been inconclusive. As of today, there are four published studies which have measured MMP-9 in serum and none using plasma. Measures of MMP-9 in serum have been suggested to have more flaws than measures in plasma. Aim To investigate the independent association between plasma levels of MMP-9 and first-time incidence of coronary events in an 8-year follow-up. Material and Methods 428 men and 438 women, aged 45–69 years, free of previous coronary events and stroke at baseline, were followed-up. Adjustments were made for sex, age, socioeconomic position, behavioral and cardiovascular risk factors, chronic disease at baseline, depressive symptoms, interleukin-6 and C-reactive protein. Results 53 events were identified during a risk-time of 6 607 person years. Hazard ratio (HR) for MMP-9 after adjustment for all covariates were HR = 1.44 (1.03 to 2.02, p = 0.033). Overall, the effect of adjustments for other cardiovascular risk factors was low. Conclusion Levels of plasma MMP-9 are independently associated with risk of first-time CHD events, regardless of adjustments. These results are in contrast to previous prospective population-based studies based on MMP-9 in serum. It is essential that more studies look at MMP-9 levels in plasma to further evaluate the association with first coronary events.

Hepatocyte growth factor in patients with coronary artery disease and its relation to periodontal condition

Hepatocyte growth factor (HGF) is an angiogenic, cardioprotective factor important for tissue and vascular repair. High levels of HGF are associated with chronic inflammatory diseases, such as coronary artery disease (CAD) and periodontitis, and are suggested as a marker of the ongoing atherosclerotic event in patients with CAD. Periodontal disease is more prevalent among patients with CAD than among healthy people. Recent studies indicate a reduced biological activity of HGF in different chronic inflammatory conditions. Biologically active HGF has high affinity to heparan sulfate proteoglycan (HSPG) on cell-membrane and extracellular matrix. The aim of the study was to investigate the serum concentration and the biological activity of HGF with ELISA and surface plasmon resonance (SPR), respectively, before and at various time points after percutaneous coronary intervention (PCI) in patients with CAD, and to examine the relationship with periodontal condition. The periodontal status of the CAD patients was examined, and the presence of P. gingivalis in periodontal pockets was analyzed with PCR. The HGF concentration was significantly higher, at all time-points, in patients with CAD compared to the age-matched controls (P< 0.001), but was independent of periodontal status. The HGF concentration and the affinity to HSPG adversely fluctuated over time, and the biological activity increased one month after intervention in patients without periodontitis. We conclude that elevated concentration of HGF but with reduced biological activity might indicate a chronic inflammatory profile in patients with CAD and periodontitis.

Exploring trends in and determinants of educational inequalities in self-rated health

Aims: Educational inequalities in self-rated health (SRH) in European welfare countries are documented, but recent trends in these inequalities are less well understood. We examined educational inequalities in SRH in different age groups, and the contribution of selected material, behavioural and psychosocial determinants from 2000 to 2008. Methods: Data were derived from cross-sectional surveys conducted in 2000, 2004 and 2008 including 37,478, 34,876 and 32,982 respondents, respectively, aged 25–75 in mid-Sweden. Inequalities were analysed by age-standardized and age-stratified rate ratios of poor SRH and age-standardized prevalence of determinants, and contribution of determinants by age-adjusted logistic regression. Results: Relative educational inequalities in SRH increased among women from 2000 (rate ratio (RR) 1.70, 95% CI 1.55–1.85) to 2008 (RR 2.07, 95% CI 1.90–2.26), but were unchanged among men (RR 1.91–2.01). The increase among women was mainly due to growing inequalities in the age group 25–34 years. In 2008, significant age differences emerged with larger inequalities in the youngest compared with the oldest age group in both genders. All determinants were more prevalent in low educational groups; the most prominent were lack of a financial buffer, smoking and low optimism. Educational differences were unchanged over the years for most determinants. In all three surveys, examined determinants together explained a substantial part of the educational inequalities in SRH. Conclusions: Increased relative educational health inequalities among women, and persisting inequalities among men, were paralleled by unchanged, large differences in material/structural, behavioural and psychosocial factors. Interventions to reduce these inequalities need to focus on early mid-life.

Psychological Resources Are Independently Associated with Markers of Inflammation in a Middle-Aged Community Sample

PurposeTo elucidate possible independent associations of psychological resources with inflammatory markers, all linked with coronary heart disease (CHD).MethodIn a middle-aged general population (n = 944), psychological resources (coping, self-esteem, and sense of coherence (SOC)), a global measure of quality of life (Cantril’s self-anchoring ladder, also called “ladder of life”), and psychological risk factors (hopelessness, vital exhaustion, and depressive symptoms) were used in linear regression models to evaluate associations with the inflammatory markers interleukin (IL)-6, C-reactive protein (CRP), and matrix metalloproteinase (MMP)-9. Adjustments were done for age, sex, medical conditions, and cardiovascular risk factors.ResultsAfter full adjustments, self-esteem was independently associated with all three biomarkers. Ladder of life was associated with IL-6 and log-CRP; coping, vital exhaustion, and depressive symptoms with IL-6; and SOC with MMP-9 (p < 0.05 for all associations).ConclusionNumerous significant associations of psychological resources and risk factors with IL-6, CRP, and MMP-9 were found in a community-based sample. The associations of psychological resources were mostly independent, while the psychological risk factors seemed preferentially dependent on lifestyle factors as smoking, physical activity, and body mass index (BMI). This suggests that the psychological resources’ (in particular self-esteem) protective effects on CHD are linked to inflammatory markers.

Socioeconomic differences in outpatient healthcare utilisation are mainly seen for musculoskeletal problems in groups with poor self-rated health

Aim: To assess whether there are socioeconomic (SES) differences in outpatient visits within groups of comparable morbidity (medical disease and self-rated health) and whether psychosocial factors can explain these differences. Methods: Baseline data for SES, presence of disease, self-rated health (SRH), and psychosocial factors were collected during 2003–04 from 923 men and women aged 45–69 years in southeast Sweden. Outcome data were all registered outpatient healthcare visits to physicians during 2004–08. Cumulative incidences and standardised rate ratios (SSR) were calculated for strata of comparable morbidity for all visits, for visits due to cardiovascular disorders (CVD)/diabetes and for musculoskeletal problems. Results: Low SES was associated with more outpatient visits due to musculoskeletal problems (SRR for education 1.52, 95% CI 1.35–1.73; for occupation 1.40, 95% CI 1.26–1.56) and accentuated in groups with poor SRH. The SES effect was significant for visits to primary care and to hospitals, for men and women, and independent of present disease, SRH, and psychosocial factors. Low SES was significantly associated with more total outpatient visits at primary healthcare centres. In contrast, for outpatient visits due to CVD/diabetes, high SES was related to more visits to hospitals among people with good SRH at baseline. Conclusions: We found a consistent pattern for outpatient visits related to musculoskeletal problems where people with low SES counted more visits and this was most prominent in groups of poor SRH. The results demonstrate the need to apply different morbidity measures when studying inequalities in healthcare utilisation.

Community-acquired pneumonia in primary care: clinical assessment and the usability of chest radiography

Abstract Objectives: To investigate the diagnostic value of different clinical and laboratory findings in pneumonia and to explore the association between the doctor’s degree of suspicion and chest X-ray (CXR) result and to evaluate whether or not CXR should be used routinely in primary care, when available. Design: A three-year prospective study was conducted between September 2011 and December 2014. Setting: Two primary care settings in Linköping, Sweden. Subjects: A total of 103 adult patients with suspected pneumonia in primary care. Main outcome measures: The physicians recorded results of a standardized medical physical examination, including laboratory results, and rated their suspicion into three degrees. The outcome of the diagnostic variables and the degree of suspicion was compared with the result of CXR. Results: Radiographic pneumonia was reported in 45% of patients. When the physicians were sure of the diagnosis radiographic pneumonia was found in 88% of cases (p < 0.001), when quite sure the frequency of positive CXR was 45%, and when not sure 28%. Elevated levels of C-reactive protein (CRP) ≥ 50mg/L were associated with the presence of radiographic pneumonia when the diagnosis was suspected (p < 0.001). Conclusion: This study indicates that CXR can be useful if the physician is not sure of the diagnosis, but when sure one can rely on one’s judgement without ordering CXR. Key points There are different guidelines but no consensus on how to manage community-acquired pneumonia in primary care. When the physician is sure of the diagnosis the judgement is reliable without chest X-ray and antibiotics can be safely prescribed. Chest X-ray can be useful in the assessment of pneumonia in primary care, when the physician is not sure of the diagnosis.