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1.
  • Garvin, Peter, 1976- (författare)
  • Plasma levels of matrix metalloproteinase‐9 in a normal population : a psychoneuroendocrinological approach
  • 2008
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • 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.
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2.
  • af Geijerstam, Peder, Doktorand, 1983-, et al. (författare)
  • P-selectin and C-reactive protein in relation to home blood pressure and coronary calcification: a SCAPIS substudy
  • 2024
  • Ingår i: Journal of Hypertension. - : Lippincott Williams & Wilkins. - 0263-6352 .- 1473-5598.
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Soluble P-selectin (sP-selectin) and high-sensitivity C-reactive protein (hsCRP) have previously been associated with hypertension, but the relation with out-of-office blood pressure (BP) and coronary artery calcification score is unknown. We aimed to examine the relationship between sP-selectin, hsCRP and home BP, as well as coronary artery calcification score and carotid artery plaques.Methods: In the Swedish CArdioPulmonary bioImage Study (SCAPIS), 5057 randomly selected participants were evaluated with office and home BP using the semi-automatic Omron M10-IT device. For this cross-sectional study, participants with sP-selectin <4 standard deviations above mean and hsCRP <5 mg/l, representing low-grade inflammation, were included. Using generalized linear models, these inflammatory markers were evaluated in relation to BP classifications, as well as coronary artery calcification score and carotid artery plaques.Results: Of participants, 4548 were included in the analyses. The median age was 57.2 (53.4–61.2) years, and 775 (17.0%) reported taking medication for hypertension. Participants in the highest quartile of sP-selectin [odds ratio (OR) 1.67, 95% confidence interval (CI) 1.40–1.98, P < 0.001] and hsCRP [OR 2.25, (95% CI 1.89–2.60), P < 0.001] were more likely to have sustained hypertension. Participants in the highest quartile of hsCRP were also more likely to have masked hypertension, OR (95% CI) 2.31 (1.72–3.10), P < 0.001 and carotid artery plaques, OR (95% CI) 1.21 (1.05–1.38), P = 0.007.Conclusion: Increased sP-selectin and hsCRP were independently associated with sustained hypertension. These findings indicate an association between hypertension and platelet activity, as expressed by sP-selectin.
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3.
  • Alfredsson, Joakim, et al. (författare)
  • Individual long-term variation of platelet reactivity in patients with dual antiplatelet therapy after myocardial infarction.
  • 2019
  • Ingår i: Platelets. - : Informa UK Limited. - 0953-7104 .- 1369-1635. ; 30:5, s. 572-578
  • Tidskriftsartikel (refereegranskat)abstract
    • There is a large inter-individual variation in response to clopidogrel treatment, and previous studies have indicated higher risk of thrombotic events in those with high residual platelet reactivity (HPR). Less is known about individual variation over time. The aim of this prospective cohort study was to investigate intra-individual variation in platelet reactivity. Platelet aggregation in whole blood was assessed in 77 patients, at 3 days, 8 days and 6 months after admission for acute myocardial infarction and loading dose of clopidogrel. All patients were treated with aspirin and clopidogrel through 6-month follow-up. We found a significant increase in median ADP-stimulated aggregation from third to eighth day (195 vs. 250 AU*min, p-value = 0.001) but not from day 8 to 6 months (250 vs. 223 AU*min, p-value = 0.666). There was no significant change in the overall rate of HPR (15.6% vs 20.8%, p-value 0.503) or low platelet reactivity (LPR) (37.7% vs 33.8%, p-value = 0.609) from day 8 to 6-month follow-up. In contrast, more than one in four changed HPR status, 15.6% from non-HPR to HPR and 10.4% HPR to non-HPR. A shift in LPR status appeared even more frequent, occurring in about one of three patients. In spite of similar median aggregation and rate of HPR during 6-month follow-up, about one in four of the patients changed HPR status and one in three changed LPR status. This may be important information for a concept of risk stratification based on a single aggregation value early after an acute coronary syndromes.
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4.
  • Alfredsson, Joakim, et al. (författare)
  • Large early variation of residual platelet reactivity in Acute Coronary Syndrome patients treated with clopidogrel : Results from Assessing Platelet Activity in Coronary Heart Disease (APACHE).
  • 2015
  • Ingår i: Thrombosis Research. - : Pergamon Press. - 0049-3848 .- 1879-2472. ; 136:2, s. 335-340
  • Tidskriftsartikel (refereegranskat)abstract
    • INTRODUCTION: There is a large inter-individual variation in response to clopidogrel treatment and previous studies have indicated higher risk of thrombotic events in patients with high residual platelet reactivity (HRPR), but the optimal time-point for testing is not established. The aim of this study was to investigate the optimal time-point for aggregometry testing and the risk of major adverse cardiac events associated with HRPR.METHOD AND RESULTS: We included 125 patients with ACS (73 with STEMI, and 71 received abciximab). The prevalence of HRPR varied substantially over time. The rate of HRPR in patients treated and not treated with abciximab were 43% vs 67% (p=0.01) before, 2% vs 23% (p=0.001) 6-8h after, 8% vs 9% (p=0.749) 3days after, and 23% vs 12% (p=0.138) 7-9 days after loading dose of clopidogrel. We found HRPR in 18% of the patients but only four ischemic events during 6months follow-up, with no significant difference between HRPR patients compared to the rest of the population. There were 3 TIMI major bleedings, all of which occurred in the low residual platelet reactivity (LRPR) group.CONCLUSION: There is a large variation in platelet reactivity over time, also depending on adjunctive therapy, which has a large impact on optimal time-point for assessment. We found HRPR in almost 1 in 5 patients, but very few MACE, and not significantly higher in HRPR patients. In a contemporary ACS population, with low risk for stent thrombosis, the predictive value of HRPR for ischemic events will probably be low.
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6.
  • Andresen, Louise C., et al. (författare)
  • Seasonal changes in nitrogen availability, and root and microbial uptake of (15)N(13)C(9)-phenylalanine and (15)N-ammonium in situ at a temperate heath
  • 2011
  • Ingår i: Applied Soil Ecology. - : Elsevier BV. - 0929-1393. ; 51, s. 94-101
  • Tidskriftsartikel (refereegranskat)abstract
    • In the plant biosynthesis of secondary compounds, phenylalanine is a precursor of condensed tannins. Tannins are deposited into the soil in plant root exudates and dead plant material and have been suggested to precipitate some soil nutrients and hence reduce nutrient availability for plants. Free amino acid, inorganic and microbial N concentration during the growing season was investigated in an ecosystem with a natural tannin chemosphere. The influence of tannins on the uptake of nitrogen in plants and microbes was followed by injecting tannic acid (TA), ammonium-(15)N and phenylalanine-(15)N/(13)C(9). Plants preferred ammonium over phenylalanine, while microbes had no preference. Soil microbes had a 77% uptake of intact phenylalanine. Phenylalanine was acquired intact by both grasses and Calluna, with 63% and 38% uptake of intact phenylalanine in grass fine roots and Calluna roots, respectively. Inorganic N and amino acid concentrations were lowest in the period with highest plant activity and grass root biomass but were unaffected by TA addition. (C) 2011 Elsevier B.V. All rights reserved.
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7.
  • Andresen, Louise C., et al. (författare)
  • Uptake of pulse injected nitrogen by soil microbes and mycorrhizal and non-mycorrhizal plants in a species-diverse subarctic heath ecosystem
  • 2008
  • Ingår i: Plant and Soil. - : Springer Science and Business Media LLC. - 0032-079X .- 1573-5036. ; 313:1-2, s. 283-295
  • Tidskriftsartikel (refereegranskat)abstract
    • N-15 labeled ammonium, glycine or glutamic acid was injected into subarctic heath soil in situ, with the purpose of investigating how the nitrogen added in these pulses was subsequently utilized and cycled in the ecosystem. We analyzed the acquisition of N-15 label in mycorrhizal and non-mycorrhizal plants and in soil microorganisms, in order to reveal probable differences in acquisition patterns between the two functional plant types and between plants and soil microorganisms. Three weeks after the label addition, with the N-15-forms added with same amount of nitrogen per square meter, we analyzed the N-15-enrichment in total soil, in soil K2SO4 (0.5 M) extracts and in the microbial biomass after vacuum-incubation of soil in chloroform and subsequent K2SO4 extraction. Furthermore the N-15-enrichment was analyzed in current years leaves of the dominant plant species sampled three, five and 21 days after label addition. The soil microorganisms had very high N-15 recovery from all the N sources compared to plants. Microorganisms incorporated most N-15 from the glutamic acid source, intermediate amounts of N-15 from the glycine source and least N-15 from the NH4+ source. In contrast to microorganisms, all ten investigated plant species generally acquired more N-15 label from the NH4+ source than from the amino acid sources. Non-mycorrhizal plant species showed higher concentration of N-15 label than mycorrhizal plant species 3 days after labeling, while 21 days after labeling their acquisition of N-15 label from amino acid injection was lower than, and the acquisition of N-15 label from NH4 injection was similar to that of the mycorrhizal species. We conclude that the soil microorganisms were more efficient than plants in acquiring pulses of nutrients which, under natural conditions, occur after e. g. freeze-thaw and dry rewet events, although of smaller size. It also appears that the mycorrhizal plants in the short term may be less efficient than non-mycorrhizal plants in nitrogen acquisition, but in a longer term show larger nitrogen acquisition than non-mycorrhizal plants. However, the differences in N-15 uptake patterns may also be due to differences in leaf longevity and woodiness between plant functional groups.
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8.
  • Backteman, Karin, et al. (författare)
  • Cytomegalovirus seropositivity is a major determinant of CD28null T cell expansion in patients with coronary artery disease
  • 2014
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Objective: Accumulation of CD4+28null cells, with a proinflammatory and senescent phenotype, has been associated with unstable conditions of coronary artery disease (CAD). Human cytomegalovirus (HCMV) is known to exert profound effects on T cells, including loss of CD28. Here, we longitudinally assessed the proportions of CD28null and CD28nullCD57+ cells in CD4+ and CD8+ T cell populations of patients with CAD and related the findings to HCMV seropositivity.Methods: HCMV antibody levels and expression of CD28 and CD57 on CD4+ and CD8+ T cells were analysed in 31 patients with acute coronary syndrome (ACS), 34 patients with stable angina (SA) and 37 healthy controls. Samples were taken prior to 34 coronary angiography and after 3 and 12 months. In a subsample, HCMV-specific IFN-γ and  TNF production was assessed ex vivo.Results: Increased proportions of CD4+CD28null, but not CD8+CD28null cells, were significantly associated with presence of CAD. Significant increases in CD28null 37 and CD28nullCD57+ cells occurred within CD4+ and CD8+ T cell compartments in both ACS and SA patients during 12-month follow-up. HCMV was the major determinant of CD28null and CD28nullCD57+ T cell levels in both patients and controls (p <0.001). There were no obvious signs of CMV reactivation in patients.Conclusion: HCMV was a major determinant of the presence of CD28null and CD28nullCD57+ T cells in patients with CAD, independent of clinical stage. Findings also indicate that HCMV might have a large impact on the T cell aging process that occurred in patients after a cardiac event.
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9.
  • Backteman, Karin, et al. (författare)
  • Lymphocyte Subpopulations in Lymph Nodes and Peripheral Blood: A Comparison between Patients with Stable Angina and Acute Coronary Syndrome
  • 2012
  • Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 7:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: Atherosclerosis is characterized by a chronic inflammatory response involving activated T cells and impairment of natural killer (NK) cells. An increased T cell activity has been associated with plaque instability and risk of acute cardiac events. Lymphocyte analyses in blood are widely used to evaluate the immune status. However, peripheral blood contains only a minor proportion of lymphocytes. In this study, we hypothesized that thoracic lymph nodes from patients with stable angina (SA) and acute coronary syndrome (ACS) might add information to peripheral blood analyses. less thanbrgreater than less thanbrgreater thanMethods: Peripheral blood and lymph nodes were collected during coronary by-pass surgery in 13 patients with SA and 13 patients with ACS. Lymphocyte subpopulations were assessed by flow cytometry using antibodies against CD3, CD4, CD8, CD19, CD16/56, CD25, Foxp3, CD69, HLA-DR, IL-18 receptor (R) and CCR4. less thanbrgreater than less thanbrgreater thanResults: Lymph nodes revealed a lymphocyte subpopulation profile substantially differing from that in blood including a higher proportion of B cells, lower proportions of CD8(+) T cells and NK cells and a 2-fold higher CD4/CD8 ratio. CD4(+)CD69(+) cells as well as Foxp3(+) regulatory T cells were markedly enriched in lymph nodes (p andlt; 0.001) while T helper 1-like (CD4(+)IL-18R(+)) cells were more frequent in blood (p andlt; 0.001). The only significant differences between ACS and SA patients involved NK cells that were reduced in the ACS group. However, despite being reduced, the NK cell fraction in ACS patients contained a significantly higher proportion of IL-18R(+) cells compared with SA patients (p andlt; 0.05). less thanbrgreater than less thanbrgreater thanConclusion: There were several differences in lymphocyte subpopulations between blood and lymph nodes. However, the lymphocyte perturbations in peripheral blood of ACS patients compared with SA patients were not mirrored in lymph nodes. The findings indicate that lymph node analyses in multivessel coronary artery disease may not reveal any major changes in the immune response that are not detectable in blood.
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11.
  • Backteman, Karin, et al. (författare)
  • Natural killer (NK) cell deficit in coronary artery disease: no aberrations in phenotype but sustained reduction of NK cells is associated with low-grade inflammation
  • 2014
  • Ingår i: Clinical and Experimental Immunology. - : Wiley-Blackwell. - 0009-9104 .- 1365-2249. ; 175:1, s. 104-112
  • Tidskriftsartikel (refereegranskat)abstract
    • Although reduced natural killer (NK) cell levels have been reported consistently in patients with coronary artery disease (CAD), the clinical significance and persistence of this immune perturbation is not clarified. In this study we characterized the NK cell deficit further by determining (i) differentiation surface markers and cytokine profile of NK cell subsets and (ii) ability to reconstitute NK cell levels over time. Flow cytometry was used to analyse NK cell subsets and the intracellular cytokine profile in 31 patients with non-ST elevation myocardial infarction (non-STEMI), 34 patients with stable angina (SA) and 37 healthy controls. In blood collected prior to coronary angiography, the proportions of NK cells were reduced significantly in non-STEMI and SA patients compared with controls, whereas NK cell subset analyses or cytokine profile measurements did not reveal any differences across groups. During a 12-month follow-up, the proportions of NK cells increased, although not in all patients. Failure to reconstitute NK cell levels was associated with several components of metabolic syndrome. Moreover, interleukin (IL)-6 levels remained high in patients with sustained NK cell deficit, whereas a decline in IL-6 (P < 0·001) was seen in patients with a pronounced increase in NK cells. In conclusion, we found no evidence that reduction of NK cells in CAD patients was associated with aberrations in NK cell phenotype at any clinical stage of the disease. Conversely, failure to reconstitute NK cell levels was associated with a persistent low-grade inflammation, suggesting a protective role of NK cells in CAD.
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12.
  • Backteman, Karin, 1960- (författare)
  • T Cells and NK Cells in Coronary Artery Disease : Longitudinal and methodological studies in humans
  • 2014
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Coronary artery disease (CAD) is the leading cause of death worldwide and most often due to atherosclerosis. Atherosclerosis is a chronic inflammatory process that involves the arteries, inclouding those that supply blood to the heart muscle. Although inflammation is an important contributing factor to atherosclerosis, the mechanisms are not fully understood. One mechanism contributing to atherogenesis may involve some infectious microorganisms such as cytomegalovirus (CMV). In atherosclerosis, the arterial wall becomes infiltrated with lipids followed by different types of leukocytes and inflammatory mediators (atherogenesis). Leukocytes recirculate continuously between the blood and lymphoid organs, such as lymph nodes, where the adaptive immune response is started and regulated.The general aim of this thesis was to increase the understanding of associations between lymphocyte populations and different conditions of CAD (unstable and stable). To assess changes over time, a longitudinal follow up design was mostly used. Therefore, also perspectives of longitudinal variation were included in the thesis.Paper I showed that flow cytometric evaluation of lymphocyte populations is a robust technique that can be used in longitudinal studies, both in clinical and research settings. It was also shown that the time of sampling over the year did not have a major impact on the findings.In paper II, thoracic lymph nodes were investigated to assess whether CAD-associated changes were more prominent in comparison with blood. As expected, there were several major differences in lymphocyte composition between lymph nodes and blood. However, the analysis of thoracic lymph nodes did not reveal any further changes that were not detected in blood. Thus, blood is still the most reliable compartment for studies of lymphocyte populations in CAD since it is not possible to examine the local findings in the artery wall.Natural killer (NK) cells are innate lymphocytes with both regulatory and effector functions. In paper II and III we confirmed previous findings that CAD patients have lower proportions of NK cells in blood. However, the NK subtype and cytokine profile (paper III, measured by subtype markers and intra-cellular cytokine staining) did not differ between patients and controls. During a 12-month follow-up, the proportions of NK cells increased, although not in all patients. Failure to reconstitute NK cell levels was associated with several components of the metabolic syndrome and with a persistent low-grade inflammation as measured by plasma IL-6 levels. The findings support the notion of a protective role for NK cells in inflammation.CD4+ but not CD8+ T cells were significantly increased in patients with both unstable and stable conditions compared with healthy individuals (paper IV). Subpopulations of CD4+ T cells (CD4+CD28null) have previously been associated with CAD. However, we show that CD28null and CD28null57+ cells within the CD4+ and CD8+ T cell populations were similar in CAD patients and healthy controls. Instead, CMV seropositivity was the major determinant of expanded CD28null and CD57+ T cell fractions in both patients and healthy individuals. During the 1 year follow up the proportion of CD4+CD28null and CD8+CD28null cells increased in patients, which may reflect an accelerated immunological ageing occurring after the cardiac event.
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13.
  • Becriovic-Agic, Mediha (författare)
  • Susceptibility to Acute Decompensated Heart Failure in Two Common Mouse Strains
  • 2019
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Heart failure is a clinical syndrome characterized by an inability of the heart to meet oxygen demands of the body. During the initial stage of heart failure development compensatory mechanisms are activated to help the heart sustain proper function. Over time these compensatory mechanisms become inadequate resulting in decompensation. Acute decompensated heart failure is characterized by rapidly escalating heart failure symptoms, such as dyspnea and congestion, which require urgent treatment. The pathophysiology of decompensation and role of genetic background on this process is not completely understood.  The aim of this thesis was to investigate the role of genetic background on susceptibility to develop acute decompensated heart failure.Balb/CJ and C57BL/6J mice are two common mouse strains that we found have different susceptibility to angiotensin II and high-salt diet (AngII+Salt) induced decompensation. Balb/CJ treated with AngII+Salt develop massive edema associated with anuria and high mortality within 4-6 days of treatment, while C57BL/6J mice do not. Due to the clinical symptoms of heart failure we hypothesized that Balb/CJ develop acute decompensated heart failure, and that the genetic background of this strain is responsible for the increased susceptibility to heart failure. AngII+Salt increased pulmonary and systemic vascular resistance, reduced left ventricle filling, and increased sodium and water retention in Balb/CJ mice. Increased pulmonary vascular resistance correlated with a higher angiotensin II response in isolated pulmonary arteries from Balb/CJ compared to C57BL/6J. Cardiac output was lower in Balb/CJ than C57BL/6J during AngII+Salt treatment even though they retained more sodium and water. This indicated that AngII+Salt impairs cardiac function in Balb/CJ mice. Oxidative stress was shown to play a role in AngII+Salt induced acute decompensation since treatment with an antioxidant reduced oxidative stress but impaired cardiac function and increased mortality in both strains. A linkage study was performed to reveal genes that are with high probability related to AngII+Salt induced decompensation in Balb/CJ mice. Quantative trait loci (QTLs) on chromosome 3 and 12 were linked to cardiac dysfunction and QTLs on chromosome 2 and 3 were linked to sodium and fluid balance. Foxo1 was found to be one of candidate genes for further study.Taken together, the data in this thesis shows that genetic background does play a large role in the development of acute decompensated heart failure. It reveals several candidate genes that could be studied in the setting of acute decompensated heart failure. Finally, it describes a new mouse model that could potentially be used for studying the pathophysiology of decompensation and identifying new drug targets.
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14.
  • Bergström, Göran, et al. (författare)
  • Self-Report Tool for Identification of Individuals With Coronary Atherosclerosis : The Swedish CardioPulmonary BioImage Study
  • Ingår i: Journal of the American Heart Association. - 2047-9980. ; , s. 1-13
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: Coronary atherosclerosis detected by imaging is a marker of elevated cardiovascular risk. However, imaging involves large resources and exposure to radiation. The aim was, therefore, to test whether nonimaging data, specifically data that can be self-reported, could be used to identify individuals with moderate to severe coronary atherosclerosis.METHODS AND RESULTS: We used data from the population-based SCAPIS (Swedish CardioPulmonary BioImage Study) in individuals with coronary computed tomography angiography (n=25 182) and coronary artery calcification score (n=28 701), aged 50 to 64 years without previous ischemic heart disease. We developed a risk prediction tool using variables that could be assessed from home (self-report tool). For comparison, we also developed a tool using variables from laboratory tests, physical examinations, and self-report (clinical tool) and evaluated both models using receiver operating characteristic curve analysis, external validation, and benchmarked against factors in the pooled cohort equation. The self-report tool (n=14 variables) and the clinical tool (n=23 variables) showed high-to-excellent discriminative ability to identify a segment involvement score ≥4 (area under the curve 0.79 and 0.80, respectively) and significantly better than the pooled cohort equation (area under the curve 0.76, P<0.001). The tools showed a larger net benefit in clinical decision-making at relevant threshold probabilities. The self-report tool identified 65% of all individuals with a segment involvement score ≥4 in the top 30% of the highest-risk individuals. Tools developed for coronary artery calcification score ≥100 performed similarly. CONCLUSIONS: We have developed a self-report tool that effectively identifies individuals with moderate to severe coronary atherosclerosis. The self-report tool may serve as prescreening tool toward a cost-effective computed tomography-based screening program for high-risk individuals.
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16.
  • Bergström, Ida, et al. (författare)
  • Annexin A1 expression in blood mononuclear cells : a potential marker of glucocorticoid activity in patients with coronary artery disease
  • 2014
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • An imbalance between pro- and anti-inflammatory actions is believed to drive progression of atherosclerosis. Annexin A1 (AnxA1) is a key player in resolution of inflammation and a mediator of anti-inflammatory effects of glucocorticoids. Here, we investigated whether expression of AnxA1 in peripheral blood mononuclear cells (PBMCs) was altered in patients with coronary artery disease (CAD) and also related findings to glucocorticoid sensitivity ex vivo.We included 57 patients 6-12 months after acute coronary syndrome (ACS), 10 patients with ACS, and healthy controls. AnxA1 mRNA was measured in PBMCs and AnxA1 protein was assessed in monocytes and lymphocyte subsets by flow cytometry. In post-ACS patients and controls, glucocorticoid sensitivity was determined by measuring inhibitory effects of dexamethasone on LPS46 induced cytokine secretion.AnxA1 mRNA levels in PBMCs were higher in patients compared with controls, although most pronounced in ACS patients. AnxA1 protein was most abundant in the monocyte fraction. ACS patients exhibited the highest levels of cell surface-associated AnxA1 protein while levels in post-ACS patients and controls were similar. Ex vivo assays showed that PBMCs from post-ACS patients were more prone to release IL-6. Glucocorticoid sensitivity correlated with cell surface-associated AnxA1 protein in peripheral monocytes. Dexamethasone also induced upregulation of AnxA1 mRNA.AnxA1 expression in PBMCs is closely associated with glucocorticoid actions and cell surface associated AnxA1 appears to be a marker of glucocorticoid sensitivity. Although still speculative, a “normal” expression of cell surface-associated AnxA1 in post-ACS patients may suggest that glucocorticoid actions in vivo are insufficient to provide adequate anti-inflammatory effects in these patients.
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17.
  • Bergström, Ida, et al. (författare)
  • Annexin A1 in blood mononuclear cells from patients with coronary artery disease : Its association with inflammatory status and glucocorticoid sensitivity
  • 2017
  • Ingår i: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 12:3
  • Tidskriftsartikel (refereegranskat)abstract
    • Annexin A1 (AnxA1) is a key player in resolution of inflammation and a mediator of glucocorticoid actions. In atherosclerotic tissue, increased expression of AnxA1 has been associated with protective plaque-stabilizing effects. Here, we investigated the expression of AnxA1 in peripheral blood mononuclear cells (PBMCs) from patients with coronary artery disease (CAD). Blood was collected from 57 patients with stable CAD (SCAD) and 41 healthy controls. We also included a minor group (n = 10) with acute coronary syndrome (ACS). AnxA1 mRNA was measured in PBMCs. Expression of AnxA1 protein (total and surface-bound) and glucocorticoid receptors (GR) were detected in PBMC subsets by flow cytometry. Also, salivary cortisol, interleukin(IL)-6 and IL-10 in plasma, and LPS-induced cytokine secretion from PBMCs, with or without dexamethasone, were assessed. AnxA1 mRNA was found to be slightly increased in PBMCs from SCAD patients compared with controls. However, protein expression of AnxA1 or GRs in PBMC subsets did not differ between SCAD patients and controls, despite SCAD patients showing a more proinflammatory cytokine profile ex vivo. Only surface expression of AnxA1 on monocytes correlated with dexamethasone-mediated suppression of cytokines. In ACS patients, a marked activation of AnxA1 was seen involving both gene expression and translocation of protein to cell surface probably reflecting a rapid glucocorticoid action modulating the acute inflammatory response in ACS. To conclude, surface expression of AnxA1 on monocytes may reflect the degree of glucocorticoid sensitivity. Speculatively, "normal" surface expression of AnxA1 indicates that anti-inflammatory capacity is impaired in SCAD patients.
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18.
  • Bergström, Ida, et al. (författare)
  • Higher expression of annexin A1 in 1 CD56+ than in CD56-T cells : Potential implications for coronary artery disease
  • 2014
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • Background: Increased proportions of circulating proinflammatory CD56+ T cells have been reported in patients with coronary artery disease (CAD). Yet, little is known about regulation of these cells. In the present study, we investigated the expression and potential role of the glucocorticoid-mediated protein annexin A1 (AnxA1) in CD56+ and CD56-T cell subsets, with focus on CAD.Methods and Results: We included totally 52 healthy individuals, 28 patients with acute coronary syndrome (ACS) and 57 patients with a history of ACS. AnxA1 mRNA expression was assessed in peripheral blood mononuclear cells. AnxA1 protein expression (total and cell surface-associated) was measured by whole blood flow cytometry in circulating CD56+ and CD56- T cell subsets. Furthermore, inhibitory effects of dexamethasone and/or recombinant AnxA1 on cytokine secretion by CD56+ and CD56- T cells were explored in vitro. We found that CD56+ T cells (the majority CD8+), expressed higher levels of AnxA1 mRNA and protein than did CD56- T cells. When comparing CAD patients with healthy controls, significantly higher levels of cell surface-associated AnxA1 expression were seen in patients, most pronounced in ACS patients. In vitro, dexamethasone reduced cytokine secretion by CD56+ T cells, whereas AnxA1 alone had no effect, and AnxA1 combined with dexamethasone abolished the dexamethasone-induced suppressive effects.Conclusion: AnxA1 was expressed more abundantly in proinflammatory CD56+ T cells. Patients with ACS exhibited increased levels of cell surface-associated AnxA1, thus indicating increased activation of the AnxA1 pathway. Our data further suggested that AnxA1 might counteract glucocorticoid mediated anti-inflammatory effects in T cells.
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19.
  • Bergström, Ida, et al. (författare)
  • Persistent accumulation of interferon-gamma-producing CD8(+)CD56(+) T cells in blood from patients with coronary artery disease
  • 2012
  • Ingår i: Atherosclerosis. - : Elsevier. - 0021-9150 .- 1879-1484. ; 224:2, s. 515-520
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: There is emerging evidence for CD8(+) T cell alterations in blood from patients with coronary artery disease (CAD). We examined whether the distribution and phenotype of CD8(+)CD56(+) T cells differed according to the clinical manifestation of CAD. less thanbrgreater than less thanbrgreater thanMethods: Patients with acute coronary syndrome (ACS, n = 30), stable angina (SA, n = 34) and controls (n = 36) were included. Blood was collected before and up to 12 months after referral for coronary investigation. CD8(+)CD56(+) T cells were assessed by flow cytometry for expression of surface markers, apoptosis, and intracellular expression of cytokines. less thanbrgreater than less thanbrgreater thanResults: The proportions of CD8(+)CD56(+) T cells were significantly higher in both ACS and SA patients compared with controls, and remained so after 3 and 12 months. This was independent of age, sex, systemic inflammation and cytomegalovirus seropositivity. CD8(+)CD56(+) T cells differed from CD8(+)CD56(-) T cells in terms of lower CD28 expression and fewer apoptotic cells. Both CD8(+) T cell subsets were positive for interferon (IFN)-gamma and tumor necrosis factor, although IFN-gamma was significantly more confined to the CD8(+)CD56(+) T cells. less thanbrgreater than less thanbrgreater thanConclusion: The persistent accumulation of CD8(+)CD56(+) T cells in ACS and SA patients share several features with immunological aging. It also contributes to a larger IFN-gamma(+) pool in blood, and may thereby hypothetically drive the atherosclerotic process in a less favorable direction.
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20.
  • Bergström, Ida (författare)
  • Pro- and anti-inflammatory actions in coronary artery disease : with focus on CD56+ T cells and Annexin A1
  • 2015
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • ¨The atherosclerotic process is considered to be driven by an imbalance between proand anti-inflammatory actions. Still, the inflammatory state in patients with coronary artery disease (CAD) remains to be clarified. Annexin A1 (AnxA1) is a glucocorticoidinduced protein which may have a key role in the anti-inflammatory response as a mediator of glucocorticoid effects.The general aim of this thesis was to deepen the knowledge of pro- and antiinflammatory mechanisms in CAD via phenotypic assessments of immune cell subsets, in particular CD56+ T cells, and exploration of AnxA1. The long-term goal is to reveal basic mechanisms that will lead to the development of biomarkers, which may be used for individualized treatment and monitoring.The AnxA1 protein was constitutively expressed in both neutrophils and peripheral blood mononuclear cells (PBMCs). However, it varied considerably across PBMC subsets, being most abundantly expressed in monocytes. The AnxA1 expression was also higher in CD56+ T cells than in CD56- T cells.The expression of total AnxA1 protein in neutrophils was higher in patients with stable angina (SA) compared with controls. However, this was not accompanied by altered neutrophil activation status. Instead, the neutrophils from patients exhibited an enhanced anti-inflammatory response to exogenous AnxA1, emphasizing the potential of AnxA1 as an inhibitor of neutrophil activity. Only patients with acute coronary syndrome (ACS) showed an increase in cell surface-associated AnxA1.CAD patients, independent of clinical presentation, had increased proportions of CD56+ T cells compared with controls, a phenomenon likely to represent immunological aging. The CD56+ T cells were found to exhibit a distinct proinflammatory phenotype compared with CD56- T cells. In all T cell subsets, the expression of cell surface-associated AnxA1 was significantly increased in ACS patients, while it tended to be increased in post-ACS patients. In addition, dexamethasone clearly inhibited activation of CD56+ T cells in in vitro assays, whereas AnxA1 did not. The findings highlight the need to clarify whether the role of AnxA1 is different in T cells than in innate immune cells.In PBMCs, the mRNA levels of AnxA1 were increased in CAD patients, particularly in ACS patients. Correspondingly, the monocytes in ACS patients exhibited increased AnxA1 protein levels, both totally and on the cell surface. However, only cell surface-associated AnxA1 in monocytes correlated with the glucocorticoid sensitivity of PBMCs ex vivo. We propose the expression of cell surfaceassociated AnxA1 to be a promising candidate marker of glucocorticoid sensitivity, which needs further investigations in larger cohorts and intervention trials. Furthermore, the fact that PBMCs in post-ACS patients exhibited pro-inflammatory activity but no increase in cell surface-associated AnxA1 allow us to speculate that the glucocorticoid action and/or availability might be insufficient in these patients.
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21.
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22.
  • Bjarnegård, Niclas, et al. (författare)
  • Long-term hyperglycaemia impairs vascular smooth muscle cell function in women with type 1 diabetes mellitus
  • 2009
  • Ingår i: DIABETES and VASCULAR DISEASE RESEARCH. - : SAGE Publications. - 1479-1641 .- 1752-8984. ; 6:1, s. 25-31
  • Tidskriftsartikel (refereegranskat)abstract
    • Observations of increased stiffness in the elastic aorta in women with diabetes, but not men, emphasise the need for further analysis regarding early abnormalities in arterial wall properties of women with type 1 diabetes mellitus (DM).Ultrasound was used to study the wall properties of the distal brachial artery (BA) in 37 type 1 diabetic women (aged 22-45 years) without evident complications and in 53 controls (C). Blood samples were drawn for later analysis.Flow-mediated dilatation (FMD) was slightly lower in DM than C, 8.1 +/- 4.3% vs. 10.3 +/- 4.9% (p<0.05), and nitrate-mediated dilatation (NMD) was markedly lower, 21.7 +/- 6.6% vs. 31.4 +/- 5.7% (p<0.001). Lumen diameter, intima-media thickness and distensibility were similar in DM and C. Insulin-like growth factor (IGF-1) was lower in DM than C, 231 +/- 65 vs. 349 +/- 68 ng/ml (p<0.001). Glycosylated haemoglobin (HbA(1C)) and matrix metalloproteinase (MMP-9) were independent predictors of the reduced NMD in the DM.Brachial artery responsiveness to an exogenous donor of nitric oxide (NO) was markedly reduced in type 1 diabetic women despite only limited reduction in endothelium-dependent dilatation. The negative association between NMD and HbA(1C) suggests that long-term hyperglycaemia impairs vascular smooth muscle cell function in DM.
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23.
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24.
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25.
  • Cherfan, P, et al. (författare)
  • Effects of simvastatin on human T cells in vivo
  • 2007
  • Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 193:1, s. 186-192
  • Tidskriftsartikel (refereegranskat)abstract
    • Objective: The use of statins has shown several anti-inflammatory actions, including modulatory effects on T cells in vitro. Since the effects on human T cells in vivo are less clarified, our aim was to investigate the effects of simvastatin on human T cells in vivo and ex vivo. Methods and results: A randomized, double-blind, placebo-controlled study design was applied. Eighty volunteers with mild to moderate hypercholesterolemia received either simvastatin 40 mg or placebo for 6 weeks. The serum levels of C-reactive protein (CRP) were significantly reduced by simvastatin. The proportions of CD4+ and CD8+ T cell subsets expressing early (CD25) or late (HLA-DR) activation markers, as assessed by flow cytometry, were not changed by simvastatin. However, simvastatin tended to increase the density of HLA-DR and L-selectin per CD8+ T cell. The T helper(h)1/Th2 response was evaluated by stimulatory assays followed by intra-cellular staining of interferon-γ and interleukin-4. Simvastatin treatment did not affect the Th1 response but the results indicated a potential to suppress Th2. Conclusion: Simvastatin treatment resulted in a few discrete changes as regards peripheral T cells. However, the findings do not provide evidence that simvastatin-induced anti-inflammatory actions are related to any significant modulatory effects on human T cells in clinically healthy men with hypercholesterolemia. © 2006 Elsevier Ireland Ltd. All rights reserved.
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26.
  • Chung, Rosanna, et al. (författare)
  • Liberation of lutein from spinach : Effects of heating time, microwavereheating and liquefaction
  • 2019
  • Ingår i: Food Chemistry. - : Elsevier. - 0308-8146 .- 1873-7072. ; 277, s. 573-578
  • Tidskriftsartikel (refereegranskat)abstract
    • Lutein, abundant in dark leafy vegetables, has been associated with several health promoting effects. Still, to what extent different preparation conditions and practices affect the liberation of lutein from food is not fully understood. Here, we compared a range of domestic methods under realistic conditions to prepare spinach, the most common lutein-rich vegetable. After preparations, samples were processed by in vitro digestion and lutein was quantified by HPLC. Data indicate that short-term and medium-term heating of spinach, independent of heating method, substantially reduced liberated lutein and reduction was most pronounced after long boiling times. Interestingly, the loss of lutein in heated samples was partly compensated when samples were reheated in the microwave. However, the highest yield of liberated lutein was obtained from liquefied spinach. Additional dairy enhanced the liquefaction effect. Thus, for optimal liberation of lutein, liquefaction of raw spinach appears to be the method of choice.
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27.
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28.
  • Chung, Rosanna W S, et al. (författare)
  • Lutein exerts anti-inflammatory effects in patients with coronary artery disease.
  • 2017
  • Ingår i: Atherosclerosis. - : Elsevier. - 0021-9150 .- 1879-1484. ; 262, s. 87-93
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND AND AIMS: Many coronary artery disease (CAD) patients exhibit chronic low-grade inflammation. Carotenoids are anti-oxidants with potential anti-inflammatory properties. Here, we first assessed relationships between interleukin (IL)-6 and individual carotenoids in plasma from CAD patients. Based on the results, we proceeded to assess anti-inflammatory effects of one carotenoid, lutein, in peripheral blood mononuclear cells (PBMCs) from CAD patients.METHODS: Lutein + zeaxanthin (isomers with lutein being dominant), β-cryptoxanthin, lycopene, α- and β-carotene and IL-6 were measured in plasma from 134 patients with stable angina (SA) and 59 patients with acute coronary syndrome. In 42 patients, plasma measurements were also performed 3 months after coronary intervention. PBMCs from SA patients were pre-treated with lutein (1, 5 and 25 μM) for 24 h followed by 24 h incubation ± lipopolysaccharide (LPS). Cell pellets were collected for IL-6, IL-1β and TNF mRNA and intracellular lutein. Cytokine secretion was measured in cell media.RESULTS: Only lutein + zeaxanthin were inversely correlated with IL-6 in SA patients at baseline (r = -0.366, p < 0.001) and follow-up (r = -0.546, p < 0.001). Ex vivo, lutein was taken up by PBMCs from SA patients in a dose- and time-dependent manner. Pre-treatment with lutein dose-dependently lowered LPS-induced secretion of IL-6, IL-1β (p < 0.01) and TNF (p < 0.05), and also reduced IL-6, IL-1β and TNF mRNA expression (p < 0.05).CONCLUSIONS: Clinical findings highlighted the inverse association between lutein and IL-6 in CAD patients. Anti-inflammatory effects of lutein in PBMCs from CAD patients were consolidated in ex vivo experiments. Taken together, these results show that lutein has the potential to play a role in resolution of chronic inflammation in CAD patients.
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29.
  • Engelbrecht Clemmensen, Karina, et al. (författare)
  • Site-dependent N uptake from N-form mixtures by arctic plants, soil microbes and ectomycorrhizal fungi
  • 2008
  • Ingår i: Oecologia. - : Springer Science and Business Media LLC. - 1432-1939 .- 0029-8549. ; 155:4, s. 771-783
  • Tidskriftsartikel (refereegranskat)abstract
    • Abstract in UndeterminedSoil microbes constitute an important control on nitrogen (N) turnover and retention in arctic ecosystems where N availability is the main constraint on primary production. Ectomycorrhizal (ECM) symbioses may facilitate plant competition for the specific N pools available in various arctic ecosystems. We report here our study on the N uptake patterns of coexisting plants and microbes at two tundra sites with contrasting dominance of the circumpolar ECM shrub Betula nana. We added equimolar mixtures of glycine-N, NH4+-N and NO3--N, with one N form labelled with N-15 at a time, and in the case of glycine, also labelled with C-13, either directly to the soil or to ECM fungal ingrowth bags. After 2 days, the vegetation contained 5.6, 7.7 and 9.1% (heath tundra) and 7.1, 14.3 and 12.5% (shrub tundra) of the glycine-, NH4+- and NO3--N-15, respectively, recovered in the plant-soil system, and the major part of N-15 in the soil was immobilized by microbes (chloroform fumigation-extraction). In the subsequent 24 days, microbial N turnover transferred about half of the immobilized N-15 to the non-extractable soil organic N pool, demonstrating that soil microbes played a major role in N turnover and retention in both tundra types. The ECM mycelial communities at the two tundras differed in N-form preferences, with a higher contribution of glycine to total N uptake at the heath tundra; however, the ECM mycelial communities at both sites strongly discriminated against NO3-. Betula nana did not directly reflect ECM mycelial N uptake, and we conclude that N uptake by ECM plants is modulated by the N uptake patterns of both fungal and plant components of the symbiosis and by competitive interactions in the soil. Our field study furthermore showed that intact free amino acids are potentially important N sources for arctic ECM fungi and plants as well as for soil microorganisms.
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30.
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31.
  • Eriksson, Andreas, et al. (författare)
  • Static platelet adhesion, flow cytometry and serum TXB2 levels for monitoring platelet inhibiting treatment with ASA and clopidogrel in coronary artery disease : a randomised cross-over study
  • 2009
  • Ingår i: Journal of Translational Medicine. - : BioMed Central. - 1479-5876. ; 7:42
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Despite the use of anti-platelet agents such as acetylsalicylic acid (ASA) and clopidogrel in coronary heart disease, some patients continue to suffer from atherothrombosis. This has stimulated development of platelet function assays to monitor treatment effects. However, it is still not recommended to change treatment based on results from platelet function assays. This study aimed to evaluate the capacity of a static platelet adhesion assay to detect platelet inhibiting effects of ASA and clopidogrel. The adhesion assay measures several aspects of platelet adhesion simultaneously, which increases the probability of finding conditions sensitive for anti-platelet treatment. Methods: With a randomised cross-over design we evaluated the anti-platelet effects of ASA combined with clopidogrel as well as monotherapy with either drug alone in 29 patients with a recent acute coronary syndrome. Also, 29 matched healthy controls were included to evaluate intra-individual variability over time. Platelet function was measured by flow cytometry, serum thromboxane B-2 (TXB2)-levels and by static platelet adhesion to different protein surfaces. The results were subjected to Principal Component Analysis followed by ANOVA, t-tests and linear regression analysis. Results: The majority of platelet adhesion measures were reproducible in controls over time denoting that the assay can monitor platelet activity. Adenosine 5-diphosphate (ADP)-induced platelet adhesion decreased significantly upon treatment with clopidogrel compared to ASA. Flow cytometric measurements showed the same pattern (r(2) = 0.49). In opposite, TXB2-levels decreased with ASA compared to clopidogrel. Serum TXB2 and ADP-induced platelet activation could both be regarded as direct measures of the pharmacodynamic effects of ASA and clopidogrel respectively. Indirect pharmacodynamic measures such as adhesion to albumin induced by various soluble activators as well as SFLLRN-induced activation measured by flow cytometry were lower for clopidogrel compared to ASA. Furthermore, adhesion to collagen was lower for ASA and clopidogrel combined compared with either drug alone. Conclusion: The indirect pharmacodynamic measures of the effects of ASA and clopidogrel might be used together with ADP-induced activation and serum TXB2 for evaluation of anti-platelet treatment. This should be further evaluated in future clinical studies where screening opportunities with the adhesion assay will be optimised towards increased sensitivity to anti-platelet treatment.
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32.
  • Eriksson, Maria, 1965- (författare)
  • Adipocyte-derived hormones and cardiovascular disease
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Obesity is increasing globally and related to major changes in lifestyle. This increase is associated with an increased risk of cardiovascular disease (CVD). Knowledge about adipose tissue as a metabolic-endocrine organ has increased during the last few decades. Adipose tissue produces a number of proteins with increased body weight, many of which are important for food intake and satiety, insulin sensitivity, and vessel integrity, and aberrations have been related to atherosclerosis. Notably, the risk for developing CVD over the course of a lifetime differs between men and women. In Northern Sweden, men have a higher risk for myocardial infarction (MI). However, the incidence is declining in men but not in women. These sex differences could be due to functional and anatomical differences in the fat mass and its functions. The primary aim of this thesis was to evaluate associations between the adipocyte-derived hormones leptin and adiponectin, and fibrinolysis and other variables associated with the metabolic syndrome, and particularly whether these associations differ between men and women. Another aim was to evaluate these associations during physical exercise and pharmacological intervention (i.e. enalapril). Finally, whether leptin and adiponectin predict a first MI or sudden cardiac death with putative sex differences was also investigated. The first study used a cross-sectional design and included 72 men and women  recruited from the WHO MONICA project. We found pronounced sex differences in the associations with fibrinolytic variables. Leptin was associated with fibrinolytic factors in men, whereas insulin resistance was strongly associated with all fibrinolytic factors in women. The second study was an experimental observational study with 20 men exposed to strenuous physical exercise. During exercise, leptin levels decreased and adiponectin levels increased, and both were strongly associated with an improved fibrinolytic capacity measured as decreased PAI-1 activity. Changes in insulin sensitivity were not associated with changing adiponectin levels. The third study was a randomised, double-blind, single centre clinical trial including 46 men and 37 women who had an earlier MI. The study duration was one year, and participating subjects were randomised to either placebo or ACE inhibitor (i.e. enalapril). Circulating leptin levels were not associated with enalapril treatment. During the one-year study, changes in leptin levels were associated with changes in circulating levels of tPA mass, PAI-1 mass, and tPA-PAI complex in men, but not vWF. These associations were found in all men and men on placebo treatment. In women on enalapril treatment there was an association between changes in leptin and changes in vWF. In the fourth study, the impact of leptin, adiponectin, and their ratio on future MI risk or sudden cardiac death was tested in a prospective nested casecontrol study within the framework of the WHO MONICA, Västerbotten Intervention Project (VIP), and Västerbotten  Mammary Screening Program (MSP). A total 564 cases (first-ever MI or sudden cardiac death) and 1082 matched controls were selected. High leptin, low adiponectin, and a high leptin/adiponectin ratio independently predicted a first-ever MI, possibly with higher risk in men in regards to leptin. The association was found for non-fatal cases with ST-elevation MI. Subjects with low adiponectin levels had their MI earlier than those with high levels. In conclusion, the adipocyte-derived hormones leptin and adiponectin are related to the development of CVD with a sex difference, and fibrinolytic mechanisms could be possible contributors to CVD risk.
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33.
  • Fröbert, Ole, 1964-, et al. (författare)
  • Design and rationale for the Influenza vaccination After Myocardial Infarction (IAMI) trial. A registry-based randomized clinical trial
  • 2017
  • Ingår i: American Heart Journal. - : MOSBY-ELSEVIER. - 0002-8703 .- 1097-6744. ; 189, s. 94-102
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Registry studies and case-control studies have demonstrated that the risk of acute myocardial infarction (AMI) is increased following influenza infection. Small randomized trials, underpowered for clinical end points, indicate that future cardiovascular events can be reduced following influenza vaccination in patients with established cardiovascular disease. Influenza vaccination is recommended by international guidelines for patients with cardiovascular disease, but uptake is varying and vaccination is rarely prioritized during hospitalization for AMI.Methods/design: The Influenza vaccination After Myocardial Infarction (IAMI) trial is a double-blind, multicenter, prospective, registry-based, randomized, placebo-controlled, clinical trial. A total of 4,400 patients with ST-segment elevation myocardial infarction (STEMI) or non-STEMI undergoing coronary angiography will randomly be assigned either to in-hospital influenza vaccination or to placebo. Baseline information is collected from national heart disease registries, and follow-up will be performed using both registries and a structured telephone interview. The primary end point is a composite of time to all cause death, a new AMI, or stent thrombosis at 1 year.Implications: The IAMI trial is the largest randomized trial to date to evaluate the effect of in-hospital influenza vaccination on death and cardiovascular outcomes in patients with STEMI or non-STEMI. The trial is expected to provide highly relevant clinical data on the efficacy of influenza vaccine as secondary prevention after AMI.
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34.
  • Garvin, Peter, 1976-, et al. (författare)
  • Association between ambulatory saliva cortisol levels and plasma levels of matrix metalloproteinase-9 in a normal population
  • Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
    • 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.
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35.
  • Garvin, Peter, 1976-, et al. (författare)
  • Circulating Matrix Metalloproteinase-9 Is Associated with Cardiovascular Risk Factors in a Middle-Aged Normal Population
  • 2008
  • Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 3:3, s. e1774-
  • Tidskriftsartikel (refereegranskat)abstract
    • 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 
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36.
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37.
  • Garvin, Peter, et al. (författare)
  • Plasma Levels of Matrix Metalloproteinase-9 are Independently Associated With Psychosocial Factors in a Middle-Aged Normal Population
  • 2009
  • Ingår i: PSYCHOSOMATIC MEDICINE. - 0033-3174. ; 71:3, s. 292-300
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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38.
  • Garvin, Peter, et al. (författare)
  • Plasma Matrix Metalloproteinase-9 Levels Predict First-Time Coronary Heart Disease: An 8-Year Follow-Up of a Community-Based Middle Aged Population
  • 2015
  • Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 10:9, s. e0138290-
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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39.
  • Garvin, Peter, 1976-, et al. (författare)
  • Psychosocial factors in atherosclerosis
  • 2006
  • Ingår i: XIV International Symposium on Atherosclerosis,2006.
  • Konferensbidrag (övrigt vetenskapligt/konstnärligt)
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40.
  • Geng, Yong-Jian, et al. (författare)
  • Linking immunity to atherosclerosis: Implications for vascular pharmacology - A tribute to Goran K. Hansson
  • 2012
  • Ingår i: Vascular pharmacology. - : Elsevier. - 1537-1891 .- 1879-3649. ; 56:1-2, s. 29-33
  • Forskningsöversikt (refereegranskat)abstract
    • For the past decade, we have deepened our understanding of the pathogenesis of atherosclerosis, a chronic arterial disease that causes cardiac and cerebral infarction and peripheral vascular disorders. Because of this extended understanding, more effective strategies for prevention and treatment of this disease are emerging. One of the fundamental mechanisms that lead to progress or regression in atherosclerosis, thus influencing its life-threatening complications, occurs through functional changes in vascular immunity and inflammation. This review briefly summarizes the discoveries in basic and translational sciences in this area and recent advances in clinical medicine against atherosclerotic vascular diseases.
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41.
  • Goncalves, Isabel, et al. (författare)
  • Effects of simvastatin on circulating autoantibodies to oxidized LDL antigens : relation with immune stimulation markers
  • 2009
  • Ingår i: AUTOIMMUNITY. - : Informa UK Limited. - 0891-6934 .- 1607-842X. ; 42:3, s. 203-208
  • Tidskriftsartikel (refereegranskat)abstract
    • Statins exert a number of anti-inflammatory and immunomodulatory effects in vitro. However, the immunomodulatory effects in vivo are less clarified. In the present study, we investigated whether simvastatin treatment changed the levels of autoantibodies against specific oxidized LDL (oxLDL) antigens as well as their association with leukocyte activation markers. Eighty volunteers with mild-to-moderate hypercholesterolemia were randomized to either simvastatin 40mg or placebo for 6 weeks. Autoantibodies against apo B peptide antigens, C-reactive protein (CRP) and interleukin (IL)-6 in plasma were determined by ELISA. Subsets of circulating B and T cells were studied by flow cytometry. Simvastatin significantly reduced CRP by 26%, whereas IL-6 remained unchanged. Levels of IgG against the apo B peptide P-240 (amino acids 3586-3605) increased by 16% (p=0.03) in the simvastatin group whereas autoantibody levels to other apo B peptides did not change. At baseline and after 6 weeks, the P-240 IgG levels were significantly correlated with the number of CD57+CD28-CD8+T cells but not to other lymphocyte subsets or inflammatory markers. The P-240 IgG levels after 6 weeks simvastatin therapy was strongly correlated to the relative increase in CD57+CD28-CD8+T cells (p=0.003). Simvastatin treatment induced an increase in autoantibodies against an oxLDL antigen. The effect was related to an expansion of a CD8+T cell subset and may involve an immunostimulation by simvastatin.
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42.
  • Good, Elin, 1983-, et al. (författare)
  • Changes in natural killer and T lymphocyte phenotypes in response to cardiovascular risk management
  • 2023
  • Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 13:1
  • Tidskriftsartikel (refereegranskat)abstract
    • The pro-inflammatory and regulatory roles of T lymphocytes in atherosclerosis are well established but less is known about natural killer (NK) cells and natural killer T (NKT)-like cells. The effects of cardiovascular risk management on the phenotypes of these cells are unknown. To assess changes in NK cell and lymphocyte phenotypes and circulating inflammatory proteins in response to cardiovascular risk management in patients with carotid atherosclerosis. Fifty patients were included in a prospective clinical study. Measurements were at baseline and after 12 months of cardiovascular risk management. Circulating NK, NKT-like and T lymphocyte subpopulations were phenotyped by multi-colour flow cytometry. Proximity extension assay was performed for 176 plasma proteins associated with inflammation and cardiovascular disease. At 12 months there were significant reductions in LDL (P=0.001) and blood pressure (P=0.028). NK cells responded with a reduction in pro-inflammatory (NKG2C(+)) cells (P=0.0003), an increase in anti-inflammatory (NKG2A(+)) cells (P=0.032), and a reduction in terminally differentiated (CD57(+)) NK cells. NKT-like cells showed a similar decrease in terminally differentiated subpopulations (P=0.000002). Subpopulations of T helper cells exhibited a significant reduction in central memory (P=1.09x10(-8)) and a significant increase in CD4(+) naive- (P=0.0008) and effector memory T cells (P=0.006). The protein analysis indicated that cardiovascular risk management affects proteins involved in the inflammatory NF-kappa B pathway. The consistent decrease in senescent phenotypes of NK, NKT-like and CD4(+) cells with a concomitant increase in more naive, phenotypes suggests a change towards a less pro-inflammatory lymphocyte profile in response to cardiovascular risk management.Trial registry name: CARotid MRI of Atherosclerosis (CARMA). ClinicalTrials.gov identifier NCT04835571 (08/04/2021). https://www.clinicaltrials.gov/study/NCT04835571.
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43.
  • Gredmark, Sara, et al. (författare)
  • Active cytomegalovirus replication in patients with coronary disease
  • 2007
  • Ingår i: Scandinavian Cardiovascular Journal. - : Informa UK Limited. - 1401-7431 .- 1651-2006. ; 41:4, s. 230-234
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives. To study the prevalence of active cytomegalovirus (CMV) infection in patients with stable and unstable conditions of coronary artery disease (CAD). Design. Forty patients with acute coronary syndrome (ACS), 50 patients with stable angina and angiographically verified CAD (SA) and 50 clinically healthy controls were included. Monocytes were isolated from peripheral blood and CMV-RNA expression was determined by a nested RT-PCR assay. CMV IgM and IgG antibodies, interleukin-(IL)-6, IL-10 and CRP were measured in serum. Results. The prevalence of active CMV infection was significantly higher in patients with ACS (15%) and in patients with SA (10%) compared with controls (2%) (p < 0.001). The presence of an active CMV infection was associated with increased serum concentrations of IL-6. Conclusions. Active CMV infection was found to a larger extent in CAD patients than in healthy controls. The data indicate that CAD patients are more susceptible to reactivation of CMV and put new focus on the role of CMV in atherosclerosis.
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44.
  • Hammaréus, Filip, 1998-, et al. (författare)
  • Plasma type I collagen α1 chain in relation to coronary artery disease : findings from a prospective population-based cohort and an acute myocardial infarction prospective cohort in Sweden.
  • 2023
  • Ingår i: BMJ Open. - : BMJ Publishing Group Ltd. - 2044-6055. ; 13:9
  • Tidskriftsartikel (refereegranskat)abstract
    • OBJECTIVES: To investigate the association between type I collagen α1 chain (COL1α1) levels and coronary artery disease (CAD) by using absolute quantification in plasma. Also, to investigate the correlates of COL1α1 to clinical characteristics and circulating markers of collagen metabolism.DESIGN: Life conditions, Stress and Health (LSH) study: prospective cohort study, here with a nested case-control design.Assessing Platelet Activity in Coronary Heart Disease (APACHE) study: prospective cohort study.SETTING: LSH: primary care setting, southeast Sweden.APACHE: cardiology department, university hospital, southeast Sweden.PARTICIPANTS: LSH: 1007 randomly recruited individuals aged 45-69 (50% women). Exclusion criteria was serious disease. After 13 years of follow-up, 86 cases with primary endpoint were identified and sex-matched/age-matched to 184 controls.APACHE: 125 patients with myocardial infarction (MI), 73 with ST-elevation MI and 52 with non-ST-elevation MI.EXCLUSION CRITERIA: Intervention study participation, warfarin treatment and short life expectancy.PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was the association between baseline COL1α1 and first-time major event of CAD, defined as fatal/non-fatal MI or coronary revascularisation after 13 years. Secondary outcomes were the association between the collagen biomarkers PRO-C1 (N-terminal pro-peptide of type I collagen)/C1M (matrix metalloproteinase-mediated degradation of type I collagen) and CAD; temporal change of COL1α1 after acute MI up to 6 months and lastly, correlates between COL1α1 and patient characteristics along with circulating markers of collagen metabolism.RESULTS: COL1α1 levels were associated with CAD, both unadjusted (HR=0.69, 95% CI=0.56 to 0.87) and adjusted (HR=0.55, 95% CI=0.41 to 0.75). PRO-C1 was associated with CAD, unadjusted (HR=0.62, 95% CI=0.47 to 0.82) and adjusted (HR=0.61, 95% CI=0.43 to 0.86), while C1M was not. In patients with MI, COL1α1 remained unchanged up to 6 months. COL1α1 was correlated to PRO-C1, but not to C1M.CONCLUSIONS: Plasma COL1α1 was independently and inversely associated with CAD. Furthermore, COL1α1 appeared to reflect collagen synthesis but not degradation. Future studies are needed to confirm whether COL1α1 is a clinically useful biomarker of CAD.
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45.
  • Hammaréus, Filip, et al. (författare)
  • Wall shear stress measured with 4D flow CMR correlates with biomarkers of inflammation and collagen synthesis in mild-to-moderate ascending aortic dilation and tricuspid aortic valves
  • 2024
  • Ingår i: European Heart Journal Cardiovascular Imaging. - : OXFORD UNIV PRESS. - 2047-2404 .- 2047-2412.
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims Understanding the mechanisms underlying ascending aortic dilation is imperative for refined risk stratification of these patients, particularly among incidentally identified patients, most commonly presenting with tricuspid valves. The aim of this study was to explore associations between ascending aortic haemodynamics, assessed using four-dimensional flow cardiovascular magnetic resonance imaging (4D flow CMR), and circulating biomarkers in aortic dilation. Methods and results Forty-seven cases with aortic dilation (diameter >= 40 mm) and 50 sex-and age-matched controls (diameter < 40 mm), all with tricuspid aortic valves, underwent 4D flow CMR and venous blood sampling. Associations between flow displacement, wall shear stress (WSS), and oscillatory shear index in the ascending aorta derived from 4D flow CMR, and biomarkers including interleukin-6, collagen type I alpha 1 chain, metalloproteinases (MMPs), and inhibitors of MMPs derived from blood plasma, were investigated. Cases with dilation exhibited lower peak systolic WSS, higher flow displacement, and higher mean oscillatory shear index compared with controls without dilation. No significant differences in biomarkers were observed between the groups. Correlations between haemodynamics and biomarkers were observed, particularly between maximum time-averaged WSS and interleukin-6 (r = 0.539, P < 0.001), and maximum oscillatory shear index and collagen type I alpha 1 chain (r = -0.575, P < 0.001 in cases). Conclusion Significant associations were discovered between 4D flow CMR derived whole-cardiac cycle WSS and circulating biomarkers representing inflammation and collagen synthesis, suggesting an intricate interplay between haemodynamics and the processes of inflammation and collagen synthesis in patients with early aortic dilation and tricuspid aortic valves.
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46.
  • Hasib, Lekbira, et al. (författare)
  • Functional and homeostatic defects of regulatory T cells in patients with coronary artery disease
  • 2016
  • Ingår i: Journal of Internal Medicine. - : WILEY-BLACKWELL. - 0954-6820 .- 1365-2796. ; 279:1, s. 63-77
  • Tidskriftsartikel (refereegranskat)abstract
    • ObjectiveRegulatory T cells (Tregs) are considered atheroprotective, and low levels have been associated with the acute coronary syndrome (ACS), particularly non-ST elevation (NSTE)-ACS. However, the functional properties as well as homeostasis of Tregs are mainly unknown in coronary artery disease (CAD). Here, we investigated the composition and functional properties of naive (n) and memory (m)Tregs in patients with NSTE-ACS and in patients 6-12months post-ACS. MethodsBased on the expression of CD25, FOXP3, CD127, CD45RA, CD39 and CTLA-4, Tregsubsets were defined by flow cytometry in whole blood or isolated CD4(+) T cells. The functional properties of nTregs and mTregs were examined in terms of proliferative capacity and modulation of cytokine secretion. To understand the potential consequences of Treg defects, we also investigated correlations with lipopolysaccharide (LPS)-induced cytokine secretion and ultrasound-defined carotid atherosclerosis. ResultsBoth NSTE-ACS and post-ACS patients exhibited reduced levels of nTregs (P<0.001) compared with healthy control subjects, but without compensatory increases in mTregs. Both nTregs and mTregs from patients showed significantly lower replicative rates and impaired capacity to modulate T-cell proliferation and secretion of interferon-gamma and IL-10. The Treg defect was also associated with LPS-induced cytokine secretion and increased burden of carotid atherosclerosis. ConclusionOur results demonstrate a functional and homeostatic Treg defect in patients with NSTE-ACS and also in stabilized patients 6-12months after ACS. Moreover, this defect was associated with a subclinical proinflammatory and atherogenic state. We believe that the failure to preserve Treg function and homeostasis reflects a need for immune-restoring strategies in CAD.
  •  
47.
  • Hellman, Urban, 1966- (författare)
  • About hyaluronan in the hypertrophic heart : studies on coordinated regulation of extracellular matrix signalling
  • 2010
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Background. Myocardial hypertrophy is a risk factor for cardiovascular morbidity and mortality. Independent of underlying disease, the cardiac muscle strives in different ways to compensate for an increased workload. This remodelling of the heart includes changes in the extracellular matrix which will affect systolic and diastolic cardiac function. Furthermore, signal transduction, molecular diffusion and microcirculation will be affected in the hypertrophic process. One important extracellular component is the glycosaminoglycan hyaluronan. It has been shown to play a major role in other conditions that feature cellular growth and proliferation, such as wound healing and malignancies. The aim of this thesis was to investigate hyaluronan and its role in both an experimental rat model of cardiac hypertrophy as well as in cultured mouse cardiomyocytes and fibroblasts. Methods. Cardiac hypertrophy was induced in rats by aortic ligation. Hyaluronan concentration was measured and expression of genes coding for hyaluronan synthases were quantified after 1, 6 and 42 days after operation, in cardiac tissue from the left ventricular wall. Localization of hyaluronan and its receptor CD44 was studied histochemically. Hyaluronan synthesis was correlated to gene transcription using microarray gene expression analysis. Cultures of cardiomyocytes and fibroblasts were stimulated with growth factors. Hyaluronan concentration was measured and expression of genes coding for hyaluronan synthases were detected. Hyaluronan size was measured and crosstalk between cardiomyocytes and fibroblasts was investigated. Results. Increased concentration of hyaluronan in hypertrophied cardiac tissue was observed together with an up-regulation of two hyaluronan synthase genes. Hyaluronan was detected in the myocardium and in the adventitia of cardiac arteries whereas CD44 staining was mainly found in and around the adventitia. Hyaluronan synthesis correlated to the expression of genes, regulated by transcription factors known to initiate cardiac hypertrophy. Stimulation of cardiomyocytes by PDGF-BB induced synthesis of hyaluronan. Cardiomyocytes also secreted a factor into culture media that after transfer to fibroblasts initiated an increased synthesis of hyaluronan. When stimulated with hyaluronan of different sizes, a change in cardiomyocyte gene expression was observed. Different growth factors induced production of different sizes of hyaluronan in fibroblasts. The main synthase detected was hyaluronan synthase-2. Cardiomyocytes were also shown to secrete microvesicles containing both DNA and RNA. Isolated microvesicles incubated with fibroblasts were observed by confocal microscopy to be internalized into fibroblasts. Altered gene expression was observed in microvesicle stimulated fibroblasts. Conclusion. This study shows that increased hyaluronan synthesis in cardiac tissue during hypertrophic development is a part of the extracellular matrix remodelling. Cell cultures revealed the ability of cardiomyocytes to both synthesize hyaluronan and to convey signals to fibroblasts, causing them to increase hyaluronan synthesis. Cardiomyocytes are likely to express receptors for hyaluronan, which mediate intracellular signalling causing the observed altered gene expression in cardiomyocytes stimulated with hyaluronan. This demonstrates the extensive involvement of hyaluronan in cardiac hypertrophy.
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48.
  • Hellström, Martin, 1979- (författare)
  • Hyaluronan and the receptor CD 44 in the heart and vessels : a study in normal and pathological conditions
  • 2007
  • Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
    • Tissues are not solely composed of cells. The extracellular matrix is important for the cell well-being and cell-cell communication. The glycosaminoglycan hyaluronan (HYA) is a widely distributed extracellular matrix (ECM) component. The molecule has prominent physicochemical properties, foremost viscoelastic and osmotic, but participates in many biological processes such as cell migration, proliferation, tissue turnover, wound healing and angiogenesis. HYA is synthesised by either of three different hyaluronan-synthesising enzymes, HAS1-3, and its main ligand is the transmembrane receptor CD44. In the heart and vessels the matrix components are of great importance for endurance and elasticity which are prerequisites for a normal function. The aims of the study were to describe the distribution of HYA and its receptor CD44 in normal cardiovascular tissue and to investigate the ECM composition in myocardial hypertrophy. Normal conditions were studied in a rat model. These studies showed that the tunica adventitia in almost all vessels stained strongly for HYA. The expression in the tunica intima and media on the venous side, differed between the vessels and was almost absent on the arterial side. In the adult animals only minute amounts of CD44 were detected. The expression of both HYA and CD44 was increased in newborn rats. In the heart HYA was unevenly distributed in the interstitium. Strong HYA-staining was seen in the valves and in the adventitia of intramyocardial vessels. Almost no CD44-staining was observed. Notably, there was no obvious difference between newborn and adult animals. In an experimental rat model of pressure-induced cardiac hypertrophy the mRNA-levels of HAS1, HAS2, CD44, basic Fibroblast Growth Factor (FGF-2) and Fibroblast Growth Factor Receptor-1 (FGFR-1) were elevated on day 1 after aortic banding. HAS2, CD44 and FGFR-1 were at basal levels on day 42. The HYA-concentration was significally elevated on day 1. HYA was detected in the interstitium by histochemistry and CD44 was detected mainly in and around the intramyocardial vessels. The HYA-staining was increased in myectomi specimens from patients with HCM compared to controls. HYA was detected in the interstitium, in fibrous septas and in the adventitia of intramyocardial vessels. No CD44 was detected in HCM or in control specimens. Our results indicate that HYA and CD44 play an active role in the maturing vessel tree and that the ECM content of HYA is increased in experimental myocardial hypertrophy and human hypertrophic cardiomyopathy.
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49.
  • Hofmann, R., et al. (författare)
  • Supplemental oxygen therapy does not affect the systemic inflammatory response to acute myocardial infarction
  • 2018
  • Ingår i: Journal of Internal Medicine. - : WILEY. - 0954-6820 .- 1365-2796. ; 283:4, s. 334-345
  • Tidskriftsartikel (refereegranskat)abstract
    • Background. Oxygen therapy has been used routinely in normoxemic patients with suspected acute myocardial infarction (AMI) despite limited evidence supporting a beneficial effect. AMI is associated with a systemic inflammation. Here, we hypothesized that the inflammatory response to AMI is potentiated by oxygen therapy. Methods. The DETermination of the role of Oxygen in suspected Acute Myocardial Infarction (DETO2X-AMI) multicentre trial randomized patients with suspected AMI to receive oxygen at 6 L min(-1) for 6-12 h or ambient air. For this prespecified subgroup analysis, we recruited patients with confirmed AMI from two sites for evaluation of inflammatory biomarkers at randomization and 5-7 h later. Ninety-two inflammatory biomarkers were analysed using proximity extension assay technology, to evaluate the effect of oxygen on the systemic inflammatory response to AMI. Results. Plasma from 144 AMI patients was analysed whereof 76 (53%) were randomized to oxygen and 68 (47%) to air. Eight biomarkers showed a significant increase, whereas 13 were decreased 5-7 h after randomization. The inflammatory response did not differ between the two treatment groups neither did plasma troponin T levels. After adjustment for increase in troponin T over time, age and sex, the release of inflammation-related biomarkers was still similar in the groups. Conclusions. In a randomized controlled setting of normoxemic patients with AMI, the use of supplemental oxygen did not have any significant impact on the early release of systemic inflammatory markers.
  •  
50.
  • Holm, Anna, 1973-, et al. (författare)
  • Sex differences in platelet reactivity in patients with myocardial infarction treated with triple antiplatelet therapy-results from assessing platelet activity in coronary heart disease (APACHE)
  • 2021
  • Ingår i: Platelets. - : Taylor & Francis. - 0953-7104 .- 1369-1635. ; 32:1, s. 524-532
  • Tidskriftsartikel (refereegranskat)abstract
    • )Several earlier studies have reported increased risk of bleeding in women with myocardial infarction, (MI) compared to men. The reasons for the observed difference are incompletely understood, but one suggested explanation has been excess dosing of antithrombotic drugs in women. The aim of this prospective observational study was to assess sex differences in platelet activity in patients treated with three different platelet inhibitors. We recruited 125 patients (37 women and 88 men) with MI, scheduled for coronary angiography. All patients received clopidogrel and aspirin. A subgroup of patients received glycoprotein (GP) IIb/IIIa-inhibitor. Platelet aggregation in whole blood was assessed at several time points, using impedance aggregometry. SolubleP-selectin was measured 3 days after admission. There were no significant differences between women and men in baseline features or comorbidities except higher frequency of diabetes, lower hemoglobin value, and lower estimated glomerular filtration rate, in women on admission. We observed significantly more in-hospital bleeding events in women compared to men (18.9% vs. 6.8%,p= .04). There were no differences in platelet aggregation using three different agonists, reflecting treatment effect of GPIIb/IIIa-inhibitors, clopidogrel, and aspirin, 6-8 hours, 3 days, 7-9 days, or 6 months after loading dose. Moreover, there was no significant difference in solubleP-selectin. The main finding of this study was a consistent lack of difference between the sexes in platelet aggregation, using three different agonists at several time-points. Our results do not support excess dosing of anti-platelet drugs as a major explanation for increased bleeding risk in women.
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