| 1. |
- Hägg, Sara, 1977-, et al.
(författare)
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Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2 : The Stockholm Atherosclerosis Gene Expression (STAGE) Study
- 2009
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Ingår i: PLoS Genetics. - : PLoS Genetics. - 1553-7390 .- 1553-7404. ; 5:12, s. e1000754-
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Tidskriftsartikel (refereegranskat)abstract
- Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n=66/tissue) and atherosclerotic and unaffected arterial wall (n=40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n=15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n=3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n=49/48) and one visceral fat (n=59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P=0.008 and P=0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n=55/54) relating to carotid stenosis (P=0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n=16/17, P<10-27and-30). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, cellular and lesion expression of LDB2, and the expression of 13 TEML genes in Ldb2-deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and together with LDB2 merits further attention in CAD research.
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| 2. |
- Kalani, Majid, et al.
(författare)
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Beneficial effects of dalteparin on haemostatic function and local tissue oxygenation in patients with diabetes, severe vascular disease and foot ulcers.
- 2007
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Ingår i: Thrombosis research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 120:5, s. 653-61
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: A state of hypercoagulation and fibrinolytic dysfunction is present in individuals with diabetes, which may contribute to disturbed skin microcirculation and impaired ulcer healing. We have previously reported an improved outcome of chronic diabetic foot ulcers during treatment with dalteparin. In the present study we investigated the effects of dalteparin on skin microcirculation and haemostatic function. MATERIALS AND METHODS: 87 patients with diabetes, peripheral arterial obliterative disease and chronic foot ulcers were investigated in a prospective, randomised, double-blind and placebo-controlled study. They were randomised to treatment with subcutaneous injections of 5000 U dalteparin (n=44) or placebo (n=43), once daily until ulcer healing or for a maximum of six months. Plasma fibrinogen, fibrin gel structure [permeability coefficient (Ks) and fiber mass/length ratio (mu)], prothrombin fragment 1+2 (F1+2) antigen, plasminogen activator inhibitor-1 (PAI-1) activity and tissue plasminogen activator (tPA) antigen were analysed before randomization (baseline value), and at the end of the treatment period. The skin microcirculation of the foot was investigated by transcutaneous oxygen tension (TcPO(2)) and laser Doppler fluxmetry (LDF). RESULTS: The changes (Delta-values) of Ks, mu, tPA and TcPO(2) were higher (p<0.05) during treatment with dalteparin, as compared to the changes during treatment with placebo. At baseline, plasma fibrinogen and Ks were significantly correlated to TcPO(2). CONCLUSIONS: Local skin oxygenation improved and a less thrombogenic fibrin gel structure was formed in patients treated with dalteparin. Beneficial effects on haemostatic function are likely to contribute to the improved skin oxygenation observed during treatment with dalteparin.
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| 3. |
- Lundman, Pia, et al.
(författare)
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A high-fat meal is accompanied by increased plasma interleukin-6 concentrations
- 2007
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Ingår i: NMCD. Nutrition Metabolism and Cardiovascular Diseases. - : Elsevier BV. - 0939-4753 .- 1590-3729. ; 17:3, s. 195-202
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIM: Enhanced and prolonged postprandial lipaemia is associated with coronary heart disease (CHD). However, the mechanisms linking postprandial lipaemia to the increased risk of atherosclerosis and CHD remain to be determined. The aim of the present study was to examine the effects of a high-fat meal on plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) and cellular adhesion molecules in CHD patients and control subjects. METHODS AND RESULTS: Forty-one middle-aged men with premature CHD and 26 healthy male controls were investigated. The plasma triglyceride response to the high-fat meal was significantly greater among cases than controls. The oral fat load induced a twofold increase in plasma concentrations of IL-6, an increase that was similar in CHD patients and control subjects. No changes could be detected in plasma concentrations of cellular adhesion molecules in response to postprandial lipaemia in either CHD patients or control subjects. CONCLUSION: The results of the present study suggest that a high-fat meal affects mechanisms that induce increased inflammatory activity, which is recognised as a key modulator in the development of atherosclerosis and CHD. However, the increased levels of plasma IL-6 appear not to be determined by the magnitude of the postprandial triglyceridaemia.
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| 4. |
- Sjögren, Per, et al.
(författare)
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Markers of endothelial activity are related to components of the metabolic syndrome, but not to circulating concentrations of the advanced glycation end-product N epsilon-carboxymethyl-lysine in healthy Swedish men
- 2007
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 195:2, s. e168-e175
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Tidskriftsartikel (refereegranskat)abstract
- Endothelial function is considered important in the development of cardiovascular diseases and type 2 diabetes. Circulating advanced glycation end-products (AGEs) and dietary components have been shown to affect endothelial function in type 2 diabetics, but determinants of endothelial function in a non-diabetic population are more poorly investigated. Therefore, we investigated relationships between dietary habits, AGEs and endothelial activation in men with isolated metabolic disturbances. Circulating markers of endothelial activation (soluble forms of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, E-selectin and von Willebrand factor) and plasma N epsilon-carboxymethyl-lysine (CML, the predominant AGE in human plasma) were analyzed in a cross-sectional study of 294 healthy men. Individuals completed a 7-day dietary record, and metabolic and inflammatory parameters were determined. NCEP/ATPIII-criteria were used to define the metabolic syndrome. Endothelial activation was higher in individuals with the metabolic syndrome, and was positively related to certain features of the syndrome (insulin, glucose, inflammation and obesity), but not to others (triacylglycerol and blood pressure). Dietary factors were related to endothelial activation, but CML was not. Multivariate analysis revealed energy and alcohol intake, along with insulin and markers of oxidative stress and inflammation, to be positive predictors of endothelial activation. In this cohort of otherwise healthy men, endothelial activation was increased in individuals with the full metabolic syndrome, but not in those with only some of the components of the metabolic syndrome. Insulin resistance, inflammation, oxidative stress, the dietary intake of energy and alcohol, but not plasma CML, predicted endothelial activation in these men.
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| 5. |
- van Rooijen, Marianne, et al.
(författare)
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APC resistance during the normal menstrual cycle
- 2007
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 98:6, s. 1246-1251
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Tidskriftsartikel (refereegranskat)abstract
- Increased serum levels of endogenous as well as exogenous estrogen are regarded to be responsible for acquired activated protein C (APC) resistance. It was the objective of this study to evaluate whether the physiological increase in serum estradiol concentration during the normal menstrual cycle affects the individual's sensitivity to APC. Seventy-two women with normal menstrual cycles were included in the study. Blood samples for analysis of estradiol (E2), progesterone (P4) and APC resistance were drawn at two time points of the menstrual cycle (day 3-5 and day 22-25). Two methods of measuringAPC resistance were used: the activated partial thromboplastin time (aPTT)-based assay and the endogenous thrombin potential (ETP)-basedAPC resistance test. Independent of the method used, no changes in APC resistance were found, even though the E2 concentration increased significantly between the two menstrual phases. No correlations between E2 levels andAPC resistance, P4 levels and APC resistance or changes in E2 concentrations and changes in APC resistance were detected. Ten women were carriers of the factor V-Leiden mutation, Their baseline APC resistance was increased, but their response to elevated E2 during the menstrual cycle did not differ from that of non-carriers. In conclusion, our observations suggest that physiological differences in serum levels of estradiol and progesterone between the early follicular and the luteal phase in a normal menstrual cycle do not have any significant impact on the individual's sensitivity to APC.
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| 6. |
- von Rooijen, Marianne, et al.
(författare)
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Rapid activation of haemostasis after hormonal emergency contraception
- 2007
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Ingår i: Thrombosis and Haemostasis. - 0340-6245 .- 2567-689X. ; 97:1, s. 15-20
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Tidskriftsartikel (refereegranskat)abstract
- Hormonal emergency contraception (EC) is a well established contraceptive method, recommended to all women, although the effects on haemostais are not fully evaluated. The aim of this study was to evaluate whether exposure to EC has effects on well established cardiovascular risk factors, and also to examine whether differences exist between two EC treatments. In a prospective randomized cross over design II women used two different EC methods, one with estrogen and levonorgestrel (EE-EC) and one with levonorgestrel only (LNG-EC). Plasma concentrations of haemostatic factors (APC resistance, antithrombin, fibrinogen, prothrombin fragment 1+2, free protein S, factor VII and PAI-I), sex-hormone-binding globulin (SHBG),the apolipoprotein (apo)B/apoAI ratio and C-reactive protein (CRP) were followed frequently during the following 48 hours.
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