| 1. |
- Hernestål-Boman, Jenny, et al.
(författare)
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Signs of dysregulated fibrinolysis precede the development of type 2 diabetes mellitus in a population-based study
- 2012
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Ingår i: Cardiovascular Diabetology. - : BioMed Central. - 1475-2840 .- 1475-2840. ; 11, s. 152-
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Tidskriftsartikel (refereegranskat)abstract
- Background: Diabetic patients experience stimulated coagulation and dysfibrinolysis, which is associated with an increased risk of cardiovascular events. This imbalance may precede the manifest diagnosis. We investigated whether elevated antigen levels of tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), the tPA/PAI-1 complex, or von Willebrand Factor (VWF) precede type 2 diabetes mellitus (T2DM) diagnosis, and whether this elevation occurs before increased fasting plasma glucose (FPG) or 2-hour plasma glucose (2hPG) in individuals who later develop T2DM.Methods: We conducted a prospective incident case-referent study within the Vasterbotten Intervention Programme. Cardiovascular risk factor data as well as FPG and 2hPG and blood samples for future research were collected at a baseline health examination between 1989 and 2000, (n= 28 736). During follow-up in January 2001, 157 cases had developed T2DM. Referents without T2DM were matched for sex, age, and year of participation (n=277). Subgroup analysis was performed for cases with normal baseline glucose levels (FPG <6.1 mmol/L and 2hPG < 8.9 mmol/L) and cases with elevated levels (FPG 6.1-6.9 mmol/L and/or 2hPG 8.9-12.1 mmol/L).Results: After adjusting for BMI, family history of diabetes, physical activity, smoking, systolic blood pressure and levels of C-reactive protein and triglycerides, independent associations were found between incident T2DM and elevated levels of tPA (OR=1.54, 95% CI 1.06-2.23), PAI-1 (OR=1.61, 95% CI 1.14-2.28), and tPA/PAI-1 complex (OR=2.45, 95% CI 1.56-3.84). In participants with normal glucose levels, PAI-1 (OR=2.06, 95% CI 1.10 - 3.86) exhibited an independent relationship with incident T2DM after the adjustments.Conclusions: Elevated levels of fibrinolytic variables precede the manifestation of T2DM after adjusting for metabolic and cardiovascular risk factors and can be detected several years before changes in glucose tolerance.
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| 2. |
- Andersson, Jonas, 1977-
(författare)
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Inflammation and lifestyle in cardiovascular medicine
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Despite major advances in the treatment and prevention of atherosclerosis the last several decades, cardiovascular disease still accounts for the majority of deaths in Sweden. With the population getting older, more obese and with rising numbers of diabetics, the cardiovascular disease burden may increase further in the future. The focus in cardiovascular disease has shifted with time from calcification and narrowing of arteries to the biological processes within the atherosclerotic plaque. C-reactive protein (CRP) has emerged as one of many proteins that reflect a low grade systemic inflammation and is suitable for analysis as it is more stable and easily measured than most other inflammatory markers. Several large prospective studies have shown that CRP is not only an inflammatory marker, but even a predictive marker for cardiovascular disease. C-reactive protein is associated with several other risk factors for cardiovascular disease including obesity and the metabolic syndrome. Our study of twenty healthy men during a two week endurance cross country skiing tour demonstrated a decline in already low baseline CRP levels immediately after the tour and six weeks later. In a study of 200 obese individuals with impaired glucose tolerance randomised to a counselling session at their health care centre or a one month stay at a wellness centre, we found decreased levels of CRP in subjects admitted to the wellness centre. The effect remained at one, but not after three years of follow-up. In a prospective, nested, case-referent study with 308 ischemic strokes, 61 intracerebral haemorrhages and 735 matched referents, CRP was associated with ischemic stroke in both uni- and multivariate analyses. No association was found with intracerebral haemorrhages. When classifying ischemic stroke according to TOAST criteria, CRP was associated with small vessel disease. The CRP 1444 (CC/CT vs. TT) polymorphism was associated with plasma levels of CRP, but neither with ischemic stroke nor with intracerebral haemorrhage. A study on 129 patients with atrial fibrillation was used to evaluate whether inflammation sensitive fibrinolytic variables adjusted for CRP could predict recurrence of atrial fibrillation after electrical cardioversion. In multivariate iv models, lower PAI-1 mass was associated with sinus rhythm even after adjusting for CRP and markers of the metabolic syndrome. In conclusion, lifestyle intervention can be used to reduce CRP levels, but it remains a challenge to maintain this effect. CRP is a marker of ischemic stroke, but there are no significant associations between the CRP1444 polymorphism and any stroke subtype, suggesting that the CRP relationship with ischemic stroke is not causal. The fibrinolytic variable, PAI-1, is associated with the risk of recurrence of atrial fibrillation after electrical cardioversion after adjustment for CRP. Our findings suggest a pathophysiological link between atrial fibrillation and PAI-1, but the relation to inflammation remains unclear.
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| 3. |
- Eriksson, Jan W., et al.
(författare)
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Hydrochlorothiazide, but not Candesartan, aggravates insulin resistance and causes visceral and hepatic fat accumulation : the mechanisms for the diabetes preventing effect of Candesartan (MEDICA) Study
- 2008
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Ingår i: Hypertension. - : American Heart Association. - 0194-911X .- 1524-4563. ; 52:6, s. 1030-1037
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Tidskriftsartikel (refereegranskat)abstract
- Treatment with angiotensin II receptor blockers is associated with lower risk for the development of type 2 diabetes mellitus compared with thiazide diuretics. The Mechanisms for the Diabetes Preventing Effect of Candesartan Study addressed insulin action and secretion and body fat distribution after treatment with candesartan, hydrochlorothiazide, and placebo. Twenty-six nondiabetic, abdominally obese, hypertensive patients were included in a multicenter 3-way crossover trial, and 22 completers (by predefined criteria; 10 men and 12 women) were included in the analyses. They underwent 12-week treatment periods with candesartan (C; 16 to 32 mg), hydrochlorothiazide (H; 25 to 50 mg), and placebo (P), respectively, and the treatment order was randomly assigned and double blinded. Intravenous glucose tolerance tests and euglycemic hyperinsulinemic (56 mU/m(2) per minute) clamps were performed. Intrahepatic and intramyocellular and extramyocellular lipid content and subcutaneous and visceral abdominal adipose tissue were measured using proton magnetic resonance spectroscopy and MRI. Insulin sensitivity (M-value) was reduced following H versus C and P (6.07+/-2.05, 6.63+/-2.04, and 6.90+/-2.10 mg/kg of body weight per minute, mean+/-SD; P
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| 4. |
- Eriksson, Olof, et al.
(författare)
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The Positron Emission Tomography ligand [11C]5-Hydroxy-Tryptophan can be used as a surrogate marker for the human endocrine pancreas
- 2014
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 63:10, s. 3428-3437
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Tidskriftsartikel (refereegranskat)abstract
- In humans a well-developed serotonin system is localized to the pancreatic islets while being absent in exocrine pancreas. Assessment of pancreatic serotonin biosynthesis could therefore be used to estimate the human endocrine pancreas. Proof of concept was tested in a prospective clinical trial by comparisons of type 1 diabetic (T1D) patients, with extensive reduction of beta cells, with healthy volunteers (HV).C-peptide negative (i.e. insulin-deficient) T1D subjects (n=10) and HV (n=9) underwent dynamic Positron Emission Tomography with the radiolabeled serotonin precursor [(11)C]5-Hydroxy-Tryptophan ([(11)C]5-HTP).A significant accumulation of [(11)C]5-HTP was obtained in the pancreas of the HV, with large inter-individual variation. A substantial and highly significant reduction (66%) in the pancreatic uptake of [(11)C]5-HTP in T1D subjects was observed, and this was most evident in the corpus and caudal regions of the pancreas where beta-cells normally are the major constituent of the islets.[(11)C]5-HTP retention in the pancreas was reduced in T1D compared to non-diabetic subjects. Accumulation of [(11)C]5-HTP in the pancreas of both HV and subjects with T1D were in agreement with previously reported morphological observations on the beta cell volume implying that [(11)C]5-HTP retention is a useful non-invasive surrogate marker for the human endocrine pancreas.
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| 5. |
- Hagg, Lovisa, et al.
(författare)
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External Validity of the ARISTOTLE Trial in Real-Life Atrial Fibrillation Patients
- 2014
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Ingår i: Cardiovascular Therapeutics. - : Wiley. - 1755-5914. ; 32:5, s. 214-218
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveOur primary objective was to determine the proportion of patients with atrial fibrillation (AF) eligible for enrollment in a randomized controlled trial for a novel oral anticoagulant, the ARISTOTLE trial. A secondary objective was to describe the reasons for trial ineligibility.MethodsWe performed a cross-sectional study of an unselected population including 2274 patients in Skelleftea, Sweden with at least one verified episode of AF on or before December 31, 2010. Patients were classified as suitable or unsuitable for anticoagulant treatment according to current guidelines. The enrollment criteria from the ARISTOTLE trial were extracted from the original publication and applied to the population.ResultsAmong all patients with AF, 1579 were classified as suitable for anticoagulant treatment. Of these, only 658 patients (42%) were eligible for participation in the ARISTOTLE trial. Among the 921 patients ineligible for participation, 498 did not meet the ECG criteria, 272 had psychosocial problems, and in addition, 78 patients were excluded due to both of these criteria.ConclusionOur study shows that a majority of the patients in an unselected population with AF suitable for anticoagulant treatment were ineligible for participation in the ARISTOTLE trial. The applicability of the ARISTOTLE trial is therefore unknown for a considerable proportion of patients with AF in real life.
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| 6. |
- Hernestål Boman, Jenny, 1980-
(författare)
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Fibrinolytic factors in relation to anthropometry and incident type 2 diabetes.
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Fibrinolytic imbalance is associated with cardiovascular disease and its risk factors. The longitudinal changes in the fibrinolytic factors tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and tPA/PAI-1 complex have been inadequately studied in the general population and in relation to incident type 2 diabetes mellitus (T2DM). The measurements, questionnaires and blood samples prospectively collected in the World Health Organisation-project MONItoring trends and determinants in CArdiovascular disease (MONICA) and in the Västerbotten Intervention Programme (VIP) enable such studies. The samples have been stored since 1985, at the Northern Sweden Medical Research Biobank. However, it is unknown how these factors are affected by long-term storage.The aims of this thesis were to evaluate the effects of long-term storage on fibrinolytic factors, and to determine how these factors are related to incident T2DM, how these factors change over time and how these factors are related to changes in anthropometric measurements.Storage time was shown to have a negligible impact on plasma antigen levels of fibrinolytic factors. After adjustments for traditional diabetic and cardiovascular risk markers the fibrinolytic factors tPA, PAI-1 and tPA/PAI-1 complex were associated with incident T2DM. PAI-1 was associated with incident T2DM in subjects with normal fasting and 2-hour plasma glucose levels. In MONICA-Västerbotten, tPA, PAI-1 and tPA/PAI-1 complex increased over 9 years in both men and women. PAI-1 appears to interact in a complex manner with anthropometric, inflammatory, glycaemic and lipidemic measurements, but the pattern of components correlating with the changes in PAI-1 differed markedly between the sexes.In conclusion, PAI-1 is a potential risk marker of incident T2DM. PAI-1 increased markedly over nine years, but the pathophysiological background to these findings needs to be further investigated, separately for each sex.
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| 7. |
- Hernestål-Boman, Jenny, 1980-, et al.
(författare)
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Individual changes in fibrinolytic factors, von Willebrand factor, and C-reactive protein over a nine-year period.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Intra-individual changes in haemostatic factor concentrations over time are unknown, in the general population.Objective: To describe intra-individual longitudinal changes in tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1), tPA/PAI-1 complex, von Willebrand factor (VWF), and C-reactive protein (CRP) over nine years, in different age groups, stratified for sex.Methods: The MONICA survey in 1990 examined randomly selected men and women in four age groups (25–64 years) who were re-examined in 1999. A total of 309 individuals donated venous blood samples in Stabilyte tubes for both surveys during the morning hours, after an overnight fast. We analysed tPA activity and antigens of tPA, PAI-1, tPA/PAI-1 complex, VWF, and CRP.Results: Over nine years, in both men and women, we found significant intra-individual increases in the antigen levels of tPA, PAI-1, tPA/PAI-1 complex, VWF, and CRP (P < 0.001). PAI-1 antigen levels increased by 75% for men and 95% for women. Compared to men, women had a significantly higher CRP increase (0.92 vs. 0.22 mg/L; P = 0.044). The P for trend for mean Δ1999–1990 across age groups showed a significant linear trend for VWF (P = 0.001 for men; P < 0.001 for women), but not for the other studied variables.Conclusions: There were intra-individual longitudinal increases in the antigen levels of tPA, PAI-1, tPA/PAI-1 complex, VWF, and CRP over nine years in both men and women, with PAI-1 showing the highest relative increase. VWF increased significantly across age groups; however, fibrinolytic variables did not.
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| 8. |
- Hernestål-Boman, Jenny, 1980-, et al.
(författare)
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Individual PAI-1 increase over nine years relates differently in men and women to changes in anthropometric, glycaemic, inflammatory and lipid markers.
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Background: Levels of plasminogen activator inhibitor-1 (PAI-1) is known to correlate to factors related to the metabolic syndrome. We have previously shown that PAI-1 antigen increased by 75% in men and 95% in women over nine years.Objective: The aim of this study was to explore relationships between intra-individual changes in PAI-1 and changes in anthropometric measurements, blood pressure, glycaemic, lipid and inflammatory markers, separately for men and women.Method: In northern Sweden, 125 men and 116 women were examined first in 1990 and re-examined in 1999 during the morning hours. Changes over time (Δ) were calculated as the value at 1999 minus the value at 1990.Results: In men, ΔPAI-1 was significantly correlated to ΔBMI (r =0.33), ΔCRP (r =0.25), Δtriglycerides (r =0.39), Δfasting plasma glucose (r =0.41) and Δ2-hour plasma glucose (r =0.29). In women, ΔPAI-1 was significantly correlated to ΔBMI (r =0.36), Δwaist circumference (r =0.38), Δhip circumference (r =0.27), ΔCRP (r =0.27) and Δtotal cholesterol (r =0.19). The multivariate linear regression analysis showed that ΔPAI-1 was significantly related to Δfasting plasma glucose and ΔCRP in men (R2 for the complete model was 0.31). In women, ΔPAI-1 was significantly related to Δwaist circumference (R2 for the complete model was 0.17).Conclusion: We expected that changes in anthropometric, glycaemic, inflammatory and lipid markers would explain a large part of the observed PAI-1 increase. However, the multivariate analysis explained only 20% of the variation in ΔPAI-1 in women and 30% in men. Interestingly, the patterns of components correlating with the changes in PAI-1 differed between sexes.
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| 9. |
- Hernestål-Boman, Jenny, et al.
(författare)
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Long-term stability of fibrinolytic factors stored at-80 degrees C
- 2010
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Ingår i: Thrombosis Research. - : Elsevier BV. - 0049-3848 .- 1879-2472. ; 125:5, s. 451-456
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Blood samples in epidemiological studies are often stored for several years and analysed at different occasions. The reagent kits are continually modified for better precision and accuracy. Our hypothesis was that epidemiological studies are affected by long-term storage and/or modifications of reagent kits. Materials and Methods: Plasma samples stored at -80 degrees C from two populations were used: A case-referent study with samples collected from 1985 to 2000 and analysed 2005 (n=1598) were used to study influence of long-term storage. A cross-sectional study analysed 1990 (n=1558) and re-analysed 2001 (n=78) and 2005 (n=828) was used to study influence of reagent kit modifications. Fibrinolytic analyses included immunoassays of tPA, PAI-1 and tPA-PAI-1 complex and chromogenic substrate assays of the activities of tPA and PAI-1. Results: Long-term storage for a median time of 11.6 years (range 5 to 20) showed an effect of time on tPA antigen R-2=0.01, PAI-1 antigen R-2=0.01 and tPA-PAI-1 complex R-2=0.02. Modifications in reagent kits affected the levels of fibrinolytic factors; for tPA antigen the slope coefficients were between 0.72 and 0.95 (R-2 0.47-0.75), whereas tPA activity showed an agreement with slope coefficients 1.06 to 1.09 (R-2 0.67-0.93). Conclusions: This study showed that long-term storage affects fibrinolytic variables to a negligible extent, but modifications in reagent kits introduced an element of bias. We conclude that analysis of samples on a single occasion is preferable to multiple occasions, as storage has negligible effect. (C) 2009 Elsevier Ltd. All rights reserved.
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| 10. |
- Johansson, Cecilia, et al.
(författare)
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Characterization of patients with atrial fibrillation not treated with oral anticoagulants
- 2014
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Ingår i: Scandinavian Journal of Primary Health Care. - : Informa Healthcare. - 0281-3432 .- 1502-7724. ; 32:4, s. 226-231
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Tidskriftsartikel (refereegranskat)abstract
- Objective: An underuse of oral anticoagulants (OAC) in patients with atrial fibrillation (AF) has been suggested, as only 50% of all patients with AF receive OAC treatment. Whether this is due to contraindications, lack of an indication to treat, or an expression of underuse is sparsely investigated. This study therefore aimed to characterize individuals without OAC treatment in a real-life population of patients with AF. Design: Retrospective cross-sectional study. The medical records were scrutinized in order to identify the type of AF, risk factors for embolism and bleeding, and other factors of importance for OAC treatment. Setting: The municipalities of Skellefteå and Norsjö, northern Sweden. Subjects: A total of 2274 living residents with at least one verified episode of AF on or before December 31, 2010. Main outcome measures: Prevalence of treatment with OAC and documented reasons to withhold OAC treatment. Results: Among all 2274 patients with AF, 1187 (52%) were not treated with OAC. Of the untreated patients, 19% had no indication or had declined or had experienced adverse effects other than bleeding on warfarin treatment. The most common reason to withhold OAC was presence of risk factors for bleeding, found in 38% of all untreated patients. Furthermore, a documented reason could be identified to withhold OAC in 75%. Conclusions: Among patients with AF without OAC treatment a reason could be identifi ed to withhold OAC in 75%. The underuse of OAC is estimated to be 25%.
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