| 1. |
- Johansson, Magdalena, 1984-
(författare)
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Epidemiology of venous thromboembolism with focus on risk markers
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Venous thromboembolism (VTE) is a vascular disease with an incidence of approximately 140 cases per 100,000 person-years in adults. The incidence of VTE has increased over the last decades, and more than 20% of affected individuals die in the first year after diagnosis. To reduce the incidence of VTE, it is important to identify modifiable risk factors for the condition.Aims: The aims of this thesis were a) To study the incidence of first-time VTE and the prevalence of risk markers for VTE at the time of VTE diagnosis, b) To determine the validity of diagnoses of deep vein thrombosis and pulmonary embolism in administrative registries, and c) To study the association between glucose levels, diabetes, alcohol consumption, physical activity and risk of first-time VTE.Methods: To determine the incidence of first-time VTE and the prevalence of risk markers for VTE at the time of VTE diagnosis, a retrospective, population-based cohort study was conducted. The study included all adult residents of Västerbotten County during the year 2006. All other aims were addressed in the prospective, population-based Venous thromboEmbolism In Northern Sweden (VEINS) cohort study. The VEINS cohort included 108,025 residents of Västerbotten County aged 30 to 60 years without previous VTE events. They were included from 1985 onwards and were followed until a VTE event, death, emigration, or the study end on September 5, 2014. All underwent a health examination within the Västerbotten Intervention Programme where weight, height, blood pressure and glucose levels were measured, and answered a questionnaire regarding smoking, education level, medication use, history of diabetes, alcohol intake and physical activity. VTE diagnoses were validated by review of medical records and radiology reports. To study the validity of diagnoses of deep vein thrombosis and pulmonary embolism in administrative registries, a registry search for International Classification of Diseases diagnosis codes indicating pulmonary embolism and/or deep vein thrombosis events was made in the Swedish National Patient Registry and the Cause of Death Registry. An additional search using an extended set of International Classification of Diseases diagnosis codes was performed in order to identify misclassified events.Results: The incidence of first-time VTE was 137 (95% confidence interval [CI] 122–154) per 100,000 adults per year. The most common risk markers for VTE were recent hospitalization and concurrent malignancy. The positive predictive value for a diagnosis of pulmonary embolism was 80.7% (95% CI 78.4–82.9), and that of deep vein thrombosis 59.2% (95% CI 56.7–61.7). Misclassification occurred in 1.1% (95% CI 0.4–1.7) of pulmonary embolism events and in 16.4% (95% CI 14.2–18.7) of deep vein thrombosis events. In the VEINS cohort, a total of 2,054 participants experienced an objectively verified first-time VTE event during approximately 1.5 million person-years of follow-up. In univariable analysis, there were associations between fasting plasma glucose, oral glucose tolerance test two-hour post-load plasma glucose, diabetes and increased risk of first-time VTE. These associations were attenuated after adjustment for potential confounders, and were no longer significant. There was an association between alcohol consumption and risk of first-time VTE in men (P for trend 0.02 after adjustments for increased risk of first-time VTE over quartiles of weekly alcohol consumption). Alcohol dependence was associated with risk of first-time VTE in men (hazard ratio [HR] 1.30; 95% CI 1.07–1.59 after adjustments). In women, there were no significant associations between alcohol consumption and risk of first-time VTE. Women who performed leisure time physical activity at least once a week had a lower risk of first-time VTE (HR 0.83; 95% CI 0.71–0.98 after adjustments) compared to women with less or no physical activity. Women with high occupational physical activity also had a lower risk of first-time VTE (HR 0.85; 95% CI 0.74–0.98 after adjustments). In men, there were no consistent association between either measure of physical activity and risk of first-time VTE. Conclusions: VTE is a common vascular disease. Registry data on diagnoses of pulmonary embolism, but not deep vein thrombosis, is of acceptable quality and can be considered for use in registry-based studies. Glucose levels and diabetes are not associated with risk of first-time VTE. Alcohol intake and alcohol dependence are associated with an increased risk of first-time VTE in men, whereas high leisure time physical activity and occupational physical activity are associated with a decreased risk of first-time VTE in women.
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| 2. |
- Byhamre, Marja Lisa, 1981-
(författare)
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Snus use and mortality : associations, potential mechanisms, and socioeconomic aspects
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Snus is a smokeless tobacco product made of a moist powder of ground tobacco. It is used mainly in the Nordic countries, although increasingly popular internationally. The Swedish snus tradition dates back to the seventeenth century, and it is now used daily by about 23% of the male and 6% of the female population. Snus contains high levels of nicotine as well as carcinogenic substances and microorganisms that could potentially cause adverse health effects. The physiological effects of snus use include acutely raised blood pressure and heart rate, and increased cardiac oxygen demand, while the psychological response results in alertness and anxiety reduction. The high nicotine content causes rapid onset of addiction. Previous research on snus use and health is largely inconclusive, but indicates increased risks of all-cause, cardiovascular and cancer mortality. This thesis aimed to further investigate the health effects of snus use, with a focus on mortality, potential underlying mechanisms, and the impact of socioeconomic factors. Four original papers form the base of this thesis. The first study was performed on a pooled dataset of eight Swedish cohorts (The Swedish Collaboration on Health Effects of Snus use), including over 169 000 men. We found an increased risk of all-cause (HR 1.28, 95% CI 1.20; 1.35), cardiovascular, and other cause mortality, and indications of raised cancer mortality. The second study was set within an interventional program in northern Sweden (Västerbotten Intervention Programme) and included 46 000 men and women. It showed increased mortality overall (estimates similar to first study), from cardiovascular diseases, and external causes (e.g., accidents and suicide) that remained after controlling for socioeconomic status. We found these associations in groups of varying socioeconomic background (e.g., both basic education and high-income groups), suggesting that increased mortality risks among snus users are not restricted to certain socioeconomic groups. Studies three and four investigated potential underlying mechanisms that might contribute to increased mortality among snus users, including established cardiometabolic risk factors in study three (the metabolic syndrome and its components: obesity, hypertension, type 2-diabetes and abnormal blood lipids) and more novel risk factors in study four (low-grade inflammation, low vitamin D-concentrations, and altered iii testosterone levels). The analytical samples were drawn from a long- term follow-up study of around 900 16-year-olds in a municipality in northern Sweden (Northern Sweden Cohort, study three) and more than 6 000 participants in another population-based cohort (the Northern Sweden MONICA study, study four). We found no associations between snus use and established cardiometabolic risk factors, but there was evidence of lower concentrations of inflammatory and vitamin D-status biomarkers in both men and women, and higher testosterone concentrations in men who were currently using snus. We conclude that snus use is associated with increased all-cause and cardiovascular mortality, and to death by other causes, that may be restricted to external causes. Cancer mortality may also be increased among snus users. The associations cannot be fully explained by differences in socioeconomic status among snus users and non-users. Established cardiometabolic risk factors do not seem to be the main mechanisms behind these associations. Lower inflammatory biomarker levels among snus users may serve as a protective factor, while lower vitamin D-concentrations and increased testosterone levels may be part of an underlying mechanism linking snus use to increased mortality. Future research should focus on the health consequences of snus use among women, on other possible links between snus use and death, and on mortality in different cancers among users of snus. The health consequences of dual use of snus and cigarettes should also be assessed.
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| 3. |
- Johansson, Kristina, 1986-
(författare)
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Biomarkers and risk of intracerebral hemorrhage : population-based studies in northern Sweden
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- BackgroundIntracerebral hemorrhage (ICH) is a disease associated with a high morbidity and mortality and treatment options for the condition are limited. Even though an ICH event usually comes as a surprise to the affected individual, pathogenetic processes often have occurred before the sudden ICH event and may have preceded disease onset by years. It is possible that individuals at increased risk of ICH could be identified using biomarkers, for example markers of hemostasis and fibrinolysis. Even if these biomarkers are not part of the causal chain, they could be used as risk indicators to better define high-risk groups. Another approach could be to measure already established risk markers for ICH, such as self-reported alcohol consumption, using a blood biomarker. That could increase measurement reliability and consequently the accuracy of the estimates of ICH risk.AimsThe aim of this thesis was to investigate potential biomarkers and risk of ICH. Specific aims were to evaluate the associations between factor XII, D-dimer, von Willebrand factor (VWF), ABO blood groups with focus on blood group O, phosphatidylethanol (PEth), and risk of ICH.MethodsIn our first study, aiming to investigate the association between factor XII and risk of hemorrhagic stroke, we followed participants of the health examination northern Sweden MONItoring trends and determinants in CArdiovascular disease (MONICA) performed in 1994 as a cohort until 2011. Factor XII concentrations were measured in blood samples drawn at the baseline health examination where the participants also answered a questionnaire regarding lifestyle factors and medical history. Diagnosis codes from the National Patient Register and the Swedish Cause of Death Register were used to find cases of hemorrhagic stroke, defined as ICH or subarachnoid hemorrhage. In the subsequent studies, the associations between biomarkers (factor XII, D-dimer, VWF, ABO blood groups, and PEth) and risk of ICH were investigated using a matched, nested case-referent design including individuals that had participated in the Västerbotten Intervention Programme, the MONICA and the Mammography Screening Project in 1985–2007. The participants donated blood samples at baseline for future research which were stored at -80 degrees C until biomarker analyses. The majority of the participants also underwent a baseline health examination including a questionnaire. First-ever ICH diagnoses during the study period 1985–2007 were validated using medical records and autopsy reports. To each case, two referents were matched for age, sex, geographical region, health examination date and health examination setting. ResultsIn the cohort study of the association between factor XII concentrations and risk of hemorrhagic stroke, 1,852 participants were included among which 30 experienced a hemorrhagic stroke event. There was an association between high factor XII and risk of hemorrhagic stroke in a multivariable model (hazard ratio 1.51; 95% confidence interval [CI] 1.03–2.21 per standard deviation [SD] of factor XII). In the case-referent study of the association between factor XII and risk of ICH, 70 cases with ICH and 137 matched referents were included. We found no association between factor XII and risk of ICH in a multivariable model (odds ratio [OR] 1.06; 95% CI 0.57–1.97 per SD of factor XII). The study of the association between D-dimer and risk of ICH included 141 cases and 255 matched referents. We found an association between D-dimer and risk of ICH in a multivariable model (OR 1.36; 95% CI 1.05–1.77 per SD of D-dimer). When stratifying the analysis for time between blood sampling and ICH event in tertiles, the association remained significant in the cases with the shortest time between blood sampling and ICH event in a multivariable model (OR 1.78; 95% CI 1.05–3.05 per SD of D-dimer). The study investigating the association between VWF and risk of ICH included 139 cases and 276 referents. We found no association between VWF and risk of ICH in a multivariable model (OR 0.85; 95% CI 0.54–1.34 per SD of VWF). In the analysis investigating the associations between ABO blood groups and risk of ICH, 162 cases and 317 referents were included. We found no association between blood group O compared to non-O blood groups and risk of ICH (OR 0.96; 95% CI 0.65–1.42). In the study of the association between PEth concentrations and risk of ICH, 97 cases and 180 referents were included. There was an association between PEth concentrations > 0.30 µmol/L compared to < 0.01 µmol/L and risk of ICH in a multivariable model (OR 4.64; 95% CI 1.49–14.40).ConclusionsHigh concentrations of D-dimer and PEth are associated with an increased risk of ICH. Our conclusion of the two studies investigating the association between factor XII and risk of hemorrhagic stroke and ICH respectively is that there is no association between factor XII and risk of ICH. We found no association between VWF or blood group O and risk of ICH.
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| 4. |
- Olofsson, Mona, 1952-
(författare)
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Heart failure in elderly with focus on diagnosis and prognosis
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Patients older than 75 years with heart failure (HF) are at increased risk for mortality and hospital admissions. Echocardiography and brain natriuretic peptides (BNP, NTproBNP) are important diagnostic tools but sparsely evaluated in elderly PHC patients. Aims: Validate the clinical diagnosis of HF, investigate the types of HF and underlying cardiovascular disorders with focus on sex and age differences. Explore the sensitivity, specificity, negative and positive predictive values (NPV, PPV) of BNP and NT-proBNP in patients with systolic HF. Study the associations of HF or NTproBNP on all-cause and cardiovascular mortality. Study the prognostic value of different biomarkers and HF, on all-cause and cardiovascular hospitalizations. Methods: Patients with suspected HF were recruited from one selected PHC and registered on a prespecified record and referred for an echocardiographic examination and a final cardiologist consultation. Blood samples for natriuretic peptides were stored frozen at – 70° C. Death certificates were used to register all-cause mortality and cardiovascular mortality. To register hospitalisations, medical records were used and classification was defined according to ICD-10. Results The GPs identified 121 women and 49 men with suspected HF of whom 39% (51 women and 16 men) were above 80 years. Myocardial infarction (OR:4,3 CL: 1,8-10,6) hypertension (OR:3,4 CI:1,6-6,9) atrial fibrillation (OR:2,8 CL:1,0-7,9) predicted a confirmed diagnosis of HF. Confirmed HF was verified in 45% of the patients and was significantly more common in men than women (p=0,02). The best NPV was 88 % for NT-proBNP (200 ng/L) and 87 % for BNP (20 pg/ml). Age and male gender were independently associated with higher levels of NT-proBNP. During the 10-year follow up, 71 out of 144 patients died. In univariate Cox regression analysis, significant associations were found for overall HF (hazard ratio [HR]: 1.86; 95% confidence interval [CI]:1.15- 3.01), isolated systolic HF (HR:1.95; 95% CI:1.06-3.61), and combined (systolic and diastolic) HF (HR:3.28; 95% CI:1.74-6.14) with all-cause mortality, but not for isolated diastolic HF. In multivariable analysis, age (HR: 1.11; 95% CI: 1.06-1.17), kidney dysfunction (HR:1.91; 95% CI:1.11- 3.29), smoking (HR:3.70; 95% CI:2.02-6.77), and NTproBNP (HR:1.01; 95% CI:1.00-1.02), but not any type of HF, significantly predicted all-cause mortality. During ten years, 136 (80%) patients were hospitalised with 660 and 207 for all-cause and cardiovascular hospitalisations, respectively. Age (OR:1.1; 95% CI:1.01-1.15) and underlying heart disease (OR:3.5; 95% CI:1.00-11.89), significantly predicted all-cause hospitalisation. Overall HF (HR:1.8; 95% CI:1.06-2.94) significantly predicted time to first all-cause hospitalisations. For cardiovascular hospitalisations age (OR:1.1;95%CI:1.01-1.12), underlying heart disease (OR:3.4;95%CI:1.04-11.40) and NTproBNP ≥800 ng/L (OR:4,3;95%CI:1.5-12.50) were significant predictors. Conclusion: A confirmed diagnosis of HF was present in 45% of the patients. NPV was high, but not as high as in younger patients with HF. Patients with systolic HF had a higher mortality than patients with diastolic HF compared to patients with no HF. Patients with combined HF were at even higher risk for all-cause mortality and cardiovascular mortality. Age, kidney dysfunction, NTproBNP and smoking predicted mortality. Age and underlying heart diseases were predictors for all-cause hospitalisations and together with NTproBNP they also predicted cardiovascular hospitalisations.
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| 5. |
- Wennberg, Maria, 1974-
(författare)
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Biomarkers of fish consumption and risk of stroke or myocardial infarction
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The effect of fish consumption on the risk of cardiovascular disease has been extensively studied. Omega-3 fatty acids present in fish, namely eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been found to have beneficial effects through several mechanisms. In addition, selenium, an antioxidant, may be protective. Fish also represents the main human exposure source to the pollutant methylmercury (MeHg), which is associated with elevated cardiovascular risk in previous studies. The aim of this thesis was to evaluate whether MeHg is associated with the risk of myocardial infarction (MI) or stroke, whether EPA+DHA or selenium (Se) have protective associations, and if the overall association between fish consumption and risk of stroke or MI is detrimental or protective. A prospective incident case-control study design was used to study effects on stroke or MI. Three hundred and sixty-nine cases with twice as many matched controls were included in the study on stroke, while 431 cases with 499 controls participated in the MI study, all from the Northern Sweden Health and Disease Study. The data was collected from health examinations of the population from 1986 until 1999. Also, time trends in burdens of mercury (Hg), lead (Pb) and cadmium (Cd) in erythrocytes (Ery) from 1990 to 1999 were examined. The food frequency questionnaire (FFQ) used in the case-control studies was correlated with measurements of fatty acids in erythrocyte membranes as biomarkers of intake. In this northern Swedish population, levels of Ery-Hg and Ery-Pb decreased during the 1990´s, but Ery-Cd decreased only in smoking men. No significant associations were found between Ery-Hg or levels of EPA+DHA and the risk of stroke. Men reporting fish consumption >3 meals/week had an elevated risk of stroke. In the MI study, higher levels of Ery-Hg were associated with lower risk of MI. No clear associations were found for reported fish consumption, levels of EPA+DHA or Ery-Se. The validated FFQ has a fair reliability in estimating intake of fatty acids EPA and DHA. However, the low variation in fish consumption in the general population in combination with different versions of the FFQ (with pre-defined, multiple choice alternatives) decreased the reliability of self-reported fish consumption in the case-control studies on risk of stroke or MI. In conclusion, MeHg has no harmful association regarding the risk of stroke or MI in this population with generally low exposure levels. The protective association regarding risk of MI is probably due to Ery-Hg being a biomarker for consumption of fish, a source of other beneficial nutrients. Thus, in this population the benefits of the nutrients in fish appear to overcome the potential harm of MeHg. The finding of elevated stroke risk related to high fish consumption in men will be investigated further.
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| 6. |
- Wennberg, Patrik, 1972-
(författare)
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Beyond the established risk factors of myocardial infarction : lifestyle factors and novel biomarkers
- 2009
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Age, male sex, hypertension, smoking, diabetes, dyslipidaemia, and obesity are considered as established risk factors for cardiovascular diseases. Several of these established cardiovascular risk factors are strongly influenced by lifestyle. Novel biomarkers from different mechanistic pathways have been associated with cardiovascular risk, but their clinical utility is still uncertain. The overall objective of the thesis was to evaluate the associations between certain lifestyle factors (physical activity and snuff use), biomarkers reflecting the haemostatic and the inflammatory systems and risk of a future first-ever myocardial infarction. A prospective incident nested case-control study design was used with a total of 651 cases of myocardial infarction and 2238 matched controls from the population-based Northern Sweden Health and Disease Study. The effects of commuting activity, occupational and leisure time physical activity on risk of myocardial infarction were studied. A clearly increased risk of myocardial infarction was found for car commuting compared to active commuting (walking, cycling or going by bus). High versus low leisure time physical activity was associated with decreased risk of myocardial infarction. Low occupational physical activity was associated with risk of myocardial infarction in men. The risk of myocardial infarction or sudden cardiac death was studied in male snuff users compared to non-tobacco users. No increased risk was found for myocardial infarction or sudden cardiac death among snuff users without a previous history of smoking. However, for sudden cardiac death the study did not have statistical power to detect small differences in risk. Plasma levels of haemostatic markers have previously shown to be associated with risk of myocardial infarction, but as haemostatic markers are also acute-phase reactants, it is not clear if their association with myocardial infarction is independent of inflammatory markers. In the present study, the haemostatic markers D-dimer, von Willebrand factor (VWF), tissue plasminogen activator (t-PA), and tissue plasminogen activator/plasminogen activator inhibitor-1 complex (t-PA/PAI-1 complex) were associated with risk of myocardial infarction after adjustment for established risk factors and the inflammatory markers C-reactive protein (CRP) and interleukin 6 (IL-6). Furthermore, the addition of eight haemostatic and inflammatory markers could improve the predictive ability for future myocardial infarction beyond that of a model utilizing only established risk factors. Established risk factors and novel biomarkers were explored as potential mediators of the reduced risk of myocardial infarction related to active commuting. A combination of established risk factors, haemostatic and inflammatory markers appeared to explain a substantial proportion (40%) of the difference in risk for myocardial infarction between active commuters and car commuters. IL-6, t-PA, t-PA/PAI-1 complex, apo B/apo A-1 ratio, and BMI seemed to be the largest potential mediators when tested individually. In conclusion, regular physical activity such as active commuting is associated with reduced risk of a first-ever myocardial infarction. This effect could in part be mediated through a beneficial influence on haemostasis and inflammation, as well as a positive impact on established risk factors. Several haemostatic markers are associated with risk of myocardial infarction independent of established risk factors and inflammatory markers. The combination of haemostatic and inflammatory markers may enhance predictive ability beyond established risk factors. Our findings do not support the hypothesis that snuff use increases the risk of myocardial infarction.
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