Atrial fibrillation is associated with cognitive decline in stroke-free subjects: the Tromsø Study.

BACKGROUND AND PURPOSE: Previous studies have shown associations between atrial fibrillation (AF) and cognitive decline. We investigated this association in a prospective population study, focusing on whether stroke risk factors modulated this association in stroke-free women and men. METHODS: We included 4983 participants (57% women) from the fifth survey of the Tromsø Study (Tromsø 5, 2001), of whom 2491 also participated in the sixth survey (Tromsø 6, 2007-2008). Information about age, education, blood pressure, body mass index, lipids, smoking, coffee consumption, physical activity, depression, coronary and valvular heart disease, heart failure and diabetes was obtained at baseline. AF status was based on hospital records. The outcome was change in cognitive score from Tromsø 5 to Tromsø 6, measured by the verbal memory test, the digit-symbol coding test and the tapping test. RESULTS: Mean age at baseline was 65.4 years. The mean reduction in the tapping test scores was significantly larger in participants with AF (5.3 taps/10 s; 95% CI: 3.9, 6.7) compared with those without AF (3.8 taps/10 s; 95% CI: 3.5, 4.1). These estimates were unchanged when adjusted for other risk factors and were similar for both sexes. AF was not associated with change in the digit-symbol coding or the verbal memory tests. CONCLUSION: Atrial fibrillation in stroke-free participants was independently associated with cognitive decline as measured with the tapping test.

HbA1c levels in non-diabetic older adults - No J-shaped associations with primary cardiovascular events, cardiovascular and all-cause mortality after adjustment for confounders in a meta-analysis of individual participant data from six cohort studies.

BACKGROUND: To determine the shape of the associations of HbA1c with mortality and cardiovascular outcomes in non-diabetic individuals and explore potential explanations. METHODS: The associations of HbA1c with all-cause mortality, cardiovascular mortality and primary cardiovascular events (myocardial infarction or stroke) were assessed in non-diabetic subjects ≥50 years from six population-based cohort studies from Europe and the USA and meta-analyzed. Very low, low, intermediate and increased HbA1c were defined as <5.0, 5.0 to <5.5, 5.5 to <6.0 and 6.0 to <6.5% (equals <31, 31 to <37, 37 to <42 and 42 to <48 mmol/mol), respectively, and low HbA1c was used as reference in Cox proportional hazards models. RESULTS: Overall, 6,769 of 28,681 study participants died during a mean follow-up of 10.7 years, of whom 2,648 died of cardiovascular disease. Furthermore, 2,493 experienced a primary cardiovascular event. A linear association with primary cardiovascular events was observed. Adjustment for cardiovascular risk factors explained about 50% of the excess risk and attenuated hazard ratios (95 confidence interval) for increased HbA1c to 1.14 (1.03-1.27), 1.17 (1.00-1.37) and 1.19 (1.04-1.37) for all-cause mortality, cardiovascular mortality and cardiovascular events, respectively. The six cohorts yielded inconsistent results for the association of very low HbA1c levels with the mortality outcomes and the pooled effect estimates were not statistically significant. In one cohort with a pronounced J-shaped association of HbA1c levels with all-cause and cardiovascular mortality (NHANES), the following confounders of the association of very low HbA1c levels with mortality outcomes were identified: race/ethnicity; alcohol consumption; BMI; as well as biomarkers of iron deficiency anemia and liver function. Associations for very low HbA1c levels lost statistical significance in this cohort after adjusting for these confounders. CONCLUSIONS: A linear association of HbA1c levels with primary cardiovascular events was observed. For cardiovascular and all-cause mortality, the observed small effect sizes at both the lower and upper end of HbA1c distribution do not support the notion of a J-shaped association of HbA1c levels because a certain degree of residual confounding needs to be considered in the interpretation of the results.

Risk factors for aneurysmal subarachnoid hemorrhage - BMI and serum lipids: 11-year follow-up of the HUNT and the Tromsø Study in Norway.

OBJECTIVES: Life-style factors have been associated with the risk for aneurysmal subarachnoid hemorrhage (aSAH), but it is not clear whether body mass index (BMI) and serum lipids are associated with risk. We prospectively assessed these associations in two large population studies. METHODS: A total of 65,526 participants in the Nord-Trøndelag Health Study (1995-1997) and 26,882 participants in the Tromsø Study (1994-1995) were included. Studies included measurements of body weight and height, serum lipids, and self-administered questionnaires. Participants who experienced aSAH were identified, and hazard ratios (HRs) were estimated using Cox regression analysis. RESULTS: During 11 years of follow-up, aSAH was diagnosed in 122 participants. Overweight (BMI 25-29.9) was negatively associated with the risk of aSAH (HR 0.7, 95% CI 0.4-1.0). There was no over all association of total serum cholesterol, HDL cholesterol, or triglycerides with the risk of aSAH, but in participants younger than 50 years, HDL cholesterol was inversely associated with the risk (HR per standard deviation increase 0.6, 95% CI 0.4-0.9). CONCLUSIONS: Overweight may be associated with reduced risk of aSAH, but there was no over all association of total serum cholesterol, HDL cholesterol, or triglycerides with the risk of aSAH in this prospective study.

Glycated hemoglobin in diagnosis of diabetes mellitus and pre-diabetes; validation by oral glucose tolerance test. The Tromsø OGTT Study.

BACKGROUND: Glycated hemoglobin (HbA(1c)) 6.5% has recently been recommended by the World Health Organization (WHO) and the American Diabetes Association (ADA) as an alternative diagnostic criterion for diabetes mellitus (DM). AIM: To evaluate HbA(1c) as an alternative to oral glucose tolerance test (OGTT) for diagnosis of DM and pre-diabetes and to find the optimal HbA(1c) cut-off points for DM and pre-diabetes in our population. SUBJECTS AND METHODS: The subjects were recruited from the Tromsø Study, performed for the 6th time in 2007-2008 with 12,984 participants. All subjects with HbA(1c) in the range 5.8-6.9% and a random sample of subjects with levels 5.3-5.7% were invited to an OGTT. RESULTS: Among 3476 subjects who completed the OGTT, 199 were diagnosed with DM. The best sensitivity (69.8%) and specificity (81.8%) were found at HbA(1c) 6.2%. For HbA(1c) 6.5% we found a sensitivity of 34.7% and specificity 97.1%. The best cut-off points for impaired fasting glucose (no.=314) and impaired glucose tolerance (no.=404) were found at HbA(1c) 5.9% and 6.0%, respectively. Pre-diabetes detected only by OGTT was associated with worse metabolic characteristics than pre-diabetes detected only by HbA(1c). CONCLUSIONS: The optimum HbA(1c) cutoff point for DM in our population was lower than that proposed by WHO and ADA. To establish more precisely the HbA(1c) levels predictive of micro- and macro-vascular complications, long-term prospective studies are needed. Population- specific optimum cut-off points may be necessary.

Incidence of aneurysmal subarachnoid hemorrhage in Norway, 1999-2007.

OBJECTIVE: To investigate changes and regional variations in annual incidence rates of aneurysmal subarachnoid hemorrhage (SAH) in Norway between 1999 and 2007. METHODS: The authors retrospectively reviewed data from the Norwegian Patient Register for the period 1999-2007. RESULTS: Crude incidence of aneurysmal SAH was 10.0/100,000 person years [95% CI (confidence interval): 9.7-10.3] and was higher in women (12.0/100,000 person years; 95% CI: 11.5-12.5) than men (8.1/100,000 person years; 95% CI: 7.7-8.4). Decreasing annual incidence rates were observed from 11.1/100,000 person years (95% CI: 10.5-11.6) in the period 1999-2001 to 8.9/100,000 person years (95% CI: 8.4-9.4) in the period 2005-2007 (P for trend <0.001). Regional variations were observed, from 8.4/100,000 person years (95% CI: 7.7-9.00) in the southern region, 10.4/100,000 person years (95% CI: 9.5-11.2) in the central region and 11.9/100,000 person years (95% CI: 10.8-12.9) in the northern region. CONCLUSIONS: Incidence of aneurysmal SAH in Norway decreased from 1999 to 2007, with significant regional variations indicating an increasing gradient from south to north.

Combined analyses and extended follow-up of two randomized controlled homocysteine-lowering B-vitamin trials.

OBJECTIVES: In the Norwegian Vitamin Trial and the Western Norway B Vitamin Intervention Trial, patients were randomly assigned to homocysteine-lowering B-vitamins or no such treatment. We investigated their effects on cardiovascular outcomes in the trial populations combined, during the trials and during an extended follow-up, and performed exploratory analyses to determine the usefulness of homocysteine as a predictor of cardiovascular outcomes. DESIGN: Pooling of data from two randomized controlled trials (1998-2005) with extended post-trial observational follow-up until 1 January 2008. SETTING: Thirty-six hospitals in Norway. SUBJECTS: 6837 patients with ischaemic heart disease. INTERVENTIONS: One capsule per day containing folic acid (0.8 mg) plus vitamin B12 (0.4 mg) and vitamin B6 (40 mg), or folic acid plus vitamin B12, or vitamin B6 alone or placebo. MAIN OUTCOME MEASURES: Major adverse cardiovascular events (MACEs; cardiovascular death, acute myocardial infarction or stroke) during the trials and cardiovascular mortality during the extended follow-up. RESULTS: Folic acid plus vitamin B12 treatment lowered homocysteine levels by 25% but did not influence MACE incidence (hazard ratio, 1.07; 95% CI, 0.95-1.21) during 39 months of follow-up, or cardiovascular mortality (hazard ratio, 1.12; 95% CI, 0.95-1.31) during 78 months of follow-up, when compared to no such treatment. Baseline homocysteine level was not independently associated with study outcomes. However, homocysteine concentration measured after 1-2 months of folic acid plus vitamin B12 treatment was a strong predictor of MACEs. CONCLUSION: We found no short- or long-term benefit of folic acid plus vitamin B12 on cardiovascular outcomes in patients with ischaemic heart disease. Our data suggest that cardiovascular risk prediction by plasma total homocysteine concentration may be confined to the homocysteine fraction that does not respond to B-vitamins.

Baseline serum 25-hydroxyvitamin D concentrations in the Tromsø Study 1994-95 and risk of developing type 2 diabetes mellitus during 11 years of follow-up.

AIMS: We wanted to test the hypothesis that low serum 25-hydroxyvitamin D (25(OH)D) concentrations are associated with increased risk of developing Type 2 diabetes mellitus (DM) in a population-based cohort during 11 years of follow-up. METHODS: The analyses included 4157 non-smokers and 1962 smokers from the Tromsø Study 1994-95 without diabetes at baseline. Subsequent Type 2 DM was defined using a hospital journal-based end-point registry, completed through the year 2005. Participants were allocated into quartiles of serum 25(OH)D within each month to account for seasonal variation, and serum 25(OH)D values both as a continuous variable and in quartiles were used in Cox regression models. The analyses were stratified by smoking. Adjustments were made for age, sex, body mass index (BMI), physical activity and, in non-smokers, former smoking. RESULTS: Type 2 DM was registered in 183 non-smoking and 64 smoking participants. Using the fourth (highest) quartile of serum 25(OH)D as the reference, non-smoking participants in the third, second and first quartiles had age- and sex-adjusted hazard ratios (95% confidence intervals) of incident Type 2 DM of 1.00 (0.62-1.61), 1.50 (0.97-2.31) and 1.89 (1.25-2.88), respectively, whereas the corresponding values for smokers were 1.79 (0.77-4.19), 2.33 (1.02-5.35) and 2.68 (1.18-6.08). Adjustment for BMI attenuated the hazard ratios, and they were no longer significant. CONCLUSIONS: Baseline serum 25(OH)D was inversely associated with subsequent Type 2 DM in a population-based 11 year follow-up study, but not after adjustment for BMI. Randomized trials are needed to define the possible role of serum 25(OH)D status, and thereby the role of supplementation, in the prevention of Type 2 DM.

Endogenous testosterone and the prospective association with carotid atherosclerosis in men: the Tromsø study.

The role of testosterone in the development of cardiovascular disease is controversial. Recent observational studies, however, suggest a protective role of normal endogenous testosterone levels in the development of atherosclerosis. In a cohort from the Tromsø study, 1,101 men had both hormone-levels measured and the right carotid artery examined by ultrasound in 1994 and 2001. We studied the prospective association between sex hormone-levels and progression of carotid intima-media thickness (IMT) and plaque area from 1994 to 2001. We also performed a cross-sectional study of 2,290 men from the population in 2001. The data were analysed by univariate correlations, analyses of covariance and multiple linear regression analyses. In the cross-sectional study, we found an inverse association between testosterone levels and total carotid plaque area (P < 0.05), after adjusting for age, systolic blood pressure, smoking and use of lipid-lowering drugs. We found no prospective associations between sex hormone-levels and change in plaque area or IMT from 1994 to 2001. The lack of prospective associations in our study may be due to increased use of anti-hypertensive and lipid-lowering drugs from 1994 baseline to follow-up.

Repeated measurements of carotid atherosclerosis and future risk of venous thromboembolism: the Tromsø Study.

Essentials The relationship between atherosclerosis and venous thromboembolism (VTE) is controversial. In total, 10 426 participants recruited from the general population were included. Carotid intima media thickness and total plaque area was not associated with VTE. There was no association between plaque initiation or plaque progression and subsequent VTE. SUMMARY: Background Whether a relationship between atherosclerosis and subsequent venous thromboembolism (VTE) exists is controversial. Objective To investigate the association between carotid atherosclerosis and VTE by using repeated measurements of intima media thickness (IMT) and total plaque area (TPA) in participants recruited from the general population. Methods Participants were recruited from the fourth (1994-1995), fifth (2001-2002) and sixth (2007-2008) surveys of the Tromsø Study. In total, 10 426 participants attended, for whom measurements of carotid IMT and TPA and potential confounders were updated at each available survey. Time-varying Cox regression models were used to calculate hazard ratios (HRs) of VTE across various levels of IMT and TPA adjusted for age, sex, and body mass index. Results There were 368 incident VTE events during a median follow-up of 10.8 years. Participants with increasing IMT were, on average, older and had a less favorable cardiovascular risk profile. There was no association between tertiles of increasing TPA and the risk of VTE in the time-varying model, and increasing IMT was not associated with an increased risk of VTE (HR 0.96, 95% confidence interval [CI] 0.86-1.07). Neither plaque formation nor plaque progression was associated with the risk of VTE (respectively: HR 1.00, 95% CI 0.98-1.02; and HR 0.96, 95% CI 0.84-1.11). Conclusion Carotid IMT and TPA were not associated with an increased risk of VTE in time-varying analyses. Furthermore, there was no association between plaque initiation or plaque progression and subsequent VTE.

C-reactive protein, obesity, and the risk of arterial and venous thrombosis.

UNLABELLED: Essentials We performed repeated measurements of C-reactive protein (CRP) and obesity in a cohort study. CRP was associated with risk of myocardial infarction and venous thromboembolism. CRP was a mediator for risk of myocardial infarction in obese men and women. CRP was a partial mediator for risk of venous thromboembolism in obese women, but not in men. SUMMARY: Background Low-grade inflammation in obesity may be a shared pathway for the risk of venous thromboembolism (VTE) and myocardial infarction (MI). Objectives To investigate the associations between repeated measurements of C-reactive protein (CRP) and the risks of MI and VTE, and to explore whether CRP mediated these risks in obese subjects. Methods CRP and obesity measures were collected from 15 134 subjects who participated in one or more surveys of the Tromsø study in 1994-1995, 2001-2002, or 2007-2008. Incident VTEs and MIs were registered until 1 January 2011. Time-varying Cox regression models were used to calculate hazard ratios of MI and VTE according to categories of CRP and obesity measures. Results There were 291 VTEs and 920 MIs during follow-up. High levels of CRP (≥ 3 mg L(-1) versus < 1 mg L(-1) ) were associated with increased risks of MI (hazard ratio [HR] 1.73; 95% confidence interval [CI] 1.32-2.26) and VTE (HR 1.84; 95% CI 1.22-2.78) in women, but only with MI in men (HR 1.93; 95% CI 1.53-2.44). All obesity measures showed stronger associations with CRP in women than in men. In obese women (body mass index [BMI] of ≥ 30 kg m(-2) versus < 25 kg m(-2) ), adjustment for CRP attenuated the risk estimate for VTE by 22%, whereas the incidence rates of VTE increased with combined categories of higher BMI and CRP. No association was found in men. Conclusions Our findings suggest that low-grade inflammation, assessed by measurement of CRP, is associated with the risks of MI and VTE, and may be a shared pathway for MI and VTE in obesity.

Impact of incident myocardial infarction on the risk of venous thromboembolism: the Tromsø Study.

UNLABELLED: Essentials Registry-based studies indicate a link between arterial- and venous thromboembolism (VTE). We studied this association in a cohort with confounder information and validated outcomes. Myocardial infarction (MI) was associated with a 4.8-fold increased short-term risk of VTE. MI was associated with a transient increased risk of VTE, and pulmonary embolism in particular. SUMMARY: Background Recent studies have demonstrated an association between venous thromboembolism (VTE) and arterial thrombotic diseases. Objectives To study the association between incident myocardial infarction (MI) and VTE in a prospective population-based cohort. Methods Study participants (n = 29 506) were recruited from three surveys of the Tromsø Study (conducted in 1994-1995, 2001-2002, and 2007-2008) and followed up to 2010. All incident MI and VTE events during follow-up were recorded. Cox regression models with age as the time scale and MI as a time-dependent variable were used to calculate hazard ratios (HRs) of VTE adjusted for sex, body mass index, blood pressure, diabetes mellitus, HDL cholesterol, smoking, physical activity, and education level. Results During a median follow-up of 15.7 years, 1853 participants experienced an MI and 699 experienced a VTE. MI was associated with a 51% increased risk of VTE (HR 1.51; 95% confidence interval [CI] 1.08-2.10) and a 72% increased risk of pulmonary embolism (PE) (HR 1.72; 95% CI 1.07-2.75), but not significantly associated with the risk of deep vein thrombosis (DVT) (HR 1.36; 95% CI 0.86-2.15). The highest risk estimates for PE were observed during the first 6 months after the MI (HR 8.49; 95% CI 4.00-18.77). MI explained 6.2% of the PEs in the population (population attributable risk) and 78.5% of the PE risk in MI patients (attributable risk). Conclusions Our findings indicate that MI is associated with a transient increased VTE risk, independently of traditional atherosclerotic risk factors. The risk estimates were particularly high for PE.

Preinfarction blood pressure and smoking are determinants for a fatal outcome of myocardial infarction: a prospective analysis from the Finnmark Study.

BACKGROUND: Serum cholesterol levels, blood pressure, and smoking are the classic coronary risk factors, but what determines whether a myocardial infarction will be fatal or not? OBJECTIVE: To investigate cardiovascular risk factors that may influence survival in subjects with coronary heart disease (myocardial infarction and sudden death). SUBJECTS AND METHODS: All inhabitants aged 35 to 52 years in Finnmark County, Norway, were invited to a cardiovascular survey in 1974-1975 and/or 1977-1978. Attendance rate was 90.5%. A total of 6995 men and 6320 women were followed up for 14 years with regard to incident myocardial infarction and sudden death. Predictors for 28-day case fatality rate after first myocardial infarction were analyzed. RESULTS: During 186 643 person-years, 635 events among men and 125 events among women were registered. The case fatality rate was 31.6% in men and 28.0% in women (P =.50). Among men (women) with baseline systolic blood pressure lower than 140 mm Hg, the 28-day case fatality rate was 24.5% (22.6%), among those with systolic blood pressure of 140 through 159 mm Hg, the case fatality rate was 35.6% (28.2%), and among those with systolic blood pressure of 160 mm Hg or higher, the case fatality rate was 48.2% (41.7%). Of the 760 subjects with myocardial infarction, 348 died during follow-up. In Cox regression analysis, systolic blood pressure at baseline was strongly related to death (relative risk per 15 mm Hg, 1.22; 95% confidence interval, 1.13-1.31). Daily smoking at baseline (relative risk, 1.40; 95% confidence interval, 1.07-1.85) and age at time of event (relative risk per 5 years, 1.12; 95% confidence interval, 1.01-1.24) were additional significant risk factors, while total serum and high-density lipoprotein cholesterol levels were unrelated to survival. Similar results were obtained with diastolic blood pressure in the model. CONCLUSIONS: Preinfarction blood pressure was an important predictor of case fatality rate in myocardial infarction. Daily smoking and age were additional significant predictors.

Physical activity improves the metabolic risk profiles in men and women: the Tromsø Study.

BACKGROUND: Because physical activity may affect risk of certain chronic diseases, we wanted to examine the effects of leisure time physical activity on the metabolic profiles. METHODS: In a population-based cohort study, 5220 men and 5869 women, aged 20 to 49 years at entry, took part in 2 surveys (1979-1980 and 1986-1987) with repeated assessments of self-reported leisure time activity. Measurements of body mass index (measured as the weight in kilograms divided by the square of the height in meters [BMI]) and levels of serum triglyceride, total cholesterol (total C), and high-density lipoprotein cholesterol (HDL-C) were studied in relation to 4 levels of physical activity. RESULTS: There was a dose-response relationship between serum lipid levels and BMI, and levels of physical activity in both sexes after adjustments for potential confounders. Differences in BMI and serum lipid levels between sedentary and sustained exercising groups were consistently more pronounced after 7 years than at baseline, especially in the oldest age group. Men reporting sustained very hard exercising compared with sedentary men had lower total C concentrations (5.65 mmol/L vs 6.21 mmol/L [218 mg/dL vs 240 mg/dL]), triglyceride levels (1.34 mmol/L vs 1.85 mmol/L [118 mg/dL vs 164 mg/dL] ), total C/HDL-C ratios by 19.0%, and BMI (23.9 kg/m2 vs 25.7 kg/m2), and higher HDL-C levels (1.52 mmol/L vs 1.36 mmol/L [59 mg/dL vs 52 mg/dL]). The combined sustained hard and very hard exercising group of women compared with sedentary women had lower total C concentrations (5.70 mmol/L vs 5.90 mmol/L [220 mg/ dL vs 228 mg/dL]), triglyceride levels (1.03 mmol/L vs 1.18 mmol/L [91 mg/dL vs 104 mg/dL]), total C/HDL-C ratios by 7.5%, BMI (23.1 kg/m2 vs 23.6 kg/m2), and higher HDL-C levels (1.73 mmol/L vs 1.66 mmol/L [67 mg/dL vs 64 mg/ dL]). An increase in leisure time activity over the 7 years improved metabolic profiles, whereas a decrease worsened them in both sexes. CONCLUSIONS: Sustained high levels and change from sedentary to higher levels of physical activity relative to sedentary men and women improved the metabolic risk profiles in both sexes. The differences observed are sufficiently large to have a beneficial effect in the prevention of certain chronic diseases.

Increase in weight in all birth cohorts in a general population: The Tromsø Study, 1974-1994.

BACKGROUND: Obesity is a risk factor for a number of chronic diseases. Few longitudinal studies have examined changes in body mass index (BMI [calculated as weight in kilograms divided by the square of the height in meters]). OBJECTIVE: To investigate the changes in mean BMI and the prevalence of obesity in a large cohort examined several times during a 20-year period. METHODS: Mean BMI, the percentage of subjects with low BMI (<20 kg/m(2)), and the percentage who were obese (BMI > or =30 kg/m(2)) were determined in a large population of men and women who were examined up to 4 times during a 20-year period (1974-1994/1995). In a longitudinal design, we observed 3541 men who attended all 4 screenings (1974-1994/1995) and 4993 women who attended the last 3 screenings (1979/1980-1994/1995). RESULTS: The age- (25-49 years) and sex-adjusted mean BMI increased 1 kg/m(2) in men from 1974 to 1994/1995 and 0.9 kg/m(2)in women from 1979/1980 to 1994/1995. In the last survey, subjects aged 25 to 85 years were included. In most age groups, the mean BMI exceeded 25 kg/m(2) and the prevalence of obesity was 10% or higher in men and women aged 45 years or older. In the longitudinal analysis, the mean BMI in men aged 20 to 49 years increased 2.0 kg/m(2) during 20 years of observation and increased 2.4 kg/m(2)in women aged 20 to 49 years during 15 years of observation. The increase in BMI was larger in younger men than in older men. CONCLUSIONS: Body mass index increased in every examined birth cohort (1925-1964) during the 15- to 20-year observation period. Primary prevention of further increased body weight should be a priority.

Atrial fibrillation and future risk of venous thromboembolism:the Tromsø study.

AIMS: Whether atrial fibrillation is related to risk of venous thromboembolism (VTE) has not been extensively studied. Therefore, we investigated the association between atrial fibrillation and future risk of VTE in a population-based cohort. METHODS: In total, 29,975 subjects were recruited from three surveys of the Tromsø study and followed from enrollment (1994-1995, 2001-2002 and 2007-2008) up to 2010. Incident events of atrial fibrillation and VTE during follow-up were recorded. Information on potential confounders was obtained at baseline. Cox-regression models with atrial fibrillation as time-dependent variable were used to calculate hazard ratios (HRs) for VTE with 95% confidence intervals (CIs). RESULTS: During 16 years of median follow-up, 1604 subjects were diagnosed with atrial fibrillation and 614 with incident VTE. The risk of VTE was substantially increased during the first 6 months after diagnosis of atrial fibrillation (HR, 8.44; 95% CI, 5.61-12.69), and remained increased throughout the study period (HR, 1.43; 95% CI, 1.43-1.99) compared with those without atrial fibrillation. Atrial fibrillation displayed higher risk estimates for pulmonary embolism (HR, 11.84; 95% CI, 6.80-20.63) than for deep vein thrombosis (HR, 6.20; 95% CI, 3.37-11.39) during the first 6 months, and was still associated with pulmonary embolism (HR, 1.96; 95% CI, 1.24-3.10) but not with deep vein thrombosis (HR, 1.08; 95% CI, 0.66-1.75) more than 6 months after diagnosis. CONCLUSION: Atrial fibrillation was associated with increased risk of VTE, and pulmonary embolism in particular. Our findings support the concept that isolated pulmonary embolism may originate from right atrial thrombi due to atrial fibrillation.

Single-nucleotide polymorphism, rs1799941 in the Sex Hormone-Binding Globulin (SHBG) gene, related to both serum testosterone and SHBG levels and the risk of myocardial infarction, type 2 diabetes, cancer and mortality in men: the Tromsø Study.

Low testosterone levels are associated with metabolic and cardiovascular disease risk factor, and have been shown to predict type 2 diabetes mellitus (T2DM), myocardial infarction (MI) and all-cause mortality. It is not known if these associations are causal or not. Recently, it has been shown that the serum testosterone levels are associated with single-nucleotide polymorphisms (SNPs), and we therefore studied the associations between one of these SNPs, rs1799941 on the Sex Hormone-Binding Globulin (SHBG) gene, and MI, T2DM, cancer and death. DNA was prepared from men who participated in the fourth survey of the Tromsø Study in 1994-1995 and who were registered with the endpoints MI, T2DM, cancer or death and a randomly selected control group. For mortality, the observation time was set from 1994, and for the other endpoints from birth. The endpoint data were completed up to 2010-2013. Genetic analyses were successfully performed in 5309 men, of whom 1454 were registered with MI, 638 with T2DM, 1534 with cancer and in 2226 who had died. Men with the minor homozygote genotype had significantly higher levels of total testosterone (14.7%) and SHBG (24.7%) compared with men with the major homozygote genotype, whereas free testosterone levels did not differ significantly between the genotypes. The SNP rs1799941 was not significantly associated with MI, T2DM, cancer or mortality. Thus, our result does not support a causal relationship between total testosterone and SHBG and MI, T2DM, cancer or mortality, suggesting that low testosterone more likely is a marker of poor health.

Hyperglycemia, assessed according to HbA1c , and future risk of venous thromboembolism: the Tromsø study.

BACKGROUND: HbA1c , a marker of average plasma glucose level during the previous 8-12 weeks, is associated with the future risk of cardiovascular disease and all-cause mortality. OBJECTIVES: To examine the association between hyperglycemia, assessed according to HbA1c , and the future risk of venous thromboembolism (VTE) in a population-based cohort. METHODS: HbA1c was measured in 16 156 unique subjects (25-87 years) who participated in one or more surveys of the Tromsø study (Tromsø 4, 1994-1995; Tromsø 5, 2001-2002; and Tromsø 6, 2007-2008). All subjects were followed, and incident VTE events were recorded up to 31 December 2010. RESULTS: There were 333 validated first VTE events, of which 137 were unprovoked, during a median follow-up of 7.1 years. HbA1c was not associated with the future risk of VTE in analyses treating HbA1c as a continuous variable, or in categorized analyses. The risk of VTE increased by 5% per one standard deviation (0.7%) increase in HbA1c (multivariable-adjusted hazard ratio [HR] 1.05; 95% confidence interval [CI] 0.97-1.14), and subjects with HbA1c  ≥ 6.5% had a 27% higher risk than those with HbA1c  < 5.7% (multivariable-adjusted HR 1.27; 95% CI 0.72-2.26). There was no significant linear trend for an increased risk of VTE across categories of HbA1c (P = 0.27). CONCLUSIONS: Serum levels of HbA1c were not associated with the future risk of VTE in multivariable analysis. Our findings suggest that hyperglycemia does not play an important role in the pathogenesis of VTE.

Cognitive function, drusen, and age-related macular degeneration: a cross-sectional study.

PURPOSE: To examine the cross-sectional relationship between drusen, late age-related macular degeneration (AMD), and cognitive function. METHODS; We included 2149 stroke-free participants from the population-based Tromsø Study in Norway. Retinal photographs were graded for presence of drusen and AMD. Cognitive function was assessed using the verbal memory test (short verbal memory), digit-symbol coding test (processing speed), and the tapping test (psychomotor tempo). We assessed the relationship between drusen, late AMD, and cognitive test scores, adjusted for potential confounders. RESULTS: Late AMD was associated with decreased performance in the verbal memory test (standardized ß=-0.23, 95% confidence interval (CI): -0.51 to -0.01). Intermediate and large drusen were associated with decreased performance in the digit-symbol coding test (standardized ß=-0.14 and -0.19, 95% CIs: -0.23 to -0.05 and -0.29 to -0.09, respectively). Participants with large drusen were more likely to have test scores in the lowest quartile of the digit-symbol coding test (odds ratio (OR)=1.9, 95% CI: 1.1-3.5) and the tapping test (OR=1.6, 95% CI: 1.0-2.6), but not in the verbal memory test (OR=1.0, 95% CI: 0.6-1.6). CONCLUSIONS: The findings suggest a relationship between drusen deposition and reduced cognitive function. Although the relationships between drusen, late AMD, and the cognitive test results varied in strength and significance across the types of cognitive test, and may partly have been caused by residual confounding, it is not unlikely that a genuine but weaker relationship exists between drusen deposition and cognitive decline.

Serum osteoprotegerin is a predictor for incident cardiovascular disease and mortality in a general population: the Tromsø Study.

BACKGROUND: Osteoprotegerin (OPG) concentration in serum is associated with the presence and severity of atherosclerosis. OBJECTIVE: To investigate the association between serum osteoprotegerin and the risk of a future myocardial infarction, ischemic stroke and mortality in a general population. PATIENTS/METHODS: OPG was measured in serum collected from 6265 subjects recruited from a general population without a prior myocardial infarction and ischemic stroke (the Tromsø Study). Incident myocardial infarction, ischemic stroke and mortality were registered during follow-up. Cox regression models were used to estimate crude and adjusted hazard ratios and 95% confidence intervals (HR; 95% CI). RESULTS: There were 575 myocardial infarctions, 284 ischemic strokes and 824 deaths (146 deaths as a result of ischemic heart disease, 78 deaths because of stroke and 600 deaths due to other causes) in the cohort during a median of 10.6 years of follow-up. Serum OPG (per SD [1.13 ng mL(-1)] increase in OPG) was associated with an increased risk of a myocardial infarction (1.20; 1.11-1.31), ischemic stroke (1.32; 1.18-1.47), total mortality (1.34; 1.26-1.42), death because of ischemic heart disease, (1.35; 1.18-1.54), stroke (1.44; 1.19-1.75) and non-vascular causes (1.31; 1.22-1.41) after adjustment for age, gender, current smoking, systolic blood pressure, body mass index, high density lipoprotein cholesterol, total cholesterol, creatinine, high sensitivity C-reactive protein (CRP) and diabetes mellitus or HbA1c > 6.1%. No association was detected between OPG and incident hemorrhagic stroke (1.02; 0.73-1.43). CONCLUSIONS: Serum OPG was associated with future risk of myocardial infarction, ischemic stroke, total mortality, mortality of ischemic heart disease, stroke and of non-vascular causes independent of traditional cardiovascular risk factors.

Sex differences in risk factors for aneurysmal subarachnoid hemorrhage: a cohort study.

OBJECTIVE: The purpose of this study was to investigate sex differences in the major established risk factors for aneurysmal subarachnoid hemorrhage (aSAH) in a large, population-based cohort. METHODS: Sex differences in the established risk factors for aSAH (smoking, hypertension, and alcohol consumption) were examined in a prospective, population-based cohort consisting of 92,462 participants of the Nord-Trøndelag and the Tromsø Health Studies in Norway. RESULTS: We identified 120 cases of aSAH during 1,002,148 person-years at risk. Compared with the risk in nonsmokers, the risk of aSAH was higher in current cigarette-smoking women than in men (hazard ratio = 8.9, 95% confidence interval [CI] 4.7-17.0 vs hazard ratio = 2.8, 95% CI 1.3-6.1, after adjustment for age and alcohol consumption). The interaction between sex and current smoking was present on an additive scale (relative excess risk due to interaction 3.1, 95% CI 0.5-5.8), indicating a higher risk of aSAH associated with current cigarette smoking in women than in men. No sex differences in the risk of aSAH were observed with respect to hypertension or alcohol consumption. CONCLUSIONS: This prospective, population-based cohort study showed that compared with the risk in nonsmokers, the risk of aSAH was higher in current cigarette-smoking women than in men. This finding may at least partially explain the gender gap in aSAH incidence. A more intensive smoking cessation intervention should be considered in women at risk of aSAH.