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.

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.

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.

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.

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.

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.

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.

La obesidad abdominal es esencial para el riesgo de tromboembolismo venoso en el síndrome metabólico: el estudio de tromso / Abdominal obesity is essential for the risk of venous thromboembolism in the metabolic syndrome: the thrombus study

ANTECEDENTES: el síndrome metabólico es un conjunto de factoresde riesgo cardiovascular, como la obesidad abdominal, hipertensión, dislipidemia y resistenciaa la insulina, asociado con un mayor riesgo de enfermedades cardiovasculares y mortalidad porcualquier causa. OBJETIVOS: el propósito del estudio fue evaluar el impacto del síndrome metabólico y sus componentes individuales, sobre el riesgo de tromboembolismo venoso (TEV) en un estudio poblacional prospectivo. MÉTODOS: Los componentes individuales del síndrome metabólico se registraron en 6170 sujetos de 25 a84 años en el Estudio de Tromsø en 1994-1995, y por primera vez los eventos de TEV se registraron hasta el 1 de septiembre de 2007...

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.

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 and mortality of aneurysmal subarachnoid hemorrhage in two Norwegian cohorts, 1984-2007.

OBJECTIVE: The incidence of aneurysmal subarachnoid hemorrhage (aSAH) ranges from 4 to 10 per 100,000 person-years in most countries, and 30-day case fatality is high. The aim of this study was to estimate the incidence and case fatality of aSAH and to assess preictal predictors of survival in 2 large Norwegian population-based cohort studies. METHODS: A total of 94,976 adults (≥20 years) in the Nord-Trøndelag Health Study and 31,753 participants (aged ≥20 years) in the Tromsø Study were included. During follow-up, aSAHs were identified, incidence rates were estimated, and predictors of survival were assessed using Cox and Poisson regression analysis. RESULTS: A total of 214 patients with aSAH were identified during 2,077,927 person-years of follow-up from 1984 to 2007. The incidence rate was 10.3 per 100,000 person-years: 13.3 for women and 7.1 for men. The incidence increased by 2% (95% confidence interval [CI] 0-4) per 5-year time period. Case fatality at 3, 7, and 30 days was 20%, 24%, and 36%. Thirty-day case fatality remained stable during follow-up (odds ratio 1.01, 95% CI 0.97-1.06 per year). Never smokers had poorer survival after aSAH than current and former smokers combined (hazard ratio 1.6, 95% CI 0.9-2.9). CONCLUSIONS: The slight increase in incidence of aSAH over time may be explained by differences in diagnostic procedures. Case fatality remained stable during 23 years of follow-up.

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.

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.

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.

Relation between serum osteoprotegerin and carotid intima media thickness in a general population - the Tromsø Study.

BACKGROUND: Previous studies have reported conflicting results on the relation between serum osteoprotegerin (OPG) concentration and carotid intima media thickness (CIMT). PATIENTS/METHODS: The present study was conducted to investigate the relations between OPG, risk factors for cardiovascular diseases (CVD) and carotid intima media thickness (CIMT) in a large cross-sectional study including 6516 subjects aged 25-85years who participated in a population-based health survey. RESULTS: CIMT increased significantly across tertiles of OPG after adjustment for traditional cardiovascular risk factors such as age, gender, smoking, total cholesterol, high-density lipoprotein (HDL) cholesterol, C-reactive protein (CRP), body mass index (BMI), systolic blood pressure, CVD and diabetes mellitus (P<0.0001). There was a significant interaction between age and OPG (P=0.026). The risk of being in the uppermost quartile of CIMT was reduced (OR 0.52, 95% CI 0.30-0.88) with each standard deviation (SD) higher level of OPG in subjects <45years (n=444), whereas subjects ≥55years of age (n=4884) had an increased risk of being in the uppermost quartile of CIMT (OR 1.19, 95% CI 1.10-1.29) after adjustment for traditional CVD risk factors. CONCLUSIONS: Age has a differential impact on the association between OPG and CIMT in a general population. The present findings may suggest that increased serum OPG does not promote early atherosclerosis in younger subjects.

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.

Serum osteoprotegerin, sRANKL and carotid plaque formation and growth in a general population--the Tromsø study.

SUMMARY BACKGROUND: Intervention studies in animal models suggest that osteoprotegerin (OPG) functions as an inhibitor or marker of atherosclerosis, whereas one prospective epidemiological study in humans indicated that OPG was an independent risk factor for progression of atherosclerosis. OBJECTIVE: To study the association between serum levels of OPG, soluble RANK ligand (sRANKL) and carotid artery plaque formation and plaque growth. PATIENTS/METHODS: The prevalence of carotid plaque and plaque area were assessed by ultrasonographic imaging at baseline and after 7 years follow-up in 2191 men and 2329 women who participated in a population-based study. RESULTS: OPG was significantly associated with atherosclerotic plaque burden and cardiovascular risk factors such as age, body mass index, blood pressure, total cholesterol, HDL cholesterol, HbA1c and fibrinogen at baseline, but not with sRANKL. In subjects without plaque at baseline, OPG predicted plaque formation in crude analysis in both women and men, but not after adjustment for age and other atherosclerotic risk factors. OPG predicted plaque growth in women (+1.8 mm(2), 0.6-3.0) (mean, 95% CI) per 1 SD increase in OPG (P = 0.003), whereas no associations were demonstrated in men (0.1 mm(2) (-1.3-1.4), P = 0.93). Soluble RANKL did not predict plaque formation or plaque growth. CONCLUSIONS: OPG was an independent predictor of plaque growth in women, but not in men, suggesting gender-specific actions of OPG in plaque growth. OPG was not associated with novel plaque formation.