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Aim: To assess whether stroke diagnoses in national health registers are sufficiently correct and complete to replace manual collection of endpoint data for the Tromsø Study, a population-based epidemiological study. Method: Using the Tromsø Study Cardiovascular Disease Register for 2013–2014 as the gold standard, we calculated correctness (defined as positive predictive value, PPV) and completeness (defined as sensitivity) of stroke cases in four different data subsets derived from the Norwegian Patient Register and the Norwegian Stroke Register. We calculated the sensitivity and PPV with 95% confidence intervals (CIs) assuming a normal approximation of the binomial distribution. Results: In the Norwegian Stroke Register we found a sensitivity of 79.8% (95% CI 74.2–85.4) and a PPV of 97.5% (95% CI 95.1–99.9). In the Norwegian Patient Register the sensitivity was 86.4% (95% CI 81.6–91.1) and the PPV was 84.2% (95% CI 79.2–89.2). The overall highest levels were found in a subset based on a linkage between the Norwegian Stroke Register and the Norwegian Patient Register, with a sensitivity of 88.9% (95% CI 84.5–93.3), and a PPV of 89.3% (95% CI 85.0–93.6). Conclusions: Data from the Norwegian Patient Register and from the linked data set between the Norwegian Patient Register and the Norwegian Stroke Register had acceptable levels of correctness and completeness to be considered as endpoint sources for the Tromsø Study Cardiovascular Disease Register. The benefits of using data from national registers as endpoints in epidemiological studies must be weighed against the impact of potentially decreased data quality. [ABSTRACT FROM AUTHOR]

Background: Secondary prevention guidelines after myocardial infarction (MI) are gender neutral, but underutilisation of treatment in women has been reported. Design: We investigated the change in total and low-density lipoprotein (LDL) cholesterol levels and lipid-lowering drug (LLD) use after first-ever MI in a population-based study. Methods: We followed 10,005 participants (54% women) attending the Tromsø Study 1994–1995 and 8483 participants (55% women) attending the Tromsø Study 2007–2008 for first-ever MI up to their participation in 2007–2008 and 2015–2016, respectively. We used linear and logistic regression models to investigate sex differences in change in lipid levels. Results: A total of 395 (MI cohort I) and 132 participants (MI cohort II) had a first-ever MI during 1994–2008 and 2007–2013, respectively. Mean change in total cholesterol was −2.34 mmol/L (SD 1.15) in MI cohort I, and in LDL cholesterol was −1.63 mmol/L (SD 1.12) in MI cohort II. Men had a larger decrease in lipid levels compared to women: the linear regression coefficient for change was −0.33 (95% confidence interval [CI] −0.51 to −0.14) for total cholesterol and −0.21 (95% CI −0.37 to −0.04) for LDL cholesterol, adjusted for baseline lipid value, age and cohort. Men had 73% higher odds (95% CI 1.15−2.61) of treatment target achievement compared to women, adjusted for baseline lipid value, age and cohort. LLD use was reported in 85% of women and 92% of men in MI cohort I, and 80% in women and 89% in men in MI cohort II. Conclusions: Compared to men, women had significantly less decrease in lipid levels after MI, and a smaller proportion of women achieved the treatment target. [ABSTRACT FROM AUTHOR]

Background The Rose Angina Questionnaire (RAQ) was constructed in the 1960s for assessing the population burden of angina. Studies have found that screening positivity by RAQ conferred an elevated risk of coronary heart disease (CHD). It is, however, not clear to what extent Rose angina represents early CHD in relatively young adults who are free of known CHD. If representing CHD, Rose angina is expected to carry prognostic information in addition to the risk conferred by other risk factors. Methods The Tromsø Study is a population-based cohort study in Northern Norway. All men aged 20–54 years (n=8238) and women aged 20–49 years (n=8001), free of known cardiovascular disease (CVD), who participated in a survey 1979–1980, were followed throughout 2010 for incident myocardial infarction (MI), and for incident MI or stroke used as proxy for incident CVD. HRs were estimated using a Cox proportional hazard regression model. Results In age-adjusted analyses, Rose angina predicted MI and CVD in both sexes. The excess risk was substantially accounted for by CVD risk factors, leaving no significantly elevated MI risk above the risk explained by these factors (adjusted HR 1.31; 95% CI 0.95 to 1.80 in men, HR 1.20; 95% CI 0.69 to 2.10 in women). A similar pattern was seen for CVD (adjusted HR 1.16; 95% CI 0.87 to 1.55 in men and 1.30; 95% CI 0.82 to 2.06 in women). Conclusions Rose angina predicted MI and CVD in a 29-years’ follow-up of a relatively young population. Established CVD risk factors were important mediators. [ABSTRACT FROM AUTHOR]

Background/Aims: Late-onset Alzheimer's disease (LOAD) comprises sporadic LOAD and familial LOAD. We wanted to determine whether total plasma homocysteine (Hcy), cardiovascular risk factors and volumetric analyses of cerebral magnetic resonance imaging (MRI) were differently associated with mild cognitive impairment (MCI) in subjects from families with aggregation of LOAD (probable familial LOAD) and MCI in subjects from families without LOAD (probable sporadic LOAD). Methods: A total of 103 subjects with MCI without known stroke or other apparent causative diseases were included as cases together with 58 controls. The cases were stratified into 3 groups according to the number of biological relatives with probable LOAD on one side of the family. Cerebral MRI was obtained from all. The case groups were compared to the control group in sex-specific analyses of covariance. Results: Hcy was significantly elevated in all cases compared to controls, except for women with probable familial LOAD. These women also had significantly smaller hippocampal volume and significantly larger lateral ventricles, unlike the women in the other case groups. Conclusions: Our findings suggest that research on Hcy, cardiovascular risk factors and other potential risk factors for LOAD might benefit from distinguishing between sporadic and familial LOAD. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background.- High prevalence of headache has been associated with high latitude, thus suggesting a relation with vitamin D. However, there are so far no reports on the association between serum 25-hydroxyvitamin D (25[OH]D) and headache. Objective.- To investigate the association between headache and serum 25(OH)D in a general population. Methods.- Cross-sectional study based on questionnaires from 11,614 persons who participated in the sixth survey of the Tromsø Study (Tromsø 6) carried out in 2007-2008. The data were stratified according to smoking status and analyzed with regard to migraine and non-migraine headache. Adjustments were done for age, body mass index (BMI), gender, season, chronic diseases, education, physical exercise, and alcohol consumption. Results.- Headache of non-migraine type was associated with low levels of serum 25(OH)D with an odds ratio (OR) of 1.20 (1.04-1.39) in the lowest quartile as compared to the highest serum 25(OH)D quartile. No significant association was found between migraine and serum 25(OH)D. Conclusion.- Non-migraine headache was associated with low levels of serum 25(OH)D. Although adjustment were done for possible confounders, this finding may still reflect lifestyle rather than causality, and further studies are needed to investigate this. No association was found between serum 25(OH)D and migraine. [ABSTRACT FROM AUTHOR]

Background: Few studies have used individual person data to study whether contemporary trends in the incidence of coronary heart disease are associated with changes in modifiable coronary risk factors.Methods and Results: We identified 29 582 healthy men and women ≥25 years of age who participated in 3 population surveys conducted between 1994 and 2008 in Tromsø, Norway. Age- and sex-adjusted incidence rates were calculated for coronary heart disease overall, out-of-hospital sudden death, and hospitalized ST-segment-elevation and non-ST-segment-elevation myocardial infarction. We measured coronary risk factors at each survey and estimated the relationship between changes in risk factors and changes in incidence trends. A total of 1845 participants had an incident acute coronary heart disease event during 375 064 person-years of follow-up from 1994 to 2010. The age- and sex-adjusted incidence of total coronary heart disease decreased by 3% (95% confidence interval, 2.0-4.0; P<0.001) each year. This decline was driven by decreases in out-of-hospital sudden death and hospitalized ST-segment-elevation myocardial infarction. Changes in coronary risk factors accounted for 66% (95% confidence interval, 48-97; P<0.001) of the decline in total coronary heart disease. Favorable changes in cholesterol contributed 32% to the decline, whereas blood pressure, smoking, and physical activity each contributed 14%, 13%, and 9%, respectively.Conclusions: We observed a substantial decline in the incidence of coronary heart disease that was driven by reductions in out-of-hospital sudden death and hospitalized ST-segment-elevation myocardial infarction. Changes in modifiable coronary risk factors accounted for 66% of the decline in coronary heart disease events. [ABSTRACT FROM AUTHOR]

Background: The relationship between high sensitivity C-reactive protein and migraine is unclear. The aim of this cross-sectional population-based study was to investigate the association between high sensitivity C-reactive protein and types of headache, and to evaluate the impact of insomnia on this association.Methods: A total of 20,486 (63%) out of 32,591 invited, aged ≥40 years or older, participated in the seventh wave of the Tromsø study conducted in 2015-2016 and had valid information on headache, insomnia and high sensitivity C-reactive protein. The influence of insomnia on the association between questionnaire-based diagnoses of headache and elevated high sensitivity C-reactive protein defined as >3.0 mg/L was assessed using multiple logistic regression, estimating prevalence odds ratio with 95% confidence intervals.Results: A total of 6290 participants (30.7%) suffered from headache during the last year. Among these, 1736 (8.5%) fulfilled the criteria of migraine, 991 (4.8%) had migraine with aura, 746 (3.6%) migraine without aura (3.8%), and 4554 (22.2%) had non-migrainous headache. In the final multi-adjusted analysis, elevated high sensitivity C-reactive protein was associated with headache (odds ratio 1.10, 95% confidence interval 1.01-1.20), migraine (odds ratio 1.17, 95% confidence interval 1.01-1.35), and migraine with aura (odds ratio 1.23, 95% confidence interval 1.01-1.53). No association was found between elevated high sensitivity C-reactive protein and migraine without aura or non-migrainous headache. The association between high sensitivity C-reactive protein and migraine was strongly dependent on insomnia status. Among individuals with insomnia, elevated high sensitivity C-reactive protein was associated with migraine (odds ratio 1.49, 95% confidence interval 1.02-2.17), and migraine with aura (odds ratio 1.59, 95% confidence interval 1.03-2.45), whereas no such relationship was found among those without insomnia.Conclusions: In this cross-sectional study, participants with migraine, in particular migraine with aura, were more likely to have elevated high sensitivity C-reactive protein, evident only among those with insomnia. [ABSTRACT FROM AUTHOR]

Background: Stroke lesions might alter pain processing and modulation by affecting the widely distributed network of brain regions involved. We aimed to compare pain tolerance in stroke survivors and stroke-free persons in the general population, with and without chronic pain., Methods: We included all participants of the sixth and seventh wave of the population-based Tromsø Study who had been tested with the cold pressor test (hand in cold water bath, 3°C, maximum time 106 s in the sixth wave and 120 s in the seventh) and who had information on previous stroke status and covariates. Data on stroke status were obtained from the Tromsø Study Cardiovascular Disease Register and the Norwegian Stroke Register. Cox regression models were fitted using stroke prior to study attendance as the independent variable, cold pressor endurance time as time variable and hand withdrawal from cold water as event. Statistical adjustments were made for age, sex, diabetes, hypertension, hyperlipidaemia, body mass index and smoking., Results: In total 21,837 participants were included, 311 of them with previous stroke. Stroke was associated with decreased cold pain tolerance time, with 28% increased hazard of hand withdrawal (hazard ratio [HR] 1.28, 95% CI 1.10-1.50). The effect was similar in participants with (HR 1.28, 95% CI 0.99-1.66) and without chronic pain (HR 1.29, 95% CI 1.04-1.59)., Conclusions: Stroke survivors, with and without chronic pain, had lower cold pressor pain tolerance, with possible clinical implications for pain in this group., Significance: We found lower pain tolerance in participants with previous stroke compared to stroke-free participants of a large, population-based study. The association was present both in those with and without chronic pain. The results may warrant increased awareness by health professionals towards pain experienced by stroke patients in response to injuries, diseases and procedures., (© 2023 European Pain Federation - EFIC®.)

Background: Myocardial infarction (MI) is associated with an increased risk of venous thromboembolism (VTE). Obesity is a recognized risk factor for both MI and VTE. Whether obesity further increases the risk of VTE in MI patients is scarcely investigated., Aim: To study the joint effect of MI and obesity on the risk of VTE., Methods: Study participants (n = 29 410) were recruited from three surveys of the Tromsø Study (conducted in 1994-1995, 2001, and 2007-2008) and followed up through 2014. All incident MI and VTE cases during follow-up were recorded. Cox regression models with MI as a time-dependent variable were used to estimate hazard ratios (HRs) of VTE (adjusted for age and sex) by combinations of MI exposure and obesity status. Joint effects were assessed by calculating relative excess risk and attributable proportion (AP) due to interaction., Results: During a median of 19.6 years of follow-up, 2090 study participants experienced an MI and 784 experienced a VTE. Among those with MI, 55 developed a subsequent VTE, yielding an overall incidence rate (IR) of VTE of 5.3 per 1000 person-years (95% confidence interval [CI]: 4.1-6.9). In the combined exposure group (MI+/Obesity+), the IR was 11.3 per 1000 person-years, and the adjusted HR indicated a 3-fold increased risk of VTE (HR 3.16, 95% CI: 1.99-4.99) compared to the reference group (MI-/Obesity-). The corresponding AP was 0.46 (95% CI: 0.17-0.74)., Conclusions: The combination of MI and obesity yielded a supra-additive effect on VTE risk of which 46% of the VTE events were attributed to the interaction., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Background and Purpose: Data on long-term survival after intracerebral hemorrhage (ICH) are scarce. In a population-based nested case-control study, we compared long-term survival and causes of death within 5 years in 30-day survivors of first-ever ICH and controls, assessed the impact of cardiovascular risk factors on 5-year mortality, and analyzed time trend in 5-year mortality in ICH patients over 2 decades., Methods: We included 219 participants from the population-based Tromsø Study, who after the baseline participation had a first-ever ICH between 1994 to 2013 and 1095 age- and sex-matched participants without ICH. Cumulative survival was presented using the Kaplan-Meier method. Hazard ratios (HRs) for mortality and for the association between cardiovascular risk factors and 5-year mortality in 30-day survivors were estimated by stratified Cox proportional hazards models. Trend in 5-year mortality was assessed by logistic regression., Results: Risk of death during follow-up (median time, 4.8 years) was increased in the ICH group compared with controls (HR, 1.62 [95% CI, 1.27-2.06]). Cardiovascular disease was the leading cause of death, with a higher proportion in ICH patients (22.9% versus 9.0%; P <0.001). Smoking increased the risk of 5-year mortality in cases and controls (HR, 1.59 [95% CI, 1.15-2.19]), whereas serum cholesterol was associated with 5-year mortality in cases only (HR, 1.39 [95% CI, 1.04-1.86]). Use of anticoagulants at ICH onset increased the risk of death (HR, 2.09 [95% CI, 1.09-4.00]). There was no difference according to ICH location (HR, 1.15 [95% CI, 0.56-2.37]). Five-year mortality did not change during the study period (odds ratio per calendar year, 1.01 [95% CI, 0.93-1.09])., Conclusions: Survival rates were significantly lower in cases than in controls, driven by a 2-fold increased risk of cardiovascular death. Smoking, serum cholesterol, and use of anticoagulant drugs were associated with increased risk of death in ICH patients. Five-year mortality rates in ICH patients remained stable over time.

Background The initial presentation to coronary angiography and extent of coronary artery disease (CAD) vary greatly among patients, from ischemia with no obstructive CAD to myocardial infarction with 3-vessel disease. Pain tolerance has been suggested as a potential mechanism for the variation in presentation of CAD. We aimed to investigate the association between pain tolerance, coronary angiography, CAD, and death. Methods and Results We identified 9576 participants in the Tromsø Study (2007-2008) who completed the cold-pressor pain test, and had no prior history of CAD. The median follow-up time was 10.4 years. We applied Cox-regression models with age as time-scale to calculate hazard ratios (HR). More women than men aborted the cold pressor test (39% versus 23%). Participants with low pain tolerance had 19% increased risk of coronary angiography (HR, 1.19 [95% CI, 1.03-1.38]) and 22% increased risk of obstructive CAD (HR, 1.22 [95% CI, 1.01-1.47]) adjusted by age as time-scale and sex. Among women who underwent coronary angiography, low pain tolerance was associated with 54% increased risk of obstructive CAD (HR, 1.54 [95% CI, 1.09-2.18]) compared with high pain tolerance. There was no association between pain tolerance and nonobstructive CAD or clinical presentation to coronary angiography (ie, stable angina, unstable angina, and myocardial infarction). Participants with low pain tolerance had increased risk of mortality after adjustment for CAD and cardiovascular risk factors (HR, 1.40 [95% CI, 1.19-1.64]). Conclusions Low cold pressor pain tolerance is associated with a higher risk of coronary angiography and death.

The main arteries that supply blood to the brain originate from the Circle of Willis (CoW). The CoW exhibits considerable anatomical variations which may have clinical importance, but the variability is insufficiently characterised in the general population. We assessed the anatomical variability of CoW variants in a community-dwelling sample (N = 1,864, 874 men, mean age = 65.4, range 40-87 years), and independent and conditional frequencies of the CoW's artery segments. CoW segments were classified as present or missing/hypoplastic (w/1mm diameter threshold) on 3T time-of-flight magnetic resonance angiography images. We also examined whether age and sex were associated with CoW variants. We identified 47 unique CoW variants, of which five variants constituted 68.5% of the sample. The complete variant was found in 11.9% of the subjects, and the most common variant (27.8%) was missing both posterior communicating arteries. Conditional frequencies showed patterns of interdependence across most missing segments in the CoW. CoW variants were associated with mean-split age (P = .0147), and there was a trend showing more missing segments with increasing age. We found no association with sex (P = .0526). Our population study demonstrated age as associated with CoW variants, suggesting reduced collateral capacity with older age., Competing Interests: The authors declare no conflict of interests. DR received salary from Icometrix during this study, but this does not alter our adherence to PLOS ONE policies on sharing data and materials.

Objectives: Large differences exist in the burden of cardiovascular disease (CVD) between Russia and Western European countries including Norway. Obesity prevalence may contribute to the differences. We investigated whether difference in the level of adiposity, assessed using body mass index and waist-to-hip ratio(WHR), could explain intercountry differences in the burden of carotid plaque, a measure of atherosclerosis, in the populations., Design: Cross-sectional analysis. Logistic and linear regression models were used., Setting: We used population-based cross-sectional Know Your Heart (KYH) study in Russia and the Tromsø 7 study (Tromsø 7) in Norway., Participants: 3262 and 1800 men and women aged 40-69 years in KYH and Tromsø 7, respectively., Primary and Secondary Outcome: The presence of carotid plaques and plaque score assessed using ultrasound., Results: The presence of carotid plaques and plaque score were higher in KYH than Tromsø 7 regardless of age group and sex. A positive association between carotid plaque burden and adiposity was found (OR of having at least one plaque per SD in WHR 1.18 (95% CI 1.06 to 1.31) for men; 1.15 (1.06 to 1.25) for women)) adjusted for age, smoking and education in a pooled analysis of the two studies. There was little evidence of the interaction between study and adiposity. These effects did not differ between the two studies. However, neither adiposity nor CVD risk factors (smoking, systolic blood pressure, cholesterol, glycosylated haemoglobin) explained the higher carotid plaque burden in KYH compared with Tromsø 7., Conclusion: Adiposity, especially abdominal adiposity, is a risk factor for carotid plaque in Russia and Norway, although neither adiposity nor established CVD risk factors explained the higher plaque burden in Russia. To reduce the CVD burden in Russia, beyond prevention and treatment of adiposity, further research is required to understand why Russia has a high burden of atherosclerosis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Few reports are available on the contribution of general and abdominal obesity to the progression of carotid atherosclerosis in late adulthood. This study investigated the impact of four simple anthropometric measures of general and abdominal obesity on the progression of carotid atherosclerosis and the extent to which the association between adiposity and the progression of plaque burden is mediated by cardiometabolic markers., Methods: Four thousand three hundred forty-five adults (median age 60) from the population-based Tromsø Study were followed over 7 years from the first carotid ultrasound screening to the next. The progression of carotid atherosclerosis was measured in three ways: incidence of plaques in previously plaque-free participants; change in the number of plaques; and total plaque area (TPA). We used generalised linear models to investigate the association between each adiposity measure - body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) - and each outcome. Models were adjusted for potential confounders (age, sex, smoking, education, physical activity). The pathways through which any associations observed might operate were investigated by further adjusting for cardiometabolic mediators (systolic blood pressure, cholesterol, and HbA1c)., Results: There was little evidence that adiposity was related to the formation of new plaques during follow-up. However, abdominal adiposity was associated with TPA progression. WHtR showed the largest effect size (mean change in TPA per one standard deviation (SD) increase in WHtR of 0.665 mm 2 , 95% confidence interval 0.198, 1.133) while BMI showed the smallest. Effect sizes were substantially reduced after the adjustment for potential mediators., Conclusions: Abdominal obesity indirectly measured with WC seems more strongly associated with the progression of TPA than general obesity. These associations appear to be largely mediated by known cardiometabolic markers.

Background: Family history of myocardial infarction (FHMI) is known to increase the risk of venous thromboembolism (VTE)., Objectives: To investigate the effect of prothrombotic genotypes on the association between FHMI and VTE in a case-cohort recruited from a general population., Methods: Cases with a first VTE (n = 1493) and a subcohort (n = 13 072) were sampled from the Tromsø study (1994-2012) and the Nord-Trøndelag health (HUNT) study (1995-2008). The DNA samples were genotyped for rs8176719 (ABO), rs6025 (F5), rs1799963 (F2), rs2066865 (FGG), and rs2036914 (F11). Participants with missing information on risk alleles (n = 175), FHMI (n = 2769), and BMI (n = 52) were excluded. Cox regression models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for VTE. To explore the role of prothrombotic genotypes for the association between FHMI and VTE, we (a) included the genotypes in the multivariable-adjusted models and (b) assessed the joint effects between FHMI and genotypes on VTE risk., Results: The FHMI was associated with a 1.3-fold increased risk of VTE (HR 1.32, 95% CI 1.16-1.50) and 1.5-fold increased risk of unprovoked VTE (HR 1.47, 95% CI 1.22-1.78). The risk of VTE by FHMI did not alter after adjustment for the five genotypes. The combination of FHMI and the different prothrombotic genotypes did not result in an excess VTE risk (i.e. no biological interaction)., Conclusions: Our findings suggest that the risk of VTE by FHMI is not explained by rs8176719 (ABO), rs6025 (F5), rs1799963 (F2), rs2066865 (FGG), and rs2036914 (F11). The combination of FHMI with prothrombotic genotypes had an additive effect on VTE risk., (© 2019 International Society on Thrombosis and Haemostasis.)

Essentials Prothrombotic genotypes may agument the risk of venous thromboembolism (VTE) after ischemic stroke. We studied this effect in a case-cohort study using a genetic risk score. In stroke patients, a one-category increase in the genetic risk score was associated with a 50% higher relative risk of VTE. The risk of VTE in stroke patients increased with an increasing number of risk alleles. SUMMARY: Background Patients with ischemic stroke have a transiently increased risk of subsequent venous thromboembolism (VTE). Prothrombotic genotypes may augment VTE risk under conditions of high thrombosis risk related to stroke. Aims To investigate the effect of prothrombotic genotypes in patients with ischemic stroke on the risk of VTE in a population-based case-cohort study. Methods Cases with incident VTE (n = 664) and a randomly selected age-weighted subcohort (n = 1817) were sampled from three surveys of the Tromsø Study (1994-2008). Participants were genotyped for ABO (rs8176719), F5 (rs6025), F2 (rs1799963), FGG (rs2066865) and F11 (rs2036914) single-nucleotide polymorphisms (SNPs). Cox regression models were used to calculate hazard ratios (HRs) for incident VTE according to individual SNPs and categories of risk alleles (5-SNP score; 0-1, 2, 3-4 and ≥ 5) in participants with and without ischemic stroke. Results There were 192 patients with incident stroke, of whom 43 developed VTE during a median of 15.2 years of follow-up. The risk alleles of individual SNPs augmented the elevated VTE risk brought about by ischemic stroke. In stroke patients, a one-category increase in the genetic risk score was associated with a 50% higher relative risk of overall VTE (HR 1.5, 95% confidence interval [CI] 1.3-1.8) and an 80% higher relative risk of provoked VTE (HR 1.8, 95% CI 1.5-2.1). Stroke patients with ≥ 5 risk alleles had a 12-fold (HR 11.7, 95% CI 4.1-33.3) higher relative risk of VTE than stroke-free participants with 0-1 risk alleles. Conclusions Prothrombotic genotypes increased the risk of VTE in stroke patients, and the risk increased with an increasing number of risk alleles., (© 2019 International Society on Thrombosis and Haemostasis.)

Background and Aims: Cardiovascular disease is a common cause of morbidity and mortality, with gender differences in pathophysiology. The endothelial glycocalyx maintains vascular integrity, and glycocalyx shedding reflects endothelial dysfunction and early atherosclerosis. Syndecan-1 and -4 are components of the glycocalyx, and increased serum levels indicate glycocalyx damage. We hypothesised that increased serum syndecan-1 and -4 were independently associated with myocardial infarction (MI), ischaemic stroke and all-cause mortality in men and women from a general population., Methods: Using a case-cohort design, we included 1495 participants from the Tromsø Study 2001-02. Syndecan-1 and -4 were measured in serum. Baseline variables also included age, gender, cardiovascular risk factors and urinary albumin-creatinine ratio (ACR). Hazard ratios were assessed using multivariable Cox regression models., Results: Between baseline in 2001-02 and December 2007 fatal or non-fatal MI was experienced by 328 and ischaemic stroke by 191 subjects, and 423 participants died. Syndecan-4 was independently associated with MI (hazard ratio per 10 ng/mL increase 1.32; 95% confidence interval 1.06-1.63), but not ischaemic stroke and mortality, and the associations were unchanged by adjustment for urinary ACR. Interaction between syndecan-4 and sex was borderline significant, and in gender-specific analysis, syndecan-4 was associated with MI in women only. Syndecan-1 was not associated with any endpoint., Conclusions: Syndecan-4 was associated with incident MI, and the association was stronger in women than in men. This suggests a link between endothelial glycocalyx shedding and coronary heart disease in women. Use of syndecan-4 as a risk marker in clinical setting needs further investigation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Physical activity and overweight are associated with myocardial infarction (MI). However, their joint association with MI remains unclear. Our objective was to examine the independent and joint association between leisure-time physical activity (LTPA), body mass index (BMI) and MI. This prospective cohort study included 16,572 men and women (47.5% women) aged 20-54 years who took part in the second Tromsø Study. At baseline in 1979-80 LTPA was assessed by questionnaire. Data on MI was collected and adjudicated through hospital and causes of death registries between 1979 and 2013. Cox proportional hazards models were used to examine the independent and joint associations between LTPA, BMI and MI. The final sample included 16,104 individuals. During a median follow up of 34 years, 1613 incident cases of MI were recorded. Physical inactivity and elevated BMI were both independently associated with MI (p for trend 0.02 and <0.001). In joint analyses, normal weight, inactive individuals had a 20% higher risk of MI compared to their active counterparts (hazard ratio (HR) 1.20 (1.02-1.41)). The highest risk of MI was seen in obese, inactive individuals when compared to normal weight, active individuals (HR 3.20 (2.30-4.44)). The risk of MI increased with increasing BMI regardless of the activity level. HRs were lower for active compared to inactive individuals within the same BMI category. The findings suggest that LTPA and BMI are independently associated with risk of MI. LTPA seems to attenuate but not eliminate the risk of MI associated with excess bodyweight., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background and Aims: Few studies have investigated the association of different measures of adiposity with carotid plaque. We aimed to investigate and compare the associations of four measures of adiposity: body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) with the presence of carotid plaque and total plaque area (TPA) in the right carotid artery., Methods: We included 4906 individuals aged 31-88 years who participated in a population-based study with ultrasonography of the right carotid artery. Adiposity measures were converted to sex-specific SD units to allow comparison of effect sizes. TPA was log transformed due to its skewed distribution. Logistic and linear regression models were used respectively to investigate the association of each adiposity measure with the presence of plaque and with log-transformed TPA. Estimates were adjusted for potential confounders and mediators such as blood pressure and lipids., Results: After adjustment for age, sex, smoking, and education level, there was strong evidence of an association between all adiposity measures and log-transformed TPA, whereas only WHR was weakly associated with presence of plaque. WHR showed the largest adjusted effect size for both log-transformed TPA (beta 0.055, 95%CI 0.028-0.081) and the presence of plaque (OR 1.07, 95%CI 1.01-1.15). Adjustment for mediators led to appreciable attenuation of observed effects., Conclusions: Adiposity is more consistently associated with extent of plaque burden than with whether an individual does or does not have any plaque. There was evidence that established biomarkers mediate much of this association. Abdominal adiposity appears to show the strongest effect., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Population statistics for carotid plaque and cardiovascular risk factors reported in scientific journals are usually presented as averages for the population or age and sex adjusted, rather than sex and age groups. Important population differences about atherosclerosis and cardiovascular risk factors may thus be missed. We compare the distribution of cardiovascular risk factors, carotids plaque and carotid intima-media thickness (CIMT) in two population-based studies., Methods: Carotid artery atherosclerotic plaque prevalence and risk factors levels for cardiovascular disease by sex in 5-year age groups from the Risk Evaluation For Infarct Estimates Reykjavik study (REFINE-Reykjavik study) were compared with data from the Tromsø 6 study., Results: The threshold of carotid plaque presence in the Tromsø 6 study fell between minimal and moderate plaque defined in the REFINE-Reykjavik study reflecting carotid plaque prevalence. The prevalence of minimal carotid plaque in the REFINE-Reykjavik study was 47% in men (40-69 years old) and 38% in women and 11% in men and 7% in women of moderate plaque. The prevalence of any plaque in the Tromsø 6 study was 35% in men and 27% in women. The mean (CIMT) was similar in the studies. In the Tromsø 6 study mean systolic blood pressure was 8 mm Hg higher in men and 10 mm Hg higher in women, mean low-density lipoprotein was 0.5 mmol/L higher in men and 0.3 mmol/L higher in women and the prevalence of smoking was 4% higher in men and 9% higher in women. However, body mass index was 0.8 kg/m 2 higher in men and 0.9 kg/m 2 in women in the REFINE-Reykjavik study., Conclusion: Comparison between Iceland and Norway revealed differences in the prevalence of carotid plaque, which was assumed to be due to different definition of plaque. However, clinically significant differences in conventional cardiovascular risk factors were seen. This underscores the importance of detailed comparison of population data across different populations., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Whether long-chain n-3 PUFAs of marine origin have an anti-atherogenic effect in the general population has hardly been studied. In this population-based study, we hypothesized that fatty fish and fish oil intake protect against development of novel atherosclerotic plaques and is associated with reduced plaque size., Methods: We obtained questionnaire-based information on fish consumption and carotid ultrasonography from 3900 persons aged 45-74 years. The questionnaires were validated by measuring serum concentrations of PUFAs and triglycerides in a subgroup. At follow-up seven years later, 2983 (76%) went through a second ultrasound scanning. Logistic regression and general linear models were used to analyze the outcome (plaque presence and plaque area) as a function of fish consumption, including analyses stratified on fish oil supplements., Results: At baseline, lean fish intake < 1 time/week vs. 1-1.9 times/week was associated with risk of plaque (OR 1.34, 95% CI 1.03-1.76). Fatty fish intake and use of fish oil supplements were not statistically significantly associated with atherosclerosis at baseline. In persons without plaque at baseline, total fish consumption ≥3 times/week vs. 1-1.9 times/week was associated with risk of novel plaque (OR 1.32, 95% CI 1.01-1.73) and larger plaque area (1.76 mm 2 vs. 1.46 mm 2 , p = 0.02) at follow-up. Adjustments for use of fish oil supplements had no impact on the associations, and no interactions were seen between total, fatty or lean fish consumption and fish oil intake., Conclusions: We found no protective effect of fatty fish eating or fish oil supplements on atherosclerotic plaque formation or plaque area in a general population. Lean fish consumption was associated with a reduced risk for plaque in cross-sectional analysis, suggesting that the beneficial effects of fish consumption on atherosclerosis may be mediated through other mechanisms than n-3 PUFAs.

Background: The joint effect of atherosclerosis and CRP (C-reactive protein) on risk of ischemic stroke (IS) and myocardial infarction (MI) has been sparsely studied. The aim of this study was to explore whether CRP mediates the risk of events in subjects with prevalent carotid plaque, examine synergism, and test whether CRP and carotid plaque add to risk prediction beyond traditional risk factors., Methods and Results: CRP and carotid total plaque area (TPA) were measured in 10 109 participants in the Tromsø Study from 1994 to 2008. Incident IS (n=671) and MI (n=1079) were registered until December 31, 2013. We calculated hazard ratios (HRs) of MI and IS according to categories of CRP (<1, 1-3, and >3 mg/L) and plaque status (no plaque and TPA below and above median) in Cox proportional hazard models with time-varying covariates. Multivariable-adjusted CRP >3 versus <1 mg/L was associated with risk of IS (HR, 1.84; 95% confidence interval, 1.49-2.26) and MI (HR, 1.46; 95% confidence interval, 1.23-1.73). TPA above median versus no plaque was associated with risk for IS (HR, 1.65; 95% confidence interval, 1.36-2.01) and MI (HR, 1.64; 95% confidence interval, 1.41-1.92). In participants with plaque, adjustment for CRP minimally attenuated the risk estimates. The highest incidence rates for MI and IS were seen in the group with both CRP >3 mg/L and TPA is above the median. TPA and CRP combined added to risk prediction beyond traditional risk factors., Conclusions: The simultaneous presence of subclinical atherosclerosis and elevated CRP was associated with increased risk of IS and MI. The combined assessment of subclinical atherosclerosis and inflammatory biomarkers may improve cardiovascular disease risk stratification., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background: Atrial fibrillation (AF) prevalence is increasing, and body mass index (BMI) is a risk factor for AF. However, sex differences in the impact of BMI on AF risk have not been fully elucidated., Methods and Results: Data from the fourth survey (1994-1995) of the Tromsø Study (Norway) were used to investigate the association of single-measurement BMI on future AF risk. To analyze the influence of BMI changes on AF risk, data from individuals who attended the third and fourth study surveys were used. AF diagnosis was derived from record linkage and end point adjudication. Cox regression analysis was conducted using fractional polynomials of BMI and BMI change with models adjusted for age, baseline BMI (change analyses), risk factors, comorbidities, and antihypertensive medications.Data were available for 24 799 individuals from the fourth survey (mean age, 45.5±14.2 years; 52.9% women). Over 15.7±5.5 years, 811 women (6.2%) and 918 men (7.9%) developed AF. In men, lower BMI decreased AF risk and higher BMI increased risk (hazard ratios [95% confidence intervals] for BMI 18 or 40 kg/m 2 compared with 23 kg/m 2 were 0.75 [0.70-0.81] and 4.42 [3.00-6.53], respectively). The same pattern was identified in women. Two surveys were attended by 14 652 individuals. In men and women, a decrease in BMI over time was associated with decreased AF risk and an increase in BMI was associated with increased AF risk., Conclusions: Within a population cohort, BMI was positively associated with AF risk. Change in BMI over time influenced AF risk in both men and women., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Background and Aims: Novel biomarkers are linked to cardiovascular disease (CVD). The aim of the present study was to investigate the association between 28 blood biomarkers and the formation and progression of carotid plaque., Methods: In a nested case control study with 703 participants from the population based Tromsø Study, a large biomarker panel was measured in blood obtained at baseline. Carotid ultrasound was assessed both at baseline and at 6 years of follow-up. Four groups were defined: Group 1: no plaque at baseline or at follow-up (reference group); Group 2: novel plaque at follow-up; Group 3: stable plaque at follow-up; Group 4: progression of plaque at follow-up. By multinomial logistic regression analyses, we assessed the risk of being in the different plaque groups with regard to traditional cardiovascular risk factors and levels of biomarkers at baseline., Results: Adjusted for traditional risk factors, interleukin-6 (IL-6) was an independent predictor of plaque progression (OR 1.44, 95% CI 1.12-1.85 per SD increase in IL-6 level). This result remained significant after inclusion of other novel biomarkers to the model, and when subjects with former CVD were excluded. Neopterin was protective of novel plaque formation (OR 0.73, 95% CI 0.57-0.93). Myeloperoxidase and Caspase-1 were independent predictors of plaque progression, but this effect disappeared when excluding subjects with former CVD., Conclusions: IL-6 is an independent predictor of plaque progression, suggesting that it may be a marker of progressive atherosclerosis in the general population and that its central role in CVD may be related to promotion of plaque growth., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Atrial fibrillation (AF) is a well-established risk factor for ischemic stroke (IS). Emerging evidence also indicates an association between AF and pulmonary embolism (PE). Because IS may potentially mediate the observed risk of PE in AF, we aimed to assess the impact of AF on the cause-specific risks of PE and IS in a large cohort recruited from the general population., Methods and Results: We observed 29 842 participants from 3 surveys of the Tromsø study (inclusion in 1994-1995, 2001-2002, and 2007-2008) to the end of 2012. Incident events of AF, IS, and PE during follow-up were recorded, and information on potential confounders was obtained at baseline. Cox regression models, with AF as a time-dependent variable, were used to calculate cause-specific hazard ratios (HRs) with 95% confidence intervals (CIs) for PE and IS. There were 2067 participants diagnosed as having AF, 296 with PE and 1164 with IS, during a median of 17.6 years of follow-up. The risks of PE (HR, 10.88; 95% CI, 6.23-18.89) and IS (HR, 6.16; 95% CI, 4.47-8.48) were substantially increased during the first 6 months after AF diagnosis, with crude incidence rates of 18.5 per 1000 person-years for PE and 52.8 per 1000 person-years for IS. The risk estimates remained elevated for both PE (HR, 1.72; 95% CI, 1.10-2.71) and IS (HR, 2.45; 95% CI, 2.05-2.92) throughout the study period., Conclusions: AF was associated with increased cause-specific risks of both PE and IS. Our findings infer that the risk of PE in AF is not explained by intermediate IS., (© 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Red cell distribution width (RDW), a measure of the variability in size of the circulating erythrocytes, is associated with cardiovascular morbidity and mortality. We aimed to investigate whether RDW was associated with incident stroke and case fatality in subjects recruited from the general population. Baseline characteristics were obtained from 25,992 subjects participating in the fourth survey of the Tromsø Study, conducted in 1994/95. Incident stroke was registered from inclusion until December 31, 2010. Cox regression models were used to calculate hazard ratios (HR) with 95% confidence intervals (95% CI) for stroke, adjusted for age, sex, body mass index, smoking, haemoglobin level, white blood cell count, thrombocyte count, hypertension, total cholesterol, triglycerides, self-reported diabetes, and red blood cell count. During a median follow-up of 15.8 years, 1152 participants experienced a first-ever stroke. A 1% increment in RDW yielded a 13% higher risk of stroke (multivariable HR: 1.13, 95% CI: 1.07-1.20). Subjects with RDW in the highest quintile compared to the lowest had a 37% higher risk of stroke in multivariable analysis (HR: 1.37, 95% CI: 1.11-1.69). Subjects with RDW above the 95-percentile had 55% higher risk of stroke compared to those in the lowest quintile (HR: 1.55, 95% CI: 1.16-2.06). All risk estimates remained unchanged after exclusion of subjects with anaemia (n=1102). RDW was not associated with increased risk of death within one year or during the entire follow-up after an incident stroke. RDW is associated with incident stroke in a general population, independent of anaemia and traditional atherosclerotic risk factors.

Objective: To investigate the association between echocardiographic measurements with emphasis on diastolic dysfunction and risk of atrial fibrillation (AF) in a population-based cohort study., Methods: We followed 2406 participants from the Tromsø Study from 1994 to 2010. Left atrial (LA) size and mitral Doppler indices as measured by echocardiography were used for evaluating diastolic dysfunction. Information concerning age, systolic blood pressure, height, heart rate, body mass index, total and high-density lipoprotein cholesterol, self-reported use of alcohol, smoking, coffee, physical activity, antihypertensive treatment, prevalent coronary heart disease, valvular heart disease, heart failure, hypertrophy, diabetes and palpitations were obtained at baseline. The outcome measure was clinical AF, documented by an ECG., Results: AF was detected in 462 subjects (193 women). Mean age at baseline was 62.6 years. Incidence rate of clinical AF was 12.6 per 1000 person-years. In multivariable Cox proportional hazards regression analysis, moderately enlarged LA was associated with 60% (95% CI 1.2 to 2.0) increased risk of AF. Severely enlarged LA had HR for AF of 4.2 (95% CI 2.7 to 6.5) with p value for linear trend <0.001, and the association was similar in both sexes. Abnormal mitral Doppler flow adjusted for predictor variables did not show a statistically significant association with AF risk. However, when LA size was also adjusted for, the risk of AF increased by 30% (95% CI 1.0 to 1.6)., Conclusions: Our findings suggest that enlarged LA as a measure for diastolic dysfunction is a significant risk factor for AF in both sexes, and adding measures of abnormal diastolic flow increased the predictive ability significantly., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background and Purpose: Ischemic stroke incidence has declined in industrialized countries the last decades, with possible exception for the youngest age groups. We estimated age- and sex-specific trends in incidence and case fatality of first-ever ischemic stroke between 1977 and 2010 in a Norwegian municipality., Methods: Age-adjusted time trends in incidence from 1977 to 2010 were estimated by fractional polynomial and Poisson regression, and case fatality by logistic regression in 36 575 participants of the population-based Tromsø Study., Results: There were 1214 first-ever ischemic strokes within a total follow-up time of 611 176 person-years. The overall age- and sex-adjusted incidence decreased by 24% in 1995 to 2010. In women aged 30 to 49 years, the incidence increased significantly from 1980 to 2010. In men aged 30 to 49 years, there was a nonsignificant, rising trend from 1977 to 2010. Men aged 50 to 64 years had similar incidence in 2010 compared with 1989. From the mid-1990s to 2010, the incidence declined significantly in women aged 50 to 74 years and in men aged 65 to 74 years, but remained stable in those aged ≥75 years. Case fatality decreased significantly in men aged 30 to 84 years from 1995 to 2010, whereas there was no significant change in women., Conclusions: Age-adjusted incidence of first-ever ischemic stroke increased in young women, declined in women aged 50 to 74 years and men aged 65 to 74 years and remained stable among the oldest. Case fatality declined in men aged 30 to 84 years, but not in women., (© 2015 American Heart Association, Inc.)

Background/aims: Estimated glomerular filtration rate (eGFR) is used extensively in epidemiological research. Validations of eGFR have demonstrated acceptable performance, but the dependence of creatinine and cystatin C on non-GFR factors could confound associations with disease. Few studies have investigated this issue in direct comparison with measured GFR (mGFR). We compared the associations between eGFR and mGFR and retinal vasculopathy, a marker of systemic microvasculopathy., Methods: Iohexol clearance and retinal photography were examined in the Renal Iohexol Clearance Survey in Tromsø 6, which consists of a representative sample of middle-aged persons from the general population. A total of 1,553 persons without self-reported kidney disease, cardiovascular disease or diabetes were investigated. Three eGFR equations based on creatinine and/or cystatin C from the Chronic Kidney Disease Epidemiology Collaboration were studied. Differences between eGFR and mGFR were analyzed with seemingly unrelated regression methods., Results: mGFR in the lowest quartile was associated with an increased multivariable-adjusted odds ratio of retinopathy (OR 1.86, 95% CI 1.16-2.97), but not with retinal artery or vein diameters. eGFR based on cystatin C (eGFRcys) was consistently biased relative to mGFR in its associations with retinal vessel diameters across different models. eGFR based on creatinine (eGFRcrea) and eGFR based on both creatinine and cystatin C were also biased in several of these models (p < 0.05). For retinopathy, the differences between the 3 eGFR and mGFR measurements were not statistically significant., Conclusions: Low mGFR is associated with retinopathy in the general population. eGFR based on creatinine and/or cystatin C are not valid substitutes for mGFR in studies of the relationship between the retina and kidney function in healthy persons., (© 2015 S. Karger AG, Basel.)

Obesity is a risk factor for arterial and venous thromboembolism. However, it is not known whether obesity mediates risk through shared mechanisms. In a population-based cohort, we aimed to compare the impact of obesity measures on risk of venous thromboembolism (VTE) and myocardial infarction (MI), and explore how obesity-related atherosclerotic risk factors influenced these relationships. Measures of body composition including body mass index , waist circumference (WC), hip circumference (HC), waist-hip ratio (WHR) and waist-to-height ratio (WHtR) were registered in 6,708 subjects aged 25-84 years, who participated in the Tromsø Study (1994-1995). Incident VTE- and MI-events were registered until January 1, 2011. There were 288 VTEs and 925 MIs during a median of 15.7 years of follow-up. All obesity measures were related to risk of VTE. In linear models, WC showed the highest risk estimates in both genders. In categorized models (highest versus lowest quintile), WC showed highest risk in men (HR 3.59; 95 % CI 1.82-7.06) and HC in women (HR 2.27; 95 % CI 1.54-4.92). Contrary, WHR and WHtR yielded the highest risk estimates for MI. The HR of MI (highest vs. lowest quintile) for WHR was 2.11 (95 % CI 1.59-2.81) in men and 1.62 (95 % CI 1.13-2.31) in women. The risk estimates for MI were substantially attenuated after adjustment for atherosclerotic risk factors, whereas the estimates for VTE remained unchanged. Our findings suggest that the impact of body fat distribution, and the causal pathway, differs for the association between obesity and arterial and venous thrombosis.

Background: A family history of myocardial infarction (FHMI) has been shown to increase the risk of venous thromboembolism (VTE). The mechanism underlying the association remains unclear. Therefore, we aimed to determine the risks of MI and VTE by FHMI using a cause-specific model and to explore whether atherosclerotic risk factors could explain the association between FHMI and VTE in a population-based cohort., Methods and Results: The study included 21 624 subjects recruited from the Tromsø Study in 1994 to 1995 and 2001 to 2002. Incident MI and VTE events were registered from date of enrollment to end of follow-up, December 31, 2010. There were 1311 MIs and 428 VTEs during a median follow-up of 15.8 years. FHMI was associated with a 52% increased risk of MI (adjusted hazard ratio, 1.52; 95% confidence interval, 1.35-1.70) and a 26% increased risk of VTE (adjusted hazard ratio, 1.26; 95% confidence interval, 1.02-1.55) in the cause-specific Cox model. Similar results were found using the traditional Cox model. The risk estimates by status of FHMI were highest for unprovoked deep vein thrombosis (adjusted hazard ratio, 1.69; 95% confidence interval, 1.12-2.56), and the risk increased with increasing number of affected relatives. Modifiable atherosclerotic risk factors slightly altered the association between FHMI and MI but had a negligible effect on the association between FHMI and VTE., Conclusions: FHMI was associated with increased risk of both MI and VTE in a cause-specific model. Apparently, the association between FHMI and VTE applied to unprovoked deep vein thrombosis and was not explained by modifiable atherosclerotic risk factors., (© 2014 American Heart Association, Inc.)

Background: Red cell distribution width (RDW), a measure of the variability in size of circulating erythrocytes, is associated with mortality and adverse outcome in selected populations with cardiovascular disease. It is scarcely known whether RDW is associated with incident myocardial infarction (MI). We aimed to investigate whether RDW was associated with risk of first-ever MI in a large cohort study with participants recruited from a general population., Methods and Results: Baseline characteristics, including RDW, were collected for 25 612 participants in the Tromsø Study in 1994-1995. Incident MI during follow-up was registered from inclusion through December 31, 2010. Cox regression models were used to calculate hazard ratios with 95% confidence intervals for MI, adjusted for age, sex, body mass index, smoking, hemoglobin, white blood cells, platelets, and other traditional cardiovascular risk factors. A total of 1779 participants experienced a first-ever MI during a median follow-up time of 15.8 years. There was a linear association between RDW and risk of MI, for which a 1% increment in RDW was associated with a 13% increased risk (hazard ratio 1.13; 95% CI, 1.07 to 1.19). Participants with RDW above the 95th percentile had 71% higher risk of MI compared with those with RDW in the lowest quintile (hazard ratio 1.71; 95% CI, 1.34 to 2.20). All effect estimates were essentially similar after exclusion of participants with anemia (n=1297) from the analyses., Conclusion: RDW is associated with incident MI in a general population independent of anemia and cardiovascular risk factors., (© 2014 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)

Background: To describe trends in cardiovascular risk factors and change over time across education levels, and study the influence from medicine use and gender., Methods: Data from participants (30-74 years) of the Tromsø Study in 1994-1995 (n=22 108) and in 2007-2008 (n=11 565). Blood samples, measurements and self-reported educational level and medicine use were collected., Results: Differences in risk factor levels across education groups were persistent for all risk factors over time, with a more unfavourable pattern in the lowest education group. The exception was cholesterol, with the reduction being largest in the lowest educated, resulting in weakened educational trends over time. While a significant educational trend in cholesterol persisted among the non-users of lipid-lowering drugs (LLD), no educational trend in cholesterol was found among the LLD users in 2007-2008. The strongest educational trends were found for daily smoking and Body Mass Index (BMI). In 2007-2008 the odds for being a smoker were five times higher among the lowest educated compared to the highest educated. In men, the odds for being in the highest quintile of the BMI distribution were, in 2007-2008, almost doubled in the lowest compared to the highest educated. The lowest educated women had 6.2 mm Hg higher mean systolic blood pressure than the highly educated, mean BMI of 26.4 kg/m 2 and smoking prevalence of 37.7%., Conclusions: The difference across education groups for cholesterol levels decreased, while the educational gap persisted over time for the other risk factors. Use of LLD seemed to contribute to the reduction of social differences in cholesterol levels., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Blood lipid levels are heritable, treatable risk factors for cardiovascular disease. We systematically assessed genome-wide coding variation to identify new genes influencing lipid traits, fine map known lipid loci and evaluate whether low-frequency variants with large effects exist for these traits. Using an exome array, we genotyped 80,137 coding variants in 5,643 Norwegians. We followed up 18 variants in 4,666 Norwegians and identified ten loci with coding variants associated with a lipid trait (P < 5 × 10(-8)). One variant in TM6SF2 (encoding p.Glu167Lys), residing in a known genome-wide association study locus for lipid traits, influences total cholesterol levels and is associated with myocardial infarction. Transient TM6SF2 overexpression or knockdown of Tm6sf2 in mice alters serum lipid profiles, consistent with the association observed in humans, identifying TM6SF2 as a functional gene within a locus previously known as NCAN-CILP2-PBX4 or 19p13. This study demonstrates that systematic assessment of coding variation can quickly point to a candidate causal gene.

Aims: Serum uric acid (SUA) has been associated with cardiovascular disease in population studies, but its relation to atrial fibrillation (AF) is largely unknown. The aim of this study was to investigate the association between baseline SUA and future AF in a large population-based cohort., Methods and Results: A total of 6308 men and women from a population survey in Tromsø, Norway in 1994-95 were followed-up for 10.8 years. The mean age at baseline was 60 years. Information on angina, myocardial infarction, diabetes, anti-hypertensive and diuretic treatment, physical activity, smoking and alcohol, and measurements of height, weight, blood pressure, SUA, total cholesterol, and high density lipoprotein-cholesterol were obtained at baseline. The outcome measure was first-ever AF, documented on an electrocardiogram. We identified 572 cases of incident AF. In multivariable Cox proportional hazards regression analysis adjusted for cardiovascular risk factors and concomitant diseases, SUA was associated with AF in both sexes. Hazard ratio per 1 SD increase in SUA (91 μmol/L) was 1.40 [95% confidence intervals (CI), 1.14-1.72] in women and 1.17 (95% CI, 1.02-1.36) in men. The upper quartile of SUA conferred a 76% increased risk for AF in women and 49% in men as compared with the lowest quartile., Conclusion: This prospective population-based cohort study showed that baseline SUA was associated with an increased risk for future AF in both sexes.

Background: Growing evidence supports an association between venous thromboembolism (VTE) and arterial thrombotic diseases (ie, myocardial infarction and ischemic stroke). We aimed to study the association between VTE and future arterial events and to determine the population attributable risk of arterial events by VTE in a large prospective cohort recruited from the general population., Methods and Results: In 1994 to 1995 and 1993 to 1997, 81 687 subjects were included in the Tromsø Study and in the Diet, Cancer and Health Study and followed up to the date of incident venous and arterial events (myocardial infarction or ischemic stroke), death or migration, or to the end of the study period (2010 and 2008, respectively). There were 1208 cases of VTE and 90 subsequent arterial events during a median follow-up of 12.2 years. An association between VTE and future arterial events was found in all women and men aged <65 years but not in men aged >65 years. Women <65 years old with VTE had 3.3-fold higher risk of arterial disease (adjusted hazard ratio, 3.28; 95% confidence interval, 1.69-6.35) compared with women of the same age without VTE. The corresponding hazard ratio in men aged <65 years was 2.06 (95% confidence interval, 1.32-3.20). Only 0.9% of the arterial events were attributed to VTE, and the VTE explained 63.8% of the risk of arterial events among VTE patients., Conclusions: Our findings imply that women and young men with VTE have higher risk of arterial thrombotic disease than those without VTE. However, only 1% of the arterial thrombotic events in the population are attributed to VTE.

Background: Pulmonary embolism (PE) may trigger atrial fibrillation through increased right atrial pressure and subsequent atrial strain, but the degree of evidence is low. In this study, we wanted to investigate the impact of incident venous thromboembolism (VTE) on future risk of atrial fibrillation in a prospective population-based study., Methods and Results: The study included 29 974 subjects recruited from the Tromsø study (1994-1995, 2001-2002, 2007-2008). Incident VTE and atrial fibrillation events were registered from date of enrolment to end of follow-up, December 31, 2010. Cox proportional hazard regression models using age as time-scale and VTE as a time-dependent variable were used to estimate crude and multivariable hazard ratios (HRs) for atrial fibrillation with 95% confidence intervals (CIs). During 16 years of follow up, 540 (1.8%) subjects had an incident VTE event, and 1662 (5.54%) were diagnosed with atrial fibrillation. Among those with VTE, 50 (9.3%) developed subsequent atrial fibrillation. Patients with VTE had 63% higher risk of atrial fibrillation compared to subjects without VTE (multivariable-adjusted HR: 1.63, 95% CI: 1.22 to 2.17). The risk of atrial fibrillation was particularly high during the first 6 months after the VTE event (HR 4.00, 95% CI: 2.21 to 7.25) and among those with PE (HR 1.78, 95% CI: 1.13 to 2.80)., Conclusions: We found that incident VTE was associated with future risk of atrial fibrillation. Our findings support the hypothesis that PE may lead to cardiac dysfunctions that, in turn, could trigger atrial fibrillation.

Purpose: To investigate if markers of iron body stores and hemoglobin are associated with retinal vascular caliber., Methods: This was a population-based study including 2993 participants of the fifth and sixth surveys of the Tromsø Study in Norway, conducted in 2001-2002 and 2007-2008. The association between levels of s-ferritin, transferrin saturation, and hemoglobin in the fifth survey and retinal vascular caliber in the sixth survey was assessed by multivariable linear regression models., Results: Men had higher levels of hemoglobin and s-ferritin than women. Hemoglobin was associated with wider retinal venules in both men and women (mean difference between highest compared to lowest sex-specific quartile: men 5.99 μm, P = 0.001; women 7.28 μm, P < 0.001). S-ferritin was associated with wider retinal venules in men but not women, independent of traditional risk factors (mean difference between highest compared to lowest sex-specific quartile: men 4.21 μm, P = 0.013; women -0.21 μm, P = 0.89). The association in men was attenuated, but still significant, with adjustment for hemoglobin. S-ferritin and level of hemoglobin were not associated with arteriolar caliber in either sex. Transferrin saturation was not associated with retinal vascular caliber., Conclusions: Level of hemoglobin was associated with wider retinal venules in both sexes while s-ferritin was associated with wider retinal venular caliber only in men. Men have higher levels of stored iron, and this may underlie the observed sex difference in the association between s-ferritin and retinal vascular caliber.

Background: Atrial fibrillation (AF) is a common cardiac arrhythmia which increases morbidity and mortality. Identification of risk factors is therefore important. We examined the impact of palpitations and cardiovascular risk factors in prediction of AF (all types) and lone AF in a large population-based cohort., Design: We carried out a prospective population-based cohort study., Methods: A total of 22,815 participants from a population survey in 1994-1995 were followed-up for a mean of 11.1 years. Mean age at baseline was 46 years. Measurements of height, weight, blood pressure, heart rate, total cholesterol and high-density lipoprotein (HDL)-cholesterol, and information on palpitations, diabetes, angina, myocardial infarction, and antihypertensive treatment were obtained at baseline. The outcome measure was first-ever AF, documented on an electrocardiogram. Cox proportional hazards regression model was used to estimate hazard ratios (HRs) for AF., Results: Palpitations were associated with increased risk of AF in both women (HR 1.62, 95% confidence interval [CI] 1.29-2.02) and men (HR 1.91, 95% CI 1.54-2.35). For hypertension the HR for AF was 1.98 (1.46-2.69) in women and 1.40 (1.13-1.74) in men. The HR for 1 SD increase in body mass index (BMI) was 1.16 (1.06-1.27) in women and 1.47 (1.32-1.63) in men. Body height and BMI were associated with increased risk for lone AF in men., Conclusion: Palpitations, hypertension and BMI were predictive of future atrial fibrillation in both sexes.

Background: Inflammatory biomarkers are reported as risk factors for atrial fibrillation (AF), but their impact is uncertain., Objective: We investigated the associations between inflammatory biomarkers and future AF in a large general cohort., Methods: Available markers were white blood cells (WBCs) with subgroups, fibrinogen, high-sensitivity C-reactive protein (hs-CRP), and osteoprotegerin (OPG). A total of 6315 men and women from a population survey in Tromsø, Norway in 1994 to 1995 were followed for a mean of 10.9 years. Mean age at baseline was 60 years. Measurements of height, weight, blood pressure, heart rate, total cholesterol, high-density lipoprotein (HDL) cholesterol, WBC count, and information on diabetes, angina, myocardial infarction, and antihypertensive treatment, were obtained at baseline. Fibrinogen, hs-CRP, and OPG were obtained at a follow-up visit. The outcome measure was first-ever AF, documented on an electrocardiogram. The Cox proportional hazards regression model was used to estimate hazard ratios of AF., Results: In the multivariable analysis, adjusted for traditional cardiovascular risk factors and other inflammatory biomarkers, hs-CRP was associated with AF in men only (hazard ratio = 1.14 for a 1 SD increase; 95% CI, 1.02-1.28). There was a significant increase in AF across quartiles of WBCs in men (P = 0.007) and in the total study population (P = 0.004). OPG was associated with AF in patients free of coronary heart disease at baseline. Fibrinogen and subgroups of WBCs showed no significant association with AF., Conclusion: This population-based cohort study showed that hs-CRP was independently associated with AF in men, but apparently not in women, and that patients with WBCs in the upper quartile had increased risk of AF., (Copyright © 2012 Elsevier HS Journals, Inc. All rights reserved.)

Background: Although the mortality of coronary heart disease (CHD) has declined in Western countries during the last decades, studies have suggested that the prevention and treatment of CHD may not have been as effective in women as in men. We examined gender- and age-specific trends in incidence, case fatality and the severity of first myocardial infarction (MI) in a large Norwegian population-based study., Design: Prospective population-based cohort study., Methods: A total of 31,323 participants enrolled between 1974 and 2001 were followed throughout 2004 for a total of 400,572 person-years. Suspected coronary events were adjudicated by a review of hospital records and death certificates. A total of 1669 events fulfilled standardized criteria of first-ever fatal or non-fatal MI., Results: In the age group 35-79 years, the age-adjusted incidence of MI declined significantly in men, whereas an increase was observed in women. For men and women ≥ 80 years the incidence rates remained unchanged. The severity of MI and the 28-day and 1-year case fatality rates declined significantly and similarly in men and women., Conclusion: Trends in MI incidence differed by sex and age; in the age group 35-79 years a marked decrease was observed among men but an increase was observed among women, while no change was observed among older patients. MI severity and case fatality were clearly reduced for both sexes. These data suggest that the burden of CHD is shifting from middle-aged men toward middle-aged women and elderly patients.

Background: Glomerular filtration rate<60 mL/min/1.73 m2 is associated with increased cardiovascular risk. Cystatin C is believed to be a better tool than creatinine for detection of mild renal dysfunction (>60 mL/min/1.73 m2) and possibly a more sensitive marker for cardiovascular risk and all-cause mortality. We examined the association of cystatin C with cardiovascular morbidity and all-cause mortality in a prospective population-based study., Methods: Cystatin C was measured in 2852 men and 3153 women in the Tromsø Study 1994/95. Gender-specific associations during 12 years of follow-up for all-cause mortality and 9.5 years for myocardial infarction (MI) and ischaemic stroke were assessed (Cox proportional hazard ratios, HRs)., Results: During follow-up, 591 MIs, 293 ischaemic strokes and 1262 deaths occurred. In women, HR for all-cause mortality was increased in the upper cystatin C quartile (≥0.93 mg/L) compared with the lowest quartile (≤0.73 mg/L); 1.38, 95% confidence interval 1.04-1.84. A significant interaction with gender was observed. One SD (0.17 mg/L) increase in cystatin C was associated with 9% higher risk of death in women, also when persons with a cancer history were excluded. Crude HRs for MI and ischaemic stroke were increased in both genders, but the associations did not persist after multivariable adjustments. No independent associations with end points were observed in non-gender-specific analyses., Conclusions: Cystatin C was not independently associated with fatal and non-fatal MI or ischaemic stroke in the general population. However, cystatin C was a risk factor for all-cause mortality in women.

Background and Purpose: The joint effect of risk factors on the risk of aneurysmal SAH (aSAH) has been studied sparsely., Methods: We examined the potential synergism between cigarette smoking, hypertension, and regular alcohol consumption and the risk of aSAH in a prospective, population-based cohort of participants from the Nord-Trøndelag Health Study and the Tromsø Study in Norway. Interaction was assessed on additive and multiplicative scales., Results: We identified 122 cases of aSAH over 977 895 person-years of follow-up. Interaction was observed between current smoking and hypertension on the additive scale, (relative excess risk because of interaction, 6.40; 95% CI, 0.88-11.92, adjusted for sex and age). We found no significant interaction between hypertension and regular alcohol consumption or current cigarette smoking and regular alcohol consumption on the additive scale. No significant interaction was detected on the multiplicative scale., Conclusions: The joint effect of current smoking and hypertension on the risk of aSAH was stronger than was the sum of the independent effects of each factor. Persons at risk of aSAH should be advised of a markedly stronger risk for aSAH with the combination of current smoking and hypertension. In addition, the finding suggests that combining smoking cessation and blood pressure lowering may have an extra risk reduction effect on preventing aSAH.

Background and Purpose: Data on risk factors for progression of intima-media thickness (IMT) and plaque are scarce. The objective was to determine long-term risk factors for total plaque area (TPA) and IMT as well as risk factors for progression (ΔTPA and ΔIMT)., Methods: Subjects were 1307 men and 1436 women who participated in a longitudinal population-based study with ultrasound examination of the right carotid artery at baseline and after 13 years of follow-up. Total cholesterol, high-density lipoprotein cholesterol, blood pressure, body mass index, and information about smoking habits, prevalent diabetes, and cardiovascular disease were obtained at baseline. Carotid atherosclerosis was assessed as TPA and mean IMT of plaque-free segments of the common carotid artery. Associations between z-scores of risk factors and carotid atherosclerosis were assessed in multiple linear regression models., Results: In multivariable models, total cholesterol, systolic blood pressure, and smoking were stronger predictors of follow-up TPA than of IMT, whereas sex and age were stronger predictors of IMT. Total cholesterol (standardized β=0.081), systolic blood pressure (standardized β=0.062), and smoking (standardized β=0.107) were significant predictors of ΔTPA, whereas only total cholesterol (standardized β=0.084) was an independent predictor of ΔIMT. The variance explained by traditional cardiovascular risk factors was somewhat greater for TPA than for IMT., Conclusions: The cardiovascular risk factors total cholesterol, smoking, and systolic blood pressure were stronger long-term predictors of TPA and TPA progression than for IMT and IMT progression.

Objective: To investigate and compare the impact of traditional atherosclerotic risk factors for the risk of arterial and venous thrombosis, taking into account competing risks., Methods and Results: In 1994-1995, 26,185 subjects were screened in the Tromsø study. Information on traditional atherosclerotic risk factors was obtained by physical examination, blood samples, and questionnaires. Subjects were followed to the first incident event of myocardial infarction (MI) or venous thromboembolism (VTE), or December 31, 2005. During a median of 10.8 years of follow-up, there were 1279 cases of incident MI and 341 VTE events. Advancing age and high body mass index were both associated with MI and VTE. Hazard ratio per decade of age was 2.34 (95% CI: 2.25-2.43) for MI and 1.87 (1.74-2.01) for VTE, and 3 kg/m(2) increase in body mass index was associated with 1.16 (1.11-1.21) and 1.20 (1.12-1.29) increased risk of MI and VTE, respectively. Blood pressure, high levels of triglycerides and total cholesterol, low HDL cholesterol, self-reported diabetes, and smoking were all associated with increased risk of MI but not associated with VTE., Conclusions: Our findings imply that traditional atherosclerotic risk factors, such as smoking, hypertension, dyslipidemia, and diabetes mellitus are not shared by arterial and venous thrombosis.

Background: A seasonal pattern with higher winter morbidity and mortality has been reported for acute myocardial infarction (MI). The magnitude of the difference between peak and nadir season has been associated with latitude, but results are inconsistent. Studies of seasonal variation of MI in population-based cohorts, based on adjudicated MI cases,are few.We investigated the monthly and seasonal variation in first-ever nonfatal and fatal MI in the population of Tromsø in northern Norway, a region with a harsh climate and extreme seasonal variation in daylight exposure., Design: Prospective population-based cohort study., Methods: A total of 37 392 participants from the Tromsø Study enrolled between 1974 and 2001 were followed throughout 2004. Each incident case of MI was validated by the review of medical records and death certificates. MI incidence rates for months and seasons were analyzed for seasonal patterns with Poisson regression and the Cosinor procedure. All analyses were stratified by sex, age and smoking status., Results: A total of 1893 first-ever MIs were registered, of which 592 were fatal. There was an 11 % (95% confidence interval: 1.00-1.23, P=0.04) increased risk of incident MI during winter (November-January) compared with non-winter seasons, with no statistically significant interaction with sex, age, smoking or calendar year. Other seasonal modelling gave similar but not statistically significant results., Conclusion: We found a small increase in risk of incident MI during the darkest winter months. Populations living in sub-Arctic areas may be adapted to face climate exposure during winter through behavioural protection.

Background: Previous studies have shown differences in the impact of regular physical exercise on the risk of venous thromboembolism. The inconsistent findings may have depended on differences in study design and specific population cohorts (men only, women only and elderly). We conducted a prospective, population-based cohort to investigate the impact of regular physical exercise on the risk of venous thromboembolism., Design and Methods: Risk factors, including self-reported moderate intensity physical exercise during leisure time, were recorded for 26,490 people aged 25-97 years old, who participated in a population health survey, the Tromsø study, in 1994-95. Incident venous thromboembolic events were registered during the follow-up until September 1, 2007., Results: There were 460 validated incident venous thromboembolic events (1.61 per 1000 person-years) during a median of 12.5 years of follow-up. Age, body mass index, the proportion of daily smokers, total cholesterol, and serum triglycerides decreased (P<0.001), whereas high density cholesterol increased (P<0.001) across categories of more physical exercise. Regular physical exercise of moderate to high intensity during leisure time did not significantly affect the risk of venous thromboembolism in the general population. However, compared to inactivity, high amounts of physical exercise (≥ 3 hours/week) tended to increase the risk of provoked venous thromboembolism (multivariable hazard ratio, 1.30; 95% confidence interval, 0.84-2.0), and total venous thromboembolism in the elderly (multivariable hazard ratio, 1.33; 95% confidence interval, 0.80-2.21) and in the obese (multivariable hazard ratio, 1.49; 95% confidence interval, 0.63-3.50). Contrariwise, compared to inactivity, moderate physical activity (1.0-2.9 hours/week) was associated with a border-line significant decreased risk of venous thromboembolism among subjects under 60 years old (multivariable hazard ratio, 0.72; 95% confidence interval, 0.48-1.08) and subjects with a body mass index of less than 25 kg/m(2) (multivariable hazard ratio, 0.59; 95% confidence interval, 0.35-1.01)., Conclusions: Our study showed that regular, moderate intensity physical exercise did not have a significant impact on the risk of venous thromboembolism in a general population. Future studies are required to assess the impact of regular physical exercise on venous thromboembolism risk in different population subgroups.

An association between body height and venous thromboembolism (VTE) has been suggested by previous studies including males only. The aim of this prospective cohort study was to investigate the sex-specific impact of body height on risk of VTE in a general population. Risk factors, including body height and weight, were registered for 26,727 subjects aged 25-96 years who participated in the Tromsø Study (Norway) in 1994-1995. Incident VTE events were registered through September 1, 2007. There were 462 VTE events during a median 12.5 years of follow-up. Body height was a risk factor for VTE in men, but not in women. Multivariable hazard ratios per 10 cm, adjusted for age, body mass index, diabetes, smoking, and hormone therapy (women), were 1.34 (95% confidence interval: 1.09, 1.64) for men and 1.13 (95% confidence interval: 0.91, 1.40) for women. Hazard ratios by quartiles of body height revealed that men in the upper quartile (>181 cm) had a 1.99-fold (95% confidence interval: 1.35, 2.92) increased risk of VTE compared with men in the lowest quartile (<173 cm) (P for trend across quartiles = 0.002). There was no significant trend (P = 0.2) across quartiles of body height for women. Study findings revealed that body height is a sex-specific risk factor for VTE in men.