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Background: Atrial fibrillation (AF) and heart failure (HF) often coexist and impact morbidity and mortality. There is limited knowledge on the association of AF subtypes with HF according to sex. Objectives: The purpose of this study was to explore sex-specific associations between AF subtypes and subsequent HF, identifying HF risk factors in participants with AF, and exploring the combined impact on mortality. Methods: 14,790 women and 13,181 men from the Tromsø Study were enrolled between 1994 and 2008 and followed for incident AF and HF through 2016. Cox regression was conducted to provide HRs and 95% CIs. Results: Those with AF had higher risk of subsequent HF in both sexes compared to those without AF. Women with permanent AF had higher relative risk of HF than men (HR: 10.52; 95% CI: 8.72-12.70, and HR: 7.65; 95% CI: 6.40-9.15, respectively). Risk factors for HF in participants with AF included smoking in all, higher diastolic blood pressure and hypertension in women, underweight, obesity, and low alcohol consumption in men. All-cause mortality was higher in women with both subtypes (paroxysmal/persistent: HR: 2.10; 95% CI: 1.78-2.48, permanent: HR: 1.40, 95% CI: 1.14-1.72) and in men with paroxysmal/persistent AF (HR: 1.66; 95% CI: 1.40-1.96). Subsequent HF increased risk of mortality in both sexes. Conclusions: All AF subtypes were associated with increased risk of HF. Smoking was a shared risk factor, while diastolic blood pressure and hypertension were specific to women, and underweight, obesity, and low alcohol intake were specific to men. Subsequent HF increased mortality risk in all.

Objectives The objective of this study was to assess the quality of ECG recordings and the concordance between the automatic detection of cardiac arrhythmia episodes by a patch ECG and an insertable cardiac monitor.Design Prospective cohort study.Setting and participants Endurance athletes diagnosed with paroxysmal atrial fibrillation (AF) and no other relevant comorbidities participating in a randomised controlled trial on the effects of training adaption.Methods A patch ECG (ECG247 Smart Heart Sensor) was sent to 29 non-elite endurance athletes with clinical paroxysmal AF. ECG247 continuously monitors, detects and categorises cardiac arrhythmias. The participants were simultaneously monitored with an insertable cardiac monitor (Confirm Rx, Abbott). ECG recording quality was assessed by an experienced physician. Training sessions were monitored using sports watches.Results Out of 29 invited athletes, 14 athletes (mean age 60.4 years, 2 women) made use of the patch ECG and were monitored for a total of 2987 hours and a median of 14 (range 1–17) days. During this period, the athletes performed a total of 112 training sessions. ECG quality varied between athletes and by type of exercise, with poor quality in 16% and 40% of recordings during cross-country skiing and running, respectively. In two athletes, the patch ECG detected AF episodes that were confirmed with insertable cardiac monitor recordings. One technical artefact was falsely classified as ventricular tachycardia by the ECG247 Smart Heart Sensor system.Conclusion Monitoring with patch ECG was feasible in endurance athletes, but ECG recording quality varied between athletes and by type of exercise.Trial registration NCT04991337 (for the related randomised controlled trial).

Doctors who work in areas of workforce shortage, such as regional, rural and remote areas or areas of low socioeconomic means need to be more self-motivated, adaptable and self-directed than their metropolitan counterparts. This study aimed to examine the goal orientation and learning characteristics of students recruited into two medical programmes, one from the Northern hemisphere and one from the Southern hemisphere; both with a commitment to producing doctors to practice medicine in rural locations. Three survey tools were administered to 263 medical students: 1. achievement goal orientation survey; 2. learning characteristics survey and 3. the study process questionnaire. Medical students from both cohorts showed a learning goal orientation, which significantly increased with age (P0.007). In terms of learning characteristics, the students from the south had significantly higher scores for curiosity (P0.003), while the northern students had significantly higher scores for methodical (p

Objective: To examine the dose-response association between estimated cardiorespiratory fitness (eCRF) and risk of myocardial infarction (MI). Patients and Methods: Adults who attended Tromsø Study surveys 4-6 (Janurary 1,1994-December 20, 2008) with no previous cardiovascular disease were followed up through December 31, 2014 for incident MI. Associations were examined using restricted cubic splines Fine and Gray regressions, adjusted for education, smoking, alcohol, diet, sex, adiposity, physical activity, study survey, and age (timescale) in the total cohort and subsamples with hyperlipidemia (n=2956), hypertension (n=8290), obesity (n=5784), metabolic syndrome (n=1410), smokers (n=3823), and poor diet (n=3463) and in those who were physically inactive (n=6255). Results: Of 14,285 participants (mean age ± SD, 53.7±11.4 years), 979 (6.9%) experienced MI during follow-up (median, 7.2 years; 25th-75th, 5.3-14.6 years). Females with median eCRF (32 mL/kg/min) had 43% lower MI risk (subdistributed hazard ratio [SHR], 0.57; 95% CI, 0.48-0.68) than those at the 10th percentile (25 mL/kg/min) as reference. The lowest MI risk was observed at 47 mL/kg/min (SHR, 0.02; 95% CI, 0.01-0.11). Males had 26% lower MI risk at median eCRF (40 mL/kg/min; SHR, 0.74; 95% CI, 0.63-0.86) than those at the 10th percentile (32 mL/kg/min), and the lowest risk was 69% (SHR, 0.31; 95% CI, 0.14-0.71) at 60 mL/kg/min. The associations were similar in subsamples with cardiovascular disease risk factors. Conclusion: Higher eCRF associated with lower MI risk in females and males, but associations were more pronounced among females than those in males. This suggest eCRF as a vital estimate to implement in medical care to identify individuals at high risk of future MI, especially for females.

Abstract Background Myocardial infarction is likely to be experienced as a life-threatening and potentially traumatic event. Approximately one-third of patients with myocardial infarction experience clinically significant symptoms of anxiety/depression. However, it is unclear how many of these patients experience these symptoms because of post-traumatic stress disorder (PTSD). We conducted a clinical screening of individuals with a confirmed myocardial infarction diagnosis. Our goal was to examine the prevalence of PTSD in myocardial infarction patients and study how PTSD symptoms were associated with exposure to potentially traumatic events. Method This is epidemiological research with a cross-sectional design following up participants from the Tromsø Study with a confirmed diagnosis of myocardial infarction. We sent invitations to participants in the Tromsø Study with clinically significant self-reported anxiety or depression symptoms following myocardial infarction. A cross-sectional sample of N = 79 participants (61 men and 18 women) was collected. During an interview, participants completed the Stressful Life Events Screening Questionnaire and the PTSD checklist PCL-5. Results We found nine participants (11.6%) with probable PTSD. This was significantly higher than the postulated population prevalence in Norway (p

Background The atherosclerotic effect of an adverse lipid profile is assumed to accumulate throughout life, leading to increased risk of myocardial infarction (MI). Still, little is known about age at onset and duration of unfavorable lipid levels before MI. Methods and Results Longitudinal data on serum lipid levels for 26 130 individuals (50.5% women, aged 20–89 years) were obtained from 7 population‐based health surveys in Tromsø, Norway. Diagnoses of MI were obtained from national registers. A linear mixed model was applied to compare age‐ and sex‐specific mean values of total cholesterol, high‐density lipoprotein cholesterol (HDL‐C), and triglyceride concentration by MI status (MI versus non‐MI). Already from young adulthood, 20 to 35 years before the incident MI, individuals with a subsequent incident MI had on average more adverse lipid levels than individuals of the same age and sex without MI. Analogous to a dose–response relationship, there was a clear trend toward more severe adverse lipid levels the lower the age at incident MI (P

Aims Endurance sport practice is associated with a high prevalence of atrial fibrillation (AF), which increases the risk of stroke in the general population. However, stroke risk in endurance athletes with AF is sparsely investigated. Most studies have been limited by design and are largely restricted to younger and middle-aged populations. Thus, we aimed to investigate AF and stroke risk in older athletes exposed to prolonged endurance training.Method During a 10-year period, 505 male athletes aged ≥65 years frequently participating in a long-distance ski race were compared with 1867 men of the same age from the general population. The main exposure was endurance sport practice with self-reported AF and stroke as outcomes. Stroke risk was further examined by joint modelling of AF and endurance practice. Statistical analysis was conducted with a modified Poisson model.Results Athletes (median age: 68, range: 65–90) participated in a long-distance ski race over a median of 14 years (range: 1–53). Prevalence (28.5% vs 17.8%) and adjusted risk of AF (risk ratio (RR): 1.88, 95% CI: 1.49 to 2.37) were higher in athletes compared with non-athletes, whereas the prevalence (5.4% vs 9.7%) and risk of stroke were lower (RR: 0.60, 95% CI: 0.37 to 0.95). Compared with athletes without AF, risk of stroke was twofold in athletes (RR: 2.38, 95% CI: 1.08 to 5.24) and nearly fourfold in non-athletes (RR: 3.87, 95% CI: 1.98 to 7.57) with AF.Conclusion Although older male endurance athletes experienced an increased risk of AF, the long-term risk of stroke was substantially reduced compared with non-athletes.

Background: The outcomes of real-world unstable angina (UA) in the high-sensitivity troponin era are unclear. We aimed to investigate the outcomes of UA referred to coronary angiography compared to stable angina (SA), non-ST-segment elevation myocardial infarction (NSTEMI), STEMI and a general population. Methods: We included the 9,694 patients with no prior coronary artery disease (CAD) referred to invasive or CT coronary angiography from 2013 to 2018 in Northern Norway (51% SA, 12% UA, 23% NSTEMI and 14% STEMI), and 11,959 asymptomatic individuals recruited from the Tromsø Study. We used Cox models to estimate the hazard ratios (HR) for all-cause mortality and major adverse cardiovascular events (MACE), defined as cardiovascular death, MI or obstructive CAD. Results: The median follow-up time was 2.8 years. The incidence rate of death was 8.5 per 1000 person-years (95 % confidence interval [CI] 8.0–9.0) in the general population, 9.7 (95 % CI 8.3–11.5) in SA, 14.9 (95 % CI 11.4–19.6) in UA, 29.7 (95 % CI 25.6–34.3) in NSTEMI and 36.5 (95 % CI 30.9–43.2) in STEMI. In multivariable adjusted analyses, compared with UA, SA had a 38 % lower risk of death and a non-significant lower risk of MACE (HR 0.62, 95 % CI 0.44–0.89; HR 0.86, 95 % CI 0.66–1.11). NSTEMI had a 2.4-fold higher risk of death (HR 2.39, 95 % CI 1.38–4.14) and a 1.6-fold higher risk of MACE (HR 1.62, 95 % CI 1.11–2.38) compared tox UA during the first year after coronary angiography, but a similar risk thereafter. There was no difference in the risk of death for UA with non-obstructive CAD and obstructive CAD (HR 0.78, 95 % CI 0.39–1.57). Conclusion: UA had a higher risk of death but a similar risk of MACE compared to SA and a lower 1-year risk of death and MACE compared to NSTEMI.

Introduction: Cardiovascular disease (CVD) is a leading cause of death and disability and living in areas with low socio-economic status (SES) is associated with increased risk of CVD. Lifestyle factors such as smoking, physical inactivity, an unhealthy diet and harmful alcohol use are main risk factors that contribute to other modifiable risk factors, such as hypertension, raised blood cholesterol, obesity, and diabetes. The potential impact of area-level socio-economic status (ASES) on metabolic CVD risk factors via lifestyle behaviors independent of individual SES has not been investigated previously. Aims: To estimate associations of ASES with CVD risk factors and the mediating role of lifestyle behaviors independent of individual-level SES. Methods: In this cross-sectional study, we included 19,415 participants (52% women) from the seventh survey of the Tromsø Study (2015–2016) (Tromsø7). The exposure variable ASES was created by aggregating individual-level SES variables (education, income, housing ownership) at the geographical subdivision level. Individual-level SES data and geographical subdivision of Tromsø municipality (36 areas) were obtained from Statistics Norway. Variables from questionnaires and clinical examinations obtained from Tromsø7 were used as mediators (smoking, snuff, alcohol, and physical activity), while the outcome variables were body mass index (BMI), total/high-density lipoprotein (HDL) cholesterol ratio, waist circumference, hypertension, diabetes. Mediation and mediated moderation analysis were performed with age as a moderator, stratified by sex. Results: ASES was significantly associated with all outcome variables. CVD risk factor level declined with an increase in ASES. These associations were mediated by differences in smoking habits, alcohol use and physical activity. The associations of ASES with total/HDL cholesterol ratio and waist circumference (women) were moderated by age, and the moderating effects were mediated by smoking and physical activity in both sexes. The largest mediated effects were seen in the associations of ASES with total/HDL cholesterol ratio, with the mediators accounting for 43% of the observed effects. Conclusions: Living in lower SES areas is associated with increased CVD risk due to unhealthy lifestyle behaviors, such as smoking, alcohol use and physical inactivity. These associations were stronger in women and among older participants.

Objectives Shift work is associated with myocardial infarction and stroke. We studied if shift work is also associated with incident atrial fibrillation (AF) and if this association differs, depending on sex and age.Methods We studied 22 339 participants (age 37.0±9.8 years, 49% women) with paid work from the third (1986–1987), fourth (1994–1995), fifth (2001) and sixth (2007–2008) surveys of the population-based Tromsø Study, Norway. Participants were followed up for ECG-confirmed AF through 2016. Shift work was assessed by questionnaire at each survey. We used unadjusted and multivariable-adjusted Cox regression models to study the association of shift work with 10-year incident AF and incident AF during extensive follow-up up to 31 years. Interactions with sex and age were tested in the multivariable model.Results Shift work was reported by 21% of participants at the first attended survey. There was an interaction between shift work and age for 10-year incident AF (p=0.069). When adjusted for AF risk factors, shift work was significantly associated with 10-year incident AF in participants

Abstract Background Atrial fibrillation (AF) is associated with increased risk of ischemic stroke and all‐cause mortality. Patients with AF are also at increased risk of venous thromboembolism (VTE), but information on how AF impacts VTE‐related mortality is scarce. Objectives To investigate the impact of AF on all‐cause mortality in subjects with and without a thromboembolic event (VTE or ischemic stroke). Methods We followed 29 833 participants from the Tromsø study (1994‐2008) through 2013 and recorded all deaths during follow‐up. Incident AF, VTE, and ischemic stroke were registered as time‐dependent exposures. We calculated mortality rates (MRs) by exposure during follow‐up and obtained hazard ratios (HRs) for death with 95% confidence intervals (CIs). Results A total of 2087 AF cases, 756 VTEs, and 1279 ischemic strokes were registered during a median follow‐up of 18.7 years, and 4797 people (16.1%) died. The age‐adjusted MR for participants without any event was 1.19 per 100 person‐years (PY; 95% CI, 1.15‐1.23). Compared to these participants, subjects with the joint AF + VTE exposure had a 3.7‐fold increased risk of death (HR, 3.67; 95% CI, 2.77‐4.66) in age‐ and sex‐adjusted analyses, similar to the risk observed for VTE alone (HR, 3.76; 95% CI, 3.28‐4.30). Participants with stroke had a 2.9‐fold increased risk of death (HR, 2.85; 95% CI, 2.56‐3.18), and the risk was further increased in participants with both AF and stroke (HR, 4.38; 95% CI, 3.85‐4.98). Conclusions AF was significantly associated with increased risk of death in participants with incident stroke. In contrast, concomitant AF was not associated with excess mortality risk in VTE patients.

BackgroundCurrent knowledge about the relationship between physical activity (PA) and cardiac remodeling is mainly derived from cross-sectional studies of athletes, and there is a knowledge gap of this association in the general adult and elderly population. Therefore, we aimed to explore the longitudinal association between cumulative PA and change in cardiac structure and function in a general adult and elderly population.MethodsThis longitudinal study includes 594 participants from the sixth (Tromsø6, 2007–08) and seventh (Tromsø7, 2015–16) survey of the Tromsø Study. Cardiac structure and function were assessed by echocardiography at two time points, and PA was self-reported by questionnaire at both time points. PA volume was expressed as cumulative PA (Low, Moderate, and Hard) and the association with left atrial (LA) and left ventricular (LV) structure and function was assessed using ANCOVA.ResultsOverall, LA diameter index (LADi) increased significantly more in Hard compared to Moderate PA (+0.08 cm/m2, 95% CI 0.01–0.15, p = 0.020) from Tromsø6 to Tromsø7. When stratified by sex or age, higher levels of cumulative PA were associated with increased LADi in males and in participants

Background Although myocardial infarction (MI) and atrial fibrillation (AF) are frequent comorbidities and share common cardiovascular risk factors, the direction and strength of the association of the risk factors with disease onset, subsequent disease incidence, and mortality are not completely understood. Methods and Results In pooled multivariable Cox regression analyses, we examined temporal relations of disease onset and identified predictors of MI, AF, and all‐cause mortality in 108 363 individuals (median age, 46.0 years; 48.2% men) free of MI and AF at baseline from 6 European population‐based cohorts. During a maximum follow‐up of 10.0 years, 3558 (3.3%) individuals were diagnosed exclusively with MI, 1922 (1.8%) with AF but no MI, and 491 (0.5%) individuals developed both MI and AF. Association of sex, systolic blood pressure, antihypertensive treatment, and diabetes appeared to be stronger with incident MI than with AF, whereas increasing age and body mass index showed a higher risk for incident AF. Total cholesterol and daily smoking were significantly related to incident MI but not AF. Combined population attributable fraction of cardiovascular risk factors was >70% for incident MI, whereas it was only 27% for AF. Subsequent MI after AF (hazard ratio [HR], 1.68; 95% CI, 1.03–2.74) and subsequent AF after MI (HR, 1.75; 95% CI, 1.31–2.34) both significantly increased overall mortality risk. Conclusions We observed different associations of cardiovascular risk factors with both diseases indicating distinct pathophysiological pathways. Subsequent diagnoses of MI and AF significantly increased mortality risk.

Objectives The increased survival rate of cardiovascular disease (CVD) implies a higher proportion of individuals who live with CVD. Using data from the Tromsø Study, we aimed to investigate mental health symptom trajectories before and after myocardial infarction, atrial fibrillation or stroke in a general population and to explore factors that contribute to the association.Design Cohort study.Setting Sample drawn from inhabitants of the municipality of Tromsø, Norway, who participated in the Tromsø Study (1994–2016).Participants A total of 18 719 participants (52.3% women) were included, and of these 2098 (32.9% women) were diagnosed with myocardial infarction, 1896 (41.9% women) with atrial fibrillation and 1263 (42.9% women) with stroke.Primary outcome measures Mental health symptoms were assessed using the Hopkins Symptom Checklist-10 and the Conor Mental Health Index.Results The participants who were diagnosed with either myocardial infarction or stroke had a significant monotonous increase in mental health symptoms before myocardial infarction (p=0.029) and stroke (p=0.029) that intensified at the time of diagnosis. After the event, the study found a higher prevalence of mental health symptoms with a decline in symptom levels over time for myocardial infarction (p

BackgroundCardiovascular diseases, cancers, chronic respiratory diseases, and diabetes are the 4 main noncommunicable diseases. These noncommunicable diseases share 4 modifiable risk factors (tobacco use, harmful use of alcohol, physical inactivity, and unhealthy diet). Short smartphone surveys have the potential to identify modifiable risk factors for individuals to monitor trends. ObjectiveWe aimed to pilot a smartphone-based information communication technology solution to collect nationally representative data, annually, on 4 modifiable risk factors. MethodsWe developed an information communication technology solution with functionalities for capturing sensitive data from smartphones, receiving, and handling data in accordance with general data protection regulations. The main survey comprised 26 questions: 8 on socioeconomic factors, 17 on the 4 risk factors, and 1 about current or previous noncommunicable diseases. For answers to the continuous questions, a keyboard was displayed for entering numbers; there were preset upper and lower limits for acceptable response values. For categorical questions, pull-down menus with response options were displayed. The second survey comprised 9 yes-or-no questions. For both surveys, we used SMS text messaging. For the main survey, we invited 11,000 individuals, aged 16 to 69 years, selected randomly from the Norwegian National Population Registry (1000 from each of the 11 counties). For the second survey, we invited a random sample of 100 individuals from each county who had not responded to the main survey. All data, except county of residence, were self-reported. We calculated the distribution for socioeconomic background, tobacco use, diet, physical activity, and health condition factors overall and by sex. ResultsThe response rate was 21.9% (2303/11,000; women: 1397/2263; 61.7%, men: 866/2263, 38.3%; missing: 40/2303, 1.7%). The median age for men was 52 years (IQR 40-61); the median age for women was 48 years (IQR 35-58). The main reported reason for nonparticipation in the main survey was that the sender of the initial SMS was unknown. ConclusionsWe successfully developed and piloted a smartphone-based information communication technology solution for collecting data on the 4 modifiable risk factors for the 4 main noncommunicable diseases. Approximately 1 in 5 invitees responded; thus, these data may not be nationally representative. The smartphone-based information communication technology solution should be further developed with the long-term goal to reduce premature mortality from the 4 main noncommunicable diseases.

Machine Learning (ML) methods have become important for enhancing the performance of decision-support predictive models. However, class imbalance is one of the main challenges for developing ML models, because it may bias the learning process and the model generalization ability. In this paper, we consider oversampling methods for generating synthetic categorical clinical data aiming to improve the predictive performance in ML models, and the identification of risk factors for cardiovascular diseases (CVDs). We performed a comparative study of several categorical synthetic data generation methods, including Synthetic Minority Oversampling Technique Nominal (SMOTEN), Tabular Variational Autoencoder (TVAE) and Conditional Tabular Generative Adversarial Networks (CTGANs). Then, we assessed the impact of combining oversampling strategies and linear and nonlinear supervised ML methods. Lastly, we conducted a post-hoc model interpretability based on the importance of the risk factors. Experimental results show the potential of GAN-based models for generating high-quality categorical synthetic data, yielding probability mass functions that are very close to those provided by real data, maintaining relevant insights, and contributing to increasing the predictive performance. The GAN-based model and a linear classifier outperform other oversampling techniques, improving the area under the curve by 2%. These results demonstrate the capability of synthetic data to help with both determining risk factors and building models for CVD prediction.

Background The main aim was to examine age-specific risk factor associations with incident atrial fibrillation (AF) and their attributable fraction in a large European cohort. Additionally, we aimed to examine risk of stroke and mortality in relation to new-onset AF across age.Methods We used individual-level data (n=66 951, 49.1% men, age range 40–98 years at baseline) from five European cohorts of the MOnica Risk, Genetics, Archiving and Monograph Consortium. The participants were followed for incident AF for up to 10 years and the association with modifiable risk factors from the baseline examinations (body mass index (BMI), hypertension, diabetes, daily smoking, alcohol consumption and history of stroke and myocardial infarction (MI)) was examined. Additionally, the participants were followed up for incident stroke and all-cause mortality after new-onset AF.Results AF incidence increased from 0.9 per 1000 person-years at baseline age 40–49 years, to 17.7 at baseline age ≥70 years. Multivariable-adjusted Cox models showed that higher BMI, hypertension, high alcohol consumption and a history of stroke or MI were associated with increased risk of AF across age groups (p

Aims To compare the population proportion at high risk of cardiovascular disease (CVD) using the Norwegian NORRISK 1 that predicts 10-year risk of CVD mortality and the Norwegian national guidelines from 2009, with the updated NORRISK 2 that predicts 10-year risk of both fatal and non-fatal risk of CVD and the Norwegian national guidelines from 2017.Methods We included participants from the Norwegian population-based Tromsø Study (2015–2016) aged 40–69 years without a history of CVD (n=16 566). The total proportion eligible for intervention was identified by NORRISK 1 and the 2009 guidelines (serum total cholesterol ≥8 mmol/L, systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg) and NORRISK 2 and the 2017 guidelines (serum total cholesterol ≥7 mmol/L, low density lipoprotein (LDL) cholesterol ≥5 mmol/L, systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg).Results The total proportion at high risk as defined by a risk score was 12.0% using NORRISK 1 and 9.8% using NORRISK 2. When including single risk factors specified by the guidelines, the total proportion eligible for intervention was 15.5% using NORRISK 1 and the 2009 guidelines and 18.9% using NORRISK 2 and the 2017 guidelines. The lowered threshold for total cholesterol and specified cut-off for LDL cholesterol stand for a large proportion of the increase in population at risk.Conclusion The population proportion eligible for intervention increased by 3.4 percentage points from 2009 to 2017 using the revised NORRISK 2 score and guidelines.

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.

Abstract Background The risk of venous thromboembolism (VTE) is increased after a myocardial infarction (MI). Some prothrombotic genotypes associated with VTE have also been associated with risk of MI. Whether prothrombotic single‐nucleotide polymorphisms (SNPs) further increase the risk of VTE in MI patients is scarcely investigated. Aim To study the combined effect of MI and prothrombotic SNPs on the risk of VTE. Methods Cases with incident VTE (n = 641) and a randomly sampled subcohort weighted for age (n = 1761) were identified from the 4 to 6 surveys of the Tromsø Study (1994‐2012). DNA was genotyped for rs8176719 (ABO), rs6025 (F5), rs1799963 (F2), rs2066865 (FGG), and rs2036914 (F11). Hazard ratios (HRs) for VTE with 95% confidence intervals (CIs) were estimated by categories of risk alleles and MI status. Results Patients with MI had a 1.4‐fold increased risk of VTE, and adjustments for the 5 SNPs, either alone or in combination, did not affect this relationship (adjusted HR, 1.52; 95% CI, 1.12‐2.07). In subjects without MI, an increased risk of VTE was observed for each of the individual SNPs (≥1 vs. 0 risk alleles), and the risk increased linearly with increasing number of risk alleles in the 5‐SNP score. The combination of MI and prothrombotic genotypes, either as individual SNPs or in the 5‐SNP score, did not result in an excess risk of VTE. Conclusion The relationship between MI and VTE was not explained by these 5 prothrombotic genotypes. Prothrombotic genotypes did not yield an excess risk of VTE in patients with MI.

Whereas left atrial (LA) enlargement is an independent predictor for adverse cardiovascular events and all-cause mortality, this is regarded a physiological adaption of exercise. Paradoxically, LA size in athletes may overlap the enlargement observed in patients with cardiac pathology. Current knowledge is mainly derived from studies of athletes, and little is known about cardiac adaptations to physical activity (PA) in the general population. We explored the association between objectively measured PA and LA volume index (LAVi), and between LAVi enlargement and indices of diastolic dysfunction stratified by PA-level.Our study included 1573 participants from the population-based Tromsø Study (2015–16). PA was assessed with an ActiGraph wGT3X-BT accelerometer. Echocardiography was performed according to current guidelines. The associations between PA and LAVi, and between LAVi enlargement and indices of diastolic dysfunction were estimated by univariable and multivariable linear regression analyses, adjusted for sex, age, and cardiovascular risk factors.Our multiple adjusted analyses showed significant linear associations between PA and LAVi in ages < 70 years, and between PA and LAVi in participants with normal diastolic function. No associations were seen in ages ≥ 70 years or for participants with abnormal diastolic function. In those 40–54 years, the most active participants had larger LAVi (4.45 mL/m2, p = 0.016) than the least active. LAVi enlargement was only associated with indices of diastolic dysfunction in the most inactive participants.In conclusion, higher levels of PA associate with greater LAVi in participants < 70 years with normal diastolic function. LAVi enlargement is only associated with diastolic dysfunction in the most inactive participants.

Objectives To describe the prevalence of general (body mass index (BMI) ≥30 kg/m2) and abdominal (waist circumference women >88 cm, men >102 cm) obesity in Tromsø 7 (2015–2016), and the secular change from Tromsø 6 (2007–2008). Furthermore, to study longitudinal changes in body weight and waist circumference from Tromsø 6 to Tromsø 7.Setting A population study in Tromsø, Norway.Participants The cross-sectional analyses included 20 855 participants in Tromsø 7 (aged ≥40 years) and 12 868 in Tromsø 6 (aged ≥30 years). The longitudinal analyses included 8592 participants with repeated measurements, aged 35–79 in Tromsø 6.Outcome measures Mean age-specific and sex-specific BMI, waist circumference, prevalence of general and abdominal overweight and obesity, as well as longitudinal changes in body weight and waist circumference according to sex and birth cohort.Results Over 8 years, the age-adjusted prevalence of general obesity increased (p

Introduction Red cell distribution width (RDW) is associated with cardiovascular diseases, including atrial fibrillation (AF) and venous thromboembolism (VTE). Whether RDW is a risk marker for thromboembolic events in AF patients is scarcely known. We aimed to assess the association between RDW and the risk of AF, and AF-related VTE and ischemic stroke, in a population-based cohort. Methods We measured RDW in 26,111 participants from the Tromsø Study (1994–1995), and registered incident AF cases through December 31, 2013. Among participants with AF, first-ever VTEs and ischemic strokes were registered from the date of AF diagnosis through the end of follow-up. We calculated hazard ratios (HRs) with 95% confidence intervals (CIs) for AF by quartiles of RDW. Furthermore, we calculated cause-specific HRs for VTE and ischemic stroke by tertiles of RDW for participants with AF. Results There were 2,081 incident AF cases during a median of 18.8 years of follow-up. Subjects with RDW in the highest quartile (RDW ≥ 13.3%) had 30% higher risk of AF than those in the lowest quartile (RDW ≤ 12.3%). Among those with AF, subjects with RDW in the upper tertile had a doubled risk of ischemic stroke (HR 2.07, 95% CI 1.20–3.57). In contrast, RDW was not associated with incident VTE in subjects with AF. Conclusion RDW was significantly associated with incident AF in a general population. Among subjects with AF, high RDW was associated with ischemic stroke, but not VTE.

Objectives The aim of this study was to use the parametric g-formula to estimate the 19-year risk of myocardial infarction (MI) under hypothetical interventions on six cardiovascular risk factors.Design and setting A populations-based cohort study with repeated measurements, the Tromsø Study.Primary outcome measure Myocardial infarction.Participants We estimated the relative and absolute risk reduction under feasible and intensive risk reduction strategies for smoking, physical activity, alcohol drinking, body mass index, total serum cholesterol and systolic blood pressure in 14 965 men and women with 19 years of follow-up (1994–2013).Results The estimated 19-year risk of MI under no intervention was 7.5% in individuals with baseline mean age 49.3 years (range 25–69). This risk was reduced by 30% (95% CI 19% to 39%) under joint feasible interventions on all risk factors, and 70% (60%, 78%) under a set of more intensive interventions. The most effective interventions were lowering of total cholesterol to 5.18 mmol/L and lowering of systolic blood pressure to 120 mm Hg (33% and 37% lower MI risk, respectively). The absolute risk reductions were significantly larger in men, in older participants, in smokers and in those with low education.Conclusion Modification of population levels of cardiovascular risk factors could have prevented close to one-third of the cases of MI in the municipality of Tromsø during 19 years of follow-up.

The data presented in this article relate to the research article entitled “Risk of incident myocardial infarction by gender: Interactions with serum lipids, blood pressure and smoking. The Tromsø Study 1979–2012” (Albrektsen et al., 2017) [1]. Data quantify the gender differences in the risk of myocardial infarction (MI) in terms of incidence rate ratios (IRR), in subgroups defined by serum lipids, blood pressure and smoking among persons aged 35–54 years, 55–74 years and 75–94 years, respectively. Data also describe the age- and gender-specific linear associations with the coronary heart disease (CHD) risk factors. IRRs for combined categories of age, gender and a CHD risk factor, with each category compared to the same reference group, are also shown. IRRs were calculated as estimates of relative risk in Poisson regression analyses of person-years at risk. Among 33,859 individuals at risk, a total of 622, 1308 and 816 were diagnosed with MI at ages 35–54, 55–74 and 75–94 years, respectively. Keywords: Myocardial infarction, Gender, Age, Lipids, Blood pressure, Smoking, Relative risk

Background: The aim of this study was to explore temporal trends in incidence and case fatality rates of intracerebral hemorrhage (ICH) over the last two decades in a Norwegian municipality. Methods: Incident cases of primary ICH were registered in the period from 1995 through 2012 in 32,530 participants of the longitudinal population-based Tromsø Study. Poisson regression models were used to obtain incidence rates over time in age- and sex-adjusted and age- and sex-specific models. Case fatality rates were calculated and age- and sex-adjusted trends over time were estimated using logistic regression. Results: A total of 226 ICHs were registered. The age- and sex-adjusted incidence rate [95% confidence interval (CI)] in the overall population was 0.42 (0.37-0.48) per 1,000 person-years. Age-adjusted incidence rates were 0.53 (0.43-0.62) in men and 0.33 (0.26-0.39) in women. In individuals aged Conclusion: No significant changes in incidence and case fatality rates of ICH were observed during the last two decades.

BackgroundAtrial 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 ResultsData 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/m2 compared with 23 kg/m2 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. ConclusionsWithin a population cohort, BMI was positively associated with AF risk. Change in BMI over time influenced AF risk in both men and women.

Red cell distribution width (RDW), a measure of variability in size of circulating erythrocytes, is associated with arterial cardiovascular disease (CVD), but the underlying mechanism remains unclear. We aimed to investigate the impact of chronic inflammation as measured by high-sensitivity C-reactive protein (hs-CRP) on this relationship, and explore whether RDW could be a mediator in the causal pathway between inflammation and arterial CVD. Baseline characteristics, including RDW and hs-CRP, were obtained from 5,765 individuals attending a population-based cohort study. We followed up participants from inclusion in the fourth survey of the Tromsø Study (1994/1995) until December 31, 2012. Multivariable Cox-regression models were used to calculate hazard ratios (HR) with 95% confidence intervals (CI) for incident myocardial infarction (MI) and ischemic stroke across quintiles of hs-CRP and RDW. Subjects with hs-CRP in the highest quintile had 44% higher risk of MI (HR: 1.44, 95% CI: 1.14–1.80), and 64% higher risk of ischemic stroke (HR: 1.64, 95% CI: 1.20–2.24) compared with subjects in the lowest quintile. RDW mediated 7.2% (95% CI: 4.0–30.8%) of the association between hs-CRP and ischemic stroke. Subjects with RDW in the highest quintile had 22% higher risk of MI (HR: 1.22, 95% CI: 0.98–1.54) and 44% higher risk of ischemic stroke (HR: 1.44, 95% CI: 1.06–1.97) compared with subjects in the lowest quintile. These risk estimates were slightly attenuated after adjustments for hs-CRP. Our findings suggest that chronic inflammation is not a primary mechanism underlying the relationship between RDW and arterial CVD.

BackgroundAtrial 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 ResultsWe 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. ConclusionsAF 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.

BACKGROUND:Vitamin D deficiency may be a risk factor for mortality but previous meta-analyses lacked standardization of laboratory methods for 25-hydroxyvitamin D (25[OH]D) concentrations and used aggregate data instead of individual participant data (IPD). We therefore performed an IPD meta-analysis on the association between standardized serum 25(OH)D and mortality. METHODS:In a European consortium of eight prospective studies, including seven general population cohorts, we used the Vitamin D Standardization Program (VDSP) protocols to standardize 25(OH)D data. Meta-analyses using a one step procedure on IPD were performed to study associations of 25(OH)D with all-cause mortality as the primary outcome, and with cardiovascular and cancer mortality as secondary outcomes. This meta-analysis is registered at ClinicalTrials.gov, number NCT02438488. FINDINGS:We analysed 26916 study participants (median age 61.6 years, 58% females) with a median 25(OH)D concentration of 53.8 nmol/L. During a median follow-up time of 10.5 years, 6802 persons died. Compared to participants with 25(OH)D concentrations of 75 to 99.99 nmol/L, the adjusted hazard ratios (with 95% confidence interval) for mortality in the 25(OH)D groups with 40 to 49.99, 30 to 39.99, and

BackgroundEven though clinical data support a relation between ischemic stroke and venous thromboembolism (VTE), the strength and time dependence of the association remain to be settled at the population level. We therefore aimed to investigate the association between ischemic stroke and VTE in a prospective population‐based cohort. Methods and ResultsParticipants (n=30 002) were recruited from 3 surveys of the Tromsø study (conducted in 1994–1995, 2001, and 2007–2008) and followed through 2010. All incident events of ischemic stroke and VTE during follow‐up were recorded. Cox‐regression models with age as time scale and ischemic stroke as a time‐dependent variable were used to calculate hazard ratios (HR) of VTE adjusted for cardiovascular risk factors. During a median follow‐up time of 15.7 years, 1360 participants developed ischemic stroke and 722 had a VTE. The risk of VTE was highest the first month (HR 19.7; 95% CI, 10.1–38.5) and from 1 to 3 months after the stroke (HR 10.6; 95% CI 5.0–22.5), but declined rapidly thereafter. The risk estimates were approximately the same for deep vein thrombosis (HR 19.1; 95% CI, 7.8–38.5), and pulmonary embolism (HR 20.2; 95% CI, 7.4–55.1). Stroke was associated with higher risk for provoked (HR 22.6; 95% CI, 12.5–40.9) than unprovoked VTE (HR 7.4; 95% CI, 2.7–20.1) the first 3 months. ConclusionsThe risk of VTE increased during the first 3 months after an ischemic stroke. The particularly high risk of provoked VTE suggests that additional predisposing factors, such as immobilization, potentiate the VTE risk in patients with ischemic stroke.

BACKGROUND:Single measurements of modifiable risk factors may underestimate associations with outcomes in cohorts. We aimed to compare risk estimates of myocardial infarction (MI) and venous thromboembolism (VTE) by atherosclerotic risk factors during long follow-up using time-fixed analyses without and with correction for regression dilution and time-varying analyses. METHODS:The study included 5970 subjects enrolled in the fourth survey of the Tromsø Study (1994/95). Blood pressure, lipid levels, body mass index (BMI), diabetes and smoking status were measured at baseline, and subjects still alive at the fifth (2001/02, n = 5179) and sixth (2007/08, n = 4391) survey were re-measured. Incident events of MI (n = 714) and VTE (n = 214) were recorded until December 2010. Time-fixed and time-varying Cox regression models were used to estimate hazard ratios (HR) for MI and VTE adjusted for age and sex. RESULTS:Variations in BMI, blood pressure and lipid levels were small, and did not alter the risk estimates when time-varying analyses were compared to time-fixed analyses. For MI, variables that changed considerably over time yielded the greatest changes in risk estimates (HR for smoking changed from 1.80 (95% CI 1.55-2.10) to 2.08 (95% CI 1.78-2.42)). For VTE, only BMI was associated with increased risk in both time-fixed and time-varying analysis, but the risk estimates weakened in the time-varying analysis. Correction of time-fixed HRs with Rosner´s method tended to overestimate risk estimates compared to time-varying analysis. COMMENT:For MI and VTE, risk estimates based on baseline and repeated measures corresponded well, whereas correction for regression dilution tended to overestimate risks.

[This corrects the article DOI: 10.1371/journal.pone.0145359.].

BackgroundThough the associations between low serum 25-hydroxyvitamin D (25(OH)D) levels and health outcomes such as type 2 diabetes (T2D), myocardial infarction (MI), cancer, and mortality are well-studied, the effect of supplementation with vitamin D is uncertain. This may be related to genetic differences. Thus, rs7968585, a single nucleotide polymorphism (SNP) of the vitamin D receptor (VDR), has recently been reported as a predictor of composite health outcome. We therefore aimed to evaluate whether rs7968585 predicts separate clinical outcomes such as T2D, MI, cancer, and mortality in a community-based Norwegian population.Methods and findingsMeasurements and DNA were obtained from the participants in the Tromsø Study in 1994-1995, registered with the outcomes of interest and a randomly selected control group. The impact of the rs7968585 genotypes was evaluated with Cox proportional hazards. A total of 8,461 subjects were included among whom 1,054 subjects were registered with T2D, 2,287 with MI, 3,166 with cancer, and 4,336 with death. Mean follow-up time from birth was 60.8 years for T2D and MI, 61.2 years for cancer, while mean follow-up time from examination date was 16.5 years for survival. Mean serum 25(OH)D levels did not differ across the rs7968585 genotypes. With the major homozygote genotype as reference, the minor homozygote subjects had hazard ratios of 1.25 (95% CI 1.05-1.49) for T2D and 1.14 (1.02-1.28) for MI (P = 0.011 and 0.023, respectively, without the Bonferroni correction). No significant interaction between serum 25(OH)D status and the rs7968585 genotype was found for any of the endpoints.ConclusionsThe VDR-related SNP rs7968585 minor allele is a significant and positive predictor for T2D and possibly for MI. Since the functional mechanism of this SNP is not yet understood, and the association with T2D is reported for the first time, confirmatory studies are needed.

In addition to its role as a transport protein, the vitamin D binding protein (DBP) may also affect lipid metabolism, inflammation and carcinogenesis. There are three common variants of the DBP, Gc1s (1s), Gc1f (1f), Gc2 (2) that result in six common phenotypes (1s/1s, 1s/1f, 1s/2, 1f/1f, 1f/2, and 2/2). These phenotypes can be identified by genotyping for the two single nucleotide polymorphisms rs7041 and rs4588 in the GC gene. The DBP variants have different binding coefficients for the vitamin D metabolites, and accordingly there may be important relations between DBP phenotypes and health.DNA was prepared from subjects who participated in the fourth survey of the Tromsø Study in 1994-1995 and who were registered with the endpoints myocardial infarction (MI), type 2 diabetes (T2DM), cancer or death as well as a randomly selected control group. The endpoint registers were complete up to 2010- 2013. Genotyping was performed for rs7041 and rs4588 and serum 25-hydroxyvitamin D (25(OH)D) was measured.Genotyping for rs7041 and rs4588 was performed successfully in 11 704 subjects. Among these, 1660 were registered with incident MI, 958 with T2DM, 2410 with cancer and 4318 had died. Subjects with the DBP phenotype 1f/1f had 23 - 26 % reduced risk of incident cancer compared to the 1s/1s and 2/2 phenotypes (P < 0.02, Cox regression with gender as covariate). Differences in serum 25(OH)D levels could not explain the apparent cancer protective effect of the DBP variant 1f. In addition to cancer and 25(OH)D, there were significant associations between DBP phenotype and body height, hip circumference and serum calcium.There are important biological differences between the common DBP phenotypes. If the relation between the DBP variant 1f and cancer is confirmed in other studies, determination of DBP phenotype may have clinical importance.

Low serum 25(OH)D levels are associated with cardiovascular risk factors, and also predict future myocardial infarction (MI), type 2 diabetes (T2DM), cancer and all-cause mortality. Recently several single nucleotide polymorphisms (SNPs) associated with serum 25-hydroxyvitamin D (25(OH)D) level have been identified. If these relations are causal one would expect a similar association between these SNPs and health.DNA was prepared from subjects 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 as well as a randomly selected control group. The endpoint registers were complete up to 2007-2010. Genotyping was performed for 17 SNPs related to the serum 25(OH)D level.A total of 9528 subjects were selected for genetic analyses which were successfully performed for at least one SNP in 9471 subjects. Among these, 2025 were registered with MI, 1092 with T2DM, 2924 with cancer and 3828 had died. The mean differences in serum 25(OH)D levels between SNP genotypes with the lowest and highest serum 25(OH)D levels varied from 0.1 to 7.8 nmol/L. A genotype score based on weighted risk alleles regarding low serum 25(OH)D levels was established. There was no consistent association between the genotype score or individuals SNPs and MI, T2DM, cancer, mortality or risk factors for disease. However, for rs6013897 genotypes (located at the 24-hydroxylase gene (CYP24A1)) there was a significant association with breast cancer (P