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Objective: Associations between occupational physical activity (OPA) and mortality risks are inconclusive. We aimed to examine associations between (1) OPA separately and (2) jointly with leisure time physical activity (LTPA), and risk of all-cause, cardiovascular disease (CVD) and cancer mortality, over four decades with updated exposure and covariates every 6-8 years., Methods: Adults aged 20-65 years from the Tromsø Study surveys Tromsø3-Tromsø7 (1986-2016) were included. We categorised OPA as low (sedentary), moderate (walking work), high (walking+lifting work) or very high (heavy manual labour) and LTPA as inactive, moderate and vigorous. We used Cox/Fine and Gray regressions to examine associations, adjusted for age, body mass index, smoking, education, diet, alcohol and LTPA (aim 1 only)., Results: Of 29 605 participants with 44 140 total observations, 4131 (14.0%) died, 1057 (25.6%) from CVD and 1660 (40.4%) from cancer, during follow-up (median: 29.1 years, 25th-75th: 16.5.1-35.3). In men, compared with low OPA, high OPA was associated with lower all-cause (HR 0.83, 95% CI 0.74 to 0.92) and CVD (subdistributed HR (SHR) 0.68, 95% CI 0.54 to 0.84) but not cancer mortality (SHR 0.99, 95% CI 0.84 to 1.19), while no association was observed for moderate or very high OPA. In joint analyses using inactive LTPA and low OPA as reference, vigorous LTPA was associated with lower all-cause mortality combined with low (HR 0.75, 95% CI 0.64 to 0.89), high (HR 0.67, 95% CI 0.54 to 0.82) and very high OPA (HR 0.74, 95% CI 0.58 to 0.94), but not with moderate OPA. In women, there were no associations between OPA, or combined OPA and LTPA, with mortality., Conclusion: High OPA, but not moderate and very high OPA, was associated with lower all-cause and CVD mortality risk in men but not in women. Vigorous LTPA was associated with lower mortality risk in men with low, high and very high OPA, but not moderate OPA., Competing Interests: Competing interests: M-LL has received lecture fees from Bayer, Sanofi and BMS/Pfizer not related to this study. The remaining authors declare no conflict of interest., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

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., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Self-reported data on educational level have been collected for decades in the Tromsø Study, but their validity has yet to be established., Aim: To investigate the completeness and correctness of self-reported educational level in the Tromsø Study, using data from Statistics Norway. In addition, we explored the consequence of using these two data sources on educational trends in cardiometabolic diseases., Methods: We compared self-reported and Statistics Norway-recorded educational level (primary, upper secondary, college/university <4 years, and college/university ⩾4 years) among 20,615 participants in the seventh survey of the Tromsø Study (Tromsø7, 2015-2016). Sensitivity, positive predictive value and weighted kappa were used to measure the validity of self-reported educational level in three age groups (40-52, 53-62, 63-99 years). Multivariable logistic regression was used to compare educational trends in cardiometabolic diseases between self-reported and Statistics Norway-recorded educational level., Results: Sensitivity of self-reported educational level was highest among those with a college/university education of 4 years or more (⩾97% in all age groups and both sexes). Sensitivity for primary educational level ranged from 67% to 92% (all age groups and both sexes). The lowest positive predictive value was observed among women with a college/university education of 4 years or more (29-46%). Weighted kappa was substantial (0.52-0.59) among men and moderate to substantial (0.41-0.51) among women. Educational trends in the risk of cardiometabolic diseases were less pronounced when self-reported educational level was used., Conclusions: Self-reported educational level in Tromsø7 is adequately complete and correct. Self-reported data may produce weaker associations between educational level and cardiometabolic diseases than registry-based data., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Biomarkers may contribute to improved cardiovascular risk estimation. Glycated hemoglobin A 1c (HbA 1c ) is used to monitor the quality of diabetes treatment. Its strength of association with cardiovascular outcomes in the general population remains uncertain. This study aims to assess the association of HbA 1c with cardiovascular outcomes in the general population., Methods: Data from six prospective population-based cohort studies across Europe comprising 36,180 participants were analyzed. HbA 1c was evaluated in conjunction with classical cardiovascular risk factors (CVRFs) for association with cardiovascular mortality, cardiovascular disease (CVD) incidence, and overall mortality in subjects without diabetes (N = 32,496) and with diabetes (N = 3684)., Results: Kaplan-Meier curves showed higher event rates with increasing HbA 1c levels (log-rank-test: p < 0.001). Cox regression analysis revealed significant associations between HbA 1c (in mmol/mol) in the total study population and the examined outcomes. Thus, a hazard ratio (HR) of 1.16 (95% confidence interval (CI) 1.02-1.31, p = 0.02) for cardiovascular mortality, 1.13 (95% CI 1.03-1.24, p = 0.01) for CVD incidence, and 1.09 (95% CI 1.02-1.17, p = 0.01) for overall mortality was observed per 10 mmol/mol increase in HbA 1c . The association with CVD incidence and overall mortality was also observed in study participants without diabetes with increased HbA 1c levels (HR 1.12; 95% CI 1.01-1.25, p = 0.04) and HR 1.10; 95% CI 1.01-1.20, p = 0.02) respectively. HbA 1c cut-off values of 39.9 mmol/mol (5.8%), 36.6 mmol/mol (5.5%), and 38.8 mmol/mol (5.7%) for cardiovascular mortality, CVD incidence, and overall mortality, showed also an increased risk., Conclusions: HbA 1c is independently associated with cardiovascular mortality, overall mortality and cardiovascular disease in the general European population. A mostly monotonically increasing relationship was observed between HbA 1c levels and outcomes. Elevated HbA 1c levels were associated with cardiovascular disease incidence and overall mortality in participants without diabetes underlining the importance of HbA 1c levels in the overall population., (© 2021. The Author(s).)

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., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Background: Russia has one of the highest rates of mortality from cardiovascular disease (CVD). At age 35-69 years, they are eight times higher than in neighbouring Norway. Comparing profiles of blood-based CVD biomarkers between these two populations can help identify reasons for this substantial difference in risk., Methods: We compared age-standardised mean levels of CVD biomarkers for men and women aged 40-69 years measured in two cross-sectional population-based studies: Know Your Heart (KYH) (Russia, 2015-2018; n=4046) and the seventh wave of the Tromsø Study (Tromsø 7) (Norway, 2015-2018; n=17 646). A laboratory calibration study was performed to account for inter-laboratory differences., Results: Levels of total, low-density lipoprotein-, high-density lipoprotein-cholesterol and triglycerides were comparable in KYH and Tromsø 7 studies. N-terminal pro-b-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT) and high-sensitivity C-reactive protein (hsCRP) were higher in KYH compared with Tromsø 7 (NT-proBNP was higher by 54.1% (95% CI 41.5% to 67.8%) in men and by 30.8% (95% CI 22.9% to 39.2%) in women; hs-cTnT-by 42.4% (95% CI 36.1% to 49.0%) in men and by 68.1% (95% CI 62.4% to 73.9%) in women; hsCRP-by 33.3% (95% CI 26.1% to 40.8%) in men and by 35.6% (95% CI 29.0% to 42.6%) in women). Exclusion of participants with pre-existing coronary heart disease (279 men and 282 women) had no substantive effect., Conclusions: Differences in cholesterol fractions cannot explain the difference in CVD mortality rate between Russia and Norway. A non-ischemic pathway to the cardiac damage reflected by raised NT-proBNP and hs-cTnT is likely to contribute to high CVD mortality in Russia., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)

Background Waist circumference and hip circumference are both strongly associated with risk of death; however, their joint association has rarely been investigated. Methods and Results The MONICA Risk, Genetics, Archiving, and Monograph (MORGAM) Project was conducted in 30 cohorts from 11 countries; 90 487 men and women, aged 30 to 74 years, predominantly white, with no history of cardiovascular disease, were recruited in 1986 to 2010 and followed up for up to 24 years. Hazard ratios were estimated using sex-specific Cox models, stratified by cohort, with age as the time scale. Models included baseline categorical obesity measures, age, total and high-density lipoprotein cholesterol, systolic blood pressure , antihypertensive drugs, smoking, and diabetes mellitus. A total of 9105 all-cause deaths were recorded during a median follow-up of 10 years. Hazard ratios for all-cause death presented J- or U-shaped associations with most obesity measures. With waist and hip circumference included in the same model, for all hip sizes, having a smaller waist was strongly associated with lower risk of death, except for men with the smallest hips. In addition, among those with smaller waists, hip size was strongly negatively associated with risk of death, with ≈20% more people identified as being at increased risk compared with waist circumference alone. Conclusions A more complex relationship between hip circumference, waist circumference, and risk of death is revealed when both measures are considered simultaneously. This is particularly true for individuals with smaller waists, where having larger hips was protective. Considering both waist and hip circumference in the clinical setting could help to best identify those at increased risk of death.

Background Alcohol drinking is an increasingly recognized risk factor for cardiovascular disease. However, there are few studies of the impact of harmful and hazardous drinking on biomarkers of myocardial health. We conducted a study in Russia to investigate the impact of heavy drinking on biomarkers of cardiac damage and inflammation. Methods and Results The Know Your Heart study recruited a random sample of 2479 participants from the population of northwest Russia (general population) plus 278 patients (narcology clinic subsample) with alcohol problems. The general population sample was categorized into harmful drinkers, hazardous drinkers, nonproblem drinkers, and nondrinkers, according to self-reported level of alcohol consumption, whereas the narcology clinic sample was treated as the separate group in the analysis. Measurements were made of the following: (1) high-sensitivity cardiac troponin T, (2) NT-proBNP (N-terminal pro-B-type natriuretic peptide), and (3) hsCRP (high-sensitivity C-reactive protein). The narcology clinic subsample had the most extreme drinking pattern and the highest levels of all 3 biomarkers relative to nonproblem drinkers in the general population: high-sensitivity cardiac troponin T was elevated by 10.3% (95% CI, 3.7%-17.4%), NT-proBNP by 46.7% (95% CI, 26.8%-69.8%), and hsCRP by 69.2% (95% CI, 43%-100%). In the general population sample, NT-proBNP was 31.5% (95% CI, 3.4%-67.2%) higher among harmful drinkers compared with nonproblem drinkers. Overall, NT-proBNP and hsCRP increased with increasing intensity of alcohol exposure (test of trend P <0.001). Conclusions These results support the hypothesis that heavy alcohol drinking has an adverse effect on cardiac structure and function that may not be driven by atherosclerosis.

Background: Primary prevention guidelines promote the use of risk assessment tools to estimate total cardiovascular risk. We aimed to study trends in cardiovascular risk and contribution of single risk factors, using the newly developed NORRISK 2 risk score, which estimates 10-year risk of fatal and non-fatal cardiovascular events., Design: Prospective population-based study., Methods: We included women and men aged 45-74 years attending the sixth and seventh survey of the Tromsø Study (Tromsø 6, 2007-2008, n  = 7284 and Tromsø 7, 2015-2016, n  = 14,858) to study secular trends in NORRISK 2 score. To study longitudinal trends, we followed participants born 1941-1962 attending both surveys ( n  = 4534). We calculated NORRISK 2 score and used linear regression models to study the relative contribution (% R 2 ) of each single risk factor to the total score., Results: Mean NORRISK 2 score decreased and distribution in risk categories moved from higher to lower risk in both sexes and all age-groups between the first and second surveys ( p  < 0.001). In birth cohorts, when age was set to baseline in NORRISK 2 calculations, risk score decreased during follow-up. Main contributors to NORRISK 2 were systolic blood pressure, smoking and total cholesterol, with some sex, age and birth cohort differences., Conclusion: We found significant favourable secular and longitudinal trends in total cardiovascular risk and single risk factors during the last decade. Change in systolic blood pressure, smoking and cholesterol were the main contributors to risk score change; however, the impact of single risk factors on the total score differed by sex, age and birth cohort.

Objective: The aim of this study was to examine the associations between changes in leisure time physical activity and changes in cardiovascular risk factors over 16 years and whether they differ between two ethnic groups in Norway., Methods: Data were extracted from two population-based studies. Altogether, 3671 men and women participated in both surveys, and 30% reported being of Sami ethnicity. Leisure time physical activity was self-reported, and cardiovascular risk factors were measured. ANCOVA analysis was used to examine associations between changes in physical activity and changes in cardiovascular risk factors., Results: After adjustment for age, sex, smoking, ethnicity and respective baseline values, favourable changes in body mass index (BMI) and levels of triglycerides were most pronounced in those who were active in both surveys (p < 0.05) whereas the opposite was the situation for cholesterol levels (p = 0.003). Changes in systolic blood pressure, diastolic blood pressure and resting heart rate were not significantly associated with change in physical activity. Ethnicity did not influence the associations between physical activity and cardiovascular risk factors., Conclusion: Traditional cardiovascular risk factors were to a small extent associated with change in leisure time physical activity. Persistent physical activity was associated with beneficial changes in BMI and triglycerides.

Objectives: To evaluate, among the elderly, the association of self-rated health (SRH) with mortality, and to identify determinants of self-rating health as "at-least-good"., Study Design: Individual data on SRH and important covariates were obtained for 424,791 European and United States residents, ≥60 years at recruitment (1982-2008), in eight prospective studies in the Consortium on Health and Ageing: Network of Cohorts in Europe and the United States (CHANCES). In each study, adjusted mortality ratios (hazard ratios, HRs) in relation to SRH were calculated and subsequently combined with random-effect meta-analyses., Main Outcome Measures: All-cause, cardiovascular and cancer mortality., Results: Within the median 12.5 years of follow-up, 93,014 (22%) deaths occurred. SRH "fair" or "poor" vs. "at-least-good" was associated with increased mortality: HRs 1.46 (95% CI 1·23-1.74) and 2.31 (1.79-2.99), respectively. These associations were evident: for cardiovascular and, to a lesser extent, cancer mortality, and within-study, within-subgroup analyses. Accounting for lifestyle, sociodemographic, somatometric factors and, subsequently, for medical history explained only a modest amount of the unadjusted associations. Factors favourably associated with SRH were: sex (males), age (younger-old), education (high), marital status (married/cohabiting), physical activity (active), body mass index (non-obese), alcohol consumption (low to moderate) and previous morbidity (absence)., Conclusion: SRH provides a quick and simple tool for assessing health and identifying groups of elders at risk of early mortality that may be useful also in clinical settings. Modifying determinants of favourably rating health, e.g. by increasing physical activity and/or by eliminating obesity, may be important for older adults to "feel healthy" and "be healthy"., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To evaluate the associations between long-term serum levels of platinum (se-Pt) and neurotoxicity and ototoxicity (NTX), endocrine gonadal function (endocrine-GF), and cardiovascular disease (CVD) in testicular cancer survivors., Material and Methods: A total of 292 cisplatin-treated testicular cancer survivors (1980-1994) participated in a national follow-up study (2007-2008). Se-Pt was quantified by inductively coupled plasma mass spectrometry, and categorized in quartiles. Symptoms of NTX were assessed with scale for chemotherapy-induced neurotoxicity (SCIN), with each symptom in 4 categories and total SCIN score categorized in quartiles. Endocrine-GF was categorized according to cutoff values for the 25, 50, and 75 percentiles of luteinizing hormone (LH) and testosterone within each decadal age group established from a control group. CVD was defined as ischemic heart disease, stroke, or artery occlusion. Associations between se-Pt levels and NTX, endocrine-GF, or risk for CVD, were analyzed with ordinal logistic regression and Cox regression, respectively., Results: Median follow-up was 19 years (range: 13-28). In ordinal regression analyses, increasing quartiles of se-Pt were significantly associated with increasing quartiles of SCIN (P for trend = 0.05), increased tinnitus (P<0.001), and increased hearing impairment (P = 0.04). The association remained significant for tinnitus when adjusting for cisplatin dose. Increasing LH quartiles was associated with increasing se-Pt quartiles (P = 0.04). No association between se-Pt in quartiles and CVD was established., Conclusion: Median 19 years after treatment, increasing quartiles of se-Pt are associated with increasing SCIN score, tinnitus, hearing impairment, and increasing LH levels. However, these associations remained significant only for tinnitus and LH when adjusting for administered cisplatin dose., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation., Objectives: The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population., Methods: We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure., Results: Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10(-14)). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10(-211)), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10(-5)). A causal effect of cystatin C was not detected for any individual component of CVD., Conclusions: Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)

Seldom have studies taken account of changes in lifestyle habits in the elderly, or investigated their impact on disease-free life expectancy (LE) and LE with cardiovascular disease (CVD). Using data on subjects aged 50+ years from three European cohorts (RCPH, ESTHER and Tromsø), we used multi-state Markov models to calculate the independent and joint effects of smoking, physical activity, obesity and alcohol consumption on LE with and without CVD. Men and women aged 50 years who have a favourable lifestyle (overweight but not obese, light/moderate drinker, non-smoker and participates in vigorous physical activity) lived between 7.4 (in Tromsø men) and 15.7 (in ESTHER women) years longer than those with an unfavourable lifestyle (overweight but not obese, light/moderate drinker, smoker and does not participate in physical activity). The greater part of the extra life years was in terms of "disease-free" years, though a healthy lifestyle was also associated with extra years lived after a CVD event. There are sizeable benefits to LE without CVD and also for survival after CVD onset when people favour a lifestyle characterized by salutary behaviours. Remaining a non-smoker yielded the greatest extra years in overall LE, when compared to the effects of routinely taking physical activity, being overweight but not obese, and drinking in moderation. The majority of the overall LE benefit is in disease free years. Therefore, it is important for policy makers and the public to know that prevention through maintaining a favourable lifestyle is "never too late".

Albuminuria is a well known risk factor for cardiovascular disease and mortality, but focus on renal tubular dysfunction as a potential risk factor is growing also. The association between the urinary activity of N-acetyl-β-D-glucosaminidase (NAG) and cardiovascular risk has been assessed mostly in cross-sectional studies. We studied the cross-sectional associations between urinary NAG and cardiovascular risk factors and the longitudinal associations between NAG, cardiovascular disease, and all-cause mortality in a general population. Urinary NAG/creatinine ratio (NAG ratio) and albumin/creatinine ratio (ACR) were measured in 6834 participants of the Tromsø Study in 1994-1995. During the median 17.5 years of follow-up, 958 myocardial infarctions, 726 ischemic strokes, and 2358 deaths were registered. In multivariable analyses adjusted for albuminuria and cardiovascular risk factors, a baseline NAG ratio in the highest quartile was associated with an increased risk of myocardial infarction (hazard ratio [HR], 1.43; 95% confidence interval [95% CI], 1.16 to 1.76), ischemic stroke (HR, 1.41; 95% CI, 1.10 to 1.80), and all-cause mortality (HR, 1.60; 95% CI, 1.39 to 1.84). Combined, ACR and NAG ratio above median associated with a 48%-80% increased risk for the three end points. However, the NAG ratio did not add significantly to the baseline risk-prediction models when assessed by area under the receiver operating characteristics curve or net reclassification improvement. In conclusion, the nonsignificant improvement of risk prediction does not support the clinical use of NAG ratio in cardiovascular risk assessment in a low-risk group., (Copyright © 2016 by the American Society of Nephrology.)

Background: We examined secular changes in resting heart rate (RHR) and their relationship with changes in other cardiovascular risk factors in adult men and women over a 22-year period., Methods: A single-centre population-based longitudinal study comprised 30,699 men and women aged 30-89 years who participated in at least one of the 1986, 1994, 2001 and 2007 surveys of the Tromsø Study, Tromsø, Norway., Results: During the study period, the age-adjusted means of RHR declined from 73.4 to 64.7 beats per minute (b.p.m.) in men, and from 78.3 to 66.4 b.p.m. in women. The decline was persistent from one survey to the next and was of similar size in both sexes and for all age groups and birth cohorts. RHR declined gradually over time for different levels of cardiovascular risk factors, and it declined more in those who moved from adverse to favourable values or categories of blood pressure, total and high-density lipoprotein cholesterol, triglycerides, body mass index, smoking and physical activity, and those who started to take blood pressure medication. The strongest predictors of individual decline in RHR were decrease in systolic blood pressure and triglycerides, increase in physical activity, taking blood pressure treatment and smoking cessation., Conclusion: A considerable decline in RHR has occurred in Tromsø over the past two decades in men and women of all ages. The decline is partly related to changes in several cardiovascular risk factors, and reasons behind this need to be further elucidated. The findings suggest that new definitions of normal RHR may be needed., (© The Author 2015; all rights reserved. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Objective: To investigate the impact of smoking and smoking cessation on cardiovascular mortality, acute coronary events, and stroke events in people aged 60 and older, and to calculate and report risk advancement periods for cardiovascular mortality in addition to traditional epidemiological relative risk measures., Design: Individual participant meta-analysis using data from 25 cohorts participating in the CHANCES consortium. Data were harmonised, analysed separately employing Cox proportional hazard regression models, and combined by meta-analysis., Results: Overall, 503,905 participants aged 60 and older were included in this study, of whom 37,952 died from cardiovascular disease. Random effects meta-analysis of the association of smoking status with cardiovascular mortality yielded a summary hazard ratio of 2.07 (95% CI 1.82 to 2.36) for current smokers and 1.37 (1.25 to 1.49) for former smokers compared with never smokers. Corresponding summary estimates for risk advancement periods were 5.50 years (4.25 to 6.75) for current smokers and 2.16 years (1.38 to 2.39) for former smokers. The excess risk in smokers increased with cigarette consumption in a dose-response manner, and decreased continuously with time since smoking cessation in former smokers. Relative risk estimates for acute coronary events and for stroke events were somewhat lower than for cardiovascular mortality, but patterns were similar., Conclusions: Our study corroborates and expands evidence from previous studies in showing that smoking is a strong independent risk factor of cardiovascular events and mortality even at older age, advancing cardiovascular mortality by more than five years, and demonstrating that smoking cessation in these age groups is still beneficial in reducing the excess risk., (© Mons et al 2015.)

Background: Oxygen saturation has been shown in risk score models to predict mortality in emergency medicine. The aim of this study was to determine whether low oxygen saturation measured by a single-point measurement by pulse oximetry (SpO2) is associated with increased mortality in the general adult population., Methods: Pulse oximetry was performed in 5,152 participants in a cross-sectional survey in Tromsø, Norway, in 2001-2002 ("Tromsø 5"). Ten-year follow-up data for all-cause mortality and cause of death were obtained from the National Population and the Cause of Death Registries, respectively. Cause of death was grouped into four categories: cardiovascular disease, cancer except lung cancer, pulmonary disease, and others. SpO2 categories were assessed as predictors for all-cause mortality and death using Cox proportional-hazards regression models after correcting for age, sex, smoking history, body mass index (BMI), C-reactive protein level, self-reported diseases, respiratory symptoms, and spirometry results., Results: The mean age was 65.8 years, and 56% were women. During the follow-up, 1,046 (20.3%) participants died. The age- and sex-adjusted hazard ratios (HRs) (95% confidence intervals) for all-cause mortality were 1.99 (1.33-2.96) for SpO2 ≤ 92% and 1.36 (1.15-1.60) for SpO2 93-95%, compared with SpO2 ≥ 96%. In the multivariable Cox proportional-hazards regression models that included self-reported diseases, respiratory symptoms, smoking history, BMI, and CRP levels as the explanatory variables, SpO2 remained a significant predictor of all-cause mortality. However, after including forced expiratory volume in 1 s percent predicted (FEV1% predicted), this association was no longer significant. Mortality caused by pulmonary diseases was significantly associated with SpO2 even when FEV1% predicted was included in the model., Conclusions: Low oxygen saturation was independently associated with increased all-cause mortality and mortality caused by pulmonary diseases. When FEV1% predicted was included in the analysis, the strength of the association weakened but was still statistically significant for mortality caused by pulmonary diseases.

Obesity has been linked with elevated levels of C-reactive protein (CRP), and both have been associated with increased risk of mortality and cardiovascular disease (CVD). Previous studies have used a single 'baseline' measurement and such analyses cannot account for possible changes in these which may lead to a biased estimation of risk. Using four cohorts from CHANCES which had repeated measures in participants 50 years and older, multivariate time-dependent Cox proportional hazards was used to estimate hazard ratios (HR) and 95 % confidence intervals (CI) to examine the relationship between body mass index (BMI) and CRP with all-cause mortality and CVD. Being overweight (≥25-<30 kg/m(2)) or moderately obese (≥30-<35) tended to be associated with a lower risk of mortality compared to normal (≥18.5-<25): ESTHER, HR (95 % CI) 0.69 (0.58-0.82) and 0.78 (0.63-0.97); Rotterdam, 0.86 (0.79-0.94) and 0.80 (0.72-0.89). A similar relationship was found, but only for overweight in Glostrup, HR (95 % CI) 0.88 (0.76-1.02); and moderately obese in Tromsø, HR (95 % CI) 0.79 (0.62-1.01). Associations were not evident between repeated measures of BMI and CVD. Conversely, increasing CRP concentrations, measured on more than one occasion, were associated with an increasing risk of mortality and CVD. Being overweight or moderately obese is associated with a lower risk of mortality, while CRP, independent of BMI, is positively associated with mortality and CVD risk. If inflammation links CRP and BMI, they may participate in distinct/independent pathways. Accounting for independent changes in risk factors over time may be crucial for unveiling their effects on mortality and disease morbidity.

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., (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: 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.)

Objective: To investigate the association between serum 25-hydroxyvitamin D concentrations (25(OH)D) and mortality in a large consortium of cohort studies paying particular attention to potential age, sex, season, and country differences., Design: Meta-analysis of individual participant data of eight prospective cohort studies from Europe and the US., Setting: General population., Participants: 26,018 men and women aged 50-79 years., Main Outcome Measures: All-cause, cardiovascular, and cancer mortality., Results: 25(OH)D concentrations varied strongly by season (higher in summer), country (higher in US and northern Europe) and sex (higher in men), but no consistent trend with age was observed. During follow-up, 6695 study participants died, among whom 2624 died of cardiovascular diseases and 2227 died of cancer. For each cohort and analysis, 25(OH)D quintiles were defined with cohort and subgroup specific cut-off values. Comparing bottom versus top quintiles resulted in a pooled risk ratio of 1.57 (95% CI 1.36 to 1.81) for all-cause mortality. Risk ratios for cardiovascular mortality were similar in magnitude to that for all-cause mortality in subjects both with and without a history of cardiovascular disease at baseline. With respect to cancer mortality, an association was only observed among subjects with a history of cancer (risk ratio, 1.70 (1.00 to 2.88)). Analyses using all quintiles suggest curvilinear, inverse, dose-response curves for the aforementioned relationships. No strong age, sex, season, or country specific differences were detected. Heterogeneity was low in most meta-analyses., Conclusions: Despite levels of 25(OH)D strongly varying with country, sex, and season, the association between 25(OH)D level and all-cause and cause-specific mortality was remarkably consistent. Results from a long term randomised controlled trial addressing longevity are being awaited before vitamin D supplementation can be recommended in most individuals with low 25(OH)D levels., (© Schöttker et al 2014.)

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.

Importance: Identification of structural heart disease in asymptomatic individuals could allow early disease-modifying treatment., Objective: To examine whether echocardiographic screening in the general population improves long-term survival or reduces the risk of cardiovascular disease., Design, Setting, and Participants: We studied 6861 middle-aged participants from the population-based Tromsø Study in Norway., Intervention: Participants were randomly allocated to an echocardiographic screening group (n = 3272) or a control group (n = 3589)., Main Outcomes and Measures: Using the as-treated approach, the data were analyzed for mortality and incidence of fatal and nonfatal myocardial infarction and stroke., Results: During 15 follow-up years, 880 persons (26.9%) in the screening group and 989 persons (27.6%) in the control group died (hazard ratio, 0.97; 95% CI, 0.89-1.06). No significant differences between the groups were observed in the secondary outcome measures (sudden death, mortality from any heart disease, or incidence of fatal and nonfatal myocardial infarction and stroke)., Conclusions and Relevance: Echocardiographic screening for structural and valvular heart disease in the general population provided no benefit for mortality or for the risk of myocardial infarction or stroke.

Background: Seasonal changes in cardiovascular disease (CVD) risk factors may be due to exposure to seasonal environmental variables like temperature and acute infections or seasonal behavioural patterns in physical activity and diet. Investigating the seasonal pattern of risk factors should help determine the causes of the seasonal pattern in CVD. Few studies have investigated the seasonal variation in risk factors using repeated measurements from the same individual, which is important as individual and population seasonal patterns may differ., Methods: The authors investigated the seasonal pattern in systolic and diastolic blood pressure, heart rate, body weight, total cholesterol, triglycerides, high-density lipoprotein cholesterol, C reactive protein and fibrinogen. Measurements came from 38 037 participants in the population-based cohort, the Tromsø Study, examined up to eight times from 1979 to 2008. Individual and population seasonal patterns were estimated using a cosinor in a mixed model., Results: All risk factors had a highly statistically significant seasonal pattern with a peak time in winter, except for triglycerides (peak in autumn), C reactive protein and fibrinogen (peak in spring). The sizes of the seasonal variations were clinically modest., Conclusions: Although the authors found highly statistically significant individual seasonal patterns for all risk factors, the sizes of the changes were modest, probably because this subarctic population is well adapted to a harsh climate. Better protection against seasonal risk factors like cold weather could help reduce the winter excess in CVD observed in milder climates.

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.

Purpose: To evaluate the prevalence of cardiovascular risk factors and long-term incidence of cardiovascular disease (CVD) in survivors of testicular cancer (TC)., Methods: Overall, 990 men treated for unilateral TC (1980 to 1994) were included in this national follow-up study (2007 to 2008). They were categorized into four treatment groups: surgery (n = 206), radiotherapy only (RT; n = 386), chemotherapy only (n = 364), and combined RT/chemotherapy (n = 34). Age-matched male controls from the general population (ie, NORMs) were included (n = 990). Survivors of TC who were diagnosed with CVD before or within 2 years after the TC diagnosis were excluded from analyses of CVD end points., Results: Median observation time was 19 years (range, 13 to 28 years). All cytotoxic treatment groups had significantly increased prevalences of antihypertensive medication, and survivors in the RT and RT/chemotherapy groups had higher prevalences of diabetes (RT: odds ratio [OR], 2.3; 95% CI, 1.5 to 3.7; RT/chemotherapy: OR, 3.9; 95% CI, 1.4 to 10.9) compared with NORMs. Overall 74 survivors of TC (8.0%) experienced atherosclerotic disease during follow-up. Increased risks for atherosclerotic disease were observed in age-adjusted Cox regression analyses after any cytotoxic treatment when compared with surgery only (RT: hazard ratio [HR], 2.3; 95% CI, 1.04 to 5.3; chemotherapy: HR, 2.6; 95% CI, 1.1 to 5.9; RT/chemotherapy: HR, 4.8; 95% CI, 1.6 to 14.4). Treatment with cisplatin, bleomycin, and etoposide (BEP) alone had a 5.7-fold higher risk (95% CI, 1.9 to 17.1 fold) for coronary artery disease compared with surgery only and a 3.1-fold higher risk (95% CI, 1.2 to 7.7 fold) for myocardial infarction compared with NORMs., Conclusion: Treatment with infradiaphragmatic RT and/or cisplatin-based chemotherapy, particularly the BEP regimen, increases the long-term risk for CVD in survivors of TC.

Purpose: The purpose of the study is to examine the association between longitudinal change in body mass index (BMI) and change in coronary heart disease (CHD) risk score by using the Framingham risk score equation., Methods: A general adult population in the municipality of Tromsø, Norway, was invited to four consecutive examinations in 1979 to 1980, 1986 to 1987, 1994 to 1995, and 2001. A total of 10,214 men and women aged 20 to 61 years at baseline attended at least three times. Associations were examined by using fixed-effects regression methods for longitudinal data., Results: We observed a significant association between BMI change and risk score change in all baseline age groups. The association was significantly strengthened by age in women, but not men. A BMI increase of 3 kg/m(2) in subjects aged 40 to 49 years was associated with risk score increases of 0.45 points (95% confidence interval [CI], 0.29-0.62) in men and 0.66 points (95% CI, 0.52-0.80) in women., Conclusions: The well-known increase in body weight is associated with adverse CHD risk in both men and women.

Background: Biomarkers may contribute to improved cardiovascular risk estimation. Glycated hemoglobin A1c (HbA1c) is used to monitor the quality of diabetes treatment. Its strength of association with cardiovascular outcomes in the general population remains uncertain. This study aims to assess the association of HbA1c with cardiovascular outcomes in the general population. Methods: Data from six prospective population-based cohort studies across Europe comprising 36,180 participants were analyzed. HbA1c was evaluated in conjunction with classical cardiovascular risk factors (CVRFs) for association with cardiovascular mortality, cardiovascular disease (CVD) incidence, and overall mortality in subjects without diabetes (N = 32,496) and with diabetes (N = 3684). Results: Kaplan–Meier curves showed higher event rates with increasing HbA1c levels (log-rank-test: p < 0.001). Cox regression analysis revealed significant associations between HbA1c (in mmol/mol) in the total study population and the examined outcomes. Thus, a hazard ratio (HR) of 1.16 (95% confidence interval (CI) 1.02–1.31, p = 0.02) for cardiovascular mortality, 1.13 (95% CI 1.03–1.24, p = 0.01) for CVD incidence, and 1.09 (95% CI 1.02–1.17, p = 0.01) for overall mortality was observed per 10 mmol/mol increase in HbA1c. The association with CVD incidence and overall mortality was also observed in study participants without diabetes with increased HbA1c levels (HR 1.12; 95% CI 1.01–1.25, p = 0.04) and HR 1.10; 95% CI 1.01–1.20, p = 0.02) respectively. HbA1c cut-off values of 39.9 mmol/mol (5.8%), 36.6 mmol/mol (5.5%), and 38.8 mmol/mol (5.7%) for cardiovascular mortality, CVD incidence, and overall mortality, showed also an increased risk. Conclusions: HbA1c is independently associated with cardiovascular mortality, overall mortality and cardiovascular disease in the general European population. A mostly monotonically increasing relationship was observed between HbA1c levels and outcomes. Elevated HbA1c levels were associated with cardiovascular disease incidence and overall mortality in participants without diabetes underlining the importance of HbA1c levels in the overall population. [ABSTRACT FROM AUTHOR]

Purpose: To assess whether acute myocardial infarction (MI) diagnoses in national health registers are sufficiently correct and complete to replace manual collection of endpoint data for a population-based, epidemiological study. Patients and Methods: Using the Tromsø Study Cardiovascular Disease Register for 2013– 2014 as gold standard, we calculated correctness (defined as positive predictive value (PPV)) and completeness (defined as sensitivity) of MI cases in the Norwegian Myocardial Infarction Register and the Norwegian Patient Register separately and in combination. We calculated the sensitivity and PPV with 95% confidence intervals using the Clopper-Pearson Exact test. Results: We identified 153 MI cases in the gold standard. In the Norwegian Myocardial Infarction Register, we found a PPV of 97.1% (95% confidence interval (CI) 92.8– 99.2) and a sensitivity of 88.2% (95% CI 82.0– 92.9). In the Norwegian Patient Register, the PPV was 96.3% (95% CI 91.6– 98.8) and the sensitivity was 85.6% (95% CI 79.0– 90.8). The combined dataset of the Norwegian Myocardial Infarction Register and the Norwegian Patient Register had a PPV of 96.6% (95% CI 92.1– 98.9) and a sensitivity of 91.5% (95% CI 85.9– 95.4). Conclusion: MI diagnoses in both the Norwegian Myocardial Infarction Register and the Norwegian Patient Register were highly correct and complete, and each of the registers could be considered as endpoint sources for the Tromsø Study. A combination of the two national registers seemed, however, to represent the most comprehensive data source overall. The benefits of using data from national registers as endpoints in epidemiological studies include faster, less resource-intensive access to nationwide data and considerably lower loss to follow-up, compared to manual data collection in a limited geographical area. [ABSTRACT FROM AUTHOR]

Aims: To examine the associations between diastolic dysfunction indices and long‐term risk of all‐cause mortality in adults over 23‐year follow‐up. Methods and results: Participants (n = 2734) of the population‐based Tromsø Study of Norway had echocardiography in 1994–1995. Of these 67% were repeated in 2001 and/or 2007–2008. Mortality between 1994 and 2016 was determined by linkage to the national death registry. Cox regression was used to model the hazard of all‐cause mortality in relation to left atrial parameters (treated as time‐dependent using repeated measurements) adjusted for traditional risk factors and cardiovascular disease. During the follow‐up, 1399 participants died. Indexed left atrial diameter, mitral peak E deceleration time, and mitral peak E to peak A ratio showed an U‐shaped association with all‐cause mortality. Combining left atrial diameter with mitral peak E deceleration time increased the prognostic accuracy for all‐cause mortality whereas adding mitral peak E to peak A ratio did not increase prognostic value. We estimated new optimal cutoff values of left atrial diameter, mitral peak E deceleration time, and mitral peak E to peak A ratio for all‐cause mortality outcome. E/e′ had a cubic relation to mortality. Conclusion: Both enlarged and small left atrial diameters were associated with increased all‐cause mortality risk. A combination of Doppler‐based left ventricle filling parameters had an incremental effect on all‐cause mortality risk. The cutoff values of diastolic dysfunction indices we determined had similar all‐cause mortality prediction ability as those recommended by American Association of Echocardiography and European Association of Cardiovascular Imaging. [ABSTRACT FROM AUTHOR]

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 <30 nmol/L were 1.15 (1.00–1.29), 1.33 (1.16–1.51), and 1.67 (1.44–1.89), respectively. We observed similar results for cardiovascular mortality, but there was no significant linear association between 25(OH)D and cancer mortality. There was also no significantly increased mortality risk at high 25(OH)D levels up to 125 nmol/L. Interpretation: In the first IPD meta-analysis using standardized measurements of 25(OH)D we observed an association between low 25(OH)D and increased risk of all-cause mortality. It is of public health interest to evaluate whether treatment of vitamin D deficiency prevents premature deaths. [ABSTRACT FROM AUTHOR]

High blood pressure is a modifiable risk factor for cardiovascular disease. Previous studies showing a blood pressure decline in recent decades lack data to follow individuals born in different decades from early and middle adulthood to older age. We investigated changes in age-specific blood pressure by repeated measurements in 37 973 women and men born 1905 to 1977 (aged 20–89 years) examined ≤5× between 1979 and 2008 in the population-based Tromsø Study. Mixed models were used to estimate time trends. Mean systolic and diastolic blood pressure decreased from 1979 to 2008 in both genders in the age groups 30 to 89 years. The decrease was similar in the 80th percentile and the 20th percentile of the population blood pressure distribution. The decrease in systolic blood pressure in age group 40 to 49 years was 10.6 mm Hg in women and 4.5 mm Hg in men. Systolic blood pressure increased with age in women and men born 1920 to 1949, whereas a decrease or flattening of curve was observed in the younger birth cohorts. Thus, we found both time periodic and cohort effects, and trends were more pronounced in women than in men. The findings suggest changes in blood pressure in the population rather than an effect of treatment of high-risk individuals. [ABSTRACT FROM AUTHOR]

Background: The American Heart Association has proposed an impact goal for the year 2020 to improve cardiovascular health by 20%. The objectives of the study were to assess the association between the proposed cardiovascular health metric score and incident myocardial infarction (MI) and to estimate the generalized impact fraction (GIF). Methods: The health metric score was derived from ideal levels of six cardiovascular risk factors from the population-based Tromsø Study of 22,121 residents of Tromsø, Norway aged 30 to 79 years, examined in 1994-95, 2001, and 2007-08. Incident events of MI were recorded from the date of enrollment in 1994-95 to the end of 2010. Adjudication of hospitalized and out-of hospital events was performed by an independent endpoints committee based on data from hospital and out-of hospital journals, autopsy records and death certificates. Cox proportional hazard regression was used to estimate hazard ratios (HR). GIF was calculated from age stratified analysis using a case-load weighted-sum method. Bootstrapping was used to estimate 95% simulation intervals. Results: A total of 1652 MIs accrued over an average of 14.7 person-years of follow-up. Few men (0.96%) and women (3.6%) had ideal levels in all 6 metrics. 64.7% (men) and 55.7% (women) had ideal levels in 2 or 3 metrics. The age-adjusted HR per point increase in health score was 0.65 (95% confidence interval: 0.61, 0.70) in men and 0.59 (0.54, 0.64) in women. A shift of 30% of subjects from low score levels ⩽3 to scores ⩾4 was estimated to prevent 13.7% (11.2, 16.2) of incident MI in men and 15.9% (12.1, 19.4) in women. Conclusions: The association between the health metric score and MI indicate that close to 15% of incident MIs could be prevented by attainable and realistic improvements in the health metrics. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: High serum thyrotropin (TSH) levels predict cardiovascular disease (CVD). Recently several single nucleotide polymorphisms (SNPs) associated with TSH levels have been identified, one of them being the rs4704397 SNP in the phosphodiesterase 8B ( PDE8B) gene. If the relation between thyroid function and CVD is causal, one could also expect rs4704397 genotypes to predict CVD and possibly health in general. Methods: DNA was prepared and genotyping performed for rs4704397 in 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. Similarly, genotyping was performed in subjects who had participated in clinical trials where serum TSH, free T4 (fT4), and free T3 (fT3) were measured. Results: From the Tromsø Study, 8938 subjects without thyroid disease or thyroid medication were successfully genotyped for rs4704397. Among these, 2098 were registered with MI, 1025 with T2DM, 2748 with cancer, and 3592 had died. The minor homozygote genotype (A:A) had a median serum TSH level that was 0.29 mIU/L higher than in the major homozygote genotype (G:G). The A:A genotype had a significantly increased risk of MI as compared to the G:G genotype (1.14 [1.00-1.29], hazard ratio [confidence interval], Cox regression with adjustment for age, sex, and body mass index). No significant associations were seen with the other endpoints or CVD risk factors. Furthermore, subjects with the G:G genotype were significantly taller than subjects with the A:A genotype (mean difference 1.5 cm). In 584 subjects with serum TSH, fT4, and fT3 measurements, the subjects with the A:A genotype had significantly higher serum TSH and nonsignificantly lower serum fT3 (mean difference 0.15 pmol/L) levels than subjects with the G:G genotype. Conclusion: rs4704397 is associated with thyroid function, risk of MI, and body height. However, confirmation in other cohorts is needed before firm conclusions can be drawn. [ABSTRACT FROM AUTHOR]

Aims The myocardium is considered to be an important target organ for parathyroid hormone and 1,25-dihydroxyvitamin D, the active metabolite of vitamin D. Vitamin D inadequacy has also been linked to cardiovascular morbidity. We aimed to evaluate the relationship between serum 25-hydroxyvitamin D [25(OH)D] and LV systolic function in a general population. Methods and results In the fourth Tromsø Study, M-mode echocardiography was performed in 2504 subjects with available serum 25(OH)D measurements. Measurements of EF and LV mass indexed by height (LVMH) were obtained. Only non-smoking men (n = 790) and women (n = 944) were included in the final analysis. Linear regression was used to assess the association between serum 25(OH)D and measurements of systolic function, and logistic regression was applied to assess the effect of serum 25(OH)D on the lowest quartile of EF (yes/no) and LV hypertrophy (LVH) (yes/no). We found no significant associations between vitamin D concentrations and measures of LV systolic function, when adjusted for other risk factors and the season when 25(OH)D sampling was performed [β –0.03, 95% confidence interval (CI) –0.08 to 0.03, and β –0.01, 95% CI –0.07 to 0.06 for LVMH and EF in men; and β 0.02, 95% CI –0.03 to 0.07, and β 0.01, 95% CI –0.05 to 0.07 for LVMH and EF in women]. Serum 25(OH)D did not predict EF and/or LVH in both genders. Conclusions In our population-based study, increased serum 25(OH)D was not associated with better LV systolic function, when adjusted for other risk factors and for season of vitamin D sampling. [ABSTRACT FROM PUBLISHER]

Objective. To develop a cardiovascular risk model simulating different clinical settings using a staged approach. Design. Using data from 27 477 men and women from the Norwegian Tromsø Study in 1986–1987 and 1994–1995, Cox regression models for either myocardial infarction (MI) or stroke combined with a similar model for the competing event a risk model that assess ten-year risk of MI and stroke was developed. Explanatory variables (questions, simple examinations and blood samples) were added gradually. The model was validated using Hosmer-Lemeshow test, the Brier score, c-index, integrated discrimination improvement (IDI) and Net Reclassification Improvement (NRI). Results. In total, 1 298 events of MI and 769 events of stroke were registered. For MI the model showed excellent discrimination in each step with c-index from 0.833 to 0.946. For stroke the c-index ranged between 0.817 and 0.898. IDI showed significant increases in discrimination. The Brier scores and goodness of fit test showed well calibrated models in all steps for all sex- and end-point specific models (p>0.05). Conclusions. Although the predictive and discriminative ability of the models increased with each step, even the simplest model containing only data from questions or blood samples alone yielded valid estimates of cardiovascular risk. [ABSTRACT FROM AUTHOR]

Electrocardiographic measures are indicative of the function of the cardiac conduction system. To search for sequence variants that modulate heart rate, PR interval and QRS duration in individuals of European descent, we performed a genome-wide association study in ∼10,000 individuals and followed up the top signals in an additional ∼10,000 individuals. We identified several genome-wide significant associations (with P < 1.6 × 10−7). We identified one locus for heart rate (MYH6), four for PR interval (TBX5, SCN10A, CAV1 and ARHGAP24) and four for QRS duration (TBX5, SCN10A, 6p21 and 10q21). We tested for association between these loci and subjects with selected arrhythmias in Icelandic and Norwegian case-control sample sets. We observed correlations between TBX5 and CAV1 and atrial fibrillation (P = 4.0 × 10−5 and P = 0.00032, respectively), between TBX5 and advanced atrioventricular block (P = 0.0067), and between SCN10A and pacemaker implantation (P = 0.0029). We also replicated previously described associations with the QT interval. [ABSTRACT FROM AUTHOR]

Tracking of cardiovascular risk factors (blood pressure, body mass index (BMI), and serum lipids) has not been studied much in a general, adult population. No known study has compared tracking of these factors for both sexes. In the present study, 17,710 men and women aged 20-61 years at baseline attended two or three population-based health surveys in Tromsø, Norway, over 16 years (between 1979-1980 and 1994-1995). Tracking coefficients were estimated by using different methods, and possible predictors of tracking were found. There was a high degree of tracking for BMI (overall tracking coefficients: 0.85 for men, 0.80 for women). Relatively high (or moderate) tracking was found for systolic blood pressure (respective sex-specific coefficients: 0.52, 0.54), diastolic blood pressure (0.48, 0.48), high density lipoprotein cholesterol (0.55, 0.64), and total cholesterol (0.77, 0.65). The lowest coefficients were for triglycerides (0.43, 0.39). Analysis of tracking in the upper sextile confirmed these results. Although some baseline predictors were associated with tracking, the effects were relatively weak. When predictors for tracking in the upper sextile were assessed, significant associations were found with relatively strong effects. No major sex differences were observed in tracking. However, women were more likely than men to remain in the upper sextile of systolic and diastolic blood pressures and of BMI. [ABSTRACT FROM AUTHOR]

Background: The aim was to describe secular trends in leisure time physical activity (LTPA) and work related physical activity (WPA) from 1979 to 2008. Additionally, we explored potential cross-sectional and longitudinal correlates of LTPA and WPA.Methods: Data are collected from 34,898 individuals (49.7% men) aged >20 years who participated in at least one Tromsø Study survey between 1979 and 2008. In each survey, the participants completed a self-administered questionnaire and underwent physical examinations. LTPA and WPA were assessed by the validated "Saltin-Grimby" 4-scale questions. Potential correlates of LTPA and WPA (sex, age, body mass index (BMI), education, smoking, self-reported cardiovascular disease, self-perceived health, and employment status) were tested using ordinal logistic regression.Results: The age-adjusted prevalence of participants being inactive in leisure time remained relatively stable around 20% from 1979 to 2008 (range 19.9-23.6%). The age-adjusted prevalence of moderate-vigorous LTPA decreased from 23.2% in 1979-80 to 16.0% in 2001, thereafter the prevalence increased to 24.3% in 2007-08 (P <0.05). The age-adjusted prevalence of being mostly sedentary at work increased gradually from 35.5% in 1979-80 to 53.4% in 2007-08 (P <0.05). Sex, age, education, and smoking were identified as cross-sectional correlates of LTPA and WPA (P <0.05). Men had higher odds of engaging in LTPA than women (adjusted OR 1.52 [95% CI 1.39-1.67] in 2007-08), whereas the association between sex and WPA shifted over time. High education level, not being a smoker, and high WPA were associated with high LTPA, whereas low education level, being a smoker, and high levels of LTPA were associated with high WPA (P <0.05). In general, odds of engaging in LTPA and WPA decreased with age (P <0.05). Individuals with healthy BMI had higher odds of being in a higher LTPA level than those who were underweight and obese (P <0.05). Longitudinal analyses identified sex, age, education, smoking, WPA, and LTPA measured in 1979-80 as determinants of LTPA in 2007-08.Conclusions: In Norwegian adults, the proportion of sedentary WPA increased from 1979 to 2008, whereas the proportion of inactive LTPA remained stable. Being female, older, smoker, obese or underweight, and low education level were associated with low LTPA levels. [ABSTRACT FROM AUTHOR]

Background and aims CRP predicts cardiovascular disease (CVD) in large epidemiologic studies. The aim of the present study was to elucidate the role of CRP in atherosclerosis formation and progression in a prospective population-based study. Methods 6503 middle-aged subjects from The Tromsø study had serum CRP, carotid ultrasound and complete covariate data collected at baseline in 1994. Of these, 4730 and 2917 attended follow-up surveys with repeated assessments in 2001 and 2007, respectively. The cross-sectional associations between CRP and subclinical carotid atherosclerosis, and the longitudinal associations between baseline CRP and novel plaque formation and plaque progression were assessed in generalized estimating equations and linear mixed models stratified by sex. Results At baseline, traditional risk factors and plaque prevalence increased by CRP risk categories (<1 mg/L, 1–3 mg/L, and >3 mg/L) in both sexes. In cross-sectional analyses, multivariable-adjusted CRP was associated with plaque prevalence and total plaque area (TPA) in men and women. Age-adjusted baseline CRP >3 mg/L compared to CRP <1 mg/L predicted novel plaque formation (OR 1.44, CI 1.08–1.92) and TPA progression (β = 0.0.029 (CI, 0.003–0.056)) in men, but not in women. In neither men nor women was baseline CRP a predictor of TPA-progression or novel plaque formation when adjusted for traditional risk factors. Conclusions CRP was associated with plaque presence and TPA in cross-sectional analyses, but was not an independent predictor of novel plaque formation or plaque progression. Our findings suggest that CRP may link to CVD by other mechanisms than promoting formation and progression of atherosclerotic plaques. [ABSTRACT FROM AUTHOR]