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To identify modifiable risk factors in early midlife associated with incident hypertension 26 years later in women and men. We used data from 1025 women and 703 men in the community-based Hordaland Health Study examined at the mean age of 42 years (baseline) and after a 26-year follow-up. Patients with hypertension at baseline were excluded. Blood pressure (BP) was classified according to European guidelines. Factors associated with incident hypertension were identified in logistic regression analyses. At baseline, women had a lower average BP and a lower prevalence of high-normal BP (19% vs 37%, p < .05). Overall, 39% of women and 45% of men developed hypertension during follow-up (p < .05). Among those with high-normal BP at baseline, 72% of women and 58% of men developed hypertension (p < .01). In multivariable logistic regression analyses, high-normal BP at baseline was a stronger predictor of incident hypertension in women (odds ratio, OR 4.8, [95% confidence interval, CI 3.4–6.9]) than in men (OR 2.1, [95% CI 1.5–2.8]), p < .01 for sex interaction. A higher baseline body mass index (BMI) was associated with incident hypertension in both sexes. High-normal BP in midlife is a stronger risk factor for developing hypertension 26 years later in women than in men, independent of BMI. There is a knowledge gap regarding the understanding of sex differences in hypertension and cardiovascular disease. The World Health Organisation has identified hypertension as the leading cause of morbidity and mortality in women.This manuscript focuses on sex differences in risk factors in early midlife associated with the development of hypertension 26 years later. We studied 1025 women and 703 men who participated in the community-based Hordaland Health Study at the age of 42 years, and after 26 years. Factors associated with hypertension were identified in statistical analyses.Our main findings were that having a high-normal blood pressure (systolic blood pressure 130–139 mmHg or a diastolic blood pressure 85–89 mmHg) in midlife was a significantly stronger risk factor for the development of hypertension in women than in men during follow-up. Having a higher body mass index in midlife was associated with the development of hypertension in both sexes.This study contributes to the understanding of sex differences in hypertension development and adds further knowledge regarding high-normal blood pressure as a particularly important risk factor for hypertension and cardiovascular disease in women. There is a knowledge gap regarding the understanding of sex differences in hypertension and cardiovascular disease. The World Health Organisation has identified hypertension as the leading cause of morbidity and mortality in women. This manuscript focuses on sex differences in risk factors in early midlife associated with the development of hypertension 26 years later. We studied 1025 women and 703 men who participated in the community-based Hordaland Health Study at the age of 42 years, and after 26 years. Factors associated with hypertension were identified in statistical analyses. Our main findings were that having a high-normal blood pressure (systolic blood pressure 130–139 mmHg or a diastolic blood pressure 85–89 mmHg) in midlife was a significantly stronger risk factor for the development of hypertension in women than in men during follow-up. Having a higher body mass index in midlife was associated with the development of hypertension in both sexes. This study contributes to the understanding of sex differences in hypertension development and adds further knowledge regarding high-normal blood pressure as a particularly important risk factor for hypertension and cardiovascular disease in women.

This is a pre-copyedited, author-produced version of an article accepted for publication in the European Journal of Preventive Cardiology following peer review. The version of record Hansen, K.W., Peytz, N., Blokstra, A., Bojesen, S.E., Celis-Morales, C., Chrysohoou, C, ... Prescott, E. (2021). Association of fatal myocardial infarction with past level of physical activity: a pooled analysis of cohort studies. European Journal of Preventive Cardiology, zwaa146, is available online at: https://doi.org/10.1093/eurjpc/zwaa146. Aims: To assess the association between past level of physical activity (PA) and risk for death during the acute phase of myocardial infarction (MI) in a pooled analysis of cohort studies. Methods and results: European cohorts including participants with a baseline assessment of PA, conventional cardiovascular (CV) risk factors, and available follow-up on MI and death were eligible. Patients with an incident MI were included. Leisure-time PA was grouped as sedentary (32 MET-hours) based on calculated net weekly energy expenditure. The main outcome measures were instant and 28-day case fatality of MI. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using multivariate random-effects models. Adjustments for age, sex, CV risk factors, alcohol consumption, and socioeconomic status were made. From 10 cohorts including a total of 1 495 254 participants, 28 140 patients with an incident MI comprised the study population. A total of 4976 (17.7%) died within 28 days—of these 3101 (62.3%) were classified as instant fatal MI. Compared with sedentary individuals, those with a higher level of PA had lower adjusted odds of instant fatal MI: low PA [OR, 0.79 (95% CI, 0.60–1.04)], moderate PA [0.67 (0.51–0.89)], and high PA [0.55 (0.40–0.76)]. Similar results were found for 28-day fatal MI: low PA [0.85 (0.71–1.03)], moderate PA [0.64 (0.51–0.80)], and high PA [0.72 (0.51–1.00)]. A low-to-moderate degree of heterogeneity was detected in the analysis of instant fatal MI (I2 = 47.3%), but not in that of 28-day fatal MI (I2 = 0.0%). Conclusion: A moderate-to-high level of PA was associated with a lower risk of instant and 28-day death in relation to a MI.

Background Although age-standardised hip fracture incidence has declined in many countries during recent decades, the number of fractures is forecast to increase as the population ages. Understanding the drivers behind this decline is essential to inform policy for targeted preventive measures. We aimed to quantify how much of this decline could be explained by temporal trends in major risk factors and osteoporosis treatment. Methods We developed a new modelling approach, Hip-IMPACT, based on the validated IMPACT coronary heart disease models. The model applied sex- and age stratified hip fracture numbers and prevalence of pharmacologic treatments and risk/preventive factors in 1999 and 2019, and best available evidence for independent relative risks of hip fracture associated with each treatment and risk/preventive factor. Findings Hip-IMPACT explained 91% (2500/2756) of the declining hip fracture rates during 1999–2019. Two-thirds of the total decline was attributed to changes in risk/preventive factors and one-fifth to osteoporosis medication. Increased prevalence of total hip replacements explained 474/2756 (17%), increased body mass index 698/2756 (25%), and increased physical activity 434/2756 (16%). Reduced smoking explained 293/2756 (11%), and reduced benzodiazepine use explained (366/2756) 13%. Increased uptake of alendronate, zoledronic acid, and denosumab explained 307/2756 (11%), 104/2756 (4%) and 161/2756 (6%), respectively. The explained decline was partially offset by increased prevalence of type 2 diabetes and users of glucocorticoids, z-drugs, and opioids. Interpretation Two-thirds of the decline in hip fractures from 1999 to 2019 was attributed to reductions in major risk factors and approximately one-fifth to osteoporosis medication. publishedVersion

Aims Using Scandinavian population-based registries, we assessed risk of stroke/systemic embolism (SE) and bleeding with non-vitamin K antagonist oral anticoagulants compared with warfarin in anticoagulation-naïve patients with atrial fibrillation (AF). Methods and results This historical cohort study included 219 545 AF patients [median age 74 years; 43% women; mean CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or transient ischaemic attack, vascular disease, age 65–74 years, sex category) score 3.3] initiating apixaban, dabigatran, rivaroxaban, or warfarin in Denmark, Norway, and Sweden (1 January 2013 to 31 December 2016). The primary endpoints were stroke/SE and major bleeding. The median follow-up times were 9.7 (3.9–21.5) months for stroke/SE and 9.6 (3.8–21.3) months for bleeding. Apixaban and warfarin initiators were older and had higher CHA2DS2-VASc scores compared with dabigatran and rivaroxaban initiators. After 1:1 propensity score matching, three cohorts were created: apixaban–warfarin (n = 111 162), dabigatran–warfarin (n = 56 856), and rivaroxaban–warfarin (n = 61 198). Adjusted hazard ratios (HRs) were estimated using a Cox regression. For stroke/SE, adjusted HRs against warfarin were 0.96 [95% confidence interval (CI): 0.87–1.06] for apixaban, 0.89 (95% CI: 0.80–1.00) for dabigatran, and 1.03 (95% CI: 0.92–1.14) for rivaroxaban. For major bleeding, the HRs against warfarin were 0.73 (95% CI: 0.67–0.78) for apixaban, 0.89 (95% CI: 0.82–0.97) for dabigatran, and 1.15 (95% CI: 1.07–1.25) for rivaroxaban. The results in the dabigatran cohort did not hold in all dose-defined subgroups. Conclusion In this large Scandinavian study among AF patients initiating oral anticoagulation, those initiating dabigatran, apixaban, and rivaroxaban had similar rates of stroke/SE to patients initiating warfarin. Rates of major bleeding were lower with apixaban and dabigatran and higher with rivaroxaban, each compared with warfarin.

Background and aims A first-time acute myocardial infarction (AMI) is a severe diagnosis that leads to initiation or intensification of lipid-lowering medication to prevent recurrent events. Individuals with familial hypercholesterolemia (FH) already use high-intensity lipid-lowering medication at the time of an incident AMI due to their diagnosis. Hence, we hypothesized that compared with matched non-FH controls, individuals with genetically verified FH have increased mortality and risk of recurrent AMI after their first event. Methods The study population comprised 4871 persons with genetically verified FH, and 96,251 age and sex matched controls randomly selected from the Norwegian population. Data were obtained from the Cardiovascular Disease in Norway Project, the Norwegian Patient Registry and the Norwegian Cause of Death Registry. Incidence of AMI, all-cause mortality and recurrent AMI after incident AMI were analyzed for the period 2001–2017. Incidence and mortality were compared using hazard ratios (HR) from Cox regression. Risk of recurrent AMI was compared using sub-hazard ratios (SHR) from competing risk regression with death as a competing event. Results We identified 232 individuals with FH and 2118 controls with an incident AMI [HR 2.10 (95% CI 1.83–2.41)]. Among survivors ≥29 days after the incident AMI, both mortality [HR = 1.45 (95% CI: 1.07–1.95)] and recurrent AMI [SHR = 2.53 (95% CI: 1.88–3.41)] were significantly increased among individuals with FH compared with non-FH controls. Conclusions Individuals with FH have increased mortality and increased risk of recurrent AMI after the first AMI event compared with controls. These findings call for intensive follow-up of individuals with FH following an AMI.

OBJECTIVE To study whether serum galectin-3 and other biomarkers of inflammation predict coronary heart disease (CHD) in subjects with long-standing childhood-onset type 1 diabetes. RESEARCH DESIGN AND METHODS A population-based nationwide cohort of 299 subjects with type 1 diabetes diagnosed in Norway at RESULTS Of 295 subjects, 40 (13.6%) had a documented CHD event during a mean follow-up of 14.4 years (range 0.5–16). IL-6 (aHR 1.32 [95% CI 1.07–1.63]), galectin-3 (aHR 1.44 [95% CI 1.09–1.80]), and TIMP-1 (aHR 1.37 [95% CI 1.04–1.81]) were significant predictors of CHD after adjustment for conventional risk factors. CONCLUSIONS Galectin-3 was significantly associated with future CHD in subjects with type 1 diabetes, and if the results are replicated in larger studies, it may aid in prediction together with conventional risk factors for CHD.

Background It is mechanically plausible that osteoporosis leads to more severe peripheral fractures, but studies investigating associations between BMD and radiographically verified complexity of distal radius fractures are scarce. This study aims to study the association between osteoporosis, as well as other risk factors for fracture, and the AO classification of distal radius fractures. Methods In this observational study, 289 consecutive patients aged ≥40 years with a distal radius fracture were included. Bone mineral density (BMD) of the hips and spine was measured by dual-energy x-ray absorptiometry (DXA), and comorbidities, medication, physical activity, smoking habits, body mass index (BMI), and history of previous fracture were registered. The distal radius fractures were classified according to the Müller AO system (AO) (type B and C regarded as most complex). Results Patients with osteoporosis (n = 130) did not have increased odds of a more complex distal radius fracture (type B + C, n = 192)) (n = vs type A (n = 92) (OR 1.1 [95% CI 0.5 to 2.3]) compared to those with osteopenia /normal BMD (n = 159). Patients with AO fracture types A or C had a higher prevalence of osteoporosis than patients with type B fracture. Conclusions Distal radius fracture patients with osteoporosis did not sustain more complex fractures than those with osteopenia/normal BMD according to the AO classification system. The AO classification of distal radius fracture cannot be used to decide which patients should be referred to DXA scan and considered for secondary fracture prevention.

Aims To compare reported level of bodily pain, overall and health‐related quality of life (QoL), depression and fatigue in people with long‐term type 1 diabetes vs. a comparison group without diabetes. Further, to examine the associations of total bodily pain with QoL, depression, fatigue and glycaemic control in the diabetes group. Methods Cross‐sectional study of 104 (76% of eligible) people with type 1 diabetes of ≥ 45 years’ duration attending the Norwegian Diabetes Centre and 75 persons without diabetes who completed questionnaires measuring bodily pain (RAND‐36 bodily pain domain), shoulder pain (Shoulder Pain and Disability Index), hand pain (Australian/Canadian Osteoarthritis Hand Index), overall QoL (World Health Organization Quality of Life – BREF), health‐related QoL (RAND‐36), diabetes‐specific QoL (Audit of Diabetes‐Dependent Quality of Life; only diabetes group), depression (Patient Health Questionnaire) and fatigue (Fatigue questionnaire). For people with type 1 diabetes, possible associations between the bodily pain domain (lower scores indicate higher levels of bodily pain) and other questionnaire scores, were measured with regression coefficients (B) per 10‐unit increase in bodily pain score from linear regression. Results The diabetes group reported higher levels of bodily (P = 0.003), shoulder and hand pain (P < 0.001) than the comparison group. In the diabetes group, bodily pain was associated with lower overall and diabetes‐specific QoL [B (95% confidence intervals)]: 0.2 (0.1, 0.2) and 0.2 (0.1, 0.3); higher levels of depression −1.0 (−1.3, −0.7) and total fatigue −1.5 (−1.9, −1.2); and worse glycaemic control HbA1c (mmol/mol; %) −0.8 (−1.5, −0.1); −0.1 (−0.1, −0.01). Conclusions People with long‐term type 1 diabetes experience a high level of bodily pain compared with a comparison group. Total bodily pain was associated with worse QoL and glycaemic control. publishedVersion

Our aim was to test sex-specific associations of circulating markers of inflammation with blood pressure (BP) and incident hypertension in midlife. Participants in the Hordaland Health study (n = 3280, 56% women, mean age 48 years) were examined at baseline and followed for 6 years. Circulating levels of inflammatory markers including high-sensitive C-reactive protein (hs-CRP), neopterin, and pyridoxic acid ratio (PAr) index were measured at follow-up. The associations with systolic/diastolic BP and incident hypertension were tested in sex-specific linear- or logistic-regression analyses adjusted for body mass index, serum triglycerides, creatinine, physical activity, smoking and diabetes. At follow-up, women had lower mean BP than men (124/72 vs. 130/78 mmHg, p β = 0.07 and β = 0.09, both p p p

Background: Trimethylamine N-oxide (TMAO) is an amine oxide generated by gut microbial metabolism. TMAO may contribute to atherothrombosis and systemic inflammation. However, the prognostic value of circulating TMAO for risk stratification is uncertain. Methods: We assessed prospective relationships of plasma TMAO with long-term risk of all-cause, cardiovascular (CV), and non-CV mortality in the Western Norway Coronary Angiography Cohort (WECAC; 4132 patients with suspected coronary artery disease) and the Hordaland Health Study (HUSK; 6393 community-based subjects). Risk associations were examined using Cox regression analyses. Results: Mean follow-up was 9.8 and 10.5 years in WECAC and HUSK, respectively. Following adjustments for established CV risk factors and indices of renal function in WECAC, the hazard ratios (HRs) (95% confidence intervals [CIs]) per one standard deviation increase in log-transformed plasma TMAO were 1.04 (0.97–1.12), 1.06 (0.95–1.18), and 1.03 (0.93–1.13) for all-cause, CV, and non-CV mortality, respectively. Essentially similar results were obtained in patients with angiographically significant coronary artery disease and patients with reduced left ventricular ejection fraction. Corresponding HRs (95% CIs) in the HUSK cohort were 1.03 (0.96–1.10), 1.01 (0.89–1.13), and 1.03 (0.95–1.12) for all-cause-, CV, and non-CV mortality, respectively. Conclusions: Circulating TMAO did not predict long-term all-cause, CV, or non-CV mortality in patients with coronary heart disease or in community-based adults. This large study does not support a role of TMAO for patient risk stratification in primary or secondary prevention. publishedVersion

Background Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with substantial morbidity and mortality. Its prevalence is currently rising partly due to population ageing. However, reported trends in incidence rates are conflicting, and the comparability of existing reports is limited due to methodological inconsistencies across studies. Purpose The main purpose of the current study was to investigate the prevalence of AF in the Danish adult population and time trends in incidence rates from 2004 through 2018. As a secondary purpose, the prevalence and incidence were compared to corresponding Norwegian estimates from 2004 through 2014 derived using the same methodology. Methods A register-based study was conducted including all individuals aged ≥18 years in Denmark from 2004–2018. AF cases were identified in the National Patient Register and the Cause of Death Register, which comprise information on all hospital contacts and deaths in Denmark, respectively. The prevalence of AF was calculated as the number of individuals alive at the end of the study period with at least one registered diagnosis from 1994 through 2018 divided by the number of Danish residents aged ≥18 years. Incidence rates were calculated as the number of annual AF cases with no previous diagnosis noted in the past 10 years divided by the person-time contributed by the population free of AF on 1 January in the same calendar year. All incidence rates were standardized according to a Nordic standard population. The comparison of the Danish and Norwegian incidence estimates focused solely on AF hospitalizations and deaths from 2004 through 2014. Results The cumulative prevalence of AF was 3.0% in the Danish adult population. The incidence increased from 391 per 100,000 person-years in 2004 to 481 per 100,000 person-years in 2015, after which it declined to 367 per 100,000 person-years in 2018 (Figure 1). On average, the incidence increased by 1.7% annually until 2015 (IRR: 1.017 (95% CI: 1.016–1.018); p Conclusions The prevalence of AF is currently around 3.0% in the Danish adult population, but the incidence rate has declined steeply since 2015. The observed decline in new cases is promising from a public health perspective and its underlying causes warrant further investigation. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation Figure 1

Background: Higher systemic concentrations of cardiac troponins and biomarkers of inflammation and endothelial dysfunction as well as obesity are associated with increased risk of cardiovascular disease (CVD) and may share pathophysiological pathways. We sought to explore the association between serum high sensitive cardiac troponin T (hs-cTnT) and future acute myocardial infarction (AMI) according to body mass index (BMI) among patients with suspected chronic coronary syndrome (CCS), as well as interactions with C-reactive protein (CRP) and asymmetric dimethylarginine (ADMA). Methods: A total of 3879 patients with baseline hs-cTnT ≤ 30 ng/L who underwent elective coronary angiography due to chronic coronary syndrome (CCS) were followed to subsequent AMI or end of 2009. Risk associations between hs-cTnT and incident AMI were explored with Cox regression according to BMI categories 30kg/m2 and quartiles of serum CRP and plasma ADMA. Results: Median (25 th −75 th percentile) age was 62 (54–69) years and 2773 (77.5%) were men. During median 7.5 (25 th −75 th percentile) (6.9–9.2) years of follow-up, 460 (11.9%) patients experienced an AMI. The risk relationship between hs-cTnT and incident AMI was stronger among patients in the higher vs lower BMI categories, HR 1.087 (1.055–1.119), P for interaction 0.043. A similar interaction was not found in categories of CRP or ADMA. Conclusion: The risk relationship of hs-cTnT with incident AMI was stronger in patients with higher BMI. Our results motivate further studies into potential pathophysiological mechanisms connecting hs-cTnT with increased cardiovascular risk.

Background Vitamin B-6 status is routinely measured as pyridoxal 5′-phosphate (PLP) in plasma. Low concentrations of PLP are associated with rheumatic, cardiovascular, and neoplastic diseases. We have previously shown that vitamin B-6 status affects the kynurenine (Kyn) pathway of tryptophan (Trp) catabolism. Objective This study aimed to comprehensively evaluate the use of Kyns as potential markers of functional vitamin B-6 status across 2 large cohorts. Methods We measured circulating concentrations of the first 6 metabolites in the Trp catabolic pathway by LC–MS-MS in the community-based Hordaland Health Study (HUSK; n = 7017) and cardiovascular patient–based Western Norway Coronary Angiography Cohort (WECAC; n = 4161). Cross-sectional and longitudinal associations of plasma PLP with Kyns were estimated using linear and nonlinear regression–based methods. Results 3′-Hydroxykynurenine (HK), a substrate, and all 4 products formed directly by the PLP-dependent enzymes kynurenine transaminase and kynureninase contributed to the explanation of circulating PLP in multivariable-adjusted regression models. The construct HK:(kynurenic acid + xanthurenic acid + 3′-hydroxyanthranilic acid + anthranilic acid), termed HK ratio (HKr), was related to plasma PLP with standardized regression coefficients (95% CIs) of −0.47 (−0.49, −0.45) and −0.46 (−0.49, −0.43) in HUSK and WECAC, respectively. Across strata of cohort and sex, HKr was 1.3- to 2.7-fold more sensitive, but also 1.7- to 2.9-fold more specific to changes in PLP than a previously proposed marker, HK:xanthurenic acid. Notably, the association was strongest at PLP concentrations < ∼20 nmol/L, a recognized threshold for vitamin B-6 deficiency. Finally, PLP and HKr demonstrated highly sex-specific and corroborating associations with age. Conclusions The results demonstrate that by combining 5 metabolites in the Kyn pathway into a simple index, HKr, a sensitive and specific indicator of intracellular vitamin B-6 status is obtained. The data also underscore the merit of evaluating alterations in Kyn metabolism when investigating vitamin B-6 and health. acceptedVersion

Background: The prognosis of unexplained chest pain patients provides valuable information for evaluation of health services. Objective: To examine prognosis of unexplained chest pain. Methods: Using data from in‐ and outpatient hospital visits in Norway of patients discharged with a main diagnosis of unexplained chest pain (ICD‐10: R072–R074) in 2010–2012, the 1‐year incidence of coronary heart disease (CHD), any cardio‐vascular disease (CVD) and mortality was evaluated. Cases with prior 2‐year history of CVD or chest pain were excluded. Cox proportional hazards evaluated outcomes by patient characteristics and standardized mortality ratios evaluated observed versus expected mortality. Results: Of 59 569 patients identified (20–89 years of age), the majority (86%) were referred to hospital by out‐of‐hours emergency care centres. Subsequent CHD was noted for 12.5%, 19.5% and 25.0% of men and 7.2%, 11.0%, 14.0% of women aged 45–64, 65–74 and 75–89 years, respectively. The per cent of deaths attributed to CVD were greatest within the first 2 months of postdischarge. Total mortality rates (per 1000 person‐years) were 6.6 in men and 4.7 in women aged 45–64 and 69.2 in men and 39.5 in women aged 75–89 years. Relative to the general population, mortality was 53% and 45% higher for men and women under 65 years of age, respectively, attributed primarily to non‐CVD causes. Conclusion: Patients in Norway discharged with unexplained chest pain are an at‐risk group in terms of incident CHD, any CVD and mortality, including non‐CVD mortality during the first‐year postdischarge. The results suggest that unexplained chest pain patients may benefit from greater healthcare coordination between medical disciplines. publishedVersion

Aims Trimethyllysine (TML) is involved in carnitine synthesis, serves as a precursor of trimethylamine N-oxide (TMAO) and is associated with cardiovascular events in patients with established coronary heart disease (CHD). We prospectively examined circulating TML as a predictor of all-cause and cardiovascular mortality in community-dwelling adults and patients with CHD. Methods and results By Cox regression modelling, risk associations were examined in 6393 subjects in the community-based Hordaland Health Study (HUSK). A replication study was conducted among 4117 patients with suspected stable angina pectoris in the Western Norway Coronary Angiography Cohort (WECAC). During a mean follow-up of 10.5 years in the HUSK-cohort, 884 (13.8%) subjects died, of whom 287 from cardiovascular causes. After multivariable adjustments for traditional cardiovascular risk factors, the hazard ratio (HR) [95% confidence interval (95% CI)] for all-cause mortality comparing the 4th vs. 1st TML-quartile was 1.66 (1.31–2.10, P Conclusions Elevated TML-levels were associated with increased risk of all-cause and cardiovascular mortality both in subjects with and without established CHD.

Funding Acknowledgements Type of funding sources: None. Background/Aim Increased plasma trimetyllysine (TML), a methylated amino acid, has recently been linked to higher risk of acute myocardial infarction (AMI). TML is also a precursor of trimethylamine-N oxide (TMAO), which has been linked to increased cardiovascular risk, including that of atrial fibrillation (AF). We investigated the association between TML and new-onset AF in two large Norwegian cohorts. Methods The primary cohort consisted of 6396 participants in the community-based Hordaland Health Study (HUSK). The validation cohort consited of 2027 patients who underwent coronary angiography due to suspected stable angina pectoris in the Western Norway Coronary Angiography Cohort (WECAC). Information on new-onset AF was obtained by linking patient data to Norwegian public health registries. Risk associations were explored by Cox regression. Results During median (25th-75th percentile) follow-up of 10.9 (10.6-11.3) and 7.0 (6.3-8.6) years, 560 (8.8%) patients in the HUSK and 210 (10.4%) in the WECAC was diagnosed with AF. In the HUSK, the age and gender adjusted HR (95 % CI) for the 4th vs. 1st plasma TML quartiles 1.84 (1.37-2.48) p Testing for collinearity between TMAO and TML revealed variance inflation factors between 1.0-1.1 in HUSK and WECAC, thus ruling out collinearity. Conclusion Plasma TML was associated with new-onset AF among subjects from the general population, and the relationship was independent from established AF risk factors. A similar trend was also seen in patients with suspected stable angina pectoris, strengthening our findings, which motivate further studies to explore potential pathophysiological relationships between one-carbon metabolism and cardiac arrhythmias

Aims Hypertension has been suggested as a stronger risk factor for acute coronary syndromes (ACS) in women than men. Whether this also applies to stage 1 hypertension [blood pressure (BP) 130–139/80–89 mmHg] is not known. Methods and results We tested associations of stage 1 hypertension with ACS in 12 329 participants in the Hordaland Health Study (mean baseline age 41 years, 52% women). Participants were grouped by baseline BP category: Normotension (BP Conclusion Among subjects in their early 40s, stage 1 hypertension was a stronger risk factor for ACS during midlife in women than in men.

Background Studies exploring risk factors for ankle fractures in adults are scarce, and with diverging conclusions. This study aims to investigate whether overweight, obesity and osteoporosis may be identified as risk factors for ankle fractures and ankle fracture subgroups according to the Danis-Weber (D-W) classification. Methods 108 patients ≥40 years with fracture of the lateral malleolus were included. Controls were 199 persons without a previous fracture history. Bone mineral density of the hips and spine was measured by dual-energy x-ray absorptiometry, and history of previous fracture, comorbidities, medication, physical activity, smoking habits, body mass index and nutritional factors were registered. Results Higher body mass index with increments of 5 gave an adjusted odds ratio (OR) of 1.30 (95% confidence interval (CI) 1.03–1.64) for ankle fracture, and an adjusted OR of 1.96 (CI 0.99–4.41) for sustaining a D-W type B or C fracture compared to type A. Compared to patients with normal bone mineral density, the odds of ankle fracture in patients with osteoporosis was 1.53, but the 95% CI was wide (0.79–2.98). Patients with osteoporosis had reduced odds of sustaining a D-W fracture type B or C compared to type A (OR 0.18, CI 0.03–0.83). Conclusions Overweight increased the odds of ankle fractures and the odds of sustaining an ankle fracture with possible syndesmosis disruption and instability (D-W fracture type B or C) compared to the stable and more distal fibula fracture (D-W type A). Osteoporosis did not significantly increase the odds of ankle fractures, thus suffering an ankle fracture does not automatically warrant further osteoporosis assessment.

Introduction: During the last 30 years, treatment of familial hypercholesterolemia (FH) has been revolutionized, but it is not known if both sexes equally benefit in these advances, and whether this could have affected the sex difference in risk of coronary heart disease (CHD). We aimed to study sex difference in the risk of CHD between men and women with FH compared to non-FH men and women. Methods: We obtained data on CHD hospitalization and death from Norwegian health registries in 4,525 individuals diagnosed with FH between 1992 and 2014 and an age and sex matched control population of 88,892. The sex distribution was about 50/50 between women and men, and the mean age at start of follow-up was 36 years. Results: The cumulative incidence of CHD (FH vs. non-FH controls) in women and men are shown in Figure 1 with a clear increased risk in FH compared to controls. The cumulative incidence starts to increase at a younger age in men compared with women, both in FH and non-FH controls. This corresponds to an age adjusted 2.6-fold higher risk of CHD in men compared with women in both the FH and control population. In the FH population, men aged 20-39 years had a hazard ratio (HR) of 5.3 (95% CI: 2.6-10.9) compared with women, whereas the corresponding HR between women and men in non-FH controls was 3.7 (95% CI: 2.6-5.3). There was no significant interaction between sex and FH status, indicating that the excess risk in men was similar in FH and non-FH controls. Stratified by sex and adjusted for age, we found that both men and women with FH had a 2-fold higher risk of CHD than controls. The highest excess risk was observed in ages 20-30 years with a of HR= 4.5 (95% CI: 2.2-9.2) and a HR of= 5.5 (95%CI: 4.60-9.34) in women and men, respectively. Conclusions: The risk of CHD among individuals with FH was higher in men than in women in all age groups presented, with no differences between the FH sample and the non-FH controls. However, the relative risk in FH compared with controls was similar for both sexes.

Background and aim We have previously reported that individuals with familial hypercholesterolemia (FH) have a two-fold increased risk of acute myocardial infarction (AMI) compared with the general population. The consequences of having an AMI on re-hospitalization and mortality are however less known. The aim of the present study was to compare the risk of re-hospitalization with AMI and CHD and risk of mortality after incident (first) AMI-hospitalization between persons with and without FH (controls). Methods The original study population comprised 5691 persons diagnosed with FH during 1992–2014 and 119511 age and sex matched controls randomly selected from the general Norwegian population. We identified 221 individuals with FH and 1947 controls with an incident AMI registered in the Norwegian Patient Registry (NPR) or the Cardiovascular Disease in Norway Project during 2001–2017. Persons with incident AMI were followed until December 31st 2017 for re-hospitalization with AMI or coronary heart disease (CHD) registered in the NPR, and for mortality through linkage to the Norwegian Cause of Death Registry. Risk of re-hospitalization was compared with sub-hazard ratios (SHR) from competing risk regression with death as competing event, and mortality was compared using hazard ratios (HR) from Cox regression. All models were adjusted for age. Results Risk of re-hospitalization was 2-fold increased both for AMI [SHR=2.53 (95% CI: 1.88–3.41)] and CHD [SHR=1.82 (95% CI: 1.44–2.28)]. However, persons with FH did not have increased 28-day mortality following an incident AMI (HR=1.05 (95% CI: 0.62–1.78), but the longer-term (>28 days) mortality after first AMI was increased in FH [HR=1.45 (95% CI: 1.07–1.95]. Conclusion This study yields the important finding that persons with FH have increased risk of re-hospitalization of both AMI and CHD after incident AMI. These findings call for more intensive follow-up of individuals with FH after an AMI. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): University of Oslo and Oslo University Hospital

Background Hypertension is a major risk factor for cardiovascular disease (CVD), but the definition of hypertension is currently debated. Little is known about whether high-normal blood pressure (BP) carries a different risk for CVD in women and men. Purpose The aim of the current study was to test associations of high-normal BP with CVD in women and men participating in the community-based Hordaland Health Study (HUSK). Methods Data from 8252 participants aged 40–43 years (52% women) participating in the HUSK survey in 1992–93 were coupled with hospitalization or death from CVD documented by ICD codes in national registries in the period 1994–2009. Attended BP was measured in accordance with current guidelines. The average of the two last measurements was taken as the clinic BP measure. The cohort was grouped into normal BP (BP Results At baseline, 17% women and 27% men had high-normal BP and 16% women and 32% men had hypertension (both p Conclusion High-normal BP was a more important risk factor for CVD in middle-aged women than men. Our findings challenges whether hypertension-associated CVD risk is optimally detected in women by the current hypertension definition in European guidelines. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): University of Bergen

Hypertensive disorders of pregnancy (HDP) have been associated with heart failure (HF). It is unknown whether concurrent pregnancy complications (small-for-gestational-age or preterm delivery) or recurrent HDP modify HDP-associated HF risk. In this cohort study, we included Norwegian women with a first birth between 1980 and 2004. Follow-up occurred through 2009. Cox models examined gestational hypertension and preeclampsia in the first pregnancy as predictors of a composite of HF-related hospitalization or HF-related death, with assessment of effect modification by concurrent small-for-gestational-age or preterm delivery. Additional models were stratified by final parity (1 versus ≥2 births) and tested associations with recurrent HDP. Among 508 422 women, 565 experienced incident HF over a median 11.8 years of follow-up. After multivariable adjustment, gestational hypertension in the first birth was not significantly associated with HF (hazard ratio, 1.41 [95% CI, 0.84–2.35], P =0.19), whereas preeclampsia was associated with a hazard ratio of 2.00 (95% CI, 1.50–2.68, P P interaction =0.42). Largest hazards of HF were observed in women whose only lifetime birth was complicated by preeclampsia and women with recurrent preeclampsia. HF risks were similar after excluding women with coronary artery disease. In summary, women with preeclampsia, especially those with one lifetime birth and those with recurrent preeclampsia, experienced increased HF risk compared to women without HDP. Further research is needed to clarify causal mechanisms.

Summary Glucocorticoid use is a risk factor for osteoporosis and fractures. We studied whether women initiating glucocorticoid treatment also started anti-osteoporotic treatment, according to clinical guidelines. Women with versus without previous fracture were twice as likely to start anti-osteoporotic treatment within 1 year after initiating glucocorticoid treatment, but the cumulative incidences were low 9.1% vs. 4.6%, respectively. Purpose Use of glucocorticoids (GC) is a risk factor for osteoporosis and fractures, and clinical guidelines suggest that preventive treatment with anti-osteoporotic drugs (AOD) should be considered when starting GC. Women with high risk of osteoporosis comprise those with previous fractures or a known inflammatory rheumatic disease, for whom the indication of AOD is even stronger. The purpose of these analyses was to investigate whether women initiating GC treatment also started AOD, especially those with high risk of osteoporosis. Methods We used data from the Norwegian Prescription Database to identify all women 55 years and older initiating GC treatment in Norway during 2010–2016 and to obtain information on use of AOD. Data from the Norwegian Patient Registry were used to obtain information on previous fractures and diagnoses. Results Among 105,477 women initiating GC treatment during 2010–2016, 3256 had started AOD and 79,638 had discontinued GC treatment after 1-year follow-up. Cumulative incidence of starting AOD after 1 year was 9.1% (95% CI: 7.9, 10.4) for women with vs. 4.6% (95% CI: 4.4%, 4.8%) for women without a previous fracture. Women with rheumatoid arthritis or another inflammatory rheumatic disease were more likely to start AOD than women with other indications. For the whole cohort, the probability of starting AOD treatment within 1 year after initiating GC increased on average 3% per year (HR = 1.03, CI: 1.01, 1.05) from 2010 to 2016. Conclusions Having had a previous fracture or an inflammatory rheumatic disease increased the probability of treatment with AOD. However, the proportions starting AOD were much lower than clinically indicated. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Background: Diabetes distress is a potential barrier to self-management and satisfactory glycaemic control. A structured focus on diabetes distress using the Problem Areas in Diabetes (PAID) scale may improve the health of people with diabetes. We designed the DiaPROM trial, evaluating the effect of using electronically captured PAID in clinical practice, to reduce diabetes distress among adults with type 1 diabetes. Methods: In this pilot trial, we aimed to evaluate PAID scores pre and post intervention and identify patients with elevated scores. We randomly assigned participants (18-≤40 yrs) at an outpatient clinic to standard care or an intervention were physicians referred individuals with a PAID score ≥30 or single item(s) ≥3 (moderately high distress) to minimum two nurse appointments. Following a communication manual based on empowerment and self-determination theory, reported problem areas were reviewed and discussed. Results: We recruited 79 adults with type 1 diabetes (age 27.2 ±5.0 yrs, diabetes duration 13.7 ±7.0 yrs, HbA1c 65.4 ±14.5 mmol/mol). In the intervention group (n=39), baseline PAID score was 27.7 ±16.8; 23 (59%) participants qualified for additional follow up and 17 (44%) accepted referral, attending a mean of 2.2 ±1.1 appointments. At 12 month follow up, the intervention group (n=31) mean score was 21.7 ±14.4 (mean change 3.7 ±13.0), with 13 (42%) reporting moderately high distress. The control group (n=40) scored 24.1 ±14.3 at baseline and 26.2 ±14.5 at 12 months (n=36), with respectively 19 (48%) and 20 (56%) patients reporting moderately high distress. Between-group difference at 12 months was 5.5 (95% CI 0.25, 10.7). Conclusion: Half of the participants reported diabetes distress levels qualifying for additional follow up, which has consequences for scaling a future RCT. Although the study was not powered to estimate intervention effects, we identified a promising PAID score reduction in the intervention group which was not observed for the controls. Disclosure I. Hernar: None. M. Graue: None. D. Richards: None. R.B. Strandberg: None. K.F. Løvaas: None. T. Madsen: None. G.S. Tell: None. A. Haugstvedt: None.

Background: A person's confidence to control eating, eating self-efficacy (ESE), has been identified as a target for long-term weight management in nonsurgical weight loss interventions, but has to a limited extent been studied after bariatric surgery. Objective: We investigated the association between ESE, weight loss, and obesity-specific quality of life (QOL) after sleeve gastrectomy (SG). Setting: A single-center longitudinal study. Methods: Data from adult patients were collected before SG, and at mean 16 months (±standard deviation 4 mo) and 55 (±4) months postoperatively. ESE was measured by the Weight Efficacy Lifestyle Questionnaire Short-Form. Multiple regression analyses were performed with excess body mass index loss (%EBMIL) and obesity-specific QOL as dependent variables. Age, sex, and other preoperative values were covariates in all models. Results: Of 114 preoperative patients, 91 (80%) and 84 (74%) were available for follow-up 16 and 55 months after SG, respectively. Mean %EBMIL from baseline to 16 and 55 months was 76% (95% confidence interval: 71.9, 79.6) and 67% (95% confidence interval: 61.9, 72.2), respectively. Preoperative ESE scores improved significantly at both 16 and 55 months (P = .002) but did not predict postoperative %EBMIL or QOL at 55 months (β = −.08, P = .485). Greater change in ESE from 0 to 16 months predicted higher %EBMIL (β = .34, P = .013) at 55 months, and improvements in ESE from 0 to 55 months were significantly associated with higher %EBMIL (β = .46, P = .001) and obesity-specific QOL (β = .50, P < .001) 55 months after SG. Conclusion: Significant improvements in ESE were seen at 16 months, and remained high at 55 months after SG in this cohort. Patients who improved their ESE the most also experienced the highest weight loss and obesity-specific QOL 5 years postoperatively. Future research should address whether enhancement of ESE corresponds to sustained improvements in eating behavior after bariatric surgery. acceptedVersion

Hip fracture patients often have comorbid conditions. We investigated whether the combination of comorbidity and hip fracture could explain the previously observed excess mortality among hip fracture patients as compared with the general population. Using a population-based matched study design with 38,126 Norwegian women who suffered a hip fracture during the period 2009–2015 and the same number of women in a matched comparison cohort, we matched participants on prefracture comorbidity, age, and education. We estimated relative survival and additive and multiplicative comorbidity–hip fracture interactions. An additive comorbidity–hip fracture interaction of 4 or 9 additional deaths per 100 patients, depending on Charlson Comorbidity Index (CCI) score, was observed 1 year after hip fracture. Among women with a CCI score of ≥3, 15 additional deaths per 100 patients were observed; of these, 9 deaths could be attributed to the interaction and 6 to the hip fracture per se. On the relative scale, we observed increasing heterogeneity in survival by comorbidity over time; survival was reduced by 39% after 6 years among patients with a CCI score of ≥3, while among women with no comorbidity, survival was reduced by 17% (hip fracture vs. no hip fracture). In summary, prefracture comorbidity was associated with short-term absolute excess mortality and long-term relative excess mortality.

In patients with stable angina, the association between high-sensitivity cardiac troponin T (hs-cTnT) and incident acute myocardial infarction (AMI), as well as pathophysiologic mechanisms accounting for an adverse prognosis, remain to be determined. We explored the association between hs-cTnT and future AMI among 3,882 patients evaluated for suspected stable angina pectoris and investigated to which extent hs-cTnT attenuated the relations between traditional coronary heart disease (CHD) risk factors and AMI. Associations between increasing hs-cTnT categories (≤3, 4 to 9, 10 to 19, and 20 to 30 ng/L) and risk of AMI were studied by Cox regression. We investigated whether the associations between traditional CHD risk factors and future AMI were influenced by adjusting for hs-cTnT. Median age was 62 years. During median (25th to 75th percentile) 8 (6.4 to 8.7) years of follow-up, 460 (11.8%) experienced an AMI. There was a strong association between hs-cTnT categories and risk of AMI. The relation was somewhat attenuated, but still present, when adjusting for potential confounders, traditional CHD risk factors, previous peripheral vascular disease, and percutaneous coronary intervention or coronary bypass surgery. Moreover, hs-cTnT slightly attenuated the risk relations between traditional CHD risk factors and incident AMI, but each risk factor remained significantly associated with AMI. In conclusion, among patients with suspected stable angina, hs-cTnT was positively related to incident AMI.

Objectives: No individual homocysteine (Hcy) metabolite has been studied as a risk marker for coronary artery disease (CAD). Our objective was to examine Hcy‐thiolactone, a chemically reactive metabolite generated by methionyl‐tRNA synthetase and cleared by the kidney, as a risk predictor of incident acute myocardial infarction (AMI) in the Western Norway B‐Vitamin Intervention Trial. Design: Single centre, prospective double‐blind clinical intervention study, randomized in a 2 × 2 factorial design. Subjects and methods: Patients with suspected CAD (n = 2049, 69.8% men; 61.2‐year‐old) were randomized to groups receiving daily (i) folic acid (0.8 mg)/vitamin B12 (0.4 mg)/vitamin B6 (40 mg); (ii) folic acid/vitamin B12; (iii) vitamin B6 or (iv) placebo. Urinary Hcy‐thiolactone was quantified at baseline, 12 and 38 months. Results: Baseline urinary Hcy‐thiolactone/creatinine was significantly associated with plasma tHcy, ApoA1, glomerular filtration rate, potassium and pyridoxal 5′‐phosphate (positively) and with age, hypertension, smoking, urinary creatinine, plasma bilirubin and kynurenine (negatively). During median 4.7‐years, 183 patients (8.9%) suffered an AMI. In Cox regression analysis, Hcy‐thiolactone/creatinine was associated with AMI risk (hazard ratio = 1.58, 95% confidence interval = 1.10–2.26, P = 0.012 for trend; adjusted for age, gender, tHcy). This association was confined to patients with pyridoxic acid below median (adjusted HR = 2.72, 95% CI = 1.47–5.03, P = 0.0001; Pinteraction = 0.020). B‐vitamin/folate treatments did not affect Hcy‐thiolactone/creatinine and its AMI risk association. Conclusions: Hcy‐thiolactone/creatinine ratio is a novel AMI risk predictor in patients with suspected CAD, independent of traditional risk factors and tHcy, but modified by vitamin B6 catabolism. These findings lend a support to the hypothesis that Hcy‐thiolactone is mechanistically involved in cardiovascular disease. publishedVersion

Background Plasma trimethylamine-N-oxide (TMAO) is associated with cardiovascular disease; however specific relationships with cardiac arrhythmias are unknown. We evaluated the association between plasma TMAO and incident atrial fibrillation (AF). Methods Risk associations were explored among 3797 patients with suspected stable angina in the Western Norway Coronary Angiography Cohort (WECAC) and verified in 3143 elderly participants in the community-based Hordaland Health Study (HUSK). Information on endpoints was obtained from nationwide registries. Results Median follow-up was 7.3 and 10.8 years in the WECAC and HUSK cohorts, respectively, and 412 (10.9%) and 484 (15.4%) subjects were registered with incident AF. The age and gender adjusted HRs were 1.16, 95% CI 1.05–1.28 and 1.10, 95% CI 1.004–1.19 per 1 SD increase in log-transformed plasma TMAO. Adjusting for hypertension, BMI, smoking, diabetes, or intake of total choline, a TMAO precursor, did not materially influence the risk associations. Among patients in WECAC, further extensive adjustment for other AF risk factors yielded similar results. Adding TMAO to traditional AF risk factors (age, gender, hypertension, BMI, smoking and diabetes) yielded a continuous net reclassification improvement of 0.108, 95% CI 0.015–0.202 and 0.139, 95% CI 0.042–0.235. Conclusions Plasma TMAO was associated with and improved reclassification of incident AF in two independent Norwegian cohorts with long-term follow-up. The relationship was independent of traditional AF risk factors, as well as of dietary choline intake. Our findings motivate further studies to explore endogenous metabolic factors influencing the relationship between TMAO and cardiovascular disease.

AimsLow-density lipoprotein cholesterol (LDL-C) is an established causal driver of atherosclerotic cardiovascular disease (ASCVD), but its performance and age-dependency as a biomarker for incident events and mortality arising from ASCVD is less clear. The aim was to determine the value of LDL-C as a susceptibility/risk biomarker for incident coronary heart disease (CHD), ASCVD, and stroke events and deaths, for the age groups Methods and resultsThe performance of LDL-C was evaluated in three cohorts, FINRISK 2002 (n = 7709), HUSK (n = 5431), and ESTHER (n = 4559), by Cox proportional hazards models, C-statistics, and net reclassification index calculations. Additionally, the hazard ratios (HRs) for the three cohorts were pooled by meta-analysis. The most consistent association was observed for CHD [95% confidence interval (CI) for HRs per standard deviation ranging from 0.99 to 1.37], whereas the results were more modest for ASCVD (0.96–1.18) due to lack of association with stroke (0.77–1.24). The association and discriminatory value of LDL-C with all endpoints in FINRISK 2002 and HUSK were attenuated in subjects 50 years and older [HRs (95% CI) obtained from meta-analysis 1.11 (1.04–1.18) for CHD, 1.15 (1.02–1.29) for CHD death, 1.02 (0.98–1.06) for ASCVD, 1.12 (1.02–1.23) for ASCVD death, and 0.97 (0.89–1.05) for stroke].ConclusionIn middle-aged and older adults, associations between LDL-C and all the studied cardiovascular endpoints were relatively weak, while LDL-C showed stronger association with rare events of pre-mature CHD or ASCVD death among middle-aged adults. The predictive performance of LDL-C also depends on the studied cardiovascular endpoint.

Background Link between inflammation and atrial fibrillation (AF) has been increasingly recognized. Neopterin, a biomarker of cellular immune activation, may be associated with incident AF. Objective To investigate the association between plasma neopterin levels and risk of an inpatient hospital diagnosis of AF, and to evaluate a joint association of neopterin and a nonspecific inflammatory marker C-reactive protein (CRP) in two prospective cohorts. Methods We performed a prospective analysis from a community-based cohort (the Hordaland Health Study (HUSK), n = 6891), and validated the findings in a cohort of patients with suspected stable angina pectoris (the Western Norway Coronary Angiography Cohort (WECAC), n = 2022). Results In both cohorts, higher plasma levels of neopterin were associated with an increased risk of incident AF after adjustment for age, sex, body mass index, current smoking, diabetes, hypertension and renal function. The multivariable-adjusted hazard ratio (HR) (95% CI) per one SD increment of log-transformed neopterin was 1.20 (1.10-1.32) in HUSK and 1.26 (1.09-1.44) in WECAC. Additional adjustment for CRP did not materially affect the risk association for neopterin. The highest risk of AF was found among individuals with both neopterin and CRP levels above the median (HR: 1.54; 95% CI: 1.16-2.05 in HUSK and HR: 1.67; 95% CI: 1.11-2.52 in WECAC). Conclusions Our findings indicate an association of plasma neopterin with risk of an inpatient hospital diagnosis of AF, which remains after adjustment for traditional risk factors as well as for CRP. This study highlights a role of cellular immune activation, in addition to inflammation, in AF pathogenesis.

Context Carnitine and its metabolites are centrally involved in fatty acid metabolism. Although elevated circulating concentrations have been observed in obesity and insulin resistance, prospective studies examining whether these metabolites are associated with incident type 2 diabetes mellitus (T2D) are sparse. Objective We performed a comprehensive evaluation of metabolites along the carnitine pathway relative to incident T2D. Design A total of 2519 patients (73.1% men) with coronary artery disease, but without T2D, were followed for median 7.7 years until the end of 2009, during which 173 (6.9%) new cases of T2D were identified. Serum levels of free carnitine, its precursors trimethyllysine (TML) and γ-butyrobetaine, and the esters acetyl-, propionyl-, (iso)valeryl-, octanoyl-, and palmitoylcarnitine were measured by liquid chromatography/tandem mass spectrometry. Risk associations were explored by logistic regression and reported per (log-transformed) standard deviation increment. Results Median age at inclusion was 62 years and median body mass index (BMI) 26.0 kg/m2. In models adjusted for age, sex, fasting status, BMI, estimated glomerular filtration rate, glycated hemoglobin A1c, triglyceride and high-density lipoprotein cholesterol levels, and study center, serum levels of TML and palmitoylcarnitine associated positively [odds ratio (95% confidence interval), 1.22 (1.04 to 1.43) and 1.24 (1.04 to 1.49), respectively], whereas γ-butyrobetaine associated negatively [odds ratio (95% confidence interval) 0.81 (0.66 to 0.98)] with T2D risk. Conclusion Serum levels of TML, γ-butyrobetaine, and the long-chained palmitoylcarnitine predict long-term risk of T2D independently of traditional risk factors, possibly reflecting dysfunctional fatty acid metabolism in patients susceptible to T2D development.

OBJECTIVE To evaluate whether telemedicine (TM) follow-up of patients with diabetes-related foot ulcers (DFUs) in primary health care in collaboration with specialist health care was noninferior to standard outpatient care (SOC) for ulcer healing time. Further, we sought to evaluate whether the proportion of amputations, deaths, number of consultations per month, and patient satisfaction differed between the two groups. RESEARCH DESIGN AND METHODS Patients with DFUs were recruited from three clinical sites in western Norway (2012–2016). The cluster-randomized controlled noninferiority trial included 182 adults (94/88 in the TM/SOC groups) in 42 municipalities/districts. The intervention group received TM follow-up care in the community; the control group received SOC. The primary end point was healing time. Secondary end points were amputation, death, number of consultations per month, and patient satisfaction. RESULTS Using mixed-effects regression analysis, we found that TM was noninferior to SOC regarding healing time (mean difference –0.43 months, 95% CI −1.50, 0.65). When competing risk from death and amputation were taken into account, there was no significant difference in healing time between the groups (subhazard ratio 1.16, 95% CI 0.85, 1.59). The TM group had a significantly lower proportion of amputations (mean difference –8.3%, 95% CI –16.3%, –0.5%), and there were no significant differences in the proportion of deaths, number of consultations, or patient satisfaction between groups, although the direction of the effect estimates for these clinical outcomes favored the TM group. CONCLUSIONS The results suggest that use of TM technology can be a relevant alternative and supplement to usual care, at least for patients with more superficial ulcers.

Kathrine J Vinknes,1 Eha Nurk,1,2 Grethe S Tell,3 Gerhard Sulo,3 Helga Refsum,1,4 Amany K Elshorbagy4,5 1Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway; 2Department of Surveillance and Evaluation, National Institute for Health Development, Tallinn, Estonia; 3Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway; 4Department of Pharmacology, University of Oxford, Oxford, UK; 5Department of Physiology, Faculty of Medicine, University of Alexandria, Alexandria, Egypt Objective: We compared Clínica Universidad de Navarra-Body Adiposity Estimator (CUN-BAE) and body mass index (BMI) as correlates of body fat percent (BF%) and the association with future risk of cardiovascular disease (CVD) and type 2 diabetes in a Caucasian population. Methods: We used data from 6796 individuals (born 1925–27 and 1950–52) from the Hordaland Health Study, a prospective cohort study in Norway. The study was conducted in 1992–1993 and 1997–1999. Cross-sectional analyses were conducted with data from 1997/99, including BF% measured by dual-energy X-ray absorptiometry. Longitudinal analyses included BMI and CUN-BAE calculated in 1992/93, and self-reported information on CVD events and diabetes in 1997/99. Results: The correlation between CUN-BAE and BF% (r=0.88) was stronger than between BMI and BF% (r=0.56). In sex-stratified analyses, CUN-BAE and BMI correlated similarly with BF% in men (r=0.77 and r=0.76, respectively) and women (r=0.82 and r=0.81, respectively). In longitudinal analyses, the odds ratio (per 1 SD increase) of CVD and type 2 diabetes was higher for BMI (ORCVD =1.23 [95% CI: 1.11–1.36]; ORdiabetes =2.11 [1.82–2.45]) than for CUN-BAE (ORCVD =1.15 [1.04–1.27]; ORdiabetes =2.06 [1.72–2.47]) in the total population. In sex-stratified analyses, CUN-BAE showed higher CVD and diabetes risk than BMI: in men BMI ORCVD =1.22 (1.04–1.44), ORdiabetes =2.13 (1.64–2.83); CUN-BAE ORCVD =1.93 (1.54–2.43), ORdiabetes =4.33 (2.80–6.71); and in women BMI ORCVD =1.22 (1.07–1.39), ORdiabetes =2.11 (1.76–2.53); CUN-BAE ORCVD =2.06 (1.69–2.51), ORdiabetes =5.45 (3.87–7.67). Conclusion: CUN-BAE is more strongly associated with future risk of type 2 diabetes and CVD compared with BMI in analysis stratified by sex. As a measure of adiposity in men and women separately, CUN-BAE has no advantage over BMI, except when the value of estimated BF% itself is of interest. Keywords: anthropometry, body composition, body fat, body mass index, cardiovascular disease risk, diabetes risk

Background and aims Heart failure (HF) and atrial fibrillation/flutter (AF) are important causes of morbidity and mortality. Subjects with familial hypercholesterolemia (FH) carry a high risk of coronary artery disease (CAD) but it is not known if the risk of HF and AF is increased in FH. The present study investigated the incidence of hospitalization for HF and AF in a genetically verified FH cohort, age 25 years and older, compared to the general population. Methods Incidence rates of hospitalization for HF and AF were estimated from national registry data. Standardized incidence ratios (SIRs) were calculated. Results 4273 genotyped FH patients (51.7% women) with a total observation period of 18,300 patient years were studied. Overall, the expected number of FH patients with HF was 27.7 and the observed number of cases was 54 (SIR (95% CI) 2.0 (1.5–2.6)). The highest excess risk was observed in the age group 25–49 years, where SIRs were 3.8 (1.2–11.8) and 4.2 (2.0–8.8) in women and men, respectively. The total expected number of FH patients with AF was 39.4 while the observed number of cases was 77 (SIR 2.0 (1.6–2.4)). Among FH patients with an incident event of HF, nearly 90% had a previous diagnosis of CAD, and nearly 40% had suffered from a myocardial infarction. Conclusions We demonstrate a doubling of the risk of hospitalization for HF or AF in patients with FH. This is could have an important prognostic impact for patients and economic impact for the society.

Background and aims Apolipoproteins B (apoB) and A1 (apoA1) are major protein constituents of low-density and high-density lipoproteins, respectively, and serum concentrations of these apolipoproteins are associated with risk of atherosclerosis. Vitamin A (VA) has been implicated in lipoprotein metabolism. We evaluated the associations of serum apoB, apoA1 and their ratio (apoBAR) with risk of incident acute myocardial infarction (AMI) and the possible modification by serum VA. Methods Risk associations were assessed by Cox regression, and presented as hazard ratios (HRs) per standard deviation (SD) increment in log-transformed values of the lipid parameters, among 4117 patients with suspected stable angina pectoris, located in Western Norway. Interactions with VA were evaluated by including interaction terms in the models. The multivariate model included age, sex, smoking, hypertension, number of stenotic coronary arteries, left ventricular ejection fraction, C-reactive protein, estimated glomerular filtration rate and statin treatment at discharge. Results Median (25th, 75th percentile) age of the 4117 patients (72% male) was 62 (55, 70) years. ApoB and apoA1 were higher among patients in the upper versus lower tertiles of VA. During a median of 4.6 (3.6, 5.7) years of follow-up, 8.2% of patients experienced an AMI. Overall, we observed no significant associations between lipid parameters and AMI after multivariate adjustment. However, apoB and apoBAR were associated with AMI among patients in the upper tertile of VA (HR per SD 1.35, (95% CI: 1.11–1.65), and 1.42 (1.16–1.74), respectively, p for interactions ≤0.003). Conclusions The associations of apoB and apoBAR with incident AMI were confined to patients with elevated VA.

Accepted manuscript version. Published version available in Journal of Bone and Mineral Research, 2017;32(10):1981-1989

Aims/hypothesis The tryptophan metabolite kynurenine has potent immune modulatory and vasoactive properties. Experimental data implicate kynurenine in obesity-related morbidities. Epidemiological studies are, however, sparse. We evaluated associations of the plasma and urine kynurenine:tryptophan ratio (KTR) to incident type 2 diabetes. Methods We followed 2519 individuals with coronary artery disease (CAD; 73.1% men) without diabetes at baseline for a median of 7.6 years, during which 173 (6.9%) new incidences of type 2 diabetes were identified. Multivariate Cox regression analyses were applied to investigate the prospective relationships of plasma and urine KTR with new onset type 2 diabetes. Results At inclusion, mean (SD) age was 61.3 (10.4) years, BMI was 25.9 (3.71) kg/m2 and median (interquartile range) HbA1c was 5.6% (5.0%–6.0%) (38 [31–42] mmol/mol). Plasma KTR was not significantly related to type 2 diabetes risk. By contrast, urine KTR showed a strong positive association. Comparing quartile 4 with quartile 1, the HRs (95% CIs) were 2.59 (1.56, 4.30) and 2.35 (1.39, 3.96) in the age- and sex-adjusted and multivariate models, respectively. Conclusions/interpretation Urine KTR is a strong predictor of incident type 2 diabetes in individuals with CAD. Potential clinical implications and possible pathogenic roles of renal kynurenine excretion in type 2 diabetes development should be further elucidated. Electronic supplementary material The online version of this article (doi:10.1007/s00125-017-4329-9) contains peer-reviewed but unedited supplementary material, which is available to authorised users.

Background and Purpose— Familial hypercholesterolemia (FH) is a common autosomal dominant disease leading to increased level of serum LDL (low-density lipoprotein) cholesterol and risk of coronary heart disease. Whether FH increases the risk of cerebrovascular disease, including ischemic stroke, is debated. Accordingly, we studied the incidence of cerebrovascular disease in a cohort of people with genetically verified FH compared with the entire Norwegian population and examined whether people in this cohort with previous cohort had increased risk of cerebrovascular disease. Methods— Incidence rates of hospitalization for cerebrovascular disease (among 3144 people with FH) and ischemic stroke (among 3166 people with FH) were estimated by linkage of FH people to Cardiovascular Disease in Norway—a nationwide database of cardiovascular disease hospitalizations (2001–2009). We calculated standardized incidence ratios and used Cox regression to estimate hazard ratios. Results— A total of 46 cases (19 women and 27 men) of cerebrovascular disease were observed in the cohort of people with FH, with no increased risk of cerebrovascular disease compared with the general population (standardized incidence ratio, 1.0; 95% CI, 0.8–1.4). Total number of ischemic strokes in the cohort of people with FH was 26 (9 women and 17 men), with no increased risk compared with the general population (standardized incidence ratio, 1.0; 95% CI, 0.7–1.5). Prior coronary heart disease significantly increased cerebrovascular disease risk in women (hazard ratio, 3.29; 95% CI, 1.20–9.00) but not in men (hazard ratio, 1.03; 95% CI, 0.45–2.37; P interaction =0.04). Conclusions— In a large cohort of genetically verified FH, risks of cerebrovascular disease and ischemic stroke were not increased compared with the total Norwegian population.

Higher concentrations of cardiac troponin T are associated with coronary artery disease (CAD) and adverse cardiovascular prognosis. The relation with incident atrial fibrillation (AF) is less explored. We studied this association among 3,568 patients evaluated with coronary angiography for stable angina pectoris without previous history of AF. The prospective association between high-sensitivity cardiac troponin T (hs-cTnT) categories (≤3 ng/L; n = 1,694, 4-9; n = 1,085, 10 to 19; n = 614 and 20 to 30; n = 175) and incident AF and interactions with the extent of CAD were studied by Kaplan-Meier plots and Cox regression. Risk prediction improvements were assessed by receiver operating characteristic area under the curve (ROC-AUC) analyses. During median (25 to 75 percentile) 7.3 (6.3 to 8.6) years of follow-up 412 (11.5%) were diagnosed with AF. In a Cox model adjusted for age, gender, body mass index, hypertension, diabetes mellitus, smoking, estimated glomerular filtration rate, and left ventricular ejection fraction, hazard ratios (HRs) (95% confidence intervals [CIs]) were 1.53 (1.16 to 2.03), 2.03 (1.49 to 2.78), and 2.15 (1.40 to 3.31) when comparing the second, third, and fourth to the first hs-cTnT group, respectively (P for trend

Aims Distinct ceramide lipids have been shown to predict the risk for cardiovascular disease (CVD) events, especially cardiovascular death. As phospholipids have also been linked with CVD risk, we investigated whether the combination of ceramides with phosphatidylcholines (PCs) would be synergistic in the prediction of CVD events in patients with atherosclerotic coronary heart disease in three independent cohort studies. Methods and results Ceramides and PCs were analysed using liquid chromatography–mass spectrometry (LC-MS) in three studies: WECAC (The Western Norway Coronary Angiography Cohort) (N = 3789), LIPID (Long-Term Intervention with Pravastatin in Ischaemic Disease) trial (N = 5991), and KAROLA (Langzeiterfolge der KARdiOLogischen Anschlussheilbehandlung) (N = 1023). A simple risk score, based on the ceramides and PCs showing the best prognostic features, was developed in the WECAC study and validated in the two other cohorts. This score was highly significant in predicting CVD mortality [multiadjusted hazard ratios (HRs; 95% confidence interval) per standard deviation were 1.44 (1.28–1.63) in WECAC, 1.47 (1.34–1.61) in the LIPID trial, and 1.69 (1.31–2.17) in KAROLA]. In addition, a combination of the risk score with high-sensitivity troponin T increased the HRs to 1.63 (1.44–1.85) and 2.04 (1.57–2.64) in WECAC and KAROLA cohorts, respectively. The C-statistics in WECAC for the risk score combined with sex and age was 0.76 for CVD death. The ceramide-phospholipid risk score showed comparable and synergistic predictive performance with previously published CVD risk models for secondary prevention. Conclusion A simple ceramide- and phospholipid-based risk score can efficiently predict residual CVD event risk in patients with coronary artery disease.

ObjectivesOxidised cholesterol metabolites are linked to increased production of the active vitamin A (Vit-A) form and monocyte/macrophage activation, which may be reflected by neopterin, a marker of both interferon-γ–mediated immune activation and coronary artery disease risk. We examined the influence of serum lipid parameters and Vit-A on the risk association between neopterin and incident acute myocardial infarction (AMI).MethodsWe included 4130 patients with suspected stable angina pectoris (SAP), of whom 80% received lipid-lowering treatment with statins. Risk associations between plasma neopterin and AMI are given as HRs per SD increase in log-transformed neopterin.ResultsDuring a median follow-up of 7.5 years, 530 (12.8%) patients experienced an AMI. In age-adjusted and sex-adjusted analysis, plasma neopterin was positively associated with incident AMI (HR (95% CI) per SD: 1.26 (1.17 to 1.35)). However, the estimates were most pronounced in patients with serum low-density lipoprotein cholesterol (LDL-C) or apolipoprotein (apo) B100 below-median (HR (95% CI) per SD: 1.35 (1.24 to 1.48) and 1.42 (1.27 to 1.58), respectively; both pinteraction ≤0.03). We also observed a particularly strong risk association in those with above-median Vit-A (HR (95% CI) per SD: 1.32 (1.21 to 1.44); pinteraction=0.03). The estimates were slightly modified after multivariable adjustment.ConclusionsIn patients with suspected SAP, the majority of whom receiving statin therapy, high plasma neopterin was associated with increased risk of AMI particularly among those with low LDL-C and apoB100 or high Vit-A levels. The particularly strong relationship of plasma neopterin with residual cardiovascular risk in patients with low lipid levels should be further investigated.

Aims: To examine trends in heart failure (HF) hospitalization rates and risk of readmissions following an incident HF hospitalization. Methods and results: During 2000–2014, we identified in the Cardiovascular Disease in Norway Project 142 109 hospitalizations with HF as primary diagnosis. Trends of incident and total (incident and recurrent) HF hospitalization rates were analysed using negative binomial regression models. Changes over time in 30-day and 3-year risk of HF recurrences or cardiovascular disease (CVD)-related readmissions were analysed using Fine and Grey competing risk regression, with death as competing events. Age-standardized rates declined on average 1.9% per year in men and 1.8% per year in women for incident HF hospitalizations (both Ptrend

Objective To study time trends in incidence of atrial fibrillation (AF) in the entire Norwegian population from 2004 to 2014, by age and sex, and to estimate the prevalence of AF at the end of the study period. Methods A national cohort of patients with AF (≥18 years) was identified from inpatient admissions with AF and deaths with AF as underlying cause (1994– 2014), and AF outpatient visits (2008–2014) in the Cardiovascular Disease in Norway (CVDNOR) project. AF admissions or out-of-hospital death from AF, with no AF admission the previous 10 years defined incident AF. Age-standardised incidence rates (IR) and incidence rate ratios (IRR) were calculated. All AF cases identified through inpatient admissions and outpatient visits and alive as of 31 December 2014 defined AF prevalence. Results We identified 175 979 incident AF cases (30% primary diagnosis, 69% secondary diagnosis, 0.6% outof-hospital deaths). AF IRs (95% confidence intervals) per 100 000 person years were stable from 2004 (433 (426–440)) to 2014 (440 (433–447)). IRs were stable or declining across strata of sex and age with the exception of an average yearly increase of 2.4% in 18–44 yearolds: IRR 1.024 (1.014–1.034). In 2014, the prevalence of AF in the adult population was 3.4%. Conclusions We found overall stable IRs of AF for the adult Norwegian population from 2004 to 2014. The prevalence of AF was 3.4% at the end of 2014, which is higher than reported in previous studies. Signs of an increasing incidence of early-onset AF (

AIM: Heart failure is a serious complication of acute myocardial infarction leading to poor prognosis. We aimed at exploring time trends of heart failure and their impact on mortality among patients with an incident acute myocardial infarction.METHODS: From the National Patient Danish Registry we collected data on all patients hospitalized with an incident of acute myocardial infarction during 2000-2009 and identified cases with in-hospital heart failure (presented on admission or developing heart failure during acute myocardial infarction hospitalization) or post-discharge heart failure (a hospitalization or outpatient visit following acute myocardial infarction discharge), and assessed in-hospital, 30-day and 1-year mortality.RESULTS: Of the 78,814 patients included in the study, 10,248 (13.0%) developed in-hospital heart failure. The odds of in-hospital heart failure declined 0.9% per year (odds ratio=0.991, 95% confidence interval: 0.983-0.999). In-hospital heart failure was associated with 13% (odds ratio=1.13, 95% confidence interval: 1.06-1.20) and 14% (odds ratio=1.14, 95% confidence interval: 1.07-1.20) higher in-hospital and 30-day mortality, respectively. Of the 61,637 patients discharged alive without in-hospital heart failure, 5978 (9.7%) experienced post-discharge heart failure, 4116 (6.7%) were hospitalized and 1862 (3.0%) were diagnosed at outpatient clinics. The risk of heart failure requiring hospitalization declined 5.5% per year (hazard ratio=0.945, 95% confidence interval: 0.934-0.955) whereas the risk of heart failure diagnosed at outpatient clinics increased 13.4% per year (hazard ratio=1.134, 95% confidence interval: 1.115-1.153). Post-discharge heart failure was associated with 239% (hazard ratio=3.39, 95% confidence interval: 3.18-3.63) higher 1-year mortality.CONCLUSIONS: In-hospital and post-discharge heart failure requiring hospitalization decreased whereas post-discharge heart failure diagnosed at outpatient clinics increased among incident acute myocardial infarction patients during 2000-2009. The development of heart failure, especially after acute myocardial infarction discharge, indicates a poor prognosis.

Purpose: We aimed to identify sex-specific factors associated with increase in blood pressure (BP) and incident hypertension in early midlife. Materials and methods: 2,008 women and 1,610 men aged 40-43 years were followed for six years in the Hordaland Health Study. Participants taking antihypertensive medication at baseline were excluded. High-normal BP was defined as baseline BP 130-139/85-89 mmHg, and incident hypertension as BP≥140/90 mmHg or use of antihypertensive medication at follow-up. Results: During follow-up, an increase in systolic (SBP) and diastolic (DBP) BP was observed in 54% and 30% of women vs. 44% and 41% of men, respectively (both p