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IMPORTANCE: Risk stratification strategies in primary prevention of coronary events lack precision.

OBJECTIVE: To determine whether prediction of first coronary events is improved by adding information on coronary atherosclerosis from coronary computed tomography angiography (CCTA) to a model using the pooled cohort equation (PCE) risk score tool and the coronary artery calcification score (CACS).

DESIGN, SETTING, AND PARTICIPANTS: Observational cohort study including individuals aged 50 to 64 years randomly recruited from the general population and examined at 6 university hospitals in Sweden from 2013 to 2018, with a median follow-up of 7.8 years. A sample of 30 154 individuals underwent cardiopulmonary imaging, physical examinations, routine laboratory tests, questionnaires, and/or functional tests. This study included 24 791 individuals without previous cardiovascular disease for whom high-quality CCTA images were available. Events were followed up via registers until September 2024.

EXPOSURES: The information used from the CCTA images was the extent of coronary atherosclerosis (segment involvement score), presence of noncalcified atherosclerosis, and presence of coronary obstructive disease (stenosis ≥50%).

MAIN OUTCOMES AND MEASURES: The outcome was a composite of first occurrence of nonfatal myocardial infarction or death from coronary heart disease.

RESULTS: During follow-up, 304 coronary events occurred. Segment involvement scores of 3 to 4 and greater than 4 and presence of noncalcified atherosclerosis were associated with hazard ratios of 2.71 (95% CI, 1.34-5.44), 5.27 (95% CI, 2.50-11.07), and 1.66 (95% CI, 1.23-2.22), respectively. In a model based on the PCE and CACS, CCTA-derived data improved risk discrimination (C statistic improved from 0.764 to 0.779; P = .004) and risk reclassification (net reclassification improvement of 0.133 [95% CI, 0.031-0.165]), conferred a net correct upward reclassification of 14.2% in those with events and incorrectly classified 1.6% of participants not experiencing an event into a higher-risk category. Because of the low event rate in the cohort, reclassification mainly occurred in the group classified as at low risk (<5%) according to the PCE.

CONCLUSIONS AND RELEVANCE: Information on coronary atherosclerosis from CCTA modestly improved risk prediction beyond traditional risk factors and CACS in identifying individuals at risk of coronary events and in need of primary prevention.

Imaging-defined atherosclerosis represents an intermediate phenotype of atherosclerotic cardiovascular disease (ASCVD). Genome-wide association studies (GWAS) on directly measured coronary plaques using coronary computed tomography angiography (CCTA) are scarce. In the so far largest population-based cohort with CCTA data, we performed a GWAS on coronary plaque burden as determined by the segment involvement score (SIS) in 24,811 European individuals. We identified 20 significant independent genetic markers for SIS, three of which were found in loci not implicated in ASCVD before. Further GWAS on coronary artery calcification showed similar results to that of SIS, whereas a GWAS on ultrasound-assessed carotid plaques identified both shared and non-shared loci with SIS. In two-sample Mendelian randomization studies using SIS-associated markers in UK Biobank and CARDIoGRAMplusC4D, one extra coronary segment with atherosclerosis corresponded to 1.8-fold increased odds of myocardial infarction. This GWAS data can aid future studies of causal pathways in ASCVD.

Background: Aortic valve calcification (AVC) is an underlying pathophysiological mechanism in aortic stenosis, which shares many risk factors with diabetes. However, the association between dysglycemia and early stages of AVC remains unclear. The aim was to examine the associations between stages of dysglycemia and signs of AVC among middle-aged individuals from the general population.

Methods: This was a cross-sectional study from the Swedish CArdioPulmonary bioImage Study (SCAPIS) randomly enrolling 30,154 middle-aged men and women from six study sites in Sweden between 2013 and 2018. Glycemic status was based on the World Health Organization criteria (fasting blood glucose and/or HbA1c) and questionnaire-based answers on previous diseases and categorized as normoglycemia, prediabetes, newly detected diabetes and known diabetes. AVC was assessed on cardiac computed tomography (CT) and defined as evident or not.

Results: Of 29,331 individuals with data on glycemic status and AVC available, mean age was 57.5 years and normoglycemia was present in 76%, prediabetes in 16%, newly detected diabetes in 3% and known diabetes in 5%. The prevalence of AVC increased progressively across glycemic categories, particularly in males (8%, 11%, 14% and 17%; P < 0.01) compared to females (5%, 6%, 8% and 9%; P < 0.01). There was an association with AVC already in the early stages of dysglycemia; prediabetes (OR 1.16, 95% CI 1.02–1.31), newly detected diabetes (1.34 [1.05–1.71]) and known diabetes (1.61 [1.34–1.93]) after adjusting for age, sex, smoking, study site, low density lipoprotein-cholesterol and hypertension.

Conclusions: In this large, contemporary, and randomly selected population of middle-aged individuals, prediabetes, newly detected diabetes and known diabetes were all associated with CT-detected AVC. Further studies are warranted to investigate if managing dysglycemia, even in its early stages, may help slow down AVC progression.

Objectives: Fear of falling (FoF) is a common problem among older adults. It can lead to reduced quality of life and less physical activity, which increases fall risk. Earlier work has shown that FoF can be a manifestation of executive dysfunction in adults over 50 years, but studies on people over age 75 years are lacking. Executive functions (EFs) are cognitive functions associated with the frontal lobes and the prefrontal cortex. The aim of this study was to assess associations of EFs and FoF among people aged 80 years or older.

Methods: This cross-sectional study was based on data from the Northern Sweden Silver-MONICA study and included 434 participants aged 80 years or older. EFs were assessed with the Frontal Assessment Battery (FAB) and FoF with the Falls Self-Efficacy Scale–International (FES-I). Multivariable linear regression analysis was used to examine associations among EF, FoF, and a comprehensive set of adjustment factors. Pearson correlation analysis was used to evaluate associations of FES-I and the subitems of the FAB.

Results: EFs as measured by FAB were inversely associated with FoF (β = -0.23; 95% confidence interval, -0.42 to -0.03; p = 0.021), even after comprehensive adjustments. The FAB subitems measuring lexical fluency, inhibitory control, sustained attention, self-organization, motor programming, and planning also were inversely associated with FoF.

Conclusions: Lower EF is associated with higher FoF among people aged 80 years or older. This information is important for treating and preventing FoF in this population.

Aim: Habitual physical activity (PA) affects metabolism and homeostasis in various tissues and organs. However, detailed knowledge of associations between PA and cardiovascular disease (CVD) risk markers is limited. We sought to identify associations between accelerometer-assessed PA classes and 183 proteomic and 154 metabolomic CVD-related biomarkers.

Method: We utilized cross-sectional data from the main SCAPIS cohort (n = 4647, median age: 57.5 yrs, 50.5% female) as a discovery sample and the SCAPIS pilot cohort (n = 910, median age: 57.5 yrs, 50.3% female) as a validation sample. PA was assessed via hip-worn accelerometers, while plasma concentrations of proteomic biomarkers were measured using Olink CVD II and III panels. Metabolomic markers were assessed using the Nightingale NMR platform. We evaluated associations between four PA classes (moderate-to-vigorous PA [MVPA], low-intensity PA [LIPA], sedentary [SED], and prolonged SED [prolSED]) and biomarkers, controlling for potential confounders and applying a false discovery rate of 5% using multiple linear regressions.

Results: A total of eighty-five metabolomic markers and forty-three proteomic markers were validated and found to be significantly associated with one or more PA classes. LIPA and SED markers demonstrated significant mirroring or opposing relations to biomarkers, while prolSED mainly shared relations with SED. Notably, HDL species were predominantly negatively associated with SED, whereas LDL species were positively associated with SED and negatively associated with MVPA. Among the proteomic markers, eighteen were uniquely associated with MVPA (among those Interleukin – 6 [IL6] and Growth/differentiation factor 15 [GDF15] both negatively related), seven with SED (among those Metalloproteinase inhibitor 4 [TIMP4] and Tumor necrosis factor receptor 2 [TNFR2], both positively related), and eight were related to both SED/prolSED (among those Lipoprotein lipase [LPL] negatively related to SED and leptin [LEP] positively related to SED) and MVPA (with LPL positively related to MVPA and LEP negatively related to MVPA).

Conclusion: Our findings suggest the existence of specific associations between PA classes and metabolomic and cardiovascular protein biomarkers in a middle-aged population. Beyond validation of previous results, we identified new associations. This multitude of connections between PA and CVD-related markers may help elucidate the previously observed relationship between PA and CVD. The identified cross-sectional associations could inform the design of future experimental studies, serving as important outcome measures.

Background: It has been hypothesized but seldom tested that the winter excess in cardiovascular disease (CVD) is related to hypovitaminosis D. The present study examined the association between CVD and (i) seasonality of 25-hydroxyvitamin D (25[OH]D) and (ii) individual 25(OH)D concentrations.

Methods and findings: Harmonized 25(OH)D data were obtained from the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project, including 79,570 participants examined between 1984 and 2010. One 25(OH)D measurement was available per participant. Primary endpoints were CVD incidence (coronary heart disease or stroke; n = 6006) and CVD mortality (n = 2985). To study (i), Poisson regression-derived rate ratios were compared according to two-month categories, ordered by baseline 25(OH)D concentrations. To study (ii), Cox regression-derived hazard ratios were compared according to quarters of baseline 25(OH)D concentrations. With respect to (i), despite a median 25(OH)D concentration ratio of 1:1.79, the trough months of 25(OH)D in March and April had a similar CVD incidence as the peak months of 25(OH)D in August and September (rate ratio: 1.07, 95% CI: 0.98–1.17). CVD mortality was slightly higher in the trough months compared to the peak months (rate ratio: 1.27, 95% CI: 1.12–1.44) but not compared to the other months (despite median 25[OH]D concentration ratios up to 1:1.62; p ≥ 0.077). The CVD mortality peak in January preceded the 25(OH)D trough, not adhering to the temporality criterion of Bradford Hill. With respect to (ii), compared to the lowest quarter, the highest quarter of 25(OH)D was associated with lower CVD incidence (hazard ratio: 0.82, 95% CI: 0.76–0.89) and CVD mortality (hazard ratio: 0.64, 95% CI: 0.57–0.72).

Conclusion: The present study does not support the hypothesis that seasonal increases in CVD are driven by short-term reductions in 25(OH)D. As in most observational studies, higher 25(OH)D concentrations were inversely associated with CVD.

Key features: 

• The Northern Sweden Health and Disease Study (NSHDS) was initiated in the mid-1980s. The NSHDS is a population-based prospective longitudinal cohort comprising >140 000 participants in the two northernmost regions in Sweden, Norrbotten and Västerbotten, with >240 000 blood samples and 1.5 million person-years of follow-up.
• The NSHDS includes three sub-cohorts: the Västerbotten Intervention Programme (VIP), the expanded Northern Sweden Monitoring of Trends and Determinants of Cardiovascular Disease (MONICA) Study, and the Mammography Screening Project (MSP). The VIP is both a community-based cardiometabolic intervention programme encouraging healthy lifestyle (targeting individuals 40, 50, and 60 years of age), and a corresponding research cohort. The MONICA is an observational study focusing on cardiovascular disease and its associated risk factors, recruiting individuals aged 25–74 years. The MSP recruited women attending mammography during 1995–2006. The NSHDS median participation age is 50 years (53% women).
• Most participants contribute data on health, lifestyle, anthropometric measures, blood pressure, blood lipids, and glucose tolerance, along with research blood samples that are fractionated, frozen within an hour of collection, and stored at –80°C. Linkage to registries, clinical cohorts, and biological tissue archives facilitates studies of well-characterized participants (often combined with intervention studies).
• Collaborations are encouraged. Additional information can be found at: info.brs@umu.se; https://www.umu.se/en/biobank

Background: In pulmonary arterial hypertension (PAH), comparative assessment of treatment effect on survival in randomized controlled settings of contemporary patients has not been feasible.

Objective: The aim of this study was to use EXPOSURE, the ongoing, real-world, post-authorization safety study, and commitment to the European Medicines Agency to perform pre-specified comparative survival analyses between patients that newly initiated selexipag versus other PAH-specific therapies by applying statistical methods to account for population differences.

Methods: EXPOSURE (EUPAS19085) is an observational study comprising patients with PAH who initiated selexipag or other PAH-specific therapy. To balance characteristics of patients in the other PAH therapy cohort with the selexipag cohort at PAH therapy initiation (baseline), propensity score weighting was applied. Mortality rate ratios (MRRs) were calculated.

Results: 2014 patients were available for analysis. Prior to applying propensity score weighting, patients in the selexipag cohort were more likely to have longer time from diagnosis, less functional impairment, and treatment with combination background therapy versus the other PAH therapy cohort. Following weighting, baseline variables for both cohorts were well balanced. Weighted treatment exposure was 827.9 and 840.5 person-years for the selexipag and modelled other PAH therapy cohort, respectively. Weighted proportion of deaths was lower in the selexipag versus modelled other PAH therapy cohort; MRR showed a higher survival rate for selexipag-treated patients (MRR [95% confidence interval]: 0.55 [0.31–0.99]).

Conclusions: Survival analyses in EXPOSURE suggest a reduced risk of mortality among the cohort of patients newly initiated on selexipag compared with the modelled cohort newly initiated with other PAH-specific therapies. Further research is needed to confirm this observation.

Trial Registry: Trial registration: EUPAS19085.

Background: General adiposity, assessed by body mass index (BMI), is a well-established cancer risk factor. This study compared waist circumference (WC), a measure of abdominal adiposity, with BMI as a risk factor for obesity-related cancers, and assessed whether WC provides additional information beyond BMI.

Methods: We analyzed data from 339 190 individuals in a pooled Swedish cohort with baseline BMI and WC assessments from 1981 to 2019 (61% objectively measured, mean age 51.4 years). Cancer diagnoses were obtained from the Swedish Cancer Register. Hazard ratios (HRs) for WC and BMI were calculated using multivariable-adjusted Cox regression. To account for WC's greater variability, we corrected HRs using regression dilution ratios. To assess WC's additional contribution beyond BMI, we analyzed WC residuals in multivariable, BMI-adjusted models.

Results: During a median follow-up of 13.9 years (interquartile range: 8.0-22.5), 18 185 IARC-established obesity-related cancers were recorded. In men, a 1-standard deviation (SD) increase in WC was associated with a 25% higher risk of obesity-related cancers (HR1-SD = 1.25, 95% CI = 1.21 to 1.30), compared to a 19% increase for BMI (HR1-SD = 1.19, 95% CI = 1.15 to 1.23, P = 0.014 for heterogeneity). Among women, associations were weaker and similar for both WC (HR1-SD = 1.13, 95% CI = 1.11 to 1.16) and BMI (HR1-SD = 1.13, 95% CI = 1.11 to 1.15, P = 0.357 for heterogeneity). Waist circumference residuals were more strongly associated with obesity-related cancer risk in men (HR1-SD = 1.09, 95% CI = 1.06 to 1.12) than in women (HR1-SD = 1.03, 95% CI = 1.02 to 1.05). Including an additional 6893 potential obesity-related cancers yielded similar patterns of associations.

Conclusion(s): Waist circumference is a stronger risk factor than BMI for obesity-related cancer in men, conveying additional risk information, whereas this is less evident in women.

Objectives: This study aimed to assess the relationship between dietary intake and disease outcomes in patients with radiographic axial spondyloarthritis (r-axSpA), focusing on inflammation and disease activity, while also evaluating other health outcomes, and to compare dietary intake between patients and controls.

Method: In a cross-sectional analysis, we studied 295 patients with r-axSpA (modified New York criteria for ankylosing spondylitis) in northern and south-western Sweden. Of these, 155 were of similar age to controls (50–64 years) from the Swedish CArdioPulmonary bioImage Study (SCAPIS) and were matched on sex, age, and geographical location to 604 controls. Dietary intake was evaluated using the MiniMealQ food frequency questionnaire. Differences in dietary intake between patients and controls were assessed in conditional logistic regression models. Nutrients with significant group differences were examined in patients (n = 295) by regression models for the outcomes Ankylosing Spondylitis Disease Activity Score with C-reactive protein (CRP) (ASDAS) and CRP.

Results: Patients had a lower dietary fibre density, as well as lower intake of marine omega-3 fatty acids, calcium, folate, iodine, phosphorus, potassium, selenium, vitamins A, C, and K, β-carotene, and alcohol. Low intake of marine omega-3 fatty acids was associated with a higher ASDAS, and a lower dietary fibre density was associated with elevated CRP.

Conclusions: Patients with r-axSpA report lower dietary quality compared with controls. Dietary intake is related to disease activity and inflammation. Further exploration of metabolic biomarkers and disease outcomes is warranted, and the impact of a health-promoting dietary intervention should be assessed.