Five-Year Outcomes of the Danish Cardiovascular Screening (DANCAVAS) Trial.

BACKGROUND: Limited data suggest a benefit of population-based screening for cardiovascular disease with respect to the risk of death. METHODS: We performed a population-based, parallel-group, randomized, controlled trial involving men 65 to 74 years of age living in 15 Danish municipalities. The participants were randomly assigned in a 1:2 ratio to undergo screening (the invited group) or not to undergo screening (the control group) for subclinical cardiovascular disease. Randomization was based on computer-generated random numbers and stratified according to municipality. Only the control group was unaware of the trial-group assignments. Screening included noncontrast electrocardiography-gated computed tomography to determine the coronary-artery calcium score and to detect aneurysms and atrial fibrillation, ankle-brachial blood-pressure measurements to detect peripheral artery disease and hypertension, and a blood sample to detect diabetes mellitus and hypercholesterolemia. The primary outcome was death from any cause. RESULTS: A total of 46,611 participants underwent randomization. After exclusion of 85 men who had died or emigrated before being invited to undergo screening, there were 16,736 men in the invited group and 29,790 men in the control group; 10,471 of the men in the invited group underwent screening (62.6%). In intention-to-treat analyses, after a median follow-up of 5.6 years, 2106 men (12.6%) in the invited group and 3915 men (13.1%) in the control group had died (hazard ratio, 0.95; 95% confidence interval [CI], 0.90 to 1.00; P = 0.06). The hazard ratio for stroke in the invited group, as compared with the control group, was 0.93 (95% CI, 0.86 to 0.99); for myocardial infarction, 0.91 (95% CI, 0.81 to 1.03); for aortic dissection, 0.95 (95% CI, 0.61 to 1.49); and for aortic rupture, 0.81 (95% CI, 0.49 to 1.35). There were no significant between-group differences in safety outcomes. CONCLUSIONS: After more than 5 years, the invitation to undergo comprehensive cardiovascular screening did not significantly reduce the incidence of death from any cause among men 65 to 74 years of age. (Funded by the Southern Region of Denmark and others; DANCAVAS ISRCTN Registry number, ISRCTN12157806.).

User-defined outcomes of the Danish cardiovascular screening (DANCAVAS) trial: A post hoc analyses of a population-based, randomised controlled trial.

BACKGROUND: The Danish cardiovascular screening (DANCAVAS) trial, a nationwide trial designed to investigate the impact of cardiovascular screening in men, did not decrease all-cause mortality, an outcome decided by the investigators. However, the target group may have varied preferences. In this study, we aimed to evaluate whether men aged 65 to 74 years requested a CT-based cardiovascular screening examination and to assess its impact on outcomes determined by their preferences. METHODS AND FINDINGS: This is a post hoc study of the randomised DANCAVAS trial. All men 65 to 74 years of age residing in specific areas of Denmark were randomised (1:2) to invitation-to-screening (16,736 men, of which 10,471 underwent screening) or usual-care (29,790 men). The examination included among others a non-contrast CT scan (to assess the coronary artery calcium score and aortic aneurysms). Positive findings prompted preventive treatment with atorvastatin, aspirin, and surveillance/surgical evaluation. The usual-care group remained unaware of the trial and the assignments. The user-defined outcome was based on patient preferences and determined through a survey sent in January 2023 to a random sample of 9,095 men from the target group, with a 68.0% response rate (6,182 respondents). Safety outcomes included severe bleeding and mortality within 30 days after cardiovascular surgery. Analyses were performed on an intention-to-screen basis. Prevention of stroke and myocardial infarction was the primary motivation for participating in the screening examination. After a median follow-up of 6.4 years, 1,800 of 16,736 men (10.8%) in the invited-to-screening group and 3,420 of 29,790 (11.5%) in the usual-care group experienced an event (hazard ratio (HR), 0.93 (95% confidence interval (CI), 0.88 to 0.98; p = 0.010); number needed to invite at 6 years, 148 (95% CI, 80 to 986)). A total of 324 men (1.9%) in the invited-to-screening group and 491 (1.7%) in the usual-care group had an intracranial bleeding (HR, 1.17; 95% CI, 1.02 to 1.35; p = 0.029). Additionally, 994 (5.9%) in the invited-to-screening group and 1,722 (5.8%) in the usual-care group experienced severe gastrointestinal bleeding (HR, 1.02; 95% CI, 0.95 to 1.11; p = 0.583). No differences were found in mortality after cardiovascular surgery. The primary limitation of the study is that exclusive enrolment of men aged 65 to 74 renders the findings non-generalisable to women or men of other age groups. CONCLUSION: In this comprehensive population-based cardiovascular screening and intervention program, we observed a reduction in the user-defined outcome, stroke and myocardial infarction, but entail a small increased risk of intracranial bleeding. TRIAL REGISTRATION: ISRCTN Registry number, ISRCTN12157806 https://www.isrctn.com/ISRCTN12157806.

Exploring Drug Re-Purposing for Treatment of Abdominal Aortic Aneurysms: a Systematic Review and Meta-analysis.

OBJECTIVE: Large abdominal aortic aneurysms (AAAs) present a significant mortality risk. While numerous medical interventions have been proposed, no drugs have convincingly reduced AAA progression, rupture rates, or repair risk. This systematic review and meta-analysis aimed to assess the impact of re-purposed drugs or dietary supplements on slowing expansion rates, reducing the risk of rupture, or minimising the risk of repair for individuals with AAA. METHODS: A systematic search was conducted in five databases. Both observational studies and randomised controlled trials were included. Unpublished data from two screening trials were incorporated. Risk of bias was assessed using the Newcastle-Ottawa scale and revised Cochrane risk of bias tool. Meta-analyses were performed for each identified drug subclass and were stratified by overall risk of bias. Results were reported following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Of 7 484 screened studies, 39 met the inclusion criteria. No studies on dietary supplements were included. A total of 84 cohorts were derived from the included studies, and twelve distinct drug groups underwent meta-analyses. Two drug groups, metformin and statins, were statistically significant in slowing AAA growth. No low risk of bias studies were included for these two drug groups, and the results had very high heterogeneity (I2 > 80%). Both groups had a GRADE certainty of very low. Metformin, excluding high risk of bias studies, presented an estimated mean growth difference of AAA diameter between users and non-users of -0.73 mm/year, whilst statins had an overall estimated mean difference of -0.84 mm/year. CONCLUSION: This systematic review and meta-analysis suggests that metformin and statins may provide some effect in slowing AAA progression. However, no definitive evidence was found for any of the investigated drugs included in this study. Further research is needed to identify effective medical treatments for AAA progression with more robust methodology.

Statistical Analysis Plan for the AIRCARD Study: Individual Long-term Air and Noise Pollution Exposure and Cardiovascular Disease Incidence and Mortality (AIRCARD): A Prospective Cohort Study Utilizing DANCAVAS and VIVA Screening Trials.

INTRODUCTION: The AIRCARD study is designed to investigate the relationship between long-term exposure to air and noise pollution and cardiovascular disease incidence and mortality. We aim to conduct a robust prospective cohort analysis assessing the cumulative and differential impacts of air and noise pollution exposure on cardiovascular disease and mortality. This study will adjust for relevant confounders, including traditional cardiovascular risk factors, socioeconomic indicators, and lipid-lowering agents. METHODS: This prospective cohort study will include 27,022 male participants aged 65-74, recruited from the two large Danish DANCAVAS and VIVA trials, both population-based randomized, multicentered, clinically controlled studies. We will assess long-term exposure to air pollutants using the state-of-the-art DEHM/UBM/AirGIS modelling system and noise pollution through the Nord2000 and SoundPLAN models, covering data from 1979 to 2019. This statistical analysis plan is strictly formulated to predefine the analytical approach for all outcomes and key study variables before data access. The primary analysis will utilize Cox proportional hazards models, adjusted for confounders identified in our cohort (age, body mass index, hypertension, diabetes, smoking status, family history of heart disease, socioeconomic factors, and lipid-lowering agents). This statistical analysis plan further includes Spearman rank correlation to explore inter-pollutant associations. CONCLUSION: The AIRCARD study addresses global concerns about the impact of air and noise pollution on cardiovascular disease. This research is important for understanding how the pollutants contribute to cardiovascular disease. We aim to provide insights into this area, emphasizing the need for public health measures to mitigate pollution exposure. Our goal is to provide policymakers and healthcare professionals with information on the role of environmental factors in cardiovascular health that could influence global strategies to reduce the cardiovascular disease burden associated with pollution. The design of this SAP ensures transparency and.

Cationic proteins from eosinophils bind bone morphogenetic protein receptors promoting vascular calcification and atherogenesis.

AIMS: Blood eosinophil count and eosinophil cationic protein (ECP) concentration are risk factors of cardiovascular diseases. This study tested whether and how eosinophils and ECP contribute to vascular calcification and atherogenesis. METHODS AND RESULTS: Immunostaining revealed eosinophil accumulation in human and mouse atherosclerotic lesions. Eosinophil deficiency in ΔdblGATA mice slowed atherogenesis with increased lesion smooth muscle cell (SMC) content and reduced calcification. This protection in ΔdblGATA mice was muted when mice received donor eosinophils from wild-type (WT), Il4-/-, and Il13-/- mice or mouse eosinophil-associated-ribonuclease-1 (mEar1), a murine homologue of ECP. Eosinophils or mEar1 but not interleukin (IL) 4 or IL13 increased the calcification of SMC from WT mice but not those from Runt-related transcription factor-2 (Runx2) knockout mice. Immunoblot analyses showed that eosinophils and mEar1 activated Smad-1/5/8 but did not affect Smad-2/3 activation or expression of bone morphogenetic protein receptors (BMPR-1A/1B/2) or transforming growth factor (TGF)-ß receptors (TGFBR1/2) in SMC from WT and Runx2 knockout mice. Immunoprecipitation showed that mEar1 formed immune complexes with BMPR-1A/1B but not TGFBR1/2. Immunofluorescence double-staining, ligand binding, and Scatchard plot analysis demonstrated that mEar1 bound to BMPR-1A and BMPR-1B with similar affinity. Likewise, human ECP and eosinophil-derived neurotoxin (EDN) also bound to BMPR-1A/1B on human vascular SMC and promoted SMC osteogenic differentiation. In a cohort of 5864 men from the Danish Cardiovascular Screening trial and its subpopulation of 394 participants, blood eosinophil counts and ECP levels correlated with the calcification scores of different arterial segments from coronary arteries to iliac arteries. CONCLUSION: Eosinophils release cationic proteins that can promote SMC calcification and atherogenesis using the BMPR-1A/1B-Smad-1/5/8-Runx2 signalling pathway.

Clinical Characteristics, Incidences, and Mortality Rates for Type A and B Aortic Dissections: A Nationwide Danish Population-Based Cohort Study From 1996 to 2016.

BACKGROUND: Population-based epidemiologic studies of aortic dissections (ADs) are needed. This study aimed to report clinical characteristics, incidences, and mortality rates for adult patients admitted to Danish hospitals with type A AD (TAAD) or type B AD (TBAD) from 1996 through 2016. METHODS: We conducted a nationwide, population-based register study. All cases of AD registered with International Classification of Diseases, Tenth Revision codes in the Danish National Patient Registry at time of admission to a hospital with available medical records underwent validation. Data were merged between nationwide health registries including the cause of death registry. Patients with validated AD were matched 1:10 on sex and age with patients with hypertension from the general Danish population. RESULTS: Of 5018 registered cases of AD, 4183 cases underwent review and 3023 (60.2%) were validated as AD. After exclusions, the distribution of validated TAAD and TBAD was 1620 (60.5%) and 1059 (39.5%; P<0.001), 67.5% and 67.0% of patients were men, and mean ages at dissection were 63.5±12.9 and 67.5±12.2 years (P<0.001), respectively. The most prevalent comorbidities for TAAD were hypertension (55.2%), thoracic aortic aneurysms (14.6%), and chronic obstructive pulmonary disease (13.1%); for TBAD, the most prevalent comorbidities were hypertension (64.1%), aortic aneurysms at any location (7.5% to 12.0%), and chronic obstructive pulmonary disease (15.7%). The overall mean annual incidence rate was 4.2/100 000 patient-years. Incidence was significantly higher for TAAD (2.2/100 000) compared with TBAD (1.5/100 000; P<0.001). The 30-day mortality rates for validated TAAD and TBAD were 22.0% and 13.9% (P<0.001), respectively, with no significant changes over time or between sexes. Adjusted 5-year overall mortality rates for TAAD and TBAD were hazard ratio 3.2 (2.9 to 3.5; P<0.001; aortic-related cause of death, 57.0%) and hazard ratio 2.1 (1.9 to 2.4; P<0.001; aortic-related cause of death, 42.8%), respectively, compared with the general hypertensive population. Among patients who survived 30 days from dissection, the adjusted 5-year overall mortality rates were hazard ratio 1.1 (1.0 to 1.3; P=0.12; aortic-related cause of death, 23.2%) and hazard ratio 1.4 (1.2 to 1.6; P<0.001; aortic-related cause of death, 25.6%) for TAAD and TBAD, respectively. CONCLUSIONS: Hypertension, aortic aneurysms, and chronic obstructive pulmonary disease were the most prevalent comorbidities. The 30-day mortality frequencies were consistent over time with no significant differences between sexes. The 5-year mortality rate was higher for TAAD than TBAD. If the patient survived 30 days from dissection, the mortality rate for patients with TAAD was comparable with that of the general hypertensive population, but the mortality rate was significantly higher in patients with TBAD.

Vitamin K2 and D in Patients With Aortic Valve Calcification: A Randomized Double-Blinded Clinical Trial.

BACKGROUND: Menaquinone-7 (MK-7), also known as vitamin K2, is a cofactor for the carboxylation of proteins involved in the inhibition of arterial calcification and has been suggested to reduce the progression rate of aortic valve calcification (AVC) in patients with aortic stenosis. METHODS: In a randomized, double-blind, multicenter trial, men from the community with an AVC score >300 arbitrary units (AU) on cardiac noncontrast computer tomography were randomized to daily treatment with tablet 720 µg MK-7 plus 25 µg vitamin D or matching placebo for 24 months. The primary outcome was the change in AVC score. Selected secondary outcomes included change in aortic valve area and peak aortic jet velocity on echocardiography, heart valve surgery, change in aortic and coronary artery calcification, and change in dp-ucMGP (dephosphorylated-undercarboxylated matrix Gla-protein). Safety outcomes included all-cause death and cardiovascular events. RESULTS: From February 1, 2018, to March 21, 2019, 365 men were randomized. Mean age was 71.0 (±4.4) years. The mean (95% CI) increase in AVC score was 275 AU (95% CI, 225-326 AU) and 292 AU (95% CI, 246-338 AU) in the intervention and placebo groups, respectively. The mean difference on AVC progression was 17 AU (95% CI, -86 to 53 AU; P=0.64). The mean change in aortic valve area was 0.02 cm2 (95% CI, -0.09 to 0.12 cm2; P=0.78) and in peak aortic jet velocity was 0.04 m/s (95% CI, -0.11 to 0.02 m/s; P=0.21). The progression in aortic and coronary artery calcification score was not significantly different between patients treated with MK-7 plus vitamin D and patients receiving placebo. There was no difference in the rate of heart valve surgery (1 versus 2 patients; P=0.99), all-cause death (1 versus 4 patients; P=0.37), or cardiovascular events (10 versus 10 patients; P=0.99). Compared with patients in the placebo arm, a significant reduction in dp-ucMGP was observed with MK-7 plus vitamin D (-212 pmol/L versus 45 pmol/L; P<0.001). CONCLUSIONS: In elderly men with an AVC score >300 AU, 2 years MK-7 plus vitamin D supplementation did not influence AVC progression. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03243890.

Eosinophils Protect Mice From Angiotensin-II Perfusion-Induced Abdominal Aortic Aneurysm.

RATIONALE: Blood eosinophil count and ECP (eosinophil cationic protein) associate with human cardiovascular diseases. Yet, whether eosinophils play a role in cardiovascular disease remains untested. The current study detected eosinophil accumulation in human and murine abdominal aortic aneurysm (AAA) lesions, suggesting eosinophil participation in this aortic disease. OBJECTIVE: To test whether and how eosinophils affect AAA growth. METHODS AND RESULTS: Population-based randomized clinically controlled screening trials revealed higher blood eosinophil count in 579 male patients with AAA than in 5063 non-AAA control (0.236±0.182 versus 0.211±0.154, 109/L, P<0.001). Univariate (odds ratio, 1.381, P<0.001) and multivariate (odds ratio, 1.237, P=0.031) logistic regression analyses indicated that increased blood eosinophil count in patients with AAA served as an independent risk factor of human AAA. Immunostaining and immunoblot analyses detected eosinophil accumulation and eosinophil cationic protein expression in human and murine AAA lesions. Results showed that eosinophil deficiency exacerbated AAA growth with increased lesion inflammatory cell contents, matrix-degrading protease activity, angiogenesis, cell proliferation and apoptosis, and smooth muscle cell loss using angiotensin-II perfusion-induced AAA in Apoe-/- and eosinophil-deficient Apoe-/-ΔdblGATA mice. Eosinophil deficiency increased lesion chemokine expression, muted lesion expression of IL (interleukin) 4 and eosinophil-associated-ribonuclease-1 (mEar1 [mouse EOS-associated-ribonuclease-1], human ECP homolog), and slanted M1 macrophage polarization. In cultured macrophages and monocytes, eosinophil-derived IL4 and mEar1 polarized M2 macrophages, suppressed CD11b+Ly6Chi monocytes, and increased CD11b+Ly6Clo monocytes. mEar1 treatment or adoptive transfer of eosinophil from wild-type and Il13-/- mice, but not eosinophil from Il4-/- mice, blocked AAA growth in Apoe-/-ΔdblGATA mice. Immunofluorescent staining and immunoblot analyses demonstrated a role for eosinophil IL4 and mEar1 in blocking NF-κB (nuclear factor-κB) activation in macrophages, smooth muscle cells, and endothelial cells. CONCLUSIONS: Eosinophils play a protective role in AAA by releasing IL4 and cationic proteins such as mEar1 to regulate macrophage and monocyte polarization and to block NF-κB activation in aortic inflammatory and vascular cells.

Relevance of the Viborg Population Based Screening Programme (VISP) for Cardiovascular Conditions Among 67 Year Olds: Attendance Rate, Prevalence, and Proportion of Initiated Cardiovascular Medicines Stratified By Sex.

OBJECTIVE: To report sex specific overall attendance rate, prevalence of screen detected cardiovascular conditions, proportion of unknown conditions before screening, and proportion initiating prophylactic medicine among 67 year olds in Denmark. DESIGN: Cross sectional cohort study. METHODS: Since 2014, all 67 year olds in Viborg, Denmark, have been invited to screening for abdominal aortic aneurysm (AAA), peripheral arterial disease (PAD), carotid plaque (CP), hypertension, cardiac disease, and type 2 diabetes. Individuals with AAA, PAD, and or CP are recommended cardiovascular prophylaxis. Combining data with registries has facilitated estimation of unknown screen detected conditions. Up to August 2019, 5 505 had been invited; registry data were available for the first 4 826 who were invited. RESULTS: The attendance rate was 83.7%, without sex difference. Screen detected prevalence was significantly lower among women than men: AAA, 5 (0.3%) vs. 38 (1.9%) (p < .001); PAD, 90 (4.5%) vs. 134 (6.6%) (p = .011); CP, 641 (31.8%) vs. 907 (44.8%) (p < .001); arrhythmia, 26 (1.4%) vs. 77 (4.2%) (p < .001); blood pressure ≥ 160/100 mmHg, 277 (13.8%) vs. 346 (17.1%) (p = .004); and HbA1c ≥ 48 mmol/mol, 155 (7.7%) vs. 198 (9.8%) (p = .019), respectively. Pre-screening proportions of unknown conditions were particularly high for AAA (95.4%) and PAD (87.5%). AAA, PAD, and or CP were found in 1 623 (40.2%), of whom 470 (29.0%) received pre-screening antiplatelets and 743 (45.8%) lipid lowering therapy. Furthermore, 413 (25.5%) started antiplatelet therapy and 347 (21.4%) started lipid lowering therapy. Only smoking was significantly associated with all vascular conditions in multivariable analysis: odds ratios (ORs) for current smoking were AAA 8.11 (95% CI 2.27 - 28.97), PAD 5.60 (95% CI 3.61 - 8.67) and CP 3.64 (95% CI 2.95 - 4.47). CONCLUSION: The attendance rate signals public acceptability for attending cardiovascular screening. Men had more screen detected conditions than women, but prophylactic medicine was started equally frequently in both sexes. Sex specific cost effectiveness follow up is warranted.

The association between diabetes and abdominal aortic aneurysms in men: results of two Danish screening studies, a systematic review, and a meta-analysis of population-based screening studies.

BACKGROUND: A paradoxical protective effect of diabetes on the development and progression of abdominal aortic aneurysms (AAA) has been known for years. This study aimed to investigate whether the protective role of diabetes on AAAs has evolved over the years. METHODS: A cross-sectional study, a systematic review and meta-analysis. This study was based on two large, population-based, randomised screening trials of men aged 65-74; VIVA (2008-2011) and DANCAVAS (2014-2018), including measurement of the abdominal aorta by ultrasound or CT, respectively. Analyses were performed using multiple logistic regressions to estimate the odds ratios (ORs) for AAAs in men with diabetes compared to those not having diabetes. Moreover, a systematic review and meta-analysis of population-based screening studies of AAAs to visualise a potential change of the association between diabetes and AAAs. Studies reporting only on women or Asian populations were excluded. RESULTS: In VIVA, the prevalence of AAA was 3.3%, crude OR for AAA in men with diabetes 1.04 (95% confidence interval, CI, 0.80-1.34), and adjusted OR 0.64 (CI 0.48-0.84). In DANCAVAS, the prevalence of AAA was 4.2%, crude OR 1.44 (CI 1.11-1.87), and adjusted OR 0.78 (CI 0.59-1.04). Twenty-three studies were identified for the meta-analysis (N = 224 766). The overall crude OR was 0.90 (CI 0.77-1.05) before 2000 and 1.16 (CI 1.03-1.30) after 1999. The overall adjusted OR was 0.63 (CI 0.59-0.69) before 2000 and 0.69 (CI 0.57-0.84) after 1999. CONCLUSION: Both the crude and adjusted OR showed a statistically non-significant trend towards an increased risk of AAA by the presence of diabetes. If this represents an actual trend, it could be due to a change in the diabetes population. TRIAL REGISTRATION: DANCAVAS: Current Controlled Trials: ISRCTN12157806. VIVA: ClinicalTrials.gov NCT00662480.

Gender-specific Predicted Normal Aortic Size and Its Consequences of the Population-Based Prevalence of Abdominal Aortic Aneurysms.

BACKGROUND: To investigate if a relative-size-index of the abdominal aortic diameter influences the prevalence estimates of abdominal aortic dilatations compared to absolute diameters. METHODS: Cross-sectional study. Participants from the Viborg Vascular Screening Trial, Viborg Women Cohort, and the Viborg Screening Program. Through multivariate linear regression analyses, 2 gender-specific prediction-equations were developed based upon body-surface area and age. The definitions of absolute and relative size of aortic ectasies were 25-29 mm and 1.25-1.49× individual-predicted size (IPS), abdominal aortic aneurysm (AAA) 30 mm and 1.5× IPS, and large repair-recommendable AAA ≥55 mm or ≥ 2.75× IPS, respectively. RESULTS: Nineteen thousand two hundred and sixty nine males (69.6 years) and 2,426 females (67.1 years) attended the population- and ultrasound-based screening studies for AAA. The mean peak systolic abdominal anterior-posterior inner to inner diameter was 19.1 mm (±5.3 mm) and 16.6 mm (±2.8 mm) (P < 0.001) in males and females, respectively. Body surface area showed the strongest correlation with aortic diameters in both males (r = 0.19, P < 0.001) and females (r = 0.17, P < 0.001). Age correlated significantly with size, but only in males (r = 0.03, P < 0.001). The prevalence in men of absolute size-defined and relative size index-defined screening-detected aortic ectasies, AAAs and repair-recommendable AAAs were: 5.9% and 9.5% (P < 0.001), 3.3% and 4.2% (P < 0.001) and 9.9% and 15.2% (P = 0.004), respectively. Prevalence in females of absolute-size-defined and relative-size-index-defined screening-detected aortic ectasies, AAAs and repair-recommendable AAAs were 1.2% and 5.8% (P < 0.001), 0.5% and 1.3% (P = 0.003) and 0.0% and 23.1% (P = 0.553), respectively. CONCLUSIONS: Despite statistical differences, ultrasound-based absolute diameters to detect AAA seem acceptable in men. In females, poor agreements were noticed concerning all 3 categories of aneurysms, indicating that the current absolute diagnostic cut-points do not reflect female anatomy.

Arabic-speaking male immigrants' perceptions of preventive initiatives: An interview study.

BACKGROUND: Arabic-speaking men are a sparsely investigated population in health promotion and disease prevention. This may hamper their ability to achieve the highest obtainable health due to less accessibility and acceptability of preventive measures. AIM: We explored Arabic-speaking (Palestinian, Iraqi and Somali) male immigrants' perceptions of preventive initiatives in general and such initiatives for cardiovascular diseases (CVD) in particular to understand how to address inequalities in engagement in prevention. METHODS: This qualitative study employed content analysis of semistructured interviews with 60-66-year-old Arabic-speaking men living in Denmark. Supplementary, structured data, for example, health data, were collected. From June to August 2020, 10 men were interviewed. FINDINGS: Preventive initiatives were found ethically and culturally acceptable alongside personally and socially relevant; they were perceived as humanitarian and caring for the participants' health, respecting of their self-determination and enabling their empowerment. Thus, the participants entreated that their fellow countrymen be assisted in achieving the prerequisite coping capabilities to address inequality in access, perceived acceptance and relevance. This led us to define one main category 'Preventive initiatives - Caring and humanitarian aid empower us' with the underlying subcategories: 'We are both hampered and strengthened by our basic assumptions' and 'We need help to achieve coping capabilities enabling us to engage in preventive initiatives'. CONCLUSION: Prevention was perceived as acceptable and relevant. Even so, Arabic-speaking men may be a hard-to-reach group due to their basic assumptions and impaired capabilities for engaging in prevention. Addressing inequality in accessibility, acceptability and relevance in regard to prevention may be promoted through a person-centred approach embracing invitees' preferences, needs and values; and by strengthening invitees' health literacy through efforts at the structural, health professional and individual levels. PUBLIC CONTRIBUTION: This study was based on interviews. The interviewees were recruited as public representatives to assist us in building an understanding of Arabic-speaking male immigrants' perceptions of preventive initiatives in general and preventive initiatives for CVD in particular.

Cost effectiveness of population screening vs. no screening for cardiovascular disease: the Danish Cardiovascular Screening trial (DANCAVAS).

AIMS: A recent trial has shown that screening of men for cardiovascular disease (CVD) may reduce all-cause mortality. This study assesses the cost effectiveness of such screening vs. no screening from the perspective of European healthcare systems. METHODS AND RESULTS: Randomized controlled trial-based cost-effectiveness evaluation with a mean 5.7 years of follow-up. Screening was based on low-dose computed tomography to detect coronary artery calcification and aortic/iliac aneurysms, limb blood pressure measurement to detect peripheral artery disease and hypertension, telemetric assessment of the heart rhythm to detect atrial fibrillation, and measurements of the cholesterol and HgbA1c levels. Censoring-adjusted incremental costs, life years (LY), and quality-adjusted LY (QALY) were estimated and used for cost-effectiveness analysis. The incremental cost of screening for the entire health care sector was €207 [95% confidence interval (CI) -24; 438, P = 0.078] per invitee for which gains of 0.019 LY (95% CI -0.007; 0.045, P = 0.145) and 0.023 QALY (95% CI -0.001; 0.046, P = 0.051) were achieved. The corresponding incremental cost-effectiveness ratios were of €10 812 per LY and €9075 per QALY, which would be cost effective at probabilities of 0.73 and 0.83 for a willingness to pay of €20 000. Assessment of population heterogeneity showed that cost effectiveness could be more attractive for younger men without CVD at baseline. CONCLUSIONS: Comprehensive screening for CVD is overall cost effective at conventional thresholds for willingness to pay and also competitive to the cost effectiveness of common cancer screening programmes. The screening target group, however, needs to be settled.

Geographical Variation in the Management of Peripheral Arterial Occlusive Disease: A Nationwide Danish Cohort Study.

OBJECTIVE: Equal access for equal needs is a key goal for many healthcare systems but geographical variation research has shown that this is often not the case in areas other than vascular surgery. This study assessed the variation across specialised vascular centres of an entire healthcare system in the costs and outcomes for patients having first time revascularisation for peripheral arterial occlusive disease. METHODS: This was a national study of all first time revascularisations performed in the Danish healthcare system between 2009 and 2014. Episodes were identified in the Danish Vascular Registry (n = 10 300) and data on one year follow up in terms of the costs of specialised healthcare (€) and amputation status were acquired from national registers. Generalised gamma and logit regressions were used to predict margins between centres while adjusting for population heterogeneity (age, sex, education, smoking, hypertension, diabetes, use of prophylactic pharmacological therapy, indication and type of revascularisation). Cost effectiveness frontiers were used to identify efficient providers and to illustrate the cost of reducing the system level risk of amputation. RESULTS: For each of the indications of chronic limb threatening and acute limb ischaemia, the one year amputation risks varied from 11% to 16% across centres (p = .003, p = .006) whereas for intermittent claudication there was no significant difference across centres. The corresponding costs of care varied across centres for all indications (p = .027, p = .028, p = .030). Linking costs and outcomes, three of seven centres were observed to provide poorer quality at higher costs. Exponentially increasing costs to obtain the maximum reduction of the amputation risk were observed. CONCLUSION: The results suggest that there is substantial variation in the clinical management of peripheral arterial occlusive disease across the Danish healthcare system and that this results in very different levels of efficiency - on top of potentially unequal treatment for equal needs. Further research is warranted.

Combined Immunoglobulin Free Light Chains Are Novel Predictors of Cardiovascular Events in Patients With Abdominal Aortic Aneurysm.

OBJECTIVE: Abdominal aortic aneurysm (AAA) is characterised by the presence of B cells and immunoglobulins in the aortic wall, mainly in the adventitia. Kappa (κ) and lambda (λ) free light chains (FLCs) are produced from B cells during immunoglobulin synthesis. This study investigated the presence and prognostic value of combined FLCs (cFLCs or summed κ and λ) in patients with AAA. METHODS: cFLCs were analysed by a turbidimetric specific assay in tissue conditioned media from AAA samples (n = 34) compared with healthy aortas (n = 34) from France and in plasma samples from patients with AAA (n = 434) and age matched controls (n = 104) selected from the Viborg Vascular (VIVA) AAA screening trial in Denmark. t test, logistic regression, and Cox regression were used to test whether plasma cFLCs serve as a marker for AAA presence and whether cFLCs were predictive of death, major adverse cardiovascular events (MACE), or major adverse lower limb events (MALE). RESULTS: Increased cFLC levels were detected in the AAA adventitial layer compared with the AAA medial layer and healthy media layer (13.65 ± 3.17 vs. 6.57 ± 1.01 vs. 0.49 ± 0.09 mg/L, respectively, p < .050). The upper tertile of plasma cFLCs was independently associated with AAA presence after correcting for confounders (odds ratio [OR] 7.596, 95% confidence intervals [CI] 3.117 - 18.513; p < .001). Of 434 patients with AAA, 89 (20.5%) died, 104 (24.0%) suffered MACE, and 63 (14.5%) suffered MALE, during a five year follow up. In univariable analysis, the cFLC upper tertile was associated with a higher risk of death, MACE, and MALE (p < .001 for all). After adjustment for confounders, cFLCs remained an independent predictor of all cause mortality (hazard ratio [HR] 4.310, 95% CI 2.157 - 8.609; p < .001), MACE (HR 2.153, 95% CI 1.218 - 3.804; p = .008), or MALE (HR 3.442, 95% CI 1.548 - 7.652; p = .002) for those in the upper tertile. CONCLUSION: Increased cFLCs are observed in adventitial tissue of patients with AAA, indicating local activation of B cells. Plasma cFLC levels are an independent predictor of death, MACE, and MALE in patients with AAA.

Lipocalin-2 and Calprotectin Potential Prognosis Biomarkers in Peripheral Arterial Disease.

OBJECTIVE: Peripheral arterial disease (PAD) is the most prevalent cardiovascular (CV) condition globally. Despite the high CV risk of PAD patients, no reliable predictors of adverse clinical evolution are yet available. In this regard, previous transcriptomic analyses revealed increased expression of calprotectin (S100A8/A9) and lipocalin-2 (LCN2) in circulating extracellular vesicles (EVs) of patients with PAD. The aim of this study was to determine the prognostic value of LCN2 and calprotectin for CV risk assessment in PAD. METHODS: LCN2 and the S100A9 subunit of calprotectin were examined in human femoral plaques by immunohistochemistry and qPCR. LCN2 and calprotectin were determined by ELISA in PAD (CHN cohort, n = 331, Fontaine II-IV, serum), and PAD diagnosed by population based screening (VIVA trial, n = 413, the majority Fontaine 0-I, plasma). Patients were followed up for a mean of four years, recording the primary outcomes; CV death or amputation in the CHN cohort and CV death or major lower limb events (MALE) in the VIVA population. Secondary outcomes were all cause death or amputation, and all cause death or MALE, respectively. RESULTS: LCN2 and S100A9 were detected in human plaques in regions rich in inflammatory cells. LCN2 and calprotectin levels were 70% and 64% lower in plasma than in serum. In the CHN cohort, high serum levels of LCN2 and calprotectin increased the risk of primary and secondary outcomes 5.6 fold (p < .001) and 1.8 fold (p = .034), respectively, after covariable adjustment. Similarly, elevated plasma levels of LCN2 and calprotectin increased by three fold the risk of primary and secondary outcomes (p < .001) in the VIVA cohort. Moreover, addition of the combined variable to basal models, considering clinically relevant risk factors, improved reclassification for the primary outcome in both cohorts (p ≤ .024). CONCLUSION: Combined assessment of the inflammatory biomarkers LCN2 and calprotectin might be useful for risk stratification in advanced and early PAD.

Long-Term Thoracic Endovascular Repair Follow-Up from 1999 to 2019: A Single-Center Experience.

BACKGROUND: Thoracic endovascular aortic repair (TEVAR) was introduced in the early 1990s and long-term follow-up studies are warranted in current guidelines. METHODS: Patients undergoing TEVAR were consecutively included from 1999 to 2019. Thoracic aortic disease includes thoracic aortic aneurysms, aortic dissection, traumatic rupture, penetrating aortic ulcer (PAU), and intramural hematoma (IMH). Our prospective database recorded baseline characteristics, endoleak or aneurysm growth, and death. Patients were included at the time of treatment and censored at death or first reintervention depending on the analysis. Primary end point was all-cause death; secondary end point was reintervention. Survival and failure analyses were done using STATA IC 16.0 and truncated at 15 years of follow-up. RESULTS: Two hundred and fifty six patients were included and 63% were men. Their mean age at intervention was 66.2 ± 14.5 years and they were followed for a mean of 5.2 ± 4.5 years. Indications for TEVAR were acute aortic syndrome in 40.6%, chronic aortic disease in 44.5%, and traumatic rupture in 14.8%. Technical success was seen in 94.1% of the operations, and the left subclavian artery was covered in 27.7%. A 30-day mortality rate was 21.2% (22/104) and 1.75% (2/114) (P < 0.001) for urgent and elective patients, respectively. Twelve patients (4.7%) died within 24 hr of treatment. Overall, long-term mortality recorded 112 (43.8%) deaths, 29 patients had reinterventions (11.3 %, 95% confidence interval: 7.7-15.9), and aneurysms accounted for 62.1% of all reinterventions. Twenty four (82.8%) reinterventions occurred within the first 5 years. CONCLUSIONS: This long-term follow-up study shows excess mortality in patients treated for acute aortic syndrome compared to chronic aortic disease, within the first 30 days; this difference diminishes at the end of follow-up. Most endoleaks occur within the first 5 years, although new endoleaks continue to develop decades after in previous endoleak-free patients calling for lifelong surveillance.

Association of cause of uremia with degree of iliac artery calcification.

OBJECTIVES: We aimed to investigate whether the cause of uremia is associated with degree of calcification, and to report the proportion excluded from kidney transplantation due to iliac artery calcification. METHOD: We enrolled 306 patients with a pre-transplant computed tomography scan who went through the comprehensive assessment program in 2013-2015. Calcification score was measured for each iliac artery segment and patient records viewed for a variety of variables. Interobserver variation was assessed for 135 paired observations. RESULTS: The patients' mean age was 55.5 years. Of the 306 patients, 133 did not undergo transplantation, and for 21 of these, heavy calcification was the primary explanation for this. External iliac artery calcification was positively associated with male sex, age, systolic blood pressure, diabetes and cardiovascular disease, and differed significantly among the causes of uremia subgroups; the least calcification was seen in patients with autoimmune causes, and the highest in those with diabetic causes. Similarly, the proportion of patients who underwent renal transplantation differed significantly with regard to causes of uremia (ranging from 72.3% for autoimmune disease to 40.6% for diabetic nephropathy). CONCLUSION: The degree of iliac artery calcification differs according to the cause of uremia and influences the likelihood of receiving a kidney transplantation.

Basement membrane proteins in various arterial beds from individuals with and without type 2 diabetes mellitus: a proteome study.

BACKGROUND: Basement membrane (BM) accumulation is a hallmark of micro-vessel disease in diabetes mellitus (DM). We previously reported marked upregulation of BM components in internal thoracic arteries (ITAs) from type 2 DM (T2DM) patients by mass spectrometry. Here, we first sought to determine if BM accumulation is a common feature of different arteries in T2DM, and second, to identify other effects of T2DM on the arterial proteome. METHODS: Human arterial samples collected during heart and vascular surgery from well-characterized patients and stored in the Odense Artery Biobank were analysed by liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). We included ascending thoracic aortas (ATA) (n = 10 (type 2 DM, T2DM) and n = 10 (non-DM)); laser capture micro-dissected plaque- and media compartments from carotid plaques (n = 10 (T2DM) and n = 9 (non-DM)); and media- and adventitia compartments from ITAs (n = 9 (T2DM) and n = 7 (non-DM)). RESULTS: We first extended our previous finding of BM accumulation in arteries from T2DM patients, as 7 of 12 pre-defined BM proteins were significantly upregulated in bulk ATAs consisting of > 90% media. Although less pronounced, BM components tended to be upregulated in the media of ITAs from T2DM patients, but not in the neighbouring adventitia. Overall, we did not detect effects on BM proteins in carotid plaques or in the plaque-associated media. Instead, complement factors, an RNA-binding protein and fibrinogens appeared to be regulated in these tissues from T2DM patients. CONCLUSION: Our results suggest that accumulation of BM proteins is a general phenomenon in the medial layer of non-atherosclerotic arteries in patients with T2DM. Moreover, we identify additional T2DM-associated effects on the arterial proteome, which requires validation in future studies.

Clinical Benefit, Harm, and Cost Effectiveness of Screening Men for Peripheral Artery Disease: A Markov Model Based on the VIVA Trial.

OBJECTIVE: Although screening for peripheral arterial disease (PAD) seems obvious due to its two to three times increased mortality, high prevalence in the elderly, ease of detection, and relatively harmless prevention, the evidence is sparse. METHODS: A Markov decision model was created to model the lifetime effectiveness and cost effectiveness of general population PAD screening and relevant intervention in 65 year old men. The model was informed by original estimates from the VIVA trial data except for ankle brachial systolic blood pressure index test accuracy, quality of life, and background mortality, which were adopted from the literature. A Markov model was designed for 65 year old men, who were distributed in the starting states of no/detected/undetected PAD. The main outcomes were life years, quality adjusted life years, and costs of healthcare. RESULTS: Screening for PAD reduced the rates of amputations and stroke by 10.9% and 2.4%, respectively, while it increased the rates of revascularisation, acute myocardial infarction, and major bleeding by 5.5%, 7.1%, and 4.3% respectively. The overall life expectancy was increased by 14 days per invited subject. The cost per life year/quality adjusted life year was estimated at €16 717/€20 673. On the addition of low dose rivaroxaban reduced the costs per life year gained by 40%. If the model ran for only five follow up years, screening reduced relative mortality by 1.71%, suggesting PAD screening accounts for one fourth of the reported overall 7% relative mortality risk reduction of combined abdominal aortic aneurysm, PAD, and hypertension screening. CONCLUSION: Screening of men for PAD is likely to be both clinically effective and cost effective in a lifetime perspective.