[Show abstract][Hide abstract] ABSTRACT: Immunoglobulin E (IgE) activates mast cells (MCs). It remains unknown whether IgE also activates other inflammatory cells, and contributes to the pathogenesis of abdominal aortic aneurysms (AAAs). This study demonstrates that CD4+ T cells express IgE receptor FcεR1, at much higher levels than do CD8+ T cells. IgE induces CD4+ T-cell production of IL6 and IFN-γ, but reduces their production of IL10. FcεR1 deficiency (Fcer1a−/−) protects apolipoprotein E-deficient (Apoe−/−) mice from angiotensin-II infusion-induced AAAs and reduces plasma IL6 levels. Adoptive transfer of CD4+ T cells (but not CD8+ T cells), MCs, and macrophages from Apoe−/− mice, but not those from Apoe−/−Fcer1a−/− mice, increases AAA size and plasma IL6 in Apoe−/−Fcer1a−/− recipient mice. Biweekly intravenous administration of an anti-IgE monoclonal antibody ablated plasma IgE and reduced AAAs in Apoe−/− mice. Patients with AAAs had significantly higher plasma IgE levels than those without AAAs. This study establishes an important role of IgE in AAA pathogenesis by activating CD4+ T cells, MCs, and macrophages and supports consideration of neutralizing plasma IgE in the therapeutics of human AAAs.
EMBO Molecular Medicine 06/2014; · 7.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Ruptured abdominal aortic aneurysm (rAAA) is associated with high mortality. Research suggests that statins may reduce abdominal aortic aneurysm (AAA) growth and improve rAAA outcomes. However, the clinical impact of statins remains uncertain in relation to both the risk and prognosis of rAAA.Methods
This nationwide, population-based, combined case–control and follow-up study included all patients (aged at least 50 years) with a first-time hospital admission for rAAA and 1 : 1 matched AAA controls without rupture in Denmark from 1996 to 2008. Individual-level data on preadmission drug use, co-morbidities, socioeconomic markers, healthcare contacts and death were obtained from Danish nationwide registries.ResultsThe study included 3584 cases and 3584 matched controls. Current statin use was registered for 418 patients with rAAA (11·7 per cent) and 539 AAA controls (15·0 per cent), corresponding to an age- and sex-matched odds ratio (OR) of 0·70 (95 per cent confidence interval (c.i.) 0·60 to 0·81) for rAAA in current statin users versus never users. The decreased risk of rAAA remained after adjustment for potential confounding factors (adjusted OR 0·73, 0·61 to 0·86). The overall 30-day mortality rate from time of hospital admission among patients with rAAA was 46·1 per cent in current statin users compared with 59·3 per cent in never users (adjusted mortality rate ratio (MRR) 0·80, 95 per cent c.i. 0·68 to 0·95). Patients who had formerly used statins did not have reduced mortality (adjusted MRR 0·98, 0·78 to 1·22).Conclusion
Statin use was associated with a reduced risk of rAAA and lower case fatality following rAAA. These results support current guidelines that recommend statin therapy in patients diagnosed with AAA.
British Journal of Surgery 05/2014; · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Iron deposits are observed in tissue of abdominal aortic aneurysm (AAA) patients, although the underlying mechanisms are not completely elucidated. Therefore we explored circulating markers of iron metabolism in AAA patients, and tested if they could serve as biomarkers of AAA. Increased red blood cell (RBC)-borne iron retention and transferrin, transferrin receptor and ferritin expression was observed in AAA tissue compared to control aorta (immunohistochemistry and western blot). In contrast, decreased circulating iron, transferrin, mean corpuscular haemoglobin concentration (MCHC) and haemoglobin concentration, along with circulating RBC count, were observed in AAA patients (aortic diameter >3 cm, n=114) compared to controls (aortic diameter <3 cm, n=88) (ELISA), whereas hepcidin concentrations were increased in AAA subjects (MS/MS assay). Moreover, iron, transferrin and haemoglobin levels were negatively, and hepcidin positively, correlated with aortic diameter in AAA patients. The association of low haemoglobin with AAA presence or aortic diameter was independent of specific risk factors. Moreover, MCHC negatively correlated with thrombus area in another cohort of AAA patients (aortic diameter 3-5 cm, n=357). We found that anaemia was significantly more prevalent in AAA patients (aortic diameter >5 cm, n=8,912) compared to those in patients with atherosclerotic aorto-iliac occlusive disease (n=17,737) [adjusted odds ratio=1.77 (95% confidence interval: 1.61;1.93)]. Finally, the mortality risk among AAA patients with anaemia was increased by almost 30% [adjusted hazard ratio: 1.29 (95% confidence interval: 1.16;1.44)] as compared to AAA subjects without anaemia. In conclusion, local iron retention and altered iron recycling associated to high hepcidin and low transferrin systemic concentrations could lead to reduced circulating haemoglobin levels in AAA patients. Low haemoglobin levels are independently associated to AAA presence and clinical outcome.
Thrombosis and Haemostasis 03/2014; 112(1). · 5.76 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Abstract Background and Objectives: The search for novel risk factors of cardiovascular disease (CVD) has provided valuable clinical data concerning underlying mechanism of disease. Increasing evidence indicates a possible involvement of insulin-like growth factor-I (IGF-I) and its binding protein 2 (IGFBP-2) in the pathogenesis of CVD disorders. The aim of this study was to examine the relationship between levels of IGF-I and IGFBP-2 with all-cause and CVD mortality in a prospective study of patients with lower-extremity peripheral artery disease (PAD). Methods and material: Serum IGF-I and IGFBP-2 levels were obtained in 440 patients (257 males) with symptomatic PAD. Patients were followed for a median of 6.1 (IQ 5.1 to 7.2) years. The relationship between times to lethal outcome and baseline serum IGF-I and IFGBP-2 levels were examined by Cox proportional hazard analysis. The role of IFGBP-2 for prognosis of CVD death was assessed with c-statistic. Results: During follow-up 115 (26%) patients (48 females and 67 males) died, and 53 (12%) - from CVD related causes. Cox regression analysis revealed that an increase of 100 µg/l of baseline IFGBP-2 were significantly associated with an increased risk for CVD mortality [crude hazard ration (HR) 1.14 (95% CI (1.05-1.23), and adjusted HR 1.12 (95% CI (1.01-1.24)]. The receiver operating characteristic (ROC) analysis yielded area under curve of 0.61 (95% CI: 0.51-0.67, P=0.022). However, the model including IFGBP-2 did not show a significant improvement in accuracy of CVD death prediction (the area under ROC curve 0.73 (0.66-0.80) vs. 0.75 (0.69-0.82), P=0.696), and net reclassification improvement was 10.3% (P = 0.23). Conclusions: Increased IFGBP-2 concentration was significantly and independently associated with long-term CVD mortality in patients with lower-extremity PAD. However, risk prediction of CVD mortality did not improve by adding IFGBP-2 to a model containing conventional CVD risk factors.
[Show abstract][Hide abstract] ABSTRACT: Galectin-3 (Gal-3) participates in different mechanisms involved in atherothrombosis, such as inflammation, proliferation, or macrophage chemotaxis. Thus, there have been committed intensive efforts to elucidate the function of Gal-3 in cardiovascular (CV) diseases. The role of Gal-3 as a circulating biomarker has been demonstrated in patients with heart failure, but its importance as a biomarker in atherothrombosis is still unknown.
Journal of the American Heart Association. 01/2014; 3(4).
[Show abstract][Hide abstract] ABSTRACT: Objective
To investigate whether the relative size of intraluminal thrombus (ILT) in abdominal aortic aneurysms (AAAs) is associated with AAA growth.
This large observational study was based on a randomised population-based screening trial. Six hundred and fifteen AAAs were diagnosed in men aged 65–74 years. The relative cross-sectional area covered by the mural thrombus was estimated by a semiautomatic method using ultrasound equipment to measure the area of the ellipses, and adapting the inner ellipse (IA) to the luminal border of the thrombus and the outer ellipse to the area inside the media border (OA). The relative thrombus area was then calculated as ((OA–IA)/OU) × 100%. Four hundred and sixteen of the patients with AAA were eligible for analysis.
The mean size of the AAA was 40.6 mm, and the mean observation time was 1.78 years. In the group with AAAs measuring 30–34 mm, 42% had ILT, with a mean relative size of 12% of the outer area. In the group with AAAs measuring >64 mm, the presence of ILT increased to 100%, with a mean relative size of 70% of the outer area. Univariate analysis showed relative ILT size, aortic diameter, smoking history, and diastolic blood pressure were significantly positively associated with growth rate, while the presence of diabetes mellitus and peripheral arterial disease were significantly negatively associated with growth rate. The relative ILT size remained significantly positively associated with the growth rate after a multivariate linear regression adjusting for potential confounders.
These findings suggest that ILT may play a part in the progression of AAAs.
European Journal of Vascular and Endovascular Surgery. 01/2014;
[Show abstract][Hide abstract] ABSTRACT: In general, it is assumed that patient education, by increasing knowledge, may change behavior and lifestyle and promote health. In this context, it is a surprise that knowledge and awareness about blood pressure and hypertension among elderly people is poor. We hypothesized that knowledge about blood pressure and hypertension would be better among individuals with self-reported hypertension compared with subjects without self-reported hypertension.
We mailed a questionnaire to a random sample of 1,000 subjects living in the municipality of Silkeborg, Denmark. The study sample was drawn from the Central Person Registry.
The response rate was 72%. Of these, 43% of responders had self-reported hypertension. The people with self-reported hypertension were older, less educated, had higher self-reported blood cholesterol levels, had higher body weight, and more often had a family history of hypertension. More than 80% reported that overweight and obesity increases blood pressure. More than 60% reported that untreated hypertension may cause heart disease or stroke. More than half of the responders did not know their blood pressure, and only 21% knew that hypertension can occur without symptoms. Knowledge about hypertension was independent of self-reported hypertension status, but awareness about blood pressure was most prominent among those with self-reported hypertension.
General knowledge about blood pressure and hypertension was reasonable, but there is still room for improvement in elderly people's knowledge and awareness of blood pressure.
[Show abstract][Hide abstract] ABSTRACT: Previous studies have reported a higher prevalence of inguinal hernia in patients with abdominal aortic aneurysm (AAA). The aim of this study was to explore the association between inguinal hernia and AAA in a large population-based cohort of men who had screening for AAA.
A total of 18 331 men aged 65-76 years had ultrasound screening for AAA in the Central Region of Denmark from 2008 to 2010. The Danish National Patient Registry was interrogated, and screened men registered with an inguinal hernia from 1977 to 2011 were identified. The association between inguinal hernia and AAA was assessed by multiple logistic regression analysis.
The prevalence of AAA was 3.3 per cent (601 of 18 331). A total of 2936 (16.0 per cent) of the 18 331 patients were registered with a diagnosis of inguinal hernia or hernia repair. Inguinal hernia was not associated with AAA: crude odds ratio (OR) 0.86 (95 per cent confidence interval 0.68 to 1.09) and adjusted OR 0.94 (0.75 to 1.20).
In contrast to smaller patient-based studies, this large population-based study found no association between inguinal hernia and AAA.
British Journal of Surgery 10/2013; 100(11):1478-82. · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: -Abdominal aortic aneurysm (AAA) is a common cardiovascular disease among older people and demonstrates significant heritability. In contrast to similar complex diseases, relatively few genetic associations with AAA have been confirmed. We reanalysed our genome-wide study and carried through to replication suggestive discovery associations at a lower level of significance.
-A genome-wide association study was conducted using 1,830 cases from the UK, New Zealand and Australia with infra-renal aorta diameter ≥30mm or ruptured AAA and 5,435 unscreened controls from the 1958 Birth Cohort and National Blood Service cohort from the Wellcome Trust Case Control Consortium. Eight suggestive associations with P<1x10(-4) were carried through to in silico replication in 1,292 AAA cases and 30,503 controls. One SNP associated with P<0.05 after Bonferroni correction in the in silico study underwent further replication (706 AAA cases and 1,063 controls from the UK, 507 AAA cases and 199 controls from Denmark and 885 AAA cases and 1,000 controls from New Zealand). Low density lipoprotein receptor (LDLR) rs6511720 A, was significantly associated overall and in three of five individual replication studies. The full study showed an association that reached genome-wide significance (odds ratio 0.76; 95% confidence interval 0.70 to 0.83; P=2.08x10(-10)).
-LDLR rs6511720 is associated with abdominal aortic aneurysm. This finding is consistent with established effects of this variant on coronary artery disease. Shared aetiological pathways with other cardiovascular diseases may present novel opportunities for preventative and therapeutic strategies for AAA.
[Show abstract][Hide abstract] ABSTRACT: In Denmark 2-3% of men aged 65 years or more die from abdominal aortic aneurysms (AAA). The lethality of ruptured AAA is 75%, while the risk of preventive surgery is 2-3%. Ultrasonographic screening for AAA is fast, safe and reliable. Randomized trials show that screening halves the mortality from AAA, and reduces total mortality by 2%. The latest health economic study concludes that it is highly cost-effective to screen 65-year-old Danish men, as a quality-adjusted life year can be gained for about 5,100 DKK (555 GBP). This is less than one tenth of the recently approved Danish colorectal cancer-screening programme.
[Show abstract][Hide abstract] ABSTRACT: Cathepsin L (CatL), cathepsin K (CatK), and cathepsin V (CatV) are potent elastases implicated in human arterial wall remodeling. Whether plasma levels of these cathepsins are altered in patients with abdominal aortic aneurysms (AAAs) remains unknown.
Plasma samples were collected from 476 male AAA patients and 200 age-matched male controls to determine CatL, CatK, and CatV levels by ELISA. Student's t-test demonstrated significantly higher plasma CatL levels in AAA patients than in controls (P < 0.0001), whereas CatK and CatV levels were lower in AAA patients than in controls (P = 0.052, P = 0.025). ROC curve analysis confirmed higher plasma CatL levels in AAA patients than in controls (P < 0.001). As potential confounders, current smoking and use of angiotensin-converting enzyme (ACE) inhibitors, aspirin, clopidogrel, and statins associated with significantly increased plasma CatL. Pearson's correlation test demonstrated that plasma CatL associated positively with CatS (r = 0.43, P < 0.0001), body-mass index (BMI) (r = 0.07, P = 0.047) and maximal aortic diameter (r = 0.29, P < 0.001), and negatively with lowest measured ankle-brachial index (ABI) (r = -0.22, P < 0.001). Plasma CatL remained associated positively with CatS (r = 0.43, P < 0.0001) and aortic diameter (r = 0.212, P < 0.001) and negatively with ABI (r = -0.10, P = 0.011) after adjusting for the aforementioned potential confounders in a partial correlation analysis. Multivariate logistic regression analysis indicated that plasma CatL was a risk factor of AAA before (odds ratio [OR] = 3.04, P < 0.001) and after (OR = 2.42, P < 0.001) the same confounder adjustment.
Correlation of plasma CatL levels with aortic diameter and the lowest ABI suggest that this cysteinyl protease plays a detrimental role in the pathogenesis of human peripheral arterial diseases and AAAs.
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: To identify proteins related to intraluminal thrombus biological activities that could help to find novel pathological mechanisms and therapeutic targets for human abdominal aortic aneurysm (AAA). APPROACH AND RESULTS: Tissue-conditioned media from patients with AAA were analyzed by a mass spectrometry-based strategy using liquid chromatography coupled to tandem mass spectrometry. Global pathway analysis by Ingenuity software highlighted the presence of several circulating proteins, among them were proteins from the complement system. Complement C3 concentration and activation were assessed in plasma from AAA patients (small AAA, AAA diameter=3-5 cm and large AAA, AAA diameter >5 cm), showing decreased C3 levels and activation in large AAA patients. No association of a combination of single-nucleotide polymorphisms in complement genes between large and small AAA patients was observed. Intense extracellular C3 inmunostaining, along with C9, was observed in AAA thrombus. Analysis of C3 in AAA tissue homogenates and tissue-conditioned media showed increased levels of C3 in AAA thrombus, as well as proteolytic fragments (C3a/C3c/C3dg), suggesting its local deposition and activation. Finally, the functional role of local complement activation in polymorphonuclear (PMN) cell activation was tested, showing that C3 blockade by anti-C3 antibody was able to decrease thrombus-induced neutrophil chemotaxis and reactive oxygen species production. CONCLUSIONS: A decrease of systemic C3 concentration and activity in the later stages of AAA associated with local complement retention, consumption, and proteolysis in the thrombus could induce PMN chemotaxis and activation, playing a detrimental role in AAA progression.
Arteriosclerosis Thrombosis and Vascular Biology 05/2013; · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE: To explore the associations between beta-blocker use and clinical outcomes (death, hospitalisation with myocardial infarction (MI) or stroke, major amputation and recurrent vascular surgery) after primary vascular reconstruction. METHODS: Patients who had primary vascular surgical or endovascular reconstruction due to symptomatic peripheral arterial disease, in Denmark between 1996 and 2007 were included. We obtained data on filled prescriptions, clinical outcomes and confounding factors from population-based healthcare registries. Beta-blocker users were matched to non-users by propensity score, and Cox-regression was performed. All medications were included as time-dependent variables. RESULTS: We studied 16,945 matched patients (7828 beta-blocker users and 9117 non-users) with a median follow-up period of 582 days (range, 30-4379 days). The cumulative risks were as follows: all-cause mortality, 17.9%; MI, 5.3%; stroke, 5.6%; major amputation, 9.1%; and recurrent vascular surgery, 23.1%. When comparing beta-blocker users with non-users: adjusted hazard ratio: MI, 1.52 (95% CI, 1.31-1.78); stroke, 1.21 (95% CI, 1.03-1.43); and major amputation, 0.80 (95% CI, 0.70-0.93). CONCLUSION: Beta-blocker use after primary vascular surgery was associated with a lower risk of major amputation but an increased risk of hospitalisation with MI and stroke. No associations were found between beta-blocker use and all-cause mortality or the risk of recurrent vascular surgery. However, our results are not sufficient to alter the indication for beta-blocker use among symptomatic peripheral arterial disease patients.
European journal of vascular and endovascular surgery: the official journal of the European Society for Vascular Surgery 05/2013; · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aims: The (cost-)effectiveness of a screening programme may be strongly influenced by the participation rate. The objective of this study was to compare participants' and non-participants' motives for the attendance decision as well as their overall preferences for participation in cardiovascular disease screening. Methods: This study sampled 1053 participants and 1006 non-participants from a screening trial and randomly allocated the participants to receive different levels of additional information about the screening programme. An ad hoc survey questionnaire about doubt and arguments in relation to the participation decision was given to participants and non-participants along with a contingent valuation task. Results: Among participants, 5% had doubt about participation and the most frequent argument was that they did not want the test result. Among non-participants, 40% would reconsider their non-participation decision after having received additional information while the remainder 60% stood by their decision and provided explicit arguments for it. After having received additional information the participants still valued the programme significantly higher than non-participants, but the difference was relatively small. Conclusions: Participants and non-participants in cardiovascular screening programmes seem to have different strengths of preferences, which signals that their behavioural choice is founded in rational thinking. Furthermore, it appears that additional information and a second reflection about the participation decision may affect a substantial proportion of non-participants to reverse their decision, a finding that should receive policy interest.
Scandinavian Journal of Public Health 02/2013; 41(1):43-50. · 1.97 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVES: Currently most abdominal aortic aneurysm screening programmes discharge patients with aortic diameter of less than 30 mm. However, sub-aneurysmal aortic dilatation (25 mm-29 mm) does not represent a normal aortic diameter. This observational study aimed to determine the outcomes of patients with screening detected sub aneurysmal aortic dilatation. DESIGN AND METHODS: Individual patient data was obtained from 8 screening programmes that had performed long term follow up of patients with sub aneurysmal aortic dilatation. Outcome measures recorded were the progression to true aneurysmal dilatation (aortic diameter 30 mm or greater), progression to size threshold for surgical intervention (55 mm) and aneurysm rupture. RESULTS: Aortic measurements for 1696 men and women (median age 66 years at initial scan) with sub-aneurysmal aortae were obtained, median period of follow up was 4.0 years (range 0.1-19.0 years). Following Kaplan Meier and life table analysis 67.7% of patients with 5 complete years of surveillance reached an aortic diameter of 30 mm or greater however 0.9% had an aortic diameter of 54 mm. A total of 26.2% of patients with 10 complete years of follow up had an AAA of greater that 54 mm. CONCLUSION: Patients with sub-aneurysmal aortic dilatation are likely to progress and develop an AAA, although few will rupture or require surgical intervention.
European journal of vascular and endovascular surgery: the official journal of the European Society for Vascular Surgery 12/2012; · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: The credibility of contingent valuation studies has been questioned because of the potential occurrence of scope insensitivity, i.e. that respondents do not react to higher quantities or qualities of a good. Objective: The aim of this study was to examine the extent of scope insensitivity and to assess the relevance of potential explanations that may help to shed light on how to appropriately handle this problem in contingent valuation studies. Methods: We surveyed a sample of 2004 men invited for cardiovascular disease screening. Each respondent had three contingent valuation tasks from which their sensitivity to larger risk reductions (test 1) and to change in travel costs associated with participation (test 2) could be assessed. Participants were surveyed while waiting for their screening session. Non-participants were surveyed by postal questionnaire. Results: The sample was overall found to be sensitive to scope, testing at the conventional sample-mean level. At the individual respondent level, however, more than half of the respondents failed the tests. Potential determinants for failing the tests were examined in alternative regression models but few consistent relationships were identified. One exception was the influence of more detailed information, which was positively associated with willingness to pay and negatively associated with scope sensitivity. Conclusion: Possible explanations for scope insensitivity are discussed; if cognitive limitations, emotional load and mental budgeting explain scope insensitivity there are grounds for rejecting valuations, whereas other factors such as the alternative theoretical framework of regret theory may render insensitivity to scope a result of rational thinking. It is concluded that future contingent valuation studies should focus more on extracting the underlying motives for the stated preferences in order to appropriately deal with responses that are seemingly irrational, and which may lead to imprecise welfare estimates.
Applied Health Economics and Health Policy 09/2012;