Basement membrane collagen IV deficiency promotes abdominal aortic aneurysm formation.

Abdominal aortic aneurysm (AAA) is a complex disease which is incompletely accounted for. Basement membrane (BM) Collagen IV (COL4A1/A2) is abundant in the artery wall, and several lines of evidence indicate a protective role of baseline COL4A1/A2 in AAA development. Using Col4a1/a2 hemizygous knockout mice (Col4a1/a2+/-, 129Svj background) we show that partial Col4a1/a2 deficiency augmented AAA formation. Although unchallenged aortas were morphometrically and biomechanically unaffected by genotype, explorative proteomic analyses of aortas revealed a clear reduction in BM components and contractile vascular smooth muscle cell (VSMC) proteins, suggesting a central effect of the BM in maintaining VSMCs in the contractile phenotype. These findings were translated to human arteries by showing that COL4A1/A2 correlated to BM proteins and VSMC markers in non-lesioned internal mammary arteries obtained from coronary artery bypass procedures. Moreover, in human AAA tissue, MYH11 (VSMC marker) was depleted in areas of reduced COL4 as assessed by immunohistochemistry. Finally, circulating COL4A1 degradation fragments correlated with AAA progression in the largest Danish AAA cohort, suggesting COL4A1/A2 proteolysis to be an important feature of AAA formation. In sum, we identify COL4A1/A2 as a critical regulator of VSMC phenotype and a protective factor in AAA formation.

Baseline findings of the population-based, randomized, multifaceted Danish cardiovascular screening trial (DANCAVAS) of men aged 65-74 years.

BACKGROUND: The challenge of managing age-related diseases is increasing; routine checks by the general practitioner do not reduce cardiovascular mortality. The aim here was to reduce cardiovascular mortality by advanced population-based cardiovascular screening. The present article reports the organization of the study, the acceptability of the screening offer, and the relevance of multifaceted screening for prevention and management of cardiovascular disease. METHODS: Danish men aged 65-74 years were invited randomly (1 : 2) to a cardiovascular screening examination using low-dose non-contrast CT, ankle and brachial BP measurements, and blood tests. RESULTS: In all, 16 768 of 47 322 men aged 65-74 years were invited and 10 471 attended (uptake 62·4 per cent). Of these, 3481 (33·2 per cent) had a coronary artery calcium score above 400 units. Thoracic aortic aneurysm was diagnosed in the ascending aorta (diameter 45 mm or greater) in 468 men (4·5 per cent), in the arch (at least 40 mm) in 48 (0·5 per cent) and in the descending aorta (35 mm or more) in 233 (2·2 per cent). Abdominal aortic aneurysm (at least 30 mm) and iliac aneurysm (20 mm or greater) were diagnosed in 533 (5·1 per cent) and 239 (2·3 per cent) men respectively. Peripheral artery disease was diagnosed in 1147 men (11·0 per cent), potentially uncontrolled hypertension (at least 160/100 mmHg) in 835 (8·0 per cent), previously unknown atrial fibrillation confirmed by ECG in 50 (0·5 per cent), previously unknown diabetes mellitus in 180 (1·7 per cent) and isolated severe hyperlipidaemia in 48 men (0·5 per cent). In all, 4387 men (41·9 per cent), excluding those with potentially uncontrolled hypertension, were referred for additional cardiovascular prevention. Of these, 3712 (35·5 per cent of all screened men, but 84·6 per cent of those referred) consented and were started on medication. CONCLUSION: Multifaceted cardiovascular screening is feasible and may optimize cardiovascular disease prevention in men aged 65-74 years. Uptake is lower than in aortic aneurysm screening.

Cost-effectiveness of population-based vascular disease screening and intervention in men from the Viborg Vascular (VIVA) trial.

BACKGROUND: Population-based screening and intervention for abdominal aortic aneurysm, peripheral artery disease and hypertension was recently reported to reduce the relative risk of mortality among Danish men by 7 per cent. The aim of this study was to investigate the cost-effectiveness of vascular screening versus usual care (ad hoc primary care-based risk assessment) from a national health service perspective. METHODS: A cost-effectiveness evaluation was conducted alongside an RCT involving all men from a region in Denmark (50 156) who were allocated to screening (25 078) or no screening (25 078) and followed for up to 5 years. Mobile nurse teams provided screening locally and, for individuals with positive test results, referrals were made to general practices or hospital-based specialized centres for vascular surgery. Intention-to-treat-based, censoring-adjusted incremental costs (2014 euros), life-years and quality-adjusted life-years (QALYs) were estimated using Lin's average estimator method. Incremental net benefit was estimated using Willan's estimator and sensitivity analyses were conducted. RESULTS: The cost of screening was estimated at €148 (95 per cent c.i. 126 to 169), and the effectiveness at 0·022 (95 per cent c.i. 0·006 to 0·038) life-years and 0·069 (0·054 to 0·083) QALYs, generating average costs of €6872 per life-year and €2148 per QALY. At a willingness-to-pay threshold of €40 000 per QALY, the probabilities of cost-effectiveness were 98 and 99 per cent respectively. The probability of cost-effectiveness was 71 per cent when all the sensitivity analyses were combined into one conservative scenario. CONCLUSION: Vascular screening appears to be cost-effective and compares favourably with current screening programmes.

Association of ficolin-3 with abdominal aortic aneurysm presence and progression.

Essentials Abdominal aortic aneurysm (AAA) is asymptomatic and its evolution unpredictable. To find novel potential biomarkers of AAA, microvesicles are an excellent source of biomarkers. Ficolin-3 is increased in microvesicles obtained from activated platelets and AAA tissue. Increased ficolin-3 plasma levels are associated with AAA presence and progression. SUMMARY: Background Abdominal aortic aneurysm (AAA) patients are usually asymptomatic and AAA evolution is unpredictable. Ficolin-3, mainly synthesized by the liver, is a molecule of the lectin complement-activation pathway involved in AAA pathophysiology. Objectives To define extra-hepatic sources of ficolin-3 in AAA and investigate the role of ficolin-3 as a biomarker of the presence and progression of AAA. Methods Microvesicles (exosomes and microparticles) were isolated from culture-conditioned medium of ADP-activated platelets, as well as from AAA tissue-conditioned medium (thrombus and wall). Ficolin-3 levels were analyzed by western-blot, real-time PCR, immunohistochemistry and ELISA. Results Increased ficolin-3 levels were observed in microvesicles isolated from activated platelets. Similarly, microvesicles released from AAA tissue display increased ficolin-3 levels as compared with those from healthy tissue. Moreover, ficolin-3 mRNA levels in the AAA wall were greatly increased compared with healthy aortic walls. Immunohistochemistry of AAA tissue demonstrated increased ficolin-3, whereas little staining was present in healthy walls. Finally, increased ficolin-3 levels were observed in AAA patients' plasma (n = 478) compared with control plasma (n = 176), which persisted after adjustment for risk factors (adjusted odds ratio [OR], 5.29; 95% confidence interval [CI], 3.27, 8.57)]. Moreover, a positive association of ficolin-3 with aortic diameter (Rho, 0.25) and need for surgical repair was observed, also after adjustment for potential confounding factors (adjusted hazard ratio, 1.55; 95% CI, 1.11, 2.15). Conclusions In addition to its hepatic expression, ficolin-3 may be released into the extracellular medium via microvesicles, by both activated cells and pathological AAA tissue. Ficolin-3 plasma levels are associated with the presence and progression of AAA, suggesting its potential role as a biomarker of AAA.

The water channel AQP1 is expressed in human atherosclerotic vascular lesions and AQP1 deficiency augments angiotensin II-induced atherosclerosis in mice.

AIM: The water channel aquaporin 1 (AQP1) promotes endothelial cell migration. It was hypothesized that AQP1 promotes neovascularization and growth of atherosclerotic plaques. METHODS: AQP1 immunoreactivity and protein abundance was examined in human and murine atherosclerotic lesions and aortic aneurysms. Apolipoprotein E (ApoE) knockout (-/-) and AQP1-/-ApoE-/- mice were developed and fed Western diet (WD) for 8 and 16 weeks to accelerate the atherosclerosis process. In ApoE-/- and AQP1-/-ApoE-/- mice abdominal aortic aneurysms (AAA) were induced by angiotensin II (ANGII) infusion by osmotic minipumps for 4 weeks. RESULTS: In human atherosclerotic lesions and AAA, AQP1 immunoreactive protein was associated with intralesional small vessels. In ApoE-/- mouse aorta, APQ1 mRNA levels were increased with time on WD (n = 7-9, P < 0.003). Both in murine lesions at the aortic root and in the abdominal aortic aneurysmal wall, AQP1 immunoreactivity was associated with microvascular structures. The atherosclerotic lesion burden was enhanced significantly in ANGII-infused AQP1-/-ApoE-/- mice compared with ApoE-/- mice, but neither incidence nor progression of AAA was different. The aortic lesion burden increased with time on WD but was not different between ApoE-/- and AQP1-/-ApoE-/- mice at either 8 or 16 weeks (n = 13-15). Baseline blood pressure and ANGII-induced hypertension were not different between genotypes. CONCLUSION: AQP1 is expressed in atherosclerotic lesion neovasculature in human and mouse arteries and AQP1 deficiency augments lesion development in ANGII-promoted atherosclerosis in mice. Normal function of AQP1 affords cardiovascular protection.

The DanCavas Pilot Study of Multifaceted Screening for Subclinical Cardiovascular Disease in Men and Women Aged 65-74 Years.

OBJECTIVE/BACKGROUND: This pilot study of a large population based randomised screening trial investigated feasibility, acceptability, and relevance (prevalence of clinical and subclinical cardiovascular disease [CVD] and proportion receiving insufficient prevention) of a multifaceted screening for CVD. METHODS: In total, 2060 randomly selected Danish men and women aged 65-74 years were offered (i) low dose non-contrast computed tomography to detect coronary artery calcification (CAC) and aortic/iliac aneurysms; (ii) detection of atrial fibrillation (AF); (iii) brachial and ankle blood pressure measurements; and (iv) blood levels of cholesterol and hemoglobin A1c. Web based self booking and data management was used to reduce the administrative burden. RESULTS: Attendance rates were 64.9% (n = 678) and 63.0% (n = 640) for men and women, respectively. In total, 39.7% received a recommendation for medical preventive actions. Prevalence of aneurysms was 12.4% (95% confidence interval [CI] 9.9-14.9) in men and 1.1% (95% CI 0.3-1.9) in women, respectively (p < .001). A CAC score > 400 was found in 37.8% of men and 11.3% of women (p < .001), along with a significant increase in median CAC score with age (p = .03). Peripheral arterial disease was more prevalent in men (18.8%, 95% CI 15.8-21.8) than in women (11.2%, 95% CI 8.7-13.6). No significant differences between the sexes were found with regard to newly discovered AF (men 1.3%, women 0.5%), potential hypertension (men 9.7%, women 11.5%), hypercholesterolemia (men 0.9%, women 1.1%) or diabetes mellitus (men 2.1%, women 1.3%). CONCLUSION: Owing to the higher prevalence of severe conditions, such as aneurysms and CAC ≥ 400, screening for CVD seemed more prudent in men than women. The attendance rates were acceptable compared with other screening programs and the logistical structure of the screening program proved successful.

Five-year outcomes following a randomized trial of femorofemoral and femoropopliteal bypass grafting with heparin-bonded or standard polytetrafluoroethylene grafts.

BACKGROUND: Cohort studies suggest superior long-term patency of luminal heparin-bonded polytetrafluoroethylene (Hb-PTFE) bypass grafts compared with standard PTFE grafts. The aim of this study was to compare the outcomes of Hb-PTFE grafts with those of standard PTFE grafts 5 years after a randomized trial. METHODS: Patients with intermittent claudication or critical limb ischaemia requiring femorofemoral or femoropopliteal bypass grafting were randomized in a clinical trial of Hb-PTFE versus standard PTFE in 11 Scandinavian centres between 2005 and 2009. Patients were followed up for 5 years with clinical assessment and surveillance Duplex ultrasound imaging. The primary endpoint of this study was primary patency. Secondary endpoints included major amputation and mortality. RESULTS: Overall, 569 patients were enrolled in the randomized trial. Some 552 had follow-up data available for analysis of the primary outcome. Use of Hb-PTFE significantly improved patency by 37 per cent at 2 years, but 5 years after randomization there was no difference in primary patency (adjusted hazard ratio (HR) 0·95, 95 per cent c.i. 0·71 to 1·28; P = 0·748). In patients with critical limb ischaemia the use of Hb-PTFE reduced the 5-year risk of loss of primary patency by 37 per cent (HR 0·63, 0·40 to 0·99; P = 0·049). CONCLUSION: In this study there was no difference in primary graft patency between Hb-PTFE and standard PTFE grafts. Patients receiving Hb-PTFE grafts for critical limb ischaemia were more likely to have a patent graft at 5 years than those with standard PTFE grafts.

Animal Models Used to Explore Abdominal Aortic Aneurysms: A Systematic Review.

OBJECTIVE: Experimental animal models have been used to investigate the formation, development, and progression of abdominal aortic aneurysms (AAAs) for decades. New models are constantly being developed to imitate the mechanisms of human AAAs and to identify treatments that are less risky than those used today. However, to the authors' knowledge, there is no model identical to the human AAA. The objective of this systematic review was to assess the different types of animal models used to investigate the development, progression, and treatment of AAA and to highlight their advantages and limitations. METHODS: A search protocol was used to perform a systematic literature search of PubMed and Embase. A total of 2,830 records were identified. After selection of the relevant articles, 564 papers on animal AAA models were included. RESULTS: The most common models in rodents, including elastase, calcium chloride, angiotensin II, xenograft, and transgenic models, and the most common models in non-rodents, including chemically induced, graft models, and patch models, all have limitations with regard to the pathological interpretation of human AAA. CONCLUSION: Although findings from animal models of AAAs cannot be directly translated to human AAAs, the identification and awareness of animal models of AAA will provide knowledge for further investigation and insight into human AAA disease.

Editor's Choice - High Heritability of Liability to Abdominal Aortic Aneurysms: A Population Based Twin Study.

OBJECTIVE: First degree relatives of patients with abdominal aortic aneurysm (AAA) have an increased risk of developing AAA; however, despite intensive investigation, the specific genetic factors involved in the development of the disease are still largely unknown. In twin studies the influence of genetic and environmental factors can be assessed by comparing concordance rates between monozygotic (MZ) and dizygotic (DZ) twins. Higher phenotypic similarity between MZ than DZ twins indicates a genetic attribution to the etiology. The objective of this study was to investigate the heritability of AAA among Danish twins using concordance rates and heritability estimates. METHODS: The Danish Twin Registry was used to identify all Danish twin pairs (born 1880-1971) where both twins were alive on January 1, 1977. AAA cases were then identified using the National Patient Registry and the Registry of Cause of Death. Probandwise concordance rates were calculated and heritability estimated using structural equation modeling. RESULTS: The study identified 414 twins with AAA; 69.8% (289/414) were men and 30.2% (125/414) women. The probandwise concordance rate in MZ twins was 30% (95% CI 20.3-43.3%) compared with 12% (95% CI 7.0-20.1%) in DZ twins. In the heritability analysis 77% (95% CI 67-85%) of the total variance was explained by additive genetic components and 23% (95% CI 15-33%) was explained by non-shared environmental factors. CONCLUSIONS: The probandwise concordance rate was found to be 2.5 times higher in MZ compared with DZ twins. An overall heritability of 77% was determined.

Baseline prevalence of abdominal aortic aneurysm, peripheral arterial disease and hypertension in men aged 65-74 years from a population screening study (VIVA trial).

BACKGROUND: Abdominal aortic aneurysm (AAA) screening has been introduced into some health systems and could easily be supplemented with broader vascular screening. The aim of this study was to evaluate the screening set-up and investigate combined screening for AAA, peripheral arterial disease (PAD) and possible hypertension (HT), and detection rates. METHODS: This observational study was based on the intervention arm of a screening trial in 25 083 Danish men aged 65-74 years. A combined screening programme for AAA, PAD and HT was offered at local hospitals. Participants with positive test results were offered secondary prophylaxis and/or referred to their general practitioner. The programme set-up included decentralized screening by three mobile teams at 14 venues. Diagnostic criteria were: aortic diameter at least 30 mm for AAA, ankle : brachial pressure index below 0·9 or above 1·4 for PAD, and BP exceeding 160/100 mmHg for HT. RESULTS: Overall, 18 749 men (uptake 74·7 per cent) attended the screening. An AAA was diagnosed in 3·3 (95 per cent c.i. 3·0 to 3·6) per cent, PAD in 10·9 (10·5 to 11·4) per cent and HT in 10·5 (10·0 to 10·9) per cent. Lipid-lowering and/or antiplatelet treatment was initiated in 34·8 per cent of the participants. CONCLUSION: Preventive actions were started in one-third of the attenders. The long-term effect of this on morbidity and mortality is an important part of future analysis. The trial confirms that the prevalence of AAA in Denmark has decreased only slightly in the past decade, from 4·0 to 3·3 per cent, in contrast to other nations.