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An aberrant right subclavian artery (ARSA) is the most common congenital variant of the aortic arch. Usually, this variation is largely asymptomatic, but sometimes it may be involved in aortic dissection (AD). Surgical management of this condition is challenging. The therapeutic options have been enriched in recent decades by establishing individualized endovascular or hybrid procedures. Whether these less invasive approaches bear advantages, and how they have changed the treatment of this rare pathology, is still unclear. Therefore, we conducted a systematic review. We performed a review of literature from the past 20 years (from January 2000 until February 2021) complying with the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. All reported patients treated for Type B AD in the presence of an ARSA were identified and classified into three groups according to the received therapy (open, hybrid, and total endovascular). Patient characteristics, as well as in-hospital mortality, and major and minor complications were determined and statistically analyzed. We identified 32 relevant publications comprising 85 patients. Open arch repair has been offered to younger patients, but significantly less often in symptomatic patients needing urgent repair. Therefore, the maximum aortic diameter was also significantly larger in the open repair group compared with that in the hybrid or total endovascular repair group. Regarding the endpoints, we did not find significant differences. The literature review revealed that open surgical therapies are preferred in patients presenting with chronic dissections and larger aortic diameters, most likely because they are unsuitable for endovascular aortic repair. Hybrid and total endovascular approaches are more often applied in emergency situations, where aortic diameters remain smaller. All therapies demonstrated good, early, and midterm outcomes. But, these therapies carry potential risks in the long term. Therefore, long-term follow-up data are urgently needed to validate that these therapies are sustainable.

The optimal treatment for patients with asymptomatic carotid artery stenosis is under debate. Since best medical treatment (BMT) has improved over time, the benefit of carotid endarterectomy (CEA) or carotid artery stenting (CAS) is unclear. Randomised data comparing the effect of CEA and CAS versus BMT alone are absent. We aimed to directly compare CEA plus BMT with CAS plus BMT and both with BMT only.SPACE-2 was a multicentre, randomised, controlled trial at 36 study centres in Austria, Germany, and Switzerland. We enrolled participants aged 50-85 years with asymptomatic carotid artery stenosis at the distal common carotid artery or the extracranial internal carotid artery of at least 70%, according to European Carotid Surgery Trial criteria. Initially designed as a three-arm trial including one group for BMT alone (with a randomised allocation ratio of 2·9:2·9:1), the SPACE-2 study design was amended (due to slow recruitment) to become two substudies with two arms each comparing CEA plus BMT with BMT alone (SPACE-2a) and CAS plus BMT with BMT alone (SPACE-2b); in each case in a 1:1 randomisation. Participants and clinicians were not masked to allocation. The primary efficacy endpoint was the cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years. The primary safety endpoint was any stroke or death from any cause within 30 days after CEA or CAS. The primary analysis was by intention-to treat, which included all randomly assigned patients in SPACE-2, SPACE-2a, and SPACE-2b, analysed using meta-analysis of individual patient data. We did two-step hierarchical testing to first show superiority of CEA and CAS to BMT alone then to assess non-inferiority of CAS to CEA. Originally, we planned to recruit 3640 patients; however, the study had to be stopped prematurely due to insufficient recruitment. This report presents the primary analysis at 5-year follow-up. This trial is registered with ISRCTN, number ISRCTN78592017.513 patients across SPACE-2, SPACE-2a, and SPACE-2b were recruited and surveyed between July 9, 2009, and Dec 12, 2019, of whom 203 (40%) were allocated to CEA plus BMT, 197 (38%) to CAS plus BMT, and 113 (22%) to BMT alone. Median follow-up was 59·9 months (IQR 46·6-60·0). The cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years (primary efficacy endpoint) was 2·5% (95% CI 1·0-5·8) with CEA plus BMT, 4·4% (2·2-8·6) with CAS plus BMT, and 3·1% (1·0-9·4) with BMT alone. Cox proportional-hazard testing showed no difference in risk for the primary efficacy endpoint for CEA plus BMT versus BMT alone (hazard ratio [HR] 0·93, 95% CI 0·22-3·91; p=0·93) or for CAS plus BMT versus BMT alone (1·55, 0·41-5·85; p=0·52). Superiority of CEA or CAS to BMT was not shown, therefore non-inferiority testing was not done. In both the CEA group and the CAS group, five strokes and no deaths occurred in the 30-day period after the procedure. During the 5-year follow-up period, three ipsilateral strokes occurred in both the CAS plus BMT and BMT alone group, with none in the CEA plus BMT group.CEA plus BMT or CAS plus BMT were not found to be superior to BMT alone regarding risk of any stroke or death within 30 days or ipsilateral stroke during the 5-year observation period. Because of the small sample size, results should be interpreted with caution.German Federal Ministry of Education and Research (BMBF) and German Research Foundation (DFG).

Target vessel catheterization remains challenging in patients with complex anatomies. Fenestrated endovascular aneurysm repair (FEVAR) is an established technique to treat aortic aneurysms. In this case report, we treated a juxtarenal aneurysm using FEVAR. Initial attempts to complete the target vessel stenting were unsuccessful because of an unfavorable orifice and tortuosity of the right renal artery. The completion of FEVAR was achieved with a bifemoral approach using a snare system, which aligned the tip of a steerable sheath at the level of the fenestration for the right renal artery to create a stable condition. Control angiography and computed tomography confirmed a successful stenting of the target vessel and the sealing of the fenestration without an endoleak.

Summary: Backgrounds: Costs for manual lymphatic drainage (MLD) paid by the Statutory Health Insurances (SHI) have increased disproportionately in Germany in the last decade. There is no obvious reason that this increase is due to an increasing number of patients with lymph edema. We therefore assume that there are large numbers of patients with obesity and obesity-associated dependency syndrome who drive the cost of MLD and did a retrospective analysis of the correlation between hospitalization rates for lymph edema and obesity and MLD prescription rates in outpatients. Patients and methods: Roughly 90 % of the German population is insured by the Statutory Health Insurance. From its reports we extracted data regarding costs and numbers of MLD session prescribed annually. Hospitalization rates for lymph edema (codes I89.*, I97.2 and Q82.0) and for obesity (ICD E66.*) were provided by the Federal Statistical Office after a specific remote analyses. Results: In the years 2008 to 2016, the MLD prescriptions in the individual federal states increased by + 43.5 % in Berlin to + 109.3 % in Mecklenburg-Western Pomerania. Number of hospitalizations with the principal diagnosis (condition, which caused the admission) hereditary and postmastectomy lymph edema are low and decreased in most federal states. Number of hospitalizations with the additional diagnosis (conditions that coexist at the time of admission or develop subsequently) obesity increased with a range from + 4.8 % in Baden-Württemberg to + 86.4 % in Mecklenburg-Western Pomerania. The correlation between the increase in prescribed MLD in the individual federal state and the increase in hospitalization rates per 1000 inhabitants of cases with obesity is greater (R2 0.4696) than with lymph edema (R2 0.0987). Conclusions: Our analysis is in line with the hypothesis that there is a correlation between the increasing prescription rate of MLD and the increasing burden of obesity in Germany.

Introduction We asked if there is a significant correlation between the increasing trend in aortic repair (AR) and decreasing aortic aneurysm (AA) and aortic dissection (AD) mortality? Therefore, we retrospectively analyzed all aortic repairs in patients with AA and AD and its correlation with disease-specific death rates and hospitalizations for ruptured AA and AD in Germany. Methods We retrieved the number of cases hospitalized for AA and AD as well as the procedures in these cases from the Federal Bureau of Statistics (DRG statistics) and death rates from the national mortality statistic published by the Federal Statistical Office in Germany for the years 2006–2017. Results From 2006 to 2017, the total number of hospitalized cases admitted with principal diagnosis of AA increased by 25.8% and that of AD by 56.7%. That of cases with the principal diagnosis of ruptured AA (rAA) remained unchanged (−2.5%) and that with rAD increased by 54.6%. The number of (open and endovascular) procedures in cases hospitalized for AA increased by 39.4% and for AD by 126.4%. The age-adjusted death rates in Germany for AA decreased from 4.0 to 2.9 per 100,000 inhabitants and that for AD increased from 1.0 to 1.4. The decrease in death attributed to AA cases can be described by linear regression as y = −0.0003*y + 6.7076 ( p < 0.0001). Accepting this association between increased elective procedures and reduced AA mortality, each/all 1000 procedures save 0.3 lives per 100,000 inhabitants. Conclusion Despite increasing numbers of AR for AA and AD, only the mortality rate for all AAs decreased, while we did not observe a decrease in overall mortality of AD in Germany.

Background While numerous interventions effectively interfered with abdominal aortic aneurysm (AAA) formation/progression in preclinical models, none of the successes translated into clinical success. Hence, a systematic exploration of parallel and divergent processes in clinical AAA disease and its 2 primary models (the porcine pancreatic elastase and angiotensin‐II infusion [AngII] murine model) was performed to identify mechanisms relevant for aneurysm disease. Methods and Results This study combines Movat staining and pathway analysis for histological and genomic comparisons between clinical disease and its models. The impact of a notable genomic signal for metabolic reprogramming was tested in a rescue trial (AngII model) evaluating the impact of 1‐(4‐pyridinyl)‐3‐(2‐quinolinyl)‐2‐propen‐1‐one (PFK15)‐mediated interference with main glycolytic switch PFKFB3. Histological evaluation characterized the AngII model as a dissection model that is accompanied by adventitial fibrosis. The porcine pancreatic elastase model showed a transient inflammatory response and aortic dilatation, followed by stabilization and fibrosis. Normalization of the genomic responses at day 14 confirmed the self‐limiting nature of the porcine pancreatic elastase model. Clear parallel genomic responses with activated adaptive immune responses, and particularly strong signals for metabolic switching were observed in human AAA and the AngII model. Rescue intervention with the glycolysis inhibitor PFK15 in the AngII model showed that interference with the glycolytic switching quenches aneurysm formation. Conclusions Despite clear morphological contrasts, remarkable genomic parallels exist for clinical AAA disease and the AngII model. The metabolic response appears causatively involved in AAA progression and provides a novel therapeutic target. The clear transient genomic response classifies the porcine pancreatic elastase model as a disease initiation model.

Exact data regarding the clinical role of maggot debridement therapy (MDT) for wound care in a specific country are not available. Thus, we analysed the use of MDT in hospitalised patients in Germany. Detailed lists of all hospitalised cases treated with MDT in Germany for the years 2011 to 2016 were provided by the Federal Statistical Office as well as the lists of the 15 most frequent principal and additional diagnoses, respectively, and the 10 most frequent procedures documented with MDT in 2016. Within the 6‐year time period of the study, the number of cases treated with MDT increased by 11% from 4513 in 2011 to 5.017 in 2016. Lower leg and foot were the most frequent anatomic sides of treatment counting up to 83.9% of all cases. In addition, MDT procedures for temporary soft tissue coverage including negative pressure wound therapy were often performed: for treatment of large areas in 36.7% and small areas in 6.2%. 41.3% of all cases treated with MDT had infection with Escherichia coli and 35.9% of all cases with Bacillus fragilis. Our analysis shows a limited use of MDT with a small increase only in the last 6 years in German hospitals. MDT is predominately used to treat foot or leg ulcers.

Background: The CXCL12/CXCR4 chemokine ligand/receptor axis controls (progenitor) cell homeostasis and trafficking. So far, an atheroprotective role of CXCL12/CXCR4 has only been implied through pharmacological intervention, in particular, because the somatic deletion of the CXCR4 gene in mice is embryonically lethal. Moreover, cell-specific effects of CXCR4 in the arterial wall and underlying mechanisms remain elusive, prompting us to investigate the relevance of CXCR4 in vascular cell types for atheroprotection. Methods: We examined the role of vascular CXCR4 in atherosclerosis and plaque composition by inducing an endothelial cell (BmxCreER T2 -driven)–specific or smooth muscle cell (SMC, SmmhcCreER T2 - or TaglnCre-driven)–specific deficiency of CXCR4 in an apolipoprotein E–deficient mouse model. To identify underlying mechanisms for effects of CXCR4, we studied endothelial permeability, intravital leukocyte adhesion, involvement of the Akt/WNT/β-catenin signaling pathway and relevant phosphatases in VE-cadherin expression and function, vascular tone in aortic rings, cholesterol efflux from macrophages, and expression of SMC phenotypic markers. Finally, we analyzed associations of common genetic variants at the CXCR4 locus with the risk for coronary heart disease, along with CXCR4 transcript expression in human atherosclerotic plaques. Results: The cell-specific deletion of CXCR4 in arterial endothelial cells (n=12–15) or SMCs (n=13–24) markedly increased atherosclerotic lesion formation in hyperlipidemic mice. Endothelial barrier function was promoted by CXCL12/CXCR4, which triggered Akt/WNT/β-catenin signaling to drive VE-cadherin expression and stabilized junctional VE-cadherin complexes through associated phosphatases. Conversely, endothelial CXCR4 deficiency caused arterial leakage and inflammatory leukocyte recruitment during atherogenesis. In arterial SMCs, CXCR4 sustained normal vascular reactivity and contractile responses, whereas CXCR4 deficiency favored a synthetic phenotype, the occurrence of macrophage-like SMCs in the lesions, and impaired cholesterol efflux. Regression analyses in humans (n=259 796) identified the C-allele at rs2322864 within the CXCR4 locus to be associated with increased risk for coronary heart disease. In line, C/C risk genotype carriers showed reduced CXCR4 expression in carotid artery plaques (n=188), which was furthermore associated with symptomatic disease. Conclusions: Our data clearly establish that vascular CXCR4 limits atherosclerosis by maintaining arterial integrity, preserving endothelial barrier function, and a normal contractile SMC phenotype. Enhancing these beneficial functions of arterial CXCR4 by selective modulators might open novel therapeutic options in atherosclerosis.

Circular RNAs (circRNAs) are broadly expressed in eukaryotic cells, but their molecular mechanism in human disease remains obscure. Here we show that circular antisense non-coding RNA in the INK4 locus (circANRIL), which is transcribed at a locus of atherosclerotic cardiovascular disease on chromosome 9p21, confers atheroprotection by controlling ribosomal RNA (rRNA) maturation and modulating pathways of atherogenesis. CircANRIL binds to pescadillo homologue 1 (PES1), an essential 60S-preribosomal assembly factor, thereby impairing exonuclease-mediated pre-rRNA processing and ribosome biogenesis in vascular smooth muscle cells and macrophages. As a consequence, circANRIL induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation, which are key cell functions in atherosclerosis. Collectively, these findings identify circANRIL as a prototype of a circRNA regulating ribosome biogenesis and conferring atheroprotection, thereby showing that circularization of long non-coding RNAs may alter RNA function and protect from human disease., Circular RNAs are widely expressed in eukaryotic cells but their functions and mechanisms of action are still being elucidated. Here the authors show that circANRIL modulates rRNA maturation and confers protection again atherosclerosis.

Background and aimsAn abdominal aortic aneurysm (AAA) is part of the atherosclerotic spectrum of diseases. The disease is hallmarked by a comprehensive localized inflammatory response with striking IL-6 hyperexpression. IL-6 is a multifaceted cytokine that, depending on the context, acts as a pro- or anti-inflammatory factor. In this study, we explore a putative role for IL-6 in AAA disease.MethodsELISA’s, Western blot analysis, real time PCR and array analysis were used to investigate IL-6 expression and signaling in aneurysm wall samples from patients undergoing elective AAA repair. A role for IL-6 in AAA disease was tested through IL-6 neutralization experiments (neutralizing antibody) in the elastase model of AAA disease.ResultsWe confirmed an extreme disparity in aortic wall IL-6 content between AAA and atherosclerotic disease (median [5th–95th percentile] aortic wall IL-6 content: 281.6 [0.0–1820.8] (AAA) vs. 1.9 [0.0–37.8] μg/g protein (atherosclerotic aorta), (p 40% 7-day mortality due to aortic rupture. In contrast, delayed IL-6 neutralization (i.e. neutralization started at day 4 after elastase induction) did not result in ruptures, and quenched AAA growth (p

Abstract. Background: Microarray analysis has been carried out in this pilot study to compare delineated gene expression profiles in the biopsies of skeletal muscle taken from patients with chronic critical limb ischaemia (CLI) and non-ischaemic control subjects. Patients and methods: Biopsy of gastrocnemius muscle was obtained from six patients with unreconstructed CLI referred for surgical major amputation. As control, biopsies of six patients undergoing elective knee arthroplasty without evidence of peripheral arterial occlusive disease were taken. The differences in gene expression associated with angiogenic processes in specimens obtained from ischaemic and non-ischaemic skeletal muscle were confirmed by quantitative real-time polymerase chain reaction (PCR) analysis. Results: Compared with non-ischaemic skeletal muscle biopsy of chronic-ischaemic skeletal muscle contained 55 significantly up-regulated and 45 down-regulated genes, out of which 64 genes had a known genetic product. Tissue samples of ischaemic muscle were characterized by increased expression of cell survival factors (e. g. tissue factor pathway inhibitor 2) in combination with reduced expression of cell proliferation effectors (e. g. microfibrillar-associated protein 5 and transferrin receptor). The expression of growth factors (e. g. early growth response 3 and chemokine receptor chemokine C-X-C motif ligand 4) which play a central role in arterial and angiogenic processes and anti-angiogenetic factors (e. g. pentraxin 3) were increased in chronic ischaemic skeletal muscle. An increased expression of extracellular matrix proteins (e. g. cysteine-rich angiogenic inducer 61) was also observed. Conclusions: Gene expression profiles in biopsies of gastrocnemius muscle in patients with chronic critical limb ischaemia showed an increase in pro-survival factors, extracellular matrix protein deposition, and impaired proliferation, compared with non-ischaemic controls. Further studies are required to analyse the endogenous repair mechanism.

Background Clinical decision making in abdominal aortic aneurysms (AAA) relies completely on diameter. At this point, improved decision tools remain an unmet medical need. Our goal was to identify changes at the molecular level specifically leading up to AAA rupture. Methods and Results Aortic wall tissue specimens were collected during open elective (e AAA ; n=31) or emergency repair of ruptured AAA (r AAA ; n=17), and gene expression was investigated using microarrays. Identified candidate genes were validated with quantitative real‐time polymerase chain reaction in an independent sample set (e AAA : n=46; r AAA : n=18). Two gene sets were identified, 1 set containing 5 genes linked to terminal progression, that is, positively associated with progression of larger AAA , and with rupture ( HILPDA , ANGPTL 4 , LOX , SRPX 2 , FCGBP ), and a second set containing 5 genes exclusively upregulated in rAAA ( ADAMTS 9 , STC 1 , GFPT 2 , GAL 3 ST 4 , CCL 4L1 ). Genes in both sets essentially associated with processes related to impaired tissue remodeling, such as angiogenesis and adipogenesis. In gene expression experiments we were able to show that upregulated gene expression for identified candidate genes is unique for AAA . Functionally, the selected upregulated factors converge at processes coordinated by the canonical HIF ‐1α signaling pathway and are highly expressed in fibroblasts but not inflammatory cells of the aneurysmatic wall. Histological quantification of angiogenesis and exploration of the HIF ‐1α network in r AAA versus e AAA shows enhanced microvessel density but also clear activation of the HIF ‐1α network in r AAA . Conclusions Our study shows a specific molecular fingerprint for terminal AAA disease. These changes appear to converge at activation of HIF ‐1α signaling in mesenchymal cells. Aspects of this cascade might represent targets for rupture risk assessment.

The aim was to evaluate the effect of structured reporting of computed tomography angiography (CTA) runoff studies on clarity, completeness, clinical relevance, usefulness of the radiology reports, further testing, and therapy in patients with known or suspected peripheral arterial disease.Conventional reports (CRs) and structured reports (SRs) were generated for 52 patients who had been examined with a CTA runoff examination of the lower extremities. The sample size was based on power calculations with a power of 95% and a significance level of .007 (adjusted for multiple testing). CRs were dictated in a free text form; SRs contained a consistent ordering of observations with standardised subheadings. CRs were compared with SRs. Two vascular medicine specialists and two vascular surgeons rated the reports regarding their satisfaction with clarity, completeness, clinical relevance, and usefulness as well as overall satisfaction. Additionally, they made hypothetical decisions on further testing and therapy. Median ratings were compared using the Wilcoxon signed rank test and generalised linear mixed effects models.SRs received higher ratings for satisfaction with clarity (median rating 9.0 vs. 7.0, p .0001) and completeness (median rating 9.0 vs. 7.5, p .0001) and were judged to be of greater clinical relevance (median rating 9.0 vs. 8.0, p .0001) and usefulness (median rating 9.0 vs. 8.0, p .0001). Overall satisfaction was also higher for SRs (median rating 9.0 vs. 7.0, p .0001) than CRs. There were no significant differences in further testing or therapy.Referring clinicians perceive SRs of CTA runoff examinations of the lower extremities as offering superior clarity, completeness, clinical relevance, and usefulness than CRs. Structured reporting does not appear to alter further testing or therapy in patients with known or suspected peripheral arterial disease.

The objective of this study was to determine the long-term quality of life (QOL) in patients with an abdominal aortic aneurysm (AAA) undergoing surveillance or after operative treatment.249 patients with AAAs completed the WHO Quality of Life-BREF (WHOQOL-BREF) test and Short Form (36) Health Survey (SF-36) survey: 78 patients with small AAAs under surveillance, 26 after ruptured AAAs (rAAAs), 47 after endovascular aneurysm repair (EVAR), and 98 after elective open repair. The results were compared with WHOQOL-BREF and SF-36 standard values from a matched German population using the Student's 2-tailed t-test.Long-term results of the WHOQOL-BREF test showed that patients undergoing AAA surveillance had a significantly lower physical QOL (P = 0.04). Patients after EVAR or open repair rated their environmental QOL significantly higher than the age- and sex-matched general population (open repair: P = 0.006; EVAR: P0.001). Patients with rAAAs had the same QOL as the matched German population. Long-term results of the QOL SF-36 showed that patients undergoing AAA surveillance rated their QOL significantly lower in the subgroup of role-physical (P = 0.02) and role-emotional (P = 0.003). Patients with rAAAs rated lower scores for role-physical (P = 0.02) and had more bodily pain (P = 0.02). Patients who underwent elective open repair had the same high QOL as the matched German population, whereas patients who underwent EVAR reported significant improvement in vitality (P = 0.002) and mental health (P = 0.03) compared with the matched German population.Based on measurements from 2 independent QOL tests, the well-established operative treatment of AAAs provided patients with a QOL comparable to that of a matched German population. The electively treated AAA groups rated environmental QOL factors significantly higher than the control group. The impaired physical and emotional QOL of the AAA group under surveillance suggests that more intense patient education could be beneficial.

The processes driving human abdominal aortic aneurysm (AAA) progression are not fully understood. Although antiinflammatory and proteolytic strategies effectively quench aneurysm progression in preclinical models, so far all clinical interventions failed. These observations hint at an incomplete understanding of the processes involved in AAA progression and rupture. Interestingly, strong clinical and molecular associations exist between popliteal artery aneurysms (PAAs) and AAAs; however, PAAs have an extremely low propensity to rupture. We thus reasoned that differences between these aneurysms may provide clues toward (auxiliary) processes involved in AAA-related wall debilitation. A better understanding of the pathophysiologic processes driving AAA growth can contribute to pharmaceutical treatments in the future.Aneurysmal wall samples were collected during open elective and emergency repair. Control perirenal aorta was obtained during kidney transplantation, and reference popliteal tissue obtained from the anatomy department. This study incorporates various techniques including (immuno)histochemistry, Western Blot, quantitative polymerase chain reaction, microarray, and cell culture.Histologic evaluation of AAAs, PAAs, and control aorta shows extensive medial (PAA) and transmural fibrosis (AAA), and reveals abundant adventitial adipocytes aggregates as an exclusive phenomenon of AAAs (P .001). Quantitative polymerase chain reaction, immunohistochemistry, Western blotting, and microarray analysis showed enrichment of adipogenic mediators (C/EBP family P = .027; KLF5 P .000; and peroxisome proliferator activated receptor-γ, P = .032) in AAA tissue. In vitro differentiation tests indicated a sharply increased adipogenic potential of AAA adventitial mesenchymal cells (P .0001). Observed enrichment of adipocyte-related genes and pathways in ruptured AAA (P .0003) supports an association between the extent of fatty degeneration and rupture.This translational study identifies extensive adventitial fatty degeneration as an ignored and distinctive feature of AAA disease. Enrichment of adipocyte genesis and adipocyte-related genes in ruptured AAA point to an association between the extent of fatty degeneration and rupture. This observation may (partly) explain the failure of medical therapy and could provide a lead for pharmaceutical alleviation of AAA progression.

Die periphere arterielle Verschlusskrankheit ist eine Manifestation der Systemerkrankung Atherosklerose. Die initiale Therapie jeder atherosklerotischen Gefaserkrankung zielt auf eine Reduktion kardiovaskularer Risikofaktoren durch Lebensstilmodifikation und medikamentose Masnahmen. Patienten, die sich einer operativen Revaskularisation im peripheren Gefassystem unterziehen mussen, benotigen zudem eine langfristige antithrombozytare Therapie bzw. Antikoagulation, die differenziert nach dem befallenen vaskularen Territorium und der verwendeten Methode zur Revaskularisation gestaltet werden muss. Die aktuelle Studienlage empfiehlt in der Langzeittherapie nach lokaler Thrombendarteriektomie und nach alloplastischen (Dacron, PTFE) Bypassen der aortalen und supragenualen Region ASS 100 mg/d oder Clopidogrel 75 mg/d. Nach Anlage kniegelenksuberschreitender alloplastischer Bypasse ist die Kombination von ASS 100 mg/d und Clopidogrel 75 mg/d empfohlen. Demgegenuber profitieren in der Langzeittherapie nach autologer (v. a. venoser) Bypassanlage jeglicher Region Patienten von einer oralen Antikoagulation mit Vit.-K-Antagonisten (INR 2–3), wenn ein niedriges Blutungsrisiko besteht. Bei Kontraindikationen empfiehlt sich die Gabe von ASS 100 mg/d. Im weiteren Verlauf ist eine systematische Kontrolle der Gefasrisikofaktoren, des Gefasstatus, der Antikoagulation bzw. der antithrombotischen Therapie indiziert.

Infectious agents are likely to play a role in the pathogenesis of chronic inflammatory diseases, including abdominal aortic aneurysms (AAAs). The goal of this study was to determine if Borrelia burgdorferi sensu lato (sl), a microorganism responsible for Lyme disease, is involved in the etiology of AAAs. The presence of serum antibodies against B. burgdorferi sl was measured with enzyme-linked immunosorbent assay (ELISA) and confirmed by Western blotting in 96 AAA and 108 peripheral artery disease (PAD) patients. Polymerase chain reaction (PCR) was used for the detection of Borrelia-specific DNA in the aneurysm wall. Among AAA patients 34% and among PAD patients 16% were seropositive for B. burgdorferi sl antibodies (Fisher’s exact test, p = 0.003; odds ratio [OR] 2.79; 95% confidence interval [CI] 1.37–5.85). In the German general population, 3–17% are seropositive for Borrelia antibodies. No Borrelia DNA was detected in the aneurysm wall. Our findings suggest a relationship between AAAs and B. burgdorferi sl. We hypothesize that the underlying mechanism for B. burgdorferi sl in AAA formation is similar to that by the spirochete Treponema pallidum; alternatively, AAAs could develop due to induced autoimmunity via molecular mimicry due to similarities between some of the B. burgdorferi sl proteins and aortic proteins.

Objective The pathophysiology underlying the chromosome (Chr) 9p21 locus of atherosclerosis susceptibility is presently unknown. Here, we sought to determine whether protein coding genes in the Chr9p21 region, i.e. cyclin-dependent kinase inhibitors CDKN2B (p15 INK4b ), CDKN2A (p16 INK4a , p14 ARF ) and methylthioadenosine phosphorylase (MTAP) were expressed in human atherosclerotic lesions and whether expression was correlated with lesion composition. Methods and results Protein expression of p15 INK4b , p16 INK4a , p14 ARF and MTAP was demonstrated by immunostaining in normal and atherosclerotic coronary arteries and co-localized with CD68 and smooth muscle alpha-actin positive cells. Quantitative RT-PCR in human endarteryectomy specimens ( n =57) revealed increased p16 INK4a and decreased MTAP expression in macrophage-rich lesions ( P P =0.007, respectively). Functional studies suggest that decreased MTAP expression in macrophage-rich lesions might be mediated through down-regulation by TNF-alpha. No clear association of p15 INK4b , p16 INK4a , p14 ARF , and MTAP expression in plaque tissue with Chr9p21 haplotypes was found. The latter finding was corroborated by the lack of correlation of RNA expression of 9p21-regulated transcripts EU741058 and NR_003529 of antisense non-coding RNA in the INK4 locus ( ANRIL ) with mRNA expression of these genes. In contrast, ANRIL DQ485454 which is not genetically determined by the 9p21 genotype was significantly correlated with MTAP expression ( P =0.01). Conclusion CDKN2B (p15 INK4b ), CDKN2A (p16 INK4a , p14 ARF ), and MTAP are abundantly expressed in atherosclerotic lesions. While expression levels showed no clear association with Chr9p21 genotype, association of high p16 INK4a and low MTAP expression with a less stable plaque phenotype suggests a more general role of these proteins in atherogenesis.

Objective— We tested the hypothesis that expression of transcripts adjacent to the chromosome 9p21 (Chr9p21) locus of coronary artery disease was affected by the genotype at this locus and associated with atherosclerosis risk. Methods and Results— We replicated the locus for coronary artery disease ( P =0.007; OR=1.28) and other manifestations of atherosclerosis such as carotid plaque ( P =0.003; OR=1.31) in the Leipzig Heart Study, a cohort of 1134 patients with varying degree of angiographically assessed coronary artery disease. Expression analysis in peripheral blood mononuclear cells (n=1098) revealed that transcripts EU741058 and NR_003529 of antisense noncoding RNA in the INK4 locus ( ANRIL ) were significantly increased in carriers of the risk haplotype ( P =2.1×10 −12 and P =1.6×10 −5 , respectively). In contrast, transcript DQ485454 remained unaffected, suggesting differential expression of ANRIL transcripts at Chr9p21. Results were replicated in whole blood (n=769) and atherosclerotic plaque tissue (n=41). Moreover, expression of ANRIL transcripts was directly correlated with severity of atherosclerosis ( EU741058 and NR_003529 ; P =0.02 and P =0.001, respectively). No consistent association of Chr9p21 or atherosclerosis was found with expression of other genes such as CDKN2A , CDKN2B , C9orf53 , and MTAP . Conclusion— Our data provide robust evidence for an association of ANRIL but not CDKN2A, CDKN2B, C9orf53 , and MTAP , with atherosclerosis and Chr9p21 genotype in a large cohort.

Background. Close therapeutic drug monitoring of Cyclosporine (CsA) in transplant outpatients is a favourable procedure to maintain the long-term blood drug levels within their respective narrow therapeutic ranges. Compared to basal levels (C0), CsA peak levels (C2) are more predictive for transplant rejection. However, the application ofC2levels is hampered by the precise time of blood sampling and the need of qualified personnel. Therefore, we evaluated a newC2self-obtained blood sampling in transplant outpatients using dried capillary and venous blood samples and compared the CsA levels, stability, and clinical practicability of the different procedures.Methods. 55 solid organ transplant recipients were instructed to use single-handed sampling of each 50μL capillary blood and dried blood spots by finger prick using standard finger prick devices. We used standardized EDTA-coated capillary blood collection systems and standardized filter paper WS 903. CsA was determined by LC-MS/MS. The patients and technicians also answered a questionnaire on the procedure and sample quality.Results. TheC0andC2levels from capillary blood collection systems (C0[ng/mL]:114.5±44.5;C2:578.2±222.2) and capillary dried blood (C0[ng/mL]:175.4±137.7;C2:743.1±368.1) significantly(P<.01)correlated with the drug levels of the venous blood samples (C0[ng/mL]:97.8±37.4;C2:511.2±201.5). The correlation atC0wasρcap.-ven.= 0.749, andρdried blood-ven= 0.432; atC2: ρcap.-ven.= 0.861 andρdried blood-ven= 0.711. The patients preferred the dried blood sampling because of the more simple and less painful procedure. Additionally, the sample quality of self-obtained dried blood spots for LC-MS/MS analytics was superior to the respective capillary blood samples.Conclusions.C2self-obtained dried blood sampling can easily be performed by transplant outpatients and is therefore suitable and cost-effective for close therapeutic drug monitoring.

Vascular injuries are an uncommon finding. In times of peace vascular injuries occur in approximately 1-4 % during traffic accidents. Especially challenging is the treatment of open fractures combined with arterial lesions. These fractures are usually accompanied with severe soft tissue damage and injuries to neurological structures. The overall prognosis of these trauma patients is dependent on fast and sufficient diagnostics and therapy. In particular, for unstable patients time-consuming diagnostics can be dispensed and a primarily operative therapy should be targeted. Vascular reconstruction by direct suture is sometimes only possible with interposition and should be the primary goal. Interposition should be performed with autologous vein material because of the high risk of infection. Here we demonstrate on the basis of our patients the interdisciplinary -management of such trauma patients in our hospital.

Abdominal aortic aneurysm (AAA) and aortic occlusive disease (AOD) represent common causes of morbidity and mortality in elderly populations which were previously believed to have common aetiologies. The aim of this study was to assess the gene expression in human AAA and AOD. We performed microarrays using aortic specimen obtained from 20 patients with small AAAs (≤ 55mm), 29 patients with large AAAs (> 55mm), 9 AOD patients, and 10 control aortic specimens obtained from organ donors. Some differentially expressed genes were validated by quantitative- PCR (qRT-PCR)/immunohistochemistry. We identified 840 and 1,014 differentially expressed genes in small and large AAAs, respectively. Immune-related pathways including cytokine-cytokine receptor interaction and T-cell-receptor signalling were upregulated in both small and large AAAs. Examples of validated genes included CTLA4 (2.01-fold upregulated in small AAA, P = 0.002), NKTR (2.37-and 2.66-fold upregulated in small and large AAA with P = 0.041 and P = 0.015, respectively), and CD8A (2.57-fold upregulated in large AAA, P = 0.004). 1,765 differentially expressed genes were identified in AOD. Pathways upregulated in AOD included metabolic and oxidative phosphorylation categories. The UCP2 gene was downregulated in AOD (3.73-fold downregulated, validated P = 0.017). In conclusion, the AAA and AOD transcriptomes were very different suggesting that AAA and AOD have distinct pathogenic mechanisms.

The chromosome 9p21 (Chr9p21) locus of coronary artery disease has been identified in the first surge of genome-wide association and is the strongest genetic factor of atherosclerosis known today. Chr9p21 encodes the long non-coding RNA (ncRNA) antisense non-coding RNA in the INK4 locus (ANRIL). ANRIL expression is associated with the Chr9p21 genotype and correlated with atherosclerosis severity. Here, we report on the molecular mechanisms through which ANRIL regulates target-genes in trans, leading to increased cell proliferation, increased cell adhesion and decreased apoptosis, which are all essential mechanisms of atherogenesis. Importantly, trans-regulation was dependent on Alu motifs, which marked the promoters of ANRIL target genes and were mirrored in ANRIL RNA transcripts. ANRIL bound Polycomb group proteins that were highly enriched in the proximity of Alu motifs across the genome and were recruited to promoters of target genes upon ANRIL over-expression. The functional relevance of Alu motifs in ANRIL was confirmed by deletion and mutagenesis, reversing trans-regulation and atherogenic cell functions. ANRIL-regulated networks were confirmed in 2280 individuals with and without coronary artery disease and functionally validated in primary cells from patients carrying the Chr9p21 risk allele. Our study provides a molecular mechanism for pro-atherogenic effects of ANRIL at Chr9p21 and suggests a novel role for Alu elements in epigenetic gene regulation by long ncRNAs., Author Summary Chromosome 9p21 is the strongest genetic factor for coronary artery disease and encodes the long non-coding RNA (ncRNA) ANRIL. Here, we show that increased ANRIL expression mediates atherosclerosis risk through trans-regulation of gene networks leading to pro-atherogenic cellular properties, such as increased proliferation and adhesion. ANRIL may act as a scaffold, guiding effector-proteins to chromatin. These functions depend on an Alu motif present in ANRIL RNA and mirrored several thousand-fold in the genome. Alu elements are a family of primate-specific short interspersed repeat elements (SINEs) and have been linked with genetic disease. Current models propose that either exonisation of Alu elements or changes of cis-regulation of adjacent genes are the underlying disease mechanisms. Our work extends the function of Alu transposons to regulatory components of long ncRNAs with a central role in epigenetic trans-regulation. Furthermore, it implies a pivotal role for Alu elements in genetically determined vascular disease and describes a plausible molecular mechanism for a pro-atherogenic function of ANRIL at chromosome 9p21.

Peripheral arterial disease (PAD) is one of the most underestimated diseases because of its high prevalence and unfavorable prognosis. Many PAD patients without suitable autologous veins or options for endovascular treatment receive prosthetic above-knee femoropopliteal bypass (PAKB). Until now predictors of prosthetic bypass failure and of increased amputation risk remain indistinct. This study aimed to identify predictive factors associated with better bypass patency and limb salvage to achieve a more favorable outcome after PAKB reconstruction.Pre-, intra-, and postoperative data of 244 PAKB procedures performed at a German university medical center were collected and analyzed using univariate and multivariate methods. To our knowledge this 12-year experience is the largest retrospective study to identify predictors for patency and limb salvage after PAKB reconstruction.Of the PAD patients 94% (229/244) were followed for an average of 34.9 months. Patient cohorts characteristics were: mean age, 66.1 years, 181 men (74%), claudication (64%), rest pain (16%), ischemic lesions (20%), arterial hypertension (92%), smoking (79%), hyperlipidemia (65%) and type 2 diabetes (43%). Cumulative primary 1- and 3-year graft patency rates were 60.8% and 50.7%, respectively, and cumulative 1- and 3-year limb salvage rates were 89.3% and 86.1%, respectively. One hundred seven bypasses (43.9%) failed, 26 patients (10.7%) required a major and seven patients (2.9%) required a minor amputation. Overall survival rates of PAD patients after 1- and 3-years were 94.4% and 82.9%, respectively. Subjective symptom improvement was found to be the most important prognostic follow-up factor for graft patency and limb salvage. Patients with recurrent symptoms in the follow-up had an increased risk of emerging bypass failure compared with patients with subjective symptom improvement (patency at 1 year: 40.8% vs 100% and at 3 years: 26% vs 100%; P .001). No patient with subjective improvement in symptoms during follow-up underwent an amputation (limb salvage at 1 year: 100% vs 79% and at 3 years: 100% vs 72.8%; P .001). Therefore, subjective symptom improvement should be the decisive criterion to determine follow-up intervals of PAD patients. In univariate analysis further significant factors associated with better graft patency and limb salvage rates were: claudication compared with critical ischemia, larger graft diameter (6 mm), pre- and postoperative antiplatelet therapy, statin therapy independent from lipid values after PAKB revascularization, and an experienced vascular surgeon.In our study, we determined the subjective improvement in symptoms as the most important prognostic factor for bypass function and limb salvage after PAKB. Furthermore, disease stage of critical ischemia, graft diameter, preoperative aspirin use, and postoperative statin medication were independent predictive factors. Therefore, PAD patients should be treated with aspirin pre- and postoperatively as well as with a statin postoperatively. In case of PAKB reconstruction only prostheses with a large diameter (6 mm) should be used and the procedure should be performed by an experienced surgeon. Considering these results with regard to the predictive factors for better graft patency and limb salvage rates a significant more favorable outcome during the follow-up and an increased 5-year patency rate for PAKB reconstructions can be expected.

Background Human ß-defensins are a family of antimicrobial peptides located at the mucosal surface. Both sequence multi-site variations (MSV) and copy-number variants (CNV) of the defensin-encoding genes are associated with increased risk for various diseases, including cancer and inflammatory conditions such as psoriasis and acute pancreatitis. In a case–control study, we investigated the association between MSV in DEFB104 as well as defensin gene (DEF) cluster copy number (CN), and pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). Results Two groups of PDAC (N=70) and CP (N=60) patients were compared to matched healthy control groups CARLA1 (N=232) and CARLA2 (N=160), respectively. Four DEFB104 MSV were haplotyped by PCR, cloning and sequencing. DEF cluster CN was determined by multiplex ligation-dependent probe amplification. Neither the PDAC nor the CP cohorts show significant differences in the DEFB104 haplotype distribution compared to the respective control groups CARLA1 and CARLA2, respectively. The diploid DEF cluster CN exhibit a significantly different distribution between PDAC and CARLA1 (Fisher’s exact test P=0.027), but not between CP and CARLA2 (P=0.867). Conclusion Different DEF cluster b CN distribution between PDAC patients and healthy controls indicate a potential protective effect of higher CNs against the disease.

Background Abdominal aortic aneurysm (AAA) is a dilatation of the aorta affecting most frequently elderly men. Histologically AAAs are characterized by inflammation, vascular smooth muscle cell apoptosis, and extracellular matrix degradation. The mechanisms of AAA formation, progression, and rupture are currently poorly understood. A previous mRNA expression study revealed a large number of differentially expressed genes between AAA and non-aneurysmal control aortas. MicroRNAs (miRNAs), small non-coding RNAs that are post-transcriptional regulators of gene expression, could provide a mechanism for the differential expression of genes in AAA. Methods To determine differences in miRNA levels between AAA (n = 5) and control (n = 5) infrarenal aortic tissues, a microarray study was carried out. Results were adjusted using Benjamini-Hochberg correction (adjusted p Results A microarray study identified eight miRNAs with significantly different expression levels between AAA and controls (adjusted p Conclusions Our genome-wide approach revealed several differentially expressed miRNAs in human AAA tissue suggesting that miRNAs play a role in AAA pathogenesis.

We compared relative survival rates of patients after various operative treatments for abdominal aortic aneurysm (AAA) to those for the general population. We calculated a point of “recovery,” defined as the survival rate equal to that of the general population. Survival data were collected from patients who underwent open repair for a ruptured AAA (rAAA), elective open repair of an AAA (OPEN), and endovascular repair (EVAR) in our hospital between 1995 and 2005. The cumulative relative survival rate and time-specific relative survival rate were calculated for these patients compared to those for the general population. The point of “recovery” was defined as the cumulative relative survival rate equaling the survival rate for the population, and the time-specific relative survival rate reaching 1.0. The cumulative relative survival rate of the patients immediately after OPEN was lower than for the comparison group at the time the cumulative relative survival rate was regained. The time-specific relative survival rate of the rAAA reached 1.0 at 16 months following emergency surgery, and for OPEN after 10 months. The cumulative relative survival rate in the EVAR group had no impairment following intervention. The relative long-term survival rate in all three surgical groups was the same as that for the general German population. Patients treated successfully for AAA have the same relative long-term survival as the general population. The time required to reach the same survival, however, differs between the treatment groups and is longest in the group with a rAAA. The variable survival rates should be taken into consideration when treating patients with an AAA.

A 77-year-old, high-risk woman with symptomatic aortic valve stenosis (aortic valve area 0.77 cm(2)) underwent coronary artery catheterization and right heart catheterization. After catheterization, she suddenly developed hemoptysis, and became hypoxic and hypotonic. She was intubated and the bleeding was stopped using positive end-expiratory pressure. Chest X-ray and computed tomography showed a pulmonary artery (PA) pseudoaneurysm with a maximum diameter of 40 mm at the right middle lobe. Endovascular treatment approaches by coil embolization failed, so surgical resection was indicated. In preparation for the procedure and to reduce perioperative risk, transapical aortic valve implantation was performed. The operation took about 40 minutes and the intraoperative activated clotting time was controlled at 180-200 sec. After successful transapical aortic valve implantation, aneurysmectomy was performed. Intraoperatively, the PA pseudoaneurysm was found to occupy nearly the entire middle lobe. A right middle lobectomy was performed. The operative course was uneventful. Transapical aortic valve implantation may have eliminated the risk of rupture or re-bleeding in such bleeding-prone patient.

The objective of this study was to investigate the effect of a specific endothelin(A) receptor antagonist (ET(A)-RA) on mRNA expression of genes encoding vasoactive mediators and proinflammatory cytokines and on the microhemodynamics (assessed by measurement of laser Doppler flow and tissue blood gases) following complete vascular exclusion of the porcine liver.Sixteen adult German landrace pigs were subjected to 120 min of warm hepatic ischemia by total vascular exclusion. To avoid portal congestion, a passive porto-femoro/jugular bypass was implanted. The animals were divided into 2 groups: the control group received saline solution and the therapy group was given the selective ET(A)-RA BSF 208075. Hepatic microcirculation was evaluated by p(O(2)) and p(CO(2)) measurement with the Paratrend sensor and by laser Doppler flow measurement. Liver tissue samples were collected 1 h after reperfusion and quantitative mRNA expression for prepro-ET-1, pro-IL-1beta, pro-IL-6, pro-TNF-alpha, eNOS was analyzed using the TaqMan system. Additionally, immunohistochemical analysis using a semiquantitative score for ET-1 was performed. Postischemic liver damage was monitored by measurement of liver enzymes and assessed by histological analysis using a semiquantitative scoring classification.Partial oxygen pressure in the hepatic tissue and laser Doppler flow were significantly improved in the therapy group. One hour after reperfusion, quantitative RT-PCR revealed significantly lower expression of prepro-ET-1, eNOS, pro-TNF-alpha, and pro-IL-6 in the therapy group compared to controls. Immunohistochemical analysis demonstrated significantly reduced ET-1 immunostaining after therapy. Furthermore, blockade of ET(A) receptors prevents tissue damage.Treatment with the selective ET(A)-RA BSF 208075 has protective effects on microcirculation after 120 min liver ischemia and reperfusion. The authors were able to show that ET(A)-RA not only affects the expression of vasoactive genes, but also decreases gene expression of proinflammatory cytokines such as TNF-alpha and IL-6.

The effect of prophylactic administration of a selective endothelin(A) receptor antagonist (ET(A)-RA) on ischemia/reperfusion injury in an experimental model of graft pancreatitis after pancreas transplantation was evaluated.It is well established that endothelin-1 (ET-1), a powerful vasoconstrictor, plays an important role in the development of pancreatitis. Recent studies have shown a beneficial effect of endothelin receptor antagonists in the therapy for experimental pancreatitis.Relevant ischemia/reperfusion injury was induced in pig pancreas transplants after 6 hours hypothermic preservation in University of Wisconsin solution. The recipients were randomized into 2 groups: control pigs received isotonic saline and the treated group received the selective ET(A)-RA BSF 208075 at the beginning of reperfusion. On postoperative days 2 and 5, animals were relaparotomized to obtain tissue specimens. Blood monitoring included lipase, amylase, C-reactive protein, trypsinogen-activation peptide, thiobarbituric acid-reacting substances, and ET-1. Partial oxygen tension (p(ti)O(2)) was measured by a Clarke-type electrode and blood flow by laser doppler. A semiquantitative score index was used for assessment of histologic injury and for immunohistochemical analysis of ET-1 and ET(A) receptor expression. Tissue mRNA levels of prepro ET-1, ET(A) receptor, pro-interleukin (IL)-6, and pro-IL-1beta were quantified using TaqMan real-time reverse transcription-polymerase chain reaction (RT-PCR).Prophylactic treatment with ET(A)-RA significantly reduced the severity of graft pancreatitis evidenced by C-reactive protein. The finding of transient capillary perfusion at the beginning of reperfusion supports the application of the ET(A)-RA during this period. The dramatic increase of plasma ET-1 in the therapy group is a clear evidence of effective receptor blockade. Mean trypsinogen-activation peptide levels from the portal venous effluent, but not mean systemic plasma TAP values were significantly lower in the treated group. Analysis of p(ti)O(2) and blood flow revealed a significant improvement of capillary perfusion and blood flow in the treated group and was associated with relevant reduction of tissue injury. Intrapancreatic ET-1 and IL-6 mRNA expression and ET-1 protein levels were significantly lower in the therapy group as compared with the control group. In contrast, ET(A) mRNA showed a marked up-regulation by ET(A) receptor blockade.Application of a ET(A)-RA reduces ischemia/reperfusion induced graft pancreatitis in a pig transplantation model by improving microcirculation and reducing tissue injury.