Outcome of Endovascular and Open Treated Penetrating Aortic Ulcers.

PURPOSE: Penetrating aortic ulcer (PAU) is a rare etiology of acute aortic syndrome. Few studies exist regarding the perioperative outcome. The aim was to analyze clinical outcome and risk factors of mortality in this treatment population. METHODS: Retrospective, monocentric study from 2010 to 2021. Clinical data of endovascular or open treated PAU were analyzed. In-hospital mortality was selected as the primary study endpoint. Angio-morphologies were analyzed and risk factors for mortality were identified by using univariate analysis. RESULTS: Overall, 133 patients were identified. 29% (n=38) of patients presented symptomatically. In 64% (n=85), the PAU was localized in the thoracic aorta. On average, PAUs had a depth of 15.4±10.1 mm and a width of 17.9±9.6 mm. The patients had a median of 2 (95% confidence interval [CI]=2-3) high-risk features (HRF) as PAU depth >10 mm, PAU width >20 mm, aortic diameter >40 mm, symptomatic, intramural hematoma (IMH), pleural effusion. Significantly more HRF were observed in symptomatic patients (p=0.01). 53% (n=71) of patients were treated with thoracic endovascular aortic repair (TEVAR), 41% (n=54) by endovascular aortic repair (EVAR), and 6% (n=8) by open surgery. A hybrid procedure with cervical debranching was performed in 16% (n=21) and complex endovascular repair with fenestrated or branched endografts in 15% (n=20). Overall, complications greater than grade II according to the Clavien-Dindo classification occurred in 19% (n=25) and of the patients. In-hospital mortality manifested in 6% (n=8). Factors associated with increased mortality were the diameter of the aorta >40 mm (88% vs 39%, p=0.03), as well as symptomatic patients (63% vs 26%, p=0.04), coincident IMHs (38% vs 10%, p=0.05), and complex endovascular procedures (50% vs 50% p<0.01). Penetrating aortic ulcer width >20 mm tended to show higher mortality (75% vs 40%, p=0.06). Routine follow-up was available for 89% (n=117) for a median of 39 months (95% CI=25-42). One-year and 5-year survival were 83% and 60%, respectively, with 1 aortic pathology-related death. CONCLUSIONS: Treatment of PAU is associated with an acceptable perioperative morbidity and mortality. Risk factors associated with increased mortality are an elevated aortic diameter, the presence of IMHs, clinical symptomatology at presentation, and complex endovascular procedures.

Targeting long non-coding RNA NUDT6 enhances smooth muscle cell survival and limits vascular disease progression.

Long non-coding RNAs (lncRNAs) orchestrate various biological processes and regulate the development of cardiovascular diseases. Their potential therapeutic benefit to tackle disease progression has recently been extensively explored. Our study investigates the role of lncRNA Nudix Hydrolase 6 (NUDT6) and its antisense target fibroblast growth factor 2 (FGF2) in two vascular pathologies: abdominal aortic aneurysms (AAA) and carotid artery disease. Using tissue samples from both diseases, we detected a substantial increase of NUDT6, whereas FGF2 was downregulated. Targeting Nudt6 in vivo with antisense oligonucleotides in three murine and one porcine animal model of carotid artery disease and AAA limited disease progression. Restoration of FGF2 upon Nudt6 knockdown improved vessel wall morphology and fibrous cap stability. Overexpression of NUDT6 in vitro impaired smooth muscle cell (SMC) migration, while limiting their proliferation and augmenting apoptosis. By employing RNA pulldown followed by mass spectrometry as well as RNA immunoprecipitation, we identified Cysteine and Glycine Rich Protein 1 (CSRP1) as another direct NUDT6 interaction partner, regulating cell motility and SMC differentiation. Overall, the present study identifies NUDT6 as a well-conserved antisense transcript of FGF2. NUDT6 silencing triggers SMC survival and migration and could serve as a novel RNA-based therapeutic strategy in vascular diseases.

Mesenteric Ischemia after Cardiac Surgery.

BACKGROUND: Mesenteric ischemia (Me-Is) after cardiac surgery is underreported in present literature but has still earned the bad reputation of a dismal prognosis. This study adds clinical outcomes in a large patient cohort. METHODS: Between 2009 and 2019 of the 22,590 patients undergoing cardiac surgery at our facility 106 (0.47%) developed Me-Is postoperatively. Retrospective patient data was analyzed. Additionally, patients were stratified by outcome-survivors and nonsurvivors. RESULTS: Patients were predominantly male (n = 68, 64.2%), mean age was 71.2 ± 9.3 years. Most procedures were elective (n = 85, 80.2%) and comprised of more complex combined procedures (50.9%) and redos (17.9%). Mean EuroSCORE II averaged 10.9 ± 12.2%. Survival at 30 days was 49.1% (n = 52). Clinical baseline and procedural characteristics did not differ significantly between survivors and nonsurvivors. The median postoperative interval until symptom onset was 5 days in both groups. Survivors were more frequently diagnosed by computed tomography and nonsurvivors based on clinical symptoms. Me-Is was predominantly nonocclusive (n = 84, 79.2%). Laparotomy was the main treatment in both groups (n = 45, 78.8% vs. n = 48, 88.9%, p = 0.94). Predictors of mortality were maximum norepinephrine doses (hazard ratio [HR] 8.29, confidence interval [CI] 3.39-20.26, p < 0.0001), lactate levels (HR 1.06, CI 1.03-1.09), and usage of inotropes (HR 2.46, CI 1.41-4.30). CONCLUSION: The prognosis of Me-Is following cardiac surgery is poor-independently from diagnostic or treatment patterns. There exists a significant asymptomatic time period postoperatively, in which pathophysiologic processes seem to cross the Rubicon. After clinical demarcation, the further course can almost no longer be influenced.

Radiation therapy for cancer is potentially associated with reduced growth of concomitant abdominal aortic aneurysm.

PURPOSE: Co-prevalence of abdominal aortic aneurysm (AAA) and cancer poses a unique challenge in medical care since both diseases and their respective therapies might interact. Recently, reduced AAA growth rates were observed in cancer patients that received radiation therapy (RT). The purpose of this study was to perform a fine-grained analysis of the effects of RT on AAA growth with respect to direct (infield) and out-of-field (outfield) radiation exposure, and radiation dose-dependency. METHODS: A retrospective single-center analysis identified patients with AAA, cancer, and RT. Clinical data, radiation plans, and aneurysm diameters were analyzed. The total dose of radiation to each aneurysm was computed. AAA growth under infield and outfield exposure was compared to patients with AAA and cancer that did not receive RT (no-RT control) and to an external noncancer AAA reference cohort. RESULTS: Between 2003 and 2020, a total of 38 AAA patients who had received well-documented RT for their malignancy were identified. AAA growth was considerably reduced for infield patients (n = 18) compared to outfield patients (n = 20), albeit not significantly (0.8 ± 1.0 vs. 1.3 ± 1.6 mm/year, p = 0.28). Overall, annual AAA growth in RT patients was lower compared to no-RT control patients (1.1 ± 1.5 vs. 1.8 ± 2.2 mm/year, p = 0.06) and significantly reduced compared to the reference cohort (1.1 ± 1.5 vs. 2.7 ± 2.1 mm/year, p < 0.001). The pattern of AAA growth reduction due to RT was corroborated in linear regression analyses correcting for initial AAA diameter. A further investigation with respect to dose-dependency of radiation effects on AAA growth, however, revealed no apparent association. CONCLUSION: In this study, both infield and outfield radiation exposure were associated with reduced AAA growth. This finding warrants further investigation, both in a larger scale clinical cohort and on a molecular level.

CXCR4 - a possible serum marker for risk stratification of abdominal aortic aneurysms.

Background: Abdominal aortic aneurysm (AAA) rupture is still associated with a mortality rate of 80-90%. Imaging techniques or molecular fingerprinting for patient-specific risk stratification to identify pending rupture are still lacking. The chemokine (C-X-C motif) receptor (CXCR4) activation by CXCL12 ligand has been identified as a marker of inflammation and atherosclerosis, associated with AAA. Both are highly expressed in the aortic aneurysm wall. However, it is still unclear whether different expression levels of CXCR4 and CXCL12 can distinguish ruptured AAAs (rAAA) from intact AAAs (iAAA). Patients and methods: Abdominal aortic tissue samples (rAAA: n=29; iAAA: n=54) were excised during open aortic repair. Corresponding serum samples from these patients (n=9 from rAAAs; n=47 from iAAA) were drawn pre-surgery. Healthy aortic tissue samples (n=8) obtained from adult kidney donors during transplantation and serum samples from healthy adult volunteers were used as controls (n=5 each). Results: CXCR4 was mainly expressed in the media of the aneurysmatic tissue. Focal positive staining was also observed in areas of inflammatory infiltrates within the adventitia. In tissue lysates, no significant differences between iAAA, rAAA, and healthy controls were observed upon ELISA analysis. In serum samples, the level of CXCR4 was significantly increased in rAAA by 4-fold compared to healthy controls (p=0.011) and 3.0-fold for rAAA compared to iAAA (p<0.001). Furthermore a significant positive correlation between aortic diameter and serum CXCR4 concentration was found for both, iAAA and rAAA (p=0.042). Univariate logistic regression analysis showed that increased CXCR4 serum concentrations were associated with AAA rupture (OR: 4.28, 95% CI: 1.95-12.1, p=0.001). Conclusions: CXCR4 concentration was significantly increased in serum of rAAA patients and showed a significant correlation with an increased aortic diameter. The level of CXCR4 in serum was associated with a more than 4-fold risk increase for rAAA and thus could possibly serve as a biomarker in the future. However, further validation in larger studies is required.

Cancer, cancer treatment and aneurysmatic ascending aorta growth within a retrospective single center study.

Background: Multi-morbidity poses a substantial challenge for health care in an aging population. Recent studies did not provide evidence for general side effects of anti-cancer therapy regarding the growth rate of coincident abdominal aortic aneurysms, although it was suggested that specific therapeutic substances might accelerate growth. Aneurysm pathology, however, differs with respect to localization. Hence, we present the first ever analysis on the association of cancer and cancer therapy with growth alteration of aneurysms of the ascending aorta (AscAA). Patients and methods: A retrospective single-center identification of AscAA+cancer patients was performed in the institutional picture archiving and communication system (PACS). Included were all patients with ≥2 CT angiograms over ≥6 months and additional malignancy. Clinical data and aneurysm diameters were retrieved and analyzed for an association of cancer (stratified by tumor entity) or cancer therapy (stratified by several classes of chemotherapeutic agents and radiation therapy) with annual growth rate, respectively. Statistics included t-test, Wilcoxon test, and a linear regression model accounting for initial AscAA diameter and type of treatment. Results: From 2003 to 2021, 151 patients (median age 70 years; 85% male) with AscAA and coincident 163 malignancies were identified. Prostate (37%) and hematologic cancer (17%) were most frequent. One-hundred-eleven patients (74%) received chemotherapy and 75 patients (50%) had radiation. After exclusion of six patients with an initial AscAA diameter >55 mm, the average annual AscAA growth rate was 0.18±0.64 mm/year, with only 12 patients experiencing a growth rate >1mm/year. Neither tumor entity nor radiation or chemotherapy - alone or in combination - were significantly associated with an alteration of the annual AscAA growth rate. Likewise, a subanalysis for singular chemotherapeutic agents did not reveal a specific association with AscAA growth alteration. Conclusions: Growth rates of AscAA are low in this cohort with coincident malignancy. Cancer and/or chemotherapy or radiation are not associated with an alteration of the annual growth rate. Additional control examinations seem unnecessary.

A prospective survey study on the education and awareness about walking exercise amongst inpatients with symptomatic peripheral arterial disease in Germany.

Background: To determine the adherence to supervised exercise training and underlying reasons for non-adherence amongst patients with inpatient treatment of symptomatic lower extremity peripheral arterial disease (PAD). Patients and methods: This was a prospective questionnaire-based survey study of all consecutively treated inpatients with treatment for either intermittent claudication or chronic limb-threatening ischaemia (CLTI) surveyed at sixteen participating centres in Germany. Results: A total of 235 patients (median age 70 years) were included, thereof 29.4% females and 34.6% with CLTI. The median time from first PAD diagnosis was 4 years (IQR: 1-8). Only 11.4% have previously participated in any walking exercise programme before the index treatment, thereby 10.0% in the IC subgroup and 12.0% with CLTI. Amongst all patients, 35.6% responded they were appropriately informed about the necessity and benefits of walking exercise programmes by their hospital physicians (25.8% by general practitioners), and 65.3% agreed that adherence to supervised exercise may improve their pain-free walking distance. A total of 24.5% responded they had access to necessary information concerning local walking exercise programmes. Amongst 127 free text comments on the reasons for non-adherence to supervised exercise training, 64% of the comments contained lack of information or consent on such measures. Conclusions: Less than 12% of the patients enrolled in the current study have ever participated in a walking exercise programme during their life course. Although all practice guidelines contain corresponding class I recommendations, especially for patients suffering from IC, most patients responded that they were not appropriately informed about the necessity of exercise training along with the fact that 65% agreed that exercise may increase the pain-free walking distance. Taken all together, these results emphasise that we miss an important opportunity in the patient-physician communication. Efforts should be made to improve acceptance and application of structured walking-exercise for patients with PAD.

Radiation and Chemotherapy are Associated with Altered Aortic Aneurysm Growth in Patients with Cancer: Impact of Synchronous Cancer and Aortic Aneurysm.

OBJECTIVE: The purpose of this study was to assess the associations between malignancy, therapeutic regimens, and aorto-iliac aneurysm (i.e., abdominal aortic aneurysm [AAA]) growth rates. METHODS: A retrospective single centre analysis identified patients with an AAA plus cancer. Patients who had two or more computed tomography angiograms over six months or more and additional malignancy were included. Clinical data and aneurysm diameters were analysed. AAA growth under cancer therapy (chemotherapy or radiation) was compared with a non-cancer AAA control cohort and to meta-analysis data. Statistics included t tests and a linear regression model with correction for initial aortic diameter and type of treatment. RESULTS: From 2003 to 2020, 217 patients (median age 70 years; 92% male) with 246 aneurysms (58.8% AAA) and 238 malignancies were identified. Prostate (26.7%) and lung (15.7%) cancer were most frequently seen. One hundred and fifty-seven patients (72.3%) received chemotherapy, 105 patients (48.4%) radiation, and 79 (36.4%) both. Annual AAA growth (mean ± standard deviation) was not statistically significantly different for cancer and non-cancer patients (2.0 ± 2.3 vs. 2.8 ± 2.1 mm/year; p = .20). However, subgroup analyses revealed that radiation was associated with a statistically significantly reduced mean aneurysm growth rate compared with cancer patients without radiation (1.1 ± 1.3 vs. 1.6 ± 2.1 mm/year; p = .046) and to the non-cancer control cohort (1.7 ± 1.9 vs. 2.8 ± 2.1 mm/year; p = .007). Administration of antimetabolites resulted in statistically significantly increased AAA growth (+ 0.9 mm/year; p = .011), while topoisomerase inhibitors (- 0.8 mm/year; p = .17) and anti-androgens (- 0.5 mm/year; p = .27) showed a possible trend for reduced growth. Similar observations were noted for iliac aneurysms (n = 85). Additionally, the effects persisted for chemotherapy combinations (2.6 ± 1.4 substances/patient). CONCLUSION: Patients with cancer and concomitant aortic aneurysms may require intensified monitoring when undergoing specific therapies, such as antimetabolite treatment, as they may experience an increased aneurysm growth rate. Radiation may be associated with reduced aneurysm growth.

Treatment of vascular graft infections: gentamicin-coated ePTFE grafts reveals strong antibacterial properties in vitro.

Vascular graft infections (VGI) are severe complications in prosthetic vascular surgery with an incidence ranging from 1 to 6%. In these cases, synthetic grafts are commonly used in combination with antimicrobial agents. Expanded polytetrafluoroethylene (ePTFE) is in clinical use as a synthetic graft material and shows promising results by influencing bacterial adhesion. However, the literature on antibiotic-bound ePTFE grafts is scarce. Gentamicin is a frequently used antibiotic for local treatment of surgical site infections, but has not been evaluated as antimicrobial agent on ePTFE grafts. In this study, we examine the antimicrobial efficacy and biocompatibility of novel types of gentamicin-coated ePTFE grafts in vitro. ePTFE grafts coated with gentamicin salt formulations with covalently-bound palmitate were evaluated in two drug concentrations (GP1.75% and GP3.5%). To investigate effects from types of formulations, also suspensions of gentamicin in palmitate as well as polylactide were used at comparable levels (GS + PA and GS + R203). Antibacterial efficacies were estimated by employing a zone of inhibition, growth inhibition and bacterial adhesion assay against Staphylococcus aureus (SA). Cytotoxicity was determined with murine fibroblasts according to the ISO standard 10993-5. Gentamicin-coated ePTFE grafts show low bacterial adherence and strong antibacterial properties in vitro against SA. Bactericidal inhibition lasted until day 11. Highest biocompatibility was achieved using gentamicin palmitate GP1.75% coated ePTFE grafts. ePTFE grafts with gentamicin-coating are effective in vitro against SA growth and adherence. Most promising results regarding antimicrobial properties and biocompatibility were shown with chemically bounded gentamicin palmitate GP1.75% coatings. Graphical abstract.

Concomitantly discovered visceral artery aneurysms do rarely grow during cancer therapy.

Visceral artery aneurysms (VAA) are a rare entity of arterial aneurysms with the imminent threat of rupture. The impact of cancer and chemotherapy on the growth of VAAs is unknown. A retrospective dual center cohort study of patients with concomitant VAA and different types of cancer was conducted and the impact of various chemotherapeutic agents on VAA growth was studied by sequential CT analysis. For comparison, a non-cancer all comer cohort with VAAs and no cancer was studied to compare different growth rates. The primary endpoint was aneurysm progress or regression >1.75 mm. Chi-square test, Fisher's exact test and Mann-Whitney test was used for statistical comparison. In the 17-year-period from January 2003 to March 2020, 59 patients with 30 splenic artery aneurysms, 14 celiac trunk aneurysms, 11 renal artery aneurysms and 4 other VAA and additional malignancy were identified. 20% of patients suffered from prostate cancer, the rest were heterogeneous. The most prevalent chemotherapies were alkylating agents (23%), antimetabolites (14%) and mitose inhibitors (10%). Eight patients had relevant growth of their VAA and one patient showed diameter regression (average growth rate 0.1 ± 0.5 mm/year). Twenty-nine patients with 14 splenic, 11 RAAs (seven right) and 4 celiac trunk aneurysms were available in the non-cancer comparison cohort (average growth rate 0.5 ± 0.9 mm/year, p = 0.058). However, the growth rate of patients receiving operative treatment for relevant VAA growth was significantly higher (p = 0.004). VAAs grow rarely, and rather slow. Cancer and/or chemotherapy do not significantly influence the annual growth rate. Additional control examinations seem unnecessary.

Acute abdominal aortic occlusion: A 16-year single-center experience.

BACKGROUND: Acute abdominal aortic occlusion (AAO) is a rare vascular emergency associated with high morbidity and mortality. In the present study, we analyzed the clinical management and outcomes for a consecutive patient series during a 16-year period. METHODS: We included all patients with an acute AAO and bilateral acute limb ischemia who had been treated between 2004 and 2019. Patients with dissection, aneurysm rupture, or chronic occlusive disease were excluded. The patient characteristics, surgical procedures, and outcomes were extracted retrospectively from a prospective aortic database, electronic patient files, and outpatient examination records. The extent of ischemia was classified according to the TASC II (Inter-Society Consensus for the Management of Peripheral Arterial Disease) section on acute limb ischemia. The primary endpoints were 30-day mortality (safety endpoint) and the combined 6-month amputation and/or death rate (efficacy endpoint). The follow-up outcomes, amputation rates, and 30-day complications were evaluated as secondary endpoints. The patient cohort was divided into four 4-year groups (2004-2007, 2008-2011, 2012-2015, 2016-2019) to assess the outcome changes over time. Statistical analysis included χ2 tests and univariate and linear regression analyses. RESULTS: A total of 74 patients (57% male; median age, 64.5 years) with an acute AAO were identified. Arterial thrombosis was the most common etiology (66%). The extent of ischemia was TASC I, IIa, IIb, and III in 7%, 39%, 40%, and 14%, respectively. The patient numbers had increased significantly over time (P = .016). Of the patients, 42% had undergone open transfemoral recanalization (including hybrid procedures), 35% open aortic surgery, 15% extra-anatomic bypass surgery, and 5% (four patients) endovascular therapy alone. The overall 30-day mortality rate was 23%, and the 6-month amputation and/or death rate was 43%. The 30-day mortality rate had declined significantly from 54% for 2004 to 2007 to 10% for 2011 to 2015 (odds ratio [OR], 0.10; 95% confidence interval [CI], 0.001-0.52) and 20% for 2016 to 2019 (OR, 0.21; 95% CI, 0.05-0.90), a statistically nonsignificant trend showing that the relative decline in the use of open aortic procedures was associated with decreased 30-day mortality (P = .06). Univariate analysis indicated that elevated serum lactate on admission (OR, 3.33; 95% CI, 1.06-10.48) and an advanced stage of limb ischemia (OR, 4.33), were strongly associated with an increased 30-day mortality rate. The incidence of severe postoperative systemic complications also indicated a greater incidence of both primary endpoints. The 6-month amputation and/or mortality rates were also affected by the presence of atrial fibrillation (OR, 3.63; 95% CI, 1.34-9.79) and increased patient age (OR, 3.96; 95% CI, 1.49-10.53). CONCLUSIONS: Acute AAO remains a life-threatening emergency. Immediate transfemoral open or endovascular techniques should be preferred, if technically possible and proper intraoperative imaging is available.

Cysteinyl leukotriene receptor 1 antagonism prevents experimental abdominal aortic aneurysm.

Cysteinyl-leukotrienes (cys-LTs) are 5-lipoxygenase-derived lipid mediators involved in the pathogenesis and progression of inflammatory disorders, in particular asthma. We have previously found evidence linking these mediators to increased levels of proteolytic enzymes in tissue specimens of human abdominal aortic aneurysm (AAA). Here we show that antagonism of the CysLT1 receptor by montelukast, an established antiasthma drug, protects against a strong aorta dilatation (>50% increase = aneurysm) in a mouse model of CaCl2-induced AAA at a dose comparable to human medical practice. Analysis of tissue extracts revealed that montelukast reduces the levels of matrix metalloproteinase-9 (MMP-9) and macrophage inflammatory protein-1α (MIP-1α) in the aortic wall. Furthermore, aneurysm progression was specifically mediated through CysLT1 signaling since a selective CysLT2 antagonist was without effect. A significantly reduced vessel dilatation is also observed when treatment with montelukast is started days after aneurysm induction, suggesting that the drug not only prevents but also stops and possibly reverts an already ongoing degenerative process. Moreover, montelukast reduced the incidence of aortic rupture and attenuated the AAA development in two additional independent models, i.e., angiotensin II- and porcine pancreatic elastase-induced AAA, respectively. Our results indicate that cys-LTs are involved in the pathogenesis of AAA and that antagonism of the CysLT1 receptor is a promising strategy for preventive and therapeutic treatment of this clinically silent and highly lethal disease.

[Open thoracic and thoracoabdominal aortic repair vs. f/bTEVAR - complementary or competitive?] / Offener thorakaler und thorakoabdominaler Aortenersatz vs. f/b(T)EVAR ­ komplementär oder kompetitiv?

The classical approach of open repair (OR) for thoracic and thoracoabdominal aortic pathologies, including aneurysms and dissection, has been outnumbered by the use of fenestrated/branched (thoracic) endovascular aortic repair (f/b[T]EVAR) in recent years. Providing OR for complex cases in an aortic service requires a dedicated surgical setup and a huge body of expertise in this particular field.In order to reduce specific complications, such as perioperative mortality, kidney failure, spinal cord ischemia, stroke or bowel ischemia, it is necessary to apply cerebrospinal-spinal fluid drainage, point-of-care coagulation therapy, distal and retrograde aortic perfusion and sequential clamping. Despite the predominance of endovascular solutions, the specific OR expertise is still needed for specific indications, such as young patients, connective tissue disorder or aortic graft infections.Currently, the short and mid term results for f/b(T)EVAR outweigh those for OR, including the shorter hospital stay and less invasive procedures. However, OR provides better long-term results for overall mortality, re-intervention rates and secondary complications.In conclusion, in our opinion OR is a service that is still necessary for dedicated aortic centres, but will most likely become more frequent again in the years to come.

Germinal Center-Derived Antibodies Promote Atherosclerosis Plaque Size and Stability.

BACKGROUND: Atherosclerosis progression is modulated by interactions with the adaptive immune system. Humoral immunity can help protect against atherosclerosis formation; however, the existence, origin, and function of putative atherogenic antibodies are controversial. How such atherosclerosis-promoting antibodies could affect the specific composition and stability of plaques, as well as the vasculature generally, remains unknown. METHODS: We addressed the overall contribution of antibodies to atherosclerosis plaque formation, composition, and stability in vivo (1) with mice that displayed a general loss of antibodies, (2) with mice that had selectively ablated germinal center-derived IgG production, or (3) through interruption of T-B-cell interactions and further studied the effects of antibody deficiency on the aorta by transcriptomics. RESULTS: Here, we demonstrate that atherosclerosis-prone mice with attenuated plasma cell function manifest reduced plaque burden, indicating that antibodies promote atherosclerotic lesion size. However, the composition of the plaque was altered in antibody-deficient mice, with an increase in lipid content and decreases in smooth muscle cells and macrophages, resulting in an experimentally validated vulnerable plaque phenotype. Furthermore, IgG antibodies enhanced smooth muscle cell proliferation in vitro in an Fc receptor-dependent manner, and antibody-deficient mice had decreased neointimal hyperplasia formation in vivo. These IgG antibodies were shown to be derived from germinal centers, and mice genetically deficient for germinal center formation had strongly reduced atherosclerosis plaque formation. mRNA sequencing of aortas revealed that antibodies are required for the sufficient expression of multiple signal-induced and growth-promoting transcription factors and that aortas undergo large-scale metabolic reprograming in their absence. Using an elastase model, we demonstrated that absence of IgG results in an increased severity of aneurysm formation. CONCLUSIONS: We propose that germinal center-derived IgG antibodies promote the size and stability of atherosclerosis plaques, through promoting arterial smooth muscle cell proliferation and maintaining the molecular identity of the aorta. These results could have implications for therapies that target B cells or B-T-cell interactions because the loss of humoral immunity leads to a smaller but less stable plaque phenotype.

Early and Midterm Outcomes of Open and Endovascular Revascularization of Chronic Mesenteric Ischemia.

BACKGROUND: Revascularization strategies for chronic mesenteric ischemia (CMI) include open (OR) and endovascular (ER) modalities. The primary objective of this study was to analyze the safety and effectiveness of OR and ER and the impact of clinical and morphological variables on early and midterm outcomes in a consecutive series of CMI patients in a tertiary referral center. PATIENTS AND METHODS: From 2004 to 2017, all CMI patients treated with OR and ER were retrospectively identified. Patient records, preoperative imaging, as well as peri- and postoperative outcomes were analyzed. Univariable and multivariable analysis was performed to identify clinical or morphological variables affecting reintervention rates within 2 years. RESULTS: In total, 63 patients (33% male; mean age 71, range 60-76 years) were treated by ER (41 patients) or OR (22 patients) for CMI. Mean follow-up was 26 (10-71) months. 30-day mortality was 0.0% after ER and 4.5% after OR (p = 0.069); 30-day morbidity was 9.8% vs. 31.8%, respectively (p = 0.030). Length of stay was significantly longer after OR (14 vs. 4 days; p < 0.001). Freedom from reintervention rate after 2 years was 82% after OR and 73% after ER (p = 0.14). Overall survival did not differ after 2 years (OR 85% vs. ER 86%; p = 0.35). Multivariable analysis revealed that smoking was associated with higher risk of reintervention (hazard ratio, HR: 4.14; 95% confidence interval, CI 1.11-15.53; p = 0.03). Additionally, a nonsignificant trend of lower reintervention rates after OR was detected (HR 0.23 95% CI 0.05-1.08; p = 0.06). CONCLUSION: Due to a lower invasiveness, despite the higher reintervention rate, an "endovascular first" strategy is justified and recommended.

Regional variation in endovascular treatment rate and in-hospital mortality of abdominal aortic aneurysms in Germany.

Background: Abdominal aortic aneurysms (AAA) can be treated by either open surgery (OAR) or endovascular aortic repair (EVAR). The aim of this study was to analyze regional variations in application of (EVAR) and in-hospital mortality after intact AAA (iAAA) repair. Methods: Using data provided by the German Federal Statistical Office, a nationwide analysis for 2012 to 2014 was conducted. Patients with a diagnosis of iAAA (I71.4) and corresponding procedure codes for OAR (5-384.5/7) or EVAR (5-38a.1) were included. Odds ratios (ORs) for use of EVAR (proportion of EVAR among total EVAR + OAR cases) and mortality were calculated for all regions in Germany. ORs for EVAR use were adjusted for age, sex, and risk (Elixhauser score). ORs for mortality were additionally adjusted for type of procedure (OAR/EVAR). Results: Finally, 31,757 procedures for iAAA were included. Median age of all patients was 73 years (interquartile range 67-78 years) and 87.1 % were male. The mean proportion of EVAR procedures was 72.6 %; however, the application of EVAR for repair of iAAA varied widely depending on region. The lowest unadjusted regional rate of EVAR use was 48.8 %, while the highest was 92.5 %. After adjustment, the lowest regional OR for EVAR use (compared to the nationwide mean) was 0.23 (95 % confidence interval [0.15-0.36]), the highest 5.93 [1.79-19.65]. Overall in-hospital mortality was 2.9 % (OAR 6.2 %; EVAR 1.7 %). The adjusted regional OR for mortality ranged from 0.31 [0.07-1.42] to 4.98 [2.08-11.93]. Conclusions: This study reveals variations in use of EVAR and in-hospital mortality for iAAA treatment in Germany. This may imply that selection of treatment might not only be influenced by patient characteristics, but also by regional location. These results need to be taken into account when discussing centralization of AAA treatment in Germany.

H19 Induces Abdominal Aortic Aneurysm Development and Progression.

BACKGROUND: Long noncoding RNAs have emerged as critical molecular regulators in various biological processes and diseases. Here we sought to identify and functionally characterize long noncoding RNAs as potential mediators in abdominal aortic aneurysm development. METHODS: We profiled RNA transcript expression in 2 murine abdominal aortic aneurysm models, Angiotensin II (ANGII) infusion in apolipoprotein E-deficient ( ApoE-/-) mice (n=8) and porcine pancreatic elastase instillation in C57BL/6 wild-type mice (n=12). The long noncoding RNA H19 was identified as 1 of the most highly upregulated transcripts in both mouse aneurysm models compared with sham-operated controls. This was confirmed by quantitative reverse transcription-polymerase chain reaction and in situ hybridization. RESULTS: Experimental knock-down of H19, utilizing site-specific antisense oligonucleotides (LNA-GapmeRs) in vivo, significantly limited aneurysm growth in both models. Upregulated H19 correlated with smooth muscle cell (SMC) content and SMC apoptosis in progressing aneurysms. Importantly, a similar pattern could be observed in human abdominal aortic aneurysm tissue samples, and in a novel preclinical LDLR-/- (low-density lipoprotein receptor) Yucatan mini-pig aneurysm model. In vitro knock-down of H19 markedly decreased apoptotic rates of cultured human aortic SMCs, whereas overexpression of H19 had the opposite effect. Notably, H19-dependent apoptosis mechanisms in SMCs appeared to be independent of miR-675, which is embedded in the first exon of the H19 gene. A customized transcription factor array identified hypoxia-inducible factor 1α as the main downstream effector. Increased SMC apoptosis was associated with cytoplasmic interaction between H19 and hypoxia-inducible factor 1α and sequential p53 stabilization. Additionally, H19 induced transcription of hypoxia-inducible factor 1α via recruiting the transcription factor specificity protein 1 to the promoter region. CONCLUSIONS: The long noncoding RNA H19 is a novel regulator of SMC survival in abdominal aortic aneurysm development and progression. Inhibition of H19 expression might serve as a novel molecular therapeutic target for aortic aneurysm disease.

Effects of Iliac Stenosis on Abdominal Aortic Aneurysm Formation in Mice and Humans.

Reduced lower-limb blood flow has been shown to lead to asymmetrical abdominal aortic aneurysms (AAAs) but the mechanism of action is not fully understood. Therefore, small animal ultrasound (Vevo2100, FUJIFILM VisualSonics) was used to longitudinally study mice that underwent standard porcine pancreatic elastase (PPE) infusion (n = 5), and PPE infusion with modified 20% iliac artery stenosis in the left (n = 4) and right (n = 5) iliac arteries. Human AAA computed tomography images were obtained from patients with normal (n = 9) or stenosed left (n = 2), right (n = 1), and bilateral (n = 1) iliac arteries. We observed rapid early growth and rightward expansion (8/9 mice) in the modified PPE groups (p < 0.05), leading to slightly larger and asymmetric AAAs compared to the standard PPE group. Further examination showed a significant increase in TGFß1 (p < 0.05) and cellular infiltration (p < 0.05) in the modified PPE group versus standard PPE mice. Congruent, yet variable, observations were made in human AAA patients with reduced iliac outflow compared to those with normal iliac outflow. Our results suggest that arterial stenosis at the time of aneurysm induction leads to faster AAA growth with aneurysm asymmetry and increased vascular inflammation after 8 weeks, indicating that moderate iliac stenosis may have upstream effects on AAA progression.

The structural atrophy of the aneurysm wall in secondary expanding aortic aneurysms with endoleak type II.

BACKGROUND: Abdominal aortic aneurysm (AAA) has an age-dependent prevalence of 2% to 11% and is a leading cause of death in men aged >65 years if not treated surgically. Today, endovascular aneurysm repair (EVAR) is performed in up to 80% of elective cases and 60% of ruptured cases. Although EVAR improves perioperative, early, and midterm outcomes, it is associated with specific complications, especially endoleaks (ELs). Type II EL occurs in up to 30% of procedures; however, aneurysm sac expansion and rupture are rare, and currently nothing is known about the morphologic changes in this condition. In this study, we investigate the aneurysm wall morphology in secondary expanding human AAA samples after EVAR with persistent type II EL in comparison to nonaneurysmatic control aortic and AAA samples. METHODS: Samples were acquired from the aneurysm sac during retroperitoneal feeder vessel ligation in a cohort of 10 patients with secondary expansion after EVAR and type II EL diagnosed by computed tomography and contrast-enhanced ultrasound. Control tissues included 42 AAAs and 13 control aortae published previously. Hematoxylin and eosin staining and immunohistochemistry for CD3/4/31/68 and Ki67 were performed for morphologic analysis. Terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling (TUNEL) assays allowed quantification of apoptosis. Reverse transcription-polymerase chain reaction was used to quantify gene expression and Western blot to quantify collagen expression. RESULTS: Secondary expansion of 33.8% ± 30% during 5 years was seen after EVAR before reoperation. The aneurysm wall after expansion shows significant thinning of the intima-media layer accompanied by a scarcity of cells, with only a little chronic inflammation left compared with AAA samples. Macrophages are seen in abundance, and matrix metalloproteinase expression is significantly upregulated. Relevant apoptosis is not noticed. Fibrous tissue is reduced, and a collagen turnover to different subtypes is noted in comparison to nonaneurysmatic control aorta and AAA. In addition, the transcription factors vascular endothelial growth factor, Kruppel-like factor 4, and BCL2, elevated in AAA, are significantly reduced after secondary expansion. CONCLUSIONS: The aneurysm sac morphology after EVAR with persistent type II EL is characterized by atrophy and proteolysis suggestive of structural weakening. These results should be considered for the follow-up schedule as well as for the potential treatment of this most frequent EVAR complication.

MicroRNA-210 Enhances Fibrous Cap Stability in Advanced Atherosclerotic Lesions.

RATIONALE: In the search for markers and modulators of vascular disease, microRNAs (miRNAs) have emerged as potent therapeutic targets. OBJECTIVE: To investigate miRNAs of clinical interest in patients with unstable carotid stenosis at risk of stroke. METHODS AND RESULTS: Using patient material from the BiKE (Biobank of Karolinska Endarterectomies), we profiled miRNA expression in patients with stable versus unstable carotid plaque. A polymerase chain reaction-based miRNA array of plasma, sampled at the carotid lesion site, identified 8 deregulated miRNAs (miR-15b, miR-29c, miR-30c/d, miR-150, miR-191, miR-210, and miR-500). miR-210 was the most significantly downregulated miRNA in local plasma material. Laser capture microdissection and in situ hybridization revealed a distinct localization of miR-210 in fibrous caps. We confirmed that miR-210 directly targets the tumor suppressor gene APC (adenomatous polyposis coli), thereby affecting Wnt (Wingless-related integration site) signaling and regulating smooth muscle cell survival, as well as differentiation in advanced atherosclerotic lesions. Substantial changes in arterial miR-210 were detectable in 2 rodent models of vascular remodeling and plaque rupture. Modulating miR-210 in vitro and in vivo improved fibrous cap stability with implications for vascular disease. CONCLUSIONS: An unstable carotid plaque at risk of stroke is characterized by low expression of miR-210. miR-210 contributes to stabilizing carotid plaques through inhibition of APC, ensuring smooth muscle cell survival. We present local delivery of miR-210 as a therapeutic approach for prevention of atherothrombotic vascular events.