Genome-wide association meta-analysis identifies risk loci for abdominal aortic aneurysm and highlights PCSK9 as a therapeutic target.

Abdominal aortic aneurysm (AAA) is a common disease with substantial heritability. In this study, we performed a genome-wide association meta-analysis from 14 discovery cohorts and uncovered 141 independent associations, including 97 previously unreported loci. A polygenic risk score derived from meta-analysis explained AAA risk beyond clinical risk factors. Genes at AAA risk loci indicate involvement of lipid metabolism, vascular development and remodeling, extracellular matrix dysregulation and inflammation as key mechanisms in AAA pathogenesis. These genes also indicate overlap between the development of AAA and other monogenic aortopathies, particularly via transforming growth factor ß signaling. Motivated by the strong evidence for the role of lipid metabolism in AAA, we used Mendelian randomization to establish the central role of nonhigh-density lipoprotein cholesterol in AAA and identified the opportunity for repurposing of proprotein convertase, subtilisin/kexin-type 9 (PCSK9) inhibitors. This was supported by a study demonstrating that PCSK9 loss of function prevented the development of AAA in a preclinical mouse model.

Type Ib endoleak repaired with a thoracic endovascular graft inside previous visceral debranching bypass in a patient with chronic type B aortic dissection.

We present the case of a patient with chronic type B aortic dissection with a previous iliac to visceral debranching graft and thoracoabdominal endograft who, because of a type Ib endoleak and aortic diameter enlargement, required a complex solution involving placement of a thoracic endovascular graft inside a Dacron graft with a 180° curved shape in three-stage surgery. At 9 months of follow-up, he had no evidence of type I endoleaks, and the aortic diameter had decreased.

Preoperative geriatric assessment, a promising tool to improve outcomes in aortic pathology interventions.

BACKGROUND: Due to population aging and the spread of endovascular techniques for aortic diseases, there has been an increase in older population intervened. Objectively assessing patient's global status becomes mandatory in advanced ages, as impaired functional status and frailty are associated with higher postoperative mortality rates. The aim of this paper is to evaluate the impact of a systematic geriatric preoperative assessment on the outcomes of aortic interventions. METHODS: All patients above 60 years old with surgical indication for aortic disease between September 2016 and May 2019 underwent a standardized geriatric assessment. It analyzed physiological reserve, frailty, and life expectancy. An algorithm was created for its application before intervention indication. Variables registered were patient's data, type of aortic disease, type of intervention, geriatric assessment result, mortality and follow-up time. A bivariate analysis was performed. RESULTS: One hundred forty-four patients were included. Geriatric report was unfavorable for intervention in 6.25% (N.=9). From these, 88% (N.=8) were finally rejected for intervention. In those undergoing aortic intervention (N.=127) there was a 7% mortality rate (N.=9) and in the no-intervention group (N.=17) mortality rate raised up to 35% (N.=6). No aortic-related mortality was reported. A relevant association between an unfavorable geriatric report and mortality was found "OR 0.036 (CI 0.0082-0.155)." A protective relationship between any aortic intervention and mortality was found, with OR 0.139 (CI 0.043-0.447). CONCLUSIONS: Geriatric assessment is a valid tool to estimate life expectancy and patient's physiological status. An unfavorable report correlates with short-term non-aortic mortality independently of undergoing intervention. This has a high clinical relevance, and it highlights its practical applicability to improve aortic surgery indication's quality and optimize resource investment.

Finite element analysis in symptomatic and asymptomatic abdominal aortic aneurysms for aortic disease risk stratification.

BACKGROUND: Advanced biomechanical models can provide additional information concerning rupture risk in abdominal aortic aneurysms (AAA). Here we evaluated the predictive value of finite element analysis (FEA) to assess AAA rupture risk. METHODS: In a case-control study, we compared FEA parameters in a group of symptomatic AAA (sAAA) patients, considered as a high risk of rupture group, with FEA parameters in asymptomatic AAA patients (aAAA). RESULTS: We included 15 sAAA and 28 aAAA patients matched for age- and maximum diameter diagnosed with infrarenal non-ruptured AAA at our center between 2009 and 2013. Mean age was 75±69 years and mean maximum diameter was 77±17 mm. Peak wall stress (PWS) was significantly higher in sAAA patients than in aAAA patients (354.3±139.6 kPa vs. 248.6±81.9 kPa; P=0.001). The C statistic for the ROC curve based on PWS was 0.748 (95% CI: 0.592-0.903; P=0.008). CART analysis classified patients into high and low PWS groups. The high-PWS group (>305.15 kPa; N.=15) had a higher incidence of sAAA (33.3% aAAA, 66.7% sAAA) than the low-PWS-group (≤305.15 kPa; N.=28. 82.1% aAAA, 17.9% sAAA). CONCLUSIONS: In conclusion, PWS was significantly higher in sAAA patients. Measuring PWS may help estimate the individual rupture risk in patients with AAA, but larger studies are needed to confirm our results.

Endovascular Management of Ureteroarterial Fistula: Single Institution Experience and Systematic Literature Review.

BACKGROUND: Ureteroarterial fistula (UAF) represents an uncommon complication after urological surgery; however, this is a well-documented condition in patients with predisposing risk factors. The aim of the present study is to report and analyze the endovascular management of a series of patients with UAF, treated in authors' hospital, and to report and analyze the same data concerning patients retrieved from a systematic literature review. METHODS: Authors conducted a retrospective analysis of prospectively collected data and a systematic literature review. The research was carried out through PubMed database searching the following keywords: "uretero arterial fistula" and "uretero iliac fistula." It includes only articles reporting the endovascular management. RESULTS: Forty-six articles were included in the present study for a total of 94 patients. Risk factors were as follows: chronic indwelling ureteral stents, pelvic surgery, radiotherapy, iliac artery pseudo-aneurysm, and chemotherapy. All patients had gross hematuria at presentation. Stent graft placement was performed in 89 patients, embolization in 5 patients, and iliac internal artery embolization combined with stent graft placement was performed in 24 patients. Four postprocedural complications were observed (4.2%). During a median follow-up of 8 months, 10 complications related to UAF were observed (10.6%): rebleeding (7 cases) and stent thrombosis (3 cases). Two patients died for causes related to UAF (2.1%): rebleeding (1) and retroperitoneal abscess (1). CONCLUSION: Based on the present data, endovascular treatment is feasible and safe with low postprocedural complications and mortality rate. Considering the increase in surgery and radiotherapy performed, UAF should be always debated in patients with massive hematuria.

Induction of histone deacetylases (HDACs) in human abdominal aortic aneurysm: therapeutic potential of HDAC inhibitors.

Clinical management of abdominal aortic aneurysm (AAA) is currently limited to elective surgical repair because an effective pharmacotherapy is still awaited. Inhibition of histone deacetylase (HDAC) activity could be a promising therapeutic option in cardiovascular diseases. We aimed to characterise HDAC expression in human AAA and to evaluate the therapeutic potential of class I and IIa HDAC inhibitors in the AAA model of angiotensin II (Ang II)-infused apolipoprotein-E-deficient (ApoE(-/-)) mice. Real-time PCR, western blot and immunohistochemistry evidenced an increased expression of HDACs 1, 2 (both class I), 4 and 7 (both class IIa) in abdominal aorta samples from patients undergoing AAA open repair (n=22) compared with those from donors (n=14). Aortic aneurysms from Ang-II-infused ApoE(-/-) mice exhibited a similar HDAC expression profile. In these animals, treatment with a class I HDAC inhibitor (MS-275) or a class IIa inhibitor (MC-1568) improved survival, reduced the incidence and severity of AAA and limited aneurysmal expansion evaluated by Doppler ultrasonography. These beneficial effects were more potent in MC-1568-treated mice. The disorganisation of elastin and collagen fibres and lymphocyte and macrophage infiltration were effectively reduced by both inhibitors. Additionally, HDAC inhibition attenuated the exacerbated expression of pro-inflammatory markers and the increase in metalloproteinase-2 and -9 activity induced by Ang II in this model. Therefore, our data evidence that HDAC expression is deregulated in human AAA and that class-selective HDAC inhibitors limit aneurysm expansion in an AAA mouse model. New-generation HDAC inhibitors represent a promising therapeutic approach to overcome human aneurysm progression.

CHIVA method for the treatment of chronic venous insufficiency.

BACKGROUND: Many surgical approaches are available to treat varicose veins secondary to chronic venous insufficiency. One of the least invasive techniques is the ambulatory conservative hemodynamic correction of venous insufficiency method (cure conservatrice et hémodynamique de l'insuffisance veineuse en ambulatoire (CHIVA)), an approach based on venous hemodynamics with deliberate preservation of the superficial venous system. This is an update of the review first published in 2013. OBJECTIVES: To compare the efficacy and safety of the CHIVA method with alternative therapeutic techniques to treat varicose veins. SEARCH METHODS: The Trials Search Co-ordinator of the Cochrane Peripheral Vascular Diseases Group searched the Specialised Register (April 2015), the Cochrane Register of Studies (2015, Issue 3) and clinical trials databases. The review authors searched PubMed (April 2015). There was no language restriction. We contacted study authors to obtain more information when necessary. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared the CHIVA method versus any other treatments. Two review authors independently selected and evaluated the studies. One review author extracted data and performed the quantitative analysis. DATA COLLECTION AND ANALYSIS: Two independent review authors extracted data from the selected papers. We calculated the risk ratio (RR), mean difference (MD), the number of people needed to treat for an additional beneficial outcome (NNTB), and the number of people needed to treat for an additional harmful outcome (NNTH), with 95% confidence intervals (CI) using Review Manager 5. MAIN RESULTS: No new studies were identified for this update. We included four RCTs with 796 participants (70.5% women). Three RCTs compared the CHIVA method with vein stripping, and one RCT compared the CHIVA method with compression dressings in people with venous ulcers. We judged the quality of the evidence of the included studies as low to moderate due to imprecision caused by the low number of events and because the studies were open. The overall risk of bias across studies was high because neither participants nor outcome assessors were blinded to the interventions. The primary endpoint, clinical recurrence, pooled between studies over a follow-up of 3 to 10 years, showed more favorable results for the CHIVA method than for vein stripping (721 people; RR 0.63; 95% CI 0.51 to 0.78; I(2) = 0%, NNTB 6; 95% CI 4 to 10) or compression dressings (47 people; RR 0.23; 95% CI 0.06 to 0.96; NNTB 3; 95% CI 2 to 17). Only one study reported data on quality of life (presented graphically) and these results significantly favored the CHIVA method.The vein stripping group had a higher risk of side effects than the CHIVA group; specifically, the RR for bruising was 0.63 (95% CI 0.53 to 0.76; NNTH 4; 95% CI 3 to 6) and the RR for nerve damage was 0.05 (95% CI 0.01 to 0.38; I(2) = 0%; NNTH 12; 95% CI 9 to 20). There were no statistically significant differences between groups regarding the incidence of limb infection and superficial vein thrombosis. AUTHORS' CONCLUSIONS: The CHIVA method reduces recurrence of varicose veins and produces fewer side effects than vein stripping. However, we based these conclusions on a small number of trials with a high risk of bias as the effects of surgery could not be concealed and the results were imprecise due to low number of events. New RCTs are needed to confirm these results and to compare CHIVA with approaches other than open surgery.

Microvascular COX-2/mPGES-1/EP-4 axis in human abdominal aortic aneurysm.

We investigated the prostaglandin (PG)E2 pathway in human abdominal aortic aneurysm (AAA) and its relationship with hypervascularization. We analyzed samples from patients undergoing AAA repair in comparison with those from healthy multiorgan donors. Patients were stratified according to maximum aortic diameter: low diameter (LD) (<55 mm), moderate diameter (MD) (55-69.9 mm), and high diameter (HD) (≥70 mm). AAA was characterized by abundant microvessels in the media and adventitia with perivascular infiltration of CD45-positive cells. Like endothelial cell markers, cyclooxygenase (COX)-2 and the microsomal isoform of prostaglandin E synthase (mPGES-1) transcripts were increased in AAA (4.4- and 1.4-fold, respectively). Both enzymes were localized in vascular cells and leukocytes, with maximal expression in the LD group, whereas leukocyte markers display a maximum in the MD group, suggesting that the upregulation of COX-2/mPGES-1 precedes maximal leukocyte infiltration. Plasma and in vitro tissue secreted levels of PGE2 metabolites were higher in AAA than in controls (plasma-controls, 19.9 ± 2.2; plasma-AAA, 38.8 ± 5.5 pg/ml; secretion-normal aorta, 16.5 ± 6.4; secretion-AAA, 72.9 ± 6.4 pg/mg; mean ± SEM). E-prostanoid receptor (EP)-2 and EP-4 were overexpressed in AAA, EP-4 being the only EP substantially expressed and colocalized with mPGES-1 in the microvasculature. Additionally, EP-4 mediated PGE2-induced angiogenesis in vitro. We provide new data concerning mPGES-1 expression in human AAA. Our findings suggest the potential relevance of the COX-2/mPGES-1/EP-4 axis in the AAA-associated hypervascularization.

CHIVA method for the treatment of chronic venous insufficiency.

BACKGROUND: Many surgical approaches are available to treat varicose veins secondary to chronic venous insufficiency. One of the least invasive techniques is the ambulatory conservative hemodynamic correction of venous insufficiency method (cure conservatrice et hémodynamique de l'insuffisance veineuse en ambulatoire (CHIVA)), an approach based on venous hemodynamics with deliberate preservation of the superficial venous system. OBJECTIVES: To compare the efficacy and safety of the CHIVA method with alternative therapeutic techniques to treat varicose veins. SEARCH METHODS: The Trials Search Co-ordinator of the Cochrane Peripheral Vascular Diseases Group searched the Specialised Register (November 2012), CENTRAL (2012, Issue 10) and clinical trials databases. The review authors searched PubMed and EMBASE (December 2012). There was no language restriction. We contacted study authors to obtain more information when necessary. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared the CHIVA method versus any other treatments. Two review authors independently selected and evaluated the studies. One review author extracted data and performed the quantitative analysis. DATA COLLECTION AND ANALYSIS: Two independent review authors extracted data from the selected papers. We calculated the risk ratio (RR), mean difference (MD), the number of people needed to treat for an additional beneficial outcome (NNTB), and the number of people needed to treat for an additional harmful outcome (NNTH), with 95% confidence intervals (CI) using Review Manager 5. MAIN RESULTS: We included four RCTs with 796 participants (70.5% women) from the 434 publications identified by the search strategy. Three RCTs compared the CHIVA method with vein stripping, and one RCT compared the CHIVA method with compression dressings in people with venous ulcers. We judged the methodological quality of the included studies as low to moderate. The overall risk of bias across studies was high because neither participants nor outcome assessors were blinded to the interventions. The primary endpoint, clinical recurrence, pooled between studies over a follow-up of 3 to 10 years, showed more favorable results for the CHIVA method than for vein stripping (721 people; RR 0.63; 95% CI 0.51 to 0.78; I(2) = 0%, NNTB 6; 95% CI 4 to 10) or compression dressings (47 people; RR 0.23; 95% CI 0.06 to 0.96; NNTB 3; 95% CI 2 to 17). Only one study reported data on quality of life and these results presented graphically significantly favored the CHIVA method.The vein stripping group had a higher risk of side effects than the CHIVA group; specifically, the RR for bruising was 0.63 (95% CI 0.53 to 0.76; NNTH 4; 95% CI 3 to 6) and the RR for nerve damage was 0.05 (95% CI 0.01 to 0.38; I(2) = 0%; NNTH 12; 95% CI 9 to 20). There were no statistically significant differences between groups regarding the incidence of limb infection and superficial vein thrombosis. AUTHORS' CONCLUSIONS: The CHIVA method reduces recurrence of varicose veins and produces fewer side effects than vein stripping. However, we based these conclusions on a small number of trials with a high risk of bias as the effects of surgery could not be concealed. New RCTs are needed to confirm these results and to compare CHIVA with approaches other than open surgery.

Compression assisted by removable coils as a new treatment for iatrogenic femoral pseudoaneurysms.

To avoid undesirable effects that sometimes result from current treatments for postpuncture femoral pseudoaneurysms, we developed a new technique involving compression assisted by removable coils. Using ultrasound-guided percutaneous puncture, an Inconel coil with synthetic microfibers is inserted in the pseudoaneurysm, leaving a part of the coil above the skin. Short-duration, ultrasound-guided compression is applied, taking advantage of the coil's thrombogenicity. Following occlusion, the coil is removed, leaving no residual foreign material. The technique was effective in the first patient treated and may minimize or obviate the adverse effects associated with current approaches.