Cytokine changes in cerebrospinal fluid following vascular surgery on the thoracic aorta.

There is growing evidence that surgery can drive an inflammatory response in the brain. However, the mechanisms behind this response are incompletely understood. Here, we investigate the hypotheses that 1. Cerebrospinal fluid (CSF) cytokines increase after vascular surgery and 2. That these changes in CSF cytokines are interrelated. Patients undergoing either open or endovascular elective surgery of the thoracic aorta were invited to participate in this study. Cerebrospinal fluid samples were taken before surgery and on the first post-operative day. These were analysed for the presence of ten cytokines by immunoassay to examine for post-operative changes in cytokine levels. After surgery, there were significant increases in six out of the ten measured CSF cytokines (IL-1ß, 2, 6, 8, 10 and 13). This included changes in both putative pro-inflammatory (IL-1ß, 6 and 8) and putative anti-inflammatory (IL-2, 10 and 13) cytokines. The greatest increases occurred in IL-6 and IL-8, which showed a 63-fold and a 31-fold increase respectively. There was strong intercorrelation between CSF cytokines after the operation. Following surgery on the thoracic aorta, there was a marked increase in CSF cytokines, consistent with a potential role in neuroinflammation. The ten measured cytokines showed intercorrelation after the operation, indicating that a balance between multiple pro- and anti-inflammatory cytokines may be present.

Low-Dose Aspirin Reduces the Rate of Renal Allograft Thrombosis in Pediatric Renal Transplant Recipients.

OBJECTIVES: Renal allograft thrombosis is an important cause of early renal allograft loss. A previous study from our unit showed thrombosis rates in patients who received heparin that were similar to those who did not receive any thromboprophylaxis. This study evaluated the impact of aspirin prophylaxis on renal allograft thrombosis rates in pediatric renal transplant recipients. MATERIALS AND METHODS: We conducted a retrospective study of 456 consecutive pediatric allografts from deceased and living related donors over age 22 years in a single center. Routine perioperative heparin was introduced in 1994 and was subsequently changed to aspirin prophylaxis in 2000. Group 1 comprised 126 patients who did not receive any thromboprophylaxis, group 2 comprised 128 patients who received heparin, and group 3 comprised 202 patients who received aspirin therapy. Variables associated with increased risk of renal allograft loss were examined using multivariable logistic regression. RESULTS: Thrombosis occurred in 11% (14/126) of grafts in group 1, 9% (11/128) of grafts in group 2, and 1% (2/202) of grafts in group 3 (odds ratio for aspirin group = 0.38, 95% confidence interval, 0.22-0.64; P = .02). In patients who received aspirin (group 3), there was only one renal allograft loss secondary to hemorrhage, and no grafts were lost in patients younger than 5 years of age. CONCLUSIONS: After our center introduced a change from heparin to aspirin prophylaxis, the thrombosis rate in pediatric renal allografts fell from 9% to 1%. Although there are a number of possible confounding variables, the introduction of aspirin has led to a reduced rate of renal allograft thrombosis.

Interwoven Nitinol Stents versus Drug Eluting Stents in the Femoro-Popliteal Segment: A Propensity Matched Analysis.

BACKGROUND: Percutaneous transluminal angioplasty (PTA) is a common procedure in patients with peripheral arterial disease (PAD) affecting the femoropopliteal segment (F-P). Biomimetic nitinol stents (Supera peripheral stent, SPS) and drug eluting stents (DES) were designed to improve the longevity of F-P PTA; however, their performance has not been compared in a pragmatic setting, taking atherosclerotic plaque characteristics into account. METHODS: Overall, 296 consecutive patients (mean age: 73 y, SD: 11 y, 65% male, 68% with chronic limb threatening ischaemia) who underwent F-P PTA using SPS or DES between 2013 and 2018 were identified from a prospectively maintained institutional database. Patient and plaque characteristics, including F-P plaque characterisation based on computed tomography, were collected; 121 case matched pairs were created using a propensity score based on patient and plaque data. RESULTS: During the median two year follow up, 28% of the cohort (32% SPS vs. 24% DES, p = .07) developed target lesion restenosis (TLR) > 50%. Among the 121 case matched pairs of patients, those with SPS vs. DES were not significantly more likely to develop TLR >50% (31% vs. 27%, p = .34), or stent occlusion (13% vs. 12%, p = .85 - secondary patency rate 87% vs. 88%), have a major amputation (10% vs. 6%, p = .16), require re-intervention (14% vs. 9%, p = .12), or die (7% vs.4%, p = .31). Plaque calcification did not predict restenosis or occlusion in either stent group, both in the matched and non matched populations. Multivariable analysis adjusted for patient and plaque characteristics revealed that the main predictors of restenosis >50% at two years were female sex [odds ratio (OR): 2.05, p = .01], hypertension (OR: 2.10, p = .04) and previous F-P occlusion (OR: 1.35, p = .04). CONCLUSION: Medium term results following F-P PTA with either SPS or DES are comparable, regardless of plaque calcification and patient characteristics.

Cerebral embolic protection in thoracic endovascular aortic repair.

BACKGROUND: Stroke occurs in 3% to 8% and silent cerebral infarction in >60% of patients undergoing thoracic endovascular aortic repair (TEVAR). We investigated the utility of a filter cerebral embolic protection device (CEPD) to reduce diffusion-weighted magnetic resonance imaging (DW-MRI) detected cerebral injury and gaseous and solid embolization during TEVAR. METHODS: Patients anatomically suitable underwent TEVAR with CEPD, together with intraoperative transcranial Doppler to detect gaseous and solid high-intensity transient signals (HITSs), pre- and postoperative DW-MRI, and clinical neurologic assessment ≤6 months after the procedure. RESULTS: Ten patients (mean age, 68 years) underwent TEVAR with a CEPD. No strokes or device-related complications developed. The CEPD added a median of 7 minutes (interquartile range [IQR], 5-16 minutes) to the procedure, increased the fluoroscopy time by 3.3 minutes (IQR, 2.4-3.9 minutes), and increased the total procedural radiation by 2.2%. The dose area product for CEPD was 1824 mGy·cm2 (IQR, 1235-3392 mGy·cm2). The average contrast volume used increased by 23 mL (IQR, 24-35 mL). New DW-MRI lesions, mostly in the hindbrain, were identified in seven of nine patients (78%). The median number was 1 (IQR, 1-3), with a median surface area of 6 mm2 (IQR, 3-16 mm2). A total of 2835 HITSs were detected in seven patients: 91% gaseous and 9% solid. The maximum number of HITSs were detected during CEPD manipulation: 142 (IQR, 59-146; 95% gaseous and 5% solid). The maximum number of HITSs during TEVAR occurred during stent deployment: 82 (IQR, 73-142; 81% gas and 11% solid). Solid HITSs were associated with an increase in surface area of new DW-MRI lesions (rs = 0.928; P = .01). Increased gaseous HITSs were associated with new DW-MRI lesions (rs = 0.912; P = .01), which were smaller (<3 mm; r = 0.88; P = .02). Embolic debris was captured in 95% of the filters. The median particle count was 937 (IQR, 146-1687), and the median surface area was 2.66 mm2 (IQR, 0.08-9.18 mm2). CONCLUSIONS: The use of a CEPD with TEVAR appeared to be safe and feasible in this first pilot study and could serve as a useful adjunct to reduce cerebral injury. The significance of gaseous embolization and its role in cerebral injury in TEVAR warrants further investigation.

Patient-specific Rehearsal Before EVAR: Influence on Technical and Nontechnical Operative Performance. A Randomized Controlled Trial.

OBJECTIVE: To assess the effect of patient-specific virtual reality rehearsal (PsR) before endovascular infrarenal aneurysm repair (EVAR) on technical performance and procedural errors. BACKGROUND: Endovascular procedures, including EVAR, are executed in a complex multidisciplinary environment, often treating high-risk patients. Consequently, this may lead to patient harm and procedural inefficiency. PsR enables the endovascular team to evaluate and practice the case in a virtual environment before treating the real patient. METHODS: A multicenter, prospective, randomized controlled trial recruited 100 patients with a nonruptured infrarenal aortic or iliac aneurysm between September 2012 and June 2014. Cases were randomized to preoperative PsR or standard care (no PsR). Primary outcome measures were errors during the real procedure and technical operative metrics (total endovascular and fluoroscopy time, contrast volume, number of angiograms, and radiation dose). RESULTS: There was a 26% [95% confidence interval (CI) 9%-40%, P = 0.004) reduction in minor errors, a 76% (95% CI 30%-92%, P = 0.009) reduction in major errors, and a 27% (95% CI 8.2%-42%, P = 0.007) reduction in errors causing procedural delay in the PsR group. The number of angiograms performed to visualize proximal and distal landing zones was 23% (95% CI 8%-36%, P = 0.005) and 21% (95% CI 7%-32%, P = 0.004) lower in the PsR group. CONCLUSIONS: PsR before EVAR can be used in different hospital settings by teams with various EVAR experience. It reduces perioperative errors and the number of angiograms required to deploy the stent graft, thereby reducing delays. Ultimately, it may improve patient safety and procedural efficiency.

Virtual reality simulation for the optimization of endovascular procedures: current perspectives.

Endovascular technologies are rapidly evolving, often requiring coordination and cooperation between clinicians and technicians from diverse specialties. These multidisciplinary interactions lead to challenges that are reflected in the high rate of errors occurring during endovascular procedures. Endovascular virtual reality (VR) simulation has evolved from simple benchtop devices to full physic simulators with advanced haptics and dynamic imaging and physiological controls. The latest developments in this field include the use of fully immersive simulated hybrid angiosuites to train whole endovascular teams in crisis resource management and novel technologies that enable practitioners to build VR simulations based on patient-specific anatomy. As our understanding of the skills, both technical and nontechnical, required for optimal endovascular performance improves, the requisite tools for objective assessment of these skills are being developed and will further enable the use of VR simulation in the training and assessment of endovascular interventionalists and their entire teams. Simulation training that allows deliberate practice without danger to patients may be key to bridging the gap between new endovascular technology and improved patient outcomes.

Management of abdominal aortic aneurysms in the UK.

Outcomes of abdominal aortic aneurysm repair are improving in the UK, at least in part as a result of vascular specialization, the reconfiguration of services to dedicated vascular centres and the advent of the national screening programme.

Endovascular treatment of thoracic aortic aneurysms with a short proximal landing zone using scalloped endografts.

BACKGROUND: The suitability of the proximal landing zone remains one of the main limitations to thoracic endovascular aortic repair (TEVAR). The advent of custom-made scalloped stent grafts widens the endovascular options for patients with challenging anatomy. The objective of this study was to present our early and midterm results of custom-made scalloped thoracic stent grafts. METHODS: Prospectively acquired data relating to patient demographics, procedure details, clinical outcome, and complications were analyzed. In addition, we analyzed preoperative and postoperative computed tomography scans to evaluate aneurysm morphology, graft placement, side-vessel patency, and endoleaks. RESULTS: Twenty-one patients with a median age of 71 years (range, 35-81 years) underwent custom-made scalloped TEVAR, eight of whom had a concomitant hybrid repair. Procedural success was achieved in all cases. Proximal seal was achieved in all cases, with no type I endoleaks. There were no cases of retrograde dissection and no conversions to open repair. The median follow-up period was 36 weeks (range, 3-183 weeks). Two patients died in the hospital. Three patients suffered a stroke. Three patients had a type II endoleak, one of whom had significant sac enlargement requiring reintervention. One patient had a type III endoleak requiring reintervention. There were no cases of graft migration. CONCLUSIONS: Our midterm results show that custom-made scalloped TEVAR is an acceptable treatment of thoracic aortic aneurysms with a short proximal landing zone. Longer term outcome data are required to establish wider use of scalloped thoracic endografts.

New-generation stent grafts for endovascular management of thoracic pseudoaneurysms after aortic coarctation repair.

OBJECTIVE: Late thoracic aneurysms develop in 5% to 12% of patients having undergone open repair for coarctation of the aorta (CoA). We report our early results for thoracic endovascular aortic repair for pseudoaneurysms after CoA repair. METHODS: From 2008 to 2013, data regarding demographics, aneurysm morphology, procedure, and follow-up were collected prospectively on all patients treated for pseudoaneurysms after CoA repair. Retrospective analysis of identified patients was then performed. RESULTS: Thirteen patients (six men, seven women) were treated. Patients were a median age, 45 years (interquartile range (IQR), 39-56; range, 27-66 years, and the median time after CoA repair to aneurysm treatment was 34 years (IQR, 24-40 years). All patients had saccular pseudoaneurysms of the aortic arch, with a median aneurysm size of 4.1 cm (IQR, 3.4-5.1 cm). The left subclavian artery (LSCA) was involved in 10 patients and was occluded at presentation in three. Four patients had concurrent LSCA revascularization with carotid-subclavian bypass, one had aortic arch hybrid repair, and the LSCA was intentionally covered in two patients. Patients underwent thoracic endovascular aortic repair using the conformable TAG (6 of 13; W. L. Gore & Associates, Flagstaff, Ariz), Valiant device (4 of 13; Medtronic, Minneapolis, Minn), and a custom-made Relay endograft with LSCA scallop (4 of 13; Bolton Medical, Barcelona, Spain). Technical success was 100%, with satisfactory deployment of the stent grafts in all patients. There was no 30-day mortality, stroke, or paraplegia. Median follow-up was 15 months (IQR, 9-19 months; range, 1-67 months). Two type II endoleaks from an intercostal artery were managed conservatively, and one type Ib endoleak was treated successfully with distal stent extension. CONCLUSIONS: In this cohort, new-generation stent grafts have good early clinical and radiologic outcomes, avoiding the need for redo open surgery. Management of the LSCA can be tailored to individual patients with new stent graft technology. Long-term follow-up of these patients is crucial to understanding whether endovascular management of this cohort is acceptable.

Endovascular repair of ruptured abdominal aortic aneurysm: technical and team training in an immersive virtual reality environment.

PURPOSE: This study evaluates a fully immersive simulated angiosuite for training and assessment of technical endovascular and human factor skills during a crisis scenario. MATERIALS AND METHODS: Virtual reality (VIST-C, Mentice) simulators were integrated into a simulated angiosuite (ORCAMP, Orzone). Teams, lead by experienced (N = 5) or trainee (N = 5) endovascular specialists, performed simulated endovascular ruptured aortic aneurysm repair (rEVAR). Timed performance metrics were recorded as surrogate measures of performance. Participants (N = 22) completed postprocedure questionnaires evaluating face validity, as well as technical and human factor aspects, of the simulation on a Likert scale from 1 (not at all) to 5 (very much). RESULTS: Experienced team leaders were significantly faster than trainees in obtaining proximal control with an intra-aortic occlusion balloon (352 vs. 501 s, p = 0.047) and all completed the procedure within the allotted time, whilst no trainee was able to do so. Total fluoroscopy times were significantly lower in the experienced group (782 vs. 1,086 s, p = 0.016). Realism of the simulated angiosuite was scored highly by experienced team leaders (median 4/5, IQR 4-5). Participants found the simulation useful for acquiring technical (4/5, IQR 4-5) and communication skills (4/5, IQR 4-5) and particularly valuable for enhancing teamwork (5/5, IQR 4-5) and patient safety (5/5, IQR 4-5). CONCLUSION: This study shows feasibility of creation of a crisis scenario in a fully immersive angiosuite simulation and team performance of a simulated rEVAR. Performance metrics differentiated between experienced specialists and trainees, and the realism of the simulation exercise and environment were rated highly by experienced endovascular specialists. This simulation has potential as a powerful training and assessment tool with opportunities to improve team performance in rEVAR through both technical and human factor skills training.

Advances in imaging and surveillance of AAA: when, how, how often?

Despite rapid technological developments for imaging the aorta, ultrasonography remains the method of choice for abdominal aortic aneurysm screening and surveillance. Randomised trials, conducted in the 20th century, have provided convincing evidence in favour of screening men at age 65 years, or older. However, in the 21st century the prevalence of aneurysms in 65 year old men has fallen by more than half, probably because of lower smoking prevalence and better cardiovascular risk prevention: screening or rescreening at an older age may be helpful. A recent meta-analysis has provided good evidence for surveillance intervals, with the majority of patients with screen-detected aneurysms (up to 4.5 cm diameter) being safely managed with 3-year surveillance intervals. Even for larger aneurysms, annual surveillance intervals are likely to be acceptable. This would reduce the number of surveillance visits by approximately half.

Salmonella mycotic thoracoabdominal aortic aneurysm associated with chronic lymphocytic leukemia.

Non-typhoidal Salmonella infections typically cause self-limiting gastroenteritis. However, extraintestinal focal infections, including mycotic aneurysms of the aorta, can also occur. We present the case of a 71-year-old man with chronic lymphocytic leukemia (CLL) and a large type V thoracoabdominal mycotic aneurysm infected with Salmonella enteritidis, complicated by thoracolumbar spondylodiscitis, paravertebral collections, and epidural abscess. This is the first report of Salmonella aortitis in the setting of CLL, and the unusual extent of local infective invasion seen here with Salmonella enteritidis infection raises a suspicion of CLL-related immunosuppression as a direct predisposing factor. This case illustrates the need to consider the possibility of an immune defect, even in CLL patients with normal leukocyte counts. The underlying mechanisms are unclear, but are likely to involve defects in cell-mediated immunity, thought to be of particular importance in invasive infections with intracellular pathogens such as Salmonella spp.

Renal artery aneurysm formation secondary to pseudoxanthoma elasticum.

This report describes a patient with pseudoxanthoma elasticum (PXE) who presented with an incidental finding of a renal artery aneurysm. PXE is a rare genetic condition. It is associated with calcification of elastin fibers and is characterized by skin, eye, and cardiovascular complications. Our patient was previously treated for retinal and gastrointestinal hemorrhage and coronary artery disease, and is under surveillance for cerebral aneurysms. Five reports in the published literature have described aneurysms in patients with PXE, but, to our knowledge, this is the first report of a patient with PXE and renal artery aneurysm. The literature on PXE and aneurysms is reviewed.

Arteriovenous fistula after endovenous ablation for varicose veins.

Endovenous ablation, using radiofrequency or laser, is becoming the mainstay of treatment for symptomatic varicose veins in the setting of saphenous vein incompetency. Both procedures have been shown to produce high rates of truncal vein occlusion with few complications. This article presents three patients who developed arteriovenous fistula (AVF) following great saphenous vein treatment: two following radiofrequency ablation (RFA) and one following laser ablation. This is the first published report of AVF following RFA for which operative details are known. We review the literature and discuss possible causes and management of this rare complication.

Trapping of BMP receptors in distinct membrane domains inhibits their function in pulmonary arterial hypertension.

Bone morphogenetic proteins (BMPs) are pleiotrophic growth factors that influence diverse processes such as skeletal development, hematopoiesis, and neurogenesis. They play crucial roles in diseases such as pulmonary arterial hypertension (PAH). In PAH, mutants of the BMP type II receptors (BMPR2) were detected, and their functions were impaired during BMP signaling. It is thought that expression levels of these receptors determine the fate of BMP signaling, with low levels of expression leading to decreased Smad activation in PAH. However, our studies demonstrate, for the first time, that the localization of receptors on the plasma membrane, in this case BMPR2, was misdirected. Three BMPR2 mutants, D485G, N519K, and R899X, which are known to be involved in PAH, were chosen as our model system. Our results show that all three BMPR2 mutants decreased BMP-dependent Smad phosphorylation and Smad signaling. Although the three mutants reached the cell membrane and their expression was lower than that of BMPR2, they formed smaller clusters and associated differently with membrane domains, such as caveolae and clathrin-coated pits. The disruption of these domains restored the Smad signaling of D485G and N519K to the level of wild-type BMPR2, showing that these mutants were trapped in the domains, rather than just expressed at a lower level on the surface. Therefore, new treatment options for PAH should also target receptor localization, rather than just expression level.

Laser saphenous ablations in more than 1,000 limbs with long-term duplex examination follow-up.

BACKGROUND: The goal of this study was to evaluate the duplex results of endovenous laser ablation in the treatment of incompetent great saphenous veins (GSV) and small saphenous veins (SSV) with at least 1-year follow-up. METHODS: A retrospective registry was entered by 11 centers from Europe and America, organized by the International Endovenous Laser Working Group. Data concerning 1,020 limbs in patients with incompetence of the GSV and/or SSV, treated with the Endovenous Laser Ablation (EVLA) procedure, were collected. EVLA failures were defined on duplex imaging as reflux confined to the saphenofemoral or saphenopopliteal junction, reflux confined to the main saphenous trunk, or reflux of both junction and main trunk (totally patent saphenous vein) were analyzed at one or more years postoperatively. RESULTS: The mean age of patients was 54 ± 5 years (range: 18-91 years). The average body mass index was 25. There was a paucity of severe complications: One case of third-degree skin burn, six patients with postsurgical deep vein thrombosis (0.6%), and 27 cases of sensory nerve damage (2.7%). At 1-year, the rate of complete occlusion of the saphenous trunk was 93.1%. There were 79 cases of treatment failures as evidenced by duplex: 22 isolated junction failures (2.2%), 44 isolated trunk failures (4.4%), and 13 totally patent veins (1.3%). Two-year duplex results were reported for 329 limbs with the identification of 19 new cases of failure. No new cases of failure were reported at 3-year follow-up of 130 limbs. Cumulative failure rates estimated by Kaplan-Meier analysis were 7.7% at 1-year and 13.1% at 2- and 3-year follow-up. CONCLUSIONS: On the basis of a duplex scan performed at least 1-year post-treatment, this multicenter registry confirms the safety and efficacy of the EVLA procedure in the treatment of GSV and SSV reflux. Considering the continued failure rate documented in the present study, an annual follow-up by duplex is recommended to 2 years after EVLA.

Failure of bone morphogenetic protein receptor trafficking in pulmonary arterial hypertension: potential for rescue.

Heterozygous germline mutations in the gene encoding the bone morphogenetic protein type II receptor cause familial pulmonary arterial hypertension (PAH). We previously demonstrated that the substitution of cysteine residues in the ligand-binding domain of this receptor prevents receptor trafficking to the cell membrane. Here we demonstrate the potential for chemical chaperones to rescue cell-surface expression of mutant BMPR-II and restore function. HeLa cells were transiently transfected with BMPR-II wild type or mutant (C118W) receptor constructs. Immunolocalization studies confirmed the retention of the cysteine mutant receptor mainly in the endoplasmic reticulum. Co-immunoprecipitation studies of Myc-tagged BMPR-II confirmed that the cysteine-substituted ligand-binding domain mutation, C118W, is able to associate with BMP type I receptors. Furthermore, following treatment with a panel of chemical chaperones (thapsigargin, glycerol or sodium 4-phenylbutyrate), we demonstrated a marked increase in cell-surface expression of mutant C118W BMPR-II by FACS analysis and confocal microscopy. These agents also enhanced the trafficking of wild-type BMPR-II, though to a lesser extent. Increased cell-surface expression of mutant C118W BMPR-II was associated with enhanced Smad1/5 phosphorylation in response to BMPs. These findings demonstrate the potential for rescue of mutant BMPR-II function from the endoplasmic reticulum. For the C118W mutation in the ligand-binding domain of BMPR-II, cell-surface rescue leads to at least partial restoration of BMP signalling. We conclude that enhancement of cell-surface trafficking of mutant and wild-type BMPR-II may have therapeutic potential in familial PAH.

Stoichiometric imbalance in the receptor complex contributes to dysfunctional BMPR-II mediated signalling in pulmonary arterial hypertension.

Heterozygous germline defects in a gene encoding a type II receptor for bone morphogenetic proteins (BMPR-II) underlie the majority of inherited cases of the vascular disorder known as pulmonary arterial hypertension (PAH). However, the precise molecular consequences of PAH causing mutations on the function of the receptor complex remain unclear. We employed novel enzymatic and fluorescence activity based techniques to assess the impact of PAH mutations on pre-mRNA splicing, nonsense-mediated decay (NMD) and receptor complex interactions. We demonstrate that nonsense and frameshift mutations trigger NMD, providing further evidence that haplo-insufficiency is a major molecular consequence of disease-related BMPR2 mutations. We identified heterogeneous functional defects in BMPR-II activity, including impaired type I receptor phosphorylation, receptor interactions and altered receptor complex stoichiometry leading to perturbation of downstream signalling pathways. Importantly, these studies demonstrate that the intracellular domain of BMPR-II is both necessary and sufficient for receptor complex interaction. Finally and to address the potential for resolution of stoichiometric balance, we investigated an agent that promotes translational readthrough of a BMPR2 nonsense reporter construct without interfering with the NMD pathway. We propose that stoichiometric imbalance, due to either haplo-insufficiency or loss of optimal receptor-receptor interactions impairs BMPR-II mediated signalling in PAH. Taken together, these studies have identified an important target for early therapeutic intervention in familial PAH.