Enrichment of type 1 innate lymphoid cells in the course of human atherosclerotic plaque development suggests contribution to atherogenesis.

Introduction: Innate lymphoid cells (ILCs) have been implicated in multiple pathologic conditions, including atherogenesis, as documented in experimental mice studies, however, their role in atherosclerosis in humans remains unexplored. Methods: Here, we identify ILCs and their dynamics in early, advanced, and complicated human carotid- and aortic atherosclerotic plaques, using a multiplex immunohistochemical quadruple-staining technique with prototypic transcription factors T-bet, GATA3, or RORgt for identification of the ILC1, ILC2 and ILC3 subsets, respectively, in combination with lineage markers CD3, CD20/ CD79a and CD56 to exclude other lymphoid cell types. ILC subsets were quantified, and to put this in perspective, their numbers were expressed as percentage of the total number of infiltrated lymphoid cells and related to the frequency of conventional T cells, B cells, NK cells, and NKT cells. Results: All ILC subsets were present in every different stage of atherogenesis. ILC1s were the most abundant ILC subset, and their numbers significantly increased in the course of plaque development, but paradoxically, their relative frequency was reduced because of a higher increment of T cells and B cells. The numbers of ILC2s and ILC3s also gradually increased, but this trend did not achieve significance. T cell subsets always significantly outnumbered their ILC counterparts, except for the early lesions where the proportion of ILC1s was markedly higher, albeit not significant. Discussion: The high abundance of ILC1s in the early stages and further significant enrichment in later stages, suggest they may participate in the initiation and development of atherogenesis, and thus, may represent a novel target to prevent or treat atherosclerosis.

Guideline recommendations on minimal blood vessel diameters and arteriovenous fistula outcomes.

OBJECTIVE: Clinical guidelines provide recommendations on the minimal blood vessel diameters required for arteriovenous fistula creation but the evidence for these recommendations is limited. We compared vascular access outcomes of fistulas created in agreement with the ESVS Clinical Practice Guidelines (i.e. arteries and veins >2 mm for forearm fistulas and >3 mm for upper arm fistulas) with fistulas created outside these recommendations. METHODS: The multicenter Shunt Simulation Study cohort contains 211 hemodialysis patients who received a first radiocephalic, brachiocephalic, or brachiobasilic fistula before publication of the ESVS Clinical Practice Guidelines. All patients had preoperative duplex ultrasound measurements according to a standardized protocol. Outcomes included duplex ultrasound findings at 6 weeks after surgery, vascular access function, and intervention rates until 1 year after surgery. RESULTS: In 55% of patients, fistulas were created in agreement with the ESVS Clinical Practice Guidelines recommendations on minimal blood vessel diameters. Concordance with the guideline recommendations was more frequent for forearm fistulas than for upper arm fistulas (65% vs 46%, p = 0.01). In the entire cohort, agreement with the guideline recommendations was not associated with an increased proportion of functional vascular accesses (70% vs 66% for fistulas created within and outside guideline recommendations, respectively; p = 0.61) or with decreased access-related intervention rates (1.45 vs 1.68 per patient-year, p = 0.20). In forearm fistulas, however, only 52% of arteriovenous fistulas created outside these recommendations developed into a timely functional vascular access. CONCLUSIONS: Whereas upper arm arteriovenous fistulas with preoperative blood vessel diameters <3 mm had similar vascular access function as fistulas created with larger blood vessels, forearm arteriovenous fistulas with preoperative blood vessel diameters <2 mm had poor clinical outcomes. These results support that clinical decision-making should be guided by an individual approach.

Editor's Choice - Interventions to Achieve Functionality in Newly Created Arteriovenous Fistulas in the Shunt Simulation Study Cohort.

OBJECTIVE: Although observational cohort studies report that interventions to achieve functionality are clinically successful in 85% of patients, the proportion of newly created autologous arteriovenous fistulas that result in functional vascular access typically is only 70 - 80%. To address this discrepancy, the selection and outcomes of interventions to achieve functionality in a multicentre prospective cohort study were analysed. METHODS: The Shunt Simulation Study enrolled 222 patients who needed a first arteriovenous fistula in nine dialysis units in The Netherlands from 2015 to 2018 and followed these patients until one year after access creation. In this observational study, the technical and clinical success rates of interventions to achieve functionality based on lesion and intervention characteristics were analysed and the clinical outcomes of arteriovenous fistulas with assisted and unassisted functionality were compared. RESULTS: For patients who were on dialysis treatment at the end of the study, unassisted fistula functionality was 54% and overall fistula functionality was 78%. Thirty-four per cent of arteriovenous fistulas required an intervention to achieve functionality, 68% of which eventually became functional. Seventy-five per cent of these interventions were percutaneous balloon angioplasties of vascular access stenoses. Patients with clinically successful interventions to achieve functionality had larger pre-operative vein diameters (2.8 ± 1.0 mm vs. 2.3 ± 0.6 mm, p = .036) and less often presented with thrombosed fistulas than patients with unsuccessful interventions (7% vs. 43%, p = .006). Arteriovenous fistulas with assisted functionality had similar secondary patency as fistulas with unassisted functionality (100% and 98% at six months, p = .44), although they required more interventions to maintain function (2.6 vs. 1.7 per year; rate ratio 1.52, 95% CI 1.04 - 2.18, p = .032). CONCLUSION: Interventions to achieve functionality were needed in about a third of newly created arteriovenous fistulas. Most thrombosed fistulas were abandoned, and when selected for thrombectomy rarely reached clinical success. On the other hand, interventions to achieve functionality of patent fistulas had high clinical success rates and therefore can be done repeatedly until the fistula has become functional.

Genetic variants in SUSD2 are associated with the risk of ischemic heart disease.

BACKGROUND: Genetic factors partly determine the risk for premature myocardial infarction (MI). OBJECTIVES: We report the identification of a novel rare genetic variant in a kindred with an autosomal dominant trait for premature MI and atherosclerosis and explored the association of a common nonsynonymous variant in the same gene with the risk of ischemic heart disease (IHD) in a population-based study. METHODS: Next-generation sequencing was performed in a small pedigree with premature MI or subclinical atherosclerosis. A common variant, rs8141797 A>G (p.Asn466Ser), in sushi domain-containing protein 2 (SUSD2) was studied in the prospective Copenhagen General Population Studies (N = 105,408) for association with IHD. RESULTS: A novel heterozygous nonsense mutation in SUSD2 (c.G583T; p.Glu195Ter) was associated with the disease phenotype in the pedigree. SUSD2 protein was expressed in aortic specimens in the subendothelial cell layer and around the vasa vasorum. Furthermore, the minor G-allele of rs8141797 was associated with per allele higher levels of SUSD2 mRNA expression in the heart and vasculature. In the Copenhagen General Population Study, hazard ratios for IHD were 0.92 (95% CI: 0.87-0.97) in AG heterozygotes and 0.86 (0.62-1.19) in GG homozygotes vs noncarrriers (P-trend = .002). Finally, in meta-analysis including 73,983 IHD cases and 215,730 controls, the odds ratio for IHD per G-allele vs A-allele was 0.93 (0.90-0.96) (P = 4.6 × 10-7). CONCLUSIONS: The identification of a truncating mutation in SUSD2, which was associated with premature MI and subclinical atherosclerosis, combined with the finding that a common missense variant in SUSD2 was strongly associated with a lower risk of IHD, suggest that SUSD2 may alter the risk of atherosclerosis.

Pre-operative Patient Specific Flow Predictions to Improve Haemodialysis Arteriovenous Fistula Maturation (Shunt Simulation Study): A Randomised Controlled Trial.

OBJECTIVE: An arteriovenous fistula (AVF) needs to mature before it becomes suitable to cannulate for haemodialysis treatment. Maturation importantly depends on the post-operative flow increase. Unfortunately, 20-40% of AVFs fail to mature (FTM). A patient specific computational model that predicts immediate post-operative flow was developed, and it was hypothesised that providing information from this model for planning of fistula creation might reduce FTM rates. METHODS: A multicentre, randomised controlled trial in nine Dutch hospitals was conducted in which patients with renal failure who were referred for AVF creation, were recruited. Patients were randomly assigned (1:1) to the control or computer simulation group. Both groups underwent a work up, with physical and duplex ultrasonography (DUS) examination. In the simulation group the data from the DUS examination were used for model simulations, and based on the immediate post-operative flow prediction, the ideal AVF configuration was recommended. The primary endpoint was AVF maturation defined as an AVF flow ≥500 mL/min and a vein inner diameter of ≥4 mm six weeks post-operatively. The secondary endpoint was model performance (i.e. comparisons between measured and predicted flows, and (multivariable) regression analysis for maturation probability with accompanying area under the receiver operator characteristic curve [AUC]). RESULTS: A total of 236 patients were randomly assigned (116 in the control and 120 in the simulation group), of whom 205 (100 and 105 respectively) were analysed for the primary endpoint. There was no difference in FTM rates between the groups (29% and 32% respectively). Immediate post-operative flow prediction had an OR of 1.15 (1.06-1.26; p < .001) per 100 mL/min for maturation, and the accompanying AUC was 0.67 (0.59-0.75). CONCLUSION: Providing pre-operative patient specific flow simulations during surgical planning does not result in improved maturation rates. Further study is needed to improve the predictive power of these simulations in order to render the computational model an adjunct to surgical planning.

Improvement of radiocephalic fistula maturation: rationale and design of the Liposomal Prednisolone to Improve Hemodialysis Fistula Maturation (LIPMAT) study - a randomized controlled trial.

BACKGROUND: Non-maturation is a frequent complication of radiocephalic arteriovenous fistulas (RCAVF). In an animal model, liposomal prednisolone improved maturation of experimental fistulas. The Liposomal Prednisolone to Improve Hemodialysis Fistula Maturation (LIPMAT) study investigates if liposomal prednisolone improves RCAVF maturation. METHODS AND RESULTS: The LIPMAT study is an investigator-initiated, multicenter, double-blinded, placebo-controlled randomized controlled trial with 1:1 randomization to liposomal prednisolone or placebo. Eighty patients receiving an RCAVF will be included. The primary outcome is the cephalic vein diameter six weeks after surgery, measured by ultrasound. The LIPMAT study started in May 2016. Enrollment is expected to be completed by the end of 2017. CONCLUSIONS: The LIPMAT study is the first to evaluate the efficacy of liposomal prednisolone to enhance RCAVF maturation.

Chronic leg ulcer: does a patient always get a correct diagnosis and adequate treatment?

Patients with chronic leg ulcers have severely impaired quality of life and account for a high percentage of annual healthcare costs. To establish the cause of a chronic leg ulcer, referral to a center with a multidisciplinary team of professionals is often necessary. Treating the underlying cause diminishes healing time and reduces costs. In venous leg ulcers adequate compression therapy is still a problem. It can be improved by training the professionals with pressure measuring devices. A perfect fitting of elastic stockings is important to prevent venous leg ulcer recurrence. In most cases, custom-made stockings are the best choice for this purpose.

Direct videoscopic approach to the descending thoracic aorta for aortic arch endograft delivery: evaluation in a porcine model.

PURPOSE: To examine the feasibility of a direct videoscopic approach to the descending thoracic aorta for endograft delivery to the aortic arch. METHODS: A double purse-string suture was placed on the aorta of 3 pigs via a thoracoscopic approach. Subsequently, the aorta was cannulated in the center of the purse-string. A 22-F delivery catheter was advanced under fluoroscopic control over a guidewire via a trocar into the proximal aorta. After deployment of a tubular endograft, the catheter was withdrawn from the aorta while simultaneously tightening the purse-string suture, without aortic cross clamping. The outcome was evaluated by post implant angiography and autopsy results. RESULTS: The procedure was successfully completed in all animals, with a mean total procedure time of 126 minutes (range 118-137). Mean endograft implantation time from needle puncture to catheter extraction was 27 minutes (range 21-37). Hemostasis was obtained in all animals after withdrawal of the delivery catheter and tightening the purse-string suture. The mean blood loss was 143 mL (range 80-220). Autopsy proved all purse-string sutures to be adequately placed and all endografts deployed in the correct position. CONCLUSION: A direct videoscopic approach to the descending thoracic aorta proved a feasible technique for endograft delivery to the aortic arch in a porcine model.