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.

Endovascular Graft Suprarenal Bare Metal Stent Separation After Endovascular Aneurysm Repair: Case Reports and Literature Review.

Objective: Suprarenal bare metal stent separation is a rare complication after endovascular aneurysm repair. In this report, two new cases of this type of device failure are presented and the literature is reviewed to identify similar cases and evaluate associated clinical characteristics. Methods: A literature search was conducted in March 2022 using PubMed, Embase, and The Cochrane Library, with MeSH terms including aortic aneurysm, stents, and device failure. Two authors independently selected studies eligible for inclusion. Results: Twelve patients with endovascular graft suprarenal bare metal stent separation were identified. Endovascular aneurysm repair (EVAR) devices were implanted between May 1996 and November 2017. Suprarenal bare metal stent separation was detected after a median duration of five years post-operatively. Conclusion: Endovascular graft suprarenal bare metal stent separation demands a high level of awareness. A better understanding of the involved failure mechanisms and associated risk factors is required to further optimise EVAR follow up protocols.

A Composite Measure for Quality of Care in Patients with Symptomatic Carotid Stenosis Using Textbook Outcome.

OBJECTIVE: Composite measures may better objectify hospital performance than individual outcome measures (IOM). Textbook outcome (TO) is an outcome measure achieved for an individual patient when all undesirable outcomes are absent. The aim of this study was to assess TO as an additional outcome measure to evaluate quality of care in symptomatic patients treated by carotid endarterectomy (CEA). METHODS: All symptomatic patients treated by CEA in 2018, registered in the Dutch Audit for Carotid Interventions, were included. TO was defined as a composite of the absence of 30 day mortality, neurological events (any stroke or transient ischaemic attack [TIA]), cranial nerve deficit, haemorrhage, 30 day readmission, prolonged length of stay (LOS; > 5 days) and any other surgical complication. Multivariable logistic regression was used to identify covariables associated with achieving TO, which were used for casemix adjustment for hospital comparison. For each hospital, an observed vs. expected number of events ratio (O/E ratio) was calculated and plotted in a funnel plot with 95% control limits. RESULTS: In total, 70.7% of patients had a desired outcome within 30 days after CEA and therefore achieved TO. Prolonged LOS was the most common parameter (85%) and mortality the least common (1.1%) for not achieving TO. Covariates associated with achieving TO were younger age, the absence of pulmonary comorbidity, higher haemoglobin levels, and TIA as index event. In the case mix adjusted funnel plot, the O/E ratios between hospitals ranged between 0.63 and 1.27, with two hospitals revealing a statistically significantly lower rate of TO (with O/E ratios of 0.63 and 0.66). CONCLUSION: In the Netherlands, most patients treated by CEA achieve TO. Variation between hospitals in achieving TO might imply differences in performance. TO may be used as an additive to the pre-existing IOM, especially in surgical care with low baseline risk such as CEA.

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.

The Effect of Mycophenolate Mofetil on Early Wound Healing in a Rodent Model.

BACKGROUND: Immunosuppressant agents are inevitable for solid organ recipients, but may have a negative effect on wound healing that is difficult to measure because of clinical use of a polydrug regime. The evidence on mycophenolate mofetil (MMF) is scarce and contradictory. This study aims to investigate the effect of MMF administration on wound healing. METHODS: Ninety-six male Wistar rats divided into 4 groups underwent anastomotic construction in ileum and colon at day 0. Three groups received daily oral doses of 20 or 40 mg/kg MMF or saline (control group) from day 0 until the end of the experiment. Half of each group was analyzed after 3 days and half after 7 days. Another group started the medication 3 days after the laparotomy and was analyzed after 7 days, half of this group received 20 mg/kg and half 40 mg/kg MMF. Wound strength in anastomoses and in the abdominal wall was measured using bursting pressure, breaking strength, and histology. Trough levels were measured. RESULTS: Significant differences in wound strength were seen in ileum tissue after 3 days, which surprisingly showed a stronger anastomosis in the experimental groups. Bursting pressure as well as breaking strength was higher in the low-dose and high-dose MMF group compared with the control group. A negative effect was measured in abdominal wall tissue for the highest-dose group, which disappeared when the medication was delayed for 3 days. Histology showed poorer bridging of the submucosal layer and more polymorphonuclear cell infiltration in the ileum specimens of the control group compared with the treatment groups. CONCLUSIONS: As a single agent in a preclinical wound healing model in the rat, MMF has no negative effect on healing of bowel anastomoses but might have a negative effect on the healing of abdominal wall.

Prednisolone-containing liposomes accumulate in human atherosclerotic macrophages upon intravenous administration.

Drug delivery to atherosclerotic plaques via liposomal nanoparticles may improve therapeutic agents' risk-benefit ratios. Our paper details the first clinical studies of a liposomal nanoparticle encapsulating prednisolone (LN-PLP) in atherosclerosis. First, PLP's liposomal encapsulation improved its pharmacokinetic profile in humans (n=13) as attested by an increased plasma half-life of 63h (LN-PLP 1.5mg/kg). Second, intravenously infused LN-PLP appeared in 75% of the macrophages isolated from iliofemoral plaques of patients (n=14) referred for vascular surgery in a randomized, placebo-controlled trial. LN-PLP treatment did however not reduce arterial wall permeability or inflammation in patients with atherosclerotic disease (n=30), as assessed by multimodal imaging in a subsequent randomized, placebo-controlled study. In conclusion, we successfully delivered a long-circulating nanoparticle to atherosclerotic plaque macrophages in patients, whereas prednisolone accumulation in atherosclerotic lesions had no anti-inflammatory effect. Nonetheless, the present study provides guidance for development and imaging-assisted evaluation of future nanomedicine in atherosclerosis. FROM THE CLINICAL EDITOR: In this study, the authors undertook the first clinical trial using long-circulating liposomal nanoparticle encapsulating prednisolone in patients with atherosclerosis, based on previous animal studies. Despite little evidence of anti-inflammatory effect, the results have provided a starting point for future development of nanomedicine in cardiovascular diseases.

Tacrolimus does not affect early wound healing in a rodent model of bowel anastomoses and abdominal wall closure.

BACKGROUND: Use of immunosuppressant drugs has been associated with complications in wound healing. The calcineurin inhibitor tacrolimus is thought to have a relatively low complication rate, but preclinical research has yielded contradictory data, prompting the current comprehensive study. METHODS: Three groups of 33 male Wistar rats received a daily subcutaneous dose of 0,5, 2 or 5 mg/kg tacrolimus. A control group received saline. On day 0 a resection of 1 cm ileum and 1 cm colon was performed, and end-to-end anastomoses were constructed. Ten rats of each group were killed on day 3 and day 5 and the remaining animals on day 7. Both anastomoses and the wound in the abdominal wall were analyzed. Wound strength was the primary outcome parameter. RESULTS: Mean strength of the abdominal wall increased significantly over time in all groups (p<0.0001). Both the breaking strength and the bursting pressure of the ileum and colon anastomoses followed the same pattern. No differences were observed between control and experimental groups. In addition, no consistent differences were found between groups regarding wound hydroxyproline content and the activities of matrix metalloproteinase-2 and -9. CONCLUSION: Tacrolimus does not affect early wound healing.

Everolimus-induced loss of wound strength can be prevented by a short postoperative delay in its administration.

The use of mammalian target of rapamycin inhibitors coincides with an increased incidence of surgical complications. In previous experiments, serious negative effects of postoperative everolimus on anastomotic strength were found. This study aims to investigate if delayed drug administration can prevent loss of wound strength. Ten groups of Wistar rats each received daily oral doses of 1.0 or 2.0 mg/kg everolimus, starting the day of anastomotic construction in both ileum and colon, or 1, 2, 3, or 4 days later. The 11th group received saline. Seven days later, wound strength in anastomoses and in the abdominal wall and wound hydroxyproline levels were measured. Mean wound strength was significantly and dose-dependently reduced if everolimus was started on the day of operation. In ileum and colon, strength was not affected if drug administration was delayed until the third or second day, respectively. In abdominal fascia, this was the case only if everolimus was withheld until day 4. In general, changes in wound hydroxyproline content showed similarities to changes in wound strength. Thus, delaying administration of everolimus for 2-4 days after operation can prevent a serious loss of wound strength, both in the intestine and in the abdominal fascia.

Aortitis with aneurysm formation as a rare complication of Wegener's granulomatosis.

Wegener's granulomatosis (WG) is a systemic vasculitis of medium-sized and small blood vessels. Aortic involvement in WG is very uncommon. We present a 43-year-old patient with an aortitis with aneurysm formation as a manifestation of WG. The patient was operated on and an aortoiliac Dacron inlay graft was inserted. Postoperatively, he recovered uneventfully. Abdominal pain occurring during a WG flare may result from vasculitis of large abdominal arteries with or without aneurysmatic changes for which surgical treatment and immunosuppressive agents are indicated to prevent a possible rupture.

Persistent effects of everolimus on strength of experimental wounds in intestine and fascia.

The introduction of mTOR-inhibitors in transplantation surgery has been associated with an increase in wound complications. We have previously reported a massive negative effect of everolimus on anastomotic strength in rat intestine at 7 days postoperatively. Because it is clinically important to know if this effect persists and occurs generally, repair in both intestine and abdominal wall has been investigated over a period of 4 weeks. Wistar rats received a daily dose of 1 or 2 mg/kg everolimus orally, from the operation day onwards. Controls received saline. In each rat a resection of ileum and colon was performed, and end-to-end anastomoses were constructed. On day 7, 14, and 28 the animals were killed and anastomoses and abdominal wall wounds were analyzed, wound strength being the primary parameter. Breaking strength of ileum, colon, and fascia was consistently and significantly reduced in the experimental groups at all time points. Anastomotic bursting pressures followed the same pattern. Loss of strength was accompanied by a decrease in hydroxyproline content after 7 days. Thus, the negative effect of everolimus on wound repair persists for at least 4 weeks after operation in this rodent model. This protracted effect may have clinical consequences and cause surgical morbidity.

Taurolidine lock is highly effective in preventing catheter-related bloodstream infections in patients on home parenteral nutrition: a heparin-controlled prospective trial.

BACKGROUND & AIMS: Catheter-related bloodstream infections remain the major threat for Home Parenteral Nutrition programs. Taurolidine, a potent antimicrobial agent, holds promise as an effective catheter lock to prevent such infections. Aim of the present study was to compare taurolidine with heparin, the most frequently used lock, in this respect in these high-risk patients. METHODS: Thirty patients from one referral centre for intestinal failure were enrolled after developing a catheter-related bloodstream infection. Following adequate treatment, either with or without a new access device (tunneled catheter or subcutaneous port), these patients were randomized to continue Home Parenteral Nutrition using heparin (n = 14) or taurolidine (n = 16) as catheter lock. RESULTS: Whereas in controls 10 re-infections were observed, in the taurolidine group during 5370 catheter days only 1 re-infection occurred (mean infection-free survival 175 (95% CI 85-266; heparin) versus 641 (95% CI 556-727; taurolidine) days; log-rank p < 0.0001). No side effects or catheter occlusions were reported in either group. Moreover, after crossing-over of 10 patients with infections on heparin to taurolidine, only 1 new infection was observed. CONCLUSION: Taurolidine lock dramatically decreased catheter-related bloodstream infections when compared with heparin in this high-risk group of Home Parenteral Nutrition patients.

Arteriovenous fistulae as an alternative to central venous catheters for delivery of long-term home parenteral nutrition.

BACKGROUND & AIMS: The success of home parenteral nutrition (HPN) programs is compromised by complications of central venous catheters (CVCs), such as occlusions and bloodstream infections. We performed a retrospective analysis of complication rates of arteriovenous fistulae versus CVCs in patients on long-term HPN. METHODS: Data were collected from 127 consecutive patients who received HPN between January 2000 and October 2006, comprising 344 access years of CVCs and 194 access years of arteriovenous fistulae. We evaluated access-related bloodstream infection and occlusion incidence rates (number of complications per access year) using Poisson-normal regression analysis. Complication incidence rate ratios were calculated by dividing complication incidence rates of CVCs by those of arteriovenous fistulae, adjusting for HPN frequency, medication use, infusion fluid composition, and underlying diseases. RESULTS: Bloodstream infection incidence rates were 0.03/year for arteriovenous fistulae, 1.37/year for long-term CVCs (Port-a-Caths and tunneled catheters), and 3.12/year for short-term CVCs (nontunneled catheters). Occlusion incidence rates were 0.60/year for arteriovenous fistulae, 0.35/year for long-term CVCs, and 0.93/year for shortterm CVCs. Adjusted incidence rate ratios of long-term CVCs over arteriovenous fistulae were 47 (95% confidence interval, 19-117) for bloodstream infections and 0.53 (95% confidence interval, 0.31-0.89) for occlusions. CONCLUSIONS: The occlusion incidence rate was higher for arteriovenous fistulae than for certain types of CVCs. The incidence rate of the most serious access-related complication (bloodstream infections) was much lower for arteriovenous fistulae than for all types of CVCs. Thus, arteriovenous fistulae are safe and valuable alternatives to CVCs for patients requiring long-term HPN.

Everolimus interferes with healing of experimental intestinal anastomoses.

BACKGROUND: Although clinical data suggest its existence, little is known about the effect of rapamycin derivatives on wound repair. This study aims to delineate the influence of the mammalian target of rapamycin inhibitor everolimus on wound healing in the rat intestine. METHODS: Four groups of 26 male Wistar rats received everolimus in daily oral dosages of 0 (controls), 0.5 (group E-0.5), 1.0 (group E-1), and 3.0 (group E-3) mg/kg every 24 hours, respectively, starting four hours before the operation until killing. After resection of 1-cm segments of colon and ileum, intestinal anastomoses were constructed. The animals were killed at days three or seven after operation. Wound healing was assessed by mechanical (bursting pressure, breaking strength), biochemical (collagen content, gelatinase activity), and histologic parameters. RESULTS: No differences between groups were recorded for any of the parameters on day three. On day seven, a dose-dependent reduction in breaking strength (P<0.05) was measured. The largest effects were found in group E-3 in which the breaking strength was reduced by 56% and 73% in colonic and ileal anastomoses, respectively. A similar pattern was observed with the bursting pressure. Loss of strength was accompanied by a reduction in hydroxyproline content and by a lessened collagen deposition in the wound area but not by an increased gelatinase activity. No further histologic abnormalities were found. CONCLUSION: Everolimus causes a massive reduction in anastomotic strength such as normally observed in the proliferative phase of repair. The data suggest this to be caused by an impaired deposition of collagen in the anastomotic area.