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.

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.

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.

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.