Sex differences in specialized pro-resolving lipid mediators and their receptors in abdominal aortic aneurysms.

Objective: In this study, we tested the hypothesis that endogenous expression of specialized pro-resolving lipid mediators (SPMs) that facilitate the resolution of inflammation, specifically Resolvin D1and -D2, as well as Maresin1 (MaR1), can impact abdominal aortic aneurysm (AAA) formation and progression in a sex-specific manner. Methods: SPM expression was quantified in aortic tissue from human AAA samples and from a murine in vivo AAA model via liquid chromatography-tandem mass spectrometry. mRNA expression for SPM receptors FPR2, LGR6, and GPR18 were quantified by real-time polymerase chain reaction. A Student t test with nonparametric Mann-Whitney or Wilcoxon test was used for pair-wise comparisons of groups. One-way analysis of variance after post hoc Tukey test was used to determine the differences among multiple comparative groups. Results: Human aortic tissue analysis revealed a significant decrease in RvD1 levels in male AAAs compared with controls, whereas FPR2 and LGR6 receptor expressions were downregulated in male AAAs compared with male controls. In vivo studies of elastase-treated mice showed higher levels of RvD2 and MaR1 as well as the SPM precursors, omega-3 fatty acids DHA and EPA, in aortic tissue from males compared with females. FPR2 expression was increased in elastase-treated females compared with males. Conclusions: Our findings demonstrate that specific differences in SPMs and their associated G-protein coupled receptors exist between sexes. These results indicate the relevance of SPM-mediated signaling pathways in sex differences impacting the pathogenesis of AAAs.

Resolution of inflammation via RvD1/FPR2 signaling mitigates Nox2 activation and ferroptosis of macrophages in experimental abdominal aortic aneurysms.

Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, leukocyte infiltration, and vascular remodeling. Resolvin D1 (RvD1) is derived from ω-3 polyunsaturated fatty acids and is involved in the resolution phase of chronic inflammatory diseases. The aim of this study was to decipher the protective role of RvD1 via formyl peptide receptor 2 (FPR2) receptor signaling in attenuating abdominal aortic aneurysms (AAA). The elastase-treatment model of AAA in C57BL/6 (WT) mice and human AAA tissue was used to confirm our hypotheses. Elastase-treated FPR2-/- mice had a significant increase in aortic diameter, proinflammatory cytokine production, immune cell infiltration (macrophages and neutrophils), elastic fiber disruption, and decrease in smooth muscle cell α-actin expression compared to elastase-treated WT mice. RvD1 treatment attenuated AAA formation, aortic inflammation, and vascular remodeling in WT mice, but not in FPR2-/- mice. Importantly, human AAA tissue demonstrated significantly decreased FPR2 mRNA expression compared to non-aneurysm human aortas. Mechanistically, RvD1/FPR2 signaling mitigated p47phox phosphorylation and prevented hallmarks of ferroptosis, such as lipid peroxidation and Nrf2 translocation, thereby attenuating HMGB1 secretion. Collectively, this study demonstrates RvD1-mediated immunomodulation of FPR2 signaling on macrophages to mitigate ferroptosis and HMGB1 release, leading to resolution of aortic inflammation and remodeling during AAA pathogenesis.

Endothelial pannexin-1 channels modulate macrophage and smooth muscle cell activation in abdominal aortic aneurysm formation.

Pannexin-1 (Panx1) channels have been shown to regulate leukocyte trafficking and tissue inflammation but the mechanism of Panx1 in chronic vascular diseases like abdominal aortic aneurysms (AAA) is unknown. Here we demonstrate that Panx1 on endothelial cells, but not smooth muscle cells, orchestrate a cascade of signaling events to mediate vascular inflammation and remodeling. Mechanistically, Panx1 on endothelial cells acts as a conduit for ATP release that stimulates macrophage activation via P2X7 receptors and mitochondrial DNA release to increase IL-1ß and HMGB1 secretion. Secondly, Panx1 signaling regulates smooth muscle cell-dependent intracellular Ca2+ release and vascular remodeling via P2Y2 receptors. Panx1 blockade using probenecid markedly inhibits leukocyte transmigration, aortic inflammation and remodeling to mitigate AAA formation. Panx1 expression is upregulated in human AAAs and retrospective clinical data demonstrated reduced mortality in aortic aneurysm patients treated with Panx1 inhibitors. Collectively, these data identify Panx1 signaling as a contributory mechanism of AAA formation.

Maresin 1 activates LGR6 signaling to inhibit smooth muscle cell activation and attenuate murine abdominal aortic aneurysm formation.

The specialized pro-resolving lipid mediator maresin 1 (MaR1) is involved in the resolution phase of tissue inflammation. It was hypothesized that exogenous administration of MaR1 would attenuate abdominal aortic aneurysm (AAA) growth in a cytokine-dependent manner via LGR6 receptor signaling and macrophage-dependent efferocytosis of smooth muscle cells (SMCs). AAAs were induced in C57BL/6 wild-type (WT) mice and smooth muscle cell specific TGF-ß2 receptor knockout (SMC-TGFßr2-/- ) mice using a topical elastase AAA model. MaR1 treatment significantly attenuated AAA growth as well as increased aortic SMC α-actin and TGF-ß2 expressions in WT mice, but not SMC-TGFßr2-/- mice, compared to vehicle-treated mice. In vivo inhibition of LGR6 receptors obliterated MaR1-dependent protection in AAA formation and SMC α-actin expression. Furthermore, MaR1 upregulated macrophage-dependent efferocytosis of apoptotic SMCs in murine aortic tissue during AAA formation. In vitro studies demonstrate that MaR1-LGR6 interaction upregulates TGF-ß2 expression and decreases MMP2 activity during crosstalk of macrophage-apoptotic SMCs. In summary, these results demonstrate that MaR1 activates LGR6 receptors to upregulate macrophage-dependent efferocytosis, increases TGF-ß expression, preserves aortic wall remodeling and attenuate AAA formation. Therefore, this study demonstrates the potential of MaR1-LGR6-mediated mitigation of vascular remodeling through increased efferocytosis of apoptotic SMCs via TGF-ß2 to attenuate AAA formation.

Treatment and Outcomes of Aortic Graft Infections Using a Decision Algorithm.

BACKGROUND: Aortic graft infection (AGI) is a rare but devastating complication requiring both explant of the infected prosthesis and lower extremity revascularization. Despite a variety of methods to treat AGI, there is a paucity of evidence that describes comparative outcomes. Moreover, controversy exists surrounding what the optimal repair strategy is with limited descriptions of how these techniques should be employed in this complex group of patients. Therefore, the purpose of this analysis was to review our experience with AGI management while highlighting a practice philosophy that can achieve acceptable outcomes. METHODS: All AGI patients between 2002-2019 were reviewed. The primary end-point was 30-day mortality. Secondary end-points included complications, re-infection, unplanned re-operation and all-cause mortality. Kaplan-Meier methodology was used to estimate time to events. Cox regression models were employed to identify association between patient factors and operative strategy with survival. Subgroup analysis included outcome comparison among four different operative approaches(extra-anatomic bypass with aortic ligation [EAB] and in-situ reconstruction [ISR] using either NAIS, cryopreserved allograft [Cryo], or antibiotic-soaked prosthetic grafts [Other]). RESULTS: 142 patients (male-69%, mean age 67 ± 11 years) were reviewed. Median time to AGI presentation was 52 (IQR 16-128) months. ISR was performed in 70% (n = 99)[ISR: NAIS-49% (n = 49), Cryo, 33% (n = 33) and Other-23% (n = 23)]. EAB was used in 26% (n = 37), of which 57% (n = 21) were staged repairs[no reconstruction, 4%: intraoperative death-2, AGI removal without reconstruction-2]. A graft enteric erosion/fistula was identified in 39% (n = 55). Mean follow-up time was 14 ± 27 (median 2.2[IQR 0.1-16]) months. Overall, 30-day mortality was 21% and 69% (n = 98) experienced a complication. The most common complications were pulmonary (35%;n = 50), vascular (28%;n = 39), gastrointestinal (22%;n = 31) and renal (21%;n = 30). Freedom from re-infection at one and three years was 78 ± 5% and 73 ± 6% while freedom from unplanned re-operation was 50 ± 5% and 40 ± 6%, respectively. Corresponding one- and five-year freedom from all-cause mortality was 67 ± 4% and 53 ± 4%. When stratified by the four different repair strategies, unadjusted rates of postoperative complications and mortality were not different. However, EAB patients had more renal complications. All-cause mortality predictors included age (HR 1.04, 95%CI 1.01-1.1; P = 0.003), CHF (HR 2.7, 1.3-5.7; P = 0.01), and graft enteric erosion/fistula (HR 2.2, 1.3-3.8;P = 0.005) while total graft excision was protective (HR 0.34, 0.2-0.7; P = 0.003). CONCLUSIONS: AGI repair, regardless of operative strategy, results in significant early morbidity, and mortality. The need for unplanned re-operation is common; however, long-term survival is acceptable in appropriately selected patients. Re-infection risk mandates life-long surveillance and consideration of indefinite anti-microbial suppression in certain subgroups. Due to the complexity and intensity of care, all AGI should be treated, when possible, at centers performing high-volume aortic surgery.

Intraoperative hypotension and complications after vascular surgery: A scoping review.

BACKGROUND: Intraoperative hypotension during major surgery is associated with adverse health outcomes. This phenomenon represents a potentially important therapeutic target for vascular surgery patients, who may be uniquely vulnerable to intraoperative hypotension. This review summarizes current evidence regarding the impact of intraoperative hypotension on postoperative complications in patients undergoing vascular surgery, focusing on potentially modifiable procedure- and patient-specific risk factors. METHODS: A scoping review of the literature from Embase, MEDLINE, and PubMed databases was conducted from inception to December 2019 to identify articles related to the effects of intraoperative hypotension on patients undergoing vascular surgery. RESULTS: Ninety-two studies met screening criteria; 9 studies met quality and inclusion criteria. Among the 9 studies that defined intraoperative hypotension objectively, there were 9 different definitions. Accordingly, the reported incidence of intraoperative hypotension ranged from 8% to 88% (when defined as a fall in systolic blood pressure of >30 mm Hg or mean arterial pressure <65). The results demonstrated that intraoperative hypotension is an independent risk factor for longer hospital length of stay, myocardial injury, acute kidney injury, postoperative mechanical ventilation, and early mortality. Vascular surgery patients with comorbid conditions that confer increased vulnerability to hypoperfusion and ischemia appear to be susceptible to the adverse effects of intraoperative hypotension. CONCLUSION: There is no validated, consensus definition of intraoperative hypotension or other hemodynamic parameters associated with increased risk for adverse outcomes. Despite these limitations, the weight of evidence suggests that intraoperative hypotension is common and associated with major postoperative complications in vascular surgery patients.

Pharmacologic inhibition of transient receptor channel vanilloid 4 attenuates abdominal aortic aneurysm formation.

Abdominal aortic aneurysm (AAA) formation is characterized by inflammation, leukocyte infiltration, and vascular remodeling. This study investigates the role of TRPV4 channels, which are transmembrane calcium channels that can regulate vascular tone, in modulating AAA formation. The elastase-treatment model of AAA in C57BL6 (WT) mice and Angiotensin II treatment model in ApoE-/- mice were used to confirm our hypotheses. The administration of a specific TRPV4 antagonist, GSK2193874, in elastase-treated WT mice and in AngII-treated ApoE-/- mice caused a significant attenuation of aortic diameter, decrease in pro-inflammatory cytokines (IL-1ß, IL-6, IL-17, MCP-1, MIP-1α, MIP-2, RANTES, and TNF-α), inflammatory cell infiltration (CD3 + T cells, macrophages, and neutrophils), elastic fiber disruption, and an increase in smooth muscle cell α-actin expression compared to untreated mice. Similarly, elastase-treated TRPV4-/- mice had a significant decrease in AAA formation, aortic inflammation, and vascular remodeling compared to elastase-treated WT mice on Day 14. In vitro studies demonstrated that the inhibition of TRPV4 channels mitigates aortic smooth muscle cell-dependent inflammatory cytokine production as well as decreases neutrophil transmigration through aortic endothelial cells. Therefore, our results suggest that TRPV4 antagonism can attenuate aortic inflammation and remodeling via decreased smooth muscle cell activation and neutrophil transendothelial migration during AAA formation.

Results of a Multicenter Feasibility Study of an Automated Bedside Glucose Monitoring System in the Burn Intensive Care Setting.

Intensive blood glucose regimens required for tight glycemic control in critically ill burn patients carry risk of hypoglycemia and are ultimately limited by the frequency of which serum glucose measurements can be feasibly monitored. Continuous inline glucose monitoring has the potential to significantly increase the frequency of serum glucose measurement. The objective of this study was to assess the accuracy of a continuous glucose monitor with inline capability (Optiscanner) in the burn intensive care setting. A multicenter, observational study was conducted at two academic burn centers. One hundred and six paired blood samples were collected from 10 patients and measured on the Optiscanner and the Yellow Springs Instrument. Values were plotted on a Clarke Error Grid and mean absolute relative difference calculated. Treatment was guided by existing hospital protocols using separately obtained values. 97.2% of results obtained from Optiscanner were within 25% of corresponding Yellow Springs Instrument values and 100% were within 30%. Mean absolute relative difference was calculated at 9.6%. Our findings suggest that a continuous glucose monitor with inline capability provides accurate blood glucose measurements among critically ill burn patients.

Paravertebral regional blocks decrease length of stay following surgery for pectus excavatum in children.

PURPOSE: Management of postoperative pain following repair of pectus excavatum has traditionally included thoracic epidural analgesia, narcotics, and benzodiazepines. We hypothesized that the use of intercostal or paravertebral regional blocks could result in decreased inpatient length of stay (LOS). METHODS: We conducted a retrospective cohort study of 137 patients (118 Nuss and 19 Ravitch - Nuss and Ravitch patients were analyzed separately) who underwent surgical repair of pectus excavatum with pain management via epidural, intercostal, or paravertebral analgesia from January 2009-December 2012. Measured outcomes included LOS, pain scores, benzodiazepine/narcotic requirements, emesis, professional fees, hospital cost, and total cost. RESULTS: In the Nuss patients, LOS was significantly reduced in the paravertebral group (p<0.005) and the intercostal group (p<0.005) compared to the epidural group, but was paradoxically countered by a nonsignificant increase in total cost (p=0.09). While benzodiazepine doses/day was not increased in the paravertebral group (p=0.08), an increase was seen in narcotic use (p<0.005). Despite increased narcotic use, no differences were seen in emesis between epidural and paravertebral use. Compared to epidural, pain scores were higher for both intercostal and paravertebral on day one (p<0.005), but equivalent for paravertebral on day three (p=0.62). The Ravitch group was too small for detailed independent statistical analysis but followed the same overall trend seen in the Nuss patients. CONCLUSION: Our use of paravertebral continuous infusion pain catheters for pectus excavatum repair was an effective alternative to epidural analgesia resulting in shorter LOS but not a decrease in overall cost.

Addressing challenges of training a new generation of clinician-innovators through an interdisciplinary medical technology design program: Bench-to-Bedside.

Graduate medical education has traditionally focused on training future physicians to be outstanding clinicians with basic and clinical science research skills. This focus has resulted in substantial knowledge gains, but a modest return on investment based on direct improvements in clinical care. In today's shifting healthcare landscape, a number of important challenges must be overcome to not only improve the delivery of healthcare, but to prepare future physicians to think outside the box, focus on and create healthcare innovations, and navigate the complex legal, business and regulatory hurdles of bringing innovation to the bedside. We created an interdisciplinary and experiential medical technology design competition to address these challenges and train medical students interested in moving new and innovative clinical solutions to the forefront of medicine. Medical students were partnered with business, law, design and engineering students to form interdisciplinary teams focused on developing solutions to unmet clinical needs. Over the course of six months teams were provided access to clinical and industry mentors, $500 prototyping funds, development facilities, and non-mandatory didactic lectures in ideation, design, intellectual property, FDA regulatory requirements, prototyping, market analysis, business plan development and capital acquisition. After four years of implementation, the program has supported 396 participants, seen the development of 91 novel medical devices, and launched the formation of 24 new companies. From our perspective, medical education programs that develop innovation training programs and shift incentives from purely traditional basic and clinical science research to also include high-risk innovation will see increased student engagement in improving healthcare delivery and an increase in the quality and quantity of innovative solutions to medical problems being brought to market.

The role of screening and prophylactic surgery for malrotation in heterotaxy patients.

PURPOSE: There are no standardized guidelines for screening or management of malrotation in Heterotaxy Syndrome (HS). We sought to review our experience to determine if evidenced based guidelines could be drafted. METHODS: A retrospective chart review was performed at our freestanding children's hospital on all patients under one year of age undergoing a Ladd procedure between 2000 and 2011. In addition, all Heterotaxy patients were reviewed during this period. RESULTS: Twenty-three Heterotaxy patients and seventy-nine Non-Heterotaxy patients underwent a Ladd procedure. Both groups had a high rate of complication. Heterotaxy was associated with significantly higher mortality 30days after Ladd procedure. In our review, we also identified seventy-six HS patients who did not undergo a Ladd procedure. Among these patients, fourteen had normal intestinal anatomy, five had malrotation, and fifty-seven were never evaluated for intestinal malrotation. No patients with intestinal malrotation or unknown intestinal rotation status suffered midgut volvulus. Average follow-up time was 5.1years. CONCLUSIONS: We conclude that prophylactic Ladd procedures in children with Heterotaxy are associated with a high morbidity and mortality. Patients who avoided screening were not exposed to a significant risk of midgut volvulus, and our experience suggests that routine screening of Heterotaxy patients for malrotation should be abandoned.