Among patients hospitalized with limb-threatening conditions and treated by a multidisciplinary amputation prevention team, PIII risk correlates with mortality whereas WIfI stage strongly predicts initial hospital duration of stay, and key mid-term limb outcomes. Surgical revascularization performed best in the limbs at greatest risk (WIfI stage 4), and autogenous vein bypass was the preferred conduit for open bypass. These data support the use of WIfI and PIII as complementary staging tools in the management of chronic limb-threatening ischemia.

Objective Lipid mediators derived from omega-3 polyunsaturated fatty acids such as Resolvin D1 (RvD1) accelerate the resolution of inflammation, and have potential as vascular therapeutics. The objective of this study was to evaluate local perivascular delivery of RvD1 as a means to attenuate neointimal hyperplasia in a rat model of arterial injury. Methods Smooth muscle cells were harvested from rat aortas to study the effects of RvD1 on rat arterial vascular smooth muscle cell (RASMC) responses in vitro, with focus on inflammation, proliferation, migration, cytoskeletal changes and cytotoxicity. The safety and efficacy of perivascular delivery of RvD1 via thin biodegradable 3-layered PLGA wraps or 25% Pluronic F127 gels were studied in a rat model of carotid angioplasty. A total of 200 ng RvD1 was loaded into each construct for perivascular delivery after injury. Morphometric and histologic analyses were performed 3 and 14 days after injury. Results RvD1 attenuated RASMC inflammatory pathways, proliferation, migration and mitogen-induced cytoskeletal changes in vitro, without evidence of cytotoxicity. RvD1-loaded wraps reduced neointimal formation after carotid angioplasty by 59% versus no-wrap controls (P = .001) and by 45% versus vehicle-wrap controls (P = .002). RvD1-loaded pluronic gels similarly reduced neointimal formation by 49% versus no-gel controls (P = .02) and by 52% versus vehicle-gel controls (P = .02). No group was associated with infection, thrombosis or negative vessel remodeling. Wraps were found to be easier to apply than gel constructs. Ki67 proliferation index was significantly lower in RvD1-loaded wrap treated arteries compared to both no-wrap and vehicle-wrap controls at both 3 and 14 days post-injury (65% versus no-wrap group and 70% versus vehicle-wrap group at day 3, 49% versus both control groups at day 14, P < .05). Similarly, oxidative stress (30% and 29%, P < .05). and NF-kB activation (42% and 45%, p<.05) were significantly lower in the RvD1-loaded wrap group compared to both no-wrap and vehicle-wrap controls at three days post-injury Conclusions Local perivascular delivery of RvD1 attenuates formation of neointimal hyperplasia without associated toxicity in a rat model of carotid angioplasty. This effect is likely due to attenuation of inflammatory pathways as well as decreased arterial smooth muscle cell proliferation and migration.

PHPT is undertreated in the elderly. We observed a progressive age-related decline in PTx rate that renders patients aged 70+ unlikely to have definitive treatment, irrespective of comorbidity and eligibility for surgery.

Unresolved inflammation is central to the pathophysiology of commonly occurring vascular diseases such as atherosclerosis, aneurysm, and deep vein thrombosis - conditions that are responsible for considerable morbidity and mortality. Surgical or catheter-based procedures performed on affected blood vessels induce acute-on-chronic inflammatory responses. The resolution of vascular inflammation is an important driver of vessel wall remodeling and functional recovery in these clinical settings. Specialized pro-resolving lipid mediators (SPMs) derived from omega-3 polyunsaturated fatty acids orchestrate key cellular processes driving resolution and a return to homeostasis. The identification of their potent effects in classic animal models of sterile inflammation triggered interest in their vascular properties. Recent studies have demonstrated that SPMs are locally synthesized in vascular tissues, have direct effects on vascular cells and their interactions with leukocytes, and play a protective role in the injury response. Early translational work has established the potential for SPMs as vascular therapeutics, and as candidate biomarkers in vascular disease. Further investigations are needed to understand the molecular and cellular mechanisms of resolution in the vasculature, to improve tools for clinical measurement, and to better define the potential for "resolution therapeutics" in vascular patients.

Acute vascular injury occurs in a number of important clinical contexts, including spontaneous disease-related events (e.g. plaque rupture, thrombosis) and therapeutic interventions such as angioplasty, stenting, or bypass surgery. Endothelial cell (EC) disruption exposes the underlying matrix, leading to a rapid deposition of platelets, coagulation proteins, and leukocytes. A thrombo-inflammatory response ensues characterized by leukocyte recruitment, vascular smooth muscle cell (VSMC) activation, and the elaboration of cytokines, reactive oxygen species and growth factors within the vessel wall. A resolution phase of vascular injury may be described in which leukocyte efflux, clearance of debris, and re-endothelialization occurs. VSMC migration and proliferation leads to the development of a thickened neointima that may lead to lumen compromise. Subsequent remodeling involves matrix protein deposition, and return of EC and VSMC to quiescence. Recent studies suggest that specialized proresolving lipid mediators (SPM) modulate key aspects of this response, and may constitute an endogenous homeostatic pathway in the vasculature. SPM exert direct effects on vascular cells that counteract inflammatory signals, reduce leukocyte adhesion, and inhibit VSMC migration and proliferation. These effects appear to be largely G-protein coupled receptor-dependent. Across a range of animal models of vascular injury, including balloon angioplasty, bypass grafting, and experimental aneurysm formation, SPM accelerate repair and reduce lesion formation. With bioactivity in the pM-nM range, a lack of discernible cytotoxicity, and a spectrum of vasculo-protective properties, SPM represent a novel class of vascular therapeutics. This review summarizes current research in this field, including a consideration of critical next steps and challenges in translation.

Objective: Inflammation is a key driver of excessive neointimal hyperplasia within vein grafts. Recent work demonstrates that specialized proresolving lipid mediators biosynthesized from omega-3 polyunsaturated fatty acids, such as resolvin D1 (RvD1), actively orchestrate the process of inflammation resolution. We investigated the effects of local perivascular delivery of RvD1 in a rabbit vein graft model. Methods: Ipsilateral jugular veins were implanted as carotid interposition grafts through an anastomotic cuff technique in New Zealand white rabbits (3–4 kg; N = 80). RvD1 (1 μg) was delivered to the vein bypass grafts in a perivascular fashion, using either 25% Pluronic F127 gel (Sigma-Aldrich, St. Louis, Mo) or a thin bilayered poly(lactic-co-glycolic acid) (PLGA) film. No treatment (bypass only) and vehicle-loaded Pluronic gels or PLGA films served as controls. Delivery of RvD1 to venous tissue was evaluated 3 days later by liquid chromatography-tandem mass spectrometry. Total leukocyte infiltration, macrophage infiltration, and cell proliferation were evaluated by immunohistochemistry. Elastin and trichrome staining was performed on grafts harvested at 28 days after bypass to evaluate neointimal hyperplasia and vein graft remodeling. Results: Perivascular treatments did not influence rates of graft thrombosis (23%), major wound complications (4%), or death (3%). Leukocyte (CD45) and macrophage (RAM11) infiltration was significantly reduced in the RvD1 treatment groups vs controls at 3 days (60%−72% reduction; P < .01). Cellular proliferation (Ki67 index) was also significantly lower in RvD1-treated vs control grafts at 3 days (40%−50% reduction; P < .01). Treatment of vein grafts with RvD1-loaded gels reduced neointimal thickness at 28 days by 61% vs bypass only (P < .001) and by 63% vs vehicle gel (P < .001). RvD1-loaded PLGA films reduced neointimal formation at 28 days by 50% vs bypass only (P < .001). RvD1 treatment was also associated with reduced collagen deposition in vein grafts at 28 days. Conclusions: Local perivascular delivery of RvD1 attenuates vein graft hyperplasia without associated toxicity in a rabbit carotid bypass model. This effect appears to be mediated by both reduced leukocyte recruitment and decreased cell proliferation within the graft. Perivascular PLGA films may also impart protection through biomechanical scaffolding in this venous arterialization model. Our studies provide further support for the potential therapeutic role of specialized proresolving lipid mediators such as D-series resolvins in modulating vascular injury and repair. (J Vasc Surg 2018;■:1–12.) Clinical Relevance: Autologous vein bypass grafts are the most durable means for revascularization in peripheral vascular disease; however, midterm and long-term outcomes are limited by vein graft hyperplasia with associated vein graft failure. Endogenous proresolving lipid mediators such as resolvin D1 have the potential to attenuate vein graft hyperplasia by accelerating repair. This study provides proof of co...

With the aggressive resource conservation necessary to face the COVID-19 pandemic, vascular surgeons face unique challenges to managing the health of their high-risk patients. Early analysis of patient outcomes following pandemic-related practice changes suggest that patients with chronic limb threatening ischemia (CLTI) have been presenting with more severe foot infections and are more likely to require major limb amputation compared to 6 months prior. As our society and health care system adapt to the new changes required in the post-COVID era, it is critical that we pay special attention to the most vulnerable subsets of patients with vascular disease, particularly those with CLTI and limited access to care.

Recent evidence suggests that specialized proresolving lipid mediators (SPMs) generated from docosahexaenoic acid (DHA) can modulate the vascular injury response. However, cellular sources for these autacoids within the vessel wall remain unclear. Here, we investigated whether isolated vascular cells and tissues can produce SPMs and assessed expression and subcellular localization of the key SPM biosynthetic enzyme 5-lipoxygenase (LOX) in vascular cells. Intact human arteries incubated with DHA produced 17-hydroxy DHA (17-HDHA) and D-series resolvins, as assessed by liquid chromatography-tandem mass spectrometry. Addition of 17-HDHA to human arteries similarly increased resolvin production. Primary cultures of human saphenous vein endothelial cells (ECs) and vascular smooth muscle cells (VSMCs) converted 17-HDHA to SPMs, including resolvin D1 (RvD1) and other D-series resolvins and protectins. This was accompanied by a rapid translocation of 5-LOX from nucleus to cytoplasm in both ECs and VSMCs, potentially facilitating SPM biosynthesis. Conditioned medium from cells exposed to 17-HDHA inhibited monocyte adhesion to TNF-α-stimulated EC monolayers. These downstream effects were partially reversed by antibodies against the RvD1 receptors ALX/FPR2 and GPR32. These results suggest that autocrine and/or paracrine signaling locally generated SPMs in the vasculature may represent a novel homeostatic mechanism of relevance to vascular health and disease.-Chatterjee, A., Komshian, S., Sansbury, B. E., Wu, B., Mottola, G., Chen, M., Spite, M., Conte, M. S. Biosynthesis of proresolving lipid mediators by vascular cells and tissues.