Description: Background Patients with peripheral artery disease (PAD) experience significant morbidity and mortality. The OMEGA-PAD I Trial, a randomized, double-blinded, placebo-controlled trial, addressed the hypothesis that short-duration, high-dose n-3 polyunsaturated fatty acids (n-3 PUFA) oral supplementation improves endothelial function and inflammation in PAD. Methods and Results Eighty patients with stable claudication received 4.4 g of fish oil or placebo for 1 month. The primary end point was endothelial function as measured by brachial artery flow-mediated vasodilation. Secondary end points included biomarkers of inflammation, n-3 polyunsaturated fatty acids metabolome changes, lipid profile, and walking impairment questionnaires. Although there was a significant increase in FMD in the fish oil group following treatment (0.7±1.8% increase from baseline, P =0.04), this response was not different then the placebo group (0.6±2.5% increase from baseline, P =0.18; between-group P =0.86) leading to a negative finding for the primary endpoint. There was, however, a significant reduction in triglycerides (fish oil: –34±46 mg/dL, P 〈0.001; placebo –10±43 mg/dL, P =0.20; between-group differential P -value: 0.02), and an increase in the omega-3 index of 4±1% ( P 〈0.001) in the fish oil group (placebo 0.1±0.9%, P =0.49; between-group P 〈0.0001). We observed a significant increase in the production of pathway markers of specialized pro-resolving mediators generated from n-3 polyunsaturated fatty acids in the fish oil group. Conclusions High-dose, short-duration fish oil supplementation did not lead to a different response in the primary end point of endothelial function between the treatment and placebo group, but improved serum triglycerides and increased the production of downstream n-3 polyunsaturated fatty acids–derived products and mediators in patients with PAD. Clinical Trial Registration URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT01310270.

Description: 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 ex vivo 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 via 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.

Description: Recent evidence suggests that specialized lipid mediators derived from polyunsaturated fatty acids control resolution of inflammation, but little is known about resolution pathways in vascular injury. We sought to determine the actions of D-series resolvin (RvD) on vascular smooth muscle cell (VSMC) phenotype and vascular injury. Human VSMCs were treated with RvD1 and RvD2, and phenotype was assessed by proliferation, migration, monocyte adhesion, superoxide production, and gene expression assays. A rabbit model of arterial angioplasty with local delivery of RvD2 (10 nM vs. vehicle control) was employed to examine effects on vascular injury in vivo . Local generation of proresolving lipid mediators (LC-MS/MS) and expression of RvD receptors in the vessel wall were assessed. RvD1 and RvD2 produced dose-dependent inhibition of VSMC proliferation, migration, monocyte adhesion, superoxide production, and proinflammatory gene expression (IC 50 0.1–1 nM). In balloon-injured rabbit arteries, cell proliferation (51%) and leukocyte recruitment (41%) were reduced at 3 d, and neointimal hyperplasia was attenuated (29%) at 28 d by RvD2. We demonstrate endogenous biosynthesis of proresolving lipid mediators and expression of receptors for RvD1 in the artery wall. RvDs broadly reduce VSMC responses and modulate vascular injury, suggesting that local activation of resolution mechanisms expedites vascular homeostasis.—Miyahara, T., Runge, S., Chatterjee, A., Chen, M., Mottola, G., Fitzgerald, J. M., Serhan, C. N., Conte, M. S. D-series resolvin attenuates vascular smooth muscle cell activation and neointimal hyperplasia following vascular injury.

Description: Background Patients with peripheral arterial disease often experience treatment failure from restenosis at the site of a prior peripheral endovascular intervention (PVI) or lower extremity bypass (LEB). The impact of these treatment failures on the utilization and outcomes of secondary interventions is poorly understood. Methods and Results In our regional vascular quality improvement collaborative, we compared 2350 patients undergoing primary infrainguinal LEB with 1154 patients undergoing secondary infrainguinal LEB (LEB performed after previous revascularization in the index limb) between 2003 and 2011. The proportion of patients undergoing secondary LEB increased by 72% during the study period (22% of all LEBs in 2003 to 38% in 2011, P 〈0.001). In-hospital outcomes, such as myocardial infarction, death, and amputation, were similar between primary and secondary LEB groups. However, in both crude and propensity-weighted analyses, secondary LEB was associated with significantly inferior 1-year outcomes, including major adverse limb event-free survival (composite of death, new bypass graft, surgical bypass graft revision, thrombectomy/thrombolysis, or above-ankle amputation; Secondary LEB MALE-free survival = 61.6% vs primary LEB MALE-free survival = 67.5%, P =0.002) and reintervention or amputation-free survival (composite of death, reintervention, or above-ankle amputation; Secondary LEB RAO-free survival = 58.9% vs Primary LEB RAO-free survival 64.1%, P =0.003). Inferior outcomes for secondary LEB were observed regardless of the prior failed treatment type (PVI or LEB). Conclusions In an era of increasing utilization of PVI, a growing proportion of patients undergo LEB in the setting of a prior failed PVI or surgical bypass. When caring for patients with peripheral arterial disease, physicians should recognize that first treatment failure (PVI or LEB) affects the success of subsequent revascularizations.

Description: Background Women have high rates of peripheral artery disease (PAD) despite fewer cardiovascular disease (CVD) risk factors, compared to men. We sought to determine the gender-specific prevalence of low ankle brachial index (ABI) and the relationship to C-reactive protein (CRP) levels and CVD risk factors in the Life Line Screening population. Methods and Results Between April 2005 and August 2011, 133 750 women and 71 996 men had ABI and CRP measured at a Life Line Screening Center. Women were slightly older than men, whereas men were more likely to be current smokers, have diabetes mellitus (DM), and coronary artery disease (CAD) ( P 〈0.001 for each). Women were more likely to have ABI≤1.0, compared to men (26.6% versus 14.4%, respectively; P 〈0.001), as well as ABI≤0.9 (4.1% women versus 2.6% men; P 〈0.001). Women had higher median CRP levels (1.94 mg/L; interquartile range [IQR], 0.89, 4.44 mg/L), compared to men (1.35 mg/L; IQR, 0.73, 2.80 mg/L; P 〈0.001). Men and women shared similar risk factors for ABI≤0.9, including older age, black race, smoking, DM, hypertension, hypercholesterolemia, CAD, and elevated CRP levels. In an adjusted model, there were significant interactions between gender and age ( P 〈0.001), CRP ( P 〈0.001), CAD ( P =0.03), and DM ( P =0.06) with ABI as the outcome. The associations between age, CRP, CAD, and DM with ABI≤0.9 were stronger in men than in women. Conclusions Women participating in the Life Line Screening had higher CRP levels and a higher prevalence of PAD, compared to men. Neither higher CRP levels nor conventional CVD risk factors explained the excess prevalence of PAD in women.

Description: The prevalence of peripheral arterial disease (PAD) is increasing worldwide, with recent global estimates exceeding 200 million people. Advanced PAD leads to a decline in ambulatory function and diminished quality of life. In its most severe form, critical limb ischemia, rest pain, and tissue necrosis are associated with high rates of limb loss, morbidity, and mortality. Revascularization of the limb plays a central role in the management of symptomatic PAD. Concomitant with advances in the pathogenesis, genetics, and medical management of PAD during the last 20 years, there has been an ongoing evolution of revascularization options. The increasing application of endovascular techniques has resulted in dramatic changes in practice patterns and has refocused the question of which patients should be offered surgical revascularization. Nonetheless, surgical therapy remains a cornerstone of management for advanced PAD, providing versatile and durable solutions to challenging patterns of disease. Although there is little high-quality comparative effectiveness data to guide patient selection, existing evidence suggests that outcomes are dependent on definable patient factors such as distribution of disease, status of the limb, comorbid conditions, and conduit availability. As it stands, surgical revascularization remains the standard against which emerging percutaneous techniques are compared. This review summarizes the principles of surgical revascularization, patient selection, and expected outcomes, while highlighting areas in need of further research and technological advancement.

Description: Background Critical limb ischemia (CLI) is increasing in prevalence, and remains a significant source of mortality and limb loss. The decision to recommend surgical or endovascular revascularization for patients who are candidates for both varies significantly among providers and is driven more by individual preference than scientific evidence. Methods and Results The Best Endovascular Versus Best Surgical Therapy for Patients With Critical Limb Ischemia (BEST-CLI) Trial is a prospective, randomized, multidisciplinary, controlled, superiority trial designed to compare treatment efficacy, functional outcomes, quality of life, and cost in patients undergoing best endovascular or best open surgical revascularization. Approximately 140 clinical sites in the United States and Canada will enroll 2100 patients with CLI who are candidates for both treatment options. A pragmatic trial design requires consensus on patient eligibility by at least 2 investigators, but leaves the choice of specific procedural strategy within the assigned revascularization approach to the individual treating investigator. Patients with suitable single-segment of saphenous vein available for potential bypass will be randomized within Cohort 1 (n=1620), while patients without will be randomized within Cohort 2 (n=480). The primary efficacy end point of the trial is Major Adverse Limb Event–Free Survival. Key secondary end points include Re-intervention and Amputation-Free-Survival and Amputation Free-Survival. Conclusions The BEST-CLI trial is the first randomized controlled trial comparing endovascular therapy to open surgical bypass in patients with CLI to be carried out in North America. This landmark comparative effectiveness trial aims to provide Level I data to clarify the appropriate role for both treatment strategies and help define an evidence-based standard of care for this challenging patient population. Clinical Trial Registration URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT02060630.

Description: The role of resolvins in abdominal aortic aneurysm (AAA) has not been established. We hypothesized that treatment with D-series resolvins (RvD2 or RvD1) would attenuate murine AAA formation through alterations in macrophage polarization and cytokine expression. Male C57/B6 mice ( n = 9 per group) 8 to 12 wk old received RvD2 (100 ng/kg/treatment), RvD1 (100 ng/kg/treatment), or vehicle only every third day beginning 3 d before abdominal aortic perfusion with elastase as prevention. Aortas were collected 14 d after elastase perfusion. Cytokine analysis ( n = 5 per group) or confocal microscopy ( n = 4 per group) was performed. In a separate experiment, RvD2 was provided to mice with small AAAs 3 d after elastase treatment ( n = 8 per group). Additionally, apolipoprotein E knockout mice treated with angiotensin II (1000 ng/kg) were treated with RvD2 or vehicle alone ( n = 10 per group) in a nonsurgical model of AAA. To determine the effect of RvD2 on macrophage polarization, confocal staining for macrophages, M1 and M2 macrophage subtypes, α-actin, and DAPI was performed. Mean aortic dilation was 96 ± 13% for vehicle-treated mice, 57 ± 9.7% for RvD2-treated mice, and 61 ± 11% for RvD1-treated mice ( P 〈 0.0001). Proinflammatory cytokines macrophage chemotactic protein 1, C-X-C motif ligand 1, and IL-1β were significantly elevated in control animals compared to RvD2- and RvD1-treated animals ( P 〈 0.05), resulting in a reduction of matrix metalloproteinase 2 and 9 activity in resolvin-treated mice in both elastase and angiotensin II models. Treatment of existing small AAAs with RvD2 demonstrated a 25% reduction in aneurysm size at d 14 compared to vehicle alone ( P = 0.018). Confocal histology demonstrated a prevalence of M2 macrophages within the aortic medium in mice treated with RvD2. Resolvin D2 exhibits a potent protective effect against experimental AAA formation. Treatment with RvD2 significantly influences macrophage polarization and decreases several important proinflammatory cytokines. Resolvins and the alteration of macrophage polarization represent potential future targets for prevention of AAA.—Pope, N. H., Salmon, M., Davis, J. P., Chatterjee, A., Su, G., Conte, M. S., Ailawadi, G., Upchurch, G. R., Jr. D-series resolvins inhibit murine abdominal aortic aneurysm formation and increase M2 macrophage polarization.