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Background: Renal toxicity from conventional, iodinated, intravenous contrast agents is a common complication in patients with peripheral artery disease (PAD). Similarly, the potential for serious side effects prevents the use of gadolinium-based agents in many patients with depressed renal function. Ferumoxytol-enhanced magnetic resonance angiography (Fe-MRA) is a novel technique that uses an intravenous, ultrasmall, superparamagnetic, iron oxide preparation, currently approved by the Food and Drug Administration for the treatment of iron deficiency anemia in adults with chronic kidney disease. Our objective was to determine the feasibility of Fe-MRA for clinical decision making in PAD patients., Methods: This was a prospective pilot study assessing 10 patients with suspected arterial occlusive disease with contrast-enhanced MRA of the aorta and lower extremities. Of those, 5 had renal insufficiency and were imaged with Fe-MRA, whereas the remainder underwent gadolinium-enhanced MRA. Qualitative and quantitative evaluations of deidentified images at each arterial station were independently performed by 4 blinded vascular surgeons., Results: All patients were men, with an average age of 68 ± 4 years. The 2 groups had similar incidences of diabetes, hypertension, hyperlipidemia, and coronary artery disease. Patients undergoing Fe-MRA had significantly decreased renal function (estimated glomerular filtration rate, 35.4 vs. 77.6; P = 0.02). There were no adverse events during contrast administration in either group. No difference was found in the overall quality of the ferumoxytol versus the gadolinium studies (7.1 ± 2.0 vs. 7.4 ± 2.4, P = 0.67). Similarly, reviewers felt comfortable basing clinical decisions on the images 89% of the time with both the ferumoxytol and gadolinium groups (P = 1.00)., Conclusions: This is the first report of an important alternative to conventional computed tomography angiography and MRA in PAD patients, particularly in the setting of renal insufficiency. Fe-MRA provides a useful tool in patients with suspected lower extremity PAD without the potential risks of gadolinium., (Copyright © 2015 Elsevier Inc. All rights reserved.)

After the creation of an autogenous lower extremity bypass graft, the vein must undergo a series of dynamic structural changes to stabilize the arterial hemodynamic forces. These changes, which are commonly referred to as remodeling, include an inflammatory response, the development of a neointima, matrix turnover, and cellular proliferation and apoptosis. The sum total of these processes results in dramatic alterations in the physical and biomechanical attributes of the arterialized vein. The most clinically obvious and easily measured of these is lumen remodeling of the graft. However, although somewhat less precise, wall thickness, matrix composition, and endothelial changes can be measured in vivo within the healing vein graft. Recent translational work has demonstrated the clinical relevance of remodeling as it relates to vein graft patency and the systemic factors influencing it. By correlating histologic and molecular changes in the vein, insights into potential therapeutic strategies to prevent bypass failure and areas for future investigation are explored., (Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Factors responsible for the variability in outcomes after lower extremity vein bypass grafting (LEVBG) are poorly understood. Recent evidence has suggested that a single nucleotide polymorphism (SNP) in the promoter region of the p27(Kip1) gene, a cell-cycle regulator, is associated with coronary in-stent restenosis. We hypothesized an association with vein graft patency., Methods: This was a retrospective genetic association study nested within a prospective cohort of 204 patients from three referral centers undergoing LEVBG for claudication or critical ischemia. The main outcome measure was primary vein graft patency., Results: All patients were followed up for a minimum of 1 year with duplex graft surveillance (median follow-up, 893 days; interquartile range, 539-1315). Genomic DNA was isolated and SNP analysis for the p27(Kip1)-838C>A variants was performed. Allele frequencies were correlated with graft outcome using survival analysis and Cox proportional hazards modeling. The p27(Kip1)-838C>A allele frequencies observed were CA, 53%; CC, 30%; and AA, 17%, satisfying Hardy-Weinberg equilibrium. Race (P = .025) and history of coronary artery disease (P = .027) were different across the genotypes; all other baseline variables were similar. Primary graft patency was greater among patients with the -838AA genotype (75% AA vs 55% CA/CC at 3 years; P = .029). In a Cox proportional hazards model including age, sex, race, diabetes, critical limb ischemia, redo (vs primary) bypass, vein type, and baseline C-reactive protein level, the p27(Kip1)-838AA genotype was significantly associated with higher graft patency (hazard ratio for failure, 0.4; 95% confidence interval, 0.17-0.93). Genotype was also associated with early (0-1 month) changes in graft lumen diameter by ultrasound imaging., Conclusions: These data suggest that the p27(Kip1)-838C>A SNP is associated with LEVBG patency and, together with previous reports, underscore a central role for p27(Kip1) in the generic response to vascular injury., (Copyright © 2013 Society for Vascular Surgery. All rights reserved.)

Objective: Successful adaptation of a vein graft to an arterial environment is incompletely understood. We sought to investigate whether early vein graft remodeling is predictive of subsequent patency., Methods: A prospective longitudinal study was conducted of 67 patients undergoing lower extremity bypass with autogenous vein between February 2004 and April 2008. Preoperative blood samples were drawn for biomarkers. During the bypass operation, a 5-cm index segment of the graft was registered for serial lumen diameter measurements at 0, 1, 3, 6, 9, and 12 months using duplex ultrasound imaging. The imaging substudy analysis included patients with at least two ultrasound assessments., Results: Patients (55% male) were a median age of 70 years (interquartile range [IQR], 59-76 years), 40% had diabetes mellitus, 49% had critical limb ischemia, 75% were taking a statin, and 91% were taking an antiplatelet medication. Median follow-up was 32 months (IQR, 15-47 months). The median baseline high-sensitivity C-reactive protein level (hsCRP) was 3.2 mg/L (IQR, 1.4-9.7 mg/L). The average intraoperative, postimplantation vein lumen diameter was 3.9±1.0 mm, increasing to 4.7±1.1 mm at 1 month, an average 24%±27% change per patient. By 3 months, the average lumen diameter was 5.1±1.6 mm, with little subsequent change observed to 12 months. Nonwhite race, baseline hsCRP ≥5 mg/L, statin use, and initial lumen diameter were significantly associated with early (0- to 1-month) vein remodeling in a multivariable regression model. The primary patency rate for the cohort was 60%±6.3% at 2 years. Initial lumen diameter of the index segment was not associated with primary patency, whereas larger lumen diameter achieved at 1 month (≥5.1 mm) was positively associated with primary patency (log-rank, P=.03). Early (30-day) remodeling behavior was used to divide patients into "poor remodelers" (<-5% lumen diameter change, n=6), "modest remodelers" (-5% to 25% change, n=29), and "robust remodelers" (>+25% change, n=30). Early remodeling category was significantly associated with primary patency rate at 2 years (log-rank, P=.02). A multivariable Cox proportional hazards model showed that modest remodelers (hazard ratio, 3.9; 95% confidence interval, 1.02-15; P=.04) and poor remodelers (hazard ratio, 13; 95% confidence interval; P=.008) had significantly higher hazard ratios for graft failure than robust early remodelers., Conclusions: Early remodeling of the arterialized vein appears to predict midterm bypass graft patency. In addition to baseline diameter, race, inflammation, hsCRP, and statin use are associated with early adaptive remodeling, but the mechanisms for these observations are not understood., (Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Patients with advanced peripheral artery disease (PAD) have a high prevalence of cardiovascular (CV) risk factors and shortened life expectancy. However, CV risk factors poorly predict midterm (<5 years) mortality in this population. This study tested the hypothesis that baseline biochemical parameters would add clinically meaningful predictive information in patients undergoing lower extremity bypass operations., Methods: This was a prospective cohort study of patients with clinically advanced PAD undergoing lower extremity bypass surgery. The Cox proportional hazard model was used to assess the main outcome of all-cause mortality. A clinical model was constructed with known CV risk factors, and the incremental value of the addition of clinical chemistry, lipid assessment, and a panel of 11 inflammatory parameters was investigated using the C statistic, the integrated discrimination improvement index, and Akaike information criterion., Results: The study monitored 225 patients for a median of 893 days (interquartile range, 539-1315 days). In this study, 50 patients (22.22%) died during the follow-up period. By life-table analysis (expressed as percent surviving ± standard error), survival at 1, 2, 3, 4, and 5 years, respectively, was 90.5% ± 1.9%, 83.4% ± 2.5%, 77.5% ± 3.1%, 71.0% ± 3.8%, and 65.3% ± 6.5%. Compared with survivors, decedents were older, diabetic, had extant coronary artery disease, and were more likely to present with critical limb ischemia as their indication for bypass surgery (P < .05). After adjustment for the above, clinical chemistry and inflammatory parameters significant (hazard ratio [95% confidence interval]) for all-cause mortality were albumin (0.43 [0.26-0.71]; P = .001), estimated glomerular filtration rate (0.98 [0.97-0.99]; P = .023), high-sensitivity C-reactive protein (hsCRP; 3.21 [1.21-8.55]; P = .019), and soluble vascular cell adhesion molecule (1.74 [1.04-2.91]; P = .034). Of the inflammatory molecules investigated, hsCRP proved most robust and representative of the integrated inflammatory response. Albumin, eGFR, and hsCRP improved the C statistic and integrated discrimination improvement index beyond that of the clinical model and produced a final C statistic of 0.82., Conclusions: A risk prediction model including traditional risk factors and parameters of inflammation, renal function, and nutrition had excellent discriminatory ability in predicting all-cause mortality in patients with clinically advanced PAD undergoing bypass surgery., (Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

The purpose of this study is to primarily evaluate the lumen area and secondarily evaluate wall area measurements of in vivo lower extremity peripheral vein bypass grafts patients using high spatial resolution, limited field of view, cardiac gated, black blood inner volume three-dimensional fast spin echo MRI. Fifteen LE-PVBG patients prospectively underwent ultrasound followed by T1-weighted and T2-weighted magnetic resonance (MR) imaging. Lumen and vessel wall areas were measured by direct planimetry. For graft lumen areas, T1- and T2-weighted measurements were compared with ultrasound. For vessel wall areas, differences between T1- and T2-weighted measurements were evaluated. There was no significant difference between ultrasound and MR lumen measurements, reflecting minimal MR blood suppression artifact. Graft wall area measured from T1-weighted images was significantly larger than that measured from T2-weighted images (P < 0.001). The mean of the ratio of T1- versus T2-weighted vessel wall areas was 1.59 (95% CI: 1.48-1.69). The larger wall area measured on T1-weighted images was due to a significantly larger outer vessel wall boundary. Very high spatial resolution LE-PVBG vessel wall MR imaging can be performed in vivo, enabling accurate measurements of lumen and vessel wall areas and discerning differences in those measures between different tissue contrast weightings. Vessel wall area differences suggest that LE-PVBG vessel wall tissues produce distinct signal characteristics under T1 and T2 MR contrast weightings.

For patients with the most severe manifestations of lower extremity arterial occlusive disease, bypass surgery using autogenous vein has been the most durable reconstruction. However, the incidence of bypass graft stenosis and graft failure remains substantial and wholesale improvements in patency are lacking. One potential explanation is that stenosis arises not only from over exuberant intimal hyperplasia, but also due to insufficient adaptation or remodeling of the vein to the arterial environment. Although in vivo human studies are difficult to conduct, recent advances in imaging technology have made possible a more comprehensive structural examination of vein bypass maturation. This review summarizes recent translational efforts to understand the structural and functional properties of human vein grafts and places it within the context of the rich existing literature of vein graft failure.

Lower-extremity vein graft failure causes significant morbidity, increases health care costs, and negatively impacts patient quality of life. Identification of risk factors is essential for patient selection, risk factor modification, and identifying individuals who would benefit from more stringent surveillance protocols. Risk factors can be considered as either patient-related or technical. Here we discuss the patient-related risk factors for vein graft failure. Nontechnical factors related to the indication for operation include operation after a previously failed graft, or redo bypass, critical limb ischemia, and infection. Risk factors for vein graft failure are distinct from the risk factors for cardiovascular events. Young age and African American and Hispanic race are risk factors for lower-extremity vein graft failure. Hypercoaguable and inflammatory states also increase risk for vein graft failure. Therapy with statins is indicated in patients with peripheral atherosclerosis and may have beneficial effects on vein graft function, although further studies are needed in this area.

Objective: As in arteries, venous endothelium modulates vessel homeostasis and tone. The effect of an arterialized environment on venous endothelial function remains poorly understood. In particular, regulation of saphenous vein graft (SVG) blood flow and lumen caliber remains undefined. We hypothesized that mature SVGs would exhibit endothelium-dependent, flow-mediated vasodilation (FMD). We further hypothesized that endothelium-derived nitric oxide (NO) was an important mediator., Methods: Patients with femoral to popliteal artery SVGs that had maintained primary patency and were at least 1 year from surgery were enrolled. High-resolution, B-mode ultrasound scans were used to measure vein graft diameter before and 1 minute after reactive hyperemia (RH) to determine FMD. RH was created through application of 220 mm Hg to the calf for 5 minutes with a sphygmomanometric cuff. After a 10-minute recovery period, nitroglycerin-mediated, endothelium-independent vasodilation was measured 3 minutes after administration of nitroglycerin 0.4 mg sublingually. Brachial artery FMD was determined by validated techniques. L-N(G)monomethyl arginine (L-NMMA; 1 mg/kg infusion over 10 minutes) was used in a subset of patients (n = 6) to competitively inhibit endothelial NO synthase., Results: Nineteen subjects were enrolled. The median age of the SVGs was 34.6 (21.0-49.7) months. SVG flow-mediated, endothelium-dependent vasodilation was measured at 5.28% +/- 3.1% mean change in lumen diameter (range, 1.99%-9.36%; P < .0001 for diameter change). Nitroglycerin-mediated vasodilation was 3.7% +/- 1.0%, (range, 16%-10.04%; P < .005). Intravenous administration of L-NMMA abolished SVG FMD (5.7 +/- 1.4% before L-NMMA vs 0.01 +/- 0.01% during L-NMMA infusion; P = .0088) and attenuated brachial artery FMD (7.54% +/- 1.0% vs 5.7 +/- 1.4; P = .05)., Conclusion: SVGs manifest flow-mediated, endothelium-dependent, and nitroglycerin-mediated endothelium-independent vasodilation. Vein graft endothelium-dependent FMD is likely mediated by NO. Further investigation will be required to determine the role of endothelial function in vein graft patency.

Background: Hybrid procedures combine endovascular and open surgical techniques. We examined utilization rates and ways of performing them more efficiently., Methods: Hybrids were selected using codes for femoral endarterectomy, infrainguinal, or aorto-iliac-femoral bypass and angioplasty from Nationwide Inpatient Sample (NIS) data, then categorized as staged, or performed on the same day. Outcomes included utilization rates, total hospital charges, and length of stay (LOS). Confounders of charges and LOS were identified and excluded from final comparisons., Results: Utilization increased 7% from 2000 to 2004. Univariate associations linked staging to variables included in linear regressions for hospital charges and LOS. Excluding identified confounders from the final subgroup analysis still showed large differences in charges (same-day = $34,206, staged = $60,087) and LOS (same-day = 3 days, staged = 7 days)., Conclusions: Utilization of hybrids is increasing. Performing hybrids on the same day, if possible, greatly reduces hospital charges and LOS, emphasizing preadmission planning and simultaneous coordination of both portions.

Background: The remodeling of vein bypass grafts after arterialization is incompletely understood. We have previously shown that significant outward lumen remodeling occurs during the first month of implantation, but the magnitude of this response is highly variable. We sought to examine the hypothesis that systemic inflammation influences this early remodeling response., Methods: A prospective observational study was done of 75 patients undergoing lower extremity bypass using autogenous vein. Graft remodeling was assessed using a combination of ultrasound imaging and two-dimensional high-resolution magnetic resonance imaging., Results: The vein graft lumen diameter change from 0 to 1 month (22.7% median increase) was positively correlated with initial shear stress (P = .016), but this shear-dependent response was disrupted in subjects with an elevated baseline high-sensitivity C-reactive protein (hsCRP) level of >5 mg/L. Despite similar vein diameter and shear stress at implantation, grafts in the elevated hsCRP group demonstrated less positive remodeling from 0 to 1 month (13.5% vs 40.9%, P = .0072). By regression analysis, the natural logarithm of hsCRP was inversely correlated with 0- to 1-month lumen diameter change (P = .018). Statin therapy (beta = 23.1, P = .037), hsCRP (beta = -29.7, P = .006), and initial shear stress (beta = .85, P = .003) were independently correlated with early vein graft remodeling. In contrast, wall thickness at 1 month was not different between hsCRP risk groups. Grafts in the high hsCRP group tended to be stiffer at 1 month, as reflected by a higher calculated elastic modulus (E = 50.4 vs 25.1 Mdynes/cm2, P = .07)., Conclusions: Early positive remodeling of vein grafts is a shear-dependent response that is modulated by systemic inflammation. These data suggest that baseline inflammation influences vein graft healing, and therefore, inflammation may be a relevant therapeutic target to improve early vein graft adaptation.

Objective: To demonstrate lower extremity peripheral vein bypass graft wall thickness changes over time in a patient using very high spatial resolution cardiac gated, black blood inner volume three-dimensional (3D) fast spin echo (FSE) magnetic resonance imaging (MRI)., Case Report: A 52-year-old diabetic man with a history of hyperlipidemia underwent uncomplicated bypass grafting for an asymptomatic 5.2 cm popliteal artery aneurysm using reversed great saphenous vein. A segment of the bypass graft was studied at 1 and 6 months after surgery with cardiac gated inner volume 3D-FSE imaging with non-interpolated 0.195 mm(3) voxel volumes (0.3125 x 0.3125 x 2 mm). T1- and T2-weighted images were acquired in 10 min per contrast weighting. Graft imaging at one month after implantation illustrates expansion of the outer wall of the graft that partially resolves 5 months later., Conclusion: In this patient, expansion of the lower extremity peripheral bypass graft wall can be characterized in clinical scan times with a 3D-FSE MRI protocol using highly selective inner volume excitation followed by non-selective refocusing pulses. The resulting 3D images can potentially be used to study the biology of the vessel wall.

Patients with the most severe manifestations of lower extremity arterial occlusive disease often require peripheral bypass surgery for limb salvage and preservation of function. Although good quality saphenous vein offers the most durable conduit for reconstruction, 5-year failure rates are 30-50% and have remained largely unchanged for the past two decades. The majority of these failures occur within the first year of implantation, which is regarded as the most biologically active time during which the vein graft adapts to the arterial environment. Although intimal hyperplasia is generally regarded as the primary culprit of vein graft failure, geometric remodeling of the healing vein graft has recently emerged as a potentially significant contributing factor. While hemodynamic forces, including an increase in shear stress and wall tension, are undoubtedly central to the magnitude and direction of vein graft remodeling, we have determined that these forces alone cannot account for the extent of variability noted in early remodeling patterns. Therefore, we hypothesize that circulating factors, such as mediators of inflammation, may modulate the vein graft response to mechanical forces. This article reviews the definition and diagnosis of vein graft failure and summarizes our current efforts to understand the mechanisms of normal and abnormal vein graft adaptation to the arterial environment.

Background: Iliac angioplasty in preparation for an infrainguinal bypass graft has been shown to be an effective strategy. We undertook this study to determine if superficial femoral artery (SFA) angioplasty offers durable inflow for distal origin grafts originating from the SFA or popliteal artery., Methods: All distal origin grafts performed at a single institution between 1988 and 2006,