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Background: We designed studies to determine whether the ApoE-/- phenotype modulates the local skeletal muscle and systemic inflammatory (plasma) responses to lower extremity demand ischemia. The ApoE-/- phenotype is an experimental model for atherosclerosis in humans., Methods: Aged female ApoE-/- and C57BL6 mice underwent femoral artery ligation, then were divided into sedentary and demand ischemia (exercise) groups on day 14. We assessed baseline and postexercise limb perfusion and hind limb function. On day 14, animals in the demand ischemia group underwent daily treadmill exercise through day 28. Sedentary mice were not exercised. On day 28, we harvested plasma and skeletal muscle from ischemic limbs from sedentary and exercised mice. We assayed muscle for angiogenic and proinflammatory proteins, markers of skeletal muscle regeneration, and evidence of skeletal muscle fiber maturation., Results: Hind limb ischemia was similar in ApoE-/- and C57 mice before the onset of exercise. Under sedentary conditions, plasma vascular endothelial cell growth factor and interleukin-6, but not keratinocyte chemoattractant factor (KC) or macrophage inflammatory protein-2 (MIP-2), were higher in ApoE (P < 0.0001). After exercise, plasma levels of vascular endothelial cell growth factor, KC, and MIP-2, but not IL-6, were lower in ApoE (P < 0.004). The cytokines KC and MIP-2 in muscle were greater in exercised ApoE-/- mice compared with C57BL6 mice (P = 0.01). Increased poly-ADP-ribose activity and mature muscle regeneration were associated with demand ischemia in the C57BL6 mice, compared with the ApoE-/- mice (P = 0.01)., Conclusions: Demand limb ischemia in the ApoE-/- phenotype exacerbated the expression of select systemic cytokines in plasma and blunted indices of muscle regeneration., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Although percutaneous intervention (PTA) is considered first-line therapy for peripheral vascular disease in many scenarios, its role in critical limb ischemia (CLI), wherein anatomic disease is more extensive, remains unclear. In the present study, late (5-year) clinical and patency data for PTA in CLI are defined., Methods: From January 2002 to December 2007, 409 patients underwent infrainguinal PTA ± stent for CLI (Rutherford IV-VI) of 447 limbs. Primary patency, assisted patency, limb salvage, and survival were assessed using Kaplan-Meier. Predictors of patency, limb salvage, and death were determined using multivariate models., Results: Demographics included age (70 ± 12 years old), diabetes (65.8%), and dialysis dependence (13%). The superficial femoral artery was treated in 58% of the patients, 16% were limited to the crural vessels, 38% had multilevel treatment, and stents were placed in 26%. Eighty percent of patients received postprocedure clopidogrel. Mean follow-up was 28 months (0-83). Five-year primary and assisted patency were 31% ± 0.04 and 75% ± 0.04, respectively. Limb salvage at 5 years was 74% ± 0.038. Sixty-three patients had major amputations. Survival at 5 years was 39% ± 0.03. Multivariate analysis identified dialysis dependence (P = .0005; 2.7 [1.6-4.8]), ≤1 vessel runoff (P = .02; 1.5 [1.1-2.0]), and warfarin use (P = .001; 1.7 [1.25-2.3]) as negative predictors of primary patency, but none of these were negative predictors of assisted patency. Dialysis dependence (P = .006; 2.5 [1.3-4.8]), female gender (P = .02; 2.0 [1.1-3.7]), and ≤1 vessel run-off (P = .04; 1.8 [1.0-3.2]) predicted limb loss. Dialysis dependence (P = .0003; 2.3 [1.5-3.5]), diabetes (P = .04; 1.5 [0.5-2.1]), and poor run-off (P = .04; 1.6 [1.2-2.1]) were predictors of mortality., Conclusion: Although primary patency is low, excellent limb salvage rates can be achieved in patients with CLI through close follow-up and secondary interventions. These data, and the 12% annual death rate, validate PTA as first-line therapy in patients with CLI., (Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Objectives: Recent reports have shown promising early results after endovascular revascularization (percutaneous transluminal angioplasty [PTA]/stent) of patients with peroneal artery-only runoff (PAOR), although the long-term durability is unclear. This study evaluated long-term primary patency and limb salvage of PTA/stent in patients with single-vessel runoff and critical limb ischemia to determine if the peroneal artery yields inferior results., Methods: From January 2002 to December 2007, 1075 infrainguinal PTA/stent procedures were performed in 920 patients. The study cohort comprised 201 limbs in 187 patients with single-vessel runoff and critical limb ischemia. End points included primary patency, assisted patency, limb salvage, and survival. Long-term outcomes were determined by Kaplan-Meier life-table and multivariate Cox regression analyses., Results: There were 104 PAOR and 97 limbs with single-vessel posterior or anterior tibial artery runoff (non-PAOR). Median follow-up was 25 months (range, 0-75 months). PAOR patients tended to be older (77.36 ± 0.92 vs 72.65 ± 1.18 years, P = .002) and were more likely to be taking clopidogrel at presentation (88% vs 76%; P = .04). There were no statistically significant differences in 5-year primary patency (26% ± 6.8% vs 30% ± 7.6%; P = .79), assisted patency (75% ± 8.8% vs 81% ± 7.0%; P = .77), limb salvage (74% ± 8.0% vs 75% ± 7.1%; P = .47), and survival (38% ± 7.7% vs 47% ± 6.6%; P = .99) between the PAOR and the non-PAOR groups, respectively. On Cox regression multivariate analysis, total occlusions predicted decreased assisted patency (hazard ratio, 2.99; 95% confidence interval, 1.21-7.41; P = .02), whereas younger age predicted poor limb salvage (hazard ratio, 0.97; 95% confidence interval, 0.94-0.99; P = .04). PAOR was not an independent predictor of any outcome on multivariate analysis., Conclusions: Patients with PAOR have similar long-term outcomes to patients with non-PAOR. Thus, infrainguinal endovascular revascularization can be considered a first-line therapy for patients with PAOR and critical limb ischemia., (Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Background: Several experiments were designed to determine whether the systemic, postischemic administration of PJ34,which is a poly-adenosine diphosphate (ADP)-ribose polymerase inhibitor, decreased tissue injury and inflammation after hind-limb ischemia reperfusion (I/R)., Methods: C57BL6 mouse limbs were subjected to 1.5 h ischemia followed by 24-h reperfusion. The treatment group (PJ) received intraperitoneal PJ34 (30 mg/kg) immediately before reperfusion, as well as 15 min and 2 h into reperfusion. The control group (CG) received lactated Ringer's alone at the same time intervals as PJ34 administration. The skeletal muscle levels of adenosine triphosphate (ATP), macrophage inflammatory protein-2 (MIP-2), keratinocyte derived chemokine (KC), and myeloperoxidase (MPO) were measured. Quantitative measurement of skeletal muscle tissue injury was assessed by microscopic analysis of fiber injury., Results: ATP levels were higher in limbs of PJ versus CG mice (absolute ATP: 4.7 +/- 0.35 vs 2.3 +/- 0.15-ng/mg tissue, P = .002). The levels of MIP-2, KC, and MPO were lower in PJ versus CG mice (MIP-2: 1.4 +/- 0.34 vs 3.67 +/- 0.67-pg/mg protein, P = .014; KC: 4.97 +/- 0.97 vs 12.65 +/- 3.05-pg/mg protein, P = .037; MPO: 46.27 +/- 10.53 vs 107.34 +/- 13.58-ng/mg protein, P = .008). Muscle fiber injury was markedly reduced in PJ versus CG mice (4.25 +/- 1.9% vs 22.68 +/- 3.0% total fibers, P = .0004)., Conclusion: Systemic postischemic administration of PJ34 preserved skeletal muscle energy levels, decreased inflammatory markers, and preserved tissue viability post-I/R. These results support PARP inhibition as a viable treatment for skeletal muscle I/R in a clinically relevant post hoc scenario., (Copyright 2010 Mosby, Inc. All rights reserved.)

Background: To date, murine models of treadmill exercise have been used to study general exercise physiology and angiogenesis in ischemic hindlimbs. The purpose of these experiments was to develop a murine model of demand ischemia in an ischemic limb to mimic claudication in humans. The primary goal was to determine whether treadmill exercise reflected a hemodynamic picture which might be consistent with the hyperemic response observed in humans., Methods: Aged hypercholesterolemic ApoE null mice (ApoE(-/-), n = 13) were subjected to femoral artery ligation (FAL) and allowed to recover from the acute ischemic response. Peripheral perfusion of the hindlimbs at rest was determined by serial evaluation using laser Doppler imaging (LDI) on days 0, 7, and 14 following FAL. During the experiments, mice were also assessed on an established five-point clinical ischemic score, which assessed the degree of digital amputation, necrosis, and cyanosis compared to the nonischemic contralateral limb. After stabilization of the LDI ratio (ischemic limb flux/contralateral nonischemic limb flux) and clinical ischemic score, mice underwent 2 days of treadmill training (10 min at 10 m/min, incline of 10 degrees ) followed by 60 min of daily treadmill exercise (13 m/min, incline of 10 degrees ) through day 25. An evaluation of preexercise and postexercise perfusion using LDI was performed on two separate occasions following the onset of daily exercise. During the immediate 15 min postexercise evaluation, LDI scanning was obtained in quadruplicate, to allow identification of peak flux ratios. Statistical analysis included unpaired t-tests and analysis of variance., Results: After FAL, the LDI flux ratio reached a nadir between days 1 and 2, then stabilized by day 14 and remained stable through day 25. The clinical ischemic score stabilized at day 7 and remained stable throughout the rest of the experiment. Based on stabilization of both the clinical ischemic score and LDI ratio, exercise training began on day 15. The peak 15 min postexercise LDI ratio increased significantly compared to the preexercise ratio on day 17 (0.48 +/- 0.04 vs. 0.34 +/- 0.04, p < 0.05) and day 25 (0.37 +/- 0.03 vs. 0.27 +/- 0.03, p < 0.01). Within 2 hr of exercise, the LDI ratio returned to preexercise levels on both days 17 and 25., Conclusion: Clinical and hemodynamic stabilization of limb perfusion is evident by 14 days after FAL. FAL followed by demand ischemia results in a reversible relative hyperemic response similar to that observed in exercising human claudicants. A murine model of FAL associated with demand ischemia may be useful to evaluate the metabolic, inflammatory, and flow-related changes associated with claudication in humans., (Copyright 2010 Annals of Vascular Surgery Inc. All rights reserved.)

Objective: Infrainguinal surgical bypass (BPG) is a durable method for lower extremity revascularization, but is accompanied by significant 30-day morbidity and mortality (MM). The goal of this study is to relate preoperative functional status, a defined metric in the National Surgical Quality Improvement Program (NSQIP) database, to perioperative MM., Methods: Between January 1, 2005 and December 31, 2007, all patients who underwent BPG from the NSQIP private sector database were reviewed. The primary end-point was 30-day MM. Patients were stratified by preoperative functional status: independent (IND) vs dependent (DEP). Associated patient demographic/clinical data were analyzed using univariate and multivariate methods. Composite odds ratios were constructed with clusters of high-risk comorbidities., Results: There were 5639 BPG patients (4600 [81.6%] IND and 1039 [18.4%]) DEP. DEP patients were significantly older (71.6 +/- 11.8 vs 66.8 +/- 11.8 years; P < .0001), had more chronic obstructive pulmonary disease (COPD) (16.7% vs 11.4%; P < .0001), diabetes (54.2% vs 40.7%; P < .0001), dialysis dependence (16.4% vs 5.6%; P < .0001), and critical limb ischemia (64.6% vs 44.0%; P < .0001). DEP patients had a higher incidence of death (6.1% vs 1.5%; P < .0001) and major complications (30.3% vs 14.2%; P < .0001). DEP was an independent predictor of major complications (odds ratio [OR]: 2.0; 95% confidence interval [CI]: [1.7-2.4]; P < .0001) major systemic complications (2.5 [1.9-3.2]; P < .0001), major operative site complications (1.6 [1.4-1.9]; P < .0001) and death (2.3[1.6-3.4]; P < .0001). The combination of DEP with emergency surgery, Cr > 1.8, or rest pain increased the odds of major complications by five, seven, or 11-fold, respectively. The combination of DEP with hemodialysis, emergency surgery, or age > or = 80 years increased the odds of death by 13, 38, or 87-fold, respectively., Conclusion: Preoperative DEP is significantly correlated with all adverse 30-day outcomes in BPG patients. Furthermore, when combined in high-risk composites with specific preoperative clinical variables, DEP is associated with prohibitive MM, thereby identifying patient cohorts that may be unsuitable for BPG., (Copyright 2010 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

The McGivney hemorrhoidal ligator (MHL), a band designed to cause tissue necrosis, is the preferred experimental tool to create hindlimb ischemia-reperfusion (I/R) injury in rodents. This report defines and compares the ex vivo band tension exerted by MHL and orthodontic rubber bands (ORBs) along with select in vivo characteristics of I/R. As to method, ex vivo band tension was measured over relevant diameters using a tensiometer. In vivo assessment of murine limb perfusion during ischemia with ORB and MHL was compared using laser Doppler imaging and measurement of wet weight-to-dry weight ratio. Neuromuscular scoring and histological extent of muscle fiber injury after I/R with MHL and ORB were also compared. A dose-response curve, between the duration of ORB-induced I/R with both mitochondrial activity (methyl-thiazol-tetrazolium) or tail perfusion [laser Doppler imaging (LDI)], was generated. As a results, ex vivo measurements showed that ORB exerted significantly less force than the MHL. Despite less tension in ORB, in vivo testing of the ORB confirmed complete ischemia by both LDI and wet weight-to-dry weight ratio. After I/R, caused by ORB, there was significantly less neuromuscular dysfunction. Histological assessment confirmed similar degrees of muscle fiber injury after I/R with either the MHL or ORB. Increasing durations of ischemia created by the ORB followed by reperfusion significantly decreased mitochondrial activity and tail perfusion after 24 h of ischemia. In conclusions, ORB produced similar levels of tissue ischemia in murine models of limb I/R with fewer levels of nonspecific injury. ORB may be the preferred model for selected studies of limb I/R.