Setting Of Peripheral Arterial Disease Research Articles

Biomarkers of Neutrophil Activation in Patients with Symptomatic Chronic Peripheral Artery Disease Predict Worse Cardiovascular Outcome

Neutrophils play a role in cardiovascular (CV) disease. However, relatively scant evidence exists in the setting of peripheral artery disease (PAD). The aims of this study were to measure biomarkers of neutrophil activation in patients with symptomatic chronic PAD compared with healthy controls, to assess their association with PAD severity, and to evaluate their prognostic value in patients with PAD. The following circulating markers of neutrophil degranulation were tested: polymorphonuclear neutrophil (PMN) elastase, neutrophil gelatinase-associated lipocalin (NGAL), and myeloperoxidase (MPO). Neutrophil extracellular traps (NETs) were quantified by measuring circulating MPO-DNA complexes. Patients with PAD underwent a comprehensive series of vascular tests. The occurrence of 6-month major adverse CV (MACE) and limb events (MALE) was assessed. Overall, 110 participants were included, 66 of which had PAD. After adjustment for conventional CV risk factors, PMN-elastase (adjusted odds ratio [OR]: 1.008; 95% confidence interval [CI]: 1.002-1.015; p = 0.006), NGAL (adjusted OR: 1.045; 95%CI: 1.024-1.066; p < 0.001), and MPO (adjusted OR: 1.013; 95%CI: 1.001-1.024; p = 0.028) were significantly associated with PAD presence. PMN-elastase (adjusted hazard ratio [HR]: 1.010; 95%CI: 1.000-1.020; p = 0.040) and MPO (adjusted HR: 1.027; 95%CI: 1.004-1.051; p = 0.019) were predictive of 6-month MACE and/or MALE. MPO displayed fair prognostic performance on receiver operating characteristic (ROC) curve analyses, with an area under the curve (AUC) of 0.74 (95%CI: 0.56-0.91) and a sensitivity and specificity of 0.80 and 0.65, respectively, for a cut-off of 108.37 ng/mL. MPO-DNA showed a weak inverse correlation with transcutaneous oximetry (TcPO2) on proximal foot (adjusted ρ -0.287; p = 0.032). In conclusion, in patients with symptomatic chronic PAD, enhanced neutrophil activity may be associated with an increased risk of acute CV events, rather than correlate with disease severity. Further research is needed to clarify the role of neutrophils in PAD natural history.

Long-Term Effects of Acute Kidney Injury Following Endovascular Femoropopliteal Intervention: Insights From a Multicenter Trial.

To examine the association between acute kidney injury (AKI) severity and duration with cardiovascular mortality, following endovascular treatment of femoropopliteal disease, and whether it is AKI in itself that confers an increased risk of cardiovascular mortality. A retrospective analysis of prospectively collected data obtained between 2014 and 2019 from 3 vascular centers. Renal function was followed up for a minimum of 90 days. Electronic records were queried to establish a cause of death, where applicable. Patients were excluded if unable to provide written informed consent or if presenting with acute limb ischemia. Primary outcomes were the hazard ratios for cardiovascular death (AKI patients vs no AKI; no AKI vs stage 1 AKI vs stage 3 AKI; and no AKI vs transient AKI vs established AKI). Propensity score-matched analysis was used to establish whether developing AKI, in patients with similar demographics and procedural characteristics, is associated with a higher risk of cardiovascular death. Overall 239 patients developed AKI, and this was associated with an increased risk of cardiovascular mortality (hazard risk [HR]: 4.3, 95% confidence intervals [CIs]: 2.1-6.8, pairwise comparison p value=0.006]. This was dependent on the severity of the AKI stage (HR 5.4, 95% CI: 2.4-7.3, pairwise comparison p value=0.01) and duration (HR 4.2, 95% CI: 2.3-6.2, pairwise comparison p value=0.04). The propensity score-matched analysis showed that even when patients are matched for comorbidity and procedural characteristics, AKI confers an increased risk of mortality (p=0.04). Acute kidney injury is common after femoropopliteal endovascular therapy. It confers an increased risk of long-term cardiovascular mortality, which is still present when renal decline is transient, and highest for patients with established decline in renal function. This is the first study in the setting of peripheral arterial disease to show that acute kidney injury has an adverse effect on cardiovascular mortality, in the long-term, that is dependent on its severity, and present even when the AKI is transient. We have also shown that this difference in cardiovascular mortality becomes more pronounced from the medium-term, and thus closer follow-up of these patients is required.

Endovascular Interventions and Flap Outcomes in Peripheral Arterial Disease Patients Undergoing Fasciocutaneous Versus Muscle Free Tissue Transfer in Lower Extremity Reconstruction

Endovascular Interventions and Flap Outcomes in Peripheral Arterial Disease Patients Undergoing Fasciocutaneous Versus Muscle Free Tissue Transfer in Lower Extremity Reconstruction

Foot Osteomyelitis Location and Rates of Primary or Secondary Major Amputations in Patients With Diabetes.

Background:Diabetic foot osteomyelitis (DFO) often leads to amputations in the lower extremity. Data on the influence of the initial anatomical DFO localization on ultimate major amputation are limited.Methods:In this retrospective analysis, 583 amputation episodes in 344 patients (78 females, 266 males) were analyzed. All received a form of amputation in combination with antibiotic therapy. A multivariate logistic regression analysis with the primary outcome “major amputation” defined as an amputation above the ankle joint was performed. The association of risk factors including location of DFO, coronary artery disease, peripheral artery disease, neuropathy, nephropathy, and Charcot neuro-osteoarthropathy was analyzed.Results:Among 583 episodes, DFO was located in the forefoot in 512 (87.8%), in the midfoot in 43 (7.4%), and in the hindfoot in 28 episodes (4.8%). Overall, 53 of 63 (84.1%) major amputations were performed because of DFO in the setting of peripheral artery disease as primary indication. Overall, limb loss occurred in 6.1% (31/512) of forefoot, 20.9% (9/43) of midfoot, and 46.4% (13/28) of hindfoot DFO. Among these, 22 (41.5%) were performed as the primary treatment, whereas 31 (58.5%) followed previously failed minor amputations. Among this latter group of secondary major amputations, the DFO was localized to the forefoot in 23 of 583 (3.9%), the midfoot in 4 of 583 (0.7%) and the hindfoot in 4 of 583 (0.7%). In multivariate logistic regression analysis, initial hindfoot localization was a significant factor (P < .05), whereas peripheral artery disease, smoking, and a midfoot DFO were not found to be risk factors.Conclusion:In our retrospective series, the frequency of limb loss in DFO increased with more proximal initial foot DFO lesions, with almost half of patients losing their limbs with a hindfoot DFO.Level of Evidence:Level IV, retrospective cohort study.

Level of Agreement Between Systematic Doppler Examination of the Lower Extremity and Diagnostic Angiography in the Setting of Peripheral Arterial Disease.

The objective of this investigation was to determine the level of agreement between a systematic clinical Doppler examination of the foot and ankle and diagnostic peripheral angiography. The described Doppler examination technique attempted to determine the patency, quality, and direction of the flow through the dorsalis pedis artery, posterior tibial artery, terminal branches of the peroneal artery, and vascular arch of the foot. These results were then compared with angiographic distal run-off images as interpreted by a blinded vascular surgeon. Levels of agreement with respect to artery patency/quality ranged from 64.0% to 84.0%. Sensitivity ranged from 53.8% to 84.2%, and specificity ranged from 64.7% to 91.7%. Agreement with respect to arterial flow direction ranged from 73.3% to 90.5%. We interpret these results to indicate that this comprehensive physical examination technique of the arterial flow to the foot and ankle with a Doppler device might serve as a reasonable initial surrogate to diagnostic angiography in some patients with peripheral arterial disease.

Atypical Pyoderma Gangrenosum in the Setting of Venous and Arterial Insufficiency.

Ulcers of mixed etiology are diagnostically elusive and challenging to treat, especially when rare conditions are superimposed. Pyoderma gangrenosum (PG) is an autoinflammatory, ulcerative skin disease that is difficult to diagnose. Diagnostic criteria exist but there are no specific clinical tests to identify it. We discuss a case of PG initially diagnosed as venous ulcer in the setting of peripheral artery disease, complicated by superinfection, refractory to standard wound care, multiple surgical debridements, revascularization, negative pressure therapy, and parenteral antibiotics. Findings differentiating PG from other wound etiologies are explored, with the aim of improving clinical recognition of this condition.

Pedal Acceleration Time (PAT): A Novel Predictor of Limb Salvage

In the setting of Peripheral Arterial Disease (PAD), pedal arch interrogation by ultrasound has not been well described. Patients with noncompressible vessels and/or open wounds of the foot may preclude the use of ankle-brachial indices, toe pressure measurements, or TcPO2, respectively. We propose that pedal artery interrogations with Pedal Acceleration Time (PAT) can be a predictor for limb salvage in patients with Chronic Limb-Threatening Ischemia (CLTI). A retrospective review of a prospectively kept database was performed from 2018 to 2019. Patients with pending amputation due to severe infection (WIFI infection class 2 and 3) were excluded from the study. We identified 73 limbs with CLTI that fit the inclusion criteria. Data included WIFI classification, age, gender, cardiovascular risk factors, PAT, ABI, and TBI when reliable, were collected. PAT measurements were categorized into 4 classifications; 1 (40-120 msec), 2 (121-180 msec), 3 (181-224 msec), and 4 (Greater than 225 msec). Statistical analyses were performed. Seventy-three limbs with CLTI were included in our study. All patients underwent arterial revascularization with either percutaneous technique or arterial bypass. Limb salvage was achieved in 59 (81%) of the 73 limbs. All 59 limbs had a 2-classification improvement in their PAT following interventions. A total of 14 (19%) limbs without improvement in their PAT underwent above ankle level amputations. An improvement in PAT classes to class 1 or 2 is associated with limb salvage. Patients with noncompressible ankle pressures or nonobtainable toe pressures poses a challenge in the complete assessment of WIFI classification. Our group has shown that PAT can be used in the scoring system for severity of ischemia in conjunction with current WIFI classification. Our data suggests that limb salvage correlates with post procedure PAT in category 1 and 2. Therefore we propose that PAT be added as part of the WIFI classification.

PC106. Pedal Acceleration Time: A Novel Predictor of Limb Salvage

In the setting of peripheral artery disease, pedal arch interrogation by ultrasound is a relatively novel technique. Patients with noncompressible vessels preclude the use of ankle-brachial indices or toe pressure measurements. Our group devised a technique for measuring pedal artery flow by measuring the pedal acceleration time (PAT) in the pedal arch. We proposed that this new method has utility in determining limb salvage comparable to current classification using the Wound, Ischemia, and foot Infection (WIfI) scoring system. We performed a retrospective review of a prospectively kept database of 70 patients in an 18-month period. Data included WIfI classification, age, sex, cardiovascular risk factors, PAT, and ankle-brachial index when reliable. PAT was calculated. The PAT measurement was classified into four categories: category 1, 40-120 milliseconds; category 2, 121 to 180 milliseconds; category 3, 181 to 224 milliseconds; and category 4, >225 milliseconds. Statistical analyses were performed using linear regression and analysis of variance testing. The primary outcome measure was limb salvage. Limb loss was defined by amputation higher than the ankle. Interventions included surgical bypass and catheter-based interventions. Seventy patients with critical limb ischemia were included in our study. Two patients underwent revascularization of both limbs for a total of 72 limbs studied. All patients underwent arterial revascularization with either percutaneous technique or arterial bypass. Limb salvage was achieved in 44 (60%) of the 72 limbs. All 44 limbs had a two-category improvement in PAT. Twenty-nine (40%) limbs underwent a higher level amputation. Of the 29 amputations, 21 patients had WIfI infection score of 2 or 3 with a postprocedure PAT category of 1 or 2. Eight patients had no infection; however, the PAT after the procedure was category 3 or 4. It is well known that patients with noncompressible ankle pressures or nonobtainable transcutaneous oxygen pressure and toe pressures cannot always provide accurate information. Our group proposes that PAT be used in the scoring system for severity of ischemia in place of the current methods when they are unreliable. Our data suggest that limb salvage correlates with postprocedure PAT in categories 1 and 2. In our population of patients, 21 limbs had an infection score of 2 or 3 (as defined by WIfI scoring), which clearly had a negative impact on limb preservation despite significant improvement in arterial perfusion. As such, a P value of <.0001 and improvement of two PAT categories may be predictive of limb salvage.

Plantar Acceleration Time: A Novel Technique to Evaluate Arterial Flow to the Foot

Arterial duplex ultrasound (DUS) and ankle-brachial indices (ABIs) are accepted methods for assessing lower limb arterial perfusion. However, in a significant number of diabetic patients, medial wall calcification often precludes an ABI measurement. Direct, noninvasive duplex imaging of the pedal arch in the setting of peripheral arterial disease (PAD) has not been well evaluated. Although plantar arch interrogation is new to vascular ultrasound, imaging the plantar arteries appears to be a reliable angiographic technique for critical limb ischemia. We sought to define the utility of Plantar Acceleration Time as a surrogate for ABIs. Patients undergoing DUS including Plantar Acceleration Time for suspicion of PAD were retrospectively reviewed in a prospective database over a 1-year period. Two hundred fifty nondiabetic patients (499 limbs) with documented ABI were studied. Plantar Acceleration Time was calculated (milliseconds [msec]) in each limb in the lateral plantar artery. Statistical analyses were performed using linear regression and analysis of variance testing using Microsoft Excel database (version 2016; Microsoft Corp, Redmond, WA). Patients were then grouped into 4 classes based on their clinical symptoms and ABI. Plantar Acceleration Time was similarly grouped into 4 distinct classes and correlated with the clinical and ABI classes. Plantar Acceleration Time correlated significantly with ABI (P<0.001). There were significant differences in Plantar Acceleration Times between each class based on ABI and clinical presentation (P<0.001 for each): Class 1 Plantar Acceleration Times 89.9±15.5msec; Class 2, 152.3±28.4msec; Class 3, 209.8±25.5msec, and Class 4, 270.2±35.3msec. Plantar Acceleration Time demonstrates a high correlation with ABI in patients with compressible arteries. Based on our results we propose the following categories of Plantar Acceleration Time, which appear to correlate with both clinical and ABI findings. ABI of 0.90-1.3 correlates with a Plantar Acceleration Time of 0-120msec, ABI of 0.69-0.89 correlates with a Plantar Acceleration Time of 121-180msec, ABI of 0.40-0.68 correlates with a Plantar Acceleration Time of 181-224msec, and an ABI of 0.00-0.39 correlates with a Plantar Acceleration Time of greater than 225msec. Further studies are ongoing to confirm whether Plantar Acceleration Time may be a suitable substitute to ABIs in patients with noncompressible arteries that preclude meaningful ABIs and gives more information regarding targeted angiosome perfusion to the foot.

Low-dose ionizing radiation induces therapeutic neovascularization in a pre-clinical model of hindlimb ischemia.

We have previously shown that low-dose ionizing radiation (LDIR) induces angiogenesis but there is no evidence that it induces neovascularization in the setting of peripheral arterial disease. Here, we investigated the use of LDIR as an innovative and non-invasive strategy to stimulate therapeutic neovascularization using a model of experimentally induced hindlimb ischemia (HLI). After surgical induction of unilateral HLI, both hindlimbs of female C57BL/6 mice were sham-irradiated or irradiated with four daily fractions of 0.3 Gy, in consecutive days and allowed to recover. We demonstrate that LDIR, significantly improved blood perfusion in the murine ischemic limb by stimulating neovascularization, as assessed by laser Doppler flow, capillary density, and collateral vessel formation. LDIR significantly increased the circulating levels of VEGF, PlGF, and G-CSF, as well as the number of circulating endothelial progenitor cells (EPCs) mediating their incorporation to ischemic muscles. These effects were dependent upon LDIR exposition on the ischemic niche (thigh and shank regions). In irradiated ischemic muscles, these effects were independent of the recruitment of monocytes and macrophages. Importantly, LDIR induced a durable and simultaneous up-regulation of a repertoire of pro-angiogenic factors and their receptors in endothelial cells (ECs), as evident in ECs isolated from the irradiated gastrocnemius muscles by laser capture microdissection. This specific mechanism was mediated via vascular endothelial growth factor (VEGF) receptor signaling, since VEGF receptor inhibition abrogated the LDIR-mediated gene up-regulation and impeded the increase in capillary density. Finally, the vasculature in an irradiated non-ischemic bed was not affected and after 52 week of LDIR exposure no differences in the incidence of morbidity and mortality were seen. These findings disclose an innovative, non-invasive strategy to induce therapeutic neovascularization in a mouse model of HLI, emerging as a novel approach in the treatment of critical limb ischemia patients.

Gene expression profiling of peripheral blood mononuclear cells in the setting of peripheral arterial disease

BackgroundPeripheral arterial disease (PAD) is a relatively common manifestation of systemic atherosclerosis that leads to progressive narrowing of the lumen of leg arteries. Circulating monocytes are in contact with the arterial wall and can serve as reporters of vascular pathology in the setting of PAD. We performed gene expression analysis of peripheral blood mononuclear cells (PBMC) in patients with PAD and controls without PAD to identify differentially regulated genes.MethodsPAD was defined as an ankle brachial index (ABI) ≤0.9 (n = 19) while age and gender matched controls had an ABI > 1.0 (n = 18). Microarray analysis was performed using Affymetrix HG-U133 plus 2.0 gene chips and analyzed using GeneSpring GX 11.0. Gene expression data was normalized using Robust Multichip Analysis (RMA) normalization method, differential expression was defined as a fold change ≥1.5, followed by unpaired Mann-Whitney test (P < 0.05) and correction for multiple testing by Benjamini and Hochberg False Discovery Rate. Meta-analysis of differentially expressed genes was performed using an integrated bioinformatics pipeline with tools for enrichment analysis using Gene Ontology (GO) terms, pathway analysis using Kyoto Encyclopedia of Genes and Genomes (KEGG), molecular event enrichment using Reactome annotations and network analysis using Ingenuity Pathway Analysis suite. Extensive biocuration was also performed to understand the functional context of genes.ResultsWe identified 87 genes differentially expressed in the setting of PAD; 40 genes were upregulated and 47 genes were downregulated. We employed an integrated bioinformatics pipeline coupled with literature curation to characterize the functional coherence of differentially regulated genes.ConclusionNotably, upregulated genes mediate immune response, inflammation, apoptosis, stress response, phosphorylation, hemostasis, platelet activation and platelet aggregation. Downregulated genes included several genes from the zinc finger family that are involved in transcriptional regulation. These results provide insights into molecular mechanisms relevant to the pathophysiology of PAD.

P150. Nitrogen oxide production in response to whole body exercise provides a potential measure of endothelial function within the setting of peripheral artery disease

P150. Nitrogen oxide production in response to whole body exercise provides a potential measure of endothelial function within the setting of peripheral artery disease