Ankle brachial indices and anaerobes: is peripheral arterial disease associated with anaerobic bacteria in diabetic foot ulcers?

Background: Lower extremity amputations from diabetic foot ulcers (DFUs) are rebounding, and new biomarkers that predict wound healing are urgently needed. Anaerobic bacteria have been associated with persistent ulcers and may be a promising biomarker beyond currently recommended vascular assessments. It is unknown whether anaerobic markers are simply a downstream outcome of peripheral arterial disease (PAD) and ischemia, however. Here, we evaluate associations between two measures of anaerobic bacteria-abundance and metabolic activity-and PAD. Methods: We built a prospective cohort of 37 patients with baseline ankle brachial index (ABI) results. Anaerobic bacteria were measured in two ways: DNA-based total anaerobic abundance using 16S rRNA gene amplicon sequencing and resulting summed relative abundance, and RNA-based metabolic activity based on bacterial read annotation of metatranscriptomic sequencing. PAD was defined three ways: PAD diagnosis, ABI results, and a dichotomous definition of mild ischemia (versus normal) based on ABI values. Statistical associations between anaerobes and PAD were evaluated using univariate odds ratios (ORs) or Spearman's correlations. Results: Total anaerobe abundance was not significantly associated with PAD diagnosis, ABI results, or mild ischemia (ORPAD = 0.47, 95% CI = 0.023-7.23, p = 0.60; Spearman's correlation coefficientABI = 0.24, p = 0.17; ORmild ischemia = 0.25, 95% CI = 0.005-5.86, p = 0.42). Anaerobic metabolic activity was not significantly associated with PAD diagnosis, ABI results, or mild ischemia (ORPAD = 1.99, 95% CI = 0.17-21.44, p = 0.57; Spearman's correlation coefficientABI = 0.12, p = 0.52; ORmild ischemia = 0.90, 95% CI = 0.03-15.16, p = 0.94). Conclusion: Neither anaerobic abundance nor metabolic activity was strongly associated with our three definitions of PAD. Therefore, anaerobic bacteria may offer additional prognostic value when assessing wound healing potential and should be investigated as potential molecular biomarkers for DFU outcomes.

Direct oral anticoagulants decrease treatment failure for acute lower extremity deep venous thrombosis.

OBJECTIVE: Optimal medical therapy for acute lower extremity deep venous thrombosis (DVT) remains an enigma. While clinical trials demonstrate non-inferiority with an oral anti-Xa inhibitor, or direct oral anticoagulant (DOAC), versus combined low-molecular weight heparin (LMWH) and oral vitamin K antagonist (VKA), the most effective regimen remains to be determined. METHODS: This study is a single-center retrospective cohort study from October 2014 to December 2015 of patients with a diagnosis of acute DVT and subsequent serial lower extremity venous duplex. Demographics, medical history, medications, serial ultrasound findings, as well as the primary anticoagulant used for treatment were collected and analyzed by two independent data extractors. Treatment failure was defined as any new DVT or progression of an existing DVT within 3 months of diagnosis of the index clot. Risk factors for treatment failure were assessed using standard odds ratios and Fischer's exact test. RESULTS: Among 496 patients with an acute lower extremity DVT, 54% (n = 266) were men, mean age was 61 years, 35% (n = 174) involved the popliteal or more proximal segments, and 442 had documentation of the primary treatment for DVT: 20% (n = 90) received nothing; 20% (n = 92) received an oral VKA; 34% (n = 149) received a DOAC; 20% (n = 90) received LMWH; and 5% (n = 21) received another class of anticoagulant. Within 3 months, 21% (n=89 out of 427) had treatment failure defined as any new DVT or progression of prior DVT. Patients treated with a DOAC were less likely to experience treatment failure when compared with any other treatment (odds ratio 0.43; 95% confidence intervals [0.23, 0.79]; p = 0.0069) and when compared with traditional oral VKA (OR 0.44; 95% CI [0.21, 0.92]; p = 0.029). None of prior history of DVT, pulmonary embolism, thrombophilia, renal insufficiency, hepatic insufficiency, cancer, or antiplatelet therapy correlated with treatment failure. Treatment outcome did not correlate with being on any anticoagulation versus none (p = 0.74), nor did it correlate with the duration of treatment (<3 months versus ≥3 months) (p = 0.42). Proximal and distal DVTs showed no difference in treatment failure (19% versus 22%, respectively; p = 0.43). CONCLUSION: In summary, the use of a DOAC for acute lower extremity DVT yielded better overall outcomes and fewer treatment failures at 3 months as compared to traditional oral VKA therapy based on serial duplex imaging.

Endoluminal Atherosclerotic Plaque Debulking Using Enzymatic and Ultrasonic Energy.

BACKGROUND: Current procedures to treat severe atherosclerosis are traumatic to the arterial wall and often result in restenosis due to neointimal hyperplasia. We developed a novel therapy using a specially designed double occlusion balloon catheter, ultrasonic wire, and enzymatic digestion solution to atraumatically debulk atherosclerotic plaques. MATERIALS AND METHODS: A combination of different enzymes, chemicals, and treatment conditions were evaluated for its effect at reducing atherosclerotic plaque harvested from human carotid artery endarterectomies ex vivo. The optimized digestion solution was examined in harvested intact human superficial femoral arteries in situ. A conventional Yorkshire/Landrace and a genetically modified Yucatan minipig homozygous for a nonfunctional LDLR mutation were used to evaluate the endovascular therapy in nonatherosclerotic and atherosclerotic environments in vivo. RESULTS: Ex vivo, the technology successfully digested human carotid artery plaques by 75%. In situ, the therapy successfully reduced plaque area in harvested superficial femoral arteries by 46%. In vivo, the endovascular therapy was technically feasible and demonstrated initial safety with no thrombosis, dissection, or aneurysmal dilatation in a nonatherosclerotic porcine model. In an atherosclerotic porcine model, the therapy demonstrated initial efficacy by successfully reducing atherosclerotic plaque while preserving the arterial wall with an intact internal elastic lamina. CONCLUSIONS: Using human plaque, human artery, and a normal and atherosclerotic pig model, we demonstrated that delivery of our therapy to the vasculature is technically feasible, appears safe, and shows initial efficacy. Our percutaneous plaque debulking method is a unique and promising therapy for the treatment of atherosclerosis and warrants further study.

Ten-year review of isolated spontaneous mesenteric arterial dissections.

OBJECTIVE: Isolated spontaneous dissection of the superior mesenteric artery (SMA) and celiac artery (CA) remains a rare condition; however, it has been increasingly noted incidentally on diagnostic imaging. The purpose of this study was to examine the natural history and outcomes of patients presenting with isolated spontaneous mesenteric artery dissection (SMAD). We hypothesized that most SMADs can be treated nonoperatively. METHODS: This was a single-center retrospective review of patients presenting with the diagnosis of SMAD between 2006 and 2016. Data analysis included demographics, clinical data, radiologic review, treatment, and outcomes. RESULTS: A total of 77 patients were found to have CA dissection, SMA dissection, or both in the absence of aortic dissection diagnosed on computed tomography or magnetic resonance imaging. The average age was 56 years (range, 26-86 years), 80% were male, and 10 patients (13%) had underlying connective tissue disorders. The majority, 64%, presented with symptoms including abdominal pain, back pain, and chest pain; the remaining 36% were asymptomatic. Combined SMA and CA dissection was found in 14 (18%) patients; 33 (43%) presented with isolated CA dissection, and 30 (39%) presented with isolated SMA dissection. Only four patients required intervention. Mesenteric bypass was performed in two patients, and SMA endarterectomy with patch angioplasty was performed in one patient for signs of bowel ischemia. No patient required bowel resection. The two bypasses were anastomosed to a branch of the SMA, and complete lumen restoration was seen on long-term imaging follow-up. One patient underwent stent grafting of the CA and hepatic artery for aneurysmal degeneration 1 month after diagnosis. The remaining 73 patients were managed nonoperatively; 40 (52%) were treated with a short course of anticoagulation, 23 (30%) were treated with antiplatelet therapy, and 10 (13%) were treated with observation alone. No other late interventions or recurrences were noted during a mean follow-up of 21 months. CONCLUSIONS: Whereas isolated SMAD poses a risk of visceral ischemia, most patients presenting with this diagnosis can be treated nonoperatively with a short course of antiplatelet or anticoagulant therapy. Only a small number of patients require surgical revascularization for bowel ischemia.

Targeted Nanotherapies for the Treatment of Surgical Diseases.

OBJECTIVE: To describe the components of targeted nanotherapeutics and to review their applications in the treatment of surgical diseases. BACKGROUND: Targeted nanotherapeutic is a novel strategy for treating a variety of diseases and is an emerging technology that offers advantages over current treatment strategies. The nanoscale size, combined with the ability to surface functionalize the delivery vehicle to enable targeting and incorporate a therapeutic payload, provides a new and innovative therapeutic platform to treat surgical diseases that has yet to be fully realized in the surgical arena. METHODS: A comprehensive literature review of nanotherapeutics, targeting strategies, and their utility in treating surgical diseases is performed. RESULTS: Targeted nanotherapeutics have demonstrated safety and biocompatibility in treating surgical diseases. The ability to surface functionalize the nanoparticles affords a unique tailorability that enables targeting specificity and therapeutic payload delivery to treat a variety of surgical diseases. Moreover, the small size and targeting capabilities allow access to biological compartments, such as the blood-brain barrier, that have previously been difficult to treat. CONCLUSIONS: Targeted nanotherapeutics represent a novel therapeutic platform and have great potential to impact the treatment of surgical diseases.

Targeted Nitric Oxide Delivery by Supramolecular Nanofibers for the Prevention of Restenosis After Arterial Injury.

AIMS: Cardiovascular interventions continue to fail as a result of arterial restenosis secondary to neointimal hyperplasia. We sought to develop and evaluate a systemically delivered nanostructure targeted to the site of arterial injury to prevent neointimal hyperplasia. Nanostructures were based on self-assembling biodegradable molecules known as peptide amphiphiles. The targeting motif was a collagen-binding peptide, and the therapeutic moiety was added by S-nitrosylation of cysteine residues. RESULTS: Structure of the nanofibers was characterized by transmission electron microscopy and small-angle X-ray scattering. S-nitrosylation was confirmed by mass spectrometry, and nitric oxide (NO) release was assessed electrochemically and by chemiluminescent detection. The balloon carotid artery injury model was performed on 10-week-old male Sprague-Dawley rats. Immediately after injury, nanofibers were administered systemically via tail vein injection. S-nitrosylated (S-nitrosyl [SNO])-targeted nanofibers significantly reduced neointimal hyperplasia 2 weeks and 7 months following balloon angioplasty, with no change in inflammation. INNOVATION: This is the first time that an S-nitrosothiol (RSNO)-based therapeutic was shown to have targeted local effects after systemic administration. This approach, combining supramolecular nanostructures with a therapeutic NO-based payload and a targeting moiety, overcomes the limitations of delivering NO to a site of interest, avoiding undesirable systemic side effects. CONCLUSION: We successfully synthesized and characterized an RSNO-based therapy that when administered systemically, targets directly to the site of vascular injury. By integrating therapeutic and targeting chemistries, these targeted SNO nanofibers provided durable inhibition of neointimal hyperplasia in vivo and show great potential as a platform to treat cardiovascular diseases.

Tissue-Factor Targeted Peptide Amphiphile Nanofibers as an Injectable Therapy To Control Hemorrhage.

Noncompressible torso hemorrhage is a leading cause of mortality in civilian and battlefield trauma. We sought to develop an i.v.-injectable, tissue factor (TF)-targeted nanotherapy to stop hemorrhage. Tissue factor was chosen as a target because it is only exposed to the intravascular space upon vessel disruption. Peptide amphiphile (PA) monomers that self-assemble into nanofibers were chosen as the delivery vehicle. Three TF-binding sequences were identified (EGR, RLM, and RTL), covalently incorporated into the PA backbone, and shown to self-assemble into nanofibers by cryo-transmission electron microscopy. Both the RLM and RTL peptides bound recombinant TF in vitro. All three TF-targeted nanofibers bound to the site of punch biopsy-induced liver hemorrhage in vivo, but only RTL nanofibers reduced blood loss versus sham (53% reduction, p < 0.05). Increasing the targeting ligand density of RTL nanofibers yielded qualitatively better binding to the site of injury and greater reductions in blood loss in vivo (p < 0.05). In fact, 100% RTL nanofiber reduced overall blood loss by 60% versus sham (p < 0.05). Evaluation of the biocompatibility of the RTL nanofiber revealed that it did not induce RBC hemolysis, did not induce neutrophil or macrophage inflammation at the site of liver injury, and 70% remained intact in plasma after 30 min. In summary, these studies demonstrate successful binding of peptides to TF in vitro and successful homing of a TF-targeted PA nanofiber to the site of hemorrhage with an associated decrease in blood loss in vivo. Thus, this therapeutic may potentially treat noncompressible hemorrhage.

Incidence of acute lower extremity venous thrombosis after percutaneous endovascular aneurysm repair.

BACKGROUND: Improvements in endovascular aortic aneurysm repair (EVAR) have led many physicians to embrace a purely percutaneous approach using the suture-mediated "preclose" technique. Whereas there are a number of theoretical benefits, the rate of periprocedural iatrogenic acute deep venous thrombosis (DVT) is unknown. We sought to determine the incidence of acute DVT after percutaneous EVAR (PEVAR). METHODS: This was a single-center, retrospective review of 52 consecutive patients undergoing elective PEVAR. Demographics, procedural data, and postprocedure lower extremity venous duplex ultrasound data were analyzed by univariate statistical analysis. RESULTS: Among the 52 patients, the average age was 73 years, and the majority were men (n = 44). Only 6% (n = 3) had a prior history of DVT. The majority of procedures were performed under general anesthesia (n = 51 [98%]) with systemic intravenous heparin. Protamine was used in only 13 cases (25%). Sheath sizes ranged from 9F to 20F, with an average of 16F, and closure was achieved using the preclose technique. Postprocedure chemoprophylaxis was administered to 85% of patients (n = 44) during their hospitalization. Median length of stay was 1 day. Acute DVT was identified in 8% of patients (n = 4) on postoperative day 1. Among the 4 DVTs, 25% were femoropopliteal (n = 1) and 75% were calf vein DVTs (n = 3). On follow-up imaging 2 weeks later, 75% of DVTs were resolved. Among the four patients with acute DVT on postoperative day 1, three had associated risk factors: history of DVT (n = 2), active smokers (n = 1), and obesity (body mass index >30; n = 3). The remaining patient had no risk factors but developed an ipsilateral calf vein DVT. CONCLUSIONS: The risk of acute DVT after PEVAR is low. Lower extremity venous duplex ultrasound screening is not necessary unless there exist preclinical risk factors or postprocedural clinical indications suggestive of DVT.

Shape-Dependent Targeting of Injured Blood Vessels by Peptide Amphiphile Supramolecular Nanostructures.

Targeting of vascular intervention by systemically delivered supramolecular nanofibers after balloon angioplasty is described. Tracking of self-assembling peptide amphiphiles using fluorescence shows selective binding to the site of vascular intervention. Cylindrical nanostructures are observed to target the site of arterial injury, while spherical nanostructures with an equivalent diameter display no binding.

Femoral vein blood flow during a total hip arthroplasty using a modified Heuter approach.

Several modifications to traditional surgical approaches for total hip arthroplasty (THA) have been introduced in an attempt to improve upon minimally invasive approaches and enhance short-term recovery. However, minimally invasive approaches are not without risk, including that of postoperative venous thromboembolism (VTE). There has been no published literature evaluating the femoral vein during an anterior approach. We aimed to study femoral vein blood flow using duplex ultrasonography during THA performed through a modified Heuter approach. Peek flow and vessel cross-sectional area were affected by limb position as well as acetabular and femoral retractor placement. No VTE was observed, but there was observed femoral vein compression, which may represent a risk of postoperative VTE similar to that seen in standard surgical approaches for THA.

Development and validation of 4 different rat models of uncontrolled hemorrhage.

IMPORTANCE: Hemorrhage is the leading cause of death in military trauma and second leading cause of death in civilian trauma. Although many well-established animal models of hemorrhage exist in the trauma and anticoagulant literature, few focus on directly quantitating blood loss. OBJECTIVE: To establish and validate a reproducible rodent model of uncontrolled hemorrhage to serve as the foundation for developing therapies for noncompressible torso trauma. DESIGN, SETTINGS, AND SUBJECTS: We developed and evaluated 4 different hemorrhage models using male Sprague-Dawley rats (6 rats/model), aged 10 to 14 weeks and weighing 330 to 460 g, at the Department of Surgery, Northwestern University. INTERVENTIONS: We used tail-cut (4 cm), liver punch biopsy (12 mm), liver laceration (3.0 × 1.5 cm), and spleen transection models. All animals underwent invasive hemodynamic monitoring. MAIN OUTCOMES AND MEASURES: Blood loss, expressed as a percentage of total blood volume (TBV), mean arterial pressure, and heart rate, which were recorded at 2- to 5-minute intervals. RESULTS: The tail-cut model resulted in a mean (SD) TBV loss of 15.4% (6.0%) with hemodynamics consistent with class I hemorrhagic shock. The liver punch biopsy model resulted in a mean (SD) TBV loss of 16.7% (3.3%) with hemodynamics consistent with class I hemorrhagic shock. The liver laceration model resulted in a mean (SD) TBV loss of 19.8% (3.0%) with hemodynamics consistent with class II hemorrhagic shock. The spleen transection model resulted in the greatest blood loss (P < .01), with a mean (SD) TBV loss of 27.9% (3.4%) and hemodynamics consistent with class II hemorrhagic shock. The liver laceration and punch biopsy models resulted in most of the blood loss within the first 2 minutes, whereas the spleen transection and tail-cut models resulted in a steady loss during 10 minutes. The liver laceration and spleen transection models resulted in the greatest degree of hemodynamic instability (mean [SD] arterial pressure decreases of 25 [1] and 41 [11] mm Hg, respectively). One-hour survival was 100% in all 4 models. CONCLUSIONS AND RELEVANCE: We established and validated the reproducibility of 4 different rat models of uncontrolled hemorrhage. These models provide a foundation to design novel nonsurgical therapies to control hemorrhage, and the different degrees of hemorrhagic shock produced from these models allow for flexibility in experimental design.

High-risk anatomic variables and plaque characteristics in carotid artery stenting.

OBJECTIVES: To determine anatomic and plaque-related risk factors for patients undergoing carotid artery stenting. METHODS: A retrospective review of patients from a prospectively maintained database undergoing carotid artery stenting at our institution between 2001 and 2010 was performed. Preoperative imaging studies (ie, ultrasound, computed tomography angiography, magnetic resonance angiography, and angiograms) were reviewed for specific anatomic criteria and plaque characteristics. Primary outcomes included 30-day stroke or transient ischemic attack (TIA). Secondary outcomes included 30-day death and myocardial infarction (MI). Statistical significance was assumed for P = .05. RESULTS: Imaging was reviewed for 381 carotid arteries in 375 patients. There were 14 (3.7%) perioperative neurologic events, which included 8 TIA and 6 strokes. Thirty-day mortality and MI were 0.5% and 0.75%, respectively. Degree of internal carotid artery stenosis was associated with primary outcomes (P = .03), and the presence of arch calcification trended toward an increase in primary outcomes (P = .07). However, arch type, ostial involvement, tandem lesions, and plaque calcification did not correlate with primary outcomes. Differences were noted between the sexes, with females having more common carotid artery tortuosity than males (34% vs 27%, P = .04). Females also had a trend toward more plaque calcification and more severe arch calcification than males. These differences did not translate to differences in perioperative neurologic events. CONCLUSION: Our data suggest that degree of internal carotid artery stenosis and aortic arch calcification may be associated with increased perioperative neurologic risk during carotid stenting, but arch type is not.