Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia.

BACKGROUND: Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes. METHODS: In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause. RESULTS: In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts. CONCLUSIONS: Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.).

Engineering diabetic human skin equivalent for in vitro and in vivo applications.

The prevalence of diabetes is increasing worldwide. Diabetes contributes to 70% of all non-traumatic lower-limb amputations, which are directly caused by diabetic foot ulcers (DFU) that are difficult to heal. Non-healing diabetic ulcers represent one of modern society's most difficult medical challenges. One of the promising initiatives to treat DFU is the grafting of autologous skin or stimulating the skin cells at the edge of the wound to proliferate and close the wound. The present study was to engineer a diabetic human skin equivalent (DHSE) that contains fibroblasts and keratinocytes extracted from the skin collected from diabetic patients. The DHSE was used to investigate whether exposure to low-intensity electrical stimulation (ES) could promote diabetic cell activity. The ES was generated by a direct current (DC) electric field of 20 or 40 mV/mm. We demonstrated that the fibroblasts and keratinocytes could be extracted from older diabetics, cultured, and used to engineer DHSE. Interestingly, the exposure of DHSE to ES led to a structural improvement through tissue stratification, increased Ki-67 expression, and the deposition of basement membrane proteins (laminin and type IV collagen). The DHSE exposed to ES showed a high level of keratin 5 and 14 expressions in the basal and supra-basal layers. The keratinocyte proliferation was supported by an increased secretion of the keratinocyte growth factor (FGF-7). Exposure to ES decreased the activity of metalloproteinases (MMP) 2 and 9. In conclusion, we extracted keratinocytes and fibroblasts from the skin of diabetic-old donors. These cells were used to engineer skin equivalents and demonstrate that ES can promote diabetic wound healing. This DHSE can be a promising tool for various in vitro studies to understand the wound healing mechanisms under chronic inflammatory conditions such as diabetes. The DHSE could also be used as an autologous substrate to cover the DFU permanently.

Electrical stimulation promotes the wound-healing properties of diabetic human skin fibroblasts.

This study evaluated the effect of low (20 and 40 mV/mm) intensities of electrical stimulation on the proliferation and migration of skin fibroblasts from diabetic donors. We also examined the effect of electrical stimulation on modulating the capacity of fibroblasts to contract collagen gel, express alpha-smooth muscle actin, and secrete proteolytic enzymes involved in regulating extracellular matrix synthesis and degradation. Our study shows that 20 and 40 mV/mm of stimulation increased the growth of fibroblasts extracted from diabetic patients but not from non-diabetic donors. Electrical stimulation increased the migration of diabetic fibroblasts, their capacity to contract collagen gel, and the expression of alpha-smooth muscle actin and promoted different proteolytic enzymes involved in accelerating wound healing. Overall results confirm the effectiveness of electrical stimulation in modulating the wound healing activities of fibroblasts extracted from diabetic skin donors. This study, therefore, suggests the possible use of electrical stimulation to promote diabetic foot ulcer healing by stimulating the wound healing properties of skin fibroblasts.

Effect of Electrical Stimulation on Diabetic Human Skin Fibroblast Growth and the Secretion of Cytokines and Growth Factors Involved in Wound Healing.

Diabetic foot ulcers are indicative of an impaired wound healing process. This delay may be resolved through electrical stimulation (ES). The goal of the present study was to evaluate the effect of ES on diabetic fibroblast adhesion and growth, and the secretion of cytokines and growth factors. Diabetic human skin fibroblasts (DHSF) were exposed to various intensities of direct current ES (100, 80, 40 and 20 mV/mm). The effect of ES on fibroblast adhesion and growth was evaluated using Hoechst staining, MTT and trypan blue exclusion assays. The secretion of cytokine and growth factor was assessed by cytokine array and ELISA assay. The long-term effects of ES on DHSF shape and growth were determined by optical microscopy and cell count. We demonstrated that ES at 20 and 40 mV/mm promoted cell adhesion, viability and growth. ES also decreased the secretion of pro-inflammatory cytokines IL-6 and IL-8 yet promoted growth factor FGF7 secretion during 48 h post-ES. Finally, the beneficial effect of ES on fibroblast growth was maintained up to 5 days post-ES. Overall results suggest the possible use of low-intensity direct current ES to promote wound healing in diabetic patients.

Innovative textile structures designed to prevent type III endoleaks in endovascular stent-grafts.

The damage caused to the fabric of endovascular stent-grafts most often occurs at the contact zones between the fabrics where they are attached to the apices of Z-shaped stents as a result of normal physiologic pulsatile movement within angulated vessels in vivo. Although design improvements were made over the years, the risks were not fully eliminated even with the newer M-shaped stent reconfiguration. In this study, we proposed to create and manufacture a novel fabric for stent-grafts with specifically designed reinforced zones to enhance resistance to fabric abrasion. These reinforced zones are set at the vicinity of the apices of the Z-shaped stents and between two adjacent Z-shaped stents where folding and pleating are commonly observed to occur in angulated vessels. Three innovative weaving structures with two different types of yarns and two controls were designed and prepared. Two commonly used commercial devices supported, respectively, with ringed stents, and Z-shaped stents were selected as the references for comparison. Textile structures including thickness, water permeability, mechanical properties, (more specifically tensile and bursting stress, as well as fatigue simulation) were tested on all fabrics. Compared to commercially available plain weaves, the fabrics with locally reinforced zones showed improved mechanical characteristics and fatigue resistant properties. A fabric designed with specifically reinforced zones has now clearly been shown to effectively reduce the abrasion caused by the apices of Z-shaped stents. However, further optimization may still be possible.

Electrical stimulation promotes the proliferation of human keratinocytes, increases the production of keratin 5 and 14, and increases the phosphorylation of ERK1/2 and p38 MAP kinases.

Effective wound healing remains a significant clinical challenge in reducing patient morbidity and improving quality of life. Wound healing is a complex process involving the endogenous electrical field. The electrical field can contribute to wound healing by activating keratinocytes to promote reepithelialization. The objective of this study was to determine the effects of exogenous electrical stimulation (ES) on human keratinocyte viability and proliferation and on production of IL-6, IL-8, and keratins (K5 and K14) and to investigate the activated signalling pathways in keratinocytes exposed to ES. Keratinocytes were cultured under ES at different intensities for 6 or 24 hr. Cell proliferation, cytokines and growth factors, K5 and K14, as well as phosphorylated ERK1/2 and p38 MAP kinases, were evaluated. The results showed that the keratinocytes exposed to ES between 100 and 150 mV/mm for 6 or 24 hr showed a significantly increased proliferation rate. However, a 24 hr exposure to 200 mV/mm revealed no significant effect in cell growth. ES at 100 and 200 mV/mm for 6 hr increased the secretion of epidermal growth factor and vascular endothelial growth factor, and the production of K5 and K14. K14 was more sensitive than K5 to ES. However, ES down-regulated the secretions of IL-6 and IL-8. Finally, ES increased the phosphorylation of ERK1/2 and p38 MAP kinases. Overall results suggested that ES can be useful in supporting skin wound healing by activating keratinocytes.

Factors Influencing the Prescription of Cardiovascular Preventive Therapies in Patients with Peripheral Arterial Disease.

BACKGROUND: Guidelines recommend that patients with peripheral arterial disease should be medically treated to reduce the occurrence of serious cardiovascular events. Despite these recommendations, studies conducted in the early 2000s reported that medical therapies for secondary cardiovascular prevention are not given systematically to patients with peripheral arterial disease (PAD). We identified factors associated with the prescription of preventive therapies in patients with symptomatic PAD. METHODS AND FINDINGS: Consecutive patients with symptomatic peripheral arterial disease (n = 362) treated between 2008 and 2010 in one tertiary care center (CHU de Quebec, Canada) were considered. Data were collected from the medical charts. The main outcome was the combined prescription of three therapies: 1) statins, 2) antiplatelets, 3) angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers. The mean age was 70 years and 43% had a pre-existing coronary artery disease. Antiplatelet therapy was the most prescribed drug (83%). A total of 52% of the patients received the three combined therapies. Less than 10% of patients had a known contraindication to one class of medication. Having at least three cardiovascular risk factors (Odds Ratio (OR) = 4.51; 95% CI: 2.76-7.37) was the factor most strongly associated with the prescription of the combined therapies. Pre-existing coronary artery disease (OR = 2.28; 95% CI: 1.43-3.65) and history of peripheral vascular surgery (OR = 2.30; 95% CI: 1.37-3.86) were two factors independently associated with the prescription of the combined therapies. However, peripheral arterial disease patients with chronic critical limb ischemia were less likely to receive the combined therapies (OR = 0.53; 95% CI: 0.32-0.87) than those with claudication. The retrospective nature of this study, not allowing for an exhaustive report of the contraindication to medication prescription, is the main limitation. CONCLUSION: About half of the patients with peripheral arterial disease were not optimally managed. Patients with multiple cardiovascular risk factors were more likely to receive the combined therapies. We still need to better understand the barriers and facilitators to the application of the guidelines.

An in Vitro Twist Fatigue Test of Fabric Stent-Grafts Supported by Z-Stents vs. Ringed Stents.

Whereas buckling can cause type III endoleaks, long-term twisting of a stent-graft was investigated here as a mechanism leading to type V endoleak or endotension. Two experimental device designs supported with Z-stents having strut angles of 35° or 45° were compared to a ringed control under accelerated twisting. Damage to each device was assessed and compared after different durations of twisting, with focus on damage that may allow leakage. Stent-grafts with 35° Z-stents had the most severe distortion and damage to the graft fabric. The 45° Z-stents caused less fabric damage. However, consistent stretching was still seen around the holes for sutures, which attach the stents to the graft fabric. Larger holes may become channels for fluid percolation through the wall. The ringed stent-graft had the least damage observed. Stent apexes with sharp angles appear to be responsible for major damage to the fabrics. Device manufacturers should consider stent apex angle when designing stent-grafts, and ensure their devices are resistant to twisting.

A Floating Thrombus Anchored at the Proximal Anastomosis of a Woven Thoracic Graft Mimicking a Genuine Aortic Dissection.

An aortoesophageal fistula following surgery for a ruptured 6.6-cm thoracic aneurysm in a 69-year-old female was repaired using a 34-mm woven prosthetic graft. A follow-up computed tomography (CT) scan at 10 days postoperatively revealed a dissection-like picture in the region of the graft, which was treated conservatively. The patient eventually died from sepsis and multiorgan failure. At autopsy, the graft was retrieved in situ and studied by detailed gross, microscopy, and scanning electron microscopy (SEM) examination. Gross observation confirmed that the dissection resulted from the rolling of the internal capsule downstream. A massive thrombus anchored at the proximal anastomosis and held by a narrow head was also noted. The thrombus demonstrated reorganization in the area of the anastomosis, with a false lumen in its distal half. The reminder of the thrombus consisted of layered fibrin. After gross examination, the fabric graft was found to be flawless. Additional detailed studies were also done using microscopy, SEM, and gross examination.

Perceived effects of the 16-hour workday restriction on surgical specialties: Quebec's experience.

OBJECTIVE: Quebec was the first Canadian province to implement a 16-hour workday restriction. Our aim was to assess and compare Quebec's surgical residents' and professors' perception regarding the effects on the educational environment, quality of care, and quality of life. DESIGN: The Surgical Theater Educational Environment Measure, the Postgraduate Hospital Educational Environment Measure, quality of the medical act, and quality-of-life questionnaires were administered 6 months after the work-hour restrictions. SETTING: Université de Montréal Surgery Department, Montréal, Québec, Canada; Université de Sherbrooke Surgery Department, Sherbrooke, Québec, Canada; Université Laval Surgery Department, Québec, Québec, Canada; and McGill University Surgery Department, Montréal, Québec, Canada. PARTICIPANTS: Surgical residents and professors of all specialties within the 4 university surgery departments in Quebec through a voluntary web-based survey. RESULTS: A total of 280 questionnaires were analyzed with response rates of 29.7% and 16.4% for residents and professors, respectively. Data were coded on a scale from 2 (strong improvement perception) to -2 (strong deterioration perception). The professors perceived a higher negative effect than the residents did on the educational environment, i.e., role of autonomy (-0.399 vs. -0.577, p < 0.001), teaching (-0.496 vs. -0.540, p < 0.001), social support (-0.345 vs. -0.535, p < 0.001), and surgical learning (-0.409 vs. -0.626, p < 0.001). The professors also observed a higher negative effect on patients' safety (-0.199 vs. -0.595, p = 0.003) and quality of care (-0.077 vs. -0.421, p = 0.014). The latter was even perceived as unchanged by residents (-0.077, 95% CI: -0.249 to 0.095). The residents perceived a negative effect on their quality of life, whereas the professors believed the contrary (0.500 vs -0.496, p < 0.001). More professors than residents believed residency should be prolonged (80.8% vs. 50.6%, p < 0.001). CONCLUSIONS: Residents and professors perceive a mild negative effect on the educational environment and quality of care, whereas their perception on quality of life is opposite. The professors seem concerned about adequate training to the point of considering increasing training length.

Stent fabric fatigue of grafts supported by Z-stents versus ringed stents: an in vitro buckling test.

Stent-grafts externally fitted with a Z-shaped stents were compared to devices fitted with ringed stents in an in vitro oscillating fatigue machine at 200 cycles per minute and a pressure of 360 mmHg for scheduled durations of up to 1 week. The devices fitted with Z-stents showed a considerably lower endurance limit to buckling compared to the controls. The contact between the apexes of adjacent Z-stents resulted in significant damage to the textile scaffolds and polyester fibers due to the sharp angle of the Z-stents. The ringed stents did not cause any fraying in the textile scaffolds.

Long-term resistance to fracture and/or corrosion of the nitinol wires of the talent stent-graft: observations from a series of explanted devices.

The biodurability of the Nitinol wires used in stent-grafts retrieved from reoperations and autopsy was analyzed to assess the possible causes of fracture and/or corrosion of the stents. The Nitinol wires of six explanted devices presented a corrosion-free surface after in vivo service. The drawing lines in the control wires were still present, but neither burrs nor flakes were observed. Pits and crevices were rare, but some shallow ones were present. Some abrasions of the surfaces of the Nitinol wires were also observed. The chemical composition of the explanted devices showed the presence of organic contamination that covered the thick layer of titanium oxide before reaching the Nitinol itself. The durability of the Nitinol employed in the manufacture of the Talent stent-grafts was confirmed; the results of this study show the Nitinol to be resistant to corrosion. We have also concluded that the fractures of the Nitinol wires in two devices were unique adverse incidents caused by compression and bending related to the sharp angle of the Nitinol wires.

Fatigue and/or failure phenomena observed in the fabric of stent-grafts explanted after adverse events.

In this study, we aimed to investigate changes to the fabric of Talent stent-grafts following implantation of aortic endografts and to determine the possible causes of fatigue and/or failure of the grafts. Six devices were explanted at reoperation (N=5) and autopsy (N=1). Selected segments were assessed nondestructively by gross observation and destructively by analyzing textile characteristics and chemical properties. All of the devices showed a 4/4 twill woven fabric of monofilament polyester. These devices, explanted at reoperation and autopsy, presented different levels of fatigue and/or failure. Numerous holes were found in the fabric of two devices. The minor damage caused by the passage of the sutures through the weave to fasten the Nitinol wires did not progress significantly over time. The sutures remained relatively intact, except for some distortions. The main failure mode was the abrasion of the yarns at the apices of adjacent Nitinol stents. In two devices, this abrasion resulted in fraying of the yarns and holes in the fabric tubes. This short series of explanted devices provides evidence of damage to polyester fabric used in aortic endografts and raises questions regarding their resistance to abrasion and the risk of endoleak associated with monofilament fabric yarn.

Absence of tissue ingrowth through the textile fabric in a series of explanted clinic stent-grafts.

Using the retrieved devices from one autopsy and five reoperations, the biocompatibility of explanted Talent stent-grafts was investigated to highlight the capacity of the fabric to act as an effective scaffold to regenerate a blood conduit. The autopsy device was encapsulated both internally and externally, but the capsules did not penetrate through the fabric structure. The reoperation devices showed discrete patches of compact fibrin and irregularly scattered mural thrombi. Positive staining of α-actin, tissue plasminogen activator (tPA), urokinase (uPA), urokinase receptor (uPAR), and urokinase inhibitors (PAI 1, PAI 2, PAI 3, and protease nexin), and D-dimer was more frequently identified in the autopsy sample than in the reoperation samples. This preliminary assessment shows that the stent-graft retrieved during autopsy was better healed than those explanted at reoperation.

Intra-operative fenestration of stent grafts: a note of caution based upon preliminary in vitro observations.

Intra-operative fenestrations of stent grafts make more frail and elderly patients amenable to endovascular surgery but require further assessment of the viability of currently used experimental techniques. Four types of polyester fabrics currently employed in stent grafts were exposed in vitro to various protocols of fenestration: cutting, trocaring, and cantering. The resulting fenestrations were examined by gross observation, light microscopy, and scanning electron microscopy. Blunt fenestration by scissors and sharp penetration led to unpredictable apertures, impairment of the integrity of the grafts, and damage to the filaments. The fenestrations were more likely to extend in the woven fabrics, whereas the knitted fabrics were more resistant to fraying. The use of the electric cautery demonstrated the ability to create a fenestration by simultaneously perforating/cutting and edge sealing. Any safe fenestration requires a perforating method that ensures the sealing of the edge of the graft material with a well-controlled diameter. A preoperative fenestration can be tolerated, but there are risks of damage to the stent grafts when reloading the device. More elegant methods of preoperative fenestration, particularly in situ retrograde laser fenestration, are in development and deserve clinical validation.

Detailed analysis of a series of explanted Talent AAA stent-grafts: biofunctionality assessment.

Six Talent stent-grafts were harvested at reoperations (N=5) and autopsy (N=1). The explants were observed nondestructively, including gross morphology, X-rays, CT scans and closed pressure system analysis. The Nitinol frames in three devices harvested at reoperations and another harvested at autopsy were intact. One had a stent fracture of the proximal bare stent, and one had a wire fracture of a thin proximal external supporting stent as well as a hole in the fabric just above the bifurcation. For the three devices structurally intact, reoperations were performed for a type 1A endoleak (one patient) and aorto-enteric fistulas (two patients). The healing characteristics were poor or absent. The fabric in the main body of the grafts harvested after aorto-enteric fistula was devoid of biological deposits. Two of the grafts harvested at reoperation demonstrated fabric holes of up to 4 mm 2. The device obtained at autopsy showed an almost continuous internal capsule with variable thickness. The luminal surface was smooth, but the capsule detached easily. The devices explanted at reoperations showed various levels of impaired biofunctionality associated with adverse outcomes. The stent-graft retrieved from autopsy was intact.

The marvel of percutaneous cardiovascular devices in the elderly.

Thanks to minimally invasive procedures, frail and elderly patients can also benefit from innovative technologies. More than 14 million implanted pacemakers deliver impulses to the heart muscle to regulate the heart rate (treating bradycardias and blocks). The first human implantation of defibrillators was performed in early 2000. The defibrillator detects cardiac arrhythmias and corrects them by delivering electric shocks. The ongoing development of minimally invasive technologies has also broadened the scope of treatment for elderly patients with vascular stenosis and aneurysmal disease as well as other complex vascular pathologies. The nonsurgical cardiac valve replacement represents one of the most recent and exciting developments, demonstrating the feasibility of replacing a heart valve by way of placement through an intra-arterial or trans-ventricular sheath. Percutaneous devices are particularly well suited for the elderly as the surgical risks of minimally invasive surgery are considerably less as compared to open surgery, leading to a shorter hospital stay, a faster recovery, and improved quality of life.