Lee J. Goldstein

Diabetic impairments in NO-mediated endothelial progenitor cell mobilization and homing are reversed by hyperoxia and SDF-1α

Endothelial progenitor cells (EPCs) are essential in vasculogenesis and wound healing, but their circulating and wound level numbers are decreased in diabetes. This study aimed to determine mechanisms responsible for the diabetic defect in circulating and wound EPCs. Since mobilization of BM EPCs occurs via eNOS activation, we hypothesized that eNOS activation is impaired in diabetes, which results in reduced EPC mobilization. Since hyperoxia activates NOS in other tissues, we investigated whether hyperoxia restores EPC mobilization in diabetic mice through BM NOS activation. Additionally, we studied the hypothesis that impaired EPC homing in diabetes is due to decreased wound level stromal cell-derived factor-1alpha (SDF-1alpha), a chemokine that mediates EPC recruitment in ischemia. Diabetic mice showed impaired phosphorylation of BM eNOS, decreased circulating EPCs, and diminished SDF-1alpha expression in cutaneous wounds. Hyperoxia increased BM NO and circulating EPCs, effects inhibited by the NOS inhibitor N-nitro-L-arginine-methyl ester. Administration of SDF-1alpha into wounds reversed the EPC homing impairment and, with hyperoxia, synergistically enhanced EPC mobilization, homing, and wound healing. Thus, hyperoxia reversed the diabetic defect in EPC mobilization, and SDF-1alpha reversed the diabetic defect in EPC homing. The targets identified, which we believe to be novel, can significantly advance the field of diabetic wound healing.

Endothelial Progenitor Cell Release into Circulation Is Triggered by Hyperoxia‐Induced Increases in Bone Marrow Nitric Oxide

Endothelial progenitor cells (EPC) are known to contribute to wound healing, but the physiologic triggers for their mobilization are often insufficient to induce complete wound healing in the presence of severe ischemia. EPC trafficking is known to be regulated by hypoxic gradients and induced by vascular endothelial growth factor‐mediated increases in bone marrow nitric oxide (NO). Hyperbaric oxygen (HBO) enhances wound healing, although the mechanisms for its therapeutic effects are incompletely understood. It is known that HBO increases nitric oxide levels in perivascular tissues via stimulation of nitric oxide synthase (NOS). Here we show that HBO increases bone marrow NO in vivo thereby increasing release of EPC into circulation. These effects are inhibited by pretreatment with the NOS inhibitor l‐nitroarginine methyl ester (l‐NAME). HBO‐mediated mobilization of EPC is associated with increased lower limb spontaneous circulatory recovery after femoral ligation and enhanced closure of ischemic wounds, and these effects on limb perfusion and wound healing are also inhibited by l‐NAME pretreatment. These data show that EPC mobilization into circulation is triggered by hyperoxia through induction of bone marrow NO with resulting enhancement in ischemic limb perfusion and wound healing.

Hyperbaric oxygen and bone marrow-derived endothelial progenitor cells in diabetic wound healing

Endothelial progenitor cells (EPCs) are the key cellular effectors of postnatal vasculogenesis and play a central role in wound healing. In diabetes, there is a significant impairment in the number and function of circulating and wound-tissue EPC. Recent evidence indicates, that tissue-level hyperoxia achieved by therapeutic hyperbaric oxygen protocols (HBO2) can increase the mobilization of EPC from the bone marrow into peripheral blood. In this paper we review the recent reports on hyperoxia-mediated mobilization of bone marrow-derived EPC and postulate avenues of future research in this area as it applies to improving healing in chronic wounds affected by diabetes and peripheral arterial disease (PAD).

Predicting Factors Associated with Postoperative Hypotension following Carotid Artery Stenting

BACKGROUND Prolonged hemodynamic instability after carotid artery stenting (CAS) has been associated with increased incidence of stroke and other major adverse events. The objective of this study is to determine the factors associated with hypotension following CAS. In particular, this study evaluates whether involvement of the carotid bifurcation/bulb and degree of calcification can predict postoperative hypotension. METHODS A retrospective review of 90 CASs performed in 88 patients at a single tertiary center was completed. In patients with proximal internal carotid stenosis involving the carotid bifurcation, the extent of bifurcation/bulb calcification on preoperative computed tomography angiography was assessed using a scoring system. Calcium scores were assigned based on the percent of circumferential calcification of carotid bifurcation as follows: grade 1, <10%; grade 2, 10-50%; grade 3, 50-90%; and grade 4, >90%. Perioperative factors associated with prolonged postoperative hypotension requiring vasopressor infusion were analyzed. RESULTS Overall, postoperative hypotension requiring vasopressors occurred in 26 (28.9%) of CAS. There were no differences in baseline demographics, comorbidities, or CAS indication between patients who required postoperative vasopressors for hypotension and those who did not. The majority of patients (64.4%) were on 2 or more antihypertensive medications preoperatively. Stenosis involved carotid bifurcation in 64 (71.1%) cases. Of these, 27 (42.2%) were grade 1, 19 (29.7%) were grade 2, 10 (15.6%) were grade 3, and 8 (12.5%) were grade 4 based on our calcium scoring system. On risk-adjusted analysis, carotid bifurcation/bulb involvement (adjusted odds ratio [aOR] 4.5, 95% confidence interval [CI] 1.1-18.5) and preoperative regimen of 2 or more antihypertensives (aOR 4.2, 95% CI 1.1-16.0) were independent predictors of hypotension requiring vasopressors following CAS. Among patients with carotid bifurcation involvement, severity of calcium score was not a significant predictor of postoperative hypotension. CONCLUSIONS CAS for carotid stenosis involving the carotid bifurcation/bulb is associated with a higher risk for postoperative hypotension requiring vasopressors. Patients with preoperative hypertension requiring 2 or more antihypertensive medications are also at increased risk. However, severity of carotid bifurcation calcification is not a significant predictor of need for postoperative vasopressors.

Minimally invasive axillary to right atrial graft for hemodialysis access utilizing the intraluminal flow guard graft

As the medical treatment of patients suffering from endstage renal disease improves, patients are being maintained with chronic hemodialysis for longer periods of time. Lack of autologous venous conduits, complex central venous occlusive disease, and indwelling catheter or arteriovenous (AV) graft infections all pose a significant risk of morbidity and mortality (1). Several advancements have been developed to address these increasingly common problems, including immediate/ early access grafts, the Hemodialysis Reliable Outflow (HeRO) graft (Cryolife, Kennesaw, Georgia, USA) (2), the Gore Hybrid Vascular Graft (Gore Medical, Inc, Flagstaff, Arizona, USA), and the Flixene IFG (intraluminal flow guard) Graft (Atrium Medical, Hudson, New Hampshire, USA). The Flixene IFG graft combines an early access PTFE graft with a perpendicular ‘T-shaped’ stented venous outflow segment intended for inline placement in the outflow vein. The intended goal of this configuration is to redirect the turbulent flow and prevent venous intimal hyperplasia (3). We present the case of a 51-year-old male suffering from end-stage renal disease for 6 years, who had exhausted all traditional access sites. A Flixene IFG graft was successfully implanted in a minimally invasive fashion from the left axillary artery to the right atrium, providing a chest wall AV graft for hemodialysis. The patient had a history of severe learning impairment, requiring care in an adult assisted living facility. He had undergone countless AV access procedures (seen as multiple prior access scars in Fig. 1A, B arrows) over the last 6 years. On presentation, he was dialyzed via a transhepatic tunneled catheter, due to complete occlusions of all other upper and lower extremity central veins. This access had had to be re-