Supplemental oxygen reverses hypoxia-induced smooth muscle cell proliferation by modulating HIF-alpha and VEGF levels in a rabbit arteriovenous fistula model.

BACKGROUND: Numerous mechanisms for the formation of intimal hyperplasia have been proposed but none have been proven or accepted. Our research focuses on the potential role of hypoxia-inducible factors (HIFs), vascular endothelial growth factor (VEGF), and platelet-derived growth factors as well as the extracellular signal-regulated kinase (ERK), phosphatidylinositide 3-kinase /protein Kinase B (PI3-K/AKT) pathway in hypoxia-mediated intimal hyperplasia processes. We hypothesize that HIF and VEGF will be downregulated with supplemental oxygen in our arteriovenous fistula rabbit model. METHODS: Rabbits were randomized into different experimental groups with varying oxygen exposure (21% O2 or 30% O2) and receipt of surgery (surgery with fistula formation, no surgery, or sham operation with skin incision only). Plasma samples were collected at designated intervals in which cytokines and smooth muscle cell proliferation were measured. In addition, cell specimens were exposed to hyperoxic, normoxic, and hypoxic environments with cytokines measured at various time points. RESULTS: Placement of an arteriovenous fistula resulted in hypoxia-induced HIF stabilization with a concurrent increase in VEGF levels. There was a 4.2-fold induction in HIF-1α levels in animals that were placed in normal air after surgery when compared with animals that were exposed to hyperoxic air. Also, VEGF level significantly increased after surgery in the normoxic group, reaching a maximum of 959 pg/mL. Plasma VEGF levels in the surgery and supplemental oxygen group were significantly lower than the normoxic surgery group with almost a 45% reduction in plasma VEGF levels (524 pg/mL). Activation of VEGF receptors on smooth muscle cells through ERK1 and AKT pathways resulted in significant smooth muscle cell proliferation and migration. These effects are dramatically reduced in animals that are exposed to a hyperoxic environment of 30% oxygen. CONCLUSIONS: Our results suggest that short-term administration of supplemental oxygen inhibits HIFs and VEGF signaling to reduce smooth muscle proliferation in the local blood vessel. These results provide strong support for the therapeutic use of supplemental oxygen after arterial surgery to reduce intimal hyperplasia. These findings also provide a nidus for future clinical trials to determine whether this is clinically applicable in humans.

The role of short-term oxygen administration in the prevention of intimal hyperplasia.

OBJECTIVE: Intimal hyperplasia (IH) is the cause of most failed arteriovenous fistulas (AVFs), resulting in repeat procedures and leading to increased utilization of scarce health care resources. Our laboratory has previously demonstrated the role of supplemental oxygen in preventing IH and smooth muscle cell proliferation (SMCp) at an artery-to-graft anastomosis and at the deployment site of an intra-arterial stent. This study examines the effect of supplemental oxygen in preventing IH and SMCp in an AVF in a rabbit model. METHODS: Ninety-six rabbits were randomized into four groups: group 1, control; group 2, no surgery with supplemental oxygen; group 3, AVF without supplemental oxygen; and group 4, AVF with supplemental oxygen. Rabbits receiving supplemental oxygen received 30% oxygen for up to 42 days. Specimens were collected in all groups at days 1, 3, 7, 21, 42, and 90. IH and SMCp were measured at the AVF site as well as in the artery and vein proximal and distal to the AVF. RESULTS: IH was first noted at day 7 and significantly increased through day 90 at all locations in the nonoxygen-supplemented groups. No significant IH was noted in the oxygen-supplemented group at any location or any time point. SMCp was noted at day 3 through day 21 in the nonoxygen-supplemented group, whereas almost no SMCp was noted in the oxygen-supplemented group at any location or time point. CONCLUSIONS: Without oxygen supplementation, SMCp begins at day 3 and is no longer noted at day 21 after creation of an AVF, whereas IH begins by day 7 and increases at least through day 90 after creation of an AVF. Forty-two days of 30% supplemental oxygen inhibits IH and SCMp after creation of an AVF. These data suggest a role for the short-term administration of low-dose O2 to prevent both IH and SMCp after creation of an AVF that may prolong patency and function.

Prognostic value of 12-lead electrocardiogram and peak troponin I level after vascular surgery.

OBJECTIVE: The aim of this investigation was to determine if the presence of ischemic electrocardiographic (ECG) changes in patients undergoing vascular surgery provides incremental prognostic information about the long-term risk of death compared with a single peak troponin level within 48 hours after surgery. METHODS: This was a retrospective analysis of 337 patients undergoing moderate-risk to high-risk vascular surgery at our institution whose ECG and biomarker data were complete. Peak cardiac troponin (cTn) I values that exceeded the upper reference limit (URL) were categorized as low-positive (+), at or exceeding the URL but less than three times the URL, or high-positive (+), at or exceeding three times the URL. ECGs were classified as ischemic or nonischemic. The primary outcome was death at 1 year after the vascular operation. Independent predictors of long-term mortality were determined by Cox proportional hazards regression analysis. RESULTS: The most common vascular problem was an expanding abdominal aortic aneurysm (n=185 [55%]). With regard to cTnI, 53 patients (16%) were classified as high (+) and 82 (24%) as low (+). The ECG in 21 patients (6%) showed evidence of myocardial ischemia. An increase in 1-year mortality of 3% for normal, 11% for low (+), and 17% for high (+) (P<.01) was seen with incremental cTn values. Independent predictors of long-term mortality were age (odds ratio [OR], 1.05, 95% confidence interval [CI], 1.02-1.07; P<.01), stratified troponin (OR, 1.62; 95% CI, 1.25-2.10; P<.01), tissue loss (OR, 3.30; 95% CI, 1.72-6.33; P<.01), stratified Revised Cardiac Risk Index (OR, 1.32; 95% CI, 0.97-1.81; P<.07), and statin use (OR, 0.62; 95% CI, 0.40-0.98; P=.04). The presence of ischemia on ECG was not a predictor of long-term mortality. CONCLUSIONS: In the presence of an elevated cTn I, the ECG is not an independent predictor of long-term mortality after vascular surgery. These results support a strategy of routine surveillance of cTns after vascular surgery for the detection of cardiac events and postoperative risk stratification.

Removal of an infected aortic endograft and open aortic reconstruction: technical remarks.

Infection of an aortic endoprosthesis is a potentially lethal complication of an endovascular abdominal aortic aneurysm repair (EVAR). Surgical treatment usually involves excision of the infected endograft and vascular reconstruction, either in-line or extraanatomic. We present a case of severe infection of an endograft with suprarenal fixation. The one-stage procedure describes an in-line aortic reconstruction using a hybrid allograft composed of cryopreserved segments of cadaveric thoracic aorta and superficial femoral vein. A novel device for the removal of suprarenal fixating struts is described, as well as other technical maneuvers related to the removal of the struts used by surgeons in the community. The technique and surgical approach should be individualized based on patient characteristics, preoperative imaging, and knowledge of endograft construction.

Hypoxia differentially regulates arterial and venous smooth muscle cell proliferation via PDGFR-ß and VEGFR-2 expression.

Despite intensive research studies, theories have yet to focus on the contribution of hypoxia to patency differences observed clinically between arterial vs. venous grafts. This study investigates the differential hypoxic response of smooth muscle cells (SMC) to hypoxia-derived endothelial cell (EC) growth factors. Initiation of SMC proliferation under hypoxia (<5% O(2)) occurred only after incubation with hypoxic endothelial cell-conditioned media (H-ECM). After the investigation of several possible growth factors in the H-ECM that may be responsible for SMC proliferation, the greatest difference was observed in vascular endothelial growth factor (VEGF-A) and platelet-derived growth factor homodimer B (PDGF-BB) expression. VEGF-A increased (2-fold) significantly (P < 0.05) in arterial-derived smooth muscle cells (ASMC) under hypoxia compared with venous-derived smooth muscle cells (VSMC), which showed no significant change. VSMC showed significant (P < 0.05) increase in VEGFR-2 expression under hypoxia compared with ASMC. Incubation with VEGFR-2-neutralizing antibody/PDGFR antagonist in VSMC before addition of H-ECM resulted in decreased proliferation. ASMC proliferation under hypoxia did not decrease during incubation with VEGFR-2-neutralizing antibody but did decrease upon PDGFR antagonist incubation. Current therapies focusing on treating intimal hyperplasia have negated the fact that combinational therapy might be required to combat induction of SMC proliferation. Clinically, therapy with PDGFR antagonists plus anti-VEGFR-2 may prove to be efficacious in managing SMC proliferation in venous-derived grafts.

Preoperative coronary artery revascularization and long-term outcomes following abdominal aortic vascular surgery in patients with abnormal myocardial perfusion scans: a subgroup analysis of the coronary artery revascularization prophylaxis trial.

BACKGROUND: Abdominal aortic operations have the highest perioperative cardiac risk. To test the impact of preoperative coronary artery revascularization (PR) in this high-risk subset, a post hoc analysis was performed in patients undergoing aortic surgery within the Coronary Artery Revascularization Prophylaxis (CARP) trial. METHODS: The study cohort was a subset of 109 CARP patients with myocardial ischemia on nuclear imaging randomized to a strategy of PR (N = 52) or no PR (N = 57) before their scheduled abdominal aortic vascular operation. The clinical indications for vascular surgery were an expanding aneurysm (N = 62) or severe claudication (N = 47). The composite end-point of death and nonfatal myocardial infarction (MI) was determined by an intention-to-treat analysis following randomization. RESULTS: The median time (Interquartiles) from randomization to vascular surgery was 56 (40, 81) days in patients assigned to PR and 19 (10, 43) days in patients assigned to no PR (P < 0.001). At 2.7 years following randomization, the probability of remaining free of death and nonfatal MI was 0.65 with PR and 0.55 with no PR [unadjusted P = 0.08, odds ratio = 1.67, 95% confidence interval (0.93, 2.99)]. Using a Cox proportional hazard model, predictors of the composite of death and nonfatal MI (odds ratio; 95% confidence interval) were no PR (1.90; 1.06-3.43; P = 0.03) and anterior ischemia on preoperative imaging (1.79; 0.99-3.23; P = 0.07). CONCLUSIONS: In patients with an abnormal cardiac imaging before abdominal aortic vascular surgery, PR was associated with a reduced risk of death and nonfatal MI while anterior ischemia was an identifier of poor outcome independent of the revascularization status.

Radial artery pseudoaneurysm in the intensive care unit.

Pseudoaneurysms may occur at the wrist after catheterization of the radial artery but may also occur after arteriovenous shunting for dialysis or after direct trauma to an artery. Radial artery pseudoaneurysms are being increasingly reported because of widespread use of invasive monitoring. We report a case of radial artery pseudoaneurysm at the wrist related to catheterization. The pseudoaneurysm thrombosed after 6 days of external compression. In selected cases, extended external compression is a useful therapeutic option, especially in patients who are medically unfit to undergo general anesthesia or operative treatment.

Current issues facing academic surgery departments: stakeholders' views.

PURPOSE: To determine the issues important to stakeholders in today's academic surgery departments, to query key stakeholders about possible solutions, and to investigate the correlation of organizational alignment among department stakeholders with department performance. METHOD: Between July 2003 and October 2005, the author designed, piloted and carried out a study in which he interviewed key stakeholders-deans, chief executive officers/chief financial officers (CEOs/CFOs) of hospitals and health system practice plans, surgery department chairs, and surgery department members-from 12 randomly selected academic surgery departments. Important issues and solutions were identified and comparisons among stakeholder groups performed. Alignment was evaluated both among and within groups and organizations. RESULTS: Stakeholders (11 deans, 9 CEO/CFOs, 12 department chairs, 10 department faculty members) identified 12 issues and offered potential solutions and responses important to today's academic surgery department. One issue identified was promotion and tenure; nearly all stakeholders stated that its current form needed to be changed. Alignment analysis was incomplete because of inconsistent outcomes reporting. CONCLUSIONS: The uniformity of issues facing academic surgery departments and the similarity of the solutions proposed to address these issues (both study findings) suggest a need to change the paradigm and think "outside the box." The study findings suggest that academic surgery departments, under strong leaders, must establish a unified culture, define a compelling vision, articulate a clear mission, and develop fully accepted values to be successful. The study findings could be useful in designing and developing academic surgery departments in today's health care environment.

The Coronary Artery Revascularization Prophylaxis (CARP) Trial: results and remaining controversies.

A high percentage of patients requiring elective vascular surgery also has indications for coronary artery revascularization, leading to varied opinions as to whether to undertake coronary artery revascularization first, to use risk stratification, or to do no coronary intervention before elective vascular surgery. The Coronary Artery Revascularization Prophylaxis (CARP) Trial determined the long-term benefit of coronary artery revascularization in patients with stable coronary artery disease undergoing elective infra-renal aortic or infra-inguinal vascular surgery. Following application of inclusion/exclusion criteria, those patients who did not require urgent vascular surgery or have significant co-existing conditions underwent cardiac evaluation and angiography. Eligible patients (stenosis >70% in one or more cardiac vessels) were randomized to either undergo coronary revascularization or to have no coronary intervention before vascular surgery; 5859 patients were screened and 4669 were excluded for clinical or other reasons. The remaining 1190 patients underwent coronary angiography following which 680 were excluded for clinical or other reasons. The remaining 510 were randomized to coronary artery revascularization (258) before vascular surgery and no coronary intervention before vascular surgery (252). Coronary artery revascularization neither improves long-term survival nor does it improve short-term outcomes for elective aortic or infra-inguinal vascular surgery.

Peak postoperative troponin levels outperform preoperative cardiac risk indices as predictors of long-term mortality after vascular surgery Troponins and postoperative outcomes.

BACKGROUND: The utility of postoperative troponins as an independent predictor of long-term mortality after vascular surgery is unknown. METHODS: One hundred sixty-four consecutive patients underwent vascular surgery and postoperative mortality was determined at 2.5 years. Troponins were drawn within 48 hours postsurgery and the peak levels, defined by the upper reference limit (URL), were categorized as negative (

Carotid endarterectomy prior to ventricular assist device placement.

While there has been considerable debate regarding the timing of carotid endarterectomy (CEA) with respect to coronary artery bypass grafting, the ventricular assist device (VAD) patient population presents possible new concerns, given the implications of stroke while on mechanical support as a bridge to transplant. We present the first report in the literature of CEA in a patient with severe carotid disease prior to elective VAD placement.

Postoperative outcomes for patients undergoing elective revascularization for critical limb ischemia and intermittent claudication: a subanalysis of the Coronary Artery Revascularization Prophylaxis (CARP) trial.

OBJECTIVE: To determine the perioperative mortality, myocardial infarction rate, and long-term survival of patients with critical limb ischemia (CLI) compared with those with intermittent claudication (IC) within a cohort selected for significant coronary artery disease, a secondary analysis was conducted of a prospective, randomized, multicenter trial of Coronary Artery Revascularization Prophylaxis (CARP) before peripheral vascular surgery. This multicenter trial was sponsored by the Cooperative Studies Program of the Department of Veterans Affairs. METHODS: Of the 510 patients enrolled in the CARP trial and randomized to coronary revascularization or no revascularization before elective vascular surgery, 143 had CLI and 164 had IC as an indication for lower limb revascularization; >95% of each group were men. The presence of coronary artery disease was determined by cardiac catheterization. Eligible patients had at least one treatable coronary lesion of > or =70%. Those with significant left main disease, ejection fraction of <20%, and aortic stenosis were excluded. Patients were randomized to coronary artery disease revascularization or no revascularization before vascular surgery and followed for mortality and morbidity perioperatively and for a median of 2.7 years postoperatively. Medical treatment of coronary artery disease was pursued aggressively. RESULTS: Patients with IC had a longer time from randomization to vascular surgery (p = .001) and more abdominal operations (p < .001). Patients with CLI had more urgent operations (p = .006), reoperations (p < .001), and limb loss (p = .008) as well as longer hospital stays (p < .001). The IC group had more perioperative myocardial infarctions (CLI, 8.4%; IC, 17.1%; p = .024), although perioperative mortality was similar (CLI, 3.5%; IC, 1.8%; p = .360). In follow-up, the IC group also had numerically more myocardial infarctions (CLI, 16.8%; IC, 25%; p = .079), but mortality was not different (CLI, 21%; IC, 22%; p = .825). Coronary artery revascularization did not lower perioperative or long-term mortality in either group. CONCLUSIONS: Our data indicate that patients with significant coronary artery disease and either CLI or IC can undergo vascular surgery with low mortality and morbidity, and these results are not improved by coronary artery revascularization before vascular surgery. Furthermore, when selected for the presence of symptomatically stable, severe coronary artery disease, there is no difference in long-term survival between patients with CLI and IC. Finally, the better-than-predicted outcomes for these patients with advanced systemic atherosclerosis may be due to aggressive medical management with beta-blockers, statins, and acetylsalicylic acid.

Moderate hyperoxia (40%) increases antioxidant levels in mouse tissue.

BACKGROUND: Oxygen is routinely administered to patients to improve clinical outcome. Since studies have shown that administering 100% oxygen can cause unwanted side effects, intermediate concentrations of 40% oxygen are used in clinical practice. In this study, we examined whether the breathing of 40% oxygen causes beneficial effects upon tissue levels of antioxidants such as vitamin E, vitamin C, and glutathione. METHODS: Four-month-old mice were separated into two groups: control (n = 11) and experimental (n = 11). The treatment group was administered 40% oxygen for 10 days. Brain, heart, lung, liver, testes, and skeletal muscle were harvested and tissue antioxidant levels were determined by HPLC. RESULTS: Vitamin E concentrations were higher in brain, heart, lung, liver, and testes of the treatment group (P < 0.05). Glutathione concentrations were higher in the lung tissue only (P < 0.05). No differences were found in vitamin C levels. CONCLUSIONS: The data suggest that mice respond to oxidative stress by increasing tissue vitamin E incorporation and cellular synthesis of glutathione in the lung when exposed to moderate levels (40%) of hyperoxia.

Use of a non-contact radiant heat bandage on ischemic dermal infections in an ovine model.

BACKGROUND: Chronic non-healing foot wounds are common complication in the diabetic population. Local radiant heat bandage has recently been proposed as an effective adjuvant. The purpose of this study was to evaluate the efficacy of such bandage in controlling infection in an ovine ischemic wound model. MATERIAL/METHODS: Bilateral flank ischemic wounds were created in a total of 42 sheep. 14 sheep were challenged with Pseudomonas aeruginosa (PA), 13 with Escherichia Coli (EC), and 15 with Methicillin resistant staphylococcus aureus (MRSA). The left flank was designated the treatment side and the right the control side. The radiant heat bandage was applied for a total of 10 days. The animal were then euthanized and the wounds harvested for bacterial quantification. RESULTS: 39 sheep completed the study. Mean bacterial counts were has follows: for MRSA, control 7.6 x 10(5) CFU/gm vs. heated 2.0 x 10(5) CFU/gm (p=0.16); for EC, control 1.1 x 10(6) CFU/gm vs. heated 2.7 x 10(5) CFU/gm (p=0.006); PA, control 1.7 x 10(6) CFU/gm vs. heated 3.9 x 10(9) CFU/gm (p=0.001). CONCLUSIONS: Non-contact radiant bandages controls bacterial growth in ischemic wounds infected with MRSA or EC and may potentially improve wound healing. Wounds infected with PA should no be submitted to such treatment.

Fate of the ectatic infrarenal aorta: expansion rates and outcomes.

The natural history of the ectatic infrarenal aorta remains undetermined. While surveillance protocols have been proposed for true aneurysms, no recommendations are currently available for ectatic aortas. The purpose of this study is to define the natural history and recommend surveillance protocols for the infrarenal aorta 2.5-2.9 cm in diameter. Screening of 12,500 yielded 223 patients with an infrarenal abdominal aorta 2.5-2.9 cm in diameter at a university-affiliated VA medical center. All patients were prospectively followed by ultrasound from August 1993 through October 2000 and expansion rates were calculated by comparing the first and last study. Multivariate analysis of risk factors classically associated with abdominal aortic aneurysm was performed. Current data suggest that ectatic infrarenal aortas expand slowly, do not rupture, and rarely meet criteria for operative repair. No risk factors linked to the development of aneurysms were identified. On the basis of this study we recommend that patients with ectatic aortas have a repeat ultrasound 5 years after the initial study.

Supplemental oxygen reduces intimal hyperplasia after intraarterial stenting in the rabbit.

HYPOTHESIS: Supplemental oxygen can reduce intimal hyperplasia (IH) after stent deployment in a rabbit model. BACKGROUND: Endovascular stent placement is technically feasible, but long-term durability in vessels outside the aortoiliac system is compromised with postinterventional IH, which causes restenosis and failure of the arterial conduit. METHODS: Groups (n = 4 to 6) of female New Zealand white rabbits underwent placement of a 3-mm intraaortic stent with laparotomy and were placed in either normoxic (21% inspired oxygen concentration) or supplemental-oxygen (40% inspired oxygen concentration) environments for 0, 7, 14, and 28 days. The transarterial wall oxygen gradient was measured at 0, 7, and 28 days with an oxygen microelectrode. 5-Bromo-2'deoxyuridine (BrdU) was injected into the peritoneum before death to assess cellular proliferation. Aortic specimens were harvested en bloc and sectioned for analysis of cellular proliferation and intimal thickness. RESULTS: Intraaortic stent placement significantly decreased the transarterial wall oxygen gradient in the outer 70% of the vessel wall and was easily reversed at 7, 14, and 28 days with application of supplemental oxygen. Cellular proliferation was significantly decreased at 14 days (0.5% +/- 0.001% versus 2.3% +/- 0.002%; P <.001) and 28 days (0.4% +/- 0.001% versus 1.0% +/- 0.001%; P <.025) as measured with count of nuclei staining for 5-Bromo-2'deoxyuridine in the intima and media. Intimal thickness was significantly decreased at 28 days in oxygen-supplemented rabbits (intimal area/medial area = 0.50 +/- 0.07) as compared with controls (intimal area/medial area = 0.89 +/- 0.11; P <.025). CONCLUSION: This study shows the ability of supplemental oxygen to reverse arterial wall hypoxia, decrease cellular proliferation, and control IH at the deployment site of an intraarterial stent in a rabbit model. Forty-percent supplemental oxygen suppresses IH by 44% at 28 days as compared with normoxic control values. Cellular proliferation is reduced four-fold at 14 days and two-fold at 28 days in oxygen-supplemented rabbits as compared with control media after deployment. The clinical implications of these findings are significant, especially as the role of endovascular interventions continues to expand.

Expansion rates and outcomes for the 3.0-cm to the 3.9-cm infrarenal abdominal aortic aneurysm.

OBJECTIVE: This study was performed for the determination of the expansion rates and outcomes and for recommendations for the surveillance of the 3.0-cm to 3.9-cm abdominal aortic aneurysm (AAA). DESIGN: The study was observational with data from patients screened with ultrasound scanning for AAA at five Veterans Affairs Medical Centers for enrollment in the Aneurysm Detection and Management Trial. The eligibility requirements included: AAA from 3.0 cm to 3.9 cm in diameter and at least one repeat ultrasound scan more than 90 days after the initial screening. Patients also completed a questionnaire for demographic data and the determination of the presence of risk factors associated with AAA. The study endpoints included: 1, both mean and median expansion rates; 2, moderate expansion (>4 mm/year); 3, no expansion; 4, all causes of death; 5, AAA rupture; 6, expansion to 4 cm or more; 7, expansion to 5.0 cm or more; and 8, operative repair. RESULTS: Ultrasound scan screening results identified 1445 patients with 3.0-cm to 3.9-cm AAAs. Seven hundred ninety men met the ultrasound scan criterion of having at least two ultrasound scan studies during the study period, and these 790 men were used for this study. Mean AAA size was 3.3 cm, with an average follow-up period of 3.89 +/- 1.93 years. The median expansion rate was 0.11 cm/year. Expansion rates were significantly different (P <.001) between 3.0-cm and 3.4-cm cm AAA and 3.5-cm and 3.9-cm AAA. There were no reported AAA ruptures during the study period, although cause of death data were available in only 43% of the patients. Few 3.0-cm to 3.9-cm AAAs expanded to 5.0 cm or more during the study period. The patients with 3.0-cm to 3.9-cm AAAs who underwent operative repair during the study period were younger, had larger initial AAA diameters, and had more rapid expansion rates. CONCLUSION: AAAs of 3.0 cm to 3.9 cm expanded slowly, did not rupture, and rarely had operative repair or expanded to more than 5.0 cm in our study of male patients. Expansion rates and the incidence rate of operative repair are more common in the 3.5-cm to 3.9-cm AAA when compared with the 3.0-cm to 3.4-cm AAA.