Rat and human aortic smooth muscle cells display differing migration and matrix metalloproteinase activities in response to dexamethasone.

OBJECTIVE: The steroid dexamethasone inhibits neointimal hyperplasia development in rats but not in humans. This study investigates the differential effects of dexamethasone on rat and human smooth muscle cell migration and matrix metalloproteinase (MMP) activity. METHODS: Rat aortic smooth muscle cells were harvested from Sprague-Dawley rats. Human aortic smooth muscle cells were obtained from Clonetics. Boyden chamber migration assays were performed with chemoattractant (platelet-derived growth factor) and varying concentrations of dexamethasone (10(-9) to 10(-5) mol/L). Zymography of culture media was used to assess MMP activity, and Western blot analysis was used for quantification of MMP-2 and tissue inhibitor of MMP-2 (TIMP-2) secretion. RESULTS: Dexamethasone inhibits rat aortic smooth muscle cell migration in a dose-dependent fashion. An increase in concentrations of dexamethasone does not effect human aortic smooth muscle cell migration. Rat aortic smooth muscle cell MMP-2 activity is inhibited with dexamethasone in a dose-dependent fashion, and human aortic smooth muscle cell MMP-2 activity is unchanged with dexamethasone. MMP-2 secretion is inhibited with dexamethasone in rat aortic smooth muscle cells but remains unaltered in human aortic smooth muscle cells. Dexamethasone increases rat aortic smooth muscle cell TIMP-2 secretion, and human aortic smooth muscle cell TIMP-2 secretion remains constant. CONCLUSION: Dexamethasone inhibits rat aortic smooth muscle cell migration, MMP-2 activity, and MMP-2 secretion and increases TIMP-2 secretion. These effects are not observed in human aortic smooth muscle cells. These findings may explain why dexamethasone inhibits neointimal hyperplasia in animal models but is ineffective in humans. Inhibition of human smooth muscle cell migration in vitro may be useful in predicting the effectiveness of future therapeutic agents for treatment of neointimal hyperplasia in humans.

Dexamethasone inhibits vascular smooth muscle cell migration via modulation of matrix metalloproteinase activity.

BACKGROUND: Dexamethasone (DEX) has been shown to inhibit development of neointimal hyperplasia in rats. We hypothesize that DEX inhibits neointimal hyperplasia by altering matrix metalloproteinase (MMP) activity, resulting in inhibition of smooth muscle cell migration. METHODS: Rat aortic smooth muscle cells (RASMC) were harvested and cultured for two to four passages. A migration assay was performed in a Boyden chamber with chemoattractant (platelet-derived growth factor) and varying concentrations of DEX (10(-9) to 10(-5) M). The number of migrated cells was counted under light microscopy. Zymography was performed on culture media to assess MMP activity, and Western blotting was performed to assay MMP and levels of tissue inhibitors of MMPs (TIMPs). RESULTS: DEX progressively inhibited RASMC migration in a dose-dependent fashion. This effect was statistically significant for concentrations of 10(-7) to 10(-5) M (P < 0.0005). Zymography showed that DEX inhibits MMP-2 activity in a dose-dependent manner. Western blots indicated that total MMP-2 secretion was inhibited and that TIMP-2 secretion was increased by DEX. CONCLUSIONS: DEX inhibits platelet-derived growth factor-induced migration of RASMCs and MMP-2 activity in vitro. Our data suggest that DEX suppresses MMP activity and secretion, resulting in the inhibition of smooth muscle cell migration. This may explain the mechanism by which DEX inhibits neointimal hyperplasia.

PECAM-1/IgG attenuates peroxynitrite-mediated extremity reperfusion injury.

OBJECTIVE: Neutrophil transendothelial migration, a key feature of skeletal muscle ischemia and reperfusion (I/R) injury, is mediated by the platelet endothelial cell adhesion molecule-1 (PECAM-1). Peroxynitrite anion, a toxic product of neutrophil superoxide anion and nitric oxide, contributes to oxidative skeletal muscle injury and can be quantified by measurement of protein tyrosine nitration after I/R. This study hypothesizes that administration of the PECAM-1/IgG antibody chimera will inhibit peroxynitrite-mediated injury after I/R. METHODS: The study was composed of five groups: an I/R group (n = 4), a sham treatment group anesthetic control (n = 3), a treatment group receiving the PECAM-1/immunoglobulin G (IgG) antibody chimera with I/R (n = 9), a treatment group receiving human IgG with I/R as an antibody control (n = 6), and a treatment group receiving normal saline solution with I/R as a vehicle control (n = 5). The right hind limb in male New Zealand white rabbits was rendered ischemic by occluding the iliac and femoral arteries for 3 hours, followed by 2 hours of reperfusion (I/R). Sham-treated rabbits underwent arterial dissection without arterial occlusion. PECAM-1/IgG-treated rabbits and IgG-treated rabbits received an infusion of 1 mg/kg in normal saline solution 20 mL via an ear vein catheter during the last 5 minutes of ischemia and the first 15 minutes of reperfusion. Saline solution-treated rabbits similarly received normal saline solution 20 mL. The anterior tibialis muscle was harvested after reperfusion. Immunohistochemical staining for nitrotyrosine was performed with monoclonal antinitrotyrosine antibodies and fluorescently labeled secondary antibodies. Computed morphometric study was performed to calculate relative fluorescence scores for each histologic section. Averaged fluorescence scores were analyzed by one-way analysis of variance with Bonferroni post hoc comparison. RESULTS: The averaged fluorescence scores (mean +/- SEM) for the sham-treated (2.88 +/- 0.78) and PECAM-1/IgG-treated (6.16 +/- 0.43) groups demonstrated a significant reduction in quantitative fluorescence compared with the IgG- (15.17 +/- 2.01) and saline solution-treated (17.46 +/- 3.71) control groups, and the I/R-treated (18.52 +/- 3.00) group, (P <.05). CONCLUSIONS: These results suggest that PECAM-1/IgG diminishes peroxynitrite-mediated oxidative skeletal muscle injury by inhibiting neutrophil transendothelial migration and may therefore prove a useful therapeutic agent in the treatment of reperfusion injury.

Combined carotid endarterectomy and coronary bypass: a decade experience at UCLA.

PURPOSE: The purpose of this review was to determine outcomes for combined carotid endarterectomy (CEA) and coronary revascularization (CABG) in patients with asymptomatic carotid stenosis. METHODS: We reviewed the medical records of consecutive combined procedures (CEA and CABG), performed at UCLA Medical Center from October, 1989 to January, 1999. FINDINGS: There were 43 patients, 27 men and 16 women, with a mean age of 71 yr (range 51-87). Thirty-four patients 79% (34/43) had asymptomatic carotid stenosis. Stroke occurred in three patients (3/43 = 6.9%). Stroke ipsilateral to the CEA occurred in two patients: one asymptomatic (1/34 = 2.9%) and one symptomatic (1/9 = 11.1%). CONCLUSIONS: The majority of patients undergoing combined CEA/CABG have asymptomatic carotid stenosis identified in preparation for elective CABG. The asymptomatic carotid subset stroke rate of 2.9% resulting from a combined CEA/CABG is higher than our reported rate for CEA performed alone. In patients with asymptomatic carotid stenosis, the combined procedure should be selectively performed.

Carotid endarterectomy with normal findings from a completion study: Is there need for early duplex scan?

OBJECTIVE: The objective of this study was to determine the value of early (< 6 months) duplex scanning after carotid endarterectomy (CEA) with an intraoperative completion study with normal results. Attention was paid to restenosis rates and reoperation for recurrent stenosis within the first 6 months. METHODS: A retrospective review was performed on 380 CEAs (338 patients) with intraoperative completion studies and duplex surveillance within the first 6 months. Results of completion studies, restenosis rates, and recurrent symptoms were evaluated for each operation. Studies were performed from 0 to 200 days postoperatively (median, 28). RESULTS: Intraoperative completion studies included 333 angiograms, 26 duplex scans, and 21 angiograms with duplex scans. Of the 380 intraoperative completion studies, 28 (7.5%) had abnormal findings, including 14 abnormal internal carotid arteries (ICAs). Twenty-four procedures were revised, and the findings of all repeat completion studies were normal. Of the initial completion studies, in four cases, abnormalities (3 ICAs) were insignificant and did not warrant further intervention. Follow-up ICA duplex scans had normal results after 364 (95.8%) CEAs. There were 14 mild recurrent ICA stenoses and two moderate recurrent ICA stenoses; neither had abnormal findings from the completion study. There were no severe recurrent ICA stenoses. External carotid artery (ECA) recurrent stenosis included 7 mild, 15 moderate, and 9 severe restenoses. CONCLUSIONS: Only 0.5% of CEAs developed moderate restenosis. No procedures had severe recurrent stenosis on duplex scan within the first 6 months, and none required intervention. Duplex surveillance in the first 6 months is relatively unproductive, providing that there were normal results from an intraoperative completion study for each patient. Routine surveillance can be started at 1 year.

Penetrating ulceration of the infrarenal aorta: case reports of an embolic and an asymptomatic lesion.

Penetrating aortic ulceration is uncommon in the infrarenal aorta. We describe a patient with a penetrating infrarenal aortic ulcer manifesting as blue toe syndrome, and a second patient with a similar lesion identified as an incidental finding. These two patients were treated for penetrating infrarenal aortic ulceration within the past 9 months at two university-affiliated hospitals, a regional Veterans Administration Medical Center, and a County Medical Center. Both lesions demonstrated aneurysm changes with varying degrees of mural thrombus. The lesion filled with fresh thrombus proved labile, with embolization manifesting as blue toe syndrome. We support the aggressive treatment of aneurysmal penetrating aortic ulcer with aortic graft replacement to eliminate the potential for distal embolization and to obviate the risk of rupture and death.

Safety and efficacy of early surgical decompression of the thoracic outlet for Paget-Schroetter syndrome.

The surgical treatment of Paget-Schroetter syndrome has evolved to include early thrombolytic therapy and an interval period of anticoagulation, followed by late surgical decompression of the thoracic outlet. More recently, we have developed an abbreviated course of therapy in which the thrombolytic therapy is followed by early surgical decompression during the same admission, then a period of anticoagulation. We compared early surgical decompression with the standard management protocol to determine safety and efficacy of the early treatment algorithm. Nine patients were treated with lysis and early operation. These were compared with the preceding nine consecutive patients treated with lysis and staged operation. Demographic data, risk factors, duration of thrombosis, lytic therapy, time to surgery, operative variables, and postoperative complications were analyzed. Our results showed that thrombolysis followed by early operation does not result in increased perioperative morbidity or mortality. Early surgical decompression of the thoracic outlet during the same admission as lysis is as safe and efficacious as the traditional (staged decompression) approach to Paget-Schroetter syndrome. Lysis followed by early surgical decompression should be considered a new standard of care in the management of Paget-Schroetter syndrome.

Endovascular therapy of iliac arteries: routine application of intraluminal stents does not improve clinical patency.

Our objective in this study was to review our experience with endovascular therapy of iliac artery occlusive disease over the past decade, and to compare the results of angioplasty alone with the addition of endovascular stents to these procedures. This report details a retrospective analysis of clinical data on 141 consecutive patients with iliac artery occlusive disease, treated by balloon angioplasty alone, or with the addition of intraluminal stents. The procedures analyzed included 58 common iliac artery interventions (26 angioplasties and 32 stent insertions) and 83 external iliac artery procedures (43 angioplasties and 40 stent insertions). Early and continued success, and their components, are reported and compared according to published standards. While endovascular therapy of iliac artery occlusive disease is effective in relieving symptoms, clinical patency rates are lower than those reported for direct reconstruction. Primary stent placement has not enhanced clinical patency in the iliac arteries, and the selective insertion of these devices for more complicated angioplasty procedures seems warranted.

Cigarette smoke impairs endothelium-dependent relaxation in rabbit superficial femoral veins.

BACKGROUND: The use of autogenous vein for arterial reconstruction provides the optimal conduit for limb salvage. Cigarette smoking is a risk factor for vascular disease and may adversely affect graft patency and limb preservation rates of extremities reconstructed with autogenous vein. This study was performed in order to determine the effects of cigarette smoke on venous endothelium-dependent relaxation which is mediated by nitric oxide. MATERIALS AND METHODS: New Zealand white rabbits were exposed to cigarette smoke in a 240-ft3 air-flow chamber for 3 h per day, 5 days per week, for 8 weeks. A control group was treated similarly without infusion of smoke into the chamber. Elevated serum cotinine and carboxyhemoglobin levels comparable to those of chronic smokers were observed in the experimental group. After 8 weeks, the superficial femoral veins were explanted, cut into 3-mm segments, and studied in organ chambers. RESULTS: No difference in contractile response to KCl (80 mM) (control, 0.10 +/- 0.06; smoke, 0.17 +/- 0.04) or norepinephrine (EC50) (control, 0.78 +/- 0.18; smoke, 0.87 +/- 0.11) was seen. A significant decrease in relaxation was noted with all doses of acetylcholine (M) (control, 10(-8) - 50.35 +/- 8.37, 3 x 10(-8) - 71.20 +/- 9.05, 10(-7) - 88.32 +/- 13.72, 3 x 10(-7) - 92. 86 +/- 13.69; and smoke, 10(-8) - 8.25 +/- 1.83*, 3 x 10(-8) - 19.11 +/- 5.11*, 10(-7) - 31.84 +/- 7.90*, 3 x 10(-7) - 39.74 +/- 8.65*; *P < 0.05). Both control and smoke veins relaxed completely with sodium nitroprusside. CONCLUSIONS: Superficial femoral veins, when exposed to cigarette smoke, demonstrated a significant decrease in endothelium-dependent relaxation in response to acetylcholine without smooth muscle injury. This loss of vasomotor tone could be detrimental over time in veins which have been placed as arterial conduits.

Peritoneal dialysis: an increasingly popular option.

Vascular surgeons well versed in peritoneal dialysis applications understand the importance of this modality among the limited options afforded to patients in renal failure. Peritoneal and hemodialysis strategies are interdependent and should be considered in concert. Careful assessment often shows that patients with diminishing vascular access have been overlooked as viable peritoneal dialysis candidates. This chapter summarizes peritoneal dialysis in terms of its history, physiological principles, indications, contraindications, catheter placement, types of administration, and the identification and management of complications.

Loss of superficial femoral artery relaxation following ischemia-reperfusion.

Acute ischemia followed by reperfusion in skeletal muscle is associated with tissue edema and necrosis. The purpose of this study was to demonstrate superficial femoral artery endothelial injury following complete ischemia with reperfusion. New Zealand white rabbits underwent total devascularization of one hindlimb for 3 hr followed by 0, 1, and 2 hr of reperfusion. Control rabbits underwent a sham operation. Superficial femoral artery rings were then studied for acetylcholine induced relaxation in vitro. The response to acetylcholine was measured as percentage relaxation at three incremental doses (1 x 10(-7) , 3 x 10(-7) and 5 x 10(-7) M). The ischemia-only (26.30 +/- 7.07, 62.63 +/- 8.64, 88.08 +/- 5.25%) and the 1-hr reperfusion group (19.35 +/- 12.99, 39.24 +/- 15.78, 62.01 +/- 14.03%) showed no significant difference (P > or = 0.05, Student's t test) in relaxation as compared to the control group (13.73 +/- 2.11, 47.88 +/- 7.23, 72.44 +/- 9.00%). The 2-hr reperfusion group (6.10 +/- 1.02, 15.33 +/- 2.56, 34.67 +/- 6.31%), however, had a significant loss of relaxation at all three doses of acetylcholine compared to that seen in the control group (P < or = 0.05, Student's t test). In this model of complete ischemia, superficial femoral artery rings lose their ability to relax in response to acetylcholine following 3 hr of ischemia and 2 hr of reperfusion, demonstrating endothelial injury. However, immediately after 3 hr of ischemia or ischemia followed by only 1 hr of reperfusion, superficial femoral artery rings did not lose their ability to relax in response to acetylcholine. This study identifies a window of opportunity for therapeutic intervention after ischemia and prior to endothelial injury from reperfusion.

Using dipyridamole-thallium imaging to reduce cardiac risk in aortic reconstruction.

UNLABELLED: Cardiac morbidity and mortality remain the major operative risk following aortic reconstruction (AR) performed for aneurysmal and occlusive disease. We reviewed the preoperative cardiac evaluation and outcome in 209 patients who had AR between 1987 and 1992. Dipyridamole-thallium stress test (DTST) was performed in 147 (70.3%) patients. Fifty-six of these patients had a normal DTST and only 1 (1.8%) had a perioperative myocardial infarction (MI). Forty-six patients had a fixed defect on their DTST and 3 (6.5%) had perioperative MI. Forty-five patients had reversible defects on their DTST and 2 (4.4%) had perioperative MI with 1 cardiac death. Following DTST, 29 coronary catheterizations were performed. Ten catheterizations were normal or had minimal one-vessel coronary artery disease with an associated postoperative death in 1 patient due to cardiac dysrhythmia. Nineteen patients had abnormal coronary angiography, 1 of whom had a perioperative myocardial infarction and 5 of whom underwent coronary artery revascularization (CABG) (3) or percutaneous transluminal angioplasty (2) prior to AR without subsequent cardiac events. Forty-three (20.6%) had either no cardiac symptoms (40) or prior CABG (3) precluding invasive cardiac evaluation. There was one fatal perioperative myocardial infarction (2.3%), resulting in a cardiac mortality of 2.3% in this group. The remaining 19 patients who did not have a DTST (9.1%) had coronary angiography based on evidence of significant cardiac disease resulting in one CABG and one percutaneous transluminal angioplasty. There was one (5.3%) perioperative myocardial infarction in this group and no cardiac deaths. Thirty-day mortality was 3.8%, perioperative MI rate was 3.8%, and perioperative cardiac mortality was 1.0%. During the follow-up period (median, 18 months; range, 1-89), there were 19 deaths (10%) and the 5-year cumulative survival was 76%. CONCLUSION: Selective use of DTST can direct further evaluation, intervention, and subsequent perioperative care. This algorithm has enabled us to perform AR even in patients with defined perfusion abnormalities with acceptable morbidity. The true sensitivity, specificity, and predictive value of DTST can only be determined by a prospective trial.

Effect of the duration of symptoms, transport time, and length of emergency room stay on morbidity and mortality in patients with ruptured abdominal aortic aneurysms.

BACKGROUND: Despite improvements in emergency medical services, surgical technology, and postoperative critical care, ruptured abdominal aortic aneurysm (AAA) is associated with constantly high morbidity and mortality. To determine the effect of the duration of symptoms, transport time to hospital, and length of emergency department assessment on outcome, we evaluated 124 consecutive patients with ruptured AAA treated during the past decade. METHODS: The medical records for 122 patients were abstracted for preoperative hypotension, cardiopulmonary resuscitation (CPR), blood loss, and three time intervals: symptom onset to operation, transport time to hospital, and emergency department assessment. RESULTS: Intraoperative mortality was 26% (n = 32), 30-day mortality was 51% (n = 63), and cumulative hospital mortality was 56% (n = 69). Death occurred in 52 (64%) of 81 patients with hypotension compared with 14 (35%) of 40 patients without hypotension (p < or = 0.01). Hypotension was present in 37 (82%) of 45 patients who arrived in the operating room in 2 hours or less compared with 26 (60%) of the 43 patients who arrived later than 2 hours (p < or = 0.05). Death followed in 21 (91%) of 23 patients who received CPR compared with 46 (46%) of 99 patients who did not receive CPR (p < or = 0.01). Bowel ischemia was observed in 18 (30%) of 60 patients who received more than 10 units of blood compared with 3 (5%) of 61 patients who received 10 units or less (p < or = 0.01). CONCLUSIONS: For patients with ruptured AAA, prolonged presurgical time was associated with a more hemodynamically stable patient and a lower mortality. Progressive bleeding in those hemodynamically stable patients was reflected by a larger blood transfusion requirement. Such patients exhibited an increased incidence of ischemic bowel complications, perhaps caused by splanchnic arterial ischemia augmented by preexisting atherosclerosis, as well as extrinsic compression by mesenteric hematomas.