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.

Acute arterial thrombosis causes endothelial dysfunction: a new paradigm for thrombolytic therapy.

PURPOSE: The goals of this study were to delineate the time course of endothelial dysfunction after arterial thrombosis, to determine the cause of endothelial dysfunction in this setting, and to determine whether modulating standard thrombolytic therapy would ameliorate the thrombosis-mediated endothelial dysfunction. METHODS: Male adult rats underwent infrarenal aortic occlusion by means of clip ligature to induce arterial thrombosis. After 30 minutes, 1, 2, and 3 hours, ring segments from the infrarenal aorta were harvested and placed into physiologic buffer baths. With the use of a force transducer, both endothelial-dependent relaxation (EDR) and endothelial-independent relaxation (EIR) were measured. Endothelial function and presence were determined by means of factor VIII immunohistochemical staining. Endothelial morphology was evaluated with scanning electron microscopy (SEM). Nitric oxide (NO) levels were determined with a chemiluminescent assay of its nitrite/nitrate metabolites (NO(x)). Standard thrombolytic therapy with urokinase (UK) was infused into thrombosed aortic ring segments and compared with UK supplemented with both low-dose L -arginine (2 mmol) and high-dose L -arginine (20 mmol). RESULTS: Arterial thrombosis decreases EDR. The nadir of EDR occurs 1 hour after thrombosis (mean +/- SE, 13% +/- 6.4% vs 94% +/- 2.6% for controls, P <.005), with persistent lowering of EDR as long as 3 hours after thrombosis. EIR is preserved, and vasoconstriction with norepinephrine or potassium buffer is unaltered. Both endothelial function and presence (n = 6 per group) were documented by means of factor VIII immunohistochemistry. An intact monolayer of endothelium at all time intervals after thrombosis was revealed by means of SEM analysis. No differences between control and thrombosed specimens were revealed by means of the grading of SEM images. Local NO(x) levels were lower after 1 hour of thrombosis, with an increase higher than baseline values at 3 hours. The addition of low-dose L -arginine resulted in a minor increase in EDR. However, high-dose L -arginine resulted in a significant increase in EDR versus controls receiving UK alone (64% +/- 6.3% vs 38% +/- 4.4%, P <.05). Correspondingly, local NO(x) levels were 20-fold higher after the high-dose L -arginine supplementation when compared with UK thrombolysis alone (2.8 +/- 0.52 micromol/L vs 0.133 +/- 0.02 micromol/L, n = 6 samples/group, P <.005). CONCLUSION: Acute arterial thrombosis causes endothelial dysfunction, without causing endothelial cell loss. Endothelial function reaches a nadir after 1 hour of thrombosis. EIR and vasoconstriction remain unaffected, indicating normal smooth muscle cell function. NO(x) levels suggest that NO levels are decreased acutely after thrombosis. Supplementing standard thrombolytic therapy with the NO precursor, l-arginine, ameliorates the endothelial dysfunction seen after acute thrombosis by increasing local NO production.

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.

Selective botulinum chemodenervation of the scalene muscles for treatment of neurogenic thoracic outlet syndrome.

Patients with thoracic outlet syndrome (TOS) who improve temporarily after anesthetic blockade of the anterior scalene muscles have been shown to improve after ultimate surgical decompressions at the interscalene triangle. Anesthetic blockade of the scalene muscles, even with the addition of steroids, however, rarely produces any prolonged relief as patients are awaiting definitive surgery. The present study was undertaken to determine if more effective and prolonged relief might be obtained with electrophysiologically and fluoroscopically guided selective injection of the scalene muscles with botulinum toxin, which has been used in the past for treating conditions associated with spasm of cervical muscles. In 14 of 22 patients (64%) with a clinical diagnosis of TOS, there was more than a 50% reduction of symptoms measured by a 101-point scale for at least 1 month after botulinum chemodenervation of the scalene muscles. Only 4 of the 22 patients (18%) had a 50% reduction of symptoms for at least 1 month after injection with lidocaine and steroids. In no patient were the results of lidocaine and steroid injection superior to botulinum chemodenervation. Chemodenervation had a mean duration of effect of 88 days. No significant side effects were encountered with botulinum chemodenervation except for mild transient dysphagia in two cases. These results appear to demonstrate that botulinum chemodenervation of the scalene muscles may be helpful in alleviating symptoms in patients with TOS awaiting definitive surgical decompression.

Dexamethasone inhibits the phosphorylation of retinoblastoma protein in the suppression of human vascular smooth muscle cell proliferation.

We have previously demonstrated that dexamethasone (DEX) suppresses neointimal hyperplasia and proliferation of rat aortic smooth muscle cells (SMC) by inducing a late G1 phase cell cycle arrest. Phosphorylation of retinoblastoma protein (Rb) regulates cell proliferation by controlling progression from G1 to S phase of the cell cycle. We hypothesized that DEX inhibits human vascular SMC proliferation and causes cell cycle arrest through inhibition of Rb phosphorylation. Human aortic SMC were cultured and treated with incremental doses of DEX. Cell counts and [(3)H]thymidine uptake were determined after 72 h. To examine the effects of DEX on the cell cycle, cells were synchronized by serum deprivation, restimulated to enter G1 phase, and treated with 10(-5) M DEX, and protein was extracted at sequential time points. Flow cytometry was performed to track cell cycle progression. Western blots were performed to examine Rb phosphorylation. DEX inhibited smooth muscle cell proliferation and DNA synthesis in a concentration-dependent fashion. Flow cytometry indicated that DEX induces a G1 phase cell cycle arrest. DEX inhibited the phosphorylation of Rb protein compared to control. DEX inhibits the proliferation of human vascular SMC by inducing G1 phase cell cycle arrest. DEX inhibited the phosphorylation of Rb, a key step in the progression of the cell from G1 to S phase. Elucidation of the mechanism of DEX may be helpful in treatment strategies for preventing neointimal hyperplasia as well as other disorders of cell proliferation.

The effects of thrombus, thrombectomy and thrombolysis on endothelial function.

OBJECTIVE: this study was undertaken to examine and compare the effects of thrombus, thrombectomy, and thrombolysis on endothelial function as measured by endothelium-dependent vasorelaxation (EDR). METHODS: adult, male New Zealand white rabbits underwent ligation of the left common iliac to femoral artery to induce thrombosis and were then randomly assigned to one of five groups, n=6 in each. Group A consisted of ligation and thrombosis for 4 h. Group B underwent similar ligation for 4 h, but without intraluminal thrombus present. Following 4 h of ligation and thrombosis, Group C underwent thrombectomy while group D was treated with urokinase (UK), 4000 U/min for 30 min. Group E underwent UK infusion alone. The right external iliac artery served as control vessel in each group. All arteries were removed and endothelial function was determined by measuring EDR. RESULTS: the presence of thrombus reduced EDR by 50% (group A) compared to control. Vessels with interrupted flow, but not exposed to thrombus, retained normal EDR (group B). Thrombectomy decreased EDR significantly (group C) compared to thrombolysis (group D) and control. UK did not significantly alter EDR (groups D, E). CONCLUSIONS: exposure of endothelium to thrombus significantly decreases EDR. EDR was not affected by interruption of blood flow in the absence of thrombus. Thrombectomy appeared to cause a further additive insult to the endothelium. In contrast, thrombolysis with UK preserved residual endothelial function. These data suggest that it is important to differentiate the effects of thrombus on endothelium from effects due to thrombectomy or thrombolysis when evaluating treatment modalities for arterial thrombosis.

Exposure to thrombus diminishes endothelial derived relaxation in the rabbit carotid artery.

PURPOSE: Thrombus is believed to be deleterious to intimal function. However, few studies have directly examined this effect. This study examines the effect of thrombus on endothelial-dependent and -independent vasorelaxation in the rabbit carotid artery. METHODS: Twelve male New Zealand white rabbits (3.5-4.5 kg) were divided into two groups of six. Thrombosis was induced in group I by segmental right carotid artery ligation. Group II underwent segmental right carotid ligation immediately followed by removal of thrombus with normal saline flush through an arteriotomy. The left carotid arteries were exposed in both groups and served as internal controls. After 4 h, left and right carotid arteries were harvested, sectioned into 6-mm rings, and mounted on isometric force transducers in a physiologic bath. Thrombus was removed from the arteries in group I during the ring preparation process. Neither group I nor group II had thrombus in contact with endothelium during ex vivo testing. The arterial rings were constricted with norepinephrine (1 x 10(-4) M). Endothelium-dependent and -independent vasorelaxation to acetylcholine (Ach) and s-nitrosoacetylpenicillamine, respectively, were measured in a dose-response manner. Results were expressed as a percentage of vasorelaxation. Statistical analysis was performed using an analysis of variance. RESULTS: Endothelial-dependent vasorelaxation, which tests for endothelial cell function, was decreased in the thrombus and endothelial ischemia group (I) compared to control as noted by vasorelaxations of 22% vs 34% at 1 x 10(-4) molar concentration Ach, and 33% vs 48% at 1 x 10(-3) molar concentration Ach, respectively (P = 0.05). By comparison, there was no difference in the endothelial-dependent vasorelaxation of the endothelial ischemia group (II) versus control. Endothelial-independent vasorelaxation, which tests for smooth muscle function, was not affected by either the thrombus and endothelial ischemia group (I) or the endothelial ischemia group (II) compared to the control group. The controls in group I and group II were slightly different. When this difference was removed, the resulting comparison of treatments in group I and group II approached significance at molar concentrations of 1 x 10(-4), 1 x 10(-5), and 1 x 10(-6) (P = 0.07, 0.06, 0.06). CONCLUSIONS: The presence of thrombus within the rabbit carotid artery for a period of 4 h decreases endothelial-dependent relaxation. Four hours of endothelial ischemia without thrombus did not change endothelial-dependent vasorelaxation. Neither thrombus nor ischemia alone had any effect on the endothelium-independent vasorelaxation. We conclude that thrombus is deleterious to endothelial function independent of smooth muscle function in the acute setting as measured by endothelial-dependent vasorelaxation.

Endovascular, transperitoneal, and retroperitoneal abdominal aortic aneurysm repair: results and costs.

PURPOSE: Contemporary treatment of abdominal aortic aneurysms (AAA) includes transabdominal (TA), retroperitoneal (RP), and endovascular (EV) repair. This study compares the cost and early (30-day) results of a consecutive series of AAA repair by means of these three methods in a single institution. METHODS: A total of 125 consecutive AAA repairs between February 1993 and August 1997 were reviewed. Risk factors, 30-day morbidity and mortality rates, and hospital stay and cost were analyzed according to method of repair (TA, RP, EV). Cost was normalized by means of a conversion factor to maintain confidentiality. Cost analysis includes conversion to TA repair (intent to treat) in the EV group. RESULTS: One hundred twenty-five AAA repairs were performed with the TA (n = 40), RP (n = 24), or EV (n = 61) approach. Risk factors among the groups (age, coronary artery disease, hypertension, diabetes, chronic obstructive pulmonary disease, and cigarette smoking) were not statistically different, and thus the groups were comparable. The average estimated blood loss was significantly lower for EV (300 mL) than for RP (700 mL) and TA (786 mL; P>.05). Statistically significant higher cost for TA and RP for pharmacy and clinical laboratories (likely related to increased length of stay [LOS]) and significantly higher cost for EV in supplies and radiology (significantly reducing cost savings in LOS) were revealed by means of an itemized cost analysis. Operating room cost was similar for EV, TA, and RP. There were six perigraft leaks (9.6%) and six conversions to TA (9.6%) in the EV group. CONCLUSION: There were no statistically significant differences in mortality rates among TA, RP, and EV. Respiratory failure was significantly more common after TA repair, compared with RP or EV, whereas wound complications were more common after RP. Overall cost was significantly higher for TA repair, with no significant difference in cost between EV and RP. EV repair significantly shortened hospital stay and intensive care unit (ICU) use and had a lower morbidity rate. Cost savings in LOS were significantly reduced in the EV group by the increased cost of supplies and radiology, accounting for a similar cost between EV and RP. Considering the increased resource use preoperatively and during follow-up for EV patients, the difference in cost between TA and EV may be insignificant. EV repair is unlikely to save money for the health care system; its use is likely to be driven by patient and physician preference, in view of a significant decrease in the morbidity rate and length of hospital stay.

Diet-induced changes in endothelial-dependent relaxation of the rat aorta.

PURPOSE: Hypertension (HTN), hyperlipidemia (HLP), and hyperinsulinemia are known risk factors for the development of cardiovascular disease. Each has independently been shown to be associated with impaired endothelial function, as demonstrated by decreased endothelial derived relaxation (EDR). Previous work in our laboratory has shown that rats fed a high-fat sucrose (HFS) diet will become insulin resistant, hypertriglyceridemic, and hypertensive. We hypothesize that the development of these diet-induced risk factors is associated with endothelial dysfunction and a significant decrease in EDR. Furthermore, the endothelial dysfunction will be improved by returning to a normal (low-fat complex carbohydrate (LFCC)) diet. METHODS: Adult, male Fischer rats were fed either a LFCC or a HFS diet for 6 months (n = 8 in each group). A third group of rats (SWITCH) was fed a HFS diet for 6 months and then changed to a LFCC diet for 4 weeks. Blood pressure was measured via the tail-cuff method weekly. The rats were sacrificed and aortic ring segments were placed in physiologic tissue baths for measurement of vascular reactivity to various agents. Arterial ring segments were constricted with potassium chloride (K) and phenylephrine (PE). Endothelial-dependent vasorelaxation was measured with acetylcholine (Ach), bradykinin (BK), and calcium ionophore (CA). Endothelial-independent relaxation was measured using sodium nitroprusside (NTP). RESULTS: The HFS diet group developed HTN compared to LFCC group. Vasoconstriction to K and PE were similar in all groups. Vasorelaxation to Ach, BK, and CA was significantly decreased in the HFS group, but returned to baseline in the diet-switched group, as did the systolic blood pressure. There were no differences in relaxation to NTP. CONCLUSIONS: HFS diet-induced HTN is associated with significantly decreased EDR. Switching to a low-fat diet reverses this effect. The vascular smooth muscle contraction and endothelial-independent relaxation are not affected by the diet-induced risk factors. There is a direct and reversible effect of an HFS diet on endothelial function and blood pressure.

Dexamethasone suppresses vascular smooth muscle cell proliferation.

BACKGROUND: Experimental studies in vivo have demonstrated that dexamethasone inhibits neointimal hyperplasia following arterial injury. The mechanisms of this inhibition have not been clearly defined. Our objective was to test the hypothesis that dexamethasone directly suppresses smooth muscle cell (SMC) proliferation by inhibiting cell cycle progression and the expression of key cell cycle-dependent genes. METHODS: Cultured rat aortic SMC were treated with incremental concentrations of dexamethasone and cell number was determined after 72 h. To determine if dexamethasone inhibited cell cycle progression, cells were synchronized, then restimulated to enter the cell cycle, and treated with or without dexamethasone. DNA synthesis was determined 24 h after restimulation by measuring [3H]thymidine incorporation. To define the point of action of dexamethasone in the cell cycle, synchronized SMC were treated with dexamethasone (10(-7) M) at various time points after entry into the cell cycle. Flow cytometry and Northern blots were performed to examine cell cycle progression and the expression of smooth muscle cell cycle-dependent genes c-fos, c-myc, and thymidine kinase (TK). RESULTS: Dexamethasone treatment induced a concentration-dependent inhibition of SMC proliferation and DNA synthesis. The cell cycle progression of synchronized SMC from G1 into S phase was inhibited by dexamethasone, even when added as late as 16 h after restimulation. The expression of TK was suppressed by dexamethasone, while c-fos and c-myc were not affected. CONCLUSIONS: Dexamethasone inhibits the proliferation of SMC in a concentration-dependent fashion. This inhibition is associated with a block in cell cycle progression late in G1 phase of the cell cycle. Consistent with this finding, dexamethasone does not alter the expression of the early cell cycle-dependent genes c-fos and c-myc, but significantly inhibits the expression of TK, a marker of late G1 phase.

Effect of cigarette smoke on endothelial regeneration in vivo and nitric oxide levels.

BACKGROUND: Cigarette smoking accelerates atherosclerosis and restenosis after vascular reconstruction. The mechanisms by which smoking alters vessel structure after injury are unclear. This study examined the effects of cigarette smoking on endothelial regeneration, an important component of arterial remodeling. MATERIALS AND METHODS: Adult male rats were subjected to balloon injury of the thoracic aorta and exposed to mainstream cigarette smoke via a Griffith-type smoking machine for 2 weeks. Control groups included rats which were restrained in the machine but not smoked and a group not utilizing the machine. Aortic reendothelialization was determined using Evan's blue staining of the arterial surface. Serum levels of nitric oxide were measured to determine if smoke exposure altered this potential endothelial cell mitogen. RESULTS: Cigarette smoking increased aortic endothelial regeneration (78.4 +/- 4.6% vs 59.2 +/- 2.1%, P < 0.05) and was associated with an increase in serum nitric oxide level (59.9 +/- 7. 1 microM vs 28.5 +/- 1.8 microM, P < 0.05). Daily restraint alone in the smoking machine had no effect on endothelial regeneration. CONCLUSIONS: This is the first report on the effects of smoking on endothelial regeneration and demonstrates that smoking increases reendothelialization after large vessel injury and serum levels of nitric oxide, an EC mitogen.

Prosthetic replacement of the inferior vena cava for malignancy.

PURPOSE: Invasion of the inferior vena cava (IVC) by tumor is generally considered a criterion of unresectability. This study was designed to review the outcomes of a strategy of aggressive resection of the vena cava to achieve complete tumor resection coupled with prosthetic graft placement to re-establish caval flow. METHODS: Retrospective review of patients treated at a university referral center. Ten patients (mean age 54; eight females, two males) underwent tumor resection that involved circumferential resection of the IVC and immediate prosthetic replacement with ringed polytetrafluoroethylene (PTFE) grafts ranging in diameter from 12 to 16 mm. RESULTS: Seven patients had replacement of the infrarenal IVC, two of their suprarenal IVC, and one had reconstruction of the IVC bifurcation. Four of the 10 patients received preoperative chemotherapy, and none received radiotherapy. The most common (7/10) pathologic diagnosis was leiomyosarcoma arising from the IVC or retroperitoneum. Additional diagnoses included teratoma (one), renal cell carcinoma (one), and adrenal lymphoma (one). There were no perioperative deaths, and one complication (prolonged ileus) occurred. Mean length of stay was 8.1 days. Anticoagulation was not routinely used intraoperatively or postoperatively. Follow-up (mean duration = 19 months) demonstrated that survival was 80% (8/10) and 88% (7/8) of patients were free of venous obstructive symptoms. CONCLUSION: Resection of the IVC with prosthetic reconstruction allows for complete tumor resection and provides durable relief from symptoms of venous obstruction.

Dexamethasone and enalapril suppress intimal hyperplasia individually but have no synergistic effect.

Vascular injury is associated with complex interactions that lead to development of intimal hyperplasia (IH). We have demonstrated previously that the corticosteroid dexamethasone and the ACE-inhibitor enalapril are effective in suppressing the development of IH. We hypothesize that due to distinctly different pharmacologic mechanisms of action, a synergistic effect would be expected if these agents were given in combination. Forty New Zealand White rabbits underwent balloon catheter denudation of the carotid artery. Animals were divided into four equal treatment groups and received daily intramuscular injections: Group 1, saline; Group 2, enalapril 0.07 mg/kg, Group 3, dexamethasone 0.125 mg/kg; and Group 4, enalapril 0.07 mg/kg plus dexamethasone 0.125 mg/kg. Vessels were harvested at 12 weeks and intimal hyperplasia was measured as a ratio of the absolute area of IH to the normalized area enclosed by the internal elastic lamina (IH/IEL). Mean values for IH/IEL are expressed as a percent (SD): Group 1, 32.31 (14.9); Group 2, 9.47 (2.11); Group 3, 5.40 (4.14); and Group 4, 8.49 (4.27). All treatment groups demonstrated significant suppression of IH compared to the control group (p < 0.01); dexamethasone was more effective than enalapril (p = 0.01). There was no statistical difference in IH suppression between respective agents and the combination group (p > 0.10). Coadministration of dexamethasone and enalapril provides no advantage over single-agent therapy in suppressing the development of IH, suggesting that maximal suppression is obtained with single-agent treatment or that these agents affect IH through a common pathway.

Rupture of the perivisceral aorta: atherosclerotic versus mycotic aneurysm.

Twelve patients with rupture of the perivisceral abdominal aorta were admitted to the UCLA Medical Center between 1984 and 1996. Six patients had atherosclerotic thoracoabdominal aneurysms (TAA) which ruptured in the visceral segment of the aorta. The remaining 6 patients proved to have ruptured mycotic aneurysm (MA). Clinical presentation was different in the two groups. Whereas all 6 patients with TAA and < 24 hr history of abdominal, chest, or back pain, patients with MA had these symptoms for 2-5 weeks (mean 3.4 weeks). History of sepsis was present in 4/6 MA and in 0/6 TAA patients. No difference in risk factors for atherosclerosis were seen between these two groups. Clinical outcomes were also different. Operation consisted of in situ vascular grafting in all patients. Operative mortality for TAA was 33% (2/6), whereas all patients with MA survived repair with no operative mortality. Two patients had cardiac arrest prior to surgery. One of these had a TAA and died 5 days after surgery, whereas the other survived repair of an MA. Follow-up ranges from 1-84 months (mean 48 months). Four survivors in the TAA group are alive at 6, 8, 14, and 84 months, with the latter having a pseudoaneurysm of the visceral patch-graft anastomosis. All 6 patients with MA are alive at 1-73 months (mean 39 months) without evidence of graft sepsis or recurrent aneurysm. We conclude that rupture of the visceral portion of the aorta is often associated with a mycotic process, with important differences noted in clinical presentation when compared to atherosclerotic TAA. Surgical intervention is effective in both MA and TAA. Operative mortality, however, is significantly higher in patients with ruptured TAA. In situ prosthetic replacement for ruptured MA is associated with low mortality and excellent long-term results.

Diagnosis and management of arterial compression at the thoracic outlet.

Neurovascular compression syndromes at the thoracic outlet generally present with predominantly arterial, venous, or neurogenic symptoms. The arterial abnormalities produce unique problems in diagnosis and management, and usually affect young, otherwise healthy, active individuals. Between 1984 and 1995 23 patients presented to our facility, with acute symptoms of arterial occlusion or embolization, found to be originating from the axillosubclavian arterial segment. The group comprised 14 females and nine males, ranging from 15 to 74 years, with an average age of 37 years. There were seven competitive athletes, three industrial workers, and 13 home, office, or service workers. The most severe presenting symptoms, occurring alone or in combination, and ranked in order of frequency observed, were: arm 'claudication' (74%), hand ischemia (48%), and digital gangrene (44%). Transaxillary thoracic outlet decompression was undertaken in 22 cases. This was combined with arterial reconstruction in 11 cases and sympathectomy for ischemic causalgia in seven cases. Transaxillary resection of a cervical rib was accomplished in 8 cases. There was one postoperative graft occlusion (PTFE), corrected by thrombectomy, with cumulative secondary patency (to 64 months), and one secondary embolic occlusion. Excepting the two secondary procedures, no patient had recurrent symptoms at a mean follow-up of 61 months. Effective and durable correction of the axillosubclavian arterial compressive abnormalities requires adequate thoracic outlet decompression, and anatomic vascular reconstruction when necessary. Failed prior procedures were a consequence of inaccurate diagnosis, failure to identify and correct the proximal embolizing arterial lesion, or inadequate decompression. Unilateral Raynaud's symptoms require meticulous investigation for arterial compression at the thoracic outlet with careful interpretation of subtle angiographic findings.

Use of the in-situ lesser saphenous vein bypass from popliteal to peroneal artery.

Lesser saphenous vein grafts have become an important element in limb salvage surgery. Their location frequently dictates that the graft be translocated for use. This incurs the disadvantages of ischemia and increased manipulation of the graft and loses the advantages of an in-situ bypass. The use of the lesser saphenous vein as an in-situ graft for tibial artery reconstruction offers the advantages of reduced vein graft injury and improved patency. Technical requirements for an in-situ lesser saphenous bypass include that graft inflow be based on the popliteal artery, the vein length suffice to reach the target artery, and the runoff vessel have adequate size, length, and collateral connections to allow reasonable likelihood of success. The surgical approach requires the patient be in a prone position allowing a posterior longitudinal incision in the leg. Exposure of the distal portion of the peroneal artery is accomplished by separating the peroneus brevis and flexor hallucis longus. The peroneal artery is then visualized when the fibular attachments of the flexor hallucis longus are divided. Our experience indicates that the lesser saphenous vein may be successfully used as an in-situ conduit for bypass to the distal peroneal artery. Technical innovations such as flexible valvulotomes with detachable heads, and tourniquet control of bleeding facilitate the operation. A posterior approach to the popliteal and crural arteries affords the ability to use the lesser saphenous vein as an in-situ bypass.