Levels of expression of Fcgamma receptor IIA (CD32) are decreased on peripheral blood monocytes in patients with severe atherosclerosis.

To obtain information in vivo concerning the role of Fcgamma receptors (FcgammaR) in atherosclerosis, we used quantitative flow cytometry to measure the levels of expression of FcgammaRI and FcgammaRIIA on peripheral monocytes in patients with severe atherosclerosis. Expression of several other markers was also measured. We found that differences in the levels of expression of FcgammaRI were not statistically significant when compared between patients and control subjects. For FcgammaRIIA, levels of expression were decreased in the patient group, a difference that was statistically significant. Levels of expression of CD14 and CD36 were also significantly decreased in the patient group. The decrease in expression of FcgammaRIIA was statistically significant when the effects of current cigarette smoking status or medication use, including statins, were taken into account. There was also a positive and statistically significant correlation between high-density lipoprotein-cholesterol and levels of expression of FcgammaRIIA for all subjects. In contrast, decreased levels of expression of CD14 and CD36 were strongly associated with current smoking status or statin use. In summary, levels of expression of FcgammaRIIA on peripheral blood monocytes were significantly decreased in patients with clinical atherosclerosis. Additional studies are warranted to determine if levels of expression of FcgammaRIIA have utility as a phenotypic marker for assessing relative risk of atherosclerotic disease.

The iron (Fe) and atherosclerosis study (FeAST): a pilot study of reduction of body iron stores in atherosclerotic peripheral vascular disease.

BACKGROUND: Levels of body iron stores, represented by the serum ferritin concentration, rise with age after adolescence in men and menopause in women. This rise has been implicated mechanistically and epidemiologically in the pathogenesis of atherosclerosis through iron-induced oxygen free radical-mediated lipid oxidation. However, the precise contribution of iron stores to atherosclerosis and its complications are unknown because prospective randomized trials designed to test effects of reduction of iron stores on clinical outcomes in this disease have not been performed. METHODS AND RESULTS: In preparation for a prospective randomized trial, a randomized pilot study was conducted to evaluate the feasibility, safety, and methodologic accuracy of calibrated reduction in iron stores by phlebotomy in a cohort of patients with advanced peripheral vascular disease. Phlebotomy resulted in a significant reduction in serum ferritin concentration to near targeted levels. Thus the formula for calculating the volume of blood to be removed to achieve a predetermined decrement in serum ferritin concentration was accurate and phlebotomy was not associated with any adverse laboratory or clinical effects. CONCLUSIONS: Reduction of body iron stores to a predetermined level is feasible and can be achieved in a timely manner with excellent patient compliance. Prospective randomized trials of calibrated reduction of body iron stores may be undertaken to define their pathophysiologic significance in atherosclerosis and other diseases in which excessive iron-induced oxidative stress has been implicated.

Thrombolysis of occluded infrainguinal vein grafts: predictors of outcome.

PURPOSE: The purpose of this study was to identify factors that influence graft patency and limb salvage rates after thrombolysis of occluded infrainguinal vein grafts. METHODS: The records of patients who underwent percutaneous catheter-directed thrombolysis of occluded infrainguinal vein bypass grafts at our institution between 1985 and 1995 were reviewed. Life table analysis was used to determine survival and patency differences. Univariate and multivariate analyses were used to identify the patient-specific factors that affected outcomes. RESULTS: Forty-four patients with 44 thrombosed infrainguinal vein grafts underwent thrombolysis with urokinase. The thrombolysis-related mortality rate was 2%, and nonfatal complications occurred in 16%. Thrombolysis was unable to restore graft patency in 25% of grafts (11 of 44). Of the remaining 33 successfully lysed grafts, 88% required adjunctive surgery or percutaneous transluminal angioplasty after thrombolysis. Overall, the primary graft patency rate was 25% at 1 year and 19% at 2 years after thrombolysis. Considering only successfully lysed grafts, the primary patency rate improved to 34% at 1 year and 25% at 2 years. Multivariate analysis revealed that the graft patency rate was substantially better in patients without diabetes and in vein grafts that had been in place for longer than 12 months (p < 0.01). The limb salvage rate was significantly improved by successful thrombolysis (63% at 2 years vs 31% if lysis failed; p < 0.01). The patient survival rate was high-89% 2 years after thrombolysis. CONCLUSIONS: Even with adjunctive therapy, vein graft thrombolysis is unlikely to yield durable patency overall. However, successful thrombolysis improves limb salvage rates and may be beneficial in patients without diabetes who have mature vein grafts but who do not have options for other autogenous revascularization procedures.

Cost-effectiveness of carotid endarterectomy in asymptomatic patients.

PURPOSE: The purpose of this study was to determine the cost-effectiveness of carotid endarterectomy for treating asymptomatic patients with > or = 60% internal carotid stenosis, based on outcomes reported in the Asymptomatic Carotid Atherosclerosis Study (ACAS). METHODS: A cost-effectiveness analysis was performed using a Markov decision model in which the probabilities for base-case analysis (average age, 67 years; 66% male; perioperative stroke plus death rate, 2.3%; ipsilateral stroke rate during medical management, 2.3% per year) were based on ACAS. The model assumed that patients who had TIAs or minor strokes during medical management crossed over to surgical treatment, and used the NASCET data to model the outcome of these now-symptomatic patients. Average cost of surgery ($8500), major stroke ($34,000 plus $18,000 per year), and other costs were based on local cost determinations plus a review of the published literature. Cost-effectiveness was calculated as the incremental cost of surgery per quality-adjusted life year (QALY) saved when compared with medical treatment, discounting at 5% per year. Sensitivity analysis was performed to determine the impact of key variables on cost-effectiveness. RESULTS: In the base-case analysis, surgical treatment improved quality-adjusted life expectancy from 7.87 to 8.12 QALYs, at an incremental lifetime cost of $2041. This yielded an incremental cost-effectiveness ratio of $8,000 per QALY saved by surgical compared with medical treatment. The high cost of care after major stroke during medical management largely offset the initial cost of endarterectomy in the surgical group. Furthermore, 26% of medically managed patients eventually underwent endarterectomy because of symptom development, which also decreased the cost differential. Sensitivity analysis demonstrated that the relative cost of surgical treatment increased substantially with increasing age, increasing perioperative stroke rate, and decreasing stroke rate during medical management. CONCLUSION: For the typical asymptomatic patient in ACAS with > or = 60% carotid stenosis, our results indicate that carotid endarterectomy is cost-effective when compared with other commonly accepted health care practices. Surgery does not appear cost-effective in very elderly patients, in settings where the operative stroke risk is high, or in patients with very low stroke risk without surgery.

Longitudinal comparison of dialysis access methods: risk factors for failure.

PURPOSE: To compare dialysis access patency rates and identify risk factors for failure. METHODS: All access procedures at our institution from 1987 to 1996 were reviewed. Primary procedures were surgically implanted dual-lumen central venous hemodialysis catheters (SIHCs), peritoneal dialysis catheters (PDCs), arteriovenous fistulas (AVFs), and prosthetic shunts (PTFEs). RESULTS: Five hundred eighty-five primary procedures (236 PTFEs, 87 AVFs, 112 SIHCs, and 150 PDCs) and 259 secondary procedures (215 PTFEs, 14 AVFs, 0 SIHCs, and 30 PDCs) were performed on 350 patients. By life table analysis, SIHCs exhibited the lowest primary patency rate (9% at 1 year; p < 0.0001), whereas PDCs had the highest primary patency rate (57% at 1 year; p < 0.02). The primary patency rates of AVFs and PTFEs was similar, with 43% and 41% 1-year patency rates, respectively (p = 0.70). Less-stringent reporting methods would have increased apparent 1-year patency rates by 9% to 41%. With regard to secondary patency, there was no significant difference between PTFEs and PDCs, with 1-year patency rates of 59% and 70%, respectively (p = 0.62), but PTFEs were more frequently revised. In addition, there was no significant difference between AVF and PTFE secondary patency rates, with 1-year patency rates of 46% and 59%, respectively. Early differences in patency rates for AVFs, PTFEs, and PDCs diminished over time, and at 4 years AVFs had the best secondary patency rate (p = 0.6). The most common reasons for access failure were: PTFEs, thrombosis; AVFs, thrombosis and failure to mature; SIHCs, inadequate dialysis; PDCs, infection and inadequate exchange. By regression analysis, a history of a previous unsalvageable PTFE was the only significant risk factor for failure of a subsequent PTFE (p < 0.01), and the risk of graft failure increased exponentially with the number of previous PTFE shunts. Diabetes was the only significant risk factor for failure of PDCs (p < 0.02; odds ratio, 2.0). CONCLUSIONS: The patency rate for PTFEs is similar to that for AVFs, but AVFs require fewer revisions. When replacing a failed access graft, the risk of PTFE failure increases with the number of prior unsalvageable PTFE shunts. PDCs have excellent patency rates, but failure rates are doubled in patients with diabetes. Because of poor patency rates and inadequate dialysis flow rates, SIHCs should be avoided when possible. Reporting methods dramatically affect apparent patency rates, and reporting standards are needed to allow meaningful comparisons in the dialysis access literature.

Carotid duplex criteria for a 60% or greater angiographic stenosis: variation according to equipment.

PURPOSE: The purpose of this study was to evaluate the carotid duplex criteria for a > or = 60% angiographic internal carotid artery (ICA) stenosis and the degree of variation among duplex scanners. METHODS: Carotid duplex criteria for a > or = 60% angiographic stenosis were evaluated in two ICAVL-accredited vascular laboratories with different brands of duplex scanners (Siemens-Quantum and Diasonics in Laboratory A, ATL and Diasonics in Laboratory B). Analysis was performed for 360 carotid bifurcations in 180 consecutive patients who had concurrent angiographic and duplex evaluation. Blinded angiogram evaluation was performed with precision electronic calipers on magnified views, with stenosis calculated by criteria of the Asymptomatic Carotid Atherosclerosis Study and the North American Symptomatic Carotid Endarterectomy Trial. Duplex data included internal carotid artery peak systolic velocity (ICA PSV), ICA end-diastolic velocity, and the ratio of ICA PSV to common carotid artery (CCA) PSV (ICA/CCA ratio). RESULTS: The most accurate determination of a > or = 60% ICA stenosis was obtained with ICA/CCA ratio and ICA PSV, but the optimal threshold differed for all four scanners. The optimal ICA/CCA ratio varied from 2.6 to 3.3, and the optimal ICA PSV varied from 190 to 240 cm/sec. All four scanners produced criteria that give a positive predictive value > 90% while maintaining accuracy at > or = 90%. Logarithmic transformation of duplex variables created a linear relationship between duplex values and angiographic stenosis, allowing statistical evaluation of scanner operating characteristics by linear regression analysis and analysis of covariance. This analysis revealed that the mathematic equation relating duplex values with angiographic percent stenosis was statistically different for one of the four scanners (p < 0.05). Scanner differences did not appear to be due to technologists, because the regression lines were nearly identical for the two Diasonics scanners despite use by different technologists. Ignoring the significant difference in operating characteristics for one of the four scanners would result in a mean error for predicting a 60% stenosis of 14% to 18% (equating a 46% or 78% stenosis with a 60% stenosis). CONCLUSIONS: We conclude that the correlation of duplex data with angiographic percent stenosis and the duplex criteria for a > or = 60% stenosis are machine-specific. Regression analysis can determine whether apparent differences are due to chance or significant differences in scanner characteristics. Future studies should include regression analysis according to equipment type.

Endothelial cells modulate smooth muscle cell morphology by inhibition of transforming growth factor-beta 1 activation.

BACKGROUND: We have previously demonstrated in a coculture model that endothelial cells (ECs) exert regulatory control over smooth muscle cell (SMC) morphology. This study was performed to test the hypothesis that ECs inhibit transforming growth factor-beta 2 (TGF-beta 1) activation through the release of plasminogen activator inhibitor (PAI-1). METHODS: Bovine SMCs were cultured on a thin, semipermeable membrane, either alone or opposite ECs in coculture (SMC/EC). Conditioned media and cell lysates at 1, 5, and 21 days were assayed for TGF-beta 1 and PAI-1 by enzyme-linked immunoabsorbent assay. Cell proliferation rates, protein, and DNA content were measured and compared with SMC morphology. RESULTS: Activation of TGF-beta 1 was significantly decreased (1.2% versus 18.9% active TGF-beta 1 p < 0.05) and PAI-1 was increased (659 pg/ml versus 343 pg/ml p < 0.05) in SMC/EC medium on day 1, compared with the medium of SMC alone. Significantly higher levels of PAI-1 were measured in cell lysates of cocultured ECs (128 pg/micrograms DNA) than in cocultured SMCs (5.8 pg/micrograms DNA, p < 0.05). SMC/EC coculture prevented the SMC hill-and-valley growth morphology seen in SMCs cultured alone. CONCLUSIONS: In a model designed to study SMC/EC interactions, it was seen that ECs can alter growth characteristics of SMCs by producing PAI-1, which interferes with the plasminogen pathway of TGF-beta 1 activation. This suggests that reduced EC PAI-1 production could play a role in alteration of SMC phenotype in vivo.

Median arcuate ligament compression syndrome in monozygotic twins.

Twin 27-year-old women had symptomatic mesenteric ischemia caused by median arcuate ligament compression. Arteriography demonstrated severe celiac artery stenosis in one twin, celiac artery occlusion in the other, and proximal superior mesenteric artery narrowing with retrograde filling from a meandering mesenteric artery in both. Division of the ligament and direct celiac artery revascularization completely relieved symptoms in both patients. Median arcuate ligament compression of the celiac and superior mesenteric arteries can result in mesenteric ischemia. Documentation of this unusual syndrome in monozygotic twins suggests that the responsible anatomic relationships are congenital.

The effect of ibuprofen on cardiac performance during abdominal aortic cross-clamping.

Decreased cardiac output and increased plasma thromboxane have been observed during aortic cross-clamping under general anesthesia. Amelioration of these changes has been reported by preoperative administration of cyclooxygenase inhibitors, but heterogeneity in patients' intravascular volume status has confounded analysis of the drugs' effects in previous studies. We studied hemodynamic conditions in 24 volume-loaded (pulmonary capillary wedge pressure greater than 10 mm Hg) patients undergoing abdominal aortic aneurysm repair under general plus epidural anesthesia, after preoperative double-blind administration of either ibuprofen 800 mg (n = 12) or placebo (n = 12). The hemodynamic response to aortic cross-clamping was similar in both groups. Pulse and mean arterial pressure remained unchanged; cardiac index decreased after aortic cross-clamping from 2.4 +/- 0.1 (mean +/- standard error of the mean [SEM]) to 2.1 +/- 0.1 1/min/m2 in the ibuprofen group and from 2.5 +/- 0.1 to 2.3 +/- 0.2 1/min/m2 in the placebo group (p less than 0.01 versus preclamp values in both groups, multivariate analysis of variance [MANOVA]), but improved after declamping. Both left and right ventricular stroke work indexes followed a similar pattern. Plasma 6-keto prostaglandin Fl alpha (6-k-PGF1 alpha) increased transiently from a baseline level of 304 +/- 44 to 2083 +/- 698 pg/ml plasma in mixed venous blood 30 minutes after incision in the placebo group (p less than 0.05), but no other significant change in plasma 6-keto prostaglandin Fl alpha or in thromboxane B2 occurred in either group at any other time.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of thromboxane receptor blockade versus thromboxane synthase inhibition on canine arterial graft patency.

This study compared the effects of a thromboxane synthase inhibitor, thromboxane receptor antagonist, and cyclooxygenase inhibitor in a canine arterial graft patency model. Fifty-six dogs were divided into a control (no treatment) and five treatment groups: thromboxane synthase inhibitor (U63557A; 15 mg/kg/tid); thromboxane receptor antagonist (SQ29548; 0.02 mg/kg/hr); high-dose aspirin (325 mg/day; low-dose aspirin (1 mg/kd/day; and aspirin plus dipyridamole (325 mg/day aspirin; 3 mg/kg/day dipyridamole). Drugs were orally administered except for thromboxane receptor antagonist, which was delivered intravenously by minosmotic pumps. After 24 hours of drug treatment, bilateral femoral artery prosthetic grafts (4 mm diameter x 7 cm; 1 polytetrafluoroethylene and 1 Dacron) were implanted. Patency was determined after 1 week. Dogs were classified before operation according to their epinephrine-enhanced arachidonate-stimulated platelet aggregation response. Polytetrafluoroethylene and Dacron graft patency rates were equivalent in all groups. Overall graft patency was significantly improved from 42% (control) to 94% by both high-dose aspirin and thromboxane receptor antagonist (p less than 0.001). Aspirin-dipyridamole also improved patency (83%; p less than 0.01 versus control), whereas thromboxane synthase inhibitor and low-dose aspirin were not effective. Baseline platelet aggregation was not predictive of patency. The drugs that promoted graft patency in this model either suppressed both thromboxane A2 and prostaglandin H2 formation (high-dose aspirin) or blocked their combined platelet receptor (thromboxane receptor antagonist). Thromboxane synthase inhibitor may be ineffective because prostaglandin H2 production is allowed. These data suggest that activation of the platelet thromboxane A2-prostaglandin H2 receptor is an essential event in early arterial graft thrombosis.

Increased platelet deposition on polytetrafluoroethylene grafts after balloon catheter thrombectomy.

Prosthetic graft rethrombosis after thrombectomy may be potentiated by increased thrombogenicity of the restored flow surface. This experiment compared platelet deposition on polytetrafluoroethylene (PTFE) grafts after balloon catheter thrombectomy with deposition on new, nonthrombosed grafts. Three models of graft thrombosis were studied in eight dogs with 4 mm diameter by 7 cm PTFE graft segments: (1) in vitro model: grafts filled with blood, stored in 37 degrees C saline solution; (2) in vivo model: blood-filled grafts stored in subcutaneous tissue; and (3) in situ model: one end of grafts anastomosed to femoral or carotid artery as a blind tube. Duration of thrombosis (1, 2, and 3 weeks) was studied by initiating one graft of each type per week in each dog. After 3 weeks, nine thrombosed grafts per dog were harvested and graft thrombectomy was performed with a 3F balloon catheter. An ex vivo flow-controlled perfusion circuit was then created in each dog and platelet deposition was measured during the initial 20 minutes of graft perfusion after 111In platelet labeling. Thrombectomized grafts were compared with new, control grafts not previously exposed to blood, as well as with grafts exposed for 1 hour to blood or plasma. Compared with control grafts, platelet deposition was significantly increased on in vivo (3.7 times control; p less than 0.01), in situ (2.6 times control; p less than 0.05), and in vitro thrombosed grafts (2.0 times control; p less than 0.05). Age of thrombus was not a significant source of variation. Blood or plasma exposure alone did not significantly increase platelet deposition. These data suggest that antiplatelet therapy may be important at the time of PTFE graft thrombectomy.

The effect of glucose infusion on survival after acute mesenteric ischemia/reperfusion.

Perfusion of ischemic tissue with glucose has been shown to be deleterious to heart, spinal cord, and kidney. Observations that glucagon improves survival after acute mesenteric ischemia, however, suggest that hyperglycemia may not be deleterious during bowel ischemia. This experiment examined the effect of glucose infusion on survival in an established rat model of acute mesenteric ischemia. The superior (cranial) mesenteric artery (SMA) was occluded for 85 min in 36 anesthetized Sprague-Dawley rats. Animals were randomized to receive 5% glucose in normal saline (n = 15; 16.5 mL/kg.min iv), normal saline alone (n = 13; 16.4 mL/kg.min iv), or no intravenous fluid (n = 8). Ninety-minute intravenous infusions were initiated 10 min after SMA occlusion. Survival to 48 h was 47% in glucose-saline-treated rats, 31% in saline-only-treated rats, and 12.5% in control rats. These results demonstrate no deleterious effect of glucose infusion on mortality after acute mesenteric ischemia in this model.

Mechanism of postsegregational killing by the hok gene product of the parB system of plasmid R1 and its homology with the relF gene product of the E. coli relB operon.

The parB region of plasmid R1 encodes two genes, hok and sok, which are required for the plasmid-stabilizing activity exerted by parB. The hok gene encodes a potent cell-killing factor, and it is regulated by the sok gene product such that cells losing a parB-carrying plasmid during cell division are rapidly killed. Coinciding with death of the host cell, a characteristic change in morphology is observed. Here we show that the killing factor encoded by the hok gene is a membrane-associated polypeptide of 52 amino acids. A gene located in the Escherichia coli relB operon, designated relF, is shown to be homologous to the hok gene. The relF gene codes for a polypeptide of 51 amino acids, which is 40% homologous to the hok gene product. Induced overexpression of the hok and relF gene products results in the same phenomena: loss of cell membrane potential, arrest of respiration, death of the host cell and change in cell morphology. The parB region and the relB genes were cloned into unstably inherited oriC minichromosomes. Whereas the parB region also conferred a high degree of genetic stability to an oriC minichromosome, the relB operon (with relF) did not; therefore the latter does not appear to 'stabilize' its replicon (the chromosome). The function of the relF gene is not known.

Sequence of the relB transcription unit from Escherichia coli and identification of the relB gene.

Escherichia coli relB mutants react to amino acid starvation by several abnormal responses, including accumulation of a translational inhibitor. We have isolated a relB-complementing plasmid from the Clarke and Carbon E. coli DNA library. From this plasmid we sequenced a 2140-bp segment which included the relB gene by the following two criteria: (i) it complements chromosomal relB mutations, (ii) the corresponding DNA segment cloned from chromosomal DNA of three relB mutants was defective in relB complementation. All three mutations fell within an open reading frame of 79 amino acids. A polypeptide of 9 kd compatible with this open reading frame was synthesized in maxicells and is in all probability the product of the relB gene. By nuclease S1 mapping we have determined the transcription start and stop of an 870 base transcript of the relB gene.