Predictors of health after operation for aortoiliac occlusive and aneurysmal disease.

BACKGROUND: We assessed the impact of comorbid conditions and revascularization for aortoiliac occlusive and aneurysmal disease and determined the functional health status of patients with the Medical Outcomes Study SF36 Health Survey. METHODS: One hundred twenty-five patients were surveyed prospectively, before operation, and at intervals ranging from 2 weeks to 2 years after operation. To identify the factors that influenced functional health, multiple regression analysis was performed to test the hypothesis that age, pulmonary disease, atherosclerotic heart disease, diabetes, aortoiliac occlusive disease (AOD) versus aneurysmal disease, and the preoperative physical summary score affected outcome. RESULTS: Regression analysis identified that before operation, the physical summary score (PCS) was affected by pulmonary disease, atherosclerotic heart disease, and AOD, and patients with AOD had significantly worse PCS than patients with aneurysmal disease (43.2 +/- 12.6 vs 30.1 +/- 8.3, P <.05). This difference was also present after 3 to 12 months, and the preoperative PCS was the strongest predictor of the postoperative score. For patients followed up between 1 and 2 years, there was no significant difference among the groups, and atherosclerotic heart disease and pulmonary disease were identified to most affect the PCS. CONCLUSIONS: Patients with AOD have significantly impaired physical function (as compared with patients with aneurysmal disease) that is successfully reversed with a surgical procedure. The functional health of patients after operation for aneurysmal disease returns to baseline after 3 and 12 months. Ultimately, cardiac and pulmonary comorbidities have a continued effect on the functional health of patients.

Heterotypic smooth muscle cell/endothelial cell interactions differ between species.

BACKGROUND: In vitro coculture models have been used to study heterotypic cell-cell interactions. This study was performed to determine if species of cell origin affects heterotypic smooth muscle cell (SMC) endothelial cell (EC) interactions in coculture. METHODS: To study the effect of ECs on SMC proliferation, ECs were cultured on porous Dacron membranes. SMCs were added opposite the ECs or on bare membranes on Day 3, and after 4 days, cells were harvested for cell counts. To study the effect of SMCs on EC proliferation, ECs at a density of 5 x 10(5) cells/membrane were added to bare membranes or on membranes opposite SMCs plated 2 days earlier. After 48 h, cells were harvested for cell counts. (N = 3/condition, experiments repeated x2.) Cells of human and bovine aortic origin were used. RESULTS: The effect of coculture on cell growth differed between species. The effect of heterotypic interactions between human cocultured cells was coinhibitory on the rate of growth as compared to the growth of cells cultured alone. Growth of cocultured ECs was 55.2 +/- 8.7% less than that of ECs cultured alone while growth of cocultured SMCs was 27.2 +/- 6.0% less than growth of SMCs cultured alone. This contrasted with the bovine EC stimulation of SMC proliferation, with 66.8 +/- 5.0% greater growth of cocultured SMCs compared to SMCs cultured alone, and failure of bovine SMCs to decrease EC proliferation. CONCLUSIONS: Since significant differences in cell-material interactions occur in vivo between species, the finding that in vitro heterotypic cell-cell interactions are species dependent is not surprising. This fundamental difference in cell behavior stresses the potential importance of using human cells in studies evaluating cell-cell and cell-material interactions in vitro.

Predictors of health after revascularization for extremity ischemia.

BACKGROUND: To assess the impact of surgical revascularization for lower extremity ischemia, we determined (with the use of the SF-36 health survey) the functional health status of patients who underwent either inflow or outflow procedures. METHODS: The SF-36 survey was given prospectively to 104 patients before operation and at intervals ranging from 10 days to 1 year after operation from January 1998 to July 1999. To determine whether revascularization was associated with improved patient health status, mean scores were compared before and after operation by univariate and multivariate analysis. To identify the factors that influenced patient health status, we performed multiple regression analysis to test the hypothesis that outcome is affected by age, gender, time since procedure, diabetes, indication, and inflow versus outflow procedure. RESULTS: There was a significant decrease in the general health score of patients before outflow bypass as compared with inflow procedure (45.3 +/- 5.3 versus 32.1 +/- 3.3 [mean +/- SEM]; P <.05). After the procedure, only those patients who had undergone inflow procedures had improved outcome scores. Diabetes, outflow procedures, limb salvage as indication, and time since operation were determined by multiple regression affecting outcome scores to be significant factors. CONCLUSIONS: The SF-36 health survey demonstrated that diabetes, procedure type, indication, and time after procedure significantly affected the functional outcome for patients who were treated surgically for lower extremity ischemia. Despite successful revascularization, significant deficits in functional health remain in patients with lower extremity ischemia.

Endovascular management of ureteroarterial fistula.

Ureteroarterial fistulas, although rare, appear to be increasing in frequency. Because open surgical repair may be difficult and associated with significant risk for complications, endovascular intervention may provide an attractive treatment alternative. We review the diagnosis and management of a ureteroarterial fistula and iliac pseudoaneurysm that presented with massive hematuria during ureteral stent removal. The patient was treated by means of the percutaneous embolization of the right hypogastric artery and placement of an expanded polytetrafluoroethylene stent-graft. Endovascular stent-graft placement may serve as a safe and practical alternative in the treatment of these patients, whose cases are challenging.

Flow modulates endothelial regulation of smooth muscle cell proliferation: a new model.

BACKGROUND: With a co-culture model, we have previously demonstrated that endothelial cells (ECs) exert regulatory control over smooth muscle cell (SMC) behavior. ECs appeared to stimulate SMC proliferation in static culture. This study was performed to test the hypothesis that the EC stimulation of SMC proliferation was effected by shear stress. METHODS: Bovine SMCs were cultured on a thin semipermeable membrane either alone or opposite ECs in co-culture (SMC/EC). A novel parallel-plate flow device was developed and used for exposing the EC side of the co-culture to shear stress. EC and SMC proliferation rates were determined after 24 hours' exposure to 0, 1, or 10 dynes/cm2 of shear stress. RESULTS: SMC proliferation decreased significantly from 362 +/- 65 cpm/microgram DNA (control, mean +/- SEM) to 68 +/- 43 cpm/microgram (1 dyne/cm2) and 99 +/- 18 cpm/microgram (10 dynes/cm2)(P < .05). EC proliferation after flow decreased as compared with no-flow controls 71 +/- 15 cpm/micrograms DNA (control, mean +/- SEM) to 29 +/- 5 cpm/microgram (1 dyne/cm2) and 21 +/- 4 cpm/microgram (10 dynes/cm2)(P < .05). CONCLUSIONS: In a model designed to study SMC/EC interactions in a flow environment, it was seen that EC exposure to shear stress alters the growth characteristics of SMCs. This suggests that hemodynamic mechanical forces may be sufficient to alter the EC regulation of SMC behavior.

Development of wall surface tangent DPIV measurement techniques for arterial branch models.

Experimental techniques for measuring unsteady flow in a glass arterial bifurcation model have been developed to aid in quantifying three-dimensional wall shear fluctuations associated with arterial disease. The unique feature of the current technique is the use of a "curved" laser sheet, which was everywhere tangent to the inner wall of a daughter tube in an arterial bifurcation model. Surface tangent velocity vector field measurements were made to demonstrate the potential of this technique. Ensemble-averaged data showing weak secondary flows as well as statistical distributions of flow angles are presented. Measurements of this type may be used to estimate mean and instantaneous wall shear magnitude and direction, data that are necessary for understanding the importance of circumferential motions on arterial disease.

Elastin degradation products induce adventitial angiogenesis in the Anidjar/Dobrin rat aneurysm model.

BACKGROUND: Infusion of the abdominal aorta with pancreatic elastase induces aneurysms in a rat model (Anidjar/Dobrin). Because elastolysis liberates elastin degradation products (EDPs), the present experiment was carried out to test the hypothesis that an EDP alone could induce features of aneurysm disease. METHODS: The EDP val/gly/val/ala/pro/gly (VGVAPG), elastase, or saline solution was infused into infrarenal aorta (n = 4/group). After 1 week aortic diameters were measured, and the tissues were prepared for histologic examination. Adventitial capillaries (vessels per high-power field) were counted over a standardized preparation of aorta. Wall thickness was measured by means of computer-aided planimetry. RESULTS: There was an increase of greater than 100-fold in mean vessels per high-power field in aortas receiving VGVAPG or elastase versus saline controls (4.10 +/- 0.68 SEM or 4.48 +/- 0.49 SEM versus 0.03 +/- 0.03 SEM, respectively, p < 0.05). The VGVAPG-perfused group had a 26% +/- 4% SEM increase in diameter from baseline that was statistically significant (p < 0.01), but the aortas did not reach aneurysmal dimensions. CONCLUSIONS: Although no aneurysms occurred at 1 week after the infusion of EDP, the results demonstrate that the EDP VGVAPG can induce a characteristic feature of aneurysm disease. The model permits study of the earliest stages of experimental aneurysm formation and raises interesting questions regarding the role of the vasa vasorum in this pathologic process.

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.

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.

The elastase infusion model of experimental aortic aneurysms: synchrony of induction of endogenous proteinases with matrix destruction and inflammatory cell response.

PURPOSE: Perfusion of the isolated aorta of the rat with a saline solution containing pancreatic elastase induces an abdominal aortic aneurysm (AAA). An interesting feature of this model is the phenomenon of latency, suggesting that additional steps beyond the initial injury are required for AAA formation. This study was performed to determine whether the latency period for aortic dilation to aneurysmal proportions is correlated with the appearance of proteinases of endogenous origin and the interval for infiltration of inflammatory cells. METHODS: Twenty Wistar rat aortas were perfused with the test solution, and 20 with normal saline solution. Laparotomy was performed on days 1, 2, 3, and 6 for measurement and harvest of the aorta. Histochemical studies were performed to analyze changes in matrix proteins, and substrate gel enzymography was used to determine the appearance of endogenous proteinases. Immunohistochemical studies were performed with monoclonal antibodies to T cells (CD-4, -5, and -8), monocytes/macrophages (ED-2), B cells (LC-A), immunoglobulin G, and immunoglobulin M. RESULTS: The exogenously administered elastase was not detectable beyond day 2, but the aortic diameter did not progress to aneurysmal dimensions until the interval between days 3 and 6. During the period from day 3 to day 6, multiple endogenous matrix proteinases became detectable in the aortic tissue preparations. Immunohistochemical study revealed progressive infiltration of the aorta with various subsets of inflammatory cells. CONCLUSION: The results suggest that the latency in AAA formation in this model corresponds with a complex sequence of biochemical and cellular events. The model provides an "early window" into these interesting early phases leading to aneurysm formation.

Analysis of elastin cross-linking and the connective tissue matrix of abdominal aortic aneurysms.

BACKGROUND: Studies of the connective tissue matrix of abdominal aortic aneurysms (AAAs) have yielded conflicting results, and the glycosaminoglycan content has not been previously reported. The present work was done to evaluate the matrix components of AAAs, including the cross-link content of the residual elastin. METHODS: Aortic specimens from AAAs and controls were sequentially extracted with salt, Brij, and urea; and the residual pellets were the subject of further studies. Elastin was purified by hot alkali treatment; other matrix components were determined by conventional methods. RESULTS: Elastin content of the purified material was reduced in AAA. The cross-link content, desmosine+isodesmosine, was also reduced in AAA as a ratio to insoluble matrix dry weight. However, the cross-link content as a ratio to valine in the purified elastin was normal. The amino acid profiles of representative AAA and controls elastin preparations were similar to that of reference elastin. The amino acid content of the insoluble matrix of AAA revealed a significant reduction of protein (controls = 820 +/- 40 micrograms/mg versus AAA = 700 +/- 20 micrograms/mg, p < 0.05); the collagen content was unaltered. The content of glycosaminoglycan in AAA was noted to be significantly reduced (controls = 33.5 +/- 3.4 micrograms/mg versus AAA = 17.1 +/- 2.0 micrograms/mg, p < 0.05). CONCLUSIONS: The data do not support the hypothesis of a primary cross-link deficiency in elastin of AAA; but the reduced contents of protein and glycosaminoglycans in AAA suggests basic biochemical alterations in the diseased aorta that warrant further investigation.

Analysis of the connective tissue matrix and proteolytic activity of primary varicose veins.

PURPOSE: Valvular incompetence and venous wall abnormalities have been suggested as primary etiologic factors responsible for the development of varicose veins. This study was conducted to evaluate the connective tissue constituents of greater saphenous varicosities. Proteolytic activity, a factor that can lead to matrix degradation and cause weakening and dilation of the venous wall, was also assessed. METHODS: The collagen and elastin contents of 16 nonthrombophlebitic greater saphenous varicose veins (VV) and seven normal greater saphenous veins (NV) were quantified. In addition, four duplex scanning-confirmed competent segments of greater saphenous veins (i.e., potential varicose veins [PV]) affected by varicosis at alternate sites were analyzed. Proteolytic activity was determined by zymography and radiolabeled substrate assay. RESULTS: The content of collagen was significantly increased in the VV and PV compared with NV (VV = 189 +/- 7 mg/gm, PV = 189 +/- 9 mg/gm vs NV = 144 +/- 10 mg/gm, p < 0.05). Conversely, the elastin content in the VV and PV was significantly reduced (VV = 53 +/- 3 mg/gm, PV = 50 +/- 4 mg/gm vs NV = 74 +/- 4 mg/gm, p < 0.05). The collagen to elastin ratio demonstrated an alteration in VV and PV compared with NV (VV = 3.7 +/- 0.3, PV = 3.9 +/- 0.4 vs NV = 2.0 +/- 0.2, p < 0.05). Casein and gelatin zymography did not demonstrate significant qualitative differences in the enzymatic activities among the three groups. Quantitative analysis of the elastase activity in the venous tissues was similarly not appreciably altered (VV = 5.1 +/- 0.2 U/gm, PV = 5.3 +/- 0.2 U/gm vs NV = 5.7 +/- 0.3 U/gm). CONCLUSION: A significant increase in the collagen content and a significant reduction in the elastin content of VV were demonstrated. The net increase in the collagen/elastin ratio is indicative of an imbalance in the connective tissue matrix. The biochemical profile of PV was similar to VV and significantly different from NV. These preliminary data support the presence of connective tissue abnormalities before valvular insufficiency. In addition, the absence of an increase in the proteolytic activity excludes enzymatic matrix degradation as an essential component in the formation of venous varicosities.

Demonstration of interstitial collagenase in abdominal aortic aneurysm disease.

This study was performed to evaluate the presence of interstitial collagenase, now known as matrix metalloproteinase-1 (MMP-1), in specimens of abdominal aortic aneurysms (AAA). Eight AAA and four control infrarenal aortas were evaluated. After homogenization and extraction of soluble proteins, immunoblots of the extracts equalized for protein content were performed with a specific antibody to MMP-1. Under native conditions, immunoreactive material was distributed between M(r) 27 kDa to > 106 kDa. When the extracts were reduced and denatured, immunoreactive bands were detected in AAA at the expected M(r)'s of the secreted isoforms (57 and 52 kDa), whereas control aortic extracts had low levels of detectable immunoreactive material. Only extracts from AAA demonstrated significant immunoreactivity to the lower M(r) isoforms (22, 25, and 27 kDa), which correspond to reported cleavage products of MMP-1. Preliminary immunofluorescent studies of AAA localized MMP-1 to cells present in the adventitia of AAA. These findings will help to resolve disagreement in the recent literature regarding the presence of collagenolytic activity in AAA disease.