Renal insufficiency and altered postoperative risk in carotid endarterectomy.

PURPOSE: Higher complication rates have been reported in patients with renal insufficiency (RI) undergoing peripheral vascular surgery. Little attention has been paid specifically to carotid endarterectomy (CEA) in patients with RI where the risk/benefit considerations are very sensitive to small increases in postoperative complications. METHODS: One thousand one consecutive CEAs performed since 1990 were reviewed from our vascular registry, and 73 CEAs on patients with RI were identified. For comparison, two groups were established: group I (n = 928), normal renal function (creatinine level, <1.5 mg/dL); and group II (n = 73), RI (creatinine level, >/=1.5 mg/dL). RESULTS: Differences in the nonfatal stroke rates and combined stroke and death rates were statistically significant (P <.02) between the groups: group I (1. 08% and 1.18%) and group II (5.56% and 6.94%) respectively. Both groups were similar in regard to operative indications. In addition with the comparison of group I to group II, there was a statistically significant increase in hematoma rate, 1.61% versus 12. 5% ( P <.001), total cardiac morbidity, 1.72% versus 6.94% (P =.003), and total complications, 6.24% versus 36.1% (P =.001). Multivariate analysis demonstrated pre-existing RI to be the only significant predictor for perioperative stroke and hematoma. CONCLUSION: Patients with preoperative RI are at a higher, but not prohibitive, risk for stroke and death after CEA than patients with normal renal function. They are also at risk for hematoma formation, cardiac morbidity, and overall complications. Care in selection of these patients for CEA must be emphasized.

Perioperative strokes after 1001 consecutive carotid endarterectomy procedures without an electroencephalogram: incidence, mechanism, and recovery.

HYPOTHESIS: That alternative methods of cerebral protection, especially routine shunting of all patients undergoing general anesthesia or shunting on the basis of neurologic assessment with the patient awake under cervical plexus block, result in outcomes of carotid endarterectomy comparable with those reported using electroencephalographic monitoring. DESIGN: Retrospective review of cases from a vascular registry established in 1990. SETTING: Tertiary care center. PATIENTS: Consecutive sample of 1001 patients who underwent carotid endarterectomy. INTERVENTIONS: Carotid endarterectomy procedures were performed without electroencephalographic monitoring, using general anesthesia with routine shunting or using regional anesthesia. MAIN OUTCOME MEASURES: Overall stroke and mortality rates and cause and consequence of the postoperative strokes. RESULTS: There were 14 nonfatal strokes (1.4%) and 2 deaths (0.2%), for a combined stroke and death rate of 1.6%. Nine (64%) of the 14 strokes appeared to result from a technical error during the endarterectomy. Mild deficits were noted after 7 strokes (50%), with the remainder resulting in deficits that required inpatient rehabilitation. Twelve patients with strokes (86%) eventually returned home without need for assistance. CONCLUSIONS: Most postoperative strokes in this series were due to technical errors. Overall, even in patients with strokes initially requiring inpatient rehabilitation, there was good recovery of function. Low stroke and mortality rates can be achieved in carotid endarterectomy without the use of electroencephalographic monitoring.

Interferon gamma up-regulates a novel protein in vascular smooth muscle cells.

PURPOSE: By means of the technique of messenger RNA (mRNA) differential display, we previously isolated a partial DNA clone found to be down-regulated at the polytetrafluoroethylene (PTFE) hyperplastic arterial anastomosis compared with the normal artery. The partial DNA gene sequence was found to be homologous with interferon gamma up-regulated protein (IGUP) first found in human psoriatic keratinocytes. We cloned the entire IGUP gene from human vascular smooth muscle cells (VSMCs) to determine its regulation by gamma interferon (gamma-IFN) and other cytokines in cultured human VSMCs. METHODS: By means of polymerase chain reaction, the IGUP gene was amplified from a QUICK-Clone complementary DNA human aorta kit using 5' and 3' oligonucleotide primers to the known IGUP sequence. Immunohistocytochemistry studies compared normal artery and distal anastomotic IH. Human VSMCs were stimulated with 1000 U/mL of gamma-IFN, 5 ng/mL of platelet-derived growth factor BB (PDGF-BB), 3. 2 ng/mL basic fibroblast growth factor, 3.3 ng/mL transforming growth factor beta(TGF-beta), 10 ng/mL of vascular endothelial growth factor, and 10% fetal bovine serum (FBS) for zero, 24, 48 and 72 hours. Western blot analysis of lysates of the stimulated VSMCs was performed to determine up-regulation of IGUP. RESULTS: DNA sequencing confirmed the cloning of the entire coding region of the IGUP gene with 100% homology to the known IGUP DNA sequence. There was strong expression of IGUP in quiescent VSMCs and marked reduction of expression of IGUP in proliferating smooth muscle cells. gamma-IFN was the only cytokine, of the cytokines evaluated, to up-regulate production of IGUP in VSMCs. CONCLUSION: IGUP is a novel protein in VSMCs found to be down-regulated in areas of anastomotic IH, as compared with a normal artery. We have now shown IGUP to be up-regulated only by gamma-IFN in human VSMCs. IGUP may, therefore, be the intermediary for the known gamma-IFN inhibition of human VSMC proliferation.

Identification of multiple genes with altered expression at the distal anastomosis of healing polytetrafluoroethylene grafts.

PURPOSE: Anastomotic intimal hyperplasia remains a significant cause of delayed prosthetic arterial graft failure. Prior studies have identified several genes with altered expression within the hyperplastic region at the downstream polytetrafluoroethylene arterial anastomosis as compared with normal arteries. The purpose of the current study was to determine the sequence of early gene-related events at the distal anastomosis of an in vivo prosthetic arterial graft model. Messenger RNA (mRNA) differential display was used to screen for alterations in gene expression between anastomotic sites and control arterial segments. METHODS: Six carotid interposition 6-mm expanded polytetrafluoroethylene grafts were placed in mongrel dogs, with the intervening carotid artery segment serving as the baseline control. Five days after graft implantation, the distal anastomotic artery segments were harvested and total RNA was isolated from both the intervening normal arteries and anastomotic segments. Differential mRNA display was used to identify candidate complementary DNA (cDNA) clones with expression that differed in anastomotic segments as compared with normal intervening arteries. Northern blot analysis confirmed alteration of gene expression. The cDNA clones were sequenced, and gene databases were searched. Novel sequences were used as probes for screening human cDNA libraries. RESULTS: Approximately 7000 mRNA species were screened, and 26 candidate clones were obtained. Northern blot analysis showed altered gene expression in 10 (38%) of the clones, undetectable signals in 13 (50%), and nonregulation in 3 (12%). Seven clones with 92% homology at the nucleotide level to human alpha1 (III) procollagen gene and novel sequence were expressed only at the distal anastomosis. A clone representing apolipoprotein J and a novel sequence had increased expression at the distal anastomosis of 364% +/- 236% and 156% +/- 47%, respectively (mean percentage, control +/- standard deviation). CONCLUSIONS: These studies identified genes with expressions that increased or were exclusive to the distal anastomosis of healing prosthetic arterial grafts in an in vivo prosthetic arterial graft model. Type III collagen may contribute significantly to the composition of the extracellular matrix associated with intimal hyperplasia by increasing lesion volume. Apolipoprotein J, through its association with proteases, may modulate some of the matrix changes seen early after grafting.

Vascular endothelial growth factor expression in canine peripheral vein bypass grafts.

PURPOSE: Autologous veins used as arterial bypass grafts undergo initial loss of the endothelial cell (EC) lining, which is followed by reendothelialization. We characterized the expression of the EC-specific angiogenic mitogen, vascular endothelial growth factor (VEGF), in vascular grafts to help elucidate the molecular and cellular events after bypass procedures. METHODS: Cephalic vein-femoral artery interposition grafts were placed in mongrel dogs. Vein grafts and arteries were harvested at either 48 hours or 4 weeks after bypass, the total RNA was isolated, and the VEGF mRNA expression was evaluated by Northern blot analysis. Tissue segments from each time period were evaluated by immunohistochemical analysis using anti-VEGF antibodies. RESULTS: VEGF mRNA expression in vein grafts as compared with control veins was increased 2.5-fold 48 hours after bypass grafting (p = 0.02) but returned to initial control levels in grafts removed at 4 weeks. Distal arterial segments, which included the anastomotic site without attached vein graft, had a 21.4-fold increase in VEGF expression at 48 hours (p = 0.02) and a 6.6-fold increase at 4 weeks (p < 0.01) as compared with control arterial segments. Vessels subjected to arteriotomy or ischemia alone also demonstrated increased VEGF expression. Immunohistochemical analysis revealed VEGF protein within ECs and smooth muscle cells of the venous bypass graft, with maximal levels observed within intimal hyperplasia at the arterial anastomosis. CONCLUSIONS: After arterial reconstruction procedures using venous conduits, VEGF is significantly increased at 48 hours in the vein graft and arterial anastomosis. VEGF expression in the vein graft normalizes within 4 weeks but remains significantly elevated in the adjacent arterial segment. Increased VEGF production after arterial grafting may facilitate reendothelialization, thus partially accounting for optimal patency rates achieved with autologous vein grafts.

Evaluation of anastomotic hyperplasia progression using the cyclin specific antibody MIB-1.

BACKGROUND: Delayed failure of prosthetic arterial grafts is primarily due to the development of anastomotic intimal hyperplasia. This report follows the proliferation of smooth muscle cells that ensues after prosthetic arterial grafting, using the cyclin-specific antibody MIB-1. METHODS: Six-mm expandable polytetrafluoroethylene (ePTFE) grafts were placed end-to-end in the carotid arteries of mongrel dogs. Animals were randomly assigned to sacrifice intervals of 2, 7, 14, and 30 days. Serial coronal sections were cut and immunohistocytochemistry performed using the MIB-1 antibody. RESULTS: The control carotid artery had no definable proliferation. Two days after grafting, there was brisk proliferation in the upper one third of the arterial media. By 7 days, proliferation and migration of smooth muscle cells was seen above the internal elastic lamina, in which 50% of the cells were MIB-1 positive. Fourteen days after graft placement, proliferation continued in the neointima; however, the proliferation index was diminished compared with previous time intervals. At 30 days, despite a dramatic increase in lesional increase, there was a marked decrease in the overall proliferation of cells. CONCLUSIONS: Following placement of a prosthetic arterial graft, there is initial brisk proliferation of cells in the arterial media, with migration, ongoing proliferation, and resultant development of a localized cellular neointima. Over a 30-day period, the percentage of cells proliferating subsides in contrast to the progressive increase in the size of the neointima. Immunohistocytochemistry with the MIB-1 antibody is a useful tool in defining the cellular kinetics after prosthetic arterial grafting.

Angiotensin-converting enzyme inhibition suppresses plasminogen activator inhibitor-1 expression in the neointima of balloon-injured rat aorta.

BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1), an important regulator of fibrinolysis and extracellular matrix turnover, has been implicated in a number of vascular diseases. Studies demonstrating angiotensin II (Ang II) to be a potent stimulator of PAI-1 expression in cultured vascular cells suggests that the renin-angiotensin system may modulate vascular PAI-1 expression. METHODS AND RESULTS: We examined the effects of the ACE inhibitor captopril on PAI-1 expression in control and balloon-injured rat aorta. Northern blot analysis demonstrated that aortic PAI-1 mRNA expression was 7.6-fold elevated 3 hours (P<.05) after balloon injury, back to baseline at 2 days, increased again at 4 days, and by 7 days after balloon injury was 3.2-fold elevated (P<.05) when compared with control. In captopril-treated rats, the induction of PAI-1 expression by balloon injury was significantly suppressed by 44% (P<.05) in the 7 day group but was not altered in the 3-hour group. Captopril also reduced baseline aortic PAI-1 mRNA. In situ hybridization and immunohistochemistry revealed dense PAI-1 staining of 7-day neointima in untreated rats and a dramatic decrease in PAI-1 in neointima of captopril-treated rats. CONCLUSIONS: This report demonstrates that balloon injury results in both a rapid ACE inhibitor-independent induction of aortic PAI-1 expression and a later increase in PAI-1 in the neointima that is significantly suppressed by captopril. This provides the first evidence that the renin-angiotensin system regulates neointimal PAI-1 expression and that ACE inhibitors can reduce PAI-1 in the vessel wall in vivo.

Isolation of genes differentially expressed at the downstream anastomosis of prosthetic arterial grafts with use of mRNA differential display.

PURPOSE: Downstream anastomotic intimal hyperplasia in prosthetic arterial grafts remains a major cause of delayed graft failure. The new method of messenger RNA (mRNA) differential display was used to screen numerous genes to gain insight into the molecular mechanisms of intimal hyperplasia. METHODS: Fifty-centimeter-long 8 mm expanded polytetrafluoroethylene grafts were placed in four mongrel dogs from the carotid artery to the distal abdominal aorta. At 3 months the distal anastomoses and adjacent normal aortas were harvested; a portion was taken for histologic examination, and total RNA was isolated from the remainder. Differential mRNA display was used to identify candidate cDNA clones whose expression differed in anastomotic intimal hyperplasia as compared with adjacent unaffected aorta. The clones were sequenced, and national gene databases were searched. Northern blot analysis confirmed alteration of gene expression. RESULTS: Approximately 5000 mRNA species were screened, and 11 candidate clones were obtained. DNA sequence revealed homology of five clones to known gene sequences. Homologous genes included an interferon-gamma-induced human gene, (IGUP I-5111), alpha-1 protease inhibitor gene, human retinoblastoma susceptibility gene, and human creatine kinase gene (two clones). Northern blot analysis revealed altered gene expression in 4 of 11, nonregulation in 1 of 11, and undetectable signals in 6 of 11. Expression of the clone representing IGUP I-5111 in the segment of intimal hyperplasia was found to be decreased over threefold to only 31% +/- 16.4% SE of the level seen in normal aorta. CONCLUSIONS: The technique of mRNA differential display has identified differences in gene expression in an in vivo model of anastomotic intimal hyperplasia. Expression of RNA with homology to an interferon-gamma-induced human gene was consistently decreased within the hyperplastic region at the downstream polytetrafluoroethylene arterial anastomosis.