Long-Term Results of Crossover Bypass for Iliac Atherosclerotic Lesions in the Era of Endovascular Treatment: The Re-ACTION Study (Retrospective Assessment of Crossover Bypass as a Treatment for Iliac LesiONs).

Objective: The aim of this study was to elucidate the long-term results of crossover bypass (CB) for iliac atherosclerotic lesions in the era of endovascular treatment (EVT). Methods: A retrospective multicenter cohort study was performed. CB was performed in 242 patients between 2003 and 2014 by vascular surgeons at multiple medical centers in Japan. Results: Perioperative mortality was 1.7%. Primary patency rates were 86% at 5 years and 82% at 8 years. Univariate analysis showed that critical limb ischemia (Rutherford class 4-6), vein graft, and superficial femoral artery occlusion were significantly associated with low primary patency. In multivariate analysis, only critical limb ischemia influenced primary patency. The secondary patency rate was 87% at both 5 and 8 years. The limb salvage rate was 98% at both 5 and 8 years. The overall survival rates were 71% at 5 years and 49% at 8 years. Conclusion: The long-term results of CB were good in our study, compared with previous reports. Our results suggest that CB remains an option for the arterial reconstruction in unilateral iliac occlusive disease after EVT failed.

Infected iliac artery aneurysm with aortocaval fistula.

Case: We report a case of an infected iliac artery aneurysm complicated by an aortocaval fistula. Outcome: A 74-year-old-man was admitted with fever, chills, general fatigue, and appetite loss. The patient was diagnosed with an infected iliac artery aneurysm, which was controlled with antibiotics preoperatively. During hospitalization, deep vein thrombosis developed with a pulmonary embolism resulting from an aortocaval fistula. The patient was successfully operated on with in situ autologous vein graft reconstruction. Conclusion: An infected iliac artery aneurysm with aortocaval shunt has rarely been reported. We successfully treated the patient with a combination of appropriate i.v. antibiotics and surgical resection.

Combined distal venous arterialization and free flap for patients with extensive tissue loss.

BACKGROUND: We evaluated the mid-term outcome of distal venous arterialization (DVA) and the role of a combined free flap as a bridgehead for blood supply. METHODS: In the past 5 years, nine patients with extensive tissue loss and lacking graftable distal arteries underwent DVA. These consisted of four primary DVAs, three combined DVA and free flap procedures, and two adjuvant DVAs for hemodynamically failed distal bypasses. After nine primary DVAs, three redo DVAs were performed for early failure. Etiologies were four Buerger disease and five arteriosclerosis obliterans, including three dialysis patients. RESULTS: Among the nine DVA cases, there were five primary failures: two underwent amputation, two had successful redo DVA, and the remaining one did not require redo DVA. Primary patency, secondary patency, and limb salvage rates were 44.4%, 55.6%, and 77.8%, respectively. The postoperative period was 1-36 months (median 12). Angiography demonstrated DVA was effective in the early period, and development of collaterals or a capillary network from the free flap replaced the DVA function in the intermediate period. CONCLUSION: DVA can be effective as a procedure for limb salvage in patients without graftable distal arteries, and a combined free flap is effective and functions as a bridgehead for blood supply to the ischemic zone.

Laminar shear stress stimulates vascular smooth muscle cell apoptosis via the Akt pathway.

Vascular smooth muscle cells (SMC) may be directly exposed to blood flow after an endothelial-denuding injury. It is not known whether direct exposure of SMC to shear stress reduces SMC turnover and contributes to the low rate of restenosis after most vascular interventions. This study examines if laminar shear stress inhibits SMC proliferation or stimulates apoptosis. Bovine aortic SMC were exposed to arterial magnitudes of laminar shear stress (11 dynes/cm(2)) for up to 24 h and compared to control SMC (0 dynes/cm(2)). SMC density was assessed by cell counting, DNA synthesis by (3)[H]-thymidine incorporation, and apoptosis by TUNEL staining. Akt, caspase, bax, and bcl-2 phosphorylation were assessed by Western blotting; caspase activity was also measured with an in vitro assay. Analysis of variance was used to compare groups. SMC exposed to laminar shear stress had a 38% decrease in cell number (n = 4, P = 0.03), 54% reduction in (3)[H]-thymidine incorporation (n = 3, P = 0.003), and 15-fold increase in TUNEL staining (n = 4, P < 0.0001). Akt phosphorylation was reduced by 67% (n = 3, P < 0.0001), whereas bax/bcl-2 phosphorylation was increased by 1.8-fold (n = 3, P = 0.01). Caspase-3 activity was increased threefold (n = 5, P = 0.03). Pretreatment of cells with ZVAD-fmk or wortmannin resulted in 42% increased cell retention (n = 3, P < 0.01) and a fourfold increase in apoptosis (n = 3, P < 0.04), respectively. Cells transduced with constitutively-active Akt had twofold decreased apoptosis (n = 3, P < 0.002). SMC exposed to laminar shear stress have decreased proliferation and increased apoptosis, mediated by the Akt pathway. These results suggest that augmentation of SMC apoptosis may be an alternative strategy to inhibit restenosis after vascular injury.

Role of AKT in cyclic strain-induced endothelial cell proliferation and survival.

Endothelial cells (ECs) are exposed to repetitive cyclic strain (CS) in vivo by the beating heart. The aim of this study was to assess the influence of CS amplitude and/or frequency on EC proliferation and survival and to determine the role of AKT in CS-induced EC proliferation and survival. Cultured bovine aortic ECs were exposed to 10% strain at a frequency of 60 (60 cpm-10%) or 100 (100 cpm-10%) cycles/min or 15.6% strain at a frequency of 60 cycles/min (60 cpm-15.6%). AKT, glycogen synthase kinase (GSK)-3beta, BAD, and cleaved caspase-3 were activated by CS in ECs. Increasing the magnitude or frequency of strain resulted in an earlier phosphorylation of GSK-3beta, although the magnitude of phosphorylation was similar. After CS at 60 cpm-10% for 24 h, the number of nontransfected ECs was significantly increased by 8.5% (P < 0.05). We found that the number of apoptotic ECs was slightly decreased with exposure to CS. ECs transfected with kinase-dead AKT (KA179) as well as plasmids containing a point mutation in the pleckstrin homology domain of AKT (RC25) not only prevented AKT, GSK-3beta, and BAD phosphorylation but also inhibited the CS-induced increase in cell number as well as the CS-induced protection against apoptosis (both P < 0.05). The ratio of 5'-bromo-2'-deoxyuridine-positive cells was increased when ECs transfected with RC25 and KA179 as well as nontransfected ECs and ECs transfected with Lipofectamine 2000 were exposed to CS. We conclude that AKT is important in enhancing the survival of ECs exposed to CS but is not involved in EC proliferation.

Sustained orbital shear stress stimulates smooth muscle cell proliferation via the extracellular signal-regulated protein kinase 1/2 pathway.

OBJECTIVE: Nonlaminar shear stress stimulates smooth muscle cell (SMC) proliferation and migration in vivo, especially after an endothelial-denuding injury. To determine whether sustained shear stress directly stimulates SMC proliferation in vitro, the effect of orbital shear stress on SMC proliferation, phenotype, and extracellular signal-regulated protein kinase 1/2 (ERK1/2) phosphorylation was examined. METHODS: Bovine SMCs were exposed to orbital shear stress (210 rpm) for up to 10 days, with and without the ERK1/2 upstream pathway inhibitor PD98059 (10 microM) or the p38 pathway inhibitor SB203580 (10 microM). Proliferation was directly counted and assessed with proliferation cell nuclear antigen. Western blotting was used to assess activation of SMC ERK1/2 and SMC phenotype markers. RESULTS: SMCs exposed to sustained orbital shear stress (10 days) had 75% increased proliferation after 10 days compared with static conditions. Expression of markers of the contractile phenotype (alpha-actin, calponin) was decreased, and markers of the synthetic phenotype (vimentin, beta-actin) were increased. ERK1/2 was phosphorylated in the presence of orbital shear stress, and orbital shear-stress-stimulated SMC proliferation was inhibited in the presence of PD98059 but sustained in the presence of SB203580. Orbital shear-stress-induced changes in SMC phenotype were also inhibited in the presence of PD98059. CONCLUSION: Orbital shear stress directly stimulates SMC proliferation in long-term culture in vitro and is mediated, at least partially, by the ERK1/2 pathway. The ERK1/2 pathway may also mediate the orbital shear-stress-stimulated switch from SMC contractile to synthetic phenotype. These results suggest that shear-stress-stimulated SMC proliferation after vascular injury is mediated by a pathway amenable to pharmacologic manipulation.

Differential responsiveness of early- and late-passage endothelial cells to shear stress.

BACKGROUND: The incidence of vascular disease increases with age. Because atherosclerosis and neointimal hyperplasia colocalize in areas of disturbed shear stress, the effects of orbital shear stress (SS) on endothelial cell proliferation, protein kinase B (Akt) activation, and functional activity were analyzed using a senescence model. METHODS: Early- (p3 to 7) and late- (p28 to 32) passage bovine aortic endothelial cells were exposed to orbital SS (210 rpm) or static conditions (0 to 5 days). Cell proliferation was directly counted and confirmed with proliferating cell nuclear antigen reactivity. Phosphorylated and total Akt were assessed with Western blotting. Endothelial cell-induced smooth muscle cell migration was assessed with a Boyden chamber. RESULTS: Late-passage endothelial cells demonstrated no increase in orbital SS stimulated proliferation compared with early-passage cells (P = .42). Late-passage endothelial cells demonstrated decreased Akt phosphorylation in response to SS compared with early passage cells (n = 6, P = .01). Late-passage cells induced 26% less smooth muscle cell migration than early-passage cells (n = 3, P = .03). CONCLUSIONS: Late-passage endothelial cells demonstrate decreased proliferation, Akt phosphorylation, and secretion of smooth muscle cell chemoattractants in response to orbital SS compared with early passage cells. These results suggest that late-passage endothelial cells respond to SS differently than early-passage cells and confirm the utility of the in vitro senescence model.

Differential effects of orbital and laminar shear stress on endothelial cells.

OBJECTIVE: Laminar shear stress is atheroprotective for endothelial cells (ECs), whereas nonlaminar, disturbed, or oscillatory shear stress correlates with development of atherosclerosis and neointimal hyperplasia. The effects of orbital and laminar shear stress on EC morphology, proliferation, and apoptosis were compared. METHODS: ECs were exposed to orbital shear stress with an orbital shaker (210 rpm) or laminar shear stress (14 dyne/cm 2) with a parallel plate. Shear stress in the orbital shaker was measured with optical velocimetry. Cell proliferation was assessed with direct counting and proliferating cell nuclear antigen staining; apoptosis was assessed with transferase-mediated deoxyuridine triphosphate nick end labeling staining. Cell surface E-selectin and intercellular adhesion molecule expression were assessed with fluorescence-activated cell sorting. Akt phosphorylation was assessed with Western blotting. RESULTS: Orbital shear stress increased EC proliferation by 29% and 3 [H]thymidine incorporation two-fold compared to 16% and 38% decreases, respectively, in ECs treated with laminar shear stress (P < .0001 and P = .03, analysis of variance). Cells in the periphery of the culture well aligned to the direction of shear stress similar to the shape change seen with laminar shear stress, whereas ECs in the center of the well appeared unaligned similar to ECs not exposed to shear stress. Shear stress at the bottom surface of the culture well was reduced in the center of the well (5 dyne/cm 2) compared to the periphery (11 dyne/cm 2); the Reynolds' number was 2066. ECs were seeded differentially in the center and periphery of the wells. ECs in the center of the well had increased proliferation, increased apoptosis, reduced Akt phosphorylation, increased intercelluar adhesion molecule expression, and reduced E-selectin down-regulation, compared with ECs in the periphery of the well. CONCLUSION: Although the orbital shaker does not apply uniform shear stress throughout the culture well, arterial magnitudes of shear stress are present in the periphery of the well. ECs cultured in the center of the well exposed to low magnitudes of orbital shear stress might be a model of the "activated" EC phenotype. CLINICAL RELEVANCE: The perfect in vitro model to study and assess treatments for atherosclerosis and neointimal hyperplasia does not exists. An extensive body of literature describing effects of laminar shear stress on endothelial cells has contributed to our understanding of the interactions between shear stress and blood vessels. Laminar shear stress is atheroprotective, whereas oscillatory or disturbed shear stress correlates with areas of atherosclerosis and neointimal hyperplasia in vivo. This study describes the orbital shear stress model, its effects on endothelial cell proliferation and apoptosis, and suggests that activation of the intracellular Akt pathway is associated with these differing effects of laminar and orbital shear stress on endothelial cells.

Shear stress-stimulated endothelial cells induce smooth muscle cell chemotaxis via platelet-derived growth factor-BB and interleukin-1alpha.

OBJECTIVE: Vascular smooth muscle cell (SMC) migration is critical to the development of atherosclerosis and neointimal hyperplasia. Hemodynamic forces such as shear stress and cyclic strain stimulate endothelial cell signal-transduction pathways, resulting in the secretion of several factors, including SMC chemoattractants such as platelet-derived growth factor (PDGF). We hypothesized that mechanical forces stimulate endothelial cells to secrete SMC chemoattractants to induce migration via the mitogen-activated protein kinase (MAPK) pathway. METHODS: Bovine aortic endothelial cells were exposed to shear stress, cyclic strain, or static conditions for 16 hours. The resulting conditioned medium was used as a SMC chemoattractant in a Boyden chamber. Activation of SMC extracellular signal-regulated protein kinase 1/2 (ERK1/2) was assessed by Western blot analysis. Pathways were inhibited with anti-PDGF-BB or anti-interleukin-1alpha (IL-1alpha) antibodies, or the ERK1/2 upstream pathway inhibitor PD98059. RESULTS: Conditioned medium from endothelial cells exposed to shear stress corresponding to arterial levels of shear stress stimulated SMC migration but lower levels of shear stress or cyclic strain did not. Both PDGF-BB and IL-1alpha were secreted into the conditioned medium by endothelial cells stimulated with shear stress. Both PDGF-BB and IL-1alpha stimulated SMC chemotaxis but were not synergistic, and both stimulated SMC ERK1/2 phosphorylation. Inhibition of PDGF-BB or IL-1alpha inhibited SMC chemotaxis and ERK1/2 phosphorylation. CONCLUSION: Shear stress stimulates endothelial cells to secrete several SMC chemoattractants, including PDGF-BB and IL-1alpha; both PDGF-BB and IL-1alpha stimulate SMC chemotaxis via the ERK1/2 signal-transduction pathway. These results suggest that the response to vascular injury may have a common pathway amenable to pharmacologic manipulation. CLINICAL RELEVANCE: One difficulty in the pharmacologic treatment of atherosclerosis or neointimal hyperplasia leading to restenosis is the multiplicity of activated pathways and thus potential treatment targets. This study demonstrates that shear stress, a hemodynamic force that may be a biologically relevant stimulus to induce vascular pathology, stimulates endothelial cells to secrete PDGF-BB and IL-1alpha. Both of these mediators stimulate the SMC ERK1/2 pathway to induce migration, a critical event in the pathogenesis of atherosclerosis and neointimal hyperplasia. Therefore, this study suggests a relevant common target pathway in SMC that is amenable to manipulation for clinical treatment.

Isolated iliac artery aneurysm caused by fibromuscular dysplasia: report of a case.

Fibromuscular dysplasia (FMD) can develop in many different arteries, but iliac artery aneurysms are rare. A 69-year-old Japanese woman was admitted to our hospital for treatment of a right common iliac artery aneurysm. Aortography revealed aneurysms in both the right common iliac artery and the left internal iliac artery. Notably, the right common iliac artery aneurysm had a "string-of-beads" appearance. At surgery, the aneurysms were resected, and replaced with Y-shaped vascular prostheses. The histopathological diagnosis was fibromuscular dysplasia (FMD). We report this case of common iliac artery aneurysm caused by FMD due to its rarity.

Novel anastomotic method enables aortofemoral bypass for patients with porcelain aorta.

PURPOSE: Porcelain aorta is an indication for axillofemoral bypass. However, the procedure has definitive flaws. We present a new method for achievement of aortofemoral bypass. METHODS: The portion of the distal aorta for anastomosis is wrapped with a double polytetrafluoroethylene mesh and fixed to the adventitia with continuous sutures. The adventitia of the anastomotic site is cut over the mesh until the calcified surface is disclosed. Margins of the mesh and the peeled adventitia are fixed along the anastomotic margin with continuous sutures. After the aorta and distal arteries are occluded with balloon catheters, an opening on the bared calcification is made with an airdrill and enlarged with a laminectomy rongeur. The anastomosis is performed between a graft and the mesh-reinforced adventitia with continuous sutures. Over 6 years, this method has been applied to nine patients with porcelain aorta who are diabetic or undergoing dialysis. The indications were disabling claudication in three patients and limb salvage in six patients. RESULTS: No anastomotic complications or operative deaths were seen, and satisfactory mid-term results were obtained, with follow-up ranging from 3 to 62 months after surgery. One patient died of coronary heart disease 3 years after surgery, but the grafts retained a good function. CONCLUSION: This method is safe and effective, and more liberal application of this method may help improve outcome and quality of life.