Impact of tibial bypass conduit on long-term amputation-free survival and primary patency in the Vascular Quality Initiative.

OBJECTIVE: Much research remains focused on tibial bypass conduit selection. We sought to describe long-term amputation-free survival (AFS) and primary patency (PP) of patients undergoing tibial bypass by conduit type and configuration across several permutations in the Society for Vascular Surgery Vascular Quality Initiative. METHODS: Patients in the Vascular Quality Initiative registry undergoing elective first-time femoral- or popliteal-to-tibial bypass for occlusive disease involving rest pain or tissue loss were identified. Prior ipsilateral infrainguinal bypass or concomitant procedures were excluded. Outcomes of interest included patient AFS at 22 months and PP at 1 year (defined as freedom from revision, thrombectomy, or graft occlusion). RESULTS: A total of 4192 bypasses were identified. The majority utilized great saphenous vein (GSV) (76.2%), followed by polytetrafluoroethylene (10.6%), nonautologous biologic (6.5%), composite (3.3%), arm vein (2.8%), and small saphenous vein (0.6%). Compared with all prosthetic and composite bypasses, vein grafts had the best AFS (76.4%; P < .0001) and PP (68.1%; P = .041). Of the single segment vein conduits, GSV bypasses had the best PP (69.1%) and arm vein the worst (60.2%). AFS and PP were similar between single-segment GSV orientations. Single-segment GSV bypasses exhibited better PP than multiple segment bypasses (69.1% vs 54.6%; P = .0016). PP was significantly better for polytetrafluoroethylene compared with nonautologous biologic (68.4% vs 51.2%; P = .0039). PP did not significantly differ between vein cuff for prosthetic bypass compared with no vein cuff (69.1% vs 59.7%; P = .091). PP was not significantly different between single-segment GSV and prosthetic grafts with vein cuff (69.1% vs 69.1%; P = .51). There were no significant differences in AFS comparing arm vein, prosthetic bypass with vein cuff, or composite grafts (67.2% vs 63.8% vs 59.3%; P = .092), as well as in PP (60.2% vs 69.1% vs 54.8%; P = .14). CONCLUSIONS: Single-segment vein bypass was only marginally the most optimal conduit. Surprisingly, there may be more equipoise among conduit types, particularly in the absence of adequate GSV. Prosthetic grafts overall may not be as disadvantaged in the long term as initially thought, especially when compared with arm vein, as prosthetic bypass with vein cuff did not significantly differ in PP. Similarly, a composite conduit may not impact long-term outcomes. These data suggest that conduit choice may not impact outcomes to the degree previously thought and that other factors may have a greater impact than presumed, especially in conduit limited situations.

A Propensity-Matched Analysis of Endovascular Intervention versus Open Nonautologous Bypass as Initial Therapy in Patients with Chronic Limb-Threatening Ischemia.

OBJECTIVES: Endovascular therapies are increasingly used in patients with complex multilevel disease and chronic limb-threatening ischemia (CLTI). Infrageniculate bypass with autologous vein conduit is considered the gold standard in these patients. However, many patients often lack optimal saphenous vein, leading to the use of nonautologous prosthetic conduit. We compared limb salvage and survival rates for patients with CLTI undergoing first time revascularization with either open nonautologous conduit or endovascular intervention. METHODS: We retrospectively reviewed consecutive patients undergoing first time endovascular or open surgical revascularization at our institution between 2009 and 2016. Patients were divided into endovascular intervention or open bypass with nonautologous conduit (NAC) cohorts. Primary endpoints were amputation-free survival (AFS), freedom from reintervention, primary patency, and overall survival. Propensity scoring was used to construct matched cohorts. Outcomes were evaluated using Kaplan-Meier and Cox Proportional Hazards models. RESULTS: A total of 125 revascularizations were identified. There were 65 endovascular interventions and 60 NAC bypasses. In unmatched analysis, there was an elevated risk of perioperative MI (7% vs. 0%, P = 0.05) and amputation (10% vs. 2%, P = 0.04) for the NAC groups compared to the endovascular group. In matched analysis, endovascular patients had a lower incidence of 30-day amputation (1.5% vs. 10% P = 0.04) and length of stay (median days, 1 vs. 9, P < 0.01) compared to the open cohort. While not statistically significant, the endovascular group trended towards increased rates of two-year AFS (76% vs. 65%, P = 0.07) compared to the NAC group. There was no significant difference in overall survival when the endovascular cohort was compared to NAC (85% vs. 77%, P = 0.29) patients. In matched Cox analysis, nonautologous conduit use was associated with an increased risk of limb loss (HR 2.03, 95% CI 0.94-4.38, P = 0.07) compared to endovascular revascularization. CONCLUSIONS: An "endovascular first" approach offers favorable perioperative outcomes and comparable AFS compared to NAC and may be preferable when autologous conduit is unavailable.

Protamine sulfate use during tibial bypass does not appear to increase thrombotic events or affect short-term graft patency.

OBJECTIVES: While the use of protamine sulfate as a heparin reversal agent has been extensively reviewed in patients undergoing carotid endarterectomy and coronary artery bypass grafting, there is a lack of literature on protamine's effects on lower extremity bypasses. The purpose of this study was to determine the risk of protamine sulfate dosing after tibial bypass on thrombotic or bleeding events, including early bypass failure. METHODS: We performed a retrospective review of our institutional database for patients undergoing primary distal peripheral bypass from January 2009 through December 2015 (contralateral bypass was considered to be a new primary bypass). Primary endpoints include composite thrombotic events (myocardial infarction, stroke, amputation at 30 days and patency less than 30 days) and composite bleeding events (bleeding or transfusion). RESULTS: A total of 152 tibial or peroneal bypasses in 136 patients with critical limb ischemia were identified. Of these, 78 (57.4%) patients received protamine sulfate intraoperatively and 58 (42.6%) did not. There were no differences in composite thrombotic or hemorrhagic outcomes. Protamine use had no effect on the rates of perioperative MI (9.0% versus 3.5%, p = 0.20), stroke (1.3% versus 1.7%, p = 0.83), or perioperative mortality (5.1% versus 3.5%, p = 0.64). There was no significant difference in composite post-operative bleeding events (20.7% versus 14.1%, p = 0.31) or composite thrombotic events (17.2% versus 18.0%, p = 0.91). Patients who received protamine undergoing bypass with non-autogenous conduit had significantly higher-recorded median operative blood loss (250 mL versus 150 mL, p = 0.0097) and median procedure lengths (265 min versus 201 min, p = 0.0229). No difference in 30-day amputation-free survival was noted (91.0% versus 91.4%, p = 0.94). Follow-up Kaplan-Meier estimation did not demonstrate a difference in 30-day patency (91.7% versus 88.5%, p = 0.52). CONCLUSIONS: Heparin reversal with protamine sulfate after tibial or peroneal bypass grafting is not associated with higher cardiovascular morbidity, bypass thrombosis, amputation, or mortality. Additionally, there was no statistically significant difference in post-operative bleeding or thrombosis complications for patients who did not receive protamine, although the findings are suggestive of a potential difference in a more adequately powered study. Our results suggest that protamine sulfate is safe for intraoperative use without increased risk of thrombotic complications or early tibial bypass graft failure.

A propensity-matched analysis of contemporary outcomes of blunt popliteal artery injury.

OBJECTIVE: Traumatic popliteal artery injury is associated with an increased propensity for limb loss, morbidity, and mortality above an already elevated baseline risk to life and limb. Previous studies of outcomes in this patient group have been limited by selection bias. This study analyzed outcomes after blunt popliteal artery injury using propensity matching to reduce confounding variables associated with multiple mechanisms of traumatic vascular injury and to identify factors associated with amputation. METHODS: A retrospective review was conducted of prospectively collected data from the National Trauma Data Bank. Patients were identified using International Classification of Diseases, Ninth Revision codes related to patterns of blunt injury associated with popliteal arterial injury or intervention. Using Trauma Quality Improvement Program variables as a reference, specific characteristics were collected. Variables found significant on univariate analysis were used to generate propensity-matched amputation and nonamputation cohorts. Multivariate logistic regression was used to assess for risk factors associated with amputation and inpatient mortality. RESULTS: In total, 3029 patients with blunt popliteal artery injury were identified; 628 (20.7%) underwent amputation. Patients who underwent amputation presented with more frequent hypotension (systolic blood pressure of 0-99 mm Hg, 22.7% vs 12.8%; P < .001) and tachycardia (heart rate >120 beats/min, 28.5% vs 14.5%; P < .001). Limb loss was also associated with concurrent popliteal vein injury (18.3% vs 8.7%; P < .001) and tibial nerve injury (5.3% vs 1.3%; P < .001) as well as with elevated Injury Severity Score (median, 13 vs 9; P < .001) and lower extremity Abbreviated Injury Scale score (3 vs 2; P < .001). Subsequently, 794 patients were divided into equal number propensity-matched amputation and nonamputation cohorts. Regression analysis revealed that patients with diabetes mellitus (odds ratio [OR], 1.763; P = .049), popliteal vein injury (OR, 1.657; P = .012), or tibial nerve injury (OR, 3.537; P = .007) were more likely to undergo amputation. Further regression analysis with patients matched for Injury Severity Score revealed that age ≥86 years (OR, 38.092; P = .009), patellar fracture (OR, 3.445; P = .036), and elevated Abbreviated Injury Scale score (OR, 1.101; P < .001) were associated with higher risk of inpatient death. CONCLUSIONS: Trauma patients who sustain blunt popliteal artery injury are at an increased risk of amputation. Propensity-matched analysis revealed that concurrent popliteal vein and tibial nerve injury but not severity of tissue injury predicted limb loss.

Influence of smoking on aneurysm recurrence after endovascular treatment of cerebrovascular aneurysms.

OBJECTIVE Smoking is a known risk factor for aneurysm development and aneurysmal subarachnoid hemorrhage, as well as subsequent vasospasm in both untreated individuals and patients who have undergone surgical clipping of cerebrovascular aneurysms. However, there is a lack of data in the current scientific literature about the long-term effects that smoking has on the integrity of endovascular repairs of cerebral aneurysms. This study was designed to determine if any smoking history increased the risk of poorer outcomes and/or aneurysm recurrence in patients who have had endovascular repair of cerebral aneurysms. METHODS The authors retrospectively analyzed the medical records of patients admitted to the University of Michigan Health System from January 1999 to December 2011 with coiled aneurysms and angiography, CT angiography, or MR angiography follow-up. Patients were identified and organized based on many criteria including age, sex, smoking history, aneurysm recurrence, aneurysm location, and Hunt and Hess grade. Analysis was targeted to the patient population with a history of smoking. Bivariate chi-square tests were used to analyze the association between a positive smoking history and documented aneurysm recurrence and were adjusted for potential confounders by fitting multivariate logistic regression models of recurrence. RESULTS A total of 247 patients who had undergone endovascular treatment of 296 documented cerebral aneurysms were included in this study. The recurrence rate among all patients treated with endovascular repair was 24.3%, and the average time to the most recent follow-up imaging studies was 1.62 years. Smokers accounted for 232 aneurysms and were followed up for an average of 1.57 years, with a recurrence rate of 26.3%. Never smokers accounted for the remaining 64 aneurysms and were followed up for an average of 1.82 years, with a recurrence rate of 17.2%. Multivariate analysis revealed that, after controlling for potential confounders, a history of smoking-whether current or former-was associated with a significantly increased risk of aneurysm recurrence. The odds ratios for aneurysm recurrence for current and former smokers were 2.739 (95% CI 1.127-7.095, p = 0.0308) and 2.698 (95% CI 1.078-7.212, p = 0.0395), respectively, compared with never smokers. CONCLUSIONS A positive smoking history is associated with a significantly increased risk of aneurysm recurrence in patients who have undergone endovascular repair of a cerebral aneurysm, compared with the risk in patients who have never smoked.

Phosphorylation of AKT and abdominal aortic aneurysm formation.

It is hypothesized that differential AKT phosphorylation between sexes is important in abdominal aortic aneurysm (AAA) formation. Male C57BL/6 mice undergoing elastase treatment showed a typical AAA phenotype (80% over baseline, P < 0.001) and significantly increased phosphorylated AKT-308 (p308) and total-AKT (T-AKT) at day 14 compared with female mice. Elastase-treated Raw cells produced increased p308 and significant amounts of matrix metalloproteinase 9 (MMP-9), and these effects were suppressed by LY294002 treatment, a known AKT inhibitor. Male and female rat aortic smooth muscle cells treated with elastase for 1, 6, or 24 hours demonstrated that the p308/T-AKT and AKT-Ser-473/T-AKT ratios peaked at 6 hours and were significantly higher in the elastase-treated cells compared with controls. Similarly, male cells had higher phosphorylated AKT/T-AKT levels than female cells. LY294002 also inhibited elastase-induced p308 formation more in female smooth muscle cells than in males, and the corresponding cell media had less pro-MMP-9. AKT siRNA significantly decreased secretion of pro-MMP-9, as well as pro-MMP-2 and active MMP-2 from elastase-treated male rat aortic smooth muscle cells. IHC of male mice AAA aortas showed increased p308, AKT-Ser-473, and T-AKT compared with female mice. Aortas from male AAA patients had a significantly higher p308/T-AKT ratio than female AAA tissues. These data suggest that AKT phosphorylation is important in the upstream regulation of MMP activity, and that differential phosphorylation may be important in sex differences in AAA.

The role of extracellular signal-related kinase during abdominal aortic aneurysm formation.

BACKGROUND: It is hypothesized that activation of extracellular signal-related kinase (ERK) is critical in activating matrix metalloproteinases (MMPs) during abdominal aortic aneurysm (AAA) formation. STUDY DESIGN: C57BL/6 male mice underwent either elastase or heat-inactivated elastase aortic perfusion (n = 9 per group). Mouse aortic smooth muscle cells were transfected with ERK-1 and 2 siRNA along with or without elastase treatment. Mouse and human aortic tissue were analyzed by Western blots, zymograms, and immunohistochemistry, and statistical analysis was done using Graphpad and Image J softwares. RESULTS: Western blot and immunohistochemistry documented increased phospho-mitogen-activated protein kinase kinase-1/2 (pMEK-1/2; 153%, p = 0.270 by Western) and pERK (171%, p = 0.004 by Western blot) in the elastase perfused aortas. Male ERK-1(-/-) mice underwent elastase perfusion, and aortic diameter was determined at day 14. ERK-1(-/-) mice failed to develop AAA, and histologic analysis depicted intact collagen and elastin fibers in the aortas. Zymography of aortas of elastase-treated ERK-1(-/-) mice showed lower levels of proMMP2 (p < 0.005) and active MMP2 (p < 0.0001), as well as proMMP9 (p = 0.037) compared with C57BL/6 mice. siRNA transfection of ERK-1 and -2 significantly reduced formation of pro- and active MMP2 (p < 0.01 for both isoforms) in aortic smooth muscle cells treated with elastase in vitro. Human AAA tissue had significantly elevated levels of pMEK-1/2 (150%, p = 0.014) and pERK (159%, p = 0.013) compared with control tissues. CONCLUSIONS: The MAPK (mitogen-activated protein kinase)/ERK pathway is an important modulator of MMPs during AAA formation. Targeting the ERK pathway by reagents that inhibit either the expression or phosphorylation of ERK isoforms could be a potential therapy to prevent AAA formation.

Gender-dependent differential phosphorylation in the ERK signaling pathway is associated with increased MMP2 activity in rat aortic smooth muscle cells.

BACKGROUND: The present experiments were conducted to explore the role of mitogen-activated protein kinase (MAPK) pathways, potential upstream regulators of MMPs, in abdominal aortic aneurysms (AAAs). METHODS: Rat aortic smooth muscle cells (RASMCs) from males and females were treated with media containing interleukin (IL)-1beta (2 ng/mL), a concentration known to be present in AAAs. Levels of both total and phosphorylated (activated) extracellular signal-regulated kinase (ERK), c-Jun amino terminal kinase/stress-activated protein kinase (JNK/SAPK), and p38 were examined by Western blotting at various time intervals up to 60 min. Similar experiments were conducted following exposure of RASMCs to elastase (6 U/mL), a concentration known to induce AAA formation in rodents. Finally, media was assayed for MMP activity by zymography. RESULTS: Total ERK (t-ERK) was consistently no different in females compared with males prior to or following IL-1beta exposure. In contrast, levels of phosphorylated ERK (p-ERK) were significantly higher in males than females throughout the postexposure period (P < 0.0001). Levels of t-p38, p-p38, and t-JNK were not altered in a gender-dependent manner. The lack of p-JNK levels detected in both male and female RASMCs did not allow for conclusions to be drawn regarding gender disparities in this pathway. Results were similar following RASMC elastase exposure, although t-ERK levels were consistently higher in females than males (P < 0.0001). Pro-MMP2 levels were significantly higher (P = 0.0035) in males than females at each time point following elastase exposure. CONCLUSIONS: These data provide evidence implicating alterations in p-ERK signaling via the up-regulation of MMPs as a potential explanation for gender-related discrepancies in AAA formation.