Fate of patients with spinal cord ischemia complicating thoracic endovascular aortic repair

ObjectiveSpinal cord ischemia (SCI) is a potentially devastating complication of thoracic endovascular aortic repair (TEVAR) that can result in varying degrees of short-term and permanent disability. This study was undertaken to describe the clinical outcomes, long-term functional impact, and influence on survival of SCI after TEVAR.MethodsA retrospective review of all TEVAR patients at the University of Florida from 2000 to 2011 was performed to identify individuals experiencing SCI, defined by any new lower extremity neurologic deficit not attributable to another cause. SCI was dichotomized into immediate or delayed onset, with immediate onset defined as SCI noted upon awakening from anesthesia, and delayed characterized as a period of normal function, followed by development of neurologic injury. Ambulatory status was determined using database query, record review, and phone interviews with patients and/or family. Mortality was estimated using life-table analysis.ResultsA total of 607 TEVARs were performed for various indications, with 57 patients (9.4%) noted to have postoperative SCI (4.3% permanent). SCI patients were more likely to be older (63.9 ± 15.6 vs 70.5 ± 11.2 years; P = .002) and have a number of comorbidities, including chronic obstructive pulmonary disease, hypertension, dyslipidemia, and cerebrovascular disease (P < .0001). At some point in their care, a cerebrospinal fluid drain was placed in 54 patients (95%), with 54% placed postoperatively. In-hospital mortality was 8.8% for the entire cohort (SCI vs no SCI; P = .45). SCI developed immediately in 12 patients, delayed onset in 40, and indeterminate in five patients due to indiscriminate timing from postoperative sedation. Three patients (25%) with immediate SCI had measurable functional improvement (FI), whereas 28 (70%) of the delayed-onset patients experienced some degree of neurologic recovery (P = .04). Of the 34 patients with complete data available, 26 (76%) reported quantifiable FI, but only 13 (38%) experienced return to their preoperative baseline. Estimated mean (± standard error) survival for patients with and without SCI was 37.2 ± 4.5 and 71.6 ± 3.9 months (P < .0006), respectively. Patients with FI had a mean survival of 53.9 ± 5.9 months compared with 9.6 ± 3.6 months for those without improvement (P < .0001). Survival and return of neurologic function were not significantly different when patients with preoperative and postoperative cerebrospinal fluid drains were compared.ConclusionsThe minority of patients experience complete return to baseline function after SCI with TEVAR, and outcomes in patients without early functional recovery are particularly dismal. Patients experiencing delayed SCI are more likely to have FI and may anticipate similar life-expectancy with neurologic recovery compared with patients without SCI. Timing of drain placement does not appear to have an impact on postdischarge FI or long-term mortality

Prediction of graft patency and mortality after distal revascularization and interval ligation for hemodialysis access-related hand ischemia

ObjectiveThe treatment goals of access-related hand ischemia (ARHI) are to reverse symptoms and salvage the access. Many procedures have been described, but the optimal treatment strategy remains unresolved. In an effort to guide clinical decision making, this study was undertaken to document our outcomes for distal revascularization and interval ligation (DRIL) and to identify predictors of bypass patency and patient mortality.MethodsA retrospective review was performed of all patients who underwent DRIL at the University of Florida from 2002 to 2011. Diagnosis of ARHI was based primarily upon clinical symptoms with noninvasive studies used to corroborate in equivocal cases. Patient demographics, procedure-outcome variables, and reinterventions were recorded. Bypass patency and mortality were estimated using cumulative incidence and Kaplan-Meier methodology, respectively. Cumulative incidence and Cox regression analysis were performed to determine predictors of bypass patency and mortality, respectively.ResultsA total of 134 DRILs were performed in 126 patients (mean [standard deviation] age, 57 [12] years) following brachial artery-based access. The postoperative complication rate was 27% (19% wound), and 30-day mortality was 2%. The wrist-brachial index and digital brachial index increased 0.31 (0.25) and 0.25 (0.29), respectively. Symptoms resolved in 82% of patients, and 85% continued to use their access. Cumulative incidences (± standard error of the mean) of loss of primary and primary-assisted patency rates were 5% ± 2% and 4% ± 2% at 1 year and 22% ± 5% and 18% ± 5% at 5 years, respectively, with mean follow-up of 14.8 months. Univariate predictors of primary patency failure were DRIL complications (odds ratio [OR], 3.3; 95% confidence interval [CI], 1.2-8.9; P = .02), configuration other than brachiobasilic/brachiocephalic autogenous access (OR, 3.4; 95% CI, 1.4-8.3; P = .009), and two or more prior access attempts (OR, 4.1; 95% CI, 1.6-10.4; P = .004). Brachiocephalic access configuration (OR, 0.2; 95% CI, 0.04-0.8; P = .02) and autogenous vein conduit (OR, 0.2; 95% CI, 0.06-0.58; P = .004) were predictors of improved bypass patency. All-cause mortality was 28% and 79% at 1 and 5 years, respectively. Multivariable predictors of mortality were age >40 (hazard ratio [HR], 8.3; 95% CI, 2.5-33.3; P = .0004), grade 3 ischemia (HR, 2.6; 95% CI, 1.5-4.6; P = .0008), complication from DRIL (HR, 2.4; 95% CI, 1.3-4.5; P = .004), and smoking history (HR, 2.2; 95% CI, 1.3-4; P = .007). Patients with no prior access attempts had lower predicted mortality (HR, 0.5; 95% CI, 0.3-0.9; P = .02).ConclusionsThe DRIL procedure effectively improves distal perfusion and reverses the symptoms of ARHI while salvaging the access, but the long-term survival of these patients is poor. Given the poor survival, preoperative risk stratification is critical. Patients at high risk for DRIL failure and mortality may be best served with alternate remedial procedures

Outcomes after redo aortobifemoral bypass for aortoiliac occlusive disease

ObjectivePatients presenting with occluded aortobifemoral (ABF) bypass grafts are managed with a variety of techniques. Redo ABF (rABF) bypass procedures are infrequently performed because of concerns about procedural complexity and morbidity. The purpose of this analysis was to compare midterm results of rABF bypass with those of primary ABF (pABF) bypass for aortoiliac occlusive disease to determine if there are significant differences in outcomes.MethodsA retrospective review was performed of all patients undergoing ABF bypass for occlusive disease between January 2002 and March 2012. A total of 19 patients underwent rABF bypass and 194 received pABF bypass during that period. Data for an indication- and comorbidity-matched case-control cohort of 19 elective pABF bypass patients were collected for comparison to the rABF bypass group. Primary end points included rate of major complications as well as 30-day and all-cause mortality. Secondary end points were amputation-free survival and freedom from major adverse limb events.ResultsThe rABF bypass patients more frequently underwent prior extra-anatomic or lower extremity bypass operations compared with pABF bypass patients (P = .02); however, no difference was found in the incidence of prior failed endovascular iliac intervention (P = .4). By design, indications for the rABF and pABF bypass groups were the same (claudication, n = 6/6 [31.6%]; P = 1; critical limb ischemia, n = 13/13 [78.4%]; P = 1). Aortic access was more frequently by retroperitoneal exposure in the rABF bypass group (n = 13 vs n = 1; P < .0001), and a significantly higher proportion of the rABF bypass patients required concomitant infrainguinal bypass or intraprocedural adjuncts such as profundaplasty (n = 14 vs n = 5; P = .01). The rABF bypass patients experienced greater blood loss (1097 ± 983 mL vs 580 ± 457 mL; P = .02), received more intraoperative fluids (3400 ± 1422 mL vs 2279 ± 993 mL; P = .01), and had longer overall procedure times (408 ± 102 minutes vs 270 ± 48 minutes; P < .0001). Length of stay (days ± standard deviation) was similar (pABF bypass, 11.2 ± 10.4; rABF bypass, 9.1 ± 4.5; P = .7), and no 30-day or in-hospital deaths occurred in either group. Similar rates of major complications occurred in the two groups (pABF bypass, n = 6 [31.6%]; rABF bypass, n = 4 [21.1%]; observed difference, 9.5%; 95% confidence interval, −17.6% to 36.7%; P = .7). Two-year freedom from major adverse limb events (±standard error mean) was 82% ± 9% vs 78% ± 10% for pABF and rABF bypass patients (log-rank, P = .6). Two-year amputation-free survival was 90 ± 9% vs 89 ± 8% between pABF and rABF bypass patients (P = .5). Two-year survival was 91% ± 9% and 90% ± 9% for pABF and rABF bypass patients (P = .8).ConclusionsPatients undergoing rABF bypass have higher procedural complexity compared with pABF bypass as evidenced by greater operative time, blood loss, and need for adjunctive procedures. However, similar perioperative morbidity, mortality, and midterm survival occurred in comparison to pABF bypass patients. These results support a role for rABF bypass in selected patients

Preoperative prediction of spinal cord ischemia after thoracic endovascular aortic repair

ObjectiveSpinal cord ischemia (SCI) is a devastating but potentially preventable complication of thoracic endovascular aortic repair (TEVAR). The purpose of this analysis was to determine what factors predict SCI after TEVAR.MethodsAll TEVAR procedures at a single institution were reviewed for patient characteristics, prior aortic repair history, aortic centerline of flow analysis, and procedural characteristics. SCI was defined as any lower extremity neurologic deficit that was not attributable to an intracranial process or peripheral neuropathy. Forty-three patient and procedural variables were evaluated individually for association with SCI. Those with the strongest relationships to SCI (P < .1) were included in a multivariable logistic regression model, and a stepwise variable elimination algorithm was bootstrapped to derive a best subset of predictors from this model.ResultsFrom 2002 to 2013, 741 patients underwent TEVAR for various indications, and 68 (9.2%) developed SCI (permanent: n = 38; 5.1%). Because of the lack of adequate imaging for centerline analysis, 586 patients (any SCI, n = 43; 7.4%) were subsequently analyzed. Patients experiencing SCI after TEVAR were older (SCI, 72 ± 11 years; no SCI, 65 ± 15 years; P < .0001) and had significantly higher rates of multiple cardiovascular risk factors. The stepwise selection procedure identified five variables as the most important predictors of SCI: age (odds ratio [OR] multiplies by 1.3 per 10 years; 95% confidence interval [CI], 0.9-1.8, P = .06), aortic coverage length (OR multiplies by 1.3 per 5 cm; CI, 1.1-1.6; P = .002), chronic obstructive pulmonary disease (OR, 1.9; CI, 0.9-4.1; P = .1), chronic renal insufficiency (creatinine concentration ≥ 1.6 mg/dL; OR, 1.9; CI, 0.8-4.2; P = .1), and hypertension (defined as chart history or medication; OR, 6.4; CI, 2.6-18; P < .0001). A logistic regression model with just these five covariates had excellent discrimination (area under the receiver operating characteristic curve = .83) and calibration (χ2 = 9.8; P = .28).ConclusionsThis analysis generated a simple model that reliably predicts SCI after TEVAR. This clinical tool can assist decision-making about when to proceed with TEVAR, guide discussions about intervention risk, and help determine when maneuvers to mitigate SCI risk should be implemented

Long-term results of open and endovascular revascularization of superficial femoral artery occlusive disease

BackgroundFirst-line treatment for patients with superficial femoral arterial (SFA) occlusive disease has yet to be determined. This study compared long-term outcomes between primary SFA stent placement and primary femoral-popliteal bypass. Periprocedural patient factors were examined to determine their effect on these results.MethodsAll femoral-popliteal bypasses and SFA interventions performed in consecutive patients with symptoms Rutherford 3 to 6 between 2001 and 2008 were reviewed. Time-dependent outcomes were analyzed using the Kaplan-Meier method and log-rank test. Cox proportional hazards were performed to determine predictors of graft patency. Multivariate analysis was completed to identify patient covariates most often associated with the primary therapy.ResultsA total of 152 limbs in 141 patients (66% male; mean age, 66 ± 22 years) underwent femoral-popliteal bypass, and 233 limbs in 204 patients (49% male; mean age, 70 ± 11 years) underwent SFA interventions. Four-year primary, primary-assisted, and secondary patency rates were 69%, 78%, and 83%, respectively, for bypass patients and 66%, 91%, and 95%, respectively, for SFA interventions. Six-year limb salvage was 80% for bypass vs 92% for stenting (P = .04). Critical limb ischemia (CLI) and renal insufficiency were predictors of bypass failure. Claudication was a predictor of success for SFA stenting. Three-year limb salvage rates for CLI patients undergoing surgery and SFA stenting were 83%. Amputation-free survival at 3 years for CLI patients was 55% for bypass and 59% for SFA interventions. Multivariate predictors (odds ratios and 95% confidence intervals) of covariates most frequently associated with first-line SFA stenting were TransAtlantic Inter-Society Consensus II A and B lesions (5.9 [3.4-9.1], P < .001), age >70 years (2.1 [1.4-3.1], P < .001), and claudication (1.7 [1.1-2.7], P = .01). Regarding bypass as first-line therapy, claudicant patients were more likely to have nondiabetic status (5.6 [3.3-9.4], P < .001), creatinine <1.8 mg/dL (4.6 [1.5-14.9], P = .01), age <70 years (2.7 [CI, 1.6-8.3], P < .001), and presence of an above-knee popliteal artery target vessel (1.9 [CI, 1.1-3.4] P = .02).ConclusionIndication, patient-specific covariates, and anatomic lesion classification have significant association when determining surgeon selection of SFA stenting or femoral-popliteal bypass as first-line therapy. Patients with SFA disease can have comparable long-term results when treatment options are well matched to patient-specific and anatomic characteristics

A20, a modulator of smooth muscle cell proliferation and apoptosis, prevents and induces regression of neointimal hyperplasia

A20 is a NF‐κB‐dependent gene that has dual anti‐inflammatory and antiapoptotic functions in endothelial cells (EC). The function of A20 in smooth muscle cells (SMC) is unknown. We demonstrate that A20 is induced in SMC in response to inflammatory stimuli and serves an anti‐inflammatory function via blockade of NF‐κB and NF‐κB‐dependent proteins ICAM‐1 and MCP‐1. A20 inhibits SMC proliferation via increased expression of cyclin‐dependent kinase inhibitors p21waf1 and p27kip1. Surprisingly, A20 sensitizes SMC to cytokine‐ and Fas‐mediated apoptosis through a novel NO‐dependent mechanism. In vivo, adenoviral delivery of A20 to medial rat carotid artery SMC after balloon angioplasty prevents neointimal hyperplasia by blocking SMC proliferation and accelerating re‐endothelialization, without causing apoptosis. However, expression of A20 in established neointimal lesions leads to their regression through increased apoptosis. This is the first demonstration that A20 exerts two levels of control of vascular remodeling and healing. A20 prevents neointimal hyperplasia through combined anti‐inflammatory and antiproliferative functions in medial SMC. If SMC evade this first barrier and neointima is formed, A20 has a therapeutic potential by uniquely sensitizing neointimal SMC to apoptosis. A20‐based therapies hold promise for the prevention and treatment of neointimal disease.—Patel, V. I., Daniel, S., Longo, C. R., Shrikhande, G. V., Scali, S. T., Czismadia, E., Groft, C. M., Shukri, T., Motley‐Dore, C., Ramsey, H. E., Fisher, M. D., Grey, S. T., Arvelo, M. B., Ferran, C. A20, a modulator of smooth muscle cell proliferation and apoptosis, prevents and induces regression of neointimal hyperplasia. FASEB J. 20, 1418–1430 (2006)Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154452/1/fsb2fj054981com.pd

Editor's Choice - Optimal Threshold for the Volume-Outcome Relationship After Open AAA Repair in the Endovascular Era : Analysis of the International Consortium of Vascular Registries

Objective: As open abdominal aortic aneurysm (AAA) repair (OAR) rates decline in the endovascular era, the endorsement of minimum volume thresholds for OAR is increasingly controversial, as this may affect credentialing and training. The purpose of this analysis was to identify an optimal centre volume threshold that is associated with the most significant mortality reduction after OAR, and to determine how this reflects contemporary practice. Methods: This was an observational study of OARs performed in 11 countries (2010 - 2016) within the International Consortium of Vascular Registry database (n = 178 302). The primary endpoint was post-operative in hospital mortality. Two different methodologies (area under the receiving operating curve optimisation and Markov chain Monte Carlo procedure) were used to determine the optimal centre volume threshold associated with the most significant mortality improvement. Results: In total, 154 912 (86.9%) intact and 23 390 (13.1%) ruptured AAAs were analysed. The majority (63.1%; n = 112 557) underwent endovascular repair (EVAR) (OAR 36.9%; n = 65 745). A significant inverse relationship between increasing centre volume and lower peri-operative mortality after intact and ruptured OAR was evident (p = 13 procedures/year volume threshold, with significant variation between nations (Germany 11%; Denmark 100%). Conclusion: An annual centre volume of 13 - 16 OARs per year is the optimal threshold associated with the greatest mortality risk reduction after treatment of intact AAA. However, in the current endovascular era, achieving this threshold requires significant re-organisation of OAR practice delivery in many countries, and would affect provision of non-elective aortic services. Low volume centres continuing to offer OAR should aim to achieve mortality results equivalent to the high volume institution benchmark, using validated data from quality registries to track outcomes.Peer reviewe

International Multi-Institutional Experience with Presentation and Management of Aortic Arch Laterality in Aberrant Subclavian Artery and Kommerell's Diverticulum

Background: Aberrant subclavian artery (ASA) with or without Kommerell's diverticulum (KD) is a rare anatomic aortic arch anomaly that can cause dysphagia and/or life-threatening rupture. The objective of this study is to compare outcomes of ASA/KD repair in patients with a left versus right aortic arch. Methods: Using the Vascular Low Frequency Disease Consortium methodology, a retrospective review was performed of patients ≥18 years old with surgical treatment of ASA/KD from 2000 to 2020 at 20 institutions. Results: 288 patients with ASA with or without KD were identified; 222 left-sided aortic arch (LAA), and 66 right-sided aortic arch (RAA). Mean age at repair was younger in LAA 54 vs. 58 years (P = 0.06). Patients in RAA were more likely to undergo repair due to symptoms (72.7% vs. 55.9%, P = 0.01), and more likely to present with dysphagia (57.6% vs. 39.1%, P < 0.01). The hybrid open/endovascular approach was the most common repair type in both groups. Rates of intraoperative complications, death within 30 days, return to the operating room, symptom relief and endoleaks were not significantly different. For patients with symptom status follow-up data, in LAA, 61.7% had complete relief, 34.0% had partial relief and 4.3% had no change. In RAA, 60.7% had complete relief, 34.4% had partial relief and 4.9% had no change. Conclusions: In patients with ASA/KD, RAA patients were less common than LAA, presented more frequently with dysphagia, had symptoms as an indication for intervention, and underwent treatment at a younger age. Open, endovascular and hybrid repair approaches appear equally effective, regardless of arch laterality

A20 Modulates Lipid Metabolism and Energy Production to Promote Liver Regeneration

Background: Liver Regeneration is clinically of major importance in the setting of liver injury, resection or transplantation. We have demonstrated that the NF-$\kappa$B inhibitory protein A20 significantly improves recovery of liver function and mass following extended liver resection (LR) in mice. In this study, we explored the Systems Biology modulated by A20 following extended LR in mice. Methodology and Principal Findings: We performed transcriptional profiling using Affymetrix-Mouse 430.2 arrays on liver mRNA retrieved from recombinant adenovirus A20 (rAd.A20) and rAd.$\beta$galactosidase treated livers, before and 24 hours after 78% LR. A20 overexpression impacted 1595 genes that were enriched for biological processes related to inflammatory and immune responses, cellular proliferation, energy production, oxidoreductase activity, and lipid and fatty acid metabolism. These pathways were modulated by A20 in a manner that favored decreased inflammation, heightened proliferation, and optimized metabolic control and energy production. Promoter analysis identified several transcriptional factors that implemented the effects of A20, including NF-$\kappa$B, CEBPA, OCT-1, OCT-4 and EGR1. Interactive scale-free network analysis captured the key genes that delivered the specific functions of A20. Most of these genes were affected at basal level and after resection. We validated a number of A20's target genes by real-time PCR, including p21, the mitochondrial solute carriers SLC25a10 and SLC25a13, and the fatty acid metabolism regulator, peroxisome proliferator activated receptor alpha. This resulted in greater energy production in A20-expressing livers following LR, as demonstrated by increased enzymatic activity of cytochrome c oxidase, or mitochondrial complex IV. Conclusion: This Systems Biology-based analysis unravels novel mechanisms supporting the pro-regenerative function of A20 in the liver, by optimizing energy production through improved lipid/fatty acid metabolism, and down-regulated inflammation. These findings support pursuit of A20-based therapies to improve patients' outcomes in the context of extreme liver injury and extensive LR for tumor treatment or donation

O-Glycosylation Regulates Ubiquitination and Degradation of the Anti-Inflammatory Protein A20 to Accelerate Atherosclerosis in Diabetic ApoE-Null Mice

Background: Accelerated atherosclerosis is the leading cause of morbidity and mortality in diabetic patients. Hyperglycemia is a recognized independent risk factor for heightened atherogenesis in diabetes mellitus (DM). However, our understanding of the mechanisms underlying glucose damage to the vasculature remains incomplete. Methodology/Principal Findings: High glucose and hyperglycemia reduced upregulation of the NF-κB inhibitory and atheroprotective protein A20 in human coronary endothelial (EC) and smooth muscle cell (SMC) cultures challenged with Tumor Necrosis Factor alpha (TNF), aortae of diabetic mice following Lipopolysaccharide (LPS) injection used as an inflammatory insult and in failed vein-grafts of diabetic patients. Decreased vascular expression of A20 did not relate to defective transcription, as A20 mRNA levels were similar or even higher in EC/SMC cultured in high glucose, in vessels of diabetic C57BL/6 and FBV/N mice, and in failed vein grafts of diabetic patients, when compared to controls. Rather, decreased A20 expression correlated with post-translational O-Glucosamine-N-Acetylation (O-GlcNAcylation) and ubiquitination of A20, targeting it for proteasomal degradation. Restoring A20 levels by inhibiting O-GlcNAcylation, blocking proteasome activity, or overexpressing A20, blocked upregulation of the receptor for advanced glycation end-products (RAGE) and phosphorylation of PKCβII, two prime atherogenic signals triggered by high glucose in EC/SMC. A20 gene transfer to the aortic arch of diabetic ApoE null mice that develop accelerated atherosclerosis, attenuated vascular expression of RAGE and phospho-PKCβII, significantly reducing atherosclerosis. Conclusions: High glucose/hyperglycemia regulate vascular A20 expression via O-GlcNAcylation-dependent ubiquitination and proteasomal degradation. This could be key to the pathogenesis of accelerated atherosclerosis in diabetes