Salvatore T. Scali

National trends and regional variation of open and endovascular repair of thoracic and thoracoabdominal aneurysms in contemporary practice

OBJECTIVES Successful surgical management of thoracic aortic aneurysms (TAA) and thoracoabdominal aortic aneurysms (TAAA) has historically relied upon open surgical repair (OSR). More recently, the advent and application of thoracic endovascular stent graft aneurysm repair (TEVAR) permutations have become increasingly performed in contemporary practice. To better determine the effect of TEVAR techniques on OSR, we examined national and regional trends in treatment use. METHODS All Medicare patients from 1998 through 2007 undergoing isolated TAA and TAAA repair were analyzed using a clinically validated algorithm using diagnostic International Classification of Disease 9th revision (ICD-9; 441.1, 441.2, 441.6, 441.7, 441.9) codes and procedural (ICD-9 OSR: 38.35, 38.45 and TEVAR: 39.73, 39.79) codes. Differential rates of OSR and TEVAR were compared across census tract regions during the study interval. RESULTS Total complex aortic repairs increased by 60%, from 10.8 to 17.8/100,000, between 1998 and 2007 (P < .001). A dramatic increase occurred in TEVAR (not performed in 1998, 5.8/100,000 in 2007) during the study period, but OSR rates remained stable during the same interval (10.7 to 12.0/100,000 in 2007, P = NS). There was substantial regional variation for both OSR and TEVAR. This regional variation was greater in OSR (range, 8.8-16.7/100,000) than in TEVAR (range, 4.5-6.9/100,000). CONCLUSIONS Degenerative TAA and TAAA aneurysms are being repaired in the United States at an increasing rate. This reflects the rapid acceptance of TEVAR, which apparently supplements rather than supplants OSR. There appears to be greater regional variation in OSR compared with TEVAR. These data may have significant implications for those interested in the effect of new technologies on health care and cost containment.

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)

Three-dimensional fusion computed tomography decreases radiation exposure, procedure time, and contrast use during fenestrated endovascular aortic repair.

OBJECTIVE Endovascular surgery has revolutionized the treatment of aortic aneurysms; however, these improvements have come at the cost of increased radiation and contrast exposure, particularly for more complex procedures. Three-dimensional (3D) fusion computed tomography (CT) imaging is a new technology that may facilitate these repairs. The purpose of this analysis was to determine the effect of using intraoperative 3D fusion CT on the performance of fenestrated endovascular aortic repair (FEVAR). METHODS Our institutional database was reviewed to identify patients undergoing branched or FEVAR. Patients treated using 3D fusion CT were compared with patients treated in the immediate 12-month period before implementation of this technology when procedures were performed in a standard hybrid operating room without CT fusion capabilities. Primary end points included patient radiation exposure (cumulated air kerma: mGy), fluoroscopy time (minutes), contrast usage (mL), and procedure time (minutes). Patients were grouped by the number of aortic graft fenestrations revascularized with a stent graft, and operative outcomes were compared. RESULTS A total of 72 patients (41 before vs 31 after 3D fusion CT implementation) underwent FEVAR from September 2012 through March 2014. For two-vessel fenestrated endografts, there was a significant decrease in radiation exposure (3400 ± 1900 vs 1380 ± 520 mGy; P = .001), fluoroscopy time (63 ± 29 vs 41 ± 11 minutes; P = .02), and contrast usage (69 ± 16 vs 26 ± 8 mL; P = .0002) with intraoperative 3D fusion CT. Similarly, for combined three-vessel and four-vessel FEVAR, significantly decreased radiation exposure (5400 ± 2225 vs 2700 ± 1400 mGy; P < .0001), fluoroscopy time (89 ± 36 vs 64 ± 21 minutes; P = .02), contrast usage (90 ± 25 vs 39 ± 17 mL; P < .0001), and procedure time (330 ± 100 vs 230 ± 50 minutes; P = .002) was noted. Estimated blood loss was significantly less (P < .0001), and length of stay had a trend (P = .07) toward being lower for all patients in the 3D fusion CT group. CONCLUSIONS These results demonstrate that use of intraoperative 3D fusion CT imaging during FEVAR can significantly decrease radiation exposure, procedure time, and contrast usage, which may also decrease the overall physiologic impact of the repair.

Efficacy of thoracic endovascular stent repair for chronic type B aortic dissection with aneurysmal degeneration

BACKGROUND The Food and Drug Administration has approved devices for endovascular management of thoracic endovascular aortic aneurysm repair (TEVAR); however, limited data exist describing the outcomes of TEVAR for aneurysms attributable to chronic type B aortic dissection (cTBAD). This study was undertaken to determine the results of endovascular treatment of cTBAD with aneurysmal degeneration. METHODS A retrospective analysis of all patients treated for cTBAD with aneurysmal degeneration at the University of Florida from 2004 to 2011 was performed. Computed tomograms with centerline reconstruction were analyzed to determine change in aortic diameter, relative proportions of aortic treatment lengths, and false lumen perfusion status. Reintervention and mortality were estimated using life-tables. Cox regression analysis was completed to predict mortality. RESULTS Eighty patients underwent TEVAR for aneurysm due to cTBAD (mean age [± standard deviation], 60 ± 13 years [male, 87.5%; n = 70]; median follow-up, 26 [range, 1-74] months). Median time from diagnosis of TBAD to TEVAR was 16 (range, 1-72) months. Prior aortic root/arch replacement had been performed in 29% (n = 23) at a median interval of 28.5 (range, 0.5-312) months. Mean preoperative aneurysm diameter was 62.0 ± 9.9 mm. In 75% (n = 60) of cases, coverage was proximal to zone 3, and 24% (n = 19) underwent carotid-subclavian bypass or other arch debranching procedure. Spinal drains were used in 78% (pre-op 71%, n = 57; post-op 6%, n = 5). Length of stay was 6.5 ± 4.7 days with a composite morbidity of 26% and in-hospital mortality of 2.5% (n = 2). Overall neurologic event rate was 17% (spinal cord ischemia 10% [n = 8], with a permanent deficit observed in 6.2% [n = 5]; stroke 7.5%). Aneurysm diameter reduced or stabilized in 65%. The false lumen thrombosed completely within the thoracic aorta in 52%, and reintervention within the treated aortic segment was required in 16% (n = 13).One- and 3-year freedom from reintervention (with 95% confidence interval [CI]) was 80% (range, 68%-88%) and 70% (range, 57%-80%), respectively. Survival at 1 and 5 years was 89% (range, 80%-94%) and 70% (range, 55%-81%) and was not significantly different among patients requiring reintervention or experiencing favorable aortic remodeling. Multivariable analysis identified coronary artery disease (hazard ratio [HR], 6.4; 95% CI, 2.3-17.7; P < .005), prior infrarenal aortic surgery (HR, 8.6; 95% CI, 2.3-31.7; P = .001), and congestive heart failure (HR, 11.9; 95% CI, 1.9-73.8; P = .008) as independent risk factors for mortality. Hyperlipidemia was found to be protective (HR, 0.2; 95% CI, 0.05-0.6; P = .004). No significant difference in predictors of mortality were found between patients who underwent reintervention vs those who did not (P = .2). CONCLUSIONS TEVAR for cTBAD with aneurysmal degeneration can be performed safely but spinal cord ischemia rates may be higher than previously reported. Liberal use of procedural adjuncts to reduce this complication, such as spinal drainage, is recommended. Reintervention is common, but long-term survival does not appear to be impacted by remediation.

Variations in Abdominal Aortic Aneurysm Care: A Report from the International Consortium of Vascular Registries

Background: This project by the ICVR (International Consortium of Vascular Registries), a collaboration of 11 vascular surgical quality registries, was designed to evaluate international variation in the contemporary management of abdominal aortic aneurysm (AAA) with relation to recommended treatment guidelines from the Society for Vascular Surgery and the European Society for Vascular Surgery. Methods: Registry data for open and endovascular AAA repair (EVAR) during 2010 to 2013 were collected from 11 countries. Variations in patient selection and treatment were compared across countries and across centers within countries. Results: Among 51 153 patients, 86% were treated for intact AAA (iAAA) and 14% for ruptured AAA. Women constituted 18% of the entire cohort (range, 12% in Switzerland–21% in the United States; P<0.01). Intact AAAs were repaired at diameters smaller than recommended by guidelines in 31% of men (<5.5 cm; range, 6% in Iceland–41% in Germany; P<0.01) and 12% of women with iAAA (<5 cm; range, 0% in Iceland–16% in the United States; P<0.01). Overall, use of EVAR for iAAA varied from 28% in Hungary to 79% in the United States (P<0.01) and for ruptured AAA from 5% in Denmark to 52% in the United States (P<0.01). In addition to the between-country variations, significant variations were present between centers in each country in terms of EVAR use and rate of small AAA repair. Countries that more frequently treated small AAAs tended to use EVAR more frequently (trend: correlation coefficient, 0.51; P=0.14). Octogenarians made up 23% of all patients, ranging from 12% in Hungary to 29% in Australia (P<0.01). In countries with a fee-for-service reimbursement system (Australia, Germany, Switzerland, and the United States), the proportions of small AAA (33%) and octogenarians undergoing iAAA repair (25%) were higher compared with countries with a population-based reimbursement model (small AAA repair, 16%; octogenarians, 18%; P<0.01). In general, center-level variation within countries in the management of AAA was as important as variation between countries. Conclusions: Despite homogeneous guidelines from professional societies, significant variation exists in the management of AAA, most notably for iAAA diameter at repair, use of EVAR, and the treatment of elderly patients. ICVR provides an opportunity to study treatment variation across countries and to encourage optimal practice by sharing these results.

A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1‐dependent mechanism

The liver has a remarkable regenerative capacity, allowing recovery following injury. Regeneration after injury is contingent on maintenance of healthy residual liver mass, otherwise fulminant hepatic failure (FHF) may arise. Understanding the protective mechanisms safeguarding hepatocytes and promoting their proliferation is critical for devising therapeutic strategies for FHF. We demonstrate that A20 is part of the physiological response of hepatocytes to injury. In particular, A20 is significantly upregulated in the liver following partial hepatectomy. A20 protects hepatocytes from apoptosis and ongoing inflammation by inhibiting NF‐κB. Hepatic expression of A20 in BALB/c mice dramatically improves survival following extended and radical lethal hepatectomy. A20 expression in the liver limits hepatocellular damage hence maintains bilirubin clearance and the liver synthetic function. In addition, A20 confers a proliferative advantage to hepatocytes via decreased expression of the cyclin‐dependent kinase inhibitor p21waf1. In conclusion, A20 provides a proliferative advantage to hepatocytes. By combining anti‐inflammatory, antiapoptotic and pro‐proliferative functions, A20‐based therapies could be beneficial in prevention and treatment of FHF. (HEPATOLOGY 2005;42:156–164.)

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.

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

OBJECTIVE Spinal 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. METHODS A 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. RESULTS A 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. CONCLUSIONS The 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.

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

BACKGROUND First-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. METHODS All 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. RESULTS A 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). CONCLUSION Indication, 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.

Treatment of acute visceral aortic pathology with fenestrated/branched endovascular repair in high-surgical-risk patients

OBJECTIVE The safety and feasibility of fenestrated/branched endovascular repair of acute visceral aortic disease in high-risk patients is unknown. The purpose of this report is to describe our experience with surgeon-modified endovascular aneurysm repair (sm-EVAR) for the urgent or emergent treatment of pathology involving the branched segment of the aorta in patients deemed to have prohibitively high medical and/or anatomic risk for open repair. METHODS A retrospective review was performed on all patients treated with sm-EVAR for acute indications. Planning was based on three-dimensional computed tomographic angiogram reconstructions and graft configurations included various combinations of branch, fenestration, or scallop modifications. RESULTS Sixteen patients (mean age [± standard deviation], 68 ± 10 years; 88% male) deemed high risk for open repair underwent urgent or emergent repair using sm-EVAR. Indications included degenerative suprarenal or thoracoabdominal aneurysm (six), presumed or known mycotic aneurysm (four), anastomotic pseudoaneurysm (three), false lumen rupture of type B dissection (two), and penetrating aortic ulceration (one). Nine (56%) had previous aortic surgery and all patients were either American Society of Anesthesiologists class IV (n = 9) or IV-E (n = 7). A total of 40 visceral vessels (celiac, 10; superior mesenteric artery, 10; right renal artery, 10; left renal artery, 10) were revascularized with a combination of fenestrations (33), directional graft branches (six), and graft scallops (one). Technical success was 94% (n = 15/16), with one open conversion. Median contrast use was 126 mL (range, 41-245) and fluoroscopy time was 70 minutes (range, 18-200). Endoleaks were identified intraoperatively in four patients (type II, n = 3; type IV, n = 1), but none have required remediation. Mean length of stay was 12 ± 15 days (median, 5.5; range, 3-59). Single complications occurred in five (31%) patients as follows: brachial sheath hematoma (one), stroke (one), ileus (one), respiratory failure (one), and renal failure (one). An additional patient experienced multiple complications including spinal cord ischemia (one) and multiorgan failure resulting in death (n = 1; in-hospital mortality, 6.3%). The majority of patients were discharged to home (63%; n = 10) or short-term rehabilitation units (25%; n = 4), while one patient required admission to a long-term acute care setting. There were no reinterventions at a median follow-up of 6.2 (range, 1-16.1) months. Postoperative computed tomographic angiogram was available for all patients and demonstrated 100% branch vessel patency, with one type III endoleak pending intervention. There were two late deaths at 1.4 and 13.4 months due to nonaortic-related pathology. CONCLUSIONS Urgent or emergent treatment of acute pathology involving the visceral aortic segment with fenestrated/branched endograft repair is feasible and safe in selected high-risk patients; however, the durability of these repairs is yet to be determined.