Practice patterns of antiplatelet and anticoagulant therapy after fenestrated/branched endovascular aortic repair.

OBJECTIVE: Antiplatelet and/or anticoagulant therapy are commonly prescribed after fenestrated/branched endovascular aortic repair (F/BEVAR). However, the optimal regimen remains unknown. We sought to characterize practice patterns and outcomes of antiplatelet and anticoagulant use in patients who underwent F/BEVAR. METHODS: Consecutive patients enrolled (2012-2023) as part of the United States Aortic Research Consortium (US-ARC) from 10 independent physician-sponsored investigational device exemption studies were evaluated. The cohort was characterized by medication regimen on discharge from index F/BEVAR: (1) Aspirin alone OR P2Y12 alone (single-antiplatelet therapy [SAPT]); (2) Anticoagulant alone; (3) Aspirin + P2Y12 (dual-antiplatelet therapy [DAPT]); (4) Aspirin + anticoagulant OR P2Y12 + anticoagulant (SAPT + anticoagulant); (5) Aspirin + P2Y12 + anticoagulant (triple therapy [TT]); and (6) No therapy. Kaplan-Meier analysis and Cox proportional hazards modeling were used to compare 1-year outcomes including survival, target artery patency, freedom from bleeding complication, freedom from all reinterventions, and freedom from stent-specific reintervention. RESULTS: Of the 1525 patients with complete exposure and outcome data, 49.6% were discharged on DAPT, 28.8% on SAPT, 13.6% on SAPT + anticoagulant, 3.2% on TT, 2.6% on anticoagulant alone, and 2.2% on no therapy. Discharge medication regimen was not associated with differences in 1-year survival, bleeding complications, composite reintervention rate, or stent-specific reintervention rate. However, there was a significant difference in 1-year target artery patency. On multivariable analysis comparing with SAPT, DAPT conferred a lower hazard of loss of target artery patency (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.27-0.84; P = .01). On sub-analyses of renal stents alone or visceral stents alone, DAPT no longer had a significantly lower hazard of loss of target artery patency (renal: HR, 0.66; 95% CI, 0.35-1.27; P = .22; visceral: HR, 0.31; 95% CI, 0.05-1.9; P = .21). Lastly, duration of DAPT therapy (1 month, 6 months, or 1 year) did not significantly affect target artery patency. CONCLUSIONS: Practice patterns for antiplatelet and anticoagulant regimens after F/BEVAR vary widely across the US-ARC. There were no differences in bleeding complications, survival or reintervention rates among different regimens, but higher branch vessel patency was noted in the DAPT cohort. These data suggest there is a benefit in DAPT therapy. However, the generalizability of this finding is limited by the retrospective nature of this data, and the clinical significance of this finding is unclear, as there is no difference in survival, bleeding, or reintervention rates amongst the different regimens. Hence, an "optimal" regimen, including the duration of such regimen, could not be clearly discerned. This suggests equipoise for a randomized trial, nested within this cohort, to identify the most effective antiplatelet/anticoagulant regimen for the growing number of patients being treated globally with F/BEVAR.

Symptomatic peripheral artery disease increases risk of perioperative mortality following open abdominal aortic aneurysm repair.

OBJECTIVE: Peripheral artery disease (PAD) is associated with worse survival following abdominal aortic aneurysm (AAA) repair. However, little is known about the impact of PAD and sex on outcomes following open infrarenal AAA repair (OAR). METHODS: All elective open infrarenal AAA cases were queried from the Society for Vascular Surgery Vascular Quality Initiative from 2003 to 2022. PAD was defined as history of non-cardiac arterial bypass, non-coronary percutaneous vascular intervention (PVI), or non-traumatic major amputation. Cohorts were stratified by sex and history of PAD. Multivariable logistic regression and Cox proportional hazards models were constructed to assess the primary endpoints: 30-day and 5-year mortality, respectively. RESULTS: Of 4910 patients who underwent elective OAR, 3421 (69.7%) were men without PAD, 298 (6.1%) were men with PAD, 1098 (22.4%) were women without PAD, and 93 (1.9%) were women with PAD. Men with PAD had prior bypass (45%), PVI (62%), and amputation (6.7%). Women with PAD had prior bypass (32%), PVI (76%), and amputation (5.4%). Thirty-day mortality was significantly higher in men with PAD compared with men without PAD (4.4% vs 1.7%; P = .001) and in women with PAD compared with women without PAD (7.5% vs 2.4%; P = .01). After risk adjustment, when compared with men without PAD, women with PAD had nearly four times the odds of 30-day mortality (odds ratio, 3.86; 95% confidence interval [CI], 1.55-9.64; P = .004) and men with PAD had almost three times the odds of 30-day mortality (odds ratio, 2.77; 95% CI, 1.42-5.40; P = .003). Five-year survival was 87.8% in men without PAD, 77.8% in men with PAD, 85% in women without PAD, and 76.2% in women with PAD (P < .001). After risk adjustment, only men with PAD had an increased hazard of death at 5 years (hazard ratio, 1.52; 95% CI, 1.07-2.17; P = .019) compared with men without PAD. CONCLUSIONS: PAD is a potent risk factor for increased perioperative mortality in both men and women following OAR. In women, this equates to nearly four times the odds of perioperative mortality compared with men without PAD. Future study evaluating risk/benefit is needed to determine if women with PAD reflect a high-risk cohort that may benefit from a more conservative OAR threshold for treatment.

Characterizing the frequency and indications for repair of abdominal aortic aneurysms with diameters smaller than recommended by societal guidelines.

OBJECTIVE: Although the Society for Vascular Surgery recommends repair of abdominal aortic aneurysms (AAA) at 5.5 cm or greater in men and 5.0 cm or greater in women, AAA repair below these thresholds has been well-documented. There are clear indications for repair other than these strict size criteria, but the expected proportion of such repairs in one's practice has not been studied. We sought to characterize the indications for repairs of aneurysms below diameter recommendations at a single academic center. Using the assumption that this real-world experience would approximate that of other practices, we then used national data to extrapolate these findings. METHODS: A single-center retrospective review was conducted of all elective open AAA (oAAA) and endovascular aneurysm repair (EVAR) from 2010 to 2020 to assess the incidence of and indications for repair of aneurysms below diameter recommendations (defined as <5.5 cm in men and <5.0 cm in women). Reasons for these repairs were defined as (1) iliac aneurysm, (2) saccular morphology, (3) rapid expansion, (4) patient anxiety, (5) distal embolization, (6) other, and (7) no documented reason. The Vascular Quality Initiative (VQI) was queried for all asymptomatic oAAA and EVAR (2010-2020) and repairs below diameter recommendations were identified. Findings from the single-center analysis were applied to the VQI cohort to extrapolate estimates of reasons for repairs done nationally. In-hospital mortality and major adverse cardiac events (MACE) were compared between those below size recommendations and those meeting size recommendations. RESULTS: Of 456 elective AAA repairs at our center, 147 (32%) were below size recommendations. This finding was more common for EVAR (35% vs 28%). Reasons were: not documented (41%), iliac aneurysm (23%), saccular (10%), rapid expansion (10%), patient anxiety (7%), other (6%), and distal embolism (3%). Of 44,820 elective AAA repairs in the VQI, 17,057 (38%) were below size recommendations (40% EVAR, 26% oAAA). Patients who were repaired below size recommendations had lower in-hospital death (oAAA, 2.4% vs 4.6% [P < .0001]; EVAR, 0.3% vs 0.8% [P < .0001]). When single-center findings were applied to the VQI dataset, an estimated 10,064 repairs were performed nationally for acceptable indications other than size criteria. Conversely, there may have been 6993 repairs (with an associated 35 deaths) performed without documented indication. CONCLUSIONS: Repairs for AAA below the recommended diameter guidelines account for approximately one-third of all elective AAA procedures in both the VQI and our single-center experience. Assuming our practice is typical, nearly 60% of repairs below size recommendations meet the criteria for other clear reasons. The remaining 40% lack a documented reason, meaning that 13% of all elective AAA repairs were done for aneurysms below size recommendations without an acceptable indication. As awareness of overuse and underuse is heightened, these data help to estimate the expected proportion of repairs for less common pathologies. They also provide a potential baseline data point for efforts at decreasing overuse.

Hemoglobin A1c monitoring practices before lower extremity bypass in patients with diabetes vary broadly and do not predict outcomes.

OBJECTIVE: Hemoglobin A1c (HbA1c) is used as a marker of glycemic control, but the role of HbA1c before lower extremity bypass (LEB) in patients with diabetes remains unclear. We sought to characterize patients with diabetes undergoing LEB with and without HbA1c monitoring and to determine if HbA1c monitoring practices correlate with better outcomes. METHODS: The Vascular Quality Initiative was queried for all LEB in patients with diabetes (2010-2020). Patients with diabetes were characterized based on therapy: diet-controlled, noninsulin medication use, or insulin use. Glycemic control was characterized by preoperative HbA1c within 6 months of surgery: unknown control (no HbA1c), well-controlled (HbA1c <7%), poorly-controlled (HbA1c 7%-10%), and uncontrolled (HbA1c >10%). Centers with >5 LEB/y were stratified into terciles according to rate of HbA1c monitoring. The unadjusted associations between glycemic control and in-hospital major adverse limb events, major adverse cardiac events, and mortality were assessed with univariate methods. The independent association of center-level HbA1c monitoring with 5-year survival and 3-year amputation-free survival (AFS) was determined with Kaplan-Meier analyses and Cox regression modeling, adjusted for differences in patient characteristics and center volume. RESULTS: Of 16,092 patients with diabetes undergoing LEB, 4055 (25%) did not have a documented HbA1c. Insulin use was less common in no A1c (48%) and well-controlled diabetes (39%) compared with poorly controlled (67%) and uncontrolled diabetes (78%) (P < .01). In univariate analyses, glycemic control was not associated with differences for in-hospital major adverse limb events, major adverse cardiac events, or mortality. Of 162 centers, HbA1c monitoring practices varied widely (range: 12.5%-100% of LEB). The 3-year AFS and 5-year survival were worse in the highest monitoring tercile vs the lowest (73.6% vs 77.3%, P < .01, 72.1% vs 77.5%, P < .01, respectively). On multivariable analyses, centers in the highest tercile of monitoring had the greatest hazard of AFS (hazard ratio: 1.21, 95% confidence interval: 1.1-1.3, P < .001) and overall mortality (hazard ratio: 1.19, 95% confidence interval: 1.1-1.3, P < 0.001), compared with the centers in the lowest tercile of monitoring. CONCLUSIONS: Patients with diabetes and no preoperative HbA1c monitoring do not have worse LEB outcomes compared with those with HbA1c monitoring. Preoperative HbA1c monitoring varies widely, suggesting broad differences in practice and documentation. Centers with the highest rates of monitoring demonstrated inferior outcomes, likely due to other confounding unmeasured variables. These findings indicate that HbA1c monitoring before LEB, unto itself, should not be used as a measure of surgical quality.

Adaptor complex AP2/PICALM, through interaction with LC3, targets Alzheimer's APP-CTF for terminal degradation via autophagy.

The hallmarks of Alzheimer's disease (AD) are the aggregates of amyloid-ß (Aß) peptides and tau protein. Autophagy is a major cellular pathway leading to the removal of aggregated proteins. We have reported recently that autophagy was responsible for amyloid precursor protein cleaved C-terminal fragment (APP-CTF) degradation and amyloid ß clearance in an Atg5-dependent manner. Here we aimed to elucidate the molecular mechanism by which autophagy mediates the degradation of APP-CTF and the clearance of amyloid ß. Through affinity purification followed by mass spectrum analysis, we identified adaptor protein (AP) 2 together with phosphatidylinositol clathrin assembly lymphoid-myeloid leukemia (PICALM) as binding proteins of microtubule-associated protein 1 light chain 3 (LC3). Further analysis showed that AP2 regulated the cellular levels of APP-CTF. Knockdown of AP2 reduced autophagy-mediated APP-CTF degradation. Immunoprecipitation and live imaging analysis demonstrated that AP2 and PICALM cross-link LC3 with APP-CTF. These data suggest that the AP-2/PICALM complex functions as an autophagic cargo receptor for the recognition and shipment of APP-CTF from the endocytic pathway to the LC3-marked autophagic degradation pathway. This molecular mechanism linking AP2/PICALM and AD is consistent with genetic evidence indicating a role for PICALM as a risk factor for AD.

Innominate artery pseudoaneurysm from a Salter-Harris fracture of the sternoclavicular joint.

Fractures and dislocations of the sternoclavicular joint (SCJ) are uncommon, accounting for <5% of all shoulder girdle injuries. They are relatively more common in the pediatric population than in the adult population and can often present concurrently as a posteriorly displaced medial clavicular dislocation with a fracture through the unfused physis. It is especially important to recognize this injury, because its management and potential sequelae are very different from those for fractures of the clavicle shaft. This type of injury frequently requires closed or open operative management because fracture-dislocation of the SCJ can be associated with potentially serious complications such as pneumothorax, brachial plexus injury, vagus nerve injury, tracheal injury, and vascular compromise. Few case reports describe fracture-dislocation of the SCJ resulting in vascular injuries. We describe the case of a 17-year-old boy who sustained a blunt hockey injury resulting in a right physeal fracture-dislocation of the SCJ causing an innominate artery pseudoaneurysm. This was treated with excision of the pseudoaneurysm, bovine pericardial patch angioplasty repair of the innominate artery, and open reduction and internal fixation of the medial clavicular physeal fracture.

Trends in General Surgery Operative Experience Obtained by Integrated Vascular Surgery Residents.

OBJECTIVE: When the integrated vascular surgery training pathway was introduced, training was comprised of nearly equal amounts of core general surgery and vascular surgery experience. However, specific requirements for case numbers or types were not defined. Over time, the time spent on core general surgery requirements has been reduced, most recently in 2018, from 24 to 18 months. We sought to determine trends in general surgery case volume and type over the past 10 years for vascular surgery residents. METHODS: We conducted a retrospective review of the Accreditation Council for Graduate Medical Education case log data for integrated vascular surgery graduates from 2012-2018. We evaluated trends in mean numbers of cases, categorized as general surgery open (GS-open), general surgery laparoscopic (GS-laparoscopic), vascular surgery open (VS-open), and vascular surgery endovascular (VS-endo). Cases were also categorized by anatomic region as head/neck, thoracic, or abdominal. RESULTS: The mean number of total head/neck, thoracic, or abdominal cases logged by graduating integrated vascular surgery trainees was 263.5. This total, as well as the proportion of general surgery cases (35%-38%, p = 0.99) has remained constant over time. The type of general surgery cases has changed significantly, with an upward trend in the mean number of GS-open cases and downward trend in mean GS-laparoscopic cases (GS-open p = 0.006, GS-laparoscopic p = 0.048). Among head/neck and thoracic subgroups, no significant changes were observed, while in the abdominal subgroup, there has been a significant increase in GS-open over time (p = 0.005). Additionally, the number of open vascular abdominal aortic cases has remained stable, with an average of 36.82 per graduating trainee per year. CONCLUSIONS: In the 10 years since the introduction of integrated vascular surgery programs, total case volume and proportion of general surgery cases have remained remarkably stable. The type of general surgery cases has shifted though, with a decrease in GS-laparoscopic cases, replaced primarily by open abdominal cases. These changes likely reflect integrated vascular residents actively seeking out these opportunities during their core rotations and a willingness by general surgery partners to provide these opportunities. At the program level, these data may help guide program directors' choices about the specific core rotations they incorporate into their curriculum. At the national level, this information may contribute to future discussions regarding the optimal number of core general surgery rotation requirements.

Explantation of infected thoracic endovascular aortic repair.

Prosthetic graft infection is a rare and serious complication of thoracic endovascular aortic repair associated with high mortality and posing unique challenges for treatment. The prosthetic graft infection is often identified late as patients present with mild nonspecific symptoms. We describe the successful medical management and surgical explantation of an infected thoracic endograft with an aorta-bronchial fistula, using an inline reconstruction with an antibiotic-soaked synthetic graft. In this report, we provide an example of a patient with an infected thoracic endograft and how inline reconstruction combined with appropriate medical management is an acceptable treatment strategy.

Amyloid-ß oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons.

Disruption of fast axonal transport (FAT) is an early pathological event in Alzheimer's disease (AD). Soluble amyloid-ß oligomers (AßOs), increasingly recognized as proximal neurotoxins in AD, impair organelle transport in cultured neurons and transgenic mouse models. AßOs also stimulate hyperphosphorylation of the axonal microtubule-associated protein, tau. However, the role of tau in FAT disruption is controversial. Here we show that AßOs reduce vesicular transport of brain-derived neurotrophic factor (BDNF) in hippocampal neurons from both wild-type and tau-knockout mice, indicating that tau is not required for transport disruption. FAT inhibition is not accompanied by microtubule destabilization or neuronal death. Significantly, inhibition of calcineurin (CaN), a calcium-dependent phosphatase implicated in AD pathogenesis, rescues BDNF transport. Moreover, inhibition of protein phosphatase 1 and glycogen synthase kinase 3ß, downstream targets of CaN, prevents BDNF transport defects induced by AßOs. We further show that AßOs induce CaN activation through nonexcitotoxic calcium signaling. Results implicate CaN in FAT regulation and demonstrate that tau is not required for AßO-induced BDNF transport disruption.

A glycine zipper motif mediates the formation of toxic ß-amyloid oligomers in vitro and in vivo.

BACKGROUND: The ß-amyloid peptide (Aß) contains a Gly-XXX-Gly-XXX-Gly motif in its C-terminal region that has been proposed to form a "glycine zipper" that drives the formation of toxic Aß oligomers. We have tested this hypothesis by examining the toxicity of Aß variants containing substitutions in this motif using a neuronal cell line, primary neurons, and a transgenic C. elegans model. RESULTS: We found that a Gly37Leu substitution dramatically reduced Aß toxicity in all models tested, as measured by cell dysfunction, cell death, synaptic alteration, or tau phosphorylation. We also demonstrated in multiple models that Aß Gly37Leu is actually anti-toxic, thereby supporting the hypothesis that interference with glycine zipper formation blocks assembly of toxic Aß oligomers. To test this model rigorously, we engineered second site substitutions in Aß predicted by the glycine zipper model to compensate for the Gly37Leu substitution and expressed these in C. elegans. We show that these second site substitutions restore in vivo Aßtoxicity, further supporting the glycine zipper model. CONCLUSIONS: Our structure/function studies support the view that the glycine zipper motif present in the C-terminal portion of Aß plays an important role in the formation of toxic Aß oligomers. Compounds designed to interfere specifically with formation of the glycine zipper could have therapeutic potential.