Incidence, predictive factors, and outcomes of intraprocedure adverse events during fenestrated-branched endovascular aortic repair of complex abdominal and thoracoabdominal aortic aneurysms.

OBJECTIVE: To evaluate the incidence of intraoperative adverse events (IAEs) and their impact on outcomes after fenestrated-branched endovascular aortic repair (FB-EVAR) of complex abdominal aortic aneurysms and thoracoabdominal aortic aneurysm (TAAAs). METHODS: We reviewed the clinical and imaging data of 600 consecutive patients (445 males; mean age, 75 ± 8 years) who underwent FB-EVAR between 2007 and 2019 in a single institution. IAE was defined as any intraoperative complication or technical problem requiring additional and unplanned procedures, and was classified as access-related, target artery (TA)-related, or graft-related. End points included rates of IAEs, 30-day or in-hospital mortality, major adverse events, patient survival, freedom from secondary intervention, and TA instability. RESULTS: A total of 122 IAEs were identified in 105 patients (18%). IAEs were TA-related in 55 patients (9%), access-related in 46 patients (8%), and graft-related in seven patients (1%). Female sex was more frequent among patients with IAEs (44% vs 22%; P < .001). Patients with IAEs had smaller renal artery diameter (-0.4 mm, 5.4 ± 0.8 mm vs 5.8 ± 0.9 mm; P < .001), and were treated more often for TAAAs (72% vs 54%; P < .03). Technical success was achieved in 96.5% of patients and was lower for patients with IAEs (82% vs 99%; P < .001). Major adverse events were significantly more frequent among patients who had IAEs (odds ratio [OR], 1.98; 95% confidence interval [CI], 1.21-3.25), most due to acute kidney injury (27% vs 11%; P < .001) including new-onset dialysis (5% vs 1%; P = .01). On multivariate logistic regression model, female sex (OR, 2.5; 95% CI, 1.5-4.0), TA stenosis >50% (OR, 2.0; 95% CI, 1.3-3.3), and Crawford Extent II TAAA (OR, 1.9; 95% CI, 1.1-3.3) were predictive of IAEs, whereas preloaded design (OR, 0.6; 95% CI, 0.4-0.9) and TA diameter (+1 mm; OR, 0.6; 95% CI, 0.4-0.9) were protective of IAEs. IAEs negatively affected secondary intervention (hazard ratio [HR], 1.6; 95% CI, 1.1-2.3) and TA instability (HR, 2.5; 95% CI, 1.2-5.4); however, IAEs did not affect patient survival (HR, 1.0; 95% CI, 0.7-1.4). CONCLUSIONS: IAEs are common, occurring in nearly one of five patients treated with FB-EVAR for complex aortic aneurysms, and have a negative impact on clinical outcomes. IAEs were associated with female sex, TA diameter, and more extensive aortic disease.

Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies Chuvash polycythemia.

Chuvash polycythemia is a rare congenital form of polycythemia caused by homozygous R200W and H191D mutations in the VHL (von Hippel-Lindau) gene, whose gene product is the principal negative regulator of hypoxia-inducible factor. However, the molecular mechanisms underlying some of the hallmark abnormalities of Chuvash polycythemia, such as hypersensitivity to erythropoietin, are unclear. Here we show that VHL directly binds suppressor of cytokine signaling 1 (SOCS1) to form a heterodimeric E3 ligase that targets phosphorylated JAK2 (pJAK2) for ubiquitin-mediated destruction. In contrast, Chuvash polycythemia-associated VHL mutants have altered affinity for SOCS1 and do not engage with and degrade pJAK2. Systemic administration of a highly selective JAK2 inhibitor, TG101209, reversed the disease phenotype in Vhl(R200W/R200W) knock-in mice, an experimental model that recapitulates human Chuvash polycythemia. These results show that VHL is a SOCS1-cooperative negative regulator of JAK2 and provide biochemical and preclinical support for JAK2-targeted therapy in individuals with Chuvash polycythemia.