The association between sex and outcomes after thoracic endovascular repair for acute type B aortic dissection.

OBJECTIVE: Prior literature has found worse outcomes for female patients after endovascular repair of abdominal aortic aneurysm and mixed findings after thoracic endovascular aortic repair (TEVAR) for thoracic aortic aneurysm. However, the influence of sex on outcomes after TEVAR for acute type B aortic dissection (aTBAD) is not fully elucidated. METHODS: We identified patients who underwent TEVAR for aTBAD (<30 days) in the Vascular Quality Initiative from 2014 to 2022. We excluded patients with an entry tear or stent seal within the ascending aorta or aortic arch and patients with an unknown proximal tear location. Included patients were stratified by biological sex, and we analyzed perioperative outcomes and 5-year mortality with multivariable logistic regression and Cox regression analysis, respectively. Furthermore, we analyzed adjusted variables for interaction with female sex. RESULTS: We included 1626 patients, 33% of whom were female. At presentation, female patients were significantly older (65 [interquartile range: 54, 75] years vs 56 [interquartile range: 49, 68] years; P = .01). Regarding indications for repair, female patients had higher rates of pain (85% vs 80%; P = .02) and lower rates of malperfusion (23% vs 35%; P < .001), specifically mesenteric, renal, and lower limb malperfusion. Female patients had a lower proportion of proximal repairs in zone 2 (39% vs 48%; P < .01). After TEVAR for aTBAD, female sex was associated with comparable odds of perioperative mortality to males (8.1 vs 9.2%; adjusted odds ratio [aOR]: 0.79 [95% confidence interval (CI): 0.51-1.20]). Regarding perioperative complications, female sex was associated with lower odds for cardiac complications (2.3% vs 4.7%; aOR: 0.52 [95% CI: 0.26-0.97]), but all other complications were comparable between sexes. Compared with male sex, female sex was associated with similar risk for 5-year mortality (26% vs 23%; adjusted hazard ratio: 1.01 [95% CI: 0.77-1.32]). On testing variables for interaction with sex, female sex was associated with lower perioperative and 5-year mortality at older ages relative to males (aOR: 0.96 [0.93-0.99] | adjusted hazard ratio: 0.97 [0.95-0.99]) and higher odds of perioperative mortality when mesenteric malperfusion was present (OR: 2.71 [1.04-6.96]). CONCLUSIONS: Female patients were older, less likely to have complicated dissection, and had more distal proximal landing zones. After TEVAR for aTBAD, female sex was associated with similar perioperative and 5-year mortality to male sex, but lower odds of in-hospital cardiac complications. Interaction analysis showed that females were at additional risk for perioperative mortality when mesenteric ischemia was present. These data suggest that TEVAR for aTBAD overall has a similar safety profile in females as it does for males.

The impact of urgency of repair on outcomes following thoracic endovascular aortic repair for blunt thoracic aortic injury.

OBJECTIVE: Current societal recommendations regarding the timing of thoracic endovascular aortic repair (TEVAR) for blunt thoracic aortic injury (BTAI) vary. Prior studies have shown that elective repair was associated with lower mortality after TEVAR for BTAI. However, these studies lacked data such as Society for Vascular Surgery (SVS) aortic injury grades and TEVAR-related postoperative outcomes. Therefore, we used the Vascular Quality Initiative registry, which includes relevant anatomic and outcome data, to examine the outcomes following urgent/emergent (≤ 24 hours) vs elective TEVAR for BTAI. METHODS: Patients undergoing TEVAR for BTAI between 2013 and 2022 were included, excluding those with SVS grade 4 aortic injuries. We included covariates such as age, sex, race, transfer status, body mass index, preoperative hemoglobin, comorbidities, medication use, SVS aortic injury grade, coexisting injuries, Glasgow Coma Scale, and prior aortic surgery in a regression model to compute propensity scores for assignment to urgent/emergent or elective TEVAR. Perioperative outcomes and 5-year mortality were evaluated using inverse probability-weighted logistic regression and Cox regression, also adjusting for left subclavian artery revascularization/occlusion and annual center and physician volumes. RESULTS: Of 1016 patients, 102 (10%) underwent elective TEVAR. Patients who underwent elective repair were more likely to undergo revascularization of the left subclavian artery (31% vs 7.5%; P < .001) and receive intraoperative heparin (94% vs 82%; P = .002). After inverse probability weighting, there was no association between TEVAR timing and perioperative mortality (elective vs urgent/emergent: 3.9% vs 6.6%; odds ratio [OR], 1.1; 95% confidence interval [CI], 0.27-4.7; P = .90) and 5-year mortality (5.8% vs 12%; hazard ratio [HR], 0.95; 95% CI, 0.21-4.3; P > .9).Compared with urgent/emergent TEVAR, elective repair was associated with lower postoperative stroke (1.0% vs 2.1%; adjusted OR [aOR], 0.12; 95% CI, 0.02-0.94; P = .044), even after adjusting for intraoperative heparin use (aOR, 0.12; 95% CI, 0.02-0.92; P = .042). Elective TEVAR was also associated with lower odds of failure of extubation immediately after surgery (39% vs 65%; aOR, 0.18; 95% CI, 0.09-0.35; P < .001) and postoperative pneumonia (4.9% vs 11%; aOR, 0.34; 95% CI, 0.13-0.91; P = .031), but comparable odds of any postoperative complication as a composite outcome and reintervention during index admission. CONCLUSIONS: Patients with BTAI who underwent elective TEVAR were more likely to receive intraoperative heparin. Perioperative mortality and 5-year mortality rates were similar between the elective and emergent/urgent TEVAR groups. Postoperatively, elective TEVAR was associated with lower ischemic stroke, pulmonary complications, and prolonged hospitalization. Future modifications in society guidelines should incorporate the current evidence supporting the use of elective TEVAR for BTAI. The optimal timing of TEVAR in patients with BTAI and the factors determining it should be the subject of future study to facilitate personalized decision-making.

Outcomes following thoracic endovascular aortic repair for blunt thoracic aortic injury stratified by Society for Vascular Surgery grade.

OBJECTIVES: Although the Society for Vascular Surgery (SVS) aortic injury grading system is used to depict the severity of injury in patients with blunt thoracic aortic injury, prior literature on its association with outcomes after thoracic endovascular aortic repair (TEVAR) is limited. METHODS: We identified patients undergoing TEVAR for BTAI within the VQI between 2013 and 2022. We stratified patients based on their SVS aortic injury grade (grade 1, intimal tear; grade 2, intramural hematoma; grade 3, pseudoaneurysm; and grade 4, transection or extravasation). We assessed perioperative outcomes and 5-year mortality using multivariable logistic and Cox regression analyses. Secondarily, we assessed the proportional trends in patients undergoing TEVAR based on SVS aortic injury grade over time. RESULTS: Overall, 1311 patients were included (grade1, 8%; grade 2, 19%; grade 3, 57%; grade 4, 17%). Baseline characteristics were similar, except for a higher prevalence of renal dysfunction, severe chest injury (Abbreviated Injury Score >3), and lower Glasgow Coma Scale with increasing aortic injury grade (Ptrend < .05). Rates of perioperative mortality by aortic injury grade were as follows: grade 1, 6.6%; grade 2, 4.9%; grade 3, 7.2%; and grade 4, 14% (Ptrend = .003) and 5-year mortality rates were 11% for grade 1, 10% for grade 2, 11% for grade 3, and 19% for grade 4 (P = .004). Patients with grade 1 injury had a high rate of spinal cord ischemia (2.8% vs grade 2, 0.40% vs grade 3, 0.40% vs grade 4, 2.7%; P = .008). After risk adjustment, there was no association between aortic injury grade and perioperative mortality (grade 4 vs grade 1, odds ratio, 1.3; 95% confidence interval, 0.50-3.5; P = .65), or 5-year mortality (grade 4 vs grade 1, hazard ratio, 1.1; 95% confidence interval, 0.52-2.30; P = .82). Although there was a trend for decrease in the proportion of patients undergoing TEVAR with a grade 2 BTAI (22% to 14%; Ptrend = .084), the proportion for grade 1 injury remained unchanged over time (6.0% to 5.1%; Ptrend = .69). CONCLUSIONS: After TEVAR for BTAI, there was higher perioperative and 5-year mortality in patients with grade 4 BTAI. However, after risk adjustment, there was no association between SVS aortic injury grade and perioperative and 5-year mortality in patients undergoing TEVAR for BTAI. More than 5% of patients with BTAI who underwent TEVAR had a grade 1 injury, with a concerning rate of spinal cord ischemia potentially attributable to TEVAR, and this proportion did not decrease over time. Further efforts should focus on enabling careful selection of patients with BTAI who will experience more benefit than harm from operative repair and preventing the inadvertent use of TEVAR in low-grade injuries.

The association between diabetes mellitus and its management with outcomes following endovascular repair for descending thoracic aortic aneurysm.

OBJECTIVE: Prior literature is conflicted regarding the effect of diabetes mellitus (DM) on outcomes after endovascular repair of aortic aneurysms. In this study, we aimed to examine the association between DM and outcomes after thoracic endovascular aneurysm repair (TEVAR) for thoracic aortic aneurysm (TAA). METHODS: We identified patients who underwent TEVAR for TAA of the descending thoracic aorta in the Vascular Quality Initiative between 2014 and 2022. We created two cohorts, DM and nonDM, based on the patient's preoperative DM status, and secondarily substratified patients with DM by management strategy: dietary management, noninsulin medications, and insulin therapy cohorts. Outcomes included perioperative and 5-year mortality, in-hospital complications, indications for repair, and 1-year sac dynamics, which were analyzed with multivariable cox regression, multivariable logistic regression, and χ2 tests, respectively. RESULTS: We identified 2637 patients, of which 473 (18%) had DM preoperatively. Among patients with DM, 25% were diet controlled, 54% noninsulin medications, and 21% insulin therapy. Within patients who underwent TEVAR for TAA, the proportions of ruptured presentation were higher in the dietary-managed (11.1%) and insulin-managed (14.3%) cohorts relative to noninsulin therapy (6.6%) and those without DM (6.9%). After multivariable regression analysis, we found that DM was associated with similar perioperative mortality (odds ratio, 1.14; 95% confidence interval [CI], 0.70-1.81) and 5-year mortality compared with patients without DM (hazard ratio, 1.15; 95% CI, 0.91-1.48). Furthermore, all in-hospital complications were comparable between patients with DM and patients without DM. Compared with patients without DM, dietary management of DM was significantly associated with higher adjusted perioperative mortality (OR, 2.16; 95% CI, 1.03-4.19) and higher 5-year mortality (hazad ratio, 1.50; 95% CI, 1.03-2.20), although this was not the case for other DM subgroups. All cohorts displayed similar 1-year sac dynamics, with sac regression occurring in 47% of patients without DM vs 46% of patients with DM (P = .27). CONCLUSIONS: Preoperatively, patients with DM who underwent TEVAR had a higher proportion of ruptured presentation when treated with diet or insulin medications than when treated with noninsulin medications. After TEVAR for descending TAA, DM was associated with a similar risk of perioperative and 5-year mortality as nonDM. In contrast, dietary therapy for DM was associated with significantly higher perioperative mortality and 5-year mortality.

Duplex ultrasound and clinical outcomes of medical management of pediatric lower extremity arterial thrombosis.

OBJECTIVES: Natural history and duplex ultrasound (DU) findings of pediatric lower extremity arterial thrombosis (PLEAT) are not well-defined. We describe acute and short-term DU findings of PLEAT to aid duplex interpretation and patient management. METHODS: From August 2018 to April 2021 children with suspected PLEAT were identified prospectively. All had DU studies and were divided into group 1 (with DU-confirmed PLEAT) and group 2 (without DU-confirmed PLEAT). Patient demographics and DU findings were compared. Those with PLEAT and follow-up DU studies were also evaluated for recanalization and post recanalization DU findings. RESULTS: We included 76 children (102 limbs) who had suspected PLEAT; 32 in group 1 and 44 group in 2. Fifty-seven percent had congenital heart disease, 26% a history prematurity (87%, 34% group 1; 11%, 14% group 2), with 14% of group 1 premature at PLEAT diagnosis and 68% aged less than 3 years-29 (94%) in group 1 and 23 (52%) in group 2. None had an arterial procedure to restore flow. Limb salvage was 100% with five group 1 mortalities unrelated to PLEAT. In group 1, 12 PLEATs were associated with an arterial line and 15 with cardiac catheterization. Occluded arteries included 7 external iliac, 20 common femoral, and 5 superficial femoral arteries (SFA). Peak systolic velocities (PSVs) distal to occluded segments in group 1 were lower than corresponding group 2 PSVs. SFA 18 ± 21 cm/s vs 84 ± 39 cm/s; popliteal artery (PA) 24 ± 18 cm/s vs 78 ± 38 cm/s; posterior tibial artery (PTA) 10 ± 8 cm/s versus 49 ± 27 cm/s (all P < .001). Twenty-one patients in group 1 had follow-up studies. Twelve (57%) were recanalized: 4 (19%) in less than 1 week and 10 (48%) by 6 months. Eighty-one percent of PLEATs were treated with anticoagulation (AC) and 57% recanalized. Fifty-nine percent of patients on AC recanalized, and 60% not on AC recanalized. Age, primary diagnosis, instrumentation type, and AC were not associated with failure to recanalize. After recanalization, PSVs in the CFA were not different than PSVs found in group 2 in the CFA (109 ± 50 cm/s vs 107 ± 57 cm/s; P = .88), but remained decreased in the SFA, PA, and PTA (SFA 68 ± 32 cm/s vs 83 ± 38 cm/s [P = .04]; PA 33 ± 13 cm/s vs 78 ± 37 [P = .0004]; and PTA 21 ± 8 cm/s vs 43 ± 20 cm/s [P = .0008]). CONCLUSIONS: PLEAT occurs in young children, results in low distal PSVs, and often does not recanalize, but does not lead to short-term limb loss or mortality or necessarily require AC for recanalization. Normalization of CFA PSVs indicates recanalization while PSVs in segments distal to the CFA do not seem to return to normal.

Human sirtuins are differentially sensitive to inhibition by nitrosating agents and other cysteine oxidants.

Sirtuins (e.g. human Sirt1-7) catalyze the removal of acyl groups from lysine residues in proteins in an NAD+-dependent manner, and loss of sirtuin deacylase activity correlates with the development of aging-related diseases. Although multiple reports suggest that sirtuin activity is regulated by oxidative post-translational modifications of cysteines during inflammation and aging, no systematic comparative study of potential direct sirtuin cysteine oxidative modifications has been performed. Here, using IC50 and kinact/KI analyses, we quantified the ability of nitrosothiols (S-nitrosoglutathione and S-nitroso-N-acetyl-d,l-penicillamine), nitric oxide, oxidized GSH, and hydrogen peroxide to post-translationally modify and inhibit the deacylase activity of Sirt1, Sirt2, Sirt3, Sirt5, and Sirt6. The inhibition was correlated with cysteine modification and assessed with chemical-probe and blot-based assays for cysteine S-nitrosation, sulfenylation, and glutathionylation. We show that the primarily nuclear sirtuins Sirt1 and Sirt6, as well as the primarily cytosolic sirtuin Sirt2, are modified and inhibited by cysteine S-nitrosation in response to exposure to both free nitric oxide and nitrosothiols (kinact/KI ≥ 5 m-1 s-1), which is the first report of Sirt2 and Sirt6 inhibition by S-nitrosation. Surprisingly, the mitochondrial sirtuins Sirt3 and Sirt5 were resistant to inhibition by cysteine oxidants. Collectively, these results suggest that nitric oxide-derived oxidants may causatively link nuclear and cytosolic sirtuin inhibition to aging-related inflammatory disease development.

Covalent-Fragment Screening of BRD4 Identifies a Ligandable Site Orthogonal to the Acetyl-Lysine Binding Sites.

BRD4, a member of the bromodomain and extraterminal domain (BET) family, has emerged as a promising epigenetic target in cancer and inflammatory disorders. All reported BET family ligands bind within the bromodomain acetyl-lysine binding sites and competitively inhibit BET protein interaction with acetylated chromatin. Alternative chemical probes that act orthogonally to the highly conserved acetyl-lysine binding sites may exhibit selectivity within the BET family and avoid recently reported toxicity in clinical trials of BET bromodomain inhibitors. Here, we report the first identification of a ligandable site on a bromodomain outside the acetyl-lysine binding site. Inspired by our computational prediction of hotspots adjacent to nonhomologous cysteine residues within the C-terminal BRD4 bromodomain (BRD4-BD2), we performed a midthroughput mass spectrometry screen to identify cysteine-reactive fragments that covalently and selectively modify BRD4. Subsequent mass spectrometry, NMR, and computational docking analyses of electrophilic fragment hits revealed a novel ligandable site near Cys356 that is unique to BRD4 among human bromodomains. This site is orthogonal to the BRD4-BD2 acetyl-lysine binding site as Cys356 modification did not impact binding of the pan-BET bromodomain inhibitor JQ1 in fluorescence polarization assays nor an acetylated histone peptide in AlphaScreen assays. Finally, we tethered our top-performing covalent fragment to JQ1 and performed NanoBRET assays to provide proof of principle that this orthogonal site can be covalently targeted in intact human cells. Overall, we demonstrate the potential of targeting sites orthogonal to bromodomain acetyl-lysine binding sites to develop bivalent and covalent inhibitors that displace BRD4 from chromatin.