Rupture Of Thoracic Aortic Aneurysm Research Articles

Postmortem contrast-enhanced computed tomography via direct large-vessel puncture

The aim of this study was to assess the usefulness of postmortem contrast-enhanced CT (PMeCT) performed via direct large-vessel puncture when routine postmortem CT suggests a vascular lesion as the cause of death. PMeCT was performed in 9 cases (4 male, 5 female) with a mean age of 76 years (range 52–92) at the time of death. The mean time elapsed since death was 29.1 h (12.0–72.0). The location of the target vessel for puncture was determined based on the CT table position and a grid placed on the body surface. An 18-G spinal needle was advanced to the puncture site, and the needle tip was confirmed to have reached the intended blood vessel. Using negative pressure with a 20-ml syringe, the needle tip was advanced until reverse bleeding was confirmed. Diluted contrast medium was injected slowly to ensure its dispersion within the blood vessels. Following confirmation of no extravasation, additional doses of diluted contrast agent were injected in 3–4 divided doses, with CT scans obtained at each step to track the distribution of contrast agent over time. PMeCT was successful in all cases, revealing cardiac tamponade in 7 (ascending aortic dissection, n = 6; cardiac rupture, n = 1), thoracic aortic aneurysm rupture, n = 1, and iliac artery aneurysm rupture, n = 1. There were no cases of procedure-related extravasation (pseudo-lesions). When postmortem CT reveals pericardial hematoma or bleeding in the thoracic or abdominal cavity, PMeCT can identify the source of bleeding.

Animal Models, Pathogenesis, and Potential Treatment of Thoracic Aortic Aneurysm.

Thoracic aortic aneurysm (TAA) has a prevalence of 0.16-0.34% and an incidence of 7.6 per 100,000 person-years, accounting for 1-2% of all deaths in Western countries. Currently, no effective pharmacological therapies have been identified to slow TAA development and prevent TAA rupture. Large TAAs are treated with open surgical repair and less invasive thoracic endovascular aortic repair, both of which have high perioperative mortality risk. Therefore, there is an urgent medical need to identify the cellular and molecular mechanisms underlying TAA development and rupture to develop new therapies. In this review, we summarize animal TAA models including recent developments in porcine and zebrafish models: porcine models can assess new therapeutic devices or intervention strategies in a large mammal and zebrafish models can employ large-scale small-molecule suppressor screening in microwells. The second part of the review covers current views of TAA pathogenesis, derived from recent studies using these animal models, with a focus on the roles of the transforming growth factor-beta (TGFβ) pathway and the vascular smooth muscle cell (VSMC)-elastin-contractile unit. The last part discusses TAA treatment options as they emerge from recent preclinical studies.

Giant Thoracic Aortic Aneurysm Rupture in a Patient with Extensive Atherosclerotic Disease.

Aneurysmal dilatations can affect any aortic segment and represent the result of various causes, atherosclerotic disease being the most common and frequently involved. We hereby illustrate a case of a patient with thoracic aortic aneurysm rupture due to extensive atherosclerotic disease, with multiple complex penetrating ulcerated atherosclerotic plaques located in the descending aorta. CT angiography evaluation included a comprehensive description of imaging features and extent of the thoracic aortic aneurysm, the presence of thrombus, relationship to adjacent structures and branches, associated complications. Teaching Point: Thoracic aortic aneurysm rupture due to extensive atherosclerotic disease with multiple penetrating ulcers.

Regnase-1 overexpression as a therapeutic approach of Marfan syndrome

Rupture or dissection of thoracic aortic aneurysms is still the leading cause of death for patients diagnosed with Marfan syndrome. Inflammation and matrix digestion regulated by matrix metalloproteases (MMPs) play a major role in the pathological remodeling of the aortic media. Regnase-1 is an endoribonuclease shown to cleave the mRNA of proinflammatory cytokines, such as interleukin-6. Considering the major anti-inflammatory effects of regnase-1, here, we aimed to determine whether adeno-associated virus (AAV)-mediated vascular overexpression of the protein could provide protection from the development and progression of aortic aneurysms in Marfan syndrome. The overexpression of regnase-1 resulted in a marked decrease in inflammatory parameters and elastin degradation in aortic smooth muscle cells invitro. Intravenous injection of a vascular-targeted AAV vector resulted in the efficient transduction of the aortic wall and overexpression of regnase-1 in a murine model of Marfan syndrome, associated with lower circulating levels of proinflammatory cytokines and decreased MMP expression and activity. Regnase-1 overexpression strongly improved elastin architecture in the media and reduced aortic diameter at distinct locations. Therefore, AAV-mediated regnase-1 overexpression may represent a novel gene therapy approach for inhibiting aortic aneurysms in Marfan syndrome.

Silent Rupture of Aortic Aneurysm Mimicking Lung Malignancy

Extra-pulmonary diseases may mimic pulmonary lesions on chest radiography. We report a case of a silent rupture of an atherosclerotic thoracic aortic aneurysm with peripheral thrombus formation, that closely mimicked a complicated lung malignancy.

A RARE PRESENTATION OF THORACIC AORTIC ANEURYSM RUPTURE

TOPIC: Signs and Symptoms of Chest Diseases TYPE: Medical Student/Resident Case Reports INTRODUCTION: Thoracic aortic aneurysm (TAA) is an uncommon clinical condition, commonly associated with atherosclerosis. It is mostly asymptomatic but aneurysm exceeding 6 cm are at risk of yearly rate of rupture or dissection of at least 6.9% and a death rate of 11.8%. We present to you a case of TAA with rupture presenting with cough, hemoptysis and pneumonitis. CASE PRESENTATION: Patient is a 68 years male who presented to the ED with cough, hemoptysis, chest discomfort for 2-3 days. He had intermittent episodes of fever. COVID test was negative 3 days ago. Past medical history was significant for HTN, Asthma, COPD, Diabetes mellitus, tobacco use disorder. Patient was afebrile with BP of 137/73, HR 72, RR 16, O2 saturation of 89% in room air. Physical examination including chest was unremarkable. Initial workup including CBC was remarkable for WBC of 12500, Hgb of 10.5, INR 0.8, PTT 24, Troponin 5 cm, smokers, COPD, advanced age, hypertension. Thoracic endovascular stent graft surgery, under epidural anesthesia, is the preferred surgical treatment especially in old TAA patients as in our case because of low morbidity, mortality and hospital stay. CONCLUSIONS: Rupture of TAAs is still very rare, but should remain on the differential for a patient with cough, hemoptysis with features of pneumonitis as it is associated with very high morbidity and mortality rates. REFERENCE #1: CL F, Esk, MK ari. Thoracic endovascular aneurysm Repair (TEVAR) for Ruptured THORACIC aortic aneurysms. Published May 2, 2017 REFERENCE #2: Inam, H., Zahid, I., Khan, S.D. et al. Hemoptysis secondary to rupture of infected aortic aneurysm– a case report. J Cardiothorac Surg 14, 144 (2019). https://doi.org/10.1186/s13019-019-0959-y REFERENCE #3: Sun D, Mehta S. Hemoptysis caused by erosion of thoracic aortic aneurysm. CMAJ. 2010;182(4):E186. doi:10.1503/cmaj.090447 DISCLOSURES: No relevant relationships by Luna Khanal, source=Web Response No relevant relationships by Adarsha Ojha, source=Web Response

Endovascular treatment of the rupture of thoracic aortic aneurysm, manifested by a neurological «mask»

The article describes a case of successful treatment of the rupture of aortic aneurysm by the endovascular method. Patient P., 71 years old, was hospitalized in a multidisciplinary hospital with a diagnosis of acute cerebral circulation disorder. The patient was examined in the intensive care unit. Signs of neurological symptoms regressed. Spiral computed tomography of the chest organs was performed with suspected pulmonary embolism, the results of which revealed an aneurysm of the descending thoracic aorta, complicated by a rupture with the formation of a right-sided hemothorax. The patient underwent endoprosthesis of the thoracic aorta with stent graft. After 2 days, thoracoscopic sanitation, drainage of the right pleural cavity was performed. The postoperative period proceeded without peculiarities. The patient was discharged on the 12th day in satisfactory condition. At control examination in 1, 6, 12 months, the long-term steady positive result was noted. Endovascular methods minimize the risk of postoperative complications, contributing to a favorable outcome of the disease.

Association of hernia with subsequent aortic aneurysm in geriatric patients

ObjectiveAlthough inguinal hernia and aortic aneurysm share similar pathogenic mechanisms of collagen and elastin destruction, their clinical association in geriatric patients is inconclusive. We assessed the association between hernia and the subsequent occurrence of aortic aneurysm in geriatric patients. MethodsAdult patients with hernias between 2000 and 2012 were identified from a longitudinal claims database of 1 million beneficiaries from Taiwan's National Health Insurance program, and a control group of patients without hernia were matched by propensity score in a ratio of 1:3. Patients previously diagnosed with aortic aneurysms or connective tissue diseases were excluded. Follow-up ended on December 31, 2013. The incidence rate of aortic aneurysm was compared between patients with hernia and those without. Cox proportional hazards models were used to estimate relative hazards. ResultsAfter propensity score matching, there were 16,933 patients with hernia (aged 20-64 years: 10,326; ≥65 years: 6607) and 50,799 patients without hernia (aged 20-64: 30,978; ≥65: 19,821). Patients with hernia had a greater incidence rate and hazard ratio of aortic aneurysm than did patients without hernia (6.4 vs 4.8/10,000 person-years; adjusted subdistribution hazard ratio [sdHR], 1.34; 95% confidence interval [CI], 1.02-1.76; P = .03), especially for those aged ≥65 years (15.6 vs 10.4/10,000 person-years; adjusted sdHR, 1.44; 95% CI, 1.07-1.94; P = .01) In addition, geriatric patients with hernia were associated with a marginally greater risk of thoracic (adjusted sdHR, 1.66; 95% CI, 0.96-2.86) and abdominal (adjusted sdHR, 1.36; 95% CI, 0.96-1.94) aortic aneurysm rupture. ConclusionsGeriatric patients with hernia were associated with a greater incidence of aortic aneurysm than were those without.

Analysis of Failure-mechanisms of Cryopreserved Vascular Allografts in Peripheral Reconstructions

Introduction: Cryopreserved vascular allografts represent a well known option in the treatment of vascular infections. Moreover several groups also suggested their use in case of patients with no suitable veins requiring an infragenicular bypass. The aim of the present study was to evaluate the failure mechanisms of cryopreserved allografts in peripheral reconstructions in a cohort of patients treated at a single Institution. Methods: We retrospectivly analized a prospectively collected database comprising all patients undergoing a peripheral reconstruction with cryopreserved arterial or venous allografts between August 2010 and January 2019. The composite result of graft failure (occlusion + degeneration + any graft-related complication) was calculated as a primary endpoint. In case of reintervention hystological analysis of a segment of allograft was performed. Results: A total of 20 patients [mean age 66.1 +/- 10.3 yy, M 66% (12/18)] underwent 25 vascular in-situ reconstruction with cryopreserved arterial or venous allografts. Indication for treatment was infection of a previous prosthetic graft in 12 cases, critical limb ischemia in 8, allograft degeneration in 3 and mycotic pseudoaneurym in 2. Type of reconstruction are reassumed in table I Table I. Type o.... In 17 cases an arterial allograft was used (11 single segment, 6 multiple segments) and in 8 cases a vein allograft (6 single segment, 2 multiple segments). At 30 days there were 3 deaths (1 myocardial infarction, 1 rupture of thoracic aortic aneurysm, 1 anastomotyc disrupture) with 2 additional deaths during follow up (1 drug overdose, 1 intestinal ischemia). Mean follow-up was 31 months (min 1 - max 81) with no patients lost to follow up. Overall graft failure occurred in 7 cases (28%) (3 aneurysmal degenerations, 2 occlusions, 2 anastomotyc disrupture) with reintervention with allograft performed in 4 cases. There was no statistical difference in the incidence of the composite endpoint between venous and arterial grafts [OR 0.71 (0.098 - 5.2), p 1], between patients with infection and without infection [OR 1.8 (0.26 - 12), p 0.66] and between single and multiple segments grafts [OR 2.8 (0.42 - 2.9), p 0.34], although occlusions occurred only in veins (2/8, 25%) and aneurismal degeneration only in arterial allografts (3/17, 17%). Hystological analysis was available for 5 allografts: 2 anastomotyc disruptures showing wall necrosis due to infection, 3 aneurysmal degenerations showing a chronic flogistic pattern suggestive of immune-mediated rejection. Kaplan-Meier estimates showed an overal 26% of freedom from graft failure at 60 months, with no difference between patients with and without infection and venous and arterial allografts (Logrank test p: 019 and 0.26 respectively). Conclusion: In our series the failure rate of allografts was not low, although their use was limited to very high risk situations. Accurate follow up is mandatory as the risk of aneurysmal degeneration is not negligible with arterial allografts, although they seem to offer a better patency rate compared to veins. Immune-mediated rejection plays a role in aneurysmal degeneration while uncontrollable infection greatly hinders the early postoperative outcome.Table IType of peripheral reconstruction with allografts and type of allografts usedType of ReconstructionN (%)Type of allografts (N)Composite axillo-femoral bypass1 (4%)Single Arterial (1)Femoral tibial bypass4 (16%)Multiple Arterial (2) Single Venous (1) Multiple Venous (1)Femoral femoral crossover bypass2 (8%)Single Arterial (2)Below knee femoral popliteal bypass5 (20%)Single Arterial (1) Multiple Arterial (3) Single Venous (1)Above knee femoral popliteal bypass2 (8%)Single Arterial (1) Single Venous (1)Iliac femoral bypass3 (12%)Single Arterial (2) Multiple Arterial (1)Femoral truncal bypass2 (8%)Single Venous (1) Multiple Venous (1)Common femoral reconstruction4 (16%)Single Arterial (3) Single Venous (1)Bypass of a dilated segment of a previous allograft2 (8%)Single Arterial (2) Open table in a new tab Disclosure: Nothing to disclose

Pivotal results for the Valiant Navion stent graft system in the Valiant EVO global clinical trial

ObjectiveThe Valiant Navion stent graft system (Medtronic, Santa Rosa, Calif) is a new iteration of a thoracic endograft for the treatment of descending thoracic aortic aneurysms. Herein, the 30-day primary safety and efficacy outcomes and secondary end points are presented. MethodsThe Valiant EVO global clinical trial is a prospective, nonrandomized, single-arm trial. Patient enrollment occurred from April 2016 to October 2017. The primary end point was defined as access and/or deployment failure and/or a major device effect (MDE), including device-related secondary procedures, device-related mortality, conversion to open surgery, or thoracic aortic aneurysm rupture within 30 days of the index procedure. Other measures of stent graft performance including procedural data, rates of secondary procedures, and frequency of endoleaks are also reported. ResultsOf the 87 consecutive patients undergoing thoracic endovascular aneurysm repair who were enrolled, 33 (37.9%) were female with 61 (70.9%) presenting with severe access artery tortuosity and 66 (85.7%) with high thoracic aortic tortuosity per core laboratory evaluation. The mean procedure duration was 88.7 ± 53.4 minutes and geographical differences existed such as percutaneous access (37/52 [71.2%]) in the United States and surgical cut down in the outside of the U.S. sites (28/35 [80.0%]). There were no access or deployment failures and only 2.3% of the patients (2/87; P < .0001; performance goal of 16%) experienced a MDE within 30 days of the index procedure. Two secondary procedures (n = 1 retrograde type A dissection; n = 1 aortic arch rupture) were required, and in the first 30 days, two patients died leading to a freedom from all-cause mortality of 97.7%. Endoleaks at 1 month were reported in 2.5% of patients (n = 1 type Ia; n = 1 type II). ConclusionsAccess/deployment failures, MDEs, and endoleaks were rare in the first 30 days of the Valiant Evo clinical trial. The Valiant Navion thoracic stent graft system has shown encouraging 30-day results in this challenging cohort and trial patients will continue to be followed through 5 years.

Small GTP-Binding Protein GDP Dissociation Stimulator Prevents Thoracic Aortic Aneurysm Formation and Rupture by Phenotypic Preservation of Aortic Smooth Muscle Cells.

Thoracic aortic aneurysm (TAA) and dissection are fatal diseases that cause aortic rupture and sudden death. The small GTP-binding protein GDP dissociation stimulator (SmgGDS) is a crucial mediator of the pleiotropic effects of statins. Previous studies revealed that reduced force generation in aortic smooth muscle cells (AoSMCs) causes TAA and thoracic aortic dissection. To examine the role of SmgGDS in TAA formation, we used an angiotensin II (1000 ng·min-1·kg-1, 4 weeks)-induced TAA model. We found that 33% of Apoe-/- SmgGDS+/- mice died suddenly as a result of TAA rupture, whereas there was no TAA rupture in Apoe-/- control mice. In contrast, there was no significant difference in the ratio of abdominal aortic aneurysm rupture between the 2 genotypes. We performed ultrasound imaging every week to follow up the serial changes in aortic diameters. The diameter of the ascending aorta progressively increased in Apoe-/- SmgGDS+/- mice compared with Apoe-/- mice, whereas that of the abdominal aorta remained comparable between the 2 genotypes. Histological analysis of Apoe-/- SmgGDS+/- mice showed dissections of major thoracic aorta in the early phase of angiotensin II infusion (day 3 to 5) and more severe elastin degradation compared with Apoe-/- mice. Mechanistically, Apoe-/- SmgGDS+/- mice showed significantly higher levels of oxidative stress, matrix metalloproteinases, and inflammatory cell migration in the ascending aorta compared with Apoe-/- mice. For mechanistic analyses, we primary cultured AoSMCs from the 2 genotypes. After angiotensin II (100 nmol/L) treatment for 24 hours, Apoe-/- SmgGDS+/- AoSMCs showed significantly increased matrix metalloproteinase activity and oxidative stress levels compared with Apoe-/- AoSMCs. In addition, SmgGDS deficiency increased cytokines/chemokines and growth factors in AoSMCs. Moreover, expressions of fibrillin-1 ( FBN1), α-smooth muscle actin ( ACTA2), myosin-11 ( MYH11), MYLLK, and PRKG1, which are force generation genes, were significantly reduced in Apoe-/- SmgGDS+/- AoSMCs compared with Apoe-/- AoSMCs. A similar tendency was noted in AoSMCs from patients with TAA compared with those from control subjects. Finally, local delivery of the SmgGDS gene construct reversed the dilation of the ascending aorta in Apoe-/- SmgGDS+/- mice. These results suggest that SmgGDS is a novel therapeutic target for the prevention and treatment of TAA.

TAA11. Pushing the Limits of Proximal Sealing Zone for Emergency Thoracic Endovascular Aortic Repair by Periprocedural Combined Embolization for Acute Thoracic Aortic Aneurysm Rupture: In the Middle of the Night

Inadequacy of a proximal landing zone (zone 3 or 4) is often a limitation for thoracic endovascular aortic repair (TEVAR), particularly in acute situations. We present a completely new technique of tackling this issue during emergency TEVAR for a ruptured aneurysm of the descending thoracic aorta encroaching on the lesser curvature of the arch. A 66-year-old man was admitted with acute thoracic back pain. Contrast-enhanced computed tomography revealed contained rupture from aneurysm and type B dissection just caudal to the left subclavian artery. Proximal landing at zone 2 was inadequate. TEVAR with debranching and revascularization of neck arteries was an option but was ruled out because of the patient's comorbidities. Branched TEVAR was not an option because of latency in device delivery. Chimney technique was not used because of risk of type IA endoleak. After a left carotid-subclavian bypass (because of dominant left vertebral artery), we deployed a Zenith Alpha thoracic stent graft (ZTA-PT-40-36-217; Cook Medical, Bloomington, Ind) covering the left subclavian artery. However, because of inadequate proximal landing area inferiorly, the inferior margin of the stent graft opened in the aneurysm sac, giving rise to a type IA endoleak (Fig 1). We entered the aneurysm sac through the left subclavian artery and deployed a few Azur detachable macrocoils (Terumo Interventional Systems, Somerset, NJ) for clot formation and stabilization (Fig 2). We then embolized the rest of the aneurysm all the way up to the stent graft margin and also the proximal subclavian artery with Onyx (ev3, Covidien, Plymouth, Minn).Fig 2Aneurysm sac and proximal left subclavian artery are adequately embolized with detachable macrocoils and Onyx.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Computed tomography angiography 1 day after TEVAR showed complete exclusion of the aneurysm without any sign of endoleak as well as a stable and well-functioning stent graft. The patient is doing well 3 months after the procedure. To our knowledge, no similar case of concomitant embolization of aneurysm sac with TEVAR by combined coils and Onyx through the subclavian artery has been described in the literature. This technique was safe and can be used as an alternative, particularly in an emergency situation. However, long-term outcome of the technique is still awaited.

PS01.085: TREATMENT STRATEGY FOR AORTO-ESOPHAGEAL FISTULA

Abstract Background Aorto-esophageal fistula (AEF) is relatively rare, but life-threatening condition. AEF is usually caused in the patients with thoracic aortic diseases, such as aneurysms, or after thoracic aortic surgery. We present our surgical strategy for AEF. Methods From May 2004 to November 2017, 12 patients with AEF were treated at our hospital. The age ranges from 44 to 83 years, and the number of male/female was 9/3. Five patients had previous thoracic endovascular aortic repair (TEVER) in the descending aorta, four patients had descending or total arch replacement. Two patients caused by rupture of thoracic aortic aneurysm, and one patient had penetration of esophagus caused by aspiration of Press Through Package. As the first procedures for surgical treatment, we perform TEVAR in order to prevent the fatal hemorrhage from aortic pseudoaneurysm. At the same day, removal of esophagus with debridement of adjacent infected tissues is performed by open thoracic procedure. After a few days, excision of the infected graft or the aorta followed by new graft replacement with omental flap installation is performed. Four patients used homograft and four patients used rifampicin-soaked graft. After the patient's general condition improve, we plan to perform open surgery for reconstruction of esophagus. Results A 3-year survival rate was 50%, and perioperative mortality was 25%. Hospital mortality was noted in 3 patients due to sepsis, brainstem infarction and pulmonary hemorrhage (6–117 days after the first surgery). Late death occurred in 4 patients (n = 2: ileus, n = 1: carcinoma, n = 1: pneumonia). Eight patients could undergo esophagus reconstruction, by colon graft in 4 patients, a pedicled jejunum and a gastric tube in 2 patients, respectively. The duration from esophageal resection to reconstruction was 1–11 months. Conclusion Because AEF usually accompanied with hemodynamic instability, immediate surgical intervention is regarded as the only effective treatment. Corporation between gastrointestinal surgeons and cardiovascular surgeons is necessary to achieve this treatment. We share our experiences of AEF treatment and discuss surgical strategy. Disclosure All authors have declared no conflicts of interest.

Anatomic and clinical characterization of the narrow distal aorta and implications after endovascular aneurysm repair

ObjectiveThe purpose of this analysis was to compare 1-year clinical outcomes after endovascular repair of abdominal aortic aneurysms with the EXCLUDER device in patients with standard and narrow aortic bifurcations (AOBs). MethodsData were prospectively collected from a 1055-participant subset of the multicenter Global Registry for Endovascular Aortic Treatment (GREAT) treated for abdominal aortic aneurysm repair between August 2010 and September 2015. There were 117 patients with a narrow AOB (NB; defined as <16 mm) and 938 patients with a standard bifurcation (SB). The 30-day and 1-year morbidity, mortality, and reintervention outcomes were analyzed, with Kaplan-Meier survival curve analysis conducted on freedom from mortality and freedom from reintervention. ResultsThe mean distal aortic neck diameter was 12.4 mm in the NB cohort and 25.3 mm in the SB cohort (P < .001), with NB patients also exhibiting significantly smaller diameter proximal aortic necks (P < .001). Patients in the NB cohort were more often female (25.6% vs 15.1%; P = .004) and with more severe comorbidity burden. There was a significantly higher rate of surgical cutdown access in the NB cohort (P < .001). Procedural survival was 100% in both groups. The 30-day mortality and safety outcomes were similar; however, all-cause mortality was significantly higher in the SB cohort through 1 year (P = .02). The 1-year freedom from mortality was estimated as 92.1% in the SB cohort and 99.1% in the NB cohort. Freedom from reintervention was estimated as 95.1% in the SB cohort and 92.8% in the NB cohort at 1 year. Through 1-year follow-up, 24 SB patients (2.6%) and 4 NB patients (3.4%) exhibited an endoleak requiring reintervention (P > .99). Type II endoleaks represented 72% and 60% of treated endoleaks, respectively. Through 1 year, 10 SB patients (1.0%) and 2 NB patients (1.7%) exhibited occlusive/thrombotic events (P = .54). There were no reported instances of kinking, migration, fracture, compression, or dissection through 1 year in either cohort. One SB patient experienced thoracic aortic aneurysm rupture. ConclusionsThe 1-year outcomes after endovascular aneurysm repair with the EXCLUDER device were comparable in the NB and SB cohorts. A narrow AOB was not found to be associated with a higher incidence of later limb occlusions or endoleaks. Female patients were disproportionately more likely to have a narrow AOB, which correlated with narrowed proximal necks and access vessels, and a more severe comorbidity burden.

Abstract 315: SmgGDS Prevents Thoracic Aortic Aneurysm Formation and Rupture by Phenotypic Preservation of Aortic Smooth Muscle Cells

Background: Thoracic aortic aneurysm (TAA) and dissection (TAD) are fatal diseases, which cause aortic rupture and sudden death. The small GTP-binding protein GDP dissociation stimulator (SmgGDS) is a crucial mediator of the pleiotropic effects of statins. Previous studies revealed that reduced force generation in AoSMCs causes TAA and TAD. Methods and Results: To examine the role of SmgGDS in TAA formation, we employed an angiotensin II (AngII, 1,000 ng/min/kg, 4weeks)-induced TAA model in Apoe -/- SmgGDS +/- mice, in which 33% died suddenly due to TAA rupture, whereas there was no TAA rupture in Apoe -/- control mice. In contrast, there was no significant difference in the ratio of AAA rupture between the two genotypes. We performed ultrasound imaging every week to follow the serial changes in aortic diameters. The diameter of the ascending aorta progressively increased in Apoe -/- SmgGDS +/- mice compared with Apoe -/- mice, whereas that of the abdominal aorta remained comparable between the two genotypes. Histological analysis of Apoe -/- SmgGDS +/- mice showed dissections of major thoracic aorta in the early phase of AngII infusion (day 3~5) and more severe elastin degradation compared with Apoe -/- mice. Mechanistically, Apoe -/- SmgGDS +/- mice showed significantly higher levels of oxidative stress, matrix metalloproteinases, and inflammatory cell migration in the ascending aorta compared with Apoe -/- mice. For mechanistic analyses, we primary cultured AoSMCs from the 2 genotypes. After AngII (100 nM) treatment for 24 hours, Apoe -/- SmgGDS +/- AoSMCs showed significantly increased MMP activity and oxidative stress levels compared with Apoe -/- AoSMCs. In addition, SmgGDS deficiency increased cytokines/chemokines and growth factors in AoSMCs. Moreover, expressions of FBN1 , ACTA2 , MYH11 , MLK and PRKG1 , which are force generation genes, were significantly reduced in Apoe -/- SmgGDS +/- AoSMCs compared with Apoe -/- AoSMCs. Similar tendency was noted in AoSMCs from TAA patients compared with those from controls. Finally, local delivery of the SmgGDS gene construct reversed the dilation of the ascending aorta in Apoe -/- SmgGDS +/- mice. Conclusions: These results suggest that SmgGDS is a novel therapeutic target for the prevention and treatment of TAA.

M7824 (MSB0011359C), a bifunctional fusion protein targeting PD-L1 and TGF-β, in Asian patients with pretreated recurrent or refractory gastric cancer: Preliminary results from a phase I trial.

100 Background: Inhibiting the transforming growth factor β (TGF-β) pathway, which plays a key role in tumor immunosuppression, may enhance the response to programmed death 1/programmed death ligand 1 (PD-1/PD-L1) monoclonal antibodies (mAbs). M7824 (MSB0011359C) is an innovative first-in-class bifunctional fusion protein composed of a mAb against PD-L1 fused with the extracellular domain of TGF-β receptor II, which serves as a TGF-β “trap.” We report preliminary results in Asian patients with heavily pretreated gastric cancer. Methods: In this expansion cohort of the ongoing, phase 1, open-label trial NCT02699515, patients with recurrent or refractory unresectable stage IV gastric or gastroesophageal junction adenocarcinoma for which no standard therapy exists or standard therapy has failed receive M7824 1200 mg q2w until confirmed progressive disease, unacceptable toxicity or trial withdrawal. The primary objective is safety; secondary objectives include best overall response (BOR) per RECIST v1.1. Results: As of 6 September 2017, 31 heavily pretreated patients with advanced gastric cancer (67.7% received ≥3 prior anticancer therapies) received M7824 for a median duration of 6.1 (range: 2-30) weeks (median number of M7824 infusions: 3 [range: 1-13]); 8 patients remained on treatment. Four patients (12.9%) experienced grade 3 treatment-related adverse events (anemia and diarrhea 1 each and 2 rash). No treatment-related grade 4 AEs occurred. One grade 5 event (total 5 doses received) was considered possibly treatment related, but suspected rupture of preexisting thoracic aortic aneurysm was cited as other probable cause by the investigator. There were 5 confirmed partial responses (4 ongoing after 4-6 months of follow-up) based on investigator assessment of BOR (overall response rate: 16.1%). This is an ongoing study; updated data will be presented. Conclusions: These preliminary data show that M7824 resulted in a manageable safety profile in heavily pretreated Asian patients with gastric cancer. Early signs of clinical efficacy are encouraging. Clinical trial information: NCT02699515.

P5164Protective roles of small GTP-binding protein GDP dissociation stimulator against angiotensin II-induced thoracic aortic aneurysm formation and rupture in mice -A possible novel therapeutic target-

P5164Protective roles of small GTP-binding protein GDP dissociation stimulator against angiotensin II-induced thoracic aortic aneurysm formation and rupture in mice -A possible novel therapeutic target-

Bone Deformities as a Complication of Giant Thoracic Aortic Aneurysm

The contained rupture of thoracic aortic aneurysm and related bone deformities is a rare condition. The diagnosis is critical due to potential and fatal complications. Radiologic evaluation is required to show the location, extension, and complications. Herein we present the X-ray radiography, ultrasonography, computed tomography, and magnetic resonance images of a giant dissected and contained rupture of the thoracic aortic aneurysm. The aneurysm destructed the adjacent vertebrae and rib, resulting in compression of dural sac and spinal cord, and obliteration of the neural foramina. Our case demonstrates a gigantic expansion of an aneurysm (14 cm) with chronic skeletal complications.

Abstract 313: Protective Roles of Small GTP-Binding Protein GDP Dissociation Stimulator Against Angiotensin II-Induced Thoracic Aortic Aneurysm Formation and Rupture in Mice -A Possible Novel Therapeutic Target

Background: Statins reduce the incidence and development of thoracic aortic aneurysm (TAA) and rupture. We have previously identified that small GTP-binding protein GDP dissociation stimulator (SmgGDS) is a crucial mediator of the pleiotropic effects of statins. Methods and Results: To examine the role of SmgGDS in TAA formation, Apoe -/- and Apoe -/- SmgGDS +/- (DKO) mice were infused with angiotensin II (AngII, 1,000 ng/min/kg) for 4 weeks. There was no significant difference in blood pressure between the 2 genotypes in response to the AngII treatment. However, during the follow-up, 36% of DKO mice died suddenly due to TAA rupture, whereas there was no TAA rupture in Apoe -/- mice ( P &lt;0.05, n =14 each). Histological analysis of DKO mice showed dissections of major thoracic aorta in the early phase of AngII infusion (day 3~5). We performed ultrasound imaging every week to follow the serial changes in aortic diameters. Diameter of the ascending aorta was progressively and significantly increased in DKO mice compared with Apoe -/- mice (1.64±0.06 vs. 1.43±0.05 mm at 4 weeks, P &lt;0.05, n =14 each), whereas that of the abdominal aorta was comparable between the 2 genotypes. Indeed, there was no significant difference in the incidence of AngII-induced abdominal aortic aneurysm (AAA) formation between the 2 genotypes (both 75%). Western blotting demonstrated that AngII-induced activations of JNK and ERK were significantly higher in the thoracic aorta of DKO mice compared with Apoe -/- mice ( P &lt;0.01, n =6 each). For mechanistic analyses, we primary cultured aortic smooth muscle cells (AoSMCs) from the 2 genotypes. After AngII (100 nM) treatment for 24 hours, DKO AoSMCs showed significantly increased JNK activity, cyclophilin A secretion, and oxidative stress levels compared with Apoe -/- AoSMCs ( P &lt;0.01, n =6 each). Interestingly, AngII-induced upregulation of Nrf2, a master regulator of cellular responses against environmental stresses, was significantly less in DKO AoSMCs compared with Apoe -/- AoSMCs ( P &lt;0.01, n =6). Finally, expressions of matrix metalloproteinase-2 and -9 were significantly increased in DKO AoSMCs compared with Apoe -/- AoSMCs. Conclusions: These results suggest that SmgGDS is a novel therapeutic target for the prevention and treatment of TAA.

Genetic and Epigenetic Regulation of Aortic Aneurysms.

Aneurysms are characterized by structural deterioration of the vascular wall leading to progressive dilatation and, potentially, rupture of the aorta. While aortic aneurysms often remain clinically silent, the morbidity and mortality associated with aneurysm expansion and rupture are considerable. Over 13,000 deaths annually in the United States are attributable to aortic aneurysm rupture with less than 1 in 3 persons with aortic aneurysm rupture surviving to surgical intervention. Environmental and epidemiologic risk factors including smoking, male gender, hypertension, older age, dyslipidemia, atherosclerosis, and family history are highly associated with abdominal aortic aneurysms, while heritable genetic mutations are commonly associated with aneurysms of the thoracic aorta. Similar to other forms of cardiovascular disease, family history, genetic variation, and heritable mutations modify the risk of aortic aneurysm formation and provide mechanistic insight into the pathogenesis of human aortic aneurysms. This review will examine the relationship between heritable genetic and epigenetic influences on thoracic and abdominal aortic aneurysm formation and rupture.