Administration of an antibody against apoptosis inhibitor of macrophage prevents aortic aneurysm progression in mice.

Apoptosis inhibitor of macrophage (AIM) is known to induce apoptosis resistance in macrophages and to exacerbate chronic inflammation, leading to arteriosclerosis. The role of AIM in aortic aneurysm (AA) remains unknown. This study examined the effects of an anti-AIM antibody in preventing AA formation and progression. In apolipoprotein E-deficient mice, AA was induced by subcutaneous angiotensin II infusion. Mice were randomly divided into two groups: (i) AIM group; weekly anti-murine AIM monoclonal antibody injection (n = 10), and (ii) IgG group; anti-murine IgG antibody injection as control (n = 14). The AIM group, compared with the IgG group, exhibited reduced AA enlargement (aortic diameter at 4 weeks: 2.1 vs. 2.7 mm, respectively, p = 0.012); decreased loss of elastic lamellae construction; reduced expression levels of IL-6, TNF-α, and MCP-1; decreased numbers of AIM-positive cells and inflammatory M1 macrophages (AIM: 1.4 vs. 8.0%, respectively, p = 0.004; M1 macrophages: 24.5 vs. 55.7%, respectively, p = 0.017); and higher expression of caspase-3 in the aortic wall (22.8 vs. 10.5%, respectively, p = 0.019). Our results suggest that administration of an anti-AIM antibody mitigated AA progression by alleviating inflammation and promoting M1 macrophage apoptosis.

Investigation of Strategies to Block Downstream Effectors of AT1R-Mediated Signalling to Prevent Aneurysm Formation in Marfan Syndrome.

Cardiovascular outcome in Marfan syndrome (MFS) patients most prominently depends on aortic aneurysm progression with subsequent aortic dissection. Angiotensin II receptor blockers (ARBs) prevent aneurysm formation in MFS mouse models. In patients, ARBs only slow down aortic dilation. Downstream signalling from the angiotensin II type 1 receptor (AT1R) is mediated by G proteins and ß-arrestin recruitment. AT1R also interacts with the monocyte chemoattractant protein-1 (MCP-1) receptor, resulting in inflammation. In this study, we explore the targeting of ß-arrestin signalling in MFS mice by administering TRV027. Furthermore, because high doses of the ARB losartan, which has been proven beneficial in MFS, cannot be achieved in humans, we investigate a potential additive effect by combining lower concentrations of losartan (25 mg/kg/day and 5 mg/kg/day) with barbadin, a ß-arrestin blocker, and DMX20, a C-C chemokine receptor type 2 (CCR2) blocker. A high dose of losartan (50 mg/kg/day) slowed down aneurysm progression compared to untreated MFS mice (1.73 ± 0.12 vs. 1.96 ± 0.08 mm, p = 0.0033). TRV027, the combination of barbadin with losartan (25 mg/kg/day), and DMX-200 (90 mg/kg/day) with a low dose of losartan (5 mg/kg/day) did not show a significant beneficial effect. Our results confirm that while losartan effectively halts aneurysm formation in Fbn1C1041G/+ MFS mice, neither TRV027 alone nor any of the other compounds combined with lower doses of losartan demonstrate a notable impact on aneurysm advancement. It appears that complete blockade of AT1R function, achieved by administrating a high dosage of losartan, may be necessary for inhibiting aneurysm progression in MFS.

Dietary vitamin C and vitamin E with the risk of aortic aneurysm and dissection: A prospective population-based cohort study.

BACKGROUND AND AIMS: The associations between dietary vitamin C (VC), vitamin E (VE) intake and aortic aneurysm and dissection (AAD) remain unclear. This study aimed to prospectively investigate the associations between dietary VC and VE with the incident risk of AAD. METHODS AND RESULTS: A total of 139 477 participants of UK Biobank cohort were included in the analysis. Dietary VC and VE consumptions were acquired through a 24-h recall questionnaire. Cox proportional regression models were used to examine the associations between VC, VE intake and the risk of AAD. Incident AAD was ascertained through hospital inpatient records and death registers. During a median follow-up of 12.5 years, 962 incident AAD events were documented. Both dietary VC [adjusted hazard ratio (HR), 0.77; 95 % confidence intervals (CI), 0.63-0.93; P-trend = 0.008] and VE (adjusted HR, 0.70; 95 % CI, 0.57-0.87; P-trend = 0.002) were inversely associated with incident AAD when comparing the participants in the highest quartile with those in the lowest. In subgroup analyses, the associations were more pronounced in participants who were over 60 years old, participants with smoking history, hypertension or hyperlipidemia, who were under the high risk of AAD. CONCLUSION: Higher dietary VC and VE intakes are associated with reduced risk of AAD. Our study emphasizes the importance of diet adjustment strategies targeted on VC and VE to lower the incidence rate of AAD especially in the high-risk population.

High-Fat Diet Has a Protective Sex-Dependent Effect on Aortic Aneurysm Severity in a Marfan Syndrome Mouse Model.

BACKGROUND: Marfan syndrome (MFS) is a genetic disorder caused by mutations in fibrillin-1 and is characterized by thoracic aortic aneurysms and other complications. Previous studies revealed sexual dimorphisms in formation of aortic aneurysm in patients with MFS. The current study aimed to investigate the combined role of a high-fat diet (HFD) and biological sex in aortic disease using the mgR/mgR MFS mouse model. METHODS: Male and female mgR/mgR mice, as well as wild-type (WT) littermate mice, were fed a control diet (CD [10% fat]) or HFD (60% fat) from 4 to 12 weeks of age. Key aortic disease parameters analyzed included the diameter of the aortic wall; elastic fibre fragmentation; proteoglycan content; mRNA levels of Mmp12, Col1a1, Col3a1, and Fbn1; and fibrillin-1 deposition in the aortic wall. RESULTS: HFD-fed female mgR/mgR mice had significantly reduced aortic diameters (35%), elastic fibre fragmentation (56%), pathologically enhanced proteoglycans (45%), and expression of Mmp12 (64%), Col1a1 (41%), and Col3a1 (43%) compared with male mgR/mgR mice on HFD. Fibrillin-1 deposition and Fbn1 mRNA levels were unaffected. The data reveal a protective effect of HFD in female mice. In contrast, CD did not exert any protective effects. CONCLUSIONS: This study demonstrates a specific sexual dimorphism in MFS mice, with HFD exerting an explicit protective effect on severity of aortic disease in female mice. These preclinical data may be useful for developing nutritional recommendations for individuals with MFS in the longer term.

Lineage-Specific Induced Pluripotent Stem Cell-Derived Smooth Muscle Cell Modeling Predicts Integrin Alpha-V Antagonism Reduces Aortic Root Aneurysm Formation in Marfan Syndrome Mice.

BACKGROUND: The role of increased smooth muscle cell (SMC) integrin αv signaling in Marfan syndrome (MFS) aortic aneurysm remains unclear. Herein, we examine the mechanism and potential efficacy of integrin αv blockade as a therapeutic strategy to reduce aneurysm progression in MFS. METHODS: Induced pluripotent stem cells (iPSCs) were differentiated into aortic SMCs of the second heart field (SHF) and neural crest (NC) lineages, enabling in vitro modeling of MFS thoracic aortic aneurysms. The pathological role of integrin αv during aneurysm formation was confirmed by blockade of integrin αv with GLPG0187 in Fbn1C1039G/+ MFS mice. RESULTS: iPSC-derived MFS SHF SMCs overexpress integrin αv relative to MFS NC and healthy control SHF cells. Furthermore, integrin αv downstream targets (FAK [focal adhesion kinase]/AktThr308/mTORC1 [mechanistic target of rapamycin complex 1]) were activated, especially in MFS SHF. Treatment of MFS SHF SMCs with GLPG0187 reduced p-FAK/p-AktThr308/mTORC1 activity back to control SHF levels. Functionally, MFS SHF SMCs had increased proliferation and migration compared to MFS NC SMCs and control SMCs, which normalized with GLPG0187 treatment. In the Fbn1C1039G/+ MFS mouse model, integrin αv, p-AktThr308, and downstream targets of mTORC1 proteins were elevated in the aortic root/ascending segment compared to littermate wild-type control. Mice treated with GLPG0187 (age 6-14 weeks) had reduced aneurysm growth, elastin fragmentation, and reduction of the FAK/AktThr308/mTORC1 pathway. GLPG0187 treatment reduced the amount and severity of SMC modulation assessed by single-cell RNA sequencing. CONCLUSIONS: The integrin αv-FAK-AktThr308 signaling pathway is activated in iPSC SMCs from MFS patients, specifically from the SHF lineage. Mechanistically, this signaling pathway promotes SMC proliferation and migration in vitro. As biological proof of concept, GLPG0187 treatment slowed aneurysm growth and p-AktThr308 signaling in Fbn1C1039G/+ mice. Integrin αv blockade via GLPG0187 may be a promising therapeutic approach to inhibit MFS aneurysmal growth.

Allopurinol blocks aortic aneurysm in a mouse model of Marfan syndrome via reducing aortic oxidative stress.

BACKGROUND: Increasing evidence indicates that redox stress participates in MFS aortopathy, though its mechanistic contribution is little known. We reported elevated reactive oxygen species (ROS) formation and NADPH oxidase NOX4 upregulation in MFS patients and mouse aortae. Here we address the contribution of xanthine oxidoreductase (XOR), which catabolizes purines into uric acid and ROS in MFS aortopathy. METHODS AND RESULTS: In aortic samples from MFS patients, XOR protein expression, revealed by immunohistochemistry, increased in both the tunicae intima and media of the dilated zone. In MFS mice (Fbn1C1041G/+), aortic XOR mRNA transcripts and enzymatic activity of the oxidase form (XO) were augmented in the aorta of 3-month-old mice but not in older animals. The administration of the XOR inhibitor allopurinol (ALO) halted the progression of aortic root aneurysm in MFS mice. ALO administrated before the onset of the aneurysm prevented its subsequent development. ALO also inhibited MFS-associated endothelial dysfunction as well as elastic fiber fragmentation, nuclear translocation of pNRF2 and increased 3'-nitrotyrosine levels, and collagen maturation remodeling, all occurring in the tunica media. ALO reduced the MFS-associated large aortic production of H2O2, and NOX4 and MMP2 transcriptional overexpression. CONCLUSIONS: Allopurinol interferes in aortic aneurysm progression acting as a potent antioxidant. This study strengthens the concept that redox stress is an important determinant of aortic aneurysm formation and progression in MFS and warrants the evaluation of ALO therapy in MFS patients.

Short-term rapamycin treatment increases life span and attenuates aortic aneurysm in a murine model of Marfan-Syndrome.

BACKGROUND: Marfan syndrome (MFS) is a genetic disorder leading to medial aortic degeneration and life-limiting dissections. To date, there is no causal prevention or therapy. Rapamycin is a potent and selective inhibitor of the mechanistic target of rapamycin (mTOR) protein kinase, regulating cell growth and metabolism. The mgR/mgR mice represent an accepted MFS model for studying aortic pathologies to understand the underlying molecular pathomechanisms. This study investigated whether rapamycin inhibits the development of thoracic aortic aneurysms and dissections in mgR/mgR mice. METHODS: Isolated primary aortic smooth muscle cells (mAoSMCs) from mgR/mgR mice were used for in vitro studies. Two mg kg/BW rapamycin was injected intraperitoneally daily for two weeks, beginning at 7-8 weeks of age. Mice were sacrificed 30 days post-treatment. Histopathological and immunofluorescence analyses were performed using adequate tissue specimens and techniques. Animal survival was evaluated accompanied by periodic echocardiographic examinations of the aorta. RESULTS: The protein level of the phosphorylated ribosomal protein S6 (p-RPS6), a downstream target of mTOR, was significantly increased in the aortic tissue of mgR/mgR mice. In mAoSMCs isolated from these animals, expression of mTOR, p-RPS6, tumour necrosis factor α, matrix metalloproteinase-2 and -9 was significantly suppressed by rapamycin, demonstrating its anti-inflammatory capacity. Short-term rapamycin treatment of Marfan mice was associated with delayed aneurysm formation, medial aortic elastolysis and improved survival. CONCLUSIONS: Short-term rapamycin-mediated mTOR inhibition significantly reduces aortic aneurysm formation and thus increases survival in mgR/mgR mice. Our results may offer the first causal treatment option to prevent aortic complications in MFS patients.

Inhibition of endothelial Nox2 activation by LMH001 protects mice from angiotensin II-induced vascular oxidative stress, hypertension and aortic aneurysm.

Endothelial oxidative stress and inflammation attributable to the activation of a Nox2-NADPH oxidase are key features of many cardiovascular diseases. Here, we report a novel small chemical compound (LMH001, MW = 290.079), by blocking phosphorylated p47phox interaction with p22phox, inhibited effectively angiotensin II (AngII)-induced endothelial Nox2 activation and superoxide production at a small dose (IC50 = 0.25 µM) without effect on peripheral leucocyte oxidative response to pathogens. The therapeutic potential of LMH001 was tested using a mouse model (C57BL/6J, 7-month-old) of AngII infusion (0.8 mg/kg/d, 14 days)-induced vascular oxidative stress, hypertension and aortic aneurysm. Age-matched littermates of p47phox knockout mice were used as controls of Nox2 inhibition. LMH001 (2.5 mg/kg/d, ip. once) showed no effect on control mice, but inhibited completely AngII infusion-induced excess ROS production in vital organs, hypertension, aortic walls inflammation and reduced incidences of aortic aneurysm. LMH001 effects on reducing vascular oxidative stress was due to its inhibition of Nox2 activation and was abrogated by knockout of p47phox. LMH001 has the potential to be developed as a novel drug candidate to treat oxidative stress-related cardiovascular diseases.

Current progress of fluoroquinolones-increased risk of aortic aneurysm and dissection.

Aortic aneurysm (AA) and aortic dissection (AD) are major life-threatening diseases around the world. AA is a localized or diffuse dilation of the aorta, while AD is the separation of the layers creating a false lumen within the aortic wall. Fluoroquinolones (FQ) remain one of the most important kind of antibiotics and have a wider clinical use and broad antibacterial spectrum. FQ were also reported to treat infected AA. The most common adverse events (AEs) of FQ are mild and reversible, like headaches, diarrhea and nausea. Due to FQ-related serious AEs, such as tendonitis and tendon rupture, chondrotoxicity, or retinal detachment, QT-prolongation and dysglycemia, the United States Food and Drug Administration (FDA) issued a black box warning for FQ for systemic use in 2016 and updated warnings for FQ several times since then. Of note, in December 2018, FDA issued several "black box warnings" against FQ with the latest safety announcement warning about an increased risk of ruptures in the aorta blood vessel in certain patients. Recently, many studies have indicated an association between FQ and an increase risk of AA and AD. However, the exact mechanism of FQ-induced AA/AD remains unclear. This review aims to highlight the latest research progress of the alarming association between FQ and AA/AD. Moreover, molecular mechanisms of FQ in increasing risk of AA and AD are explored. Hopefully, this review can provide novel insights into FQ-increased the risk of AA/AD and a starting place for stewardship interventions.

Anti-TGFß (Transforming Growth Factor ß) Therapy With Betaglycan-Derived P144 Peptide Gene Delivery Prevents the Formation of Aortic Aneurysm in a Mouse Model of Marfan Syndrome.

Objective: We investigated the effect of a potent TGFß (transforming growth factor ß) inhibitor peptide (P144) from the betaglycan/TGFß receptor III on aortic aneurysm development in a Marfan syndrome mouse model. Approach and Results: We used a chimeric gene encoding the P144 peptide linked to apolipoprotein A-I via a flexible linker expressed by a hepatotropic adeno-associated vector. Two experimental approaches were performed: (1) a preventive treatment where the vector was injected before the onset of the aortic aneurysm (aged 4 weeks) and followed-up for 4 and 20 weeks and (2) a palliative treatment where the vector was injected once the aneurysm was formed (8 weeks old) and followed-up for 16 weeks. We evaluated the aortic root diameter by echocardiography, the aortic wall architecture and TGFß signaling downstream effector expression of pSMAD2 and pERK1/2 by immunohistomorphometry, and Tgfß1 and Tgfß2 mRNA expression levels by real-time polymerase chain reaction. Marfan syndrome mice subjected to the preventive approach showed no aortic dilation in contrast to untreated Marfan syndrome mice, which at the same end point age already presented the aneurysm. In contrast, the palliative treatment with P144 did not halt aneurysm progression. In all cases, P144 improved elastic fiber morphology and normalized pERK1/2-mediated TGFß signaling. Unlike the palliative treatment, the preventive treatment reduced Tgfß1 and Tgfß2 mRNA levels. Conclusions: P144 prevents the onset of aortic aneurysm but not its progression. Results indicate the importance of reducing the excess of active TGFß signaling during the early stages of aortic disease progression.

Risk reduction and pharmacological strategies to prevent progression of aortic aneurysms.

INTRODUCTION: While size thresholds exist to determine when aortic aneurysms warrant surgical intervention, there is no consensus on how best to treat this disease before aneurysms reach the threshold for intervention. Since a landmark study in 1994 first suggested ß-blockers may be useful in preventing aortic aneurysm growth, there has been a surge in research investigating different pharmacologic therapies for aortic aneurysms - with very mixed results. AREAS COVERED: We have reviewed the existing literature on medical therapies used for thoracic and abdominal aortic aneurysms in humans. These include ß-blockers, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors as well as miscellaneous drugs such as tetracyclines, macrolides, statins, and anti-platelet medications. EXPERT OPINION: While multiple classes of drugs have been explored for risk reduction in aneurysm disease, with few exceptions results have been disappointing with an abundance of contradictory findings. The vast majority of studies have been done in patients with abdominal aortic aneurysms or thoracic aortic aneurysm patients with Marfan Syndrome. There exists a striking gap in the literature when it comes to pharmacologic management of non-Marfan Syndrome patients with thoracic aortic aneurysms. Given the differences in pathogenesis, this is an important future direction for aortic aneurysm research.

Concerns About Fluoroquinolones and Aortic Aneurysm.

Recent research indicates that all adults may be at risk for aortic aneurysm after fluoroquinolone use, not only those with aortic aneurysm risk factors.

Diabetes Mellitus Lowers the Risk of Aortic Dissection: a Systematic Review and Meta-Analysis.

BACKGROUND: This systematic review and meta-analysis aimed to investigate the association between diabetes mellitus and aortic dissection. METHODS: The PubMed and Embase databases were searched until December 2019 to identify all articles reporting diabetes mellitus and aortic dissection. The pooled odds ratio and 95% confidence interval were calculated using random-effects model. RESULTS: A total of 14 articles with 15,794 participants, of which 2133 diabetes mellitus patients, were eligible and included in this meta-analysis. The data suggested that diabetes mellitus decreased the risk of aortic dissection. In the subgroup analysis, this association was significant in worldwide studies except for the Chinese cohort and in studies adjusted for confounding factors. The results were stable after sensitivity analysis and no evidence of publication bias was found among studies. CONCLUSIONS: The result of this meta-analysis indicated that diabetes mellitus was associated with a lower risk of aortic dissection.

AAV-mediated AP-1 decoy oligonucleotide expression inhibits aortic elastolysis in a mouse model of Marfan syndrome.

AIMS: Marfan syndrome is one of the most common inherited disorders of connective tissue caused by fibrillin-1 mutations, characterized by enhanced transcription factor AP-1 DNA binding activity and subsequently abnormally increased expression and activity of matrix-metalloproteinases (MMPs). We aimed to establish a novel adeno-associated virus (AAV)-based strategy for long-term expression of an AP-1 neutralizing RNA hairpin (hp) decoy oligonucleotide (dON) in the aorta to prevent aortic elastolysis in a murine model of Marfan syndrome. METHODS AND RESULTS: Using fibrillin-1 hypomorphic mice (mgR/mgR), aortic grafts from young (9 weeks old) donor mgR/mgR mice were transduced ex vivo with AAV vectors and implanted as infrarenal aortic interposition grafts in mgR/mgR mice. Grafts were explanted after 30 days. For in vitro studies, isolated primary aortic smooth muscle cells (SMCs) from mgR/mgR mice were used. Elastica-van-Giesson staining visualized elastolysis, reactive oxygen species (ROS) production was assessed using dihydroethidine staining. RNA F.I.S.H. verified AP-1 hp dON generation in the ex vivo transduced aortic tissue. MMP expression and activity were assessed by western blotting and immunoprecipitation combined with zymography.Transduction resulted in stable therapeutic dON expression in endothelial and SMCs. MMP expression and activity, ROS formation as well as expression of monocyte chemoattractant protein-1 were significantly reduced. Monocyte graft infiltration declined and the integrity of the elastin architecture was maintained. RNAseq analysis confirmed the beneficial effect of AP-1 neutralization on the pro-inflammatory environment in SMCs. CONCLUSION: This novel approach protects from deterioration of aortic stability by sustained delivery of nucleic acids-based therapeutics and further elucidated how to interfere with the mechanism of elastolysis.

Open surgical repair of juxtarenal abdominal aortic aneurysms in the elderly is not associated with increased thirty-day mortality compared with fenestrated endovascular grafting.

OBJECTIVE: Endovascular repair of juxtarenal abdominal aortic aneurysms (JAAAs) with fenestrated grafts (fenestrated endovascular aneurysm repair [FEVAR]) has been reported to decrease operative mortality and morbidity compared with open surgical repair (OSR). However, previous comparisons of OSR and FEVAR have not necessarily included patients with comparable clinical profiles and aneurysm extent. Although FEVAR has often been chosen as the first-line therapy for high-risk patients such as the elderly, many patients will not have anatomy favorable for FEVAR. At present, a paucity of data has examined the operative outcomes of OSR in elderly patients for JAAAs relative to FEVAR. Therefore, we chose to perform a propensity-matched comparison of OSR and FEVAR for JAAA repair in patients aged ≥70 years. METHODS: Patients aged ≥70 years who had undergone elective nonruptured JAAA repairs from 2012 to 2018 were identified in the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) targeted endovascular aneurysm repair (EVAR) and AAA databases. Patients who had undergone FEVAR were identified in the targeted EVAR database as those who had received the Cook Zenith Fenestrated endograft (Cook Medical, Bloomington, Ind). Because our study specifically examined JAAAs, those patients who had undergone OSR with supraceliac proximal clamping or concomitant renal/visceral revascularization were excluded. A 1:1 propensity-match algorithm matched the OSR and FEVAR patients by preoperative clinical and demographic characteristics, operative indications, and aneurysm extent. The 30-day outcomes, including mortality, major adverse cardiovascular events, and pulmonary and renal complications, were compared between the propensity-matched OSR and FEVAR groups. RESULTS: A 1:1 propensity match was achieved, and the final analysis included 136 OSR patients and 136 FEVAR patients. No significant differences were found in 30-day mortality (4.4% vs 3.7%; odds ratio [OR], 1.21; 95% confidence interval [CI], 0.36-4.06; P = .759) between the OSR and FEVAR groups. OSR was associated with a higher incidence of major adverse cardiovascular events compared with FEVAR; however, the trend was not statistically significant (8.1% vs 3.7%; OR, 2.31; 95% CI, 0.78-6.82; P = .131). Compared with FEVAR, the OSR group had significantly greater rates of pulmonary complications (19.1% vs 3.7%; OR, 6.19; 95% CI, 2.30-16.67; P < .001) and renal complications (8.1% vs 2.2%; OR, 3.90; 95% CI, 1.06-14.31; P = .040). CONCLUSIONS: In the samples assessed in the present study, the results with OSR of JAAAs in the elderly did not differ from those of FEVAR with respect to 30-day mortality despite a greater incidence of pulmonary and renal complications. Although FEVAR should remain the first-line therapy for JAAAs in elderly patients, OSR might be an acceptable alternative for select patients with anatomy unfavorable for FEVAR.

Effect of celiac axis compression on target vessel-related outcomes during fenestrated-branched endovascular aortic repair.

OBJECTIVE: To report the effect of median arcuate ligament (MAL) compression on outcomes and technical aspects of celiac artery (CA) stenting during fenestrated-branched endovascular aneurysm repair for thoracoabdominal aortic aneurysms (TAAA) or pararenal aortic aneurysms. METHODS: We retrospectively reviewed the clinical and anatomic data on 300 consecutive patients enrolled in a prospective nonrandomized physician-sponsored investigational device exemption study from 2013 to 2018. From this group, 230 patients with CA incorporation by fenestration or directional branch were included. MAL compression was defined by preoperative computed tomography angiogram as a J-hook narrowing of the proximal CA at the level of the ligament; the shift angle between the downward and upward segments within the CA was measured. End points were technical success, rates of intraoperative or early (30-days) CA branch revision, and freedom from target vessel instability, defined by any death or rupture owing to target vessel complication, occlusion, or reintervention for stenosis, endoleak, or disconnection. RESULTS: CA incorporation was performed using fenestrations in 118 patients (51%) and directional branches in 112 (49%). MAL compression was present in 97 patients (42%), resulting in a stenosis of more than 50% in 48 (49%). MAL compression was more often present in patients with extent I to III TAAAs compared with extent IV TAAA-pararenal aortic aneurysms (56% vs 31%; P < .001). Technical success rate was 99%. Patients with MAL compression more often received a directional branch (65% vs 37%; P < .001), self-expanding bridging stent grafts (32% vs 16%; P = .007), adjunctive bare metal stents (46% vs 24%; P = .001), and coverage of the gastric artery (44% vs 22%; P < .001). An intraoperative (n = 6, 2.6%) or early (n = 1, 0.4%) revision of the CA branch was required in seven patients (3%) owing to dissection/occlusion (n = 2 [0.9%]), kinking/stenosis (n = 3 [1.3%]), stent dislodgement (n = 1 [0.4%]), or type IC endoleak (n = 1 [0.4%]). A shift angle of less than 120° was the most significant factor associated with CA branch revision (odds ratio, 10.9; 95% confidence interval, 2.3-88.9; P = .013). Freedom from CA branch instability was 97 ± 2% at 4 years, and this outcome was not associated with MAL compression (hazard ratio, 0.83; 95% confidence interval, 0.14-5.02; P = .588) or any other predictor. CONCLUSIONS: MAL compression was more common in extent I to III TAAAs, and related to additional challenges for CA stenting in fenestrated-branched endovascular aneurysm repair. This process may include bare metal stenting, gastric artery coverage, or early revision, especially in presence of an angulation of less than 120°. However, durable results can be achieved for CA incorporation despite these difficulties.