Aortic Root Aneurysm Research Articles

Three decades of reimplantation of the aortic valve-the Brussels experience.

Over the last three decades, the importance of native valve preservation has increasingly become evident. Valve-sparing root replacement procedures, such as the reimplantation or remodeling technique, are therefore being progressively used for aortic root replacement and/or aortic valve repair. Herein, we are summarizing our single-center experience with the reimplantation technique. We queried our prospective database for aortic valve repair and recruited all adult (≥18 years) patients who have undergone valve-sparing root replacement with the reimplantation technique between March 1998 and January 2022. We subcategorized the patients into three distinct groups: root aneurysm without aortic regurgitation (AR) (grade ≤1+), root aneurysm with AR (grade >1+) and isolated chronic AR (root <45 mm). Univariable logistic regression analysis was performed to identify variables of interest, which were further analyzed by multivariable Cox-regression analysis. Survival, freedom from valve reintervention, and freedom from recurrent regurgitation, were analyzed with the Kaplan-Meier method. A total of 652 patients were recruited for this study; 213 patients underwent reimplantation for aortic aneurysm without AR, 289 patients for aortic aneurysm with AR, and 150 patients with isolated AR. Cumulative survival was 95.4% (95% CI: 92.9-97.0%) after 5 years, 84.8% (80.0-88.5%) after 10 years, and 79.5% (73.3-84.5%) after 12 years, which was comparable to the age-matched Belgian population. Older age (HR 1.06, P≤0.001) and male gender (HR 2.1, P=0.02) were associated with late mortality. Freedom from reoperation on the aortic valve at 5 years was 96.2% (95% CI: 93.8-97.7%), and 90.4% (95% CI: 87.4-94.2%) at 12 years. Age (P=0.001) and preoperative left ventricular end-diastolic dimension (LVEDD) (P=0.03) were associated with late reoperation. Our long-term data supports our reimplantation approach as a viable option for aortic root aneurysms and/or aortic regurgitation, with long-term survival that mirrors that of the general population.

The natural history of aortic root aneurysms.

The aortic root has a different embryologic origin from all other segments of the human aorta, a feature that likely confers unique susceptibilities, anatomical patterns, and clinical behavior of aneurysm disease in this vital location. In this manuscript, we review the natural history of ascending aortic aneurysm, with a specific focus on the aortic root. The specific central message is that root dilatation is more malignant than ascending dilatation.

Smooth Muscle Cell Klf4 Expression Is Not Required for Phenotype Modulation or Aneurysm Formation in Marfan Syndrome Mice-Brief Report.

Smooth muscle cell (SMC) phenotypic reprogramming toward a mixed synthetic-proteolytic state is a central feature of aortic root aneurysm in Marfan syndrome (MFS). Previous work identified Klf4 as a potential mediator of SMC plasticity in MFS. MFS (Fbn1C1041G/+) mouse strains with an inducible vascular SMC fluorescent reporter (MFSSMC) with or without SMC-specific deletion of Klf4 exons 2 to 3 (MFSSMC-Klf4Δ) were generated. Simultaneous SMC tracing and Klf4 loss-of-function (Klf4Δ mice) was induced at 6 weeks of age. Aneurysm growth was assessed via serial echocardiography (4-24 weeks). Twenty-four-week-old mice were assessed via histology, RNA in situ hybridization, and aortic single-cell RNA sequencing. MFS mice demonstrated progressive aortic root dilatation compared with control (WTSMC) mice regardless of Klf4 genotype (P<0.001), but there was no difference in aneurysm growth in MFSSMC-Klf4Δ versus MFSSMC (P=0.884). Efficient SMC Klf4 deletion was confirmed via lineage-stratified genotyping, RNA in situ hybridization, and immunohistochemistry. Single-cell RNA sequencing of traced SMCs revealed a highly similar pattern of phenotype modulation marked by loss of contractile markers (eg, Myh11, Cnn1) and heightened expression of matrix genes (eg, Col1a1, Fn1) between Klf4 genotypes. Pseudotemporal quantitation of SMC dedifferentiation confirmed that Klf4 deletion did not alter the global extent of phenotype modulation, but reduced expression of 23 genes during this phenotype transition in MFSSMC-Klf4Δmice, including multiple chondrogenic genes expressed by only the most severely dedifferentiated SMCs (eg, Cytl1, Tnfrsf11b). Klf4 is not required to initiate SMC phenotype modulation in MFS aneurysm but may exert regulatory control over chondrogenic genes expressed in highly dedifferentiated SMCs.

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.

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. 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. 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. 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.

Association between the sinus of Valsalva height and biometric parameters in patients with Marfan syndrome associated with aortic root aneurysm

Patients with Marfan syndrome and aortic root aneurysm require pre-surgical analysis of aortic root geometry for aortic reconstruction. The aim of this study is to perform the morphometric analysis of the sinus of Valsalva height and correlation between the former, age, weight, height, body mass index (BMI), and body surface area (BSA) in patients with Marfan syndrome and aortic root aneurysm. Data from 34 patients (28 men, 6 women) with Marfan syndrome and an ascending aortic diameter exceeding 45 cm were obtained using computed tomography angiography. Gender-based differences were observed in the height of the left aortic sinus – by 47.23% (36.47±12.48 mm in men against 24.77±4.26 mm in women, р=0.0003). In men, a strong direct correlation has been identified between height and the right aortic sinus height (r=+0.75, р&lt;0.0001), the posterior aortic sinus height (r=+0.71, р&lt;0.0001), and the left aortic sinus height (r=+0.75, р&lt;0.0001). Moderate reverse correlation has been discovered between the sinus of Valsalva height and BMI. No correlations have been identified between weight, BSA and the sinus of Valsalva height (р&gt;0.05). In women, a strong direct correlation (Pearson) has been identified between age and the right aortic sinus height (r=+0.84, p=0.04), between weight and the left aortic sinus (r=+0.73, p=0.04) and between BSA and the left aortic sinus (r=+0.73, р=0.04). Aortic sinus height in men increases with height and decreases with higher BMI and age. Weight and BSA do not affect the sinus of Valsalva height. In women, the sinus of Valsalva height is impacted by age, weight and BSA.

Twenty-year experience of aortic valve reimplantation using the Valsalva graft: a successful technique with well-made device!

The introduction of the aortic valve (AV) reimplantation, also called David procedure, by David and Feindel in 1992 have placed a milestone for AV sparing [1]. This, one of the most 2 important valve-sparing aortic root replacement operations became the standard technique for patients with aortic root aneurysm with or without AV regurgitation with excellent short- and long-term results [2]. Over the years, the surgical technique of AV reimplantation has evolved significantly from the originally described technique aiming to mimic the anatomical form of the aortic root. Many modifications, including the ‘so-called’ David I–V operations, using different techniques such as plication stitches to create pseudo-/neo-sinuses [3, 4], 2 cylindrical grafts [5] or even special anatomically designed bulged grafts [6] have been described. In this issue of the European Journal of Cardiothoracic Surgery, Chirichilli et al. describe their 20-year-long experience with AV reimplantation using the Gelweave Valsalva graft Vascutek Ltd, Terumo Company (Renfrewshire, Scotland, UK) in 265 patients with aortic root aneurysm with or without AV regurgitation [7]. This device has been designed and invented by the senior author of the current article De Paulis [6] at the end of the last millennium and implemented in the routine practise at the beginning of 2000. The presented study belongs to the largest published cohorts describing AV reimplantation with this graft. The early- and long-term outcomes (mean of 7.1 years) are excellent. The overall survival at 15 years was 87.6 ± 3.4% and freedom from cardiac death was excellent and stable at 99.6 ± 0.4% up to 15 years. Freedom from recurrent AR ≥moderate and freedom from reoperation remained stable up to 15 years at 92.2 ± 2.1% and 95.9 ± 1.6%, respectively. In addition, the incidence of infective endocarditis, thromboembolism and haemorrhage was extremely low. Importantly, a clear message that can be derived from this paper is that David procedure using this particular graft is an excellent and durable option for the surgical treatment of the patients with aortic root aneurysm with or without AV regurgitation. The authors also report that long-term results might have improved after the implementation of routine performance of AV analysis with calliper.

Preoperative assessment of the technical complexity of minimally invasive aortic root repair.

The aim of this study was to assess predictors of technical complexity of minimally invasive aortic root repairs (MIARR) performed through J-shaped mini-sternotomies in patients with aortic root aneurysm. This study included 49 patients with aortic root aneurysm who underwent MIARR via an upper median J-shaped mini-sternotomy between January 2017 and April 2020. Preoperative high-resolution computed tomographic images synchronised with electrocardiography were mandatory for inclusion. Predictors of technical complexity were identified, and a scoring system was created. The correlation between technical complexity and intraoperative/postoperative parameters was explored. There was a significant association between technical complexity and increased procedure time (Spearmen's ρ=-0.45, P=0.001), blood loss (Spearmen's ρ=-0.384, P=0.006), cardiopulmonary bypass time (Spearmen's ρ=-0.301, P=0.035), and postoperative bleeding (Spearmen's ρ=-0.265, P=0.066). The anatomical aorta-sternal relationship (distance of >22.1 mm in the axial plane between the midline of the sternotomy plane and the left coronary), distance between the sternal notch and the aortic valve annulus (>14.5 cm in the sagittal plane), distance between the skin and the left coronary artery (>9.53 cm in the axial plane), obesity (Body Mass Index >30), and-diameter at the brachiocephalic trunk level (>37 mm), were strongly associated with procedural complexity. Overall test accuracy was 75.5%, sensitivity was 73.1%, and specificity 78.3%. Finally, we created an online calculator that surgeons can use to determine the probability of a technically difficult of MIARR based on these factors. This novel scoring system can be used to assess the technical complexity of minimally invasive aortic root repairs and to aid in preoperative planning.

Right Coronary Artery Narrowing by Stretching on Aortic Root Aneurysm

Right Coronary Artery Narrowing by Stretching on Aortic Root Aneurysm

Marfan Syndrome: an uncommon cause of heart failure with late presentation and management challenges in a Nigerian (case report)

Marfan syndrome is an autosomal dominant disorder with life-threatening cardiovascular complications. It is an uncommon cause of heart failure in our environment. We hereby highlight a case of Marfan syndrome presenting with heart failure, challenges of late presentation and management of Marfan syndrome in our environment. A 56-year-old man with a 4-year history of hypertension presented with 3 months history of exertional dyspnoea and orthopnoea. He had associated musculoskeletal abnormalities and reduced vision since childhood. No family history of Marfan syndrome. Examination revealed features of severe chronic aortic regurgitation, bilateral supero-nasally dislocated lenses, kyphoscoliosis, positive thumb and wrist signs. The resting electrocardiogram showed left ventricular hypertrophy with strain pattern. Ocular ultrasound confirmed bilateral ectopia lentis. Echocardiography revealed aortic root aneurysm, severe aortic regurgitation, left ventricular dilatation and reduced ejection fraction. The computed tomography (CT) aortogram revealed aortic root aneurysm, tortuous abdominal aorta, thoracolumbar scoliosis and pectus excavatum. Using revised Ghent's criteria, a diagnosis of Marfan syndrome in heart failure was made. Management was multidisciplinary with plans for aortic root replacement, family and genetic screening. He commenced beta blocker and angiotensin receptor blocker with symptomatic relief. He reportedly died at home after sudden onset tiredness. His management was hampered by late clinical presentation, difficulty assessing surgery and out of pocket health funding.

Twenty-year experience of aortic valve reimplantation using the Valsalva graft.

Over the past 20 years, valve-sparing aortic root replacement has aroused increasing interest because of a progressive attitude towards the preservation of natural tissue. Aortic reimplantation is the most used technique to spare the valve, allowing simultaneously aortic root replacement and aortic annular stabilization. The reimplantation into a graft with sinuses guarantees an optimal anatomic and functional reconstruction with established good results at 15 years. The aim of this study is to report the world longest follow-up (up to 20 years) of aortic valve reimplantation using the Valsalva graft. From February 2000 to December 2021, 265 consecutive patients with aortic root aneurysm received aortic valve reimplantation using the Valsalva graft. From 2018, leaflet plication with the routine use of calliper was performed. For each patient, we performed both intraoperative and post-procedural transoesophageal echocardiography. All patients were followed with clinical assessment and echocardiography. The mean duration of follow-up was 85 ± 63 months. The study cohort had a median age of 55 ± 18 and 87.2% were male. The aortic root aneurysm was associated to bicuspid aortic valve in 18.9% of patients and to Marfan syndrome in 10.6% of cases. 55.9% had an aortic regurgitation ≥ 2+. Overall survival at 15 was 87.6 ± 3.4. Freedom from cardiac death was stable at 99.6 ± 0.4 at 5, 10 and 15 years. Freedom from recurrent AR ≥3+ and freedom from reoperation remained stable at 10 and 15 years at 92.2 ± 2.1 and 95.9 ± 1.6, respectively. There was a minimal incidence of infective endocarditis (0.8%), thromboembolism (2.2%) and haemorrhage (2.0%). Six out of 7 patients requiring reoperation had surgery in the first period of our experience (last in 2004). Early suboptimal results had a negative effect on residual aortic regurgitation. Moreover, we hypothesized that the routine use of calliper may have contributed to a further improvement of the outcome, even if these data need to be confirmed by a longer follow-up. The first long-term follow-up after aortic valve reimplantation using the Valsalva graft demonstrated excellent results. These long-term results gradually improved with learning curve, remaining stable during the second decade of observation. The systematic use of calliper may have contributed to a further improvement of the outcome.

Bentall Operation: Early Surgical Results, Seven-Year Outcomes, and Risk Factors Analysis.

Aim: To analyze early and mid-term outcomes of the Bentall operation. Methods: Two hundred and seventeen patients (mean age 65.6 ± 15.9 years, males/females 172/45) underwent Bentall operation in a 7-year period (January 2015−December 2021), on average, 30 Bentall operations occurred per year, using biological (n = 104) or mechanical (n = 113) valved conduits for the treatment of ascending aorta−aortic root aneurysms. Associate procedures were performed in 58 patients (26.7%); coronary artery bypass grafting (CABG) in 35 (16%). Mean follow-up was 55.2 ± 24 (median 60.2) months. Cox model analysis was used to assess risk factors, Kaplan−Meier and log-rank tests were used to assess different survival rates. Results: Operative mortality was 1.38%. At 7 years, survival, freedom from cardiac death, and event-free survival were 93% ± 2%, 99% ± 1%, and 81% ± 5%. NYHA class (p < 0.0001), trans-aortic valve mean (p < 0.0001) and maximum (p < 0.000) gradients, left ventricular hypertrophy (p < 0.05), and pulmonary arterial pressure (p = 0.002) significantly improved vs. preoperative values. Concomitant CABG during Bentall operation independently affected late outcomes (HR 1.9−2.3; p-values < 0.05). Late survival was affected by concomitant CABG (84% ± 8% vs. 95% ± 2%, p = 0.04), preoperative myocardial infarction (91% ± 9% vs. 97% ± 2%, p = 0.02), and biological vs. mechanical prostheses valved conduits (91% ± 9% vs. 95% ± 3%, p = 0.02). Event-free survival also was affected by concomitant CABG (62% ± 14% vs. 85% ± 5%, p = 0.005) and biological prostheses (78% ± 8% vs. 84% ± 6%, p = 0.06). Freedom from endocarditis−redo operation was 83% ± 9% for biological prostheses vs. 89% ± 6% for mechanical prostheses (p = 0.49). Conclusions: Low rates of operative mortality and late complications make Bentall operation the gold standard for the treatment of ascending aorta−aortic root aneurysms. Coronary ischemic disease affects late outcomes. Biological prostheses should be preferred for the elderly.

Straightforward Contemporary Step-by-Step Approach to Aortic Root Replacement With Valve-Sparing Tricuspid Aortic Valve Repair

Valve-sparing aortic root replacement (VSARR) has become an appealing choice for replacing an aneurysmal root when the patient's anatomic characteristics are favorable, especially in patients with heritable thoracic aortic disease. It is a technically challenging procedure, and the learning curve is considerable. This approach's chief advantages are that the patient's own aortic valve apparatus is preserved, the repair (in expert hands) is durable, and it avoids the need for lifelong anticoagulation associated with the mechanical valves in the aortic root prostheses. In this report, we provide a step-by-step approach for aortic root replacement in patients with a tricuspid aortic valve suitable for VSARR. Valve-sparing aortic root replacement (VSARR) has become an appealing choice for replacing an aneurysmal root when the patient's anatomic characteristics are favorable, especially in patients with heritable thoracic aortic disease. It is a technically challenging procedure, and the learning curve is considerable. This approach's chief advantages are that the patient's own aortic valve apparatus is preserved, the repair (in expert hands) is durable, and it avoids the need for lifelong anticoagulation associated with the mechanical valves in the aortic root prostheses. In this report, we provide a step-by-step approach for aortic root replacement in patients with a tricuspid aortic valve suitable for VSARR. Commentary on Baylor's Technique of Aortic Valve ReimplantationOperative Techniques in Thoracic and Cardiovascular SurgeryPreviewDoctors Preventza, Huu, and Coselli described the technique they use to do reimplantation of the aortic valve to treat aortic root aneurysms.1 I will limit my comments to areas that I disagree with what was written in their manuscript. Full-Text PDF

Transthoracic echocardiographic assessment of cardiac valves in patients with Behçet's disease.

The main objectives of the current study are to investigate valvular involvement in patients with cardiac Behçet's disease (BD) and find out the risk factors of valvular involvement in cardiac BD. We retrospectively assessed the clinical and echocardiographic data in the medical records of 121 patients with BD admitted to Beijing Anzhen Hospital from January 2015 to January 2022. We evaluated the valvular structure and function mainly by echocardiography. A total of 77 BD patients (77/121, 63.64%) had cardiac valvular involvement. Valvular lesions occurred more frequently in males (p = 0.022). Aortic regurgitation (AR) (62/77, 80.52%) was the most common finding and severe AR occupied 80.65% (50/62). The most common manifestations of BD patients with severe AR was aortic valve prolapse (25/50, 50%), followed by echo-free spaces within the aortic annulus (11/50, 22%), vegetation-like lesions (10/50, 20%), and aortic root aneurysm (10/50, 20%). The incidence of paravalvular leaks (PVL) in BD patients was 14.29% (7/49). The diameter of the sinus of Valsalva and proximal ascending aorta, and total cholesterol (TCHO) were the independent risk factors of moderate-severe aortic valvular regurgitation (p < 0.01). Left ventricular end-diastolic dimension (LVEDD), left ventricular ejection fraction (LVEF) and brain natriuretic peptide (BNP) were significantly associated with moderate-severe mitral valvular regurgitation (p < 0.01). The most common valvular abnormality in BD is AR. Echocardiography has great value in the comprehensive evaluation and accurate diagnosis of valvular involvement in BD patients.

DO NOT RUSH TO BLAME THE ARTERIAL LINE. BEFORE TAKING IT OUT, SCAN THE AORTA

<h3>Objective</h3> Cardiac Anaesthesiologists has the unique advantage of assessing the cardiovascular system through various methods. Non-invasive and invasive hemodynamic monitoring accompanied by Transoesophageal Echocardiography (TOE) with 3D imaging, create an integrated profile of pressure, volume, flow velocity and anatomical information for every patient. In the current case report, we highlight the role of TOE and 3D imaging in diagnosing a previously unknown Coarctation of the Aorta (CoA), and thus interpreting correctly the arterial waveform of a femoral arterial line that was initially considered to be malfunctioning. <h3>Design and Method</h3> A 53yr old male patient was scheduled for Aortic Valve plus partial Aortic Root plus Ascending Aorta replacement. The background included a bicuspid aortic valve (Sievers Type 0: no raphe) with moderate mixed valvular disease, aortic root aneurysm with unequal dilatation of the sinuses of Valsalva, and an ascending aorta aneurysm. Intraoperatively, a right brachial cuff for Non-Invasive Blood Pressure (NIBP) was placed before the anesthesia induction, whilst after that an arterial line was introduced in the left femoral artery (Figure 1). Because of the fact that the arterial waveform had a damped shape, a delayed upslope and a 30mmHg difference with the NIBP, after having ruled out any connection issues, a second arterial line was inserted into the left radial artery. The second waveform had a normal shape and was numerically matching the NIBP, having therefore the same pressure difference with the femoral line (Figure 2,3). Keeping in mind the patient's background, the suspicion of CoA was raised. <h3>Results and Conclusion</h3> The comprehensive TOE examination that followed, including 3D imaging, confirmed the already known patient's background, but more importantly proved the existence of CoA, showed its precise anatomy and appreciated quite accurately the previously noticed pressure difference between the two arterial waveforms (Figure 4,5,6,7,8). Due to the fact that the summary of the preoperative CT angiography was not describing any pathology in the descending aorta, a further analysis of the CT with 3D reconstruction was requested at that moment; the clinical suspicion and the echocardiographic findings were verified (Figure 9,10). As fas as the surgical procedure is concerned, the patient underwent a mechanical aortic valve replacement, replacement of the non-coronary sinus of Valsalva and of the ascending aorta with an interposition graft. No intervention regarding the CoA was performed. In conclusion, in this case report we showed that a damped arterial waveform - a clinical finding that could have been overlooked and the arterial line to be consequently removed - constituted the first step towards a definite diagnosis. Undoubtedly, crucial in the diagnostic process proved to be the role of TOE, and more specifically a comprehensive and not only focused to the main pathology TOE examination. However, it is the clinical suspicion that should be always kept high.

Abstract 11327: De Novo Heart Failure in a Young Adult: A Case of Severe Aortic Regurgitation Secondary to an Aortic Root Aneurysm in a Patient With Marfan's Syndrome

A 24-year-old male, with no past medical history, presented to the ER with a 15-day history of insidious abdominal pain and distention, associated with progressive dyspnea on exertion and bilateral lower extremity pitting edema. In the previous 48 hours before his hospital admission, patient began presenting orthopnea and paroxysmal nocturnal dyspnea.On presentation patient was normotensive and tachycardic, with low oxygen saturation on pulse oximetry. On auscultation a loud early diastolic decrescendo murmur was heard at the parasternal border, with and audible S3 gallop. Characteristic Marfanoid habitus was observed. Patient underwent TTE were there was a notable aortic root dilation, mainly at the level of the sinuses of Valsalva, which had a diameter of 85 mm and 62 mm at the sinotubular junction. Ascending and descending aorta had a normal diameter. An eccentric jet of severe aortic regurgitation was also noted, which collided with the anterior mitral valve leaflet causing an Austin Flint phenomenon. Left ventricular ejection fraction was estimated at 24%, severe dilation was noted on all chambers. There were no echocardiographic signs of aortic dissection. Patient underwent genetic testing and ophthalmic evaluation, confirming the diagnosis of Marfan’s syndrome. A contrast enhanced CT angiogram confirmed the presence of severe aortic root dilation without dissection. Patient underwent Bentall procedure and began treatment for HFrEF at discharge. Marfan Syndrome is an autosomal dominant connective tissue disorder, due to mutations mostly in the FBN1 gene. Most cardiovascular symptoms are related to dilation of the aortic root and subsequent aortic regurgitation due to aortic annulus dilation. In patients with Marfan’s syndrome, all aortic root aneurysms ≥5.0 mm should undergo surgical repair regardless of symptoms.

Abstract 11748: Prophylactic Aortic Arch Replacement in Patients With Loeys-Dietz Syndrome: Surgical Outcomes and Molecular Rationale

Introduction: Loeys-Dietz syndrome (LDS) patients typically develop focal aortic root aneurysm but have substantial risk of distal aortic events (arch aneurysm and type B dissection) after root replacement. We offer prophylactic arch replacement to LDS patients of all genotypes undergoing elective valve-sparing aortic root replacement (VSARR) to prevent late aortic events. We hypothesized that non-dilated LDS aortic arch tissue demonstrates ongoing deterioration at the time of VSARR. Methods: Aortic tissue was anatomically segmented (root, ascending, arch) then examined via histology and single-cell RNA sequencing (‘scRNAseq’, n=4 patients) to comprehensively profile cellular phenotypes. Results: LDS patients (n=8, mean age 37.9 years, 87.5% male) had root aneurysm (mean 45.1 ± 8.9mm) without ascending (35.1± 7.8mm) or arch dilation (28.7 ± 2.8mm) and underwent concurrent VSARR and branched graft total arch replacement. There were no perioperative deaths or strokes and no distal aortic events or reoperations after median 1.26 years follow-up. Histologically, elastin fragmentation and collagen deposition were detectable in each aortic segment (n=4). scRNAseq identified a continuum of smooth muscle cell (SMC) phenotype modulation associated with progressively reduced contractile gene expression. Pathway analysis of 260 genes enriched during SMC modulation identified heightened integrin signaling, transforming growth factor-beta-responsiveness, cell adhesion, and extracellular matrix remodeling. Histologic confirmation using RNA probes specific for modulated SMCs (TGF-beta responsive gene SERPINE1 and glycoprotein TNFRSF11B ) identified these cells in the tunica media layer of each aortic segment, with greatest density in the root aneurysm but extending to the arch. In age-matched donor aortas, TNFRSF11B + cells were restricted to the atherosclerotic tunica intima, confirming specificity of medial SMC modulation in aneurysm. Conclusions: Total arch replacement during elective VSARR is feasible without substantial morbidity. In LDS patients with root aneurysm, matrix deterioration and SMC phenotype modulation are present in the non-dilated aortic arch, providing molecular rationale for aggressive arch replacement.

Abstract 14616: Lineage-Specific Integrin alpha-V Augmentation Promotes Integrin/Akt/mTORC1 Signaling Pathway in Marfan Syndrome Aortic Aneurysm

Introduction: Marfan syndrome (MFS) patients classically develop focal aortic root aneurysms. Previously, we demonstrated in vitro activation of the integrin/Akt/mTORC1 signaling pathway in MFS second heart field iPSC derived SMCs. Integrin αV (ITGAV) antagonism via selective inhibitor GLPG0187 attenuated the signaling cascade. Therefore, we hypothesize that ITGAV blockade may have a potential therapeutic effect to reduce MFS aneurysmal growth. Methods: Fbn1 C1039G/+ mice were treated with (1) ITGAV antagonism (GLPG0187, 100mg/kg/day, IP) or (2) vehicle control (age 6-14 weeks). WB and ELISA were performed at baseline and after treatment. Aneurysm growth and elastin fragmentation were measured with ultrasound and histology respectively. Proliferation marker Ki-67 was used with IHC staining. Results: ITGAV and p-Akt protein levels were elevated in Fbn1 C1039G/+ aortic specimens at both 6 and 14 weeks of age compared to wild-type littermate controls. P-Akt and mTORC1 activities were attenuated following GLPG treatment compared to vehicle control (p-Akt Thr308 : 1.37- vs. 1.11-fold, p&lt;0.05; p-RPS6 Ser235/236 : 5.13- vs. 1.15-fold, p&lt;0.001; p-RPS6 Ser240/244 : 4.36- vs. 1.25-fold, p&lt;0.05, n=6). Compared to vehicle control, GLPG reduced aneurysm growth (2.12±0.14mm vs. 1.82±0.19mm, p&lt;0.001, n=12) and elastin fragmentation (1.09 [0.99-1.18] vs. 0.84 [0.75-1.01] breaks/lamina, p&lt;0.05, n=6) in Fbn1 C1039G/+ mice. Ki-67 expression was suppressed with GLPG treatment. Conclusions: As biological proof of concept, GLPG0187 treatment in Fbn1 C1039G/+ mice decreased aneurysm growth via reduced ITGAV signaling. Mechanistically, blockade of ITGAV leads to diminished Akt and mTORC1 activation. Ultimately reducing aortic SMC proliferation, migration and phenotype modulation, which have all been associated with aortic aneurysm development and growth. ITGAV blockade via GLPG0187 may be a promising therapeutic approach to slow MFS aneurysmal growth.

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

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. 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. 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.

Valve Sparing Root Replacement in Bicuspid Aortic Valve Disease

A dysfunctional bicuspid aortic valve (BAV) with associated an aortic root aneurysm represents complex pathology with multiple options for surgical repair. Traditionally Bentall aortic root replacement has been the gold standard to ensure a properly functioning valve and minimize the risk of recurrent root disease. Given the known disadvantages of prosthetic valve conduits with either a mechanical or bioprosthetic valve in these often young patients, there has recently been increasing interest and application of valve-sparing operations in BAV patients with aortic root enlargement. Over the pasts 15 years, our institution has been able to safely perform valve-sparing root replacement in select patients with diseased bicuspid aortic valve and root aortopathy. The outcomes are excellent and long-term follow-up data shows 10-year freedom from aortic valve or root replacement at 96%. This success can be attributed to appropriate patient selection, sound operative technique with meticulous post-operative care as well as a lifetime post-operative follow-up strategy. Here in we describe our operative technique and key tenets to ensure optimal patient outcomes. A dysfunctional bicuspid aortic valve (BAV) with associated an aortic root aneurysm represents complex pathology with multiple options for surgical repair. Traditionally Bentall aortic root replacement has been the gold standard to ensure a properly functioning valve and minimize the risk of recurrent root disease. Given the known disadvantages of prosthetic valve conduits with either a mechanical or bioprosthetic valve in these often young patients, there has recently been increasing interest and application of valve-sparing operations in BAV patients with aortic root enlargement. Over the pasts 15 years, our institution has been able to safely perform valve-sparing root replacement in select patients with diseased bicuspid aortic valve and root aortopathy. The outcomes are excellent and long-term follow-up data shows 10-year freedom from aortic valve or root replacement at 96%. This success can be attributed to appropriate patient selection, sound operative technique with meticulous post-operative care as well as a lifetime post-operative follow-up strategy. Here in we describe our operative technique and key tenets to ensure optimal patient outcomes.

Intestinal barrier dysfunction is involved in the development of systemic inflammatory responses and lung injury in type A aortic dissection: a case-control study

BackgroundThe definite pathogenesis of lung injury complicated by type A aortic dissection (TAAD) remains unclear. In this paper, we investigated the relationship between intestinal injury, lung injury, and systemic inflammatory responses, with the aim of exploring the mechanism underlying intestinal injury and its impact on systemic inflammatory responses and lung injury in patients with TAAD.MethodsPatients with TAAD (n=36) and those with aortic root aneurysm (ARA) (n=30) were compared. TAAD patients were younger and had higher creatinine (Cr) than ARA patients. White blood cell (WBC) count, neutrophil count, neutrophil percentage, interleukin (IL)-6, IL-8, tumor necrosis factor α (TNF-α), C-reactive protein (CRP), histamine (HIS) levels, PaO2-FiO2 ratio, diamine oxidase (DAO), intestinal fatty acid binding protein (iFABP), and peptidoglycan (PGN) were measured using the same laboratory methods between the two groups.ResultsIncreased WBC [(9.70±4.05)×109/L vs. (5.88±1.2)×109/L, P<0.001], neutrophil [(7.65±4.27)×109/L vs. (3.40±0.97)×109/L, P<0.001], neutrophil percentage [(74.73±13.42)% vs. (57.67±9.45)%, P<0.001], IL-6 (37.48±4.87 vs. 20.90±0.92 pg/mL, P<0.001), IL-8 (97.15±9.11 vs. 69.46±3.17 pg/mL, P<0.001), TNF-α (71.32±10.35 vs. 33.90±2.27 pg/mL, P<0.001), CRP (10.67±1.62 vs. 4.43±0.26 µg/mL, P<0.001), HIS (13.29±1.88 vs. 7.63±0.58 ng/mL, P<0.001), DAO (24.94±4.72 vs. 10.92±2.44 U/L, P<0.001), iFABP (879.01±190.12 vs. 206.35±42.20 pg/mL, P<0.001), and PGN (31.10±5.51 vs. 12.52±2.20 ng/mL, P<0.001) and decreased PaO2-FiO2 ratio (365.35±146.47 vs. 447.86±70.80 mmHg, P=0.01) were detected in TAAD group relative to ARA group. In TAAD group, positive correlations were detected between DAO and inflammatory cytokines [IL-6 (r=0.56, P<0.001), IL-8 (r=0.61, P<0.001), TNF-α (r=0.71, P<0.001), and CRP (r=0.68, P<0.001)], between iFABP and inflammatory cytokines [IL-6 (r=0.72, P<0.001), IL-8 (r=0.71, P<0.001), TNF-α (r=0.90, P<0.001), and CRP (r=0.89, P<0.001)], between DAO and PGN (r=0.52, P<0.001), between iFABP and PGN (r=0.74, P<0.001), between PGN and inflammatory cytokines [IL-6 (r=0.85, P<0.001), IL-8 (r=0.44, P<0.001), TNF-α (r=0.61, P<0.001), and CRP (r=0.73, P<0.001)]. In acute TAAD subgroup, PGN and PaO2-FiO2 ratio were negatively correlated (r=−0.50, P=0.036).ConclusionsSystemic inflammatory responses in TAAD patients may lead to lung and intestine injury, and the latter may be involved in the development of systemic inflammatory responses and lung injury in these patients.