3-Year Outcomes From the Evolut Low Risk TAVR Bicuspid Study.

BACKGROUND: Outcomes from transcatheter aortic valve replacement (TAVR) in low-surgical risk patients with bicuspid aortic stenosis beyond 2 years are limited. OBJECTIVES: This study aimed to evaluate 3-year clinical and echocardiographic outcomes from the Evolut Low Risk Bicuspid Study. METHODS: The Evolut Low Risk Bicuspid Study is a prospective, multicenter, single-arm study conducted in 25 U.S. CENTERS: Patients with severe aortic stenosis at low surgical risk with bicuspid aortic valve anatomy (all subtypes) underwent TAVR with a self-expanding, supra-annular Evolut R or PRO (Medtronic) bioprosthesis. An independent clinical events committee adjudicated all deaths and endpoint-related adverse events, and a central echocardiographic core laboratory assessed hemodynamic endpoints. RESULTS: An attempted implant was performed in 150 patients from December 2018 to October 2019. The mean age was 70.3 ± 5.5 years, 48% (72/150) of the patients were women, and the mean Society of Thoracic Surgeons Predicted Risk of Mortality score was 1.3% (Q1-Q3: 0.9%-1.7%). Sievers type 1 was the dominant bicuspid morphology (90.7%, 136/150). The Kaplan-Meier rates of all-cause mortality or disabling stroke were 1.3% (95% CI: 0.3%-5.3%) at 1 year, 3.4% (95% CI: 1.4%-8.1%) at 2 years, and 4.1% (95% CI: 1.6%-10.7%) at 3 years. The incidence of new permanent pacemaker implantation was 19.4% (95% CI: 12.4%-29.6%) at 3 years. There were no instances of moderate or severe paravalvular aortic regurgitation at 2 and 3 years after TAVR. CONCLUSIONS: The 3-year results from the Evolut Low Risk Bicuspid Study demonstrate low rates of all-cause mortality or disabling stroke and favorable hemodynamic performance.

Infective endocarditis in a cohort of adult CHD patients.

BACKGROUND: CHD increases the risk of infective endocarditis due to the substrate of prosthetic materials and residual lesions. However, lesion-specific and mortality risks data are lacking. We sought to analyse clinical course and mortality of infective endocarditis in a cohort of adult CHD. METHODS: Retrospective analysis of all cases of proven and probable infective endocarditis (Duke's criteria) followed in our adult CHD clinic between 1970 and August, 2021. Epidemiological, clinical and imaging data were analysed. Predictors of surgical treatment and mortality were assessed using regression analysis. RESULTS: During a mean follow-up of 15.8 ± 10.9 years, 96 patients had 105 infective endocarditis episodes, half with previous cardiac surgery (corrective or palliative). The most frequent diagnoses were: ventricular septal defect, bicuspid aortic valve, Tetralogy of Fallot and pulmonary atresia. The site of infection was identified by echocardiography in 82 episodes (91%), most frequently in aortic (n = 27), tricuspid (n = 15), and mitral (n = 13) valves. Blood cultures were positive in 79% of cases, being streptococci (n = 29) and staphylococci (n = 23) the predominant pathogens. Surgery was necessary in 40% and the in-hospital mortality was 10.5%, associated with heart failure (p < 0.001; OR 13.5) and a non-surgical approach (p = 0.003; OR 5.06). CONCLUSIONS: In an adult CHD cohort, infective endocarditis was more frequent in patients with ventricular septal defect and bicuspid aortic valves, which contradicts the current guidelines that excludes them from prophylaxis. Surgical treatment is often required and mortality remains substantial. Prevention of this serious complication should be one of the major tasks in the care of adults with CHD.

The clinical effect of a combined technical system for bicuspid aortic valves repair / 中国胸心血管外科临床杂志

@#Objective    To summarize the clinical result of a combined technical system for bicuspid aortic valve (BAV) repair. Methods    Patients who diagnosed as BAV and sever aortic regurgitation (AR) underwent a strategy of combined repair technics including annuloplasty, sinus plasty, leaflet plasty, sinus-tubular junction (STJ) plasty depending on anatomy pathological characteristics between October 2019 and January 2021 were enrolled. The clinical data of the patients were analyzed. Results    A total of 17 patients were enrolled. There were 11 males and 6 females with an average age of 18-49 (32.4±13.6) years. Fifteen patients had typeⅠand 2 patients had typeⅡBAV according to Sievers classification. Annuloplasty was applicated in 13 patients, sinus plasty in 8 patients, leaflet plasty in 17 patients, and STJ plasty in 11 patients, respectively. The cardiopulmonary bypass (CPB) time was 95 (84, 135) min, aortic cross-clamping time was 68 (57, 112) min, and the ICU stay time was 17 (12, 25) h. After the operation, mild AR was presented in 14 patients, moderate AR in 1 patient and severe AR in 2 patients. The latter 3 patients underwent second operation under CPB, after then, 1 patient had mild AR and 2 patients had moderate AR. The follow-up time was 13.1±4.6 months. At the latest follow-up, 12 patients had mild AR and 5 patients had moderate AR, and no patient had reoperation. Conclusion    A combined technical system for BAV repair can be used effectively and safely with an acceptable short and middle-term result.

AVNeo improves early haemodynamics in regurgitant bicuspid aortic valves compared to aortic valve repair.

OBJECTIVES: Calcified or fibrotic cusps in patients with bicuspid aortic valves and aortic regurgitation complicate successful aortic valve (AV)-repair. Aortic valve neocuspidization (AVNeo) with autologous pericardium offers an alternative treatment to prosthetic valve replacement. We compared patients with regurgitant bicuspid valves undergoing AV-repair or AVNeo. METHODS: We retrospectively analysed patients with regurgitant bicuspid valves undergoing AV-repair or AVNeo. We focused on residual regurgitation, pressure gradients and effective orifice area, determined preoperatively and at discharge. RESULTS: AV-repair was performed in 61 patients (mean age: 43.2 ± 11.3 years) and AVNeo in 22 (45.7 ± 14.1). Prior to the operation patients of the AV-repair group showed severe regurgitation in 38 cases (62.3%) and moderate in 23 (37.6%); in the AVNeo group, all patients exhibited severe regurgitation. Postoperatively, 57 patients (93.4%) patients had no or mild regurgitation after AV-repair and 21 (95.4%) after AVNeo. In AVNeo-patients, peak (10.6 ± 3.1 mmHg vs 22.7 ± 11 mmHg, P< 0.001) and mean pressure gradients (5.9 ± 2 mmHg vs 13.8 ± 7.3 mmHg, P < 0.001) were significantly lower and the orifice area significantly larger (2.9 ± 0.8 cm2 vs 1.9 ± 0.7 cm2, P < 0.001) compared to repair. CONCLUSIONS: Compared to AV-repair, patients AVNeo showed lower mean pressure gradients and larger orifice areas at discharge. The functional result was not different.

Tissue-Specific Roles for the Slit-Robo Pathway During Heart, Caval Vein, and Diaphragm Development.

Background Binding of Slit ligands to their Robo receptors regulates signaling pathways that are important for heart development. Genetic variants in ROBO1and ROBO4 have been linked to congenital heart defects in humans. These defects are recapitulated in mouse models with ubiquitous deletions of the Slit ligands or Robo receptors and include additional heart defects not currently linked to SLIT or ROBO mutations in humans. Given the broad expression patterns of these genes, the question remains open which tissue-specific ligand-receptor interactions are important for the correct development of different cardiac structures. Methods and Results We used tissue-specific knockout mouse models of Robo1/Robo2, Robo4, Slit2 andSlit3 and scored cardiac developmental defects in perinatal mice. Knockout of Robo2 in either the whole heart, endocardium and its derivatives, or the neural crest in ubiquitous Robo1 knockout background resulted in ventricular septal defects. Neural crest-specific removal of Robo2 in Robo1 knockouts showed fully penetrant bicuspid aortic valves (BAV). Endocardial knock-out of either Slit2or Robo4 caused low penetrant BAV. In contrast, endocardial knockout of Slit3 using a newly generated line resulted in fully penetrant BAV, while removal from smooth muscle cells also resulted in BAV. Caval vein and diaphragm defects observed in ubiquitous Slit3 mutants were recapitulated in the tissue-specific knockouts. Conclusions Our data will help understand defects observed in patients with variants in ROBO1 and ROBO4. The results strongly indicate interaction between endocardial Slit3and neural crest Robo2 in the development of BAV, highlighting the need for further studies of this connection.

Prosthesis Position after TAVI with Balloon-Expandable SAPIEN 3 in Bicuspid Aortic Valves.

BACKGROUND: Prior data suggest a correlation between the position of transcatheter heart valves (THV) and the occurrence of complications after transcatheter aortic valve implantation (TAVI) in patients with tricuspid aortic valves (TAV). However, data including a detailed analysis of prosthesis positioning in bicuspid aortic valves (BAV) are limited. Therefore, the purpose of this study was to investigate THV position after TAVI in BAV. METHODS: We evaluated the THV position in 50 BAV and 50 TAV patients (all received the balloon-expandable Sapien 3 prosthesis) using fusion imaging of pre- and post-procedural computed tomography angiography. According to the manufacturers' recommendations, a low implantation position was defined as >30% of the prosthesis below the annulus. RESULTS: THV position was appropriate in the majority of the patients within both groups (90.0% for BAV vs. 96.0% for TAV, p = 0.240). In BAV, we observed a more pronounced THV waist (7.4 ± 4.5% vs. 5.8 ± 3.0%, p = 0.043) and a lower average THV expansion (91.9 ± 12.2% vs. 95.5 ± 2.7% of nominal expansion, p = 0.044). CONCLUSIONS: Accurate positioning in relation to the aortic annulus of the TAVI Sapien 3 prosthesis is possible in patients with BAV with results comparable to TAV. However, there is a more pronounced prosthesis waist and a lower average THV expansion in BAV.

Transcatheter aortic valve replacement in bicuspid valves: The synergistic effects of eccentric and incomplete stent deployment.

Bicuspid aortic valve is a congenital cardiac anomaly and common etiology of aortic stenosis. Given the positive outcomes of transcatheter aortic valve replacement (TAVR) in low-risk patients, TAVR will become more prevalent in the future in the treatment of severe bicuspid valve stenosis. However, asymmetrical bicuspid valve anatomy and calcification can prevent the circular and complete expansion of transcatheter aortic valves (TAVs). In previous studies, examining the impact of elliptical TAV deployment on leaflet stress distribution, asymmetric expansion of balloon-expandable intra-annular devices was studied up to an ellipticity index (long/short TAV diameter) of 1.4. However, such a high degree of eccentricity has not been observed in clinical studies with balloon-expandable devices. High degrees of stent eccentricity have been observed in self-expanding TAVs, such as CoreValve. However, CoreValve is a supra-annular device, and it was not clear if eccentric and incomplete stent deployment at the annulus would alter leaflet stress and strain distributions. This study aimed to assess the effects of eccentric and incomplete stent deployment of CoreValves in bicuspid aortic valves and compare the results to that of SAPIEN 3. Leaflet stress distribution and leaflet kinematics of 26-mm CoreValve and 26-mm SAPIEN 3 devices in bicuspid valves were obtained in a range that was observed in previous clinical studies. The results indicated that elliptical and incomplete stent deployment of TAVs increase leaflet stress and impair leaflet kinematics. The changes were more pronounced in CoreValve than SAPIEN 3. Increased leaflet stress can reduce long-term valve durability, and impaired leaflet kinematics can potentially increase blood stasis on the TAV leaflets. The study provides complementary insights into the mechanics of TAVs in bicuspid aortic valves.

Short-term outcomes of aortic valve neocuspidization for various aortic valve diseases.

Objectives: Bioprosthetic valve deterioration remains a major limitation following aortic valve replacement. Favorable results have been reported with an autologous pericardium aortic valve neocuspidization. Methods: Seventy patients (31 women and 39 men) (mean age, 62 ± 12 years) with aortic stenosis (n = 52 [74%]) or aortic regurgitation (n = 18 [26%]) underwent the aortic valve neocuspidization procedure. Thirty-four patients (49%) had a tricuspid valve, 35 (50%) had a bicuspid valve, and 1 (1%) had a monocuspid valve. European System for Cardiac Operative Risk Evaluation and Society of Thoracic Surgeons scores were, respectively, 2.2% ± 2% and 2.0% ± 1.8%. Four patients (6%) had active endocarditis and 2 (3%) had endocarditis sequelae. One patient (1%) had fibroelastoma. A combined procedure was performed in 33 patients (46%). Results: The follow-up period was 24 ± 12 months. One patient (1%) died in hospital and 1 patient (1%) underwent conventional valve replacement for significant aortic regurgitation. Postoperative peak and mean pressure gradients were respectively 14 ± 5 and 8 ± 3 mm Hg. Aortic valve area was 2.5 ± 0.6 cm2. During follow-up, no patients died. Reintervention occurred in 2 patients (3%). At last follow-up, peak pressure gradient was 13 ± 7 mm Hg, mean pressure gradient was 7 ± 4 mm Hg, and aortic valve area was 2.3 ± 0.7 cm2. There was 1 recurrence of moderate aortic stenosis (1%). All patients were in New York Heart Association functional class I (90%) or II (10%). Freedom from major valve-related events was 92.1%, (98.5% for death, 95.2% for reintervention, and 95.2% for endocarditis). Conclusions: In our experience, the midterm outcomes of the aortic valve neocuspidization procedure with autologous glutaraldehyde fixed pericardium were acceptable for survival, operative risk and valve-related complications, for our all-comer patient population with various aortic valve diseases.

Progress in the pathogenesis of congenital bicuspid aortic valves and the associated complications / 国际儿科学杂志

Congenital bicuspid aortic valves(BAV)is one of the most common congenital heart diseases.It is generally diagnosed by echocardiography when deterioration of the abnormal leaflets becomes clinically evident.Patients with BAV are at increased risks of developing serious complications, including aortic stenosis, aortic regurgitation, aortic dilation, aortic dissection and/or aneurysm, which seriously threatens the health of patients.Although its diagnosis and surgical treatment have been clear, the specific pathogenesis has not been completely revealed.Recently, studies have found that gene mutations and related signaling pathway abnormalities are associated with BAV and its complications.And epigenetics and environmental factors are involved in the development and progress of BAV.Understanding the underlying cellular and molecular basis of normal and pathological aortic valve development may improve the preventative and therapeutic approaches to valve degeneration.

Transcatheter aortic valve replacement outcomes in bicuspid compared to trileaflet aortic valves.

AIM: TAVR in patients with bicuspid aortic valves (BAV) is more challenging compared to individuals with trileaflet aortic valves (TAV). BAV have been excluded from the large randomized clinical trials assessing transcatheter aortic valve replacements (TAVR) and has been considered as a relative contraindication to TAVR. To report the outcomes of TAVR in BAV and compare them to TAV in the National Inpatient Sample (NIS). METHODS AND RESULTS: TAVR procedures were identified between 2011 and 2014 in the NIS dataset. Endpoints assessed included in-hospital mortality, periprocedural complications, length of stay and cost. Of 40,604 identified TAVR procedures, 407 (1%) were BAV and the 40,197 (99%) were TAV. Patients with BAV were younger and had a lower comorbidity burden. In hospital mortality (4.89% vs 4.17%, OR: 1.71, 95%CI: 0.57-5.12, P = 0.21), AMI (3.49% vs 3.58%, OR: 1.12, 95%CI: 0.36-3.54, P = 0.85), stroke and TIA (2.49% vs 3.55%, OR: 0.75, 95%CI: 0.18-3.16, P = 0.70), vascular complications (2.39% vs 5.58%, OR:0.47, 95%CI: 0.11-1.93, P = 0.29), major bleeding (16.96% vs 23.50%, OR: 0.63, 95%CI: 0.34-1.17, P = 0.15) and rates of permanent pacemaker (PPM) (9.88% vs 10.88%, OR: 1.19, 95%CI: 0.57-2.51, P = 0.64) were similar in both cohorts. CONCLUSIONS: With multimodality imaging and further improvement in technology, our study demonstrates off-label TAVR should not be considered prohibitive and can be successfully performed for BAV with similar peri-procedural outcomes compared to those with TAV. However, there is a need for robust large prospective studies.

Successful transcatheter aortic valve replacement in an oversized 800 mm2 annulus and bicuspid aortic valve.

The current iterations of balloon-expandable transcatheter aortic valve replacement (TAVR) valves consist of a maximum size of 29 mm, corresponding to maximum annulus area of 680 mm2. However, a number of patients who qualify for TAVR based on surgical risk may have anatomical features outside the FDA-approved descriptions. The technique of overexpansion of TAVR valves during deployment allows for more patients to be treated successfully. This particular case demonstrates that overexpansion is safe and efficacious in a very large annulus of >800 mm2. Careful planning and consideration of aortic root calcification is helpful for technique of overexpansion and, ultimately, the technique may increase the number of patients eligible for TAVR.

Anomalous origin of the right coronary artery from the pulmonary artery and congenital bicuspid aortic valve in a California sea lion (Zalophus californianus).

A 27-year-old captive female California sea lion (Zalophus californianus) died suddenly. Necropsy findings showed severe hemopericardium, the right coronary artery arose from the sinus of the pulmonary trunk, and the aortic valve was composed of two semilunar cusps. Coronary artery branches emerging from the epicardium were dilated and tortuous. Pampiniform vascular plexus formation existed along the adventitia from the coronal sulcus to the pulmonary trunk. This is the first report of multiple congenital cardiac malformations with an anomalous origin of the right coronary artery from the pulmonary artery and a bicuspid aortic valve in a marine mammal.

Mechanisms of Smooth Muscle Cell Differentiation Are Distinctly Altered in Thoracic Aortic Aneurysms Associated with Bicuspid or Tricuspid Aortic Valves.

Cellular and molecular mechanisms of thoracic aortic aneurysm are not clear and therapeutic approaches are mostly absent. Thoracic aortic aneurysm is associated with defective differentiation of smooth muscle cells (SMC) of aortic wall. Bicuspid aortic valve (BAV) comparing to tricuspid aortic valve (TAV) significantly predisposes to a risk of thoracic aortic aneurysms. It has been suggested recently that BAV-associated aortopathies represent a separate pathology comparing to TAV-associated dilations. The only proven candidate gene that has been associated with BAV remains NOTCH1. In this study we tested the hypothesis that Notch-dependent and related TGF-ß and BMP differentiation pathways are differently altered in aortic SMC of BAV- vs. TAV-associated aortic aneurysms. SMC were isolated from aortic tissues of the patients with BAV- or TAV-associated aortic aneurysms and from healthy donors used as controls. Gene expression was verified by qPCR and Western blotting. For TGF-ß induced differentiation SMC were treated with the medium containing TGF-ß1. To induce proosteogenic signaling we cultured SMC in the presence of specific osteogenic factors. Notch-dependent differentiation was induced via lentiviral transduction of SMC with activated Notch1 domain. MYOCD expression, a master gene of SMC differentiation, was down regulated in SMC of both BAV and TAV patients. Discriminant analysis of gene expression patterns included a set of contractile genes specific for SMC, Notch-related genes and proosteogenic genes and revealed that control cells form a separate cluster from both BAV and TAV group, while BAV- and TAV-derived SMC are partially distinct with some overlapping. In differentiation experiments TGF-ß caused similar patterns of target gene expression for BAV- and TAV derived cells while the induction was higher in the diseased cells than in control ones. Osteogenic induction caused significant change in RUNX2 expression exclusively in BAV group. Notch activation induced significant ACTA2 expression also exclusively in BAV group. We show that Notch acts synergistically with proosteogenic factors to induce ACTA2 transcription and osteogenic differentiation. In conclusion we have found differences in responsiveness of SMC to Notch and to proosteogenic induction between BAV- and TAV-associated aortic aneurysms.

The natural history of guidelines: the case of aortopathy related to bicuspid aortic valves.

Clinical guidelines represent statements that seek to synthesize the best evidence to guide a course of action to improve health outcomes and more cost-effective use of resources. However, even when the evidence is not definitive, comprehensive documents are still needed to guide clinical decision-making. In these circumstances, guidelines are inevitably affected by perceptions of the problem and their possible solutions. From 1998 to 2014, 10 different international guidelines have focused on the aortopathy related to bicuspid aortic valves. Recommended thresholds for intervention started at a cutoff level of 5.5cm in 1998, reached a nadir of 4 to 4.5cm in 2010, and returned to a 5.5cm cutoff level in 2014. During this time, no conclusive objective proof was published to support either an aggressive or conservative strategy. The consequence was that an undefined number of patients underwent surgery (and potential complications thereof) at an earlier disease stage than might have been necessary. This experience might provide a clue as to how guidelines evolve, and provide insight as to how to avoid a similar process in the future.

Disrupted Slit-Robo signalling results in membranous ventricular septum defects and bicuspid aortic valves.

AIMS: The mesenchymal cushions lining the early embryonic heart undergo complex remodelling to form the membranous ventricular septum as well as the atrioventricular and semilunar valves in later life. Disruption of this process underlies the most common congenital heart defects. Here, we identified a novel role for Slit-Robo signalling in the development of the murine membranous ventricular septum and cardiac valves. METHODS AND RESULTS: Expression of Robo1 and Robo2 receptors and their ligands, Slit2 and Slit3, was present in or adjacent to all cardiac cushions/valves. Loss of Robo1 or both Robo1 and Robo2 resulted in membranous ventricular septum defects at birth, a defect also found in Slit3, but not in Slit2 mutants. Additionally, Robo1;Robo2 double mutants showed thickened immature semilunar and atrioventricular valves as well as highly penetrant bicuspid aortic valves. Slit2 mutants recapitulated the semilunar phenotype, whereas Slit3 mutants displayed thickened atrioventricular valves. Bicuspid aortic cushions were already observed at E12.5 in the Robo1;Robo2 double mutants. Expression of Notch- and downstream Hey and Hes genes was down-regulated in Robo1 mutants, suggesting that reduced Notch signalling in mice lacking Robo might underlie the defects. Luciferase assays confirmed regulation of Notch signalling by Robo. CONCLUSION: Cardiac defects in mutants for Robo or Slit range from membranous ventricular septum defects to bicuspid aortic valves. These ligands and receptors have unique functions during development of specific cardiac cushion derivatives, and the Slit-Robo signalling pathway likely enforces its role by regulating Notch signalling, making these mutants a valuable new model to study cardiac valve formation.