RESUMEN
OPINION STATEMENT: The bicuspid aortic valve (BAV) phenotype is becoming increasingly recognized as a complex and heterogeneous clinical entity, with some but not all patients developing accelerated degrees of both aortic insufficiency (AI) and aortic stenosis (AS) in comparison to patients with tricuspid aortic valves (TAV). In addition, there remains a well-established association between the BAV phenotype and aortic enlargement independent of valve function as well as progression among some to ascending aortic aneurysm and the attendant concern over risk of aortic dissection. Because the understanding of the complexity of the BAV phenotype is evolving as quickly as are the options for medical, surgical, and interventional therapy, this review aims to provide an update on the most clinically relevant recent advances in the realm of BAV and associated aortopathy from a genetic, morphologic, and clinical outcomes perspective in order to give the practicing clinician a deeper understanding of how to approach both medical and surgical decision-making in the patient with BAV. The following major principles have emerged in recent years including (1) the importance of cusp anatomy and its implications on the long-term risk of AI, aortic dilation, and aortic dissection, (2) the role of post-valvular flow dynamics in the pathogenesis of aortic dilation in BAV patients, (3) the ability of aortic valve replacement to halt accelerated dilation rates, and (4) the finding that the risk of aortic dissection, while still overall intermediate is much more akin to the baseline risk present in TAV patients rather than the much higher rates observed in patients with Marfan's disease. Together, these data support the less aggressive approach to aortic replacement in BAV patients as reflected in the most recent ACC/AHA guidelines and provide a stronger basis upon which future studies, including those aimed at medical and transcatheter therapies, stand to make further impact on our ability to optimally treat this epidemiologically important and complex population of patients.
RESUMEN
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.