Pathogenic Mechanisms of Bicuspid Aortic Valve Aortopathy

Abstract

Bicuspid aortic valve (BAV) is the most common congenital valvular defect and is associated with ascending aortic dilation (AAD) in a quarter of patients. AAD has been ascribed both to the hemodynamic consequences of normally functioning and abnormal BAV morphology, and to the effect of rare and common genetic variation upon function of the ascending aortic media. AAD manifests in two overall and sometimes overlapping phenotypes: that of aortic root aneurysm, similar to the AAD of Marfan syndrome; and that of tubular AAD, similar to the AAD seen with tricuspid aortic valves (TAVs). These aortic phenotypes appear to be independent of BAV phenotype, have different embryologic origins and have unique etiologic factors, notably, regarding the role of hemodynamic changes inherent to the BAV phenotype. Further, in contrast to Marfan syndrome, the AAD seen with BAV is infrequently present as a strongly inherited syndromic phenotype; rather, it appears to be a less-penetrant, milder phenotype. Both reduced levels of normally functioning transcriptional proteins and structurally abnormal proteins have been observed in aneurysmal aortic media. We provide evidence that aortic root AAD has a stronger genetic etiology, sometimes related to identified common non-coding fibrillin-1 (FBN1) variants and other aortic wall protein variants in patients with BAV. In patients with BAV having tubular AAD, we propose a stronger hemodynamic influence, but with pathology still based on a functional deficit of the aortic media, of genetic or epigenetic etiology. Although it is an attractive hypothesis to ascribe common mechanisms to BAV and AAD, thus far the genetic etiologies of AAD have not been associated to the genetic etiologies of BAV, notably, not including BAV variants in NOTCH1 and GATA4.

Clinical and pathophysiological aspects of bicuspid aortic valve disease

“…Cardiac mesodermal cells from the primitive streak give origin to the first and second heart fields in the embryo. 20 The first heart field cells give origin to the early heart tube. Then, cells from the second heart field contribute to the development of the conotruncal tissue that gives origin to the outflow tracts.…”

A novel SMAD6 variant in a patient with severely calcified bicuspid aortic valve and thoracic aortic aneurysm

“…Many BAV patients have TAA, which was attributed to the hemodynamic consequence of BAV or the effect of genetic variation. Yassine et al proposed that aortic root dilation below the STJ was strongly associated with genetic etiology and ascending aortic dilatation above the STJ was associated with hemodynamic influence (Yassine, Shahram, & Body, ). In this study, a patient with p.Gly390_Ile391dup had ascending aortic dilatation above the STJ, which might be attributed to a hemodynamic stress such as high‐velocity and turbulent flow induced by a severely stenotic BAV.…”

The bicuspid aortic valve: Is it an immunological disease process?

“…A further two mutations of NOTCH1 leading to BAV were identified by Garg et al in a study published in 2005; the first, p.R1108X, in a family of European‐American descent was linked to a single locus on chromosome 9q34‐35 and the second, p.H1505del, was present in three affected family members. An impairment of NOTCH signaling has also been associated with the development and progression of aortic aneurysm and will be further discussed in this review …”