Bicuspid aortic valve and thoracic aortic aneurysm: three patient populations, two disease phenotypes, and one shared genotype

Abstract

Bicuspid aortic valve (BAV) and thoracic aortic aneurysm (TAA) are two discrete cardiovascular phenotypes characterized by latent progressive disease states. There is a clear association between BAV and TAA; however the nature and extent of this relationship is unclear. There are both distinct and overlapping developmental pathways that have been established to contribute to the formation of the aortic valve and the aortic root, and the mature anatomy of these different tissue types is intimately intertwined. Likewise, human genetics studies have established apparently separate and common contributions to these clinical phenotypes, suggesting complex inheritance and a shared genetic basis and translating 3 patient populations, namely, BAV, TAA, or both, into a common but diverse etiology. A better understanding of the BAV-TAA association will provide an opportunity to leverage molecular information to modify clinical care through more sophisticated diagnostic testing, improved counseling, and ultimately new pharmacologic therapies.

Figure 1

Spectrum of aortic valve malformation. Parasternal short-axis echocardiographic views at the base of the heart showing the aortic valve en face (a–h). Normal tricommissural aortic valve (TAV) morphology is demonstrated in diastole (a) and systole (b). Distinct morphologies are based on fusion patterns of the commissures (dotted lines, (b)) as they relate to the right (R), left (L), and non-(N) coronary sinuses of Valsalva (a). Aortic valve malformation ranges from unicuspid (UAV) to bicuspid (BAV) to a thickened tricuspid (not shown) to quadricuspid (QAV) morphology. Three normal commissures are demonstrated in (a), and normal opening of the commissures results in complete cusp separation to the wall of the aorta at the sinotubular junction (yellow arrowheads). UAV manifests as either partial fusion of all three commissures (red arrowheads, (c)) or complete fusion of both the RN and RL commissures (d). Bicuspid aortic valve (BAV) may manifest as fusion of the RL (e), RN (f), and rarely LN (g) commissures. Rarely, a quadricuspid aortic valve (QAV, (h)) is identified.

Figure 2

Spectrum of thoracic aortic aneurysm. Pathologic specimen identifies aortic dimensions (1–4) and intimate anatomic relationship of aortic valve and thoracic aorta (a). Parasternal long-axis echocardiographic views of the proximal aorta demonstrating the aortic valve annulus (1), aortic root (2), sinotubular junction (3), and ascending aorta (4) dimensions in normal (b) and discrete patterns of disease (c–f). Some patients are characterized by “high normal” dimensions throughout the proximal aorta (yellow lines, (c)), for example, patients with BAV. TAA may manifest as isolated dilation of the aortic root (red line, (d)), isolated dilation of the ascending aorta (red line, (e)), or dilation of multiple dimensions (red lines, (f)). AOV: aortic valve; AO: aorta; LA: left atrium; LV: left ventricle; MV: mitral valve. Reproduced with permission [22].

Figure 3

Potential relationships between BAV and TAA. From a disease standpoint, AVD and thoracic dissection (TAAD) represent distinct entities that affect different tissue types (a). However, in light of the clinical association between the respective endophenotypes BAV and TAA, there are 3 patient populations, namely, those with BAV (with or without AVD), those with TAA, and those with BAV and TAA (b). From a genetic and developmental perspective, there is increasing evidence of etiologic overlap, suggesting a shared complex genotype (c).

Figure 4

Cardiovascular phenotypes related to malformations of the aortic valve and thoracic aorta. Trilaminar ECM organization of the normal aortic valve (a,c) is characterized by cusps organized into Fibrosa (F), Spongiosa (S), and Ventricularis (V) layers, while the normal proximal aorta (B,D) is characterized by Adventitia (A), Media (M), and Intima (I) layers. Histopathology of a functional BAV, that is a malformed valve without disease, demonstrates preserved ECM organization and normal morphometrics in both the valve (e) and aorta (f). Similarly, the small bicuspid aortic valve of a patient with hypoplastic left heart syndrome, a severe form of aortic valve malformation, shows normal trilaminar ECM organization and morphometrics (g,h). However, BAV with AVD in a younger patient (I) shows ECM disorganization (black arrowheads), in both the affected valve (i) and the aorta with normal dimensions (j). In an older patient with BAV-TAA, there is advanced AVD characterized by marked valve thickening, ECM disorganization (black arrowheads) and calcification (asterisk) and TAA characterized by subintimal hyperplasia, elastic fiber fragmentation, proteoglycan accumulation (white arrowheads), and adventitial fibrosis (asterisk).

Figure 5

Hypothetical model of shared complex genotype in BAV-TAA. Multiple susceptibility genes exist for both BAV and TAA, and some of these genes are common to both phenotypes (yellow letters, Normal). An unaffected genotype might have 8 BAV susceptibility genes (a–d, j–m) and 8 TAA susceptibility genes (j–m, w–z), 4 in common (j–m). If the manifestation of each phenotype is dependent on a liability threshold of predisposing variants, for example, greater than or equal to 3 variants, then there are multiple ways in which an individual may realize an affected status (BAV, TAA, BAV-TAA), and the specific pattern of variants may contribute to phenotypic variability. Importantly, this model does not take into account the likely importance of additional insults (epigenetic modifiers, environmental factors) that may be necessary for phenotype manifestation.