The genetic and molecular basis of bicuspid aortic valve associated thoracic aortopathy: a link to phenotype heterogeneity.

Abstract

Bicuspid aortic valve (BAV) is the most common congenital cardiac anomaly, affecting 0.5-1.4% of the general population (1-4). BAV is a clinically heterogeneous disorder with a high rate of surgically relevant aortic valve and ascending aortic complications, which occur in over 35% of those affected (5). As such, BAV confers a greater burden of disease than all other congenital heart diseases combined (3,6). Familial clustering and genetic studies have established that BAV is a heritable trait, with approximately 9% prevalence amongst firstdegree relatives, and up to 24% in families with more than one affected family member (3,7,8). Despite its importance, the etiology of BAV is largely undetermined, although it is likely to involve genetic heterogeneity, abnormal signaling pathways and aberrant neural crest cell migration (3). BAV is not only a disorder of valvular development, but also represents a complex coexistent genetic disease of the aorta and cardiac development (3,7). Thoracic aortic enlargement is common in BAV, reported in up to 50-60% of affected individuals (6,9,10). Significant phenotype heterogeneity, which may occur independently of the underlying valvular morphology and function (6,9-11), has been described, most commonly manifesting as asymmetric ascending aortic dilatation beyond the sinotubular junction with variable arch involvement and/or varying degrees of annuloaortic ectasia, predisposing to aortic dissection/ rupture, a feared complication. Indeed, BAV conveys an 8-fold increased risk of aortic dissection and over a 25-year period, the risk for aneurysm formation is 26% and for aortic surgery is 25% (2), further highlighting its health burden. Presently, ongoing controversies exist in the literature regarding the underlying pathogenesis of BAV-associated thoracic aortopathy (BAV-TA), specifically whether it is genetic or hemodynamic in origin, which have important implications for planning intervention. Intense work is currently ongoing to address this question, which has shed light on the pathogenesis of BAV-TA. Therefore, it is timely to review the current state of knowledge in this common association of BAV, focusing primarily on the interaction between genetics, molecular pathway and hemodynamic factors in influencing the heterogeneous manifestation of aortopathy seen in BAV patients.