Clinical, pathological and genetic basis of bicuspid aortic valve disease

Abstract

Bicuspid aortic valve (BAV), the most common congenital heart defect, is a clinically heterogeneous disorder with valve dysfunction and related aortopathy being the major complications. While familial clustering and heritability of BAV have been increasingly recognised, the underlying genetic basis of BAV disease in humans remains mostly undetermined. The genes and molecular pathways that drive specific phenotypic expression and determine clinical outcome are poorly understood. Further, identification of individuals with BAV who are at the highest risk for complications presents a challenging task for most clinicians today. The works described in this thesis aimed to address these gaps on our present knowledge of BAV disease. These included the investigation of genetics underlying BAV development using candidate gene approach and exome sequencing, elucidation of genes and molecular pathway that determine valve degeneration in adults with BAV using RNA-sequencing, and efforts to identify novel imaging biomarkers that can be used to predict those with the highest risk for aortic complications using state-of-the-art real-time exercise CMR imaging. Overall, these works have provided an important step forward in our efforts to gain greater understanding on the pathogenetic basis of BAV disease, as well as forming an important foundation for future research within the field.