Bicuspid aortic valve and associated aortopathy: a combined biomechanics, histological and genetic analysis

Abstract

Bicuspid aortic valve (BAV) is the most common inborn heart defect and a continuum of a disease process affecting the aortic valve and the thoracic aorta with an increased risk of thoracic aortic aneurysm (TAA) formation and dissection. Aortic dilatation may be related to haemodynamic perturbations or intrinsic wall abnormalities. The aim of this thesis was to investigate the relative contribution of these parameters to BAV aortopathy via integrated analyses. Distribution of circumferential stress in the aorta of BAV patients planned to undergo surgery was analysed using computed tomography imaging and computational modelling. During surgery, aortic biopsies were taken from discrete areas and examined for histological abnormalities. Maximal mechanical stress occurred in the medial ascending aorta in the majority of cases with integrated analyses exhibiting a positive correlation between aortic fibrosis and mechanical stress, both in the root and the ascending aorta. The degree of histological abnormalities and transforming growth factor beta (TGFβ) activation was also assessed in collected tissue biopsies. Patients with either root dilatation and/or predominant regurgitant valve disease had greater levels of medial wall degeneration in their ascending aorta whereas enhanced TGFβ signalling was present in aneurysmal but also, non-dilated BAV aortic segments, pointing to a genetic trigger. Copy number variation (CNV) analyses in a larger BAV cohort revealed a large heterozygous deletion in the angiotensin converting enzyme (ACE) gene and targeted next-generation sequencing revealed previously reported variants in NOTCH1, COL3A1, and APOE genes with additional discovery of a large number of likely pathogenic variants in genes related to BAV formation and aortopathy. In conclusion, different BAV aortic phenotypes were recognised and further analysed. The presence of multiple likely pathogenic variants in sequenced patients suggests a polygenic nature of BAV disease which, in conjuction with local haemodynamic perturbations, supports a mutlifactorial origin of BAV aortopathy.