miR-151-3p and miR-214 Expression Associate With Clinical Phenotypes in BAV Aortopathy

Bicuspid Aortic Valve (BAV) is clinically heterogeneous, with unexplained variability in valve dysfunction and development of thoracic aortic aneurysm (TAA) complicating decisions on surgical intervention. Dysregulated miRNA expression is implicated in both BAV and TAA but phenotype correlations are lacking. This study aimed to explore miRNA expression in a heterogeneous BAV cohort to help explain clinical variability. Total RNA was isolated from BAV aortic tissue resected during elective aortic surgery (n=51; age 55±13 years, 84% male). RT-qPCR was performed for 11 miRNAs of interest, selected from literature review and a previous BAV-TAA global miRNA array. miRNA expression was evaluated according to valve dysfunction (aortic regurgitation [BAV-AR] and/or stenosis [BAV-AS]), diameters of the aortic root and ascending aorta, and graded histopathology. Sixteen miRNA correlations were observed (p<0.05). All dysregulated miRNAs are involved in vascular homeostasis (miR-16, miR-22, miR-24, miR-145, miR-151-3p, miR-214*, miR-497, miR-708). Notably, miR-151-3p was found to decrease with increasing aortic root diameter, and miR-214* was increased in association with: (1) increasing ascending aortic diameter among BAV-AR; (2) severity of aortic medial degeneration; and (3) severity of elastic fibre fragmentation/loss. miR-151-3p is oscillatory-stress sensitive, and loss of expression may trigger aortic root dilatation through pathological upregulation of the TWIST1 mechanosensitive transcription factor. miR-214* upregulates matrix metalloproteinases in response to increased wall stress, thus may participate in maladaptive remodelling leading to TAA. This work shows that phenotypic variability in BAV aortopathy may be partly mediated by epigenetic dysregulation, with two putative mechanisms for further study.