Bicuspid Aortic Valve: Genetic and Clinical Insights

Figures

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  Fig. 1. Transthoracic echocardiogram of bicuspid aortic valve (BAV), short axis view. ( A ) Diastolic image demonstrating a raphe that may mimic tricuspid valve. ( B ) Systolic image demonstrating only two leaflets with elliptical opening pattern. Morphology assessment of BAV must include systolic imaging, as diastolic imaging may be misleading. 40

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  Fig. 2. Examples of bicuspid aortic valve pedigrees, consistent with autosomal dominant inheritance, and low penetrance, as reflected by the limited number of clinically affected individuals. 40

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  Fig. 3. Illustration of the underling process in bicuspid aortic valve (BAV) development. Involvement of one or more genes is the primary insult. This might be modulated by epigenetic factors, such as chromatin modifications and DNA methylation affecting genetic regulatory elements. Environmental factors, such as longstanding abnormal blood flow and hypertension, may also contribute to BAV outcome. The epigenetics illustration was modified from the ENCODE portal (https://www.encodeproject.org/).

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  Fig. 4. Bicuspid aortic valve (BAV)–associated pathways. ( A ) NOTCH pathway. A graphical representation of NOTCH pathway activation: (1) NOTCH receptor extracellular domain binds to its ligand's extracellular domain; (2) Notch ligand ubiquitination allowing endocytosis of the ligand in the signal-sending cell; (3) then, the notch receptor undergoes sequential proteolytic cleavages that result in the release of the Notch intracellular domain (NICD) and the notch extracellular domain; and (4) the NICD translocates to the nucleus and acts as a transcriptional regulator. *Genes associated with BAV: MIB1 KO mice developed; JAG1 was associated with BAV in family and mice studies; Variants in SMARCA4 , JARID2 and MAML were identified in familial BAV. ( B ) TGF-β signaling pathway. The interaction between the TGF-β signaling pathway and the SMAD proteins: (1) TGF-β binding to its receptors triggering the signaling activation in the receiving cell; among others modifiers, the signal transduction is regulated by the SMAD proteins, while SMAD6 functions as the negative regulator; and (3) nuclear regulation affects cell proliferation, differentiation and growth. JARID2 , Jumonji and AT-rich…