Genetic and Developmental Contributors to Aortic Stenosis

Abstract

Aortic stenosis (AS) remains one of the most common forms of valve disease, with significant impact on patient survival. The disease is characterized by left ventricular outflow obstruction and encompasses a series of stenotic lesions starting from the left ventricular outflow tract to the descending aorta. Obstructions may be subvalvar, valvar, or supravalvar and can be present at birth (congenital) or acquired later in life. Bicuspid aortic valve, whereby the aortic valve forms with two instead of three cusps, is the most common cause of AS in younger patients due to primary anatomic narrowing of the valve. In addition, the secondary onset of premature calcification, likely induced by altered hemodynamics, further obstructs left ventricular outflow in bicuspid aortic valve patients. In adults, degenerative AS involves progressive calcification of an anatomically normal, tricuspid aortic valve and is attributed to lifelong exposure to multifactoral risk factors and physiological wear-and-tear that negatively impacts valve structure-function relationships. AS continues to be the most frequent valvular disease that requires intervention, and aortic valve replacement is the standard treatment for patients with severe or symptomatic AS. While the positive impacts of surgical interventions are well documented, the financial burden, the potential need for repeated procedures, and operative risks are substantial. In addition, the clinical management of asymptomatic patients remains controversial. Therefore, there is a critical need to develop alternative approaches to prevent the progression of left ventricular outflow obstruction, especially in valvar lesions. This review summarizes our current understandings of AS cause; beginning with developmental origins of congenital valve disease, and leading into the multifactorial nature of AS in the adult population.

Keywords: aortic valve; bicuspid aortic valve disease; endothelial cells; extracellular matrix.

Figure 1.. Representation of congenital AS is largely influenced by genetics and pathogenesis is initiated in the embryo and present at birth.

Structural malformations of the aortic valve as a result of developmental defects are a common cause of congenital AS in the pediatric population. Healthy aortic valves form with three cusps (tricuspid) but congenital aortic valve malformations include those that form with one (unicuspid), two (bicuspid) or four (quadricuspid) valve cusps. Bicuspid aortic valve is the most common and presents as fusion between the right-left cusps (R/L), right-noncoronary cusps (R/NC) and left-noncoronary cusps (L/N). As a result of these structural abnormalities, the hemodynamic environment around the bicuspid valve is disturbed and dependent on the fusion pattern. The tricuspid valve features a centrally-aligned flow jet through the valve orifice at physiologic velocity as well as symmetrical vortex formation in the leaflet sinuses. The smaller valve orifice and impaired mobility of the fused leaflet in both BAV R/L and BAV R/NC result in a higher velocity flow jet that is skewed toward the nonfused leaflet and impinging on the wall of the ascending aorta (right posterior wall in R/NC and right anterior wall in R/L). This leads to increased wall shear stress at these locations as well as the formation of asymmetrical vortices in the leaflet sinuses and abnormal helical flow patterns (not shown) downstream in the aorta. Secondary effects of BAV, likely mediated by disturbed hemodynamics, include aortopathies (not shown) in addition to calcification which further exacerbates left-sided outflow obstruction. AAo, Ascending Aorta; L, left; R, right; NC, non-coronary; BAV, bicuspid aortic valve

Figure 2.

Acquired AS is most prevalent in the aging population and largely influenced by long-life exposure to several known (and unknown) risk factors as indicated. Degenerative calcification of the otherwise anatomically normal, tricuspid aortic valve is a major contributor to acquired AS as a result of mineralization of the cusp tissue leading to reduced compliance, increased stiffness leading to restricted movement of the cusp.