Abnormal 3-dimensional MRI Flow Patterns and Plasma Matrix Metalloproteinase Levels Predict Dilatation of Ascending Aorta in Adolescent Patients With Bicuspid Aortic Valve

Introduction-Background The reported incidence of bicuspid aortic valve (BAV) based largely on autopsy studies varies between 0.4% to 2.25% of the population. At least a third of patients with a bicuspid aortic valve will eventually develop complications which include aortic stenosis, aortic regurgitation, infective endocarditis, aortic dilatation, aortic aneurysm formation, or aortic dissection. Given that in combination all other forms of congenital heart disease are thought to be present in 0.8% of live births, Ward has suggested that bicuspid aortic valves are likely to result in more morbidity and possibly mortality than the effects of all other congenital heart defects combined. Since many patients with bicuspid aortic valves do not develop significant problems until well into adulthood, clinicians have not focused much attention on the "normally" functioning bicuspid aortic valve. However, at a mean age of 17.8 years 52% of males with normally functioning aortic valves already have aortic dilatation, implying that associated aortic stenosis and/or regurgitation is not an obligate precursor.

Previous studies have demonstrated an association between bicuspid aortic valves and dilatation of the aorta. Gurvitz et al. performed echocardiographic measurements of the aortas of children and found that those with bicuspid aortic valves had significantly larger aortas compared with controls, regardless of the presence of aortic stenosis or regurgitation. Nevertheless, the definition of clinical predictors of the risk for the development of aortic dilatation/dissection and an understanding of the mechanisms leading to aortic dilatation are lacking. Specifically, it remains unclear as yet whether such dilatation is secondary to abnormal flow patterns and shear stresses resulting from the bicuspid valve morphology or whether it is a manifestation of a distinct underlying structural problem with not only the aortic valve but also the aortic root including the ascending aorta.

Fernandes et al. recently reviewed the echocardiograms of 1,135 children with bicuspid aortic valves and found that there were differences among the patients related to aortic valve morphology. For instance, associated moderate or greater aortic stenosis was present in 9.7% of patients with fusion of the intercoronary commissure of the aortic valve, vs 25.9% of patients with fusion of the right-coronary and non-coronary commissure, and in none of the patients with fusion of the left coronary and non-coronary aortic valve leaflets. Moreover, fusion of the right coronary and non-coronary cusps resulted in a two-fold higher risk of at least moderate aortic regurgitation compared with the other types of bicuspid aortic valves. However, this generalized division of bicuspid aortic valves into three types based on which commissure is fused is likely an oversimplification, and Fernandes did not report on the relationship between valve morphology and aortic root dilatation. However, Novaro et al. found that adult patients (mean age of 54 year) with fusion of the right/non-coronary commissure tended to have larger mid-ascending aortas compared with patients with fusion of the intercoronary commissure, but the difference did not reach statistical significance. Nevertheless, both personal clinical observations and recent publications support the assertion that individual bicuspid aortic valves may function quite differently from one another. For instance, there are bicuspid aortic valves in which there are two nearly symmetric leaflets whereas others may have a dominant cusp to varying degrees, resulting in a markedly eccentric orifice when the valve opens. In an elegant experimental model using excised bicuspid valves analyzed with intravascular ultrasound and high-resolution videography, Robicsek et al demonstrated that asymmetric bicuspid valves "induced extensive recirculation vortices in the ascending aorta." They found that the vortex was not "trapped" in the sinuses of Valsalva as it is in a normal tricuspid aortic valve, but instead is extended into the ascending aorta and aimed toward the right anterolateral aspect of the aorta (the convexity of the aorta). This correlates with published reports and our own personal experience in performing clinical cardiac magnetic resonance imaging (CMR) studies on patients with bicuspid aortic valves and aortic root dilatation in whom there is oft-noted asymmetry in the pattern of dilatation of the ascending aorta and resulting in an oval-shaped rather than a circular aortic root and ascending aorta.

Extrapolating from the studies of Robicsek, variations present in the geometry of bicuspid valves are likely to result in varying degrees of turbulence even in the absence aortic valve stenosis. In theory, the turbulent blood flow directed at a particular segment of the aortic wall may result in local changes to the aortic wall leading to asymmetric aortic dilatation. These changes are postulated to result from receptors present on both endothelial and smooth muscle cells that have the ability to adapt to sheer stress by altering local gene expression which in turn modulates the tension between focal adhesion sites, integrins, and the extracellular matrix. Moreover, fibrillin-1, which is deficient in patients with dilated aortic roots and Marfan syndrome, has also been found to be deficient in the aortas of patients with bicuspid aortic valves. Similarly, Cotrufo et al. found asymmetric patterns of matrix protein expression and content and asymmetric patterns of elastic medial wall degeneration in the aortic walls of patients with bicuspid aortic valves. In addition, these investigators found differences between patients with bicuspid aortic valves and associated stenosis vs regurgitation, suggesting that focally-directed aortic turbulence may be influencing local gene expression and potentially explaining the asymmetric pattern of aortic dilatation that is often observed. Lastly, several recent studies have highlighted the relationship between circulating plasma MMP-2 and MMP-9 levels either in aortic dilatation in adult patients with thoracic or abdominal aortic aneurysms or in adults with aortic dilatation secondary to systemic hypertension. In addition, histologic examination of aortic aneurysm tissue in adult patients with bicuspid aortic valves demonstrated increased MMP-2 expression vs. aortic aneurysms in adults with trileaflet aortic valves.

Recently investigators have used cardiac MRI (CMR) to study flow patterns in the aorta. CMR is a noninvasive technique that permits 3-dimensional anatomic characterization as well as assessment of aortic flow. Markl et al. have used time-resolved 3-dimensional phase-contrast magnetic resonance imaging (3D-PCMRI) techniques to characterize aortic flow in both normal adults and in adults after aortic root replacement. These authors established that 3-dimensional magnetic resonance velocity mapping was a useful technique to visualize and qualitatively assess the complex aortic flow patterns in both normal controls and in patients with aortic pathology. Similarly, Kvitting et al., who studied both adult volunteers and 2 patients with Marfan syndrome following aortic valve sparing operations, found that the alterations to the normal aortic sinus architecture following surgery resulted in a loss of the normal vortical flow patterns seen in the aortic sinuses.