Bicuspid aortic valve: identifying knowledge gaps and rising to the challenge from the International Bicuspid Aortic Valve Consortium (BAVCon)

Hector I Michelena, Siddharth K Prakash, Alessandro Della Corte, Malenka M Bissell, Nandan Anavekar, Patrick Mathieu, Yohan Bossé, Giuseppe Limongelli, Eduardo Bossone, D Woodrow Benson, Patrizio Lancellotti, Eric M Isselbacher, Maurice Enriquez-Sarano, Thoralf M Sundt 3rd, Philippe Pibarot, Artur Evangelista, Dianna M Milewicz, Simon C Body, BAVCon Investigators, Hector I Michelena, Siddharth K Prakash, Alessandro Della Corte, Malenka M Bissell, Nandan Anavekar, Patrick Mathieu, Yohan Bossé, Giuseppe Limongelli, Eduardo Bossone, D Woodrow Benson, Patrizio Lancellotti, Eric M Isselbacher, Maurice Enriquez-Sarano, Thoralf M Sundt 3rd, Philippe Pibarot, Artur Evangelista, Dianna M Milewicz, Simon C Body, BAVCon Investigators

No abstract available

Keywords: aortic aneurysm, thoracic; aortic valve stenosis; aortic valve, bicuspid; heart defects, congenital.

Figures

Figure 1

Transthoracic echocardiogram anatomy of the aortic valve. A, Schematic of the normal tricuspid aortic valve in the parasternal short-axis view. The right coronary cusp (small R) is anterior and positioned between the tricuspid valve and pulmonic valve. The left coronary cusp (small L) is posterior and related to the left atrium, whereas the noncoronary cusp (N) is related to the interatrial septum (IAS). Note the origin of the coronary arteries at the right and left cusps. The anatomic relations of each cusp relative to adjacent structures are critical in determining which 2 cusps are fused. B, The aortic valve annular circumference can be visualized like the face of a clock. Bicuspid valves are classified as type 1 (right-left coronary cusp fusion, 70%–80% prevalence) if the commissures are at 4 to 10, 5 to 11, or 3 to 9 o'clock and the anatomy relative to adjacent structures suggests right-left fusion, type 2 (right-noncoronary cusp fusion, 20%–30% prevalence) if the commissures are at 1 to 7 or 12 to 6 o'clock and the anatomy relative to adjacent structures suggests right-nonfusion, and type 3 (left-noncoronary cusp fusion, 1% prevalence) if the commissures are at 2 to 8 o'clock and the anatomy relative to adjacent structures suggests left-nonfusion. It is important to note that there can be an overlap between the clock positions, and, thus, it is critical to know the anatomic relations of each cusp. Identification of the raphe can be invaluable in determining the conjoined cusp. Identification of the origin of the left and right coronary arteries (as shown) may also be invaluable. LA indicates left atrium; large L, left side of the patient; large R, right side of the patient; P, posterior aspect of the heart; PA, pulmonary artery; PV, pulmonic valve; RA, right atrium; RVOT, right ventricular outflow tract; and TV, tricuspid valve.

Figure 2

Schematic of BAV phenotypes as seen by transthoracic echocardiogram. The standard imaging technique for BAV diagnosis is transthoracic echocardiogram. The diagnosis is based on parasternal long- and short-axis imaging of the aortic valve. The schematics presented represent the parasternal short-axis echocardiographic view. Bicuspid valves are classified as type 1 (right-left coronary cusp fusion), type 2 (right-noncoronary cusp fusion), and type 3 (left-noncoronary cusp fusion). The figure demonstrates BAV phenotypes. Top left shows a type 1 BAV (commissures at 10 and 5 o'clock) with complete raphe, asymmetrical (the nonfused cusp [noncoronary] is smaller than the conjoined anterior cusp). Top middle shows a type 2 BAV (commissures at 1 and 7 o'clock) with complete raphe and asymmetrical (the nonfused cusp [left] is larger than the conjoined cusp). Top right shows a type 3 BAV (shown with commissures at 2 and 8 o'clock, but could be 1 and 7 o'clock) with complete raphe, asymmetrical (the nonfused cusp [right] is larger than the conjoined one). Bottom left shows a symmetrical type 1 BAV with complete raphe. Bottom middle shows a symmetrical type 1 BAV without raphe (true BAV). Bottom right shows a type 1 BAV with incomplete raphe, partially fused. BAV indicates bicuspid aortic valve; L, left cusp; N, noncoronary cusp; and R, right cusp.

Figure 3

Schematic of variable aorta phenotypes encountered in BAV. Figure demonstrates the different aortic dilatation patterns that may occur in BAV in comparison with a normal aorta (Top left). Although the most common portion to dilate is the tubular ascending aorta (A), the entire ascending aorta may be affected, including sinuses of Valsalva and tubular aorta with sinotubular junction effacement (B). There is a subgroup of BAV patients who exhibit dilatation of the sinuses of Valsalva preferentially (C). This pattern is associated with type 1(right-left fusion) BAV and male sex., BAV indicates bicuspid aortic valve.

Figure 4

Twenty-five year risk of aortic valve replacement versus surgery of the aorta. Kaplan-Meier risk of AVR and aorta surgery (all causes) 25 years after definitive diagnosis of BAV. After 25 years of follow-up, the risk of undergoing AVR doubles that of aortic surgery. Based on data from Michelena et al. AVR indicates aortic valve replacement; and BAV, bicuspid aortic valve.

Figure 5

Roadmap for advancing the science. After identifying basic and advanced clinical targets, the critical next steps are precise BAV diagnosis and phenotyping, and accurate aortic size multi-imaging measurement, as well. Advanced imaging allows for additional CT and CMR innovative evaluations. The bidirectional feedback between clinical imaging and pathobiology-genetics (double-headed arrows) leads to biomarker discovery, sophisticated risk stratification, and the development of specific therapies for basic and advanced clinical targets. BAV indicates bicuspid aortic valve; CMR, cardiac magnetic resonance imaging; CT, computed tomography; ECM, extracellular matrix; and TAA, thoracic aortic aneurysm.

Figure 6

CMR ascending aortic flow patterns in BAV. A, Normal ascending aortic flow pattern in a healthy volunteer. B, Typical ascending aortic flow pattern in a patient with bicuspid aortic valve; helical flow is seen in the ascending aorta, a forward-moving rotational movement of the aortic blood flow. BAV indicates bicuspid aortic valve; and CMR, cardiac magnetic resonance imaging.

Figure 7

Double-oblique CTA ascending aorta measurement. Figure demonstrates a coronal multiplanar reformation. An imaging plane longitudinal to the aorta (A) results in a subsequent image depicted in B, through which another plane is aligned longitudinal to the aorta (green) and a plane orthogonal to the latter (red) is also prescribed. The resulting image (C) is a plane that is axial to the ascending aorta at the level of the pulmonary arterial bifurcation. CTA indicates computed tomography angiography.

Figure 8

The roadmap to translate genetic discoveries into clinical applications. A key priority is to identify candidate genes for BAV-associated phenotypes, a critical step in the development of translational therapies. First, suggestive findings from family-based or case-control studies must be independently validated in separate groups of BAV cases. The roles of candidate genes in valve development or disease can then be assessed by using in vitro or animal models, which may facilitate the development of interventions that target these genes and biological pathways. Finally, genetic tests or therapies need to be tested in randomized clinical trials of BAV patients. Knockout animal models include tissue-specific and whole organism deletion of genes, and knock-in models are generated by introducing a specific human sequence variant into a similar gene in a model organism. BAV indicates bicuspid aortic valve; CNV, copy number variant; and GWA, genome-wide association.