The Association Between Aortic Valve Leaflet Morphology and Patterns of Aortic Dilation in Patients With Bicuspid Aortic Valves Mark Ruzmetov, MD, PhD, Jitendra J. Shah, MD, Randall S. Fortuna, MD, and Karl F. Welke, MD
Background. Dilation of the aorta is a frequent complication in patients with bicuspid aortic valves. The aim of this study was to determine the relationship between the subtype of leaflet fusion, right and noncoronary leaflet (R/N) fusion versus right and left leaflet (R/L) fusion, and the patterns of aortic dilation and valve dysfunction in young patients with bicuspid aortic valves. Methods. We performed a retrospective review of 642 patients who presented with bicuspid aortic valves between 1994 and 2014. Of these patients, 210 (33%) had aortic dilation (z score >3) by echocardiogram. For each patient, the most recent study or the last study before intervention was reviewed. Results. Median patient age was 15 years (range, 0 to 40 years) with patients with R/N fusion being younger. The most prevalent subtype was R/N fusion (R/N, n [ 114, 54% versus R/L, n [ 96, 46%). Dilation of the ascending aorta was seen more often in patients with R/N fusion (R/ N, 88% versus R/L, 68%; p [ 0.004), whereas the prevalence of dilation of the sinuses of Valsalva was significantly higher in patients with R/L fusion (R/L, 46% versus R/N, 20%; p [ 0.01). The magnitude of dilation differed
as well. The z value of the sinuses of Valsalva was significantly higher in patients with R/L fusion (R/L, 2.03 versus R/N, 1.2; p [ 0.003), whereas the z values of the ascending aorta and sinotubular junction were similar between the groups. Patients with R/N fusion were more likely to have aortic stenosis, and within the R/N group, patients with aortic insufficiency had a greater degree of ascending aorta dilation (p [ 0.04). Conclusions. Our study suggests that in young patients with bicuspid aortic valves and aortic dilation, aortic valve morphology may be associated with the patterns of aortic dilation and valve dysfunction. Patients with R/N fusion were more likely to have ascending aorta dilation, whereas patients with R/L fusion were more likely to have dilation of the aortic root. In addition, patients with R/N fusion presented at a younger age and were more likely to have aortic stenosis. Recognition of these differences may eventually be helpful for patient counseling and the planning of follow-up.
B
factor for ascending aorta and aortic root disease, even without valve disease [3]. Fusion of the right and left coronary leaflets (R/L), the right and noncoronary leaflets (R/N), or the left and noncoronary leaflets (L/N) leads to the development of BAV [4–8]. Currently there is limited information regarding whether the type of leaflet morphology in BAV is associated with abnormalities of valve function and the aorta. Some have suggested that different fusion subtypes may be the result of different embryologic and developmental mechanisms [9]. Although aortic stenosis (AS) and aortic insufficiency (AI) are the most common complications of a BAV, dilation of any or all segments of the proximal aorta from the aortic root to the aortic arch, called bicuspid aortopathy, is also present in approximately 40% to 50% of affected persons [10, 11]. The majority of young patients with BAV have mild dilation; the rare patient can have progressive dilation that places them at risk for morbidity and premature death [7, 12]. The aim of this study was to
icuspid aortic valve (BAV) is the most common congenital heart anomaly in the general population, affecting 1% to 2% of individuals worldwide, and is responsible for more deaths and complications than the combined effects of all the other congenital heart defects [1, 2]. Bicuspid aortic valve, which results from abnormal aortic leaflet formation during valvulogenesis, is most likely caused by a complex developmental process rather than the fusion of two normal leaflets [3]. Different BAV morphologies may result from different genotypes: indeed, recent studies have highlighted a connection between the morphologic pattern of BAV as a prognostic
Accepted for publication Feb 12, 2015. Presented at the Sixty-first Annual Meeting of the Southern Thoracic Surgical Association, Tucson, AZ, Nov 5–8, 2014. Address correspondence to Dr Welke, University of Illinois College of Medicine at Peoria, Children’s Hospital of Illinois, OSF Saint Francis Medical Center, 420 NE Glen Oak Ave, Ste 301, Peoria, IL 63603; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2015;99:2101–8) Ó 2015 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.02.036
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Section of Pediatric Cardiovascular Surgery and Pediatric Cardiology, University of Illinois College of Medicine at Peoria, Children’s Hospital of Illinois, OSF Saint Francis Medical Center, Peoria, Illinois
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determine the relationship between the subtype of leaflet fusion, R/N versus R/L, and the patterns of aortic dilation and valve dysfunction in young patients with BAV.
Material and Methods
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Patients We performed a retrospective search for patients with BAV who were referred to our Congenital Heart Center between January 1994 and August 2014. The University of Illinois College of Medicine at Peoria Institutional Review Board approved the study, and the need for parental consent was waived. We reviewed hospital records, clinic records, surgical records, and echocardiographic data for patient demographic information, aortic valve morphology, AS and degree thereof, AI and severity thereof, ascending aortic dimensions, and presence or absence of aortic coarctation. Most of the patients (66%) had more than one echocardiogram. The most recent echocardiogram, or one preceding surgical or catheter intervention, was considered for overall incidence of associated lesions. When a patient had endocarditis, a study at least 1 year before the episode of endocarditis was reviewed. Cuspal fusion was determined by review of echocardiographic images by a single observer. Patients were grouped by age to determine the prevalence of associated abnormalities in R/L fusion and R/N fusion. For each age group, the latest echocardiogram in that age group was reviewed and considered for data analysis. For example, for a patient with echocardiograms at age 3, 5, 7, and 9 years, the 9year echocardiogram was used. Aortic stenosis was evaluated by Doppler echocardiography using standard techniques of interrogation, and peak and mean pressure gradients were calculated by modified Bernoulli equation. Peak Doppler velocity across the aortic valve of 2 m/s or greater was considered abnormal and mild if less than 3.5 m/s and moderate or
Fig 1. Bicuspid aortic valve cusp morphology. (LC ¼ left coronary leaflet; LCA ¼ left coronary artery; L/N ¼ left coronary/noncoronary; NC ¼ noncoronary leaflet; RC ¼ right coronary leaflet; RCA ¼ right coronary artery; R/L ¼ right-coronary/left coronary; R/N ¼ rightcoronary/noncoronary.)
more if greater than 3.5 m/s. These velocities correspond to peak instantaneous gradients of 16 mm Hg for mild stenosis and greater than 50 mm Hg for moderate or greater stenosis. Aortic insufficiency was evaluated using established criteria [1], including the regurgitant jet width relative to annular diameter ratio, pressure halftime, the presence of abnormal diastolic retrograde flow in the descending thoracic aorta, and left ventricular diastolic dimension. Aortic insufficiency was categorized as none (0), trivial (1þ), mild (2þ), moderate (3þ), or severe (4þ). Aortic measurements were performed in parasternal long-axis views using two-dimensional imaging, inneredge to inner-edge, at maximal excursion. The aortic root diameter was measured at the sinuses of Valsalva, and the ascending aortic diameter was recorded as the largest diameter distal to the sinotubular junction. Aortic dimensions were compared with published data and
Table 1. Characteristics of Patients With Bicuspid Aortic Valve at Most Recent Echocardiogram R/N (n ¼ 114)
R/L (n ¼ 96)
p Value
15.8 8.4 (0.33–40) 55 25 (6–112) 153 27 (27–153) 70/44 7 (6%) 21 (18%) 56 (50%) 60 (53%)
18.6 11.5 (1.5–40) 57 27 (7.6–115) 151 28 (71–193) 56/40 10 (10%) 32 (63%) 27 (28%) 40 (42%)
0.04 0.55 0.71 0.33 0.62 0.01 0.001 0.08
Characteristic Age (mean, range; y) Weight (mean, range; kg) Height (mean, range; cm) Sex (M/F) Congenital heart defect other than BAV Aortic coarctation Aortic stenosis Aortic insufficiency (mild) Type of dilated aortic shape (n, %)a “N” “A” “E” a
4 (4%) 60 (53%) 49 (43%)
14 (15%) 46 (48%) 36 (37%)
0.02
Shapes were defined according to Schaefer and associates [8].
A ¼ ascending distention; BAV ¼ bicuspid aortic valve; fusion; R/N ¼ right coronary and noncoronary leaflet fusion.
E ¼ effaced;
N ¼ normal;
R/L ¼ right coronary and left coronary leaflet
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Table 2. Aortic Root Dimensions R/N (n ¼ 114)
Site 2
Aortic annulus (cm/m ) Sinus of Valsalva (cm/m2) Sinotubular junction (cm/m2) Ascending aorta (cm/m2)
2.2 2.7 2.6 3.4
0.4 0.5 0.5 0.7
R/L (n ¼ 96)
p Value
0.79 0.03 0.25 0.87
2.2 2.9 2.6 3.4
R/L ¼ right coronary and left coronary leaflet fusion; coronary and noncoronary leaflet fusion.
0.4 0.6 0.6 0.8
R/N ¼ right
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expressed as z scores relative to body surface area (BSA) (calculated according to the formula of Haycock and colleagues [13]). For the purposes of this study, we defined mild or moderate aortic dilation as a z score above the mean for BSA of greater than 3 but equal to 6 or less, and severe dilation as a z score greater than 6. Aortic root shapes were defined and classified using criteria established by Schaefer and colleagues [8]. Patients were included in the study if they had dilation of the aortic root, measured at the level of the sinuses of Valsalva, the sinotubular junction, or the ascending aorta.
Statistical Analysis Data are presented as the mean standard deviation. Continuous variables were analyzed with the Student’s t test, and categorical variables were compared using the c2 test. Variables for the two cohorts were compared using two-tailed unpaired t tests. Kaplan-Meier curves for actuarial survival and freedom from any type of intervention on the aortic valve were created. The log-rank test was used to estimate the statistical difference between the two types of groups of patients. The significance level was set at a probability value of 0.05 or less.
Results We identified 624 patients with BAV of which 212 met the inclusion criterion of having a dilated aorta (z value 3). All subsequent data and analyses refer to the group of 212 patients. The median age at the time of the most recent
Fig 2. Comparison of z scores between patients with right-coronary/ noncoronary leaflet fusion (R/N) and those with right-coronary/left coronary leaflet fusion (R/L). (SD ¼ standard deviation.)
Fig 3. Comparison of z scores between patients with aortic stenosis (AS) and without AS (non-AS) in (A) patients with right-coronary/ left coronary leaflet fusion, (B) patients with right-coronary/ noncoronary leaflet fusion, and (C) all patients. (SD ¼ standard deviation.)
echocardiogram was 15 years (mean, 17.0 9.7 years; range, 4 months to 40 years); 72% of the patients were children younger than 18 years. Fusion of the R/N leaflets was the most prevalent dilated BAV subtype (R/N, n ¼ 114, 54%; R/L, n ¼ 96, 45%; L/N, n ¼ 2, 1%; Fig 1). Because of the small number of patients with L/N type of fusion, these 2 patients were excluded from subsequent analyses. Clinical characteristics of the compared groups (R/N and R/L) are shown in Table 1. The BAV subgroups of patients had similar characteristics with regard to sex, weight, and height. Patients with R/N leaflet fusion were significantly younger than
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Fig 4. Comparison of z scores between patients with aortic insufficiency (AI) and without AI (non-AI) in (A) patients with right-coronary/left coronary leaflet fusion, (B) patients with right-coronary/noncoronary leaflet fusion, and (C) all patients. (SD ¼ standard deviation.)
patients with R/L leaflet fusion (R/N, mean age, 15.8 8.4 years versus R/L, mean age, 18.6 11.5 years; p ¼ 0.04). The majority of patients with aortic coarctation had fusion of the R/L leaflets (R/L, n ¼ 32, 63% versus R/N, n ¼ 21, 18%; p ¼ 0.01). Sixty-three percent (n ¼ 132) of all patients with BAV and a dilated aorta had mild or greater AS. Moderate or greater AS was observed in 30% (n ¼ 65). Mild or greater AS was observed in 73% of patients with R/N fusion (n ¼ 83) and in 51% of patients with R/L fusion (n ¼ 49; p ¼ 0.002). Moderate or greater AS was observed in 23% of patients (n ¼ 22) with fusion of the R/L leaflets, and in 38% of patients (n ¼ 43) with fusion of the R/N leaflets
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(p ¼ 0.03). The peak instantaneous Doppler gradient across the aortic valve was significantly higher in patients with R/N fusion (mean, 41.2 29 mm Hg; range 0 to 146 mm Hg) compared with those with R/L fusion (29.6 29 mm Hg, range 0 to 100 mm Hg; p ¼ 0.004). Aortic insufficiency was observed in 100 patients with BAV and dilated aorta (48%), with the degree of insufficiency being mild or greater in 26% (n ¼ 54) and moderate or greater in 22% (n ¼ 46) of patients. Both mild and greater AI (R/N, n ¼ 60, 53% versus R/L, n ¼ 40, 42%; p ¼ 0.08) and moderate or greater AI (R/N, n ¼ 30, 26% versus R/L, n ¼ 16, 17%; p ¼ 0.07) were not significantly different between the BAV fusion subgroups. In contrast, the grade of AI was significantly more severe in R/N compared with R/L (R/N, 2.0 1.3 versus R/L, 1.6 1.5; p ¼ 0.04). The most prevalent aortic root anatomy was aortic root shape “A.” Shape “E” was less common, but both were mainly seen in patients with R/N leaflet fusion. Aortic root shape “N” was the least common and was mainly seen in patients with R/L leaflet fusion (R/L, 15% versus R/N, 4%; p ¼ 0.005). In addition to aortic root shape, there were significant size differences between R/N and R/L subtypes of patients (Table 2). Dilation of the ascending aorta was seen more often in patients with R/N leaflet fusion (R/N, 88% versus R/L, 68%; p ¼ 0.004), whereas the prevalence of dilation of the sinuses of Valsalva was significantly higher in patients with R/L leaflet fusion (R/L, 46% versus R/N, 20%; p ¼ 0.01). The magnitude of dilation differed as well. The z value of the sinuses of Valsalva was significantly higher in patients with R/L leaflet fusion (R/L, 2.03 versus R/N, 1.2; p ¼ 0.003), whereas the z values of the proximal ascending aorta, aortic valve annulus, and sinotubular junction were similar between the groups (Fig 2). Dilation of the ascending aorta was significantly higher in patients with stenotic valves (AS, 4.8 1.5 versus nonAS, 4.1 1.1; p < 0.001) and within this subgroup was predominantly present in patients with R/L leaflet fusion (Fig 3). Dilation of the ascending aorta was also significantly higher in patients with regurgitant valves (AI, 4.9 1.7 versus non-AI, 4.3 1.1; p ¼ 0.02), and within this subgroup was more common in patients with R/N leaflet fusion (Fig 4). When all patients with AS were compared with all patients with AI, no difference was seen in the measurements of the aortic root between patient groups, except at the level of the aortic annulus (AS, 1.1 1.1 versus AI, 1.7 1.2; p < 0.001). When these groups were divided by leaflet fusion pattern, patients with R/N leaflet fusion and AI had larger aortic diameters at the annulus, sinuses of Valsalva, and sinotubular junction than did those with AS (Fig 5). Little difference was seen between patients with R/L fusion and AS or AI. Eighty-nine patients (42%) had at least one intervention on the aortic valve during follow-up, with the majority of patients undergoing surgical valve repair or replacement. The indications for first intervention were AS (n ¼ 49), AI (n ¼ 9), both (n ¼ 24), and aneurysmatic dilated ascending aorta (n ¼ 7). Freedom from any intervention on the aortic valve was not significantly different between the subtypes (R/L 62% versus R/N 53%; p ¼ 0.21) nor was freedom
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from ascending aortic repair or replacement (R/L 69% versus R/N 65%; p ¼ 0.66). However, patients with R/N leaflet fusion were significantly younger at the time of intervention (R/N, mean age, 18.7 9.9 years versus R/L, mean age, 25.7 13.6 years; p ¼ 0.02).
Comment
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Bicuspid aortic valve is the most common congenital cardiac malformation and is present in 1% to 2% of the general population [4]. Both genetic and environmental causes of BAV have been suggested, but the pathogenesis remains unclear [9, 14–16]. Our study demonstrates that aortic valve morphology is an important determinant of the risk for AS and regurgitation, at least through childhood and adolescence. We found that patients with BAV with fusion of the R/N leaflets had greater risk of AS and regurgitation compared with patients with R/L leaflet fusion. In contrast, in the majority of papers reporting adult patients with BAV, those with fusion of the R/L leaflets have an increased incidence of aortic valve disease and aortic dilation [6, 17]. Information concerning the natural history of BAV in children remains limited. Because progressive dilation of the proximal ascending aorta is described in adults with BAV and the diagnosis of BAV is frequently made during childhood, it is important to describe the time course of the development of aortic dilation. Holmes and colleagues [18] described an early onset and progressive nature of ascending aortic dilation during childhood in children with BAV. They found that R/N leaflet fusion and the severity of AS were associated with a more rapid increase in ascending aortic diameter in univariate analysis [18]. Twelve percent of children demonstrated marked ascending aortic dilation (z score >4), and 25% were moderately abnormal (z score between 2 and 4). The morphology of R/N leaflet fusion has been implicated in other types of congenital heart disease. Levine and associates [19] noted that this pattern of valve morphology was a risk factor for the development of late-onset left-sided obstructive disease in infants presenting with aortic coarctation. The pathogenesis of BAV is still unclear. Multiple factors are of importance in the formation of the semilunar valves. Several genes or gene products have been implicated in formation of BAV, and some forms of BAV seem to be heritable [2, 15]. A mutation in NOTCH-1 has been shown to cause cardiac abnormalities, including BAV with severe calcification [8, 14]. Animal studies suggest involvement of neural crest cells in the development of the aortic valve and the ascending aorta [9]. Bicuspid aortic valve is associated with accelerated degeneration of the aortic media, indicating that BAV is an ongoing pathologic process, not a discrete developmental event. Fedak and associates [15] have identified focal abnormalities within the aortic media of patients with BAV, such as matrix disruption and smooth muscle cell loss, suggesting a degenerative process that may result in structural weakness of the aortic wall. These lesions are similar in fibrillin-1–deficient aorta (Marfan syndrome). Matrix metalloproteinases, endogenous
Fig 5. Comparison of z scores between patients with primary aortic stenosis (AS) and primary aortic insufficiency (AI) in (A) patients with right-coronary/left coronary leaflet fusion, (B) patients with right-coronary/noncoronary leaflet fusion, and (C) all patients. (SD ¼ standard deviation.)
enzymes that degrade matrix components, have been implicated in atherosclerotic aortic aneurysm formation, and matrix metalloproteinases become activated in fibrillin-1–deficient tissues, degrading the structural support of the aorta and resulting in dilation, aneurysms, and dissection [2, 15, 18]. Fedak and associates [15] found that matrix metalloproteinases activity may be elevated in the aorta of patients with BAV. Aortic stenosis is one of the most frequent complications of BAV, in many cases requiring aortic valve replacement. Bicuspid aortic valves are present in the majority of patients aged 15 to 65 years with significant AS, reflecting the propensity for premature fibrosis,
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stiffening, and calcium deposition in these abnormally functioning valves [15]. Aortic stenosis is also associated with congenital valve malformations and is age dependent; the fewer the cusps, the greater the chance that the valve is stenotic from birth. In our series, we found that patients with R/N fusion presented at a younger age and were more likely to have AS. In addition, adult patients with poor lipid profiles and those who smoke are also at an elevated risk of developing hemodynamically significant BAV stenosis that may result in aortic valve replacement [2, 5, 6, 15]. In fact, the main indication for aortic valve replacement in adult patients with BAV is calcification of congenitally deformed leaflets leading to valve stenosis and insufficiency. Aortic regurgitation occurs in the presence of a BAV, usually from cusp prolapse, fibrotic retraction, or finally dilation of the sinotubular junction. Endocarditis is a potentially devastating complication that occurs in patients with BAV (30%), particularly with regurgitant valves and in younger patients [15]. There is limited knowledge about clinical or echocardiographic features that may help to identify patients with BAV who are prone to aortic dilation with time. Data from different groups [17, 20] demonstrated that patients with BAV are at increased risk for aortic complications and that aortic valve replacement does not prevent progressive aortic dilation. Borger and associates [21] suggested that patients undergoing operations for BAV should be considered for concomitant replacement of the ascending aorta if the diameter is 4.5 cm or greater. Recent guidelines from the American College of Cardiology/American Heart Association confirm such a strategy [22]. However, all patients with BAV (even without AS or AI) will exhibit aortic dilation with time. In our study only one third of patients had aortic dilation at the last follow-up echocardiogram; however, our population was relatively young. Novaro and coworkers [23] observed that male sex, sinus diameter, and R/N cusp fusion predicted dilation of the ascending aorta in aortic regurgitation, whereas in AS only age and sinus dimension were significant predictors. The presence of a BAV is an independent risk factor for progressive aortic dilation, aneurysm formation, and dissection. Despite considerable controversy, some believe that the vascular complications of BAV are not secondary to valvular dysfunction and can manifest in young adults without significant AS or regurgitation and in patients in whom the native BAV was replaced with a prosthesis [1, 15]. Nistri and colleagues [1] found that more than 50% of young patients with normally functioning BAVs have echocardiographic evidence of aortic dilation. In our series, 33% of young patients with BAV have evidence of dilation (z score >3). Recognizing associated aortic dilation in BAV, Schaefer and coworkers [8] proposed an integrated classification system based on both leaflet fusion and root shape. The authors found that patients with R/L leaflet fusion most commonly presented with type “N” (normal shape), whereas those with R/N leaflet fusion were more likely to have a type “A” (ascending dilation) or type “E” (effaced
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root) root anatomy. In our series, we also found that type “N” was significantly more frequent in patients with R/L leaflet fusion, but types “A” and “E” were more frequent in patients with R/N leaflet fusion. Our study has several limitations. Being a singleinstitution, retrospective cohort study limited the patient population and suffered the potential loss of data over time, and only 66% of patients had more than one echocardiogram. We could only include patients who presented for investigation or treatment. Therefore, the true incidence of BAV may be underestimated because some individuals may not be evaluated owing to lack of physical findings and symptoms. Early mass screening of a given population by echocardiography could provide a truer prevalence of BAV and the types of fusion. In addition, the lack of tissue samples or detailed flow studies and hemodynamic data limits our ability to delineate the relative influence of genetic factors versus flow disturbances caused by abnormal leaflet morphology. Our study suggests that in young patients with BAV and aortic dilation, aortic valve morphology may be associated with the patterns of aortic dilation and valve dysfunction. Patients with R/N fusion were more likely to have ascending aortic dilation, whereas patients with R/L fusion were more likely to have dilation of the aortic root. In addition, patients with R/N fusion presented at a younger age and were more likely to have AS. The etiologic factors that determine the formation of R/N and R/L BAVs may also be involved in the occurrence and progression of the diseases associated with each subtype. Recognition of these differences may eventually be helpful for patient counseling and the planning of follow-up.
References 1. Nistri S, Basso C, Marzari C, Mormino P, Thiene G. Frequency of bicuspid aortic valve in young male conscripts by echocardiogram. Am J Cardiol 2005;96:718–21. 2. Losenno KL, Goodman RL, Chu MWA. Bicuspid aortic valve disease and ascending aortic aneurysms: gaps in knowledge. Cardiol Res Pract 2012;2012:145202. 3. Evangelista A, Flachskampf FA, Erbel R, et al, European Association of Echocardiography; Document Reviewers. Echocardiography in aortic diseases: EAE recommendations for clinical practice. Eur J Echocardiogr 2010;11:645–58. 4. Fernandes SM, Sanders SP, Khairy P, et al. Morphology of bicuspid aortic valve in children and adolescents. J Am Coll Cardiol 2004;44:1648–51. 5. Sievers H-H, Schmidtke C. A classification system for the bicuspid aortic valve from 304 surgical specimens. J Thorac Cardiovasc Surg 2007;133:1226–33. 6. Della Corte A, Bancone C, Dialetto G, et al. Towards an individualized approach to bicuspid aortopathy: different valve types have unique determinants of aortic dilatation. Eur J Cardiothorac Surg 2014;45:e118–24. 7. Fernandes S, Khairy P, Graham DA, et al. Bicuspid aortic valve and associated aortic dilation in the young. Heart 2012;98:1014–9. 8. Schaefer BM, Lewin MB, Stout KK, et al. The bicuspid aortic valve: an integrated phenotypic classification of leaflet morphology and aortic root shape. Heart 2008;94:1634–8. 9. Fernandez B, Dur an AC, Fern andez-Gallego T, et al. Bicuspid aortic valves with different spatial orientations of the leaflets are distinct etiological entities. J Am Coll Cardiol 2009;54:2312–8.
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aortic valve anatomy in patients with valvular disease? J Thorac Cardiovasc Surg 2008;136:937–42. Holmes KW, Lehmann CU, Dalal D, et al. Progressive dilation of the ascending aorta in children with isolated bicuspid aortic valve. Am J Cardiol 2007;99:978–83. Levine JC, Sanders SP, Colan SD, Jonas RA, Spevak PJ. The risk of having additional obstructive lesions in neonatal coarctation of the aorta. Cardiol Young 2001;11: 44–53. Yasuda H, Nakatani S, Stugaard M, et al. Failure to prevent progressive dilation of ascending aorta by aortic valve replacement in patients with bicuspid aortic valve: comparison with tricuspid aortic valve. Circulation 2003;108(Suppl 1):II291–4. Borger MA, Preston M, Ivanov J, et al. Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve disease? J Thorac Cardiovasc Surg 2004;128: 677–83. Bonow RO. Bicuspid aortic valves and dilated aortas: a critical review of the ACC/AHA practice guidelines recommendations. Am J Cardiol 2008;102:111–4. Novaro GM, Tiong IY, Pearce GL, Grimm RA, Smedira N, Griffin BP. Features and predictors of ascending aortic dilatation in association with a congenital bicuspid aortic valve. Am J Cardiol 2003;92:99–101.
DISCUSSION DR DUKE CAMERON (Baltimore, MD): Thank you, Karl, and congratulations to you and your coauthors for this study, which provides some additional insight into this developing field of bicuspid aortic valve and its related aortopathy. Your study provides a slightly different perspective from others in that it focuses on children and adolescents, and you have shown us that they have a different pattern of distribution of bicuspid aortic valve configurations and aneurysm compared to adults. They have more right nonfused valves, and those valves are associated with more stenosis and more ascending aortic rather than root dilatation. Now, other recent adult studies have also described associations between bicuspid aortic valve type and aneurysm morphology, and some have even included elegant MRI [magnetic resonance imaging] aortic flow studies to show that the bicuspid aortic valve pattern creates a unique flow disturbance and wall stresses that might account for these aneurysm shapes. Again, your study is unique in that the vast majority of your patients were less than 18 years of age, and they presumably presented earlier in life to your clinic for a reason, and that’s what my question is getting at. I’m guessing that they presented earlier because their flow disturbances were more severe, there was more stenosis, and that this led to earlier recognition. And therefore, this group of patients really isn’t representative of the broader group of bicuspid aortic valve patients. It is a very selected series. Notably, the most common pattern of fusion in your group was the right-non, which was 54% in your series, but in bicuspid aortic valve it’s the left-right that occurs in 80%. So it’s really a unique distribution in childhood. And we have to consider that this is a series heavily weighted towards patients with early hemodynamic abnormalities. So my questions are, first, can you tell us why were these patients referred to your clinic in the first place? Was it usually because of a murmur? DR WELKE: Thank you very much for your assessment and comments. You are absolutely right. The patients with right-non
leaflet fusion are probably presenting earlier and undergoing treatment earlier. As a result, they are not included in as large of numbers in adult series. Right-non leaflet fusion may be the more severe subtype of bicuspid aortic valve. Most of the patients in our series presented with murmurs, although some presented early in life with symptoms of aortic stenosis. DR CAMERON: Great. Now, second, do you have any evidence to support whether the preop[erative] echo[cardiograph] determination of the valve morphology was actually confirmed at surgery? And I ask this because I continue to be surprised at how often the preop[erative] transthoracic echo[cardiograph] doesn’t get this right. Now, that may reflect my experience more with adults who have much more calcified valves where it’s more difficult to assess the original configuration. But did your intraoperative assessment of the valve morphology always conform or agree with the preop[erative] echo[cardiograph]? DR WELKE: In looking back through the operative notes, I can tell you that we were better in more recent years of recording what we saw in the operating room as surgeons. For some of the earlier patients, it was more difficult to find that information. When I looked at more recent years, I found we were accurate on the assessment. DR CAMERON: Very good. And finally, do you think your study supports the argument that aneurysm shape is the result of valve hemodynamics or is it intrinsic to the aortopathy or is it some combination of both? DR WELKE: It is an ongoing debate, isn’t it? Animal studies suggest there may be a genetic difference. In the last week I have talked to people from two different institutions. One said, yes, we have found a cohort of patients that may have a genetic predisposition and another said that in their data, there was no genetic predisposition. If we look at subgroups of these patients, like those with Shone’s complex, which tend to be patients with right-
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10. Verma S, Yanagawa B, Kalra S, et al. Knowledge, attitudes, and practice patterns in surgical management of bicuspid aortopathy: a survey of 100 cardiac surgeons. J Thorac Cardiovasc Surg 2013;146:1033–40.e4. 11. Girdauskas E, Rouman M, Borger MA, Kuntze T. Comparison of aortic media changes in patients with bicuspid aortic valve stenosis versus bicuspid valve insufficiency and proximal aortic aneurysm. Interact Cardiovasc Thorac Surg 2013;17:931–7. 12. Braverman AC. Bicuspid aortic valve and associated aortic wall abnormalities. Curr Opin Cardiol 1996;11:501–3. 13. Haycock GB, Schwartz GJ, Wisotsky DH. Geometric method for measuring body surface area: a height-weight formula validated in infants, children, and adults. J Pediatr 1978;93:62–6. 14. Garg V, Muth AN, Ransom JF, et al. Mutations in NOTCH1 cause aortic valve disease. Nature 2005;437:270–4. 15. Fedak PWM, Verma S, David TE, Leask RL, Weisel RD, Butany J. Clinical and pathophysiological implications of a bicuspid aortic valve. Circulation 2002;106:900–4. 16. Sabet HY, Edwards WD, Tazelaar HD, Daly RC. Congenitally bicuspid aortic valves: a surgical pathology study of 542 cases (1991 through 1996) and a literature review of 2715 additional cases. Mayo Clin Proc 1999;74:14–26. 17. Russo CF, Cannata A, Lanfranconi M, Vitali E, Garatti A, Bonacina E. Is aortic wall degeneration related to bicuspid
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left leaflet fusion, the pattern suggests there is a genetic predisposition. Also, when we look at patients that have had valve replacement surgery, the progression of the aortic dilatation post-operatively seems to be associated with the preoperative morphology to some degree. So I think there is a genetic component. As an engineer, I have to think there is a hemodynamic component as well. It is probably mixed. DR CAMERON: Well, thanks again on a great presentation.
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DR WELKE: Thank you for your questions. DR ROSS M. UNGERLEIDER (Winston-Salem, NC): Karl, excellent, very instructive. I have one comment. I think there is a good takeaway for people here that we should all be perhaps, if we haven’t been, more assiduous about reporting the morphology of bicuspid valves in our operative reports so that we can get these kinds of data going forward. It might be a good data field for the STS [Society of Thoracic Surgeons] Congenital Heart Surgery Database to include if we can get that kind of granularity in terms of outcomes.
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My question would be, does it influence the kinds of procedures that you do for these children? Of course, we are going to hear perhaps one option related to that in the next talk. But is it having an influence now in your clinical practice in terms of what you are doing or are you still treating all these patients the same based on their symptoms? DR WELKE: That is a good question. We have just started to look at this topic in the last year, so it has not impacted our clinical practice yet. Based on the fact that we have some data, which hopefully we will present next spring, which shows there may be a correlation between the valve subtype and what happens postoperatively, it may in time influence our operations, but it has not yet. So thank you. And I agree with you. Looking at bicuspid valve morphology as a field in The Society of Thoracic Surgeons Congenital Heart Surgery Database would be informative. It also may be something that would be well suited to the Congenital Heart Surgeons Society, where we are better at long-term follow-up, because that is really what we need with this group. As was mentioned, in adults, it is a different patient mix. So it is something to think about. But thank you for your thoughts.
Background. Dilation of the aorta is a frequent complication in patients with bicuspid aortic valves. The aim of this study was to determine the relationship between the subtype of leaflet fusion, right and noncoronary leaflet (R/N) fusion versus right and left leaflet (R/L) fusion, and the patterns of aortic dilation and valve dysfunction in young patients with bicuspid aortic valves. Methods. We performed a retrospective review of 642 patients who presented with bicuspid aortic valves between 1994 and 2014. Of these patients, 210 (33%) had aortic dilation (z score >3) by echocardiogram. For each patient, the most recent study or the last study before intervention was reviewed. Results. Median patient age was 15 years (range, 0 to 40 years) with patients with R/N fusion being younger. The most prevalent subtype was R/N fusion (R/N, n [ 114, 54% versus R/L, n [ 96, 46%). Dilation of the ascending aorta was seen more often in patients with R/N fusion (R/ N, 88% versus R/L, 68%; p [ 0.004), whereas the prevalence of dilation of the sinuses of Valsalva was significantly higher in patients with R/L fusion (R/L, 46% versus R/N, 20%; p [ 0.01). The magnitude of dilation differed
as well. The z value of the sinuses of Valsalva was significantly higher in patients with R/L fusion (R/L, 2.03 versus R/N, 1.2; p [ 0.003), whereas the z values of the ascending aorta and sinotubular junction were similar between the groups. Patients with R/N fusion were more likely to have aortic stenosis, and within the R/N group, patients with aortic insufficiency had a greater degree of ascending aorta dilation (p [ 0.04). Conclusions. Our study suggests that in young patients with bicuspid aortic valves and aortic dilation, aortic valve morphology may be associated with the patterns of aortic dilation and valve dysfunction. Patients with R/N fusion were more likely to have ascending aorta dilation, whereas patients with R/L fusion were more likely to have dilation of the aortic root. In addition, patients with R/N fusion presented at a younger age and were more likely to have aortic stenosis. Recognition of these differences may eventually be helpful for patient counseling and the planning of follow-up.
B
factor for ascending aorta and aortic root disease, even without valve disease [3]. Fusion of the right and left coronary leaflets (R/L), the right and noncoronary leaflets (R/N), or the left and noncoronary leaflets (L/N) leads to the development of BAV [4–8]. Currently there is limited information regarding whether the type of leaflet morphology in BAV is associated with abnormalities of valve function and the aorta. Some have suggested that different fusion subtypes may be the result of different embryologic and developmental mechanisms [9]. Although aortic stenosis (AS) and aortic insufficiency (AI) are the most common complications of a BAV, dilation of any or all segments of the proximal aorta from the aortic root to the aortic arch, called bicuspid aortopathy, is also present in approximately 40% to 50% of affected persons [10, 11]. The majority of young patients with BAV have mild dilation; the rare patient can have progressive dilation that places them at risk for morbidity and premature death [7, 12]. The aim of this study was to
icuspid aortic valve (BAV) is the most common congenital heart anomaly in the general population, affecting 1% to 2% of individuals worldwide, and is responsible for more deaths and complications than the combined effects of all the other congenital heart defects [1, 2]. Bicuspid aortic valve, which results from abnormal aortic leaflet formation during valvulogenesis, is most likely caused by a complex developmental process rather than the fusion of two normal leaflets [3]. Different BAV morphologies may result from different genotypes: indeed, recent studies have highlighted a connection between the morphologic pattern of BAV as a prognostic
Accepted for publication Feb 12, 2015. Presented at the Sixty-first Annual Meeting of the Southern Thoracic Surgical Association, Tucson, AZ, Nov 5–8, 2014. Address correspondence to Dr Welke, University of Illinois College of Medicine at Peoria, Children’s Hospital of Illinois, OSF Saint Francis Medical Center, 420 NE Glen Oak Ave, Ste 301, Peoria, IL 63603; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2015;99:2101–8) Ó 2015 by The Society of Thoracic Surgeons
0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.02.036
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Section of Pediatric Cardiovascular Surgery and Pediatric Cardiology, University of Illinois College of Medicine at Peoria, Children’s Hospital of Illinois, OSF Saint Francis Medical Center, Peoria, Illinois
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determine the relationship between the subtype of leaflet fusion, R/N versus R/L, and the patterns of aortic dilation and valve dysfunction in young patients with BAV.
Material and Methods
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Patients We performed a retrospective search for patients with BAV who were referred to our Congenital Heart Center between January 1994 and August 2014. The University of Illinois College of Medicine at Peoria Institutional Review Board approved the study, and the need for parental consent was waived. We reviewed hospital records, clinic records, surgical records, and echocardiographic data for patient demographic information, aortic valve morphology, AS and degree thereof, AI and severity thereof, ascending aortic dimensions, and presence or absence of aortic coarctation. Most of the patients (66%) had more than one echocardiogram. The most recent echocardiogram, or one preceding surgical or catheter intervention, was considered for overall incidence of associated lesions. When a patient had endocarditis, a study at least 1 year before the episode of endocarditis was reviewed. Cuspal fusion was determined by review of echocardiographic images by a single observer. Patients were grouped by age to determine the prevalence of associated abnormalities in R/L fusion and R/N fusion. For each age group, the latest echocardiogram in that age group was reviewed and considered for data analysis. For example, for a patient with echocardiograms at age 3, 5, 7, and 9 years, the 9year echocardiogram was used. Aortic stenosis was evaluated by Doppler echocardiography using standard techniques of interrogation, and peak and mean pressure gradients were calculated by modified Bernoulli equation. Peak Doppler velocity across the aortic valve of 2 m/s or greater was considered abnormal and mild if less than 3.5 m/s and moderate or
Fig 1. Bicuspid aortic valve cusp morphology. (LC ¼ left coronary leaflet; LCA ¼ left coronary artery; L/N ¼ left coronary/noncoronary; NC ¼ noncoronary leaflet; RC ¼ right coronary leaflet; RCA ¼ right coronary artery; R/L ¼ right-coronary/left coronary; R/N ¼ rightcoronary/noncoronary.)
more if greater than 3.5 m/s. These velocities correspond to peak instantaneous gradients of 16 mm Hg for mild stenosis and greater than 50 mm Hg for moderate or greater stenosis. Aortic insufficiency was evaluated using established criteria [1], including the regurgitant jet width relative to annular diameter ratio, pressure halftime, the presence of abnormal diastolic retrograde flow in the descending thoracic aorta, and left ventricular diastolic dimension. Aortic insufficiency was categorized as none (0), trivial (1þ), mild (2þ), moderate (3þ), or severe (4þ). Aortic measurements were performed in parasternal long-axis views using two-dimensional imaging, inneredge to inner-edge, at maximal excursion. The aortic root diameter was measured at the sinuses of Valsalva, and the ascending aortic diameter was recorded as the largest diameter distal to the sinotubular junction. Aortic dimensions were compared with published data and
Table 1. Characteristics of Patients With Bicuspid Aortic Valve at Most Recent Echocardiogram R/N (n ¼ 114)
R/L (n ¼ 96)
p Value
15.8 8.4 (0.33–40) 55 25 (6–112) 153 27 (27–153) 70/44 7 (6%) 21 (18%) 56 (50%) 60 (53%)
18.6 11.5 (1.5–40) 57 27 (7.6–115) 151 28 (71–193) 56/40 10 (10%) 32 (63%) 27 (28%) 40 (42%)
0.04 0.55 0.71 0.33 0.62 0.01 0.001 0.08
Characteristic Age (mean, range; y) Weight (mean, range; kg) Height (mean, range; cm) Sex (M/F) Congenital heart defect other than BAV Aortic coarctation Aortic stenosis Aortic insufficiency (mild) Type of dilated aortic shape (n, %)a “N” “A” “E” a
4 (4%) 60 (53%) 49 (43%)
14 (15%) 46 (48%) 36 (37%)
0.02
Shapes were defined according to Schaefer and associates [8].
A ¼ ascending distention; BAV ¼ bicuspid aortic valve; fusion; R/N ¼ right coronary and noncoronary leaflet fusion.
E ¼ effaced;
N ¼ normal;
R/L ¼ right coronary and left coronary leaflet
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Table 2. Aortic Root Dimensions R/N (n ¼ 114)
Site 2
Aortic annulus (cm/m ) Sinus of Valsalva (cm/m2) Sinotubular junction (cm/m2) Ascending aorta (cm/m2)
2.2 2.7 2.6 3.4
0.4 0.5 0.5 0.7
R/L (n ¼ 96)
p Value
0.79 0.03 0.25 0.87
2.2 2.9 2.6 3.4
R/L ¼ right coronary and left coronary leaflet fusion; coronary and noncoronary leaflet fusion.
0.4 0.6 0.6 0.8
R/N ¼ right
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expressed as z scores relative to body surface area (BSA) (calculated according to the formula of Haycock and colleagues [13]). For the purposes of this study, we defined mild or moderate aortic dilation as a z score above the mean for BSA of greater than 3 but equal to 6 or less, and severe dilation as a z score greater than 6. Aortic root shapes were defined and classified using criteria established by Schaefer and colleagues [8]. Patients were included in the study if they had dilation of the aortic root, measured at the level of the sinuses of Valsalva, the sinotubular junction, or the ascending aorta.
Statistical Analysis Data are presented as the mean standard deviation. Continuous variables were analyzed with the Student’s t test, and categorical variables were compared using the c2 test. Variables for the two cohorts were compared using two-tailed unpaired t tests. Kaplan-Meier curves for actuarial survival and freedom from any type of intervention on the aortic valve were created. The log-rank test was used to estimate the statistical difference between the two types of groups of patients. The significance level was set at a probability value of 0.05 or less.
Results We identified 624 patients with BAV of which 212 met the inclusion criterion of having a dilated aorta (z value 3). All subsequent data and analyses refer to the group of 212 patients. The median age at the time of the most recent
Fig 2. Comparison of z scores between patients with right-coronary/ noncoronary leaflet fusion (R/N) and those with right-coronary/left coronary leaflet fusion (R/L). (SD ¼ standard deviation.)
Fig 3. Comparison of z scores between patients with aortic stenosis (AS) and without AS (non-AS) in (A) patients with right-coronary/ left coronary leaflet fusion, (B) patients with right-coronary/ noncoronary leaflet fusion, and (C) all patients. (SD ¼ standard deviation.)
echocardiogram was 15 years (mean, 17.0 9.7 years; range, 4 months to 40 years); 72% of the patients were children younger than 18 years. Fusion of the R/N leaflets was the most prevalent dilated BAV subtype (R/N, n ¼ 114, 54%; R/L, n ¼ 96, 45%; L/N, n ¼ 2, 1%; Fig 1). Because of the small number of patients with L/N type of fusion, these 2 patients were excluded from subsequent analyses. Clinical characteristics of the compared groups (R/N and R/L) are shown in Table 1. The BAV subgroups of patients had similar characteristics with regard to sex, weight, and height. Patients with R/N leaflet fusion were significantly younger than
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Fig 4. Comparison of z scores between patients with aortic insufficiency (AI) and without AI (non-AI) in (A) patients with right-coronary/left coronary leaflet fusion, (B) patients with right-coronary/noncoronary leaflet fusion, and (C) all patients. (SD ¼ standard deviation.)
patients with R/L leaflet fusion (R/N, mean age, 15.8 8.4 years versus R/L, mean age, 18.6 11.5 years; p ¼ 0.04). The majority of patients with aortic coarctation had fusion of the R/L leaflets (R/L, n ¼ 32, 63% versus R/N, n ¼ 21, 18%; p ¼ 0.01). Sixty-three percent (n ¼ 132) of all patients with BAV and a dilated aorta had mild or greater AS. Moderate or greater AS was observed in 30% (n ¼ 65). Mild or greater AS was observed in 73% of patients with R/N fusion (n ¼ 83) and in 51% of patients with R/L fusion (n ¼ 49; p ¼ 0.002). Moderate or greater AS was observed in 23% of patients (n ¼ 22) with fusion of the R/L leaflets, and in 38% of patients (n ¼ 43) with fusion of the R/N leaflets
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(p ¼ 0.03). The peak instantaneous Doppler gradient across the aortic valve was significantly higher in patients with R/N fusion (mean, 41.2 29 mm Hg; range 0 to 146 mm Hg) compared with those with R/L fusion (29.6 29 mm Hg, range 0 to 100 mm Hg; p ¼ 0.004). Aortic insufficiency was observed in 100 patients with BAV and dilated aorta (48%), with the degree of insufficiency being mild or greater in 26% (n ¼ 54) and moderate or greater in 22% (n ¼ 46) of patients. Both mild and greater AI (R/N, n ¼ 60, 53% versus R/L, n ¼ 40, 42%; p ¼ 0.08) and moderate or greater AI (R/N, n ¼ 30, 26% versus R/L, n ¼ 16, 17%; p ¼ 0.07) were not significantly different between the BAV fusion subgroups. In contrast, the grade of AI was significantly more severe in R/N compared with R/L (R/N, 2.0 1.3 versus R/L, 1.6 1.5; p ¼ 0.04). The most prevalent aortic root anatomy was aortic root shape “A.” Shape “E” was less common, but both were mainly seen in patients with R/N leaflet fusion. Aortic root shape “N” was the least common and was mainly seen in patients with R/L leaflet fusion (R/L, 15% versus R/N, 4%; p ¼ 0.005). In addition to aortic root shape, there were significant size differences between R/N and R/L subtypes of patients (Table 2). Dilation of the ascending aorta was seen more often in patients with R/N leaflet fusion (R/N, 88% versus R/L, 68%; p ¼ 0.004), whereas the prevalence of dilation of the sinuses of Valsalva was significantly higher in patients with R/L leaflet fusion (R/L, 46% versus R/N, 20%; p ¼ 0.01). The magnitude of dilation differed as well. The z value of the sinuses of Valsalva was significantly higher in patients with R/L leaflet fusion (R/L, 2.03 versus R/N, 1.2; p ¼ 0.003), whereas the z values of the proximal ascending aorta, aortic valve annulus, and sinotubular junction were similar between the groups (Fig 2). Dilation of the ascending aorta was significantly higher in patients with stenotic valves (AS, 4.8 1.5 versus nonAS, 4.1 1.1; p < 0.001) and within this subgroup was predominantly present in patients with R/L leaflet fusion (Fig 3). Dilation of the ascending aorta was also significantly higher in patients with regurgitant valves (AI, 4.9 1.7 versus non-AI, 4.3 1.1; p ¼ 0.02), and within this subgroup was more common in patients with R/N leaflet fusion (Fig 4). When all patients with AS were compared with all patients with AI, no difference was seen in the measurements of the aortic root between patient groups, except at the level of the aortic annulus (AS, 1.1 1.1 versus AI, 1.7 1.2; p < 0.001). When these groups were divided by leaflet fusion pattern, patients with R/N leaflet fusion and AI had larger aortic diameters at the annulus, sinuses of Valsalva, and sinotubular junction than did those with AS (Fig 5). Little difference was seen between patients with R/L fusion and AS or AI. Eighty-nine patients (42%) had at least one intervention on the aortic valve during follow-up, with the majority of patients undergoing surgical valve repair or replacement. The indications for first intervention were AS (n ¼ 49), AI (n ¼ 9), both (n ¼ 24), and aneurysmatic dilated ascending aorta (n ¼ 7). Freedom from any intervention on the aortic valve was not significantly different between the subtypes (R/L 62% versus R/N 53%; p ¼ 0.21) nor was freedom
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from ascending aortic repair or replacement (R/L 69% versus R/N 65%; p ¼ 0.66). However, patients with R/N leaflet fusion were significantly younger at the time of intervention (R/N, mean age, 18.7 9.9 years versus R/L, mean age, 25.7 13.6 years; p ¼ 0.02).
Comment
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Bicuspid aortic valve is the most common congenital cardiac malformation and is present in 1% to 2% of the general population [4]. Both genetic and environmental causes of BAV have been suggested, but the pathogenesis remains unclear [9, 14–16]. Our study demonstrates that aortic valve morphology is an important determinant of the risk for AS and regurgitation, at least through childhood and adolescence. We found that patients with BAV with fusion of the R/N leaflets had greater risk of AS and regurgitation compared with patients with R/L leaflet fusion. In contrast, in the majority of papers reporting adult patients with BAV, those with fusion of the R/L leaflets have an increased incidence of aortic valve disease and aortic dilation [6, 17]. Information concerning the natural history of BAV in children remains limited. Because progressive dilation of the proximal ascending aorta is described in adults with BAV and the diagnosis of BAV is frequently made during childhood, it is important to describe the time course of the development of aortic dilation. Holmes and colleagues [18] described an early onset and progressive nature of ascending aortic dilation during childhood in children with BAV. They found that R/N leaflet fusion and the severity of AS were associated with a more rapid increase in ascending aortic diameter in univariate analysis [18]. Twelve percent of children demonstrated marked ascending aortic dilation (z score >4), and 25% were moderately abnormal (z score between 2 and 4). The morphology of R/N leaflet fusion has been implicated in other types of congenital heart disease. Levine and associates [19] noted that this pattern of valve morphology was a risk factor for the development of late-onset left-sided obstructive disease in infants presenting with aortic coarctation. The pathogenesis of BAV is still unclear. Multiple factors are of importance in the formation of the semilunar valves. Several genes or gene products have been implicated in formation of BAV, and some forms of BAV seem to be heritable [2, 15]. A mutation in NOTCH-1 has been shown to cause cardiac abnormalities, including BAV with severe calcification [8, 14]. Animal studies suggest involvement of neural crest cells in the development of the aortic valve and the ascending aorta [9]. Bicuspid aortic valve is associated with accelerated degeneration of the aortic media, indicating that BAV is an ongoing pathologic process, not a discrete developmental event. Fedak and associates [15] have identified focal abnormalities within the aortic media of patients with BAV, such as matrix disruption and smooth muscle cell loss, suggesting a degenerative process that may result in structural weakness of the aortic wall. These lesions are similar in fibrillin-1–deficient aorta (Marfan syndrome). Matrix metalloproteinases, endogenous
Fig 5. Comparison of z scores between patients with primary aortic stenosis (AS) and primary aortic insufficiency (AI) in (A) patients with right-coronary/left coronary leaflet fusion, (B) patients with right-coronary/noncoronary leaflet fusion, and (C) all patients. (SD ¼ standard deviation.)
enzymes that degrade matrix components, have been implicated in atherosclerotic aortic aneurysm formation, and matrix metalloproteinases become activated in fibrillin-1–deficient tissues, degrading the structural support of the aorta and resulting in dilation, aneurysms, and dissection [2, 15, 18]. Fedak and associates [15] found that matrix metalloproteinases activity may be elevated in the aorta of patients with BAV. Aortic stenosis is one of the most frequent complications of BAV, in many cases requiring aortic valve replacement. Bicuspid aortic valves are present in the majority of patients aged 15 to 65 years with significant AS, reflecting the propensity for premature fibrosis,
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stiffening, and calcium deposition in these abnormally functioning valves [15]. Aortic stenosis is also associated with congenital valve malformations and is age dependent; the fewer the cusps, the greater the chance that the valve is stenotic from birth. In our series, we found that patients with R/N fusion presented at a younger age and were more likely to have AS. In addition, adult patients with poor lipid profiles and those who smoke are also at an elevated risk of developing hemodynamically significant BAV stenosis that may result in aortic valve replacement [2, 5, 6, 15]. In fact, the main indication for aortic valve replacement in adult patients with BAV is calcification of congenitally deformed leaflets leading to valve stenosis and insufficiency. Aortic regurgitation occurs in the presence of a BAV, usually from cusp prolapse, fibrotic retraction, or finally dilation of the sinotubular junction. Endocarditis is a potentially devastating complication that occurs in patients with BAV (30%), particularly with regurgitant valves and in younger patients [15]. There is limited knowledge about clinical or echocardiographic features that may help to identify patients with BAV who are prone to aortic dilation with time. Data from different groups [17, 20] demonstrated that patients with BAV are at increased risk for aortic complications and that aortic valve replacement does not prevent progressive aortic dilation. Borger and associates [21] suggested that patients undergoing operations for BAV should be considered for concomitant replacement of the ascending aorta if the diameter is 4.5 cm or greater. Recent guidelines from the American College of Cardiology/American Heart Association confirm such a strategy [22]. However, all patients with BAV (even without AS or AI) will exhibit aortic dilation with time. In our study only one third of patients had aortic dilation at the last follow-up echocardiogram; however, our population was relatively young. Novaro and coworkers [23] observed that male sex, sinus diameter, and R/N cusp fusion predicted dilation of the ascending aorta in aortic regurgitation, whereas in AS only age and sinus dimension were significant predictors. The presence of a BAV is an independent risk factor for progressive aortic dilation, aneurysm formation, and dissection. Despite considerable controversy, some believe that the vascular complications of BAV are not secondary to valvular dysfunction and can manifest in young adults without significant AS or regurgitation and in patients in whom the native BAV was replaced with a prosthesis [1, 15]. Nistri and colleagues [1] found that more than 50% of young patients with normally functioning BAVs have echocardiographic evidence of aortic dilation. In our series, 33% of young patients with BAV have evidence of dilation (z score >3). Recognizing associated aortic dilation in BAV, Schaefer and coworkers [8] proposed an integrated classification system based on both leaflet fusion and root shape. The authors found that patients with R/L leaflet fusion most commonly presented with type “N” (normal shape), whereas those with R/N leaflet fusion were more likely to have a type “A” (ascending dilation) or type “E” (effaced
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root) root anatomy. In our series, we also found that type “N” was significantly more frequent in patients with R/L leaflet fusion, but types “A” and “E” were more frequent in patients with R/N leaflet fusion. Our study has several limitations. Being a singleinstitution, retrospective cohort study limited the patient population and suffered the potential loss of data over time, and only 66% of patients had more than one echocardiogram. We could only include patients who presented for investigation or treatment. Therefore, the true incidence of BAV may be underestimated because some individuals may not be evaluated owing to lack of physical findings and symptoms. Early mass screening of a given population by echocardiography could provide a truer prevalence of BAV and the types of fusion. In addition, the lack of tissue samples or detailed flow studies and hemodynamic data limits our ability to delineate the relative influence of genetic factors versus flow disturbances caused by abnormal leaflet morphology. Our study suggests that in young patients with BAV and aortic dilation, aortic valve morphology may be associated with the patterns of aortic dilation and valve dysfunction. Patients with R/N fusion were more likely to have ascending aortic dilation, whereas patients with R/L fusion were more likely to have dilation of the aortic root. In addition, patients with R/N fusion presented at a younger age and were more likely to have AS. The etiologic factors that determine the formation of R/N and R/L BAVs may also be involved in the occurrence and progression of the diseases associated with each subtype. Recognition of these differences may eventually be helpful for patient counseling and the planning of follow-up.
References 1. Nistri S, Basso C, Marzari C, Mormino P, Thiene G. Frequency of bicuspid aortic valve in young male conscripts by echocardiogram. Am J Cardiol 2005;96:718–21. 2. Losenno KL, Goodman RL, Chu MWA. Bicuspid aortic valve disease and ascending aortic aneurysms: gaps in knowledge. Cardiol Res Pract 2012;2012:145202. 3. Evangelista A, Flachskampf FA, Erbel R, et al, European Association of Echocardiography; Document Reviewers. Echocardiography in aortic diseases: EAE recommendations for clinical practice. Eur J Echocardiogr 2010;11:645–58. 4. Fernandes SM, Sanders SP, Khairy P, et al. Morphology of bicuspid aortic valve in children and adolescents. J Am Coll Cardiol 2004;44:1648–51. 5. Sievers H-H, Schmidtke C. A classification system for the bicuspid aortic valve from 304 surgical specimens. J Thorac Cardiovasc Surg 2007;133:1226–33. 6. Della Corte A, Bancone C, Dialetto G, et al. Towards an individualized approach to bicuspid aortopathy: different valve types have unique determinants of aortic dilatation. Eur J Cardiothorac Surg 2014;45:e118–24. 7. Fernandes S, Khairy P, Graham DA, et al. Bicuspid aortic valve and associated aortic dilation in the young. Heart 2012;98:1014–9. 8. Schaefer BM, Lewin MB, Stout KK, et al. The bicuspid aortic valve: an integrated phenotypic classification of leaflet morphology and aortic root shape. Heart 2008;94:1634–8. 9. Fernandez B, Dur an AC, Fern andez-Gallego T, et al. Bicuspid aortic valves with different spatial orientations of the leaflets are distinct etiological entities. J Am Coll Cardiol 2009;54:2312–8.
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aortic valve anatomy in patients with valvular disease? J Thorac Cardiovasc Surg 2008;136:937–42. Holmes KW, Lehmann CU, Dalal D, et al. Progressive dilation of the ascending aorta in children with isolated bicuspid aortic valve. Am J Cardiol 2007;99:978–83. Levine JC, Sanders SP, Colan SD, Jonas RA, Spevak PJ. The risk of having additional obstructive lesions in neonatal coarctation of the aorta. Cardiol Young 2001;11: 44–53. Yasuda H, Nakatani S, Stugaard M, et al. Failure to prevent progressive dilation of ascending aorta by aortic valve replacement in patients with bicuspid aortic valve: comparison with tricuspid aortic valve. Circulation 2003;108(Suppl 1):II291–4. Borger MA, Preston M, Ivanov J, et al. Should the ascending aorta be replaced more frequently in patients with bicuspid aortic valve disease? J Thorac Cardiovasc Surg 2004;128: 677–83. Bonow RO. Bicuspid aortic valves and dilated aortas: a critical review of the ACC/AHA practice guidelines recommendations. Am J Cardiol 2008;102:111–4. Novaro GM, Tiong IY, Pearce GL, Grimm RA, Smedira N, Griffin BP. Features and predictors of ascending aortic dilatation in association with a congenital bicuspid aortic valve. Am J Cardiol 2003;92:99–101.
DISCUSSION DR DUKE CAMERON (Baltimore, MD): Thank you, Karl, and congratulations to you and your coauthors for this study, which provides some additional insight into this developing field of bicuspid aortic valve and its related aortopathy. Your study provides a slightly different perspective from others in that it focuses on children and adolescents, and you have shown us that they have a different pattern of distribution of bicuspid aortic valve configurations and aneurysm compared to adults. They have more right nonfused valves, and those valves are associated with more stenosis and more ascending aortic rather than root dilatation. Now, other recent adult studies have also described associations between bicuspid aortic valve type and aneurysm morphology, and some have even included elegant MRI [magnetic resonance imaging] aortic flow studies to show that the bicuspid aortic valve pattern creates a unique flow disturbance and wall stresses that might account for these aneurysm shapes. Again, your study is unique in that the vast majority of your patients were less than 18 years of age, and they presumably presented earlier in life to your clinic for a reason, and that’s what my question is getting at. I’m guessing that they presented earlier because their flow disturbances were more severe, there was more stenosis, and that this led to earlier recognition. And therefore, this group of patients really isn’t representative of the broader group of bicuspid aortic valve patients. It is a very selected series. Notably, the most common pattern of fusion in your group was the right-non, which was 54% in your series, but in bicuspid aortic valve it’s the left-right that occurs in 80%. So it’s really a unique distribution in childhood. And we have to consider that this is a series heavily weighted towards patients with early hemodynamic abnormalities. So my questions are, first, can you tell us why were these patients referred to your clinic in the first place? Was it usually because of a murmur? DR WELKE: Thank you very much for your assessment and comments. You are absolutely right. The patients with right-non
leaflet fusion are probably presenting earlier and undergoing treatment earlier. As a result, they are not included in as large of numbers in adult series. Right-non leaflet fusion may be the more severe subtype of bicuspid aortic valve. Most of the patients in our series presented with murmurs, although some presented early in life with symptoms of aortic stenosis. DR CAMERON: Great. Now, second, do you have any evidence to support whether the preop[erative] echo[cardiograph] determination of the valve morphology was actually confirmed at surgery? And I ask this because I continue to be surprised at how often the preop[erative] transthoracic echo[cardiograph] doesn’t get this right. Now, that may reflect my experience more with adults who have much more calcified valves where it’s more difficult to assess the original configuration. But did your intraoperative assessment of the valve morphology always conform or agree with the preop[erative] echo[cardiograph]? DR WELKE: In looking back through the operative notes, I can tell you that we were better in more recent years of recording what we saw in the operating room as surgeons. For some of the earlier patients, it was more difficult to find that information. When I looked at more recent years, I found we were accurate on the assessment. DR CAMERON: Very good. And finally, do you think your study supports the argument that aneurysm shape is the result of valve hemodynamics or is it intrinsic to the aortopathy or is it some combination of both? DR WELKE: It is an ongoing debate, isn’t it? Animal studies suggest there may be a genetic difference. In the last week I have talked to people from two different institutions. One said, yes, we have found a cohort of patients that may have a genetic predisposition and another said that in their data, there was no genetic predisposition. If we look at subgroups of these patients, like those with Shone’s complex, which tend to be patients with right-
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10. Verma S, Yanagawa B, Kalra S, et al. Knowledge, attitudes, and practice patterns in surgical management of bicuspid aortopathy: a survey of 100 cardiac surgeons. J Thorac Cardiovasc Surg 2013;146:1033–40.e4. 11. Girdauskas E, Rouman M, Borger MA, Kuntze T. Comparison of aortic media changes in patients with bicuspid aortic valve stenosis versus bicuspid valve insufficiency and proximal aortic aneurysm. Interact Cardiovasc Thorac Surg 2013;17:931–7. 12. Braverman AC. Bicuspid aortic valve and associated aortic wall abnormalities. Curr Opin Cardiol 1996;11:501–3. 13. Haycock GB, Schwartz GJ, Wisotsky DH. Geometric method for measuring body surface area: a height-weight formula validated in infants, children, and adults. J Pediatr 1978;93:62–6. 14. Garg V, Muth AN, Ransom JF, et al. Mutations in NOTCH1 cause aortic valve disease. Nature 2005;437:270–4. 15. Fedak PWM, Verma S, David TE, Leask RL, Weisel RD, Butany J. Clinical and pathophysiological implications of a bicuspid aortic valve. Circulation 2002;106:900–4. 16. Sabet HY, Edwards WD, Tazelaar HD, Daly RC. Congenitally bicuspid aortic valves: a surgical pathology study of 542 cases (1991 through 1996) and a literature review of 2715 additional cases. Mayo Clin Proc 1999;74:14–26. 17. Russo CF, Cannata A, Lanfranconi M, Vitali E, Garatti A, Bonacina E. Is aortic wall degeneration related to bicuspid
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left leaflet fusion, the pattern suggests there is a genetic predisposition. Also, when we look at patients that have had valve replacement surgery, the progression of the aortic dilatation post-operatively seems to be associated with the preoperative morphology to some degree. So I think there is a genetic component. As an engineer, I have to think there is a hemodynamic component as well. It is probably mixed. DR CAMERON: Well, thanks again on a great presentation.
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DR WELKE: Thank you for your questions. DR ROSS M. UNGERLEIDER (Winston-Salem, NC): Karl, excellent, very instructive. I have one comment. I think there is a good takeaway for people here that we should all be perhaps, if we haven’t been, more assiduous about reporting the morphology of bicuspid valves in our operative reports so that we can get these kinds of data going forward. It might be a good data field for the STS [Society of Thoracic Surgeons] Congenital Heart Surgery Database to include if we can get that kind of granularity in terms of outcomes.
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My question would be, does it influence the kinds of procedures that you do for these children? Of course, we are going to hear perhaps one option related to that in the next talk. But is it having an influence now in your clinical practice in terms of what you are doing or are you still treating all these patients the same based on their symptoms? DR WELKE: That is a good question. We have just started to look at this topic in the last year, so it has not impacted our clinical practice yet. Based on the fact that we have some data, which hopefully we will present next spring, which shows there may be a correlation between the valve subtype and what happens postoperatively, it may in time influence our operations, but it has not yet. So thank you. And I agree with you. Looking at bicuspid valve morphology as a field in The Society of Thoracic Surgeons Congenital Heart Surgery Database would be informative. It also may be something that would be well suited to the Congenital Heart Surgeons Society, where we are better at long-term follow-up, because that is really what we need with this group. As was mentioned, in adults, it is a different patient mix. So it is something to think about. But thank you for your thoughts.
