Background
In patients with bicuspid aortic valve (BAV), complications including progressive aortic stenosis and aortic dilatation develop over time. The morphology of cusp fusion is one of the determinants of the type and severity of these complications. We present the association of morphology of cusp fusion in BAV patients with distinctive genetic syndromes.
Methods
The Mayo Clinic echocardiography database was retrospectively reviewed to identify patients (age ≤ 22 years) diagnosed with BAV from 1990 to 2016. Cusp fusion morphology was determined from the echocardiographic studies, while coexisting cardiac defects and genetic syndromes were determined from chart review.
Results
A total of 1,037 patients with BAV were identified: 550 (53%) had an isolated BAV, 299 (29%) had BAV and a coexisting congenital heart defect, and 188 (18%) had BAV and a coexisting genetic syndrome or disorder. There were no differences in distribution of morphology across the three groups. However, right-noncoronary (RN) cusp fusion was the predominant morphology associated with Down syndrome ( P = .002) and right-left (RL) cusp fusion was the predominant morphology associated with Turner syndrome ( P = .02), DiGeorge syndrome ( P = .02), and Shone syndrome ( P = .0007), when compared with valve morphology in patients with isolated BAV. Isolated BAV patients with RN cusp fusion had larger ascending aorta diameter ( P = .001) and higher number of patients with ≥ moderate aortic regurgitation ( P = .02), while those with RL cusp fusion had larger sinus of Valsalva diameter ( P = .0006).
Conclusions
Morphological subtypes of BAV are associated with different genetic syndromes, suggesting distinct perturbations of developmental pathways in aortic valve malformation.
Highlights
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Morphology of BAV varies with the associated genetic syndromes.
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Right noncoronary cusp fusion morphology is associated with Down syndrome.
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Right left cusp fusion is associated with Turner, DiGeorge, and Shone syndromes.
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Morphology of BAV is determined by associated heart defects or underlying genes.
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Methods
The study was approved by the Institutional Review Board of the Mayo Clinic. We retrospectively identified pediatric and young adult patients (age ≤ 22 years) diagnosed with BAV by echocardiography at the Mayo Clinic from 1990 to 2016. BAV was defined as a complete fusion of two aortic valve cusps, with or without the presence of a distinct raphe, resulting in two functional cusps. Subjects with unicuspid or quadricuspid aortic valves or valves described as having “partial cusp fusion” were excluded from the study. Three types of BAV were defined based on the cusps participating in the fusion (raphe), as determined by the origin of right and left coronary artery: RL cusp fusion, RN cusp fusion, and left-noncoronary (LN) cusp fusion as shown in Figure 1 . Three-dimensional (3D) echocardiographic clip of RL and RN cusp fusion and two-dimensional (2D) echocardiographic clip of LN cusp fusion are shown in the videos ( Videos 1-3 , available at www.onlinejase.com ). The morphology of cusp fusion was determined by two blinded independent reviewers (T.N., D.J.H.), using the transthoracic or transesophageal echocardiograms performed prior to any intervention on the aortic valve in all patients. Video tapes were retrieved and reviewed for the echocardiographic images that were not electronically stored in our database. Patients with ambiguous morphology or incompletely defined anatomy were excluded from the study. Electronic medical records were extensively reviewed to identify coexisting genetic syndromes or disorders in these subjects. The main cohort was divided into three groups. Group 1 consisted of patients with isolated BAV, excluding patients with coexisting congenital heart defects or genetic syndromes or disorders and patients with dysmorphic facial features. Group 2 consisted of patients with BAV and coexisting congenital heart defects with no genetic syndrome or disorder. Group 3 consisted of patients with BAV and coexisting genetic syndromes or disorders, irrespective of the presence or absence of coexisting congenital heart defects.
All statistical calculations were performed with JMP version 10.0 software (SAS Institute, Cary, NC). Categorical variables were compared by using Fisher’s exact t -test or z -test as appropriate. P < .05 was considered statistically significant.
Methods
The study was approved by the Institutional Review Board of the Mayo Clinic. We retrospectively identified pediatric and young adult patients (age ≤ 22 years) diagnosed with BAV by echocardiography at the Mayo Clinic from 1990 to 2016. BAV was defined as a complete fusion of two aortic valve cusps, with or without the presence of a distinct raphe, resulting in two functional cusps. Subjects with unicuspid or quadricuspid aortic valves or valves described as having “partial cusp fusion” were excluded from the study. Three types of BAV were defined based on the cusps participating in the fusion (raphe), as determined by the origin of right and left coronary artery: RL cusp fusion, RN cusp fusion, and left-noncoronary (LN) cusp fusion as shown in Figure 1 . Three-dimensional (3D) echocardiographic clip of RL and RN cusp fusion and two-dimensional (2D) echocardiographic clip of LN cusp fusion are shown in the videos ( Videos 1-3 , available at www.onlinejase.com ). The morphology of cusp fusion was determined by two blinded independent reviewers (T.N., D.J.H.), using the transthoracic or transesophageal echocardiograms performed prior to any intervention on the aortic valve in all patients. Video tapes were retrieved and reviewed for the echocardiographic images that were not electronically stored in our database. Patients with ambiguous morphology or incompletely defined anatomy were excluded from the study. Electronic medical records were extensively reviewed to identify coexisting genetic syndromes or disorders in these subjects. The main cohort was divided into three groups. Group 1 consisted of patients with isolated BAV, excluding patients with coexisting congenital heart defects or genetic syndromes or disorders and patients with dysmorphic facial features. Group 2 consisted of patients with BAV and coexisting congenital heart defects with no genetic syndrome or disorder. Group 3 consisted of patients with BAV and coexisting genetic syndromes or disorders, irrespective of the presence or absence of coexisting congenital heart defects.
All statistical calculations were performed with JMP version 10.0 software (SAS Institute, Cary, NC). Categorical variables were compared by using Fisher’s exact t -test or z -test as appropriate. P < .05 was considered statistically significant.
Results
We identified a total of 1,095 patients with BAV from the Mayo Clinic echocardiography database, of whom 1,037 had BAV with clearly defined valve morphology. A total of 550 (53%) had isolated BAV (group 1), 299 (29%) had BAV and coexisting congenital heart defects (group 2), and 188 (18%) had BAV and a coexisting genetic syndrome or disorder (group 3). The complete study design is shown in Figure 2 .
There was no statistically significant difference in overall distribution of BAV morphology in the three groups. However, subanalysis of individual genetic syndromes or disorders revealed significant associations ( Table 1 ). In the subgroup of patients with Turner syndrome and BAV, RL cusp fusion was present in 87% patients compared with in 67% patients in group 1 with isolated BAV ( P = .02). Similarly, in subjects with Shone syndrome and BAV, RL was the predominant morphology in 94% patients ( P = .0007). In the subgroup of patients with DiGeorge syndrome and BAV, all the subjects, 100%, had RL cusp fusion morphology ( P = .02). However, in the subgroup of Down syndrome and BAV, RN cusp fusion was present in 69% patients as compared with in 33% patients in group 1 with isolated BAV ( P = .002). The morphology of cusp fusion in other individual genetic syndromes and disorders was not significantly different from isolated BAV ( Table 1 ).
| n | RL | RN | LN | P value | |
|---|---|---|---|---|---|
| Total BAV patients | 1,037 | 728 (70.2) | 293 (28.3) | 16 (1.5) | |
| Group1: Isolated BAV | 550 | 369 (67) | 181 (33) | 0 | |
| Group 2: BAV + CHD | 299 | 226 (75.6) | 63 (21.1) | 10 (3.3) | |
| Group 3: BAV + genetic syndromes or disorders | 188 | 133 (70.7) | 49 (26.1) | 6 (3.2) | |
| Chromosomal aneuploidy | |||||
| Turner syndrome (XO) | 31 | 27 (87) | 4 (13) | 0 (0) | .02 * |
| Down syndrome (trisomy 21) | 16 | 4 (25) | 11 (69) | 1 (6) | .002 * |
| Edward syndrome (trisomy 18) | 5 | 2 (40) | 2 (40) | 1 (20) | NS |
| Patau syndrome (trisomy 13) | 1 | 1 (100) | 0 (0) | 0 (0) | NS |
| Trisomy 7 | 1 | 0 (0) | 0 (0) | 1 (100) | NS |
| Genetic syndromes | |||||
| Shone syndrome | 33 | 31 (94) | 2 (6) | 0 (0) | .0007 * |
| DiGeorge syndrome | 11 | 11 (100) | 0 (0) | 0 (0) | .02 * |
| Noonan syndrome | 5 | 4 (80) | 1 (20) | 0 (0) | NS |
| Arrhythmia syndromes | |||||
| WPW syndrome | 4 | 3 (75) | 1 (25) | 0 (0) | NS |
| Long QT syndrome | 4 | 3 (75) | 1 (25) | 0 (0) | NS |
| Connective tissue disorders | |||||
| Marfan syndrome | 4 | 4 (100) | 0 (0) | 0 (0) | NS |
| Ehlers Danlos syndrome | 5 | 3 (60) | 2 (40) | 0 (0) | NS |
| Others † | 12 | 10 (83.3) | 1 (8.3) | 1 (8.3) | NS |
| Genetic associations | |||||
| CHARGE | 4 | 0 (0) | 3 (67) | 1 (33) | NS |
| VACTERL | 2 | 1 (50) | 1 (50) | 0 (0) | NS |
| Others | |||||
| Miscellaneous genetic disorders and mutations ‡ | 37 | 22 (59) | 14 (38) | 1 (3) | NS |
| Dysmorphic features with no identified genetic syndrome | 13 | 7 (54) | 6 (46) | 0 (0) | NS |
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