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Dilation of the Ascending Aorta After Balloon Valvuloplasty for Aortic Stenosis During Infancy and Childhood
Dilation of the Ascending Aorta After Balloon Valvuloplasty for Aortic Stenosis During Infancy and Childhood Doff B. McElhinney, MDa,b,*, Ronald V. Lacro, MDa,b, Kimberlee Gauvreau, DSca,b, Cheryl M. O’Brien, RDCSa,b, Selcen Yaroglu Kazanci, MDa,b, Melanie Vogel, MDa,b, Sitaram Emani, MDc,d, and David W. Brown, MDa,b Dilation of the ascending aorta (AA) is common in patients with a bicuspid aortic valve. The natural history of the aortic root and AA and the risk factors for dilation have not been characterized in patients with congenital aortic stenosis (AS) treated with balloon valvuloplasty during childhood. The present study was performed to determine the prevalence of aortic dilation in patients with congenital AS before and up to 20 years after balloon valvuloplasty performed during childhood. In patients who underwent balloon valvuloplasty for AS at age <18 years from 1984 to 2005, the aortic diameter measurements before intervention and at 5-year intervals afterward were recorded and the Z scores calculated. Among 156 patients (median age 1.5 years at valvuloplasty), the AA Z scores were significantly larger than normal before intervention (median Z score 1.5) and at all follow-up points (all p <0.001). Using mixed modeling, with time as a categorical variable (before intervention, 5-year window, 10-year window, and so forth), the mean AA Z score was greater at all postvalvuloplasty points than before the intervention, with mean Z score increases of 1.20 at 5 years and 2.11 at 20 years (p <0.001). Moderate or greater aortic regurgitation early after valvuloplasty was associated with greater AA Z scores than mild or less aortic regurgitation, with a progressive difference over time. More significant residual AS after valvuloplasty was associated with lower AA Z scores over time. In conclusion, AA dilation is common in children with congenital AS and continues to progress over many years after balloon valvuloplasty. © 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:702–708) Dilation of the aortic root and ascending aorta (AA) is a common and frequently progressive finding in adults and children with a bicuspid aortic valve (BAV).1–11 Aortic dilation in the setting of a BAV tends to be more severe and to progress more rapidly in older patients and in those with hypertension; however, data are conflicting about the risks of aortic dilation and progression according to leaflet morphology and the severity of aortic valve stenosis (AS) and aortic regurgitation (AR).3– 6,9,10 Although there have been inconsistent findings regarding the relations between aortic dilation and both AS and AR in patients with a BAV, no published data are available specifically concerning the natural history of the AA and aortic root in children and adolescents with important congenital AS and/or postintervention AR. The characterization of the aortic dimensions and growth in children with aortic valve disease could help inform a better understanding of how they should be evaluated and managed. Given that residual and recurrent AS and AR are relatively common after balloon valvuloplasty in children12 and that the valve morphology is abnormal, the relation between these factors and aortic growth in the long Departments of aCardiology and cCardiac Surgery, Children’s Hospital Boston, Boston, Massachusetts; Departments of bPediatrics and dSurgery, Harvard Medical School, Boston, Massachusetts. Manuscript received March 7, 2012; revised manuscript received and accepted April 26, 2012. *Corresponding author: Tel: (617) 355-9656; fax: (617) 713-3808. E-mail address: [email protected] (D.B. McElhinney). 0002-9149/12/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2012.04.053
term could facilitate an improved understanding of this complex patient population. Methods We studied all patients who underwent balloon aortic valvuloplasty at Children’s Hospital Boston at ⱕ18 years of age from December 1984 through February 2005 (to allow ⱖ4 years of follow-up), had undergone precatheterization echocardiography at our institution within 6 months of the procedure, and had ⱖ1 follow-up echocardiogram at our institution ⱖ4 years after balloon valvuloplasty. These patients were drawn from a larger cohort analyzed for a study of reintervention after balloon aortic valvuloplasty.12 The follow-up echocardiographic data were collected at 5-year intervals, with 1- to 2-year windows on either side (4 to 6, 8 to 12, 13 to 17, and 18 to 22 years). The patients were not required to have data in consecutive follow-up windows, such that follow-up data availability varied (e.g., some patients could have had data at all points, others 10-year data only, others 5- and 20-year data). For patients with multiple echocardiograms within 1 window, the study closest to the 5-year interval that included adequate selected. For patients who underwent aortic or aortic valve surgery during followup, the echocardiographic data were included up to, but not after, the surgery. The patients who underwent repeat balloon aortic valvuloplasty were included. The maximal systolic diameters of the aortic annulus, aortic root, and AA were measured off-line using a standard www.ajconline.org
Valvular Heart Disease/Aortic Dimensions in Congenital AS Table 1 Demographic, diagnostic, and procedural details Characteristic Age at balloon aortic valvuloplasty (years) Median Range (minimum to maximum) Neonates (age ⬍1 mo) Infants (age 1–12 mo) Aortic valve morphology Unicommissural Left–right and right–noncommissural fusion Left–right and left–noncommissural fusion Substantial fusion of all 3 commissures Bicommissural Left–right commissural fusion Right–noncommissural fusion Peak aortic stenosis gradient (mm Hg) Before valvuloplasty Acutely after valvuloplasty Aortic regurgitation severity acutely after valvuloplasty None or trivial Mild Moderate to severe Associated cardiovascular anomalies Previous cardiovascular interventions Surgical or balloon aortic valvuloplasty Aortic arch repair Ventricular septal defect closure Subaortic stenosis resection
Value 1.5 1 day to 16.4 years 49 (31%) 77 (49%) 54 (35%) 50 1 3 102 (65%) 60 42 66.6 ⫾ 2.0 29.3 ⫾ 14.4
78 (50%) 51 (33%) 27 (17%) 41 (26%) 32 (21%) 12 (8%) 20 (13%) 9 (6%) 7 (4%)
Data are presented as mean ⫾ SD, median (range), or n (% of total).
method, at peak flow during midsystole, from the parasternal long-axis, high left parasternal, or high right parasternal views. The AA was typically measured at the level of the right pulmonary artery, although in patients with atypical dilation, the maximum diameter of the AA was used regardless of location. The aortic annulus, aortic root, and AA Z scores were calculated on the basis of normative data obtained at our center. Valve morphology was characterized as unicommissural (unicuspid), bicommissural (bicuspid), or tricommissural (tricuspid) and by the commissures that were fused or underdeveloped. Valves with fusion or underdevelopment of 1 commissure and minor partial fusion of another were classified as bicommissural; those with complete fusion of 2 commissures or significant fusion of all 3 commissures were considered unicommissural. The degree of AR was measured on the first available echocardiogram within 1 year after balloon valvuloplasty according to standard methods, including vena contracta width in the orthogonal planes, the presence of left ventricular dilation, and the presence/degree of retrograde diastolic flow in the abdominal aortic Doppler pattern. AR severity was taken from the report of the interpreting noninvasive cardiologist and was collapsed into 2 categories thought to represent a clinically relevant delineation (less than moderate or moderate or greater) for the purposes of the analysis. Angiographic grading of AR was used for the analysis in 7 patients who did not have a postcatheterization echocardiogram within 1 year. The pre- and postdilation peak AS gradients, as measured in the catheterization laboratory, were used for analysis.
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The aortic Z scores were compared with normal (Z ⫽ 0) using 1-sample t test. A comparison of the baseline aortic dimensions using the demographic and diagnostic features was performed using an independent samples t test. The categorical variables were compared between groups using chi-square analysis. The changes in aortic dimensions over time were characterized using linear mixed effects models, which accounted for the correlation among repeated measurements of the same subject. Individual patients were treated as random effects, and additional clinical covariates were treated as fixed effects. If changes in the aortic dimensions over time were not linear, the quadratic and piecewise relations were explored. The rates of change in the aortic Z scores using this analytic approach reflect the average change across patients over time. When statistically significant relations between the aortic dimensions and clinical covariates were identified, interaction terms were used to determine whether the trends over time differed between the patient groups. The data are presented as the mean ⫾ SD, median (minimum to maximum), or frequencies. Results The study cohort included 156 patients, whose demographic, diagnostic, and procedural data are summarized in Table 1. The median duration from the precatheterization echocardiogram to balloon valvuloplasty was 1 day (range 0 days to 6 months). An average of 1.8 ⫾ 0.9 follow-up studies were evaluated per patient, with 112 patients studied in the 5-year window, 78 in the 10-year window, 47 in the 15-year window, and 16 in the 20-year window. Patients often had data in nonconsecutive follow-up windows; thus, a total of 95 patients had data at ⱖ10 years and 53 had data at ⱖ15 years. The AA Z scores were larger than normal before intervention and at all follow-up points (Table 2). Although not significantly different from normal before the intervention, the aortic annulus and root Z scores were larger than normal at all follow-up points, except the 20-year window (Table 2). Figure 1 depicts the aortic dimensions plotted against the body surface area, and Figure 2 shows the aortic Z scores in each of the evaluation windows. The AA was dilated (larger than normal, Z score ⬎2) before valvuloplasty in 49 patients (31%) and became dilated during follow-up in another 48 (total 62%). The aortic root was dilated before intervention in 10 patients (6%) and progressed to a dilated state during follow-up in 28 (total 24%). Before intervention, the patients with a unicommissural aortic valve had smaller aortic annulus Z scores than those with a bicommissural valve (⫺1.0 ⫾ 1.5 vs 0.1 ⫾ 1.3, p ⬍0.001), and a trend was seen toward smaller aortic root Z scores (⫺0.5 ⫾ 1.8 vs 0.0 ⫾ 1.2, p ⫽ 0.07). However, no difference was found in the AA Z scores (1.6 ⫾ 1.7 vs 1.4 ⫾ 1.6, p ⫽ 0.5). Patients who had undergone previous aortic coarctation repair had significantly smaller AA Z scores before valvuloplasty than those without arch obstruction (0.5 ⫾ 1.2 vs 1.6 ⫾ 1.6, p ⫽ 0.004). However, no differences were found in the annulus or root Z scores. Among patients with a bicommissural valve, no differences were found in the aortic Z scores according to the patterns of commissural fusion. None of the other demographic or diagnostic
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Table 2 Aortic annulus, root, and ascending aorta (AA) Z scores before intervention and at each follow-up interval Variable
Aortic annulus Z score Mean ⫾ SD Mean difference* Aortic root Z score Mean ⫾ SD Mean difference* Ascending aorta Z score Mean ⫾ SD Mean difference*
Before Balloon Valvuloplasty (n ⫽ 156)
Follow-up Interval (years) 5 (n ⫽ 112)
10 (n ⫽ 78)
15 (n ⫽ 47)
20 (n ⫽ 16)
⫺0.3 ⫾ 1.5
1.0 ⫾ 1.5 ⫹1.18
0.8 ⫾ 1.6 ⫹1.05
0.5 ⫾ 1.5 ⫹0.62
0.3 ⫾ 1.9 ⫹0.70
⫺0.2 ⫾ 1.5
0.8 ⫾ 1.4 ⫹0.93
0.8 ⫾ 1.6 ⫹0.89
0.9 ⫾ 1.3 ⫹0.98
0.7 ⫾ 1.5 ⫹1.01
1.5 ⫾ 1.6
2.6 ⫾ 2.2 ⫹1.20
2.6 ⫾ 2.7 ⫹1.21
3.1 ⫾ 2.5 ⫹1.73
2.6 ⫾ 2.1 ⫹2.11
Data are presented as mean ⫾ SD and median. All p ⬍0.001 versus normal, except aortic annulus and aortic root Z scores before balloon valvuloplasty (p ⫽ 0.06 and p ⫽ 0.09, respectively) and at 20 years (p ⫽ 0.6 and p ⫽ 0.11, respectively). * Compared with before balloon valvuloplasty.
variables assessed were associated with significant differences in the preintervention aortic annulus, aortic root, or AA Z scores. Using mixed modeling with time as a categorical variable (before intervention, 5-year window, and so forth), the mean AA Z score was greater at all postvalvuloplasty points than before intervention (all p ⬍0.001; Table 2). Quadratic and piecewise linear models fit the data better than a linear approach and showed a progressively increasing AA Z score over time. Using a piecewise model, the slope was steeper between the preintervention and 5-year window than later; however, the increase remained significant beyond 5 years (p ⫽ 0.017). The AA Z scores at all points tended to be greater in the patients with higher preintervention Z scores, but there was a significant interaction with time, such that the rate of increase was significantly greater for patients with lower preintervention Z scores. When the preintervention AA Z score was dichotomized, those with a Z score ⬍1 had significant increases over time, and there was a very modest and statistically insignificant increase among patients with a baseline Z score of ⱖ1 (Figure 3). Moderate or greater AR early after valvuloplasty was associated with greater AA Z scores than was mild or less AR, with a progressive difference over time (p ⫽ 0.04 for interaction with time; Figure 3). No difference was seen before valvuloplasty. In contrast, more significant residual AS early after valvuloplasty was associated with lower AA Z scores over time (for each 10-mm Hg increase in the gradient, the AA Z score was lower by ⫺0.20 on average; p ⫽ 0.05). The AA Z scores were also lower in patients with cardiovascular anomalies, in addition to AS (mean difference ⫺1.06, p ⫽ 0.001), and those who had undergone treatment of coarctation of the aorta (mean difference ⫺1.19, p ⫽ 0.004) or any cardiovascular intervention before valvuloplasty (mean difference ⫺1.34, p ⬍0.001), consistently across all points (i.e., no interaction with time). Valve morphology, age at intervention, preintervention AS gradient, and previous balloon aortic valvuloplasty were not significantly related to the AA Z score. Treating time as a categorical variable, the mean aortic root Z score was greater at all postvalvuloplasty points
than before intervention (all p ⬍0.001; Table 2). Piecewise linear modeling provided the best fit for the data, demonstrating a significant increase in the aortic root Z score from before intervention to the 5-year window (p ⬍0.001) but a flat slope from 5 to 20 years (p ⫽ 0.8). No statistically significant relation was found between the aortic root Z score and age at balloon dilation (p ⫽ 0.3), valve morphology (p ⫽ 0.9), or severity of postvalvuloplasty AR (p ⫽ 0.2). Treating time as a categorical variable, the mean aortic annulus diameter Z score was greater at all postvalvuloplasty evaluation windows than before intervention (p ⬍0.001 for 5 and 10 years, p ⫽ 0.005 for 15 years, and p ⫽ 0.04 for 20 years; Table 2). The best fit for the data were achieved with piecewise linear modeling, which demonstrated a significant increase in the aortic annulus Z score from before intervention to the 5-year window (p ⬍0.001) but a slightly negative slope from 5 to 20 years (p ⫽ 0.03). The mean aortic annulus Z scores were greater for patients with a bicommissural valve across all points (mean difference 0.57, p ⫽ 0.002), but no significant interaction was seen with time. The aortic annulus Z scores were also greater across time in patients with moderate or greater AR early after valvuloplasty (mean difference 0.95, p ⬍0.001), and patients who were older at the intervention (mean difference 0.07 for each additional year of age, p ⬍0.001). No significant interactions were found for either of these relations. Of the 156 patients in the present cohort, none were known to develop aortic dissection or rupture or to die from suspected complications related to AA dilation or disease. However, 7 underwent surgery for a dilated or aneurysmal AA a median of 11.8 years (range 9.9 to 22.4) after balloon aortic valvuloplasty. In 5 of these patients, the primary indication for surgery was aortic valve disease (mixed disease with predominant AR). The aortic valve was repaired at AA surgery in 3 of these patients and replaced in 2. The aortic valve had been repaired 6 years earlier in the patient who underwent aneurysmorrhaphy. The AA surgery consisted of supracoronary replacement with a 21- to 30-mm Dacron tube graft in 6 (median age 16.7 years, range 9.9 to 23.6) and a vertical plication aneurysmorrhaphy without
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Figure 2. Box plots demonstrating the Z scores of the aortic annulus, aortic root, and AA before aortic valvuloplasty and at 5-, 10-, 15-, and 20-year follow-up intervals. The colored boxes indicate the interquartile range for the patients with measurements at the indicated point, the line in the box indicates the median, error bars indicate the 10th and 90th percentiles, and circles indicate outliers.
able for the resected segment of the aorta in the 6 patients who had undergone replacement and revealed cystic medial degeneration in all cases. During a median follow-up of 4.1 years (range 0.7 to 6.9) after AA surgery, none of these patients had undergone reintervention on the aorta or valve. One patient had mild-to-moderate AR, and the others had mild or less. At a follow-up examination 6.9 years after surgery, the AA diameter was 4.1 cm (Z score 4.6) in the patient who had undergone aneurysmorrhaphy compared to 4.5 cm (Z score 11.5) before and 3.3 cm (Z score 5.4) 6 months after surgery. Discussion
Figure 1. Dimensions of the (A) aortic annulus, (B) aortic root, and (C) AA plotted against body surface area. The solid lines indicate the mean normal dimension (Z score 0) and 2 SDs above (Z score ⫹2) and below (Z score ⫺2) the normal mean. Open blue circles indicate preintervention values; measurements at the various follow-up points are represented by the symbols indicated.
cardiopulmonary bypass in 1 (age 12 years). The median preoperative AA diameter in these 7 patients was 4.5 cm (range 3.7 to 4.9 cm), and the median AA Z score was 7.3 (range 5.9 to 11.5). No operative deaths or major adverse events were recorded. Histopathologic findings were avail-
In pediatric patients with hemodynamically important valvar AS who underwent balloon aortic valvuloplasty, AA enlargement was common before intervention and became progressively more prominent and prevalent after valvuloplasty. For reasons that are not clear, increases in the AA Z score were greatest during the first 5 years but persisted at a more gradual rate across the entire 20-year follow-up period. Patients with smaller AA Z scores before intervention experienced greater increases over time, particularly during the first 5 years. Overall, 62% of the patients were documented to have an indexed AA diameter that was larger than normal during the study period. In contrast, the cumulative incidence of aortic root dilation was only 24%. Patients with moderate or severe AR early after valvuloplasty had larger AA Z scores during follow-up than those with mild or less AR, and the difference increased over time. In contrast, an inverse relation was found between residual AS early after valvuloplasty and AA Z scores, and no relation was found between valve morphology and AA dimension. These findings are limited because the analysis of postvalvuloplasty AS and AR, which can evolve over time, was limited to the early postintervention period; thus, the potential effect of later changes in aortic valve function on aortic dimensions could not be discerned.
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Figure 3. AA Z scores at baseline (Pre) and during follow-up after balloon aortic valvuloplasty (years after intervention) according to (A) preintervention AA Z score (Z score ⬍1 is indicated by solid circles and line; Z score ⱖ1 is indicated by open circles and dashed line), and (B) the severity of early postvalvuloplasty AR (less than moderate AR indicated by the open circles and solid line; moderate AR or greater is indicated by the closed circles and dashed line). No difference was seen in ascending aortic Z scores between the AR groups before intervention.
The contribution of hemodynamic aberrations to aortic dilation in patients with a congenitally abnormal aortic valve is unclear. Historically, aortic enlargement in patients with AS has often been considered a form of poststenotic dilation, which has been supported by the demonstration of post-stenotic vascular dilation in experimental settings and the occurrence of similar downstream arterial enlargement in patients with valvar pulmonary stenosis.13,14 However, degenerative changes are often found in the medial layer of the aorta in patients with a BAV, similar to those that occur in association with connective tissue disease, independent of the severity of aortic valve dysfunction, suggesting that aortic dilation might be related in part to an underlying aortopathy.15–17 This hypothesis, supported by the lack of a clear association between aortic dilation and aortic valve function or morphology in patients with BAV,3– 6,9,10 seems to suggest that flow disturbances are not primarily responsible for aortic dilation in this population, casting into doubt the concept of it being post-stenotic dilation. However,
more recently, studies using sophisticated imaging technologies and computational fluid dynamics have demonstrated abnormal flow patterns and wall stresses in the AA of patients with a BAV, even in the absence of AS.18 –21 Moreover, several studies found that aortic valve replacement without AA intervention prevented progressive aortic enlargement in patients with a BAV and degenerative disease of trileaflet valves, which might be interpreted as supporting evidence for the argument that AA dilation was exacerbated or caused by hemodynamic factors related to the aortic valve.22,23 Thus, the relative importance of hemodynamic factors in the etiology and prognosis of aortic dilation in this population is unclear. The risk of adverse outcomes related to AA dilation in children and adolescents with AS is unknown, and criteria for intervention have not been defined. Elucidation of these issues was beyond the scope of the present study. In adults with a BAV, the risk of aortic dissection ranges from 3 to 10/10,000 patient-years of follow-up.1,3 No studies of sufficient power to develop estimates in young patients have been performed6,7,9; however, given the lifelong presence of BAV as a congenital abnormality and the preponderance of older patients in studies of aortic dissection, the risk is almost certainly much lower during childhood and adolescence than later in life.11,24,25 Congenital AS is less common than a BAV, and it is unclear whether the natural history of aortic disease is similar in these populations. In our previous study of ⬎500 patients with congenital AS who were followed up for a median of 12 years after balloon valvuloplasty, 1 death occurred related to an aortic aneurysm in a patient with Turner syndrome, 22 years after balloon valvuloplasty had been performed during infancy.26 Turner syndrome is associated with aortic dilation and dissection, independent of other cardiovascular anomalies, which might have been pertinent.27 Also, the patient had an intimal flap in the AA after the initial valvuloplasty procedure that was still present at a follow-up catheterization 2 years later and might have been a contributing factor. No other known deaths related to, or surgery for, aortic dissection or rupture occurred in that series.26 Aortic rupture and dissection can occur in adult patients with a BAV or other congenital cardiovascular conditions at a relatively young age; however, they appear to be rare in children and young adults.6,11,14,24,28,29 Appropriate preventive management strategies in patients who have undergone therapy for congenital valvar AS and have a dilated AA or aortic root, whether exercise restriction or pharmacotherapy, are unknown, as are the appropriate timing and thresholds for surgical intervention. The same holds true for aortic dilation in the context of other congenital cardiovascular anomalies.30 Seven patients in the present cohort underwent surgery for AA aneurysm/ dilation, 5 of whom underwent concurrent aortic valve procedures, all with an AA diameter ⬍5 cm, a common consensus threshold for AA surgery. At a median of 4.1 years after surgery, all were alive and free of reintervention or aortic complications, with no deterioration in valve function. In our larger cohort of patients treated for valvar AS,12 8 additional patients underwent AA replacement concurrent with aortic valve replacement during follow-up, a median of 8.0 years after balloon valvuloplasty, with no deaths or
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major adverse events (unpublished data). No conclusions can be drawn from this small experience. The importance of monitoring aortic growth over time in this population is unknown, insofar as the clinical significance of aortic dilation has not been determined. To the extent that aortic dilation might be relevant, however, the present study has demonstrated that indexed AA growth is greatest during the first 5 years after aortic valvuloplasty and more modest, albeit ongoing, thereafter. The AA Z score increased an average of 1.2 during the first 5 years (0.24/year) and 2.1 from baseline to 20 years (0.105/year). From this gradual rate of growth, it seems unlikely that frequent monitoring is routinely necessary. A deeper understanding of how, and how often, to evaluate the aortic dimensions in this population requires additional investigation. One finding from the present study that might have implications for evaluation of patients with AS after balloon valvuloplasty is that significant postintervention AR was associated with progressively greater AA dilation over time. Thus, patients with moderate or greater AR might merit closer evaluation, both for AA dilation and because they have a greater risk of aortic valve replacement.12 The present study had several potentially important limitations. Because only patients with AS who underwent balloon valvuloplasty and had follow-up echocardiograms available at our center were included, a potential selection bias was present, and our findings might not be generalizable. Only patients with echocardiographic follow-up of ⱖ4 years were studied; thus, those who died before the first follow-up window were not represented, which might have introduced a survival bias. In a previous review of pediatric patients who underwent balloon valvuloplasty for AS at our center,26 no deaths occurred from AA or root-related causes within that period; however, we cannot be certain that aortic dimensions and growth were not subject to bias in this regard. Also, postvalvuloplasty AR and residual AS data were only included from the early postintervention period. These variables could change over time, and our study did not account for the potential time variance of these factors, significantly limiting our insight into the potential role of hemodynamics in aortic growth in this population. Given the modest rates of change beyond the initial 5-year evaluation interval, it is unlikely that accounting for the time variance of AR and AS would have substantially altered our findings. Similarly, the severity of AR was determined by a clinical reading of the echocardiogram early after intervention and was not determined by a separate core reader. Thus, our analyses might be confounded by an inconsistency in AR grading. Collapsing AR severity into 2 categories should have mitigated this confounder. Also, we did not assess the relations between the aortic dimensions and pharmacologic therapy, which is frequently prescribed in patients with aortic dilation in the current era, because an analysis of this factor would have been confounded by a variety of other factors.
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22. Andrus BW, O’Rourke DJ, Dacey LJ, Palac RT. Stability of ascending aortic dilatation following aortic valve replacement. Circulation 2003; 108:II295–II299. 23. Gaudino M, Anselmi A, Morelli M, Pragliola C, Tsiopoulos V, Glieca F, Possati G. Aortic expansion rate in patients with dilated poststenotic ascending aorta submitted only to aortic valve replacement long-term follow-up. J Am Coll Cardiol 2011;58:581–584. 24. Edwards WD, Leaf DS, Edwards JE. Dissecting aortic aneurysm associated with congenital bicuspid aortic valve. Circulation 1978;57: 1022–1025. 25. Homme JL, Aubry MC, Edwards WD, Bagniewski SM, Shane Pankratz V, Kral CA, Tazelaar HD. Surgical pathology of the ascending aorta: a clinicopathologic study of 513 cases. Am J Surg Pathol 2006;30:1159 –1168.
26. Brown DW, Dipilato AE, Chong EC, Gauvreau K, McElhinney DB, Colan SD, Lock JE. Sudden unexpected death after balloon valvuloplasty for congenital aortic stenosis. J Am Coll Cardiol 2010;56:1939 – 1946. 27. Bondy CA. Aortic dissection in Turner syndrome. Curr Opin Cardiol 2008;23:519 –526. 28. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980 –2006. Circulation 2009;119:1085–1092. 29. Hatzaras I, Tranquilli M, Coady M, Barrett PM, Bible J, Elefteriades JA. Weight lifting and aortic dissection: more evidence for a connection. Cardiology 2007;107:103–106. 30. Yetman AT, Graham T. The dilated aorta in patients with congenital cardiac defects. J Am Coll Cardiol 2009;53:461– 467.
term could facilitate an improved understanding of this complex patient population. Methods We studied all patients who underwent balloon aortic valvuloplasty at Children’s Hospital Boston at ⱕ18 years of age from December 1984 through February 2005 (to allow ⱖ4 years of follow-up), had undergone precatheterization echocardiography at our institution within 6 months of the procedure, and had ⱖ1 follow-up echocardiogram at our institution ⱖ4 years after balloon valvuloplasty. These patients were drawn from a larger cohort analyzed for a study of reintervention after balloon aortic valvuloplasty.12 The follow-up echocardiographic data were collected at 5-year intervals, with 1- to 2-year windows on either side (4 to 6, 8 to 12, 13 to 17, and 18 to 22 years). The patients were not required to have data in consecutive follow-up windows, such that follow-up data availability varied (e.g., some patients could have had data at all points, others 10-year data only, others 5- and 20-year data). For patients with multiple echocardiograms within 1 window, the study closest to the 5-year interval that included adequate selected. For patients who underwent aortic or aortic valve surgery during followup, the echocardiographic data were included up to, but not after, the surgery. The patients who underwent repeat balloon aortic valvuloplasty were included. The maximal systolic diameters of the aortic annulus, aortic root, and AA were measured off-line using a standard www.ajconline.org
Valvular Heart Disease/Aortic Dimensions in Congenital AS Table 1 Demographic, diagnostic, and procedural details Characteristic Age at balloon aortic valvuloplasty (years) Median Range (minimum to maximum) Neonates (age ⬍1 mo) Infants (age 1–12 mo) Aortic valve morphology Unicommissural Left–right and right–noncommissural fusion Left–right and left–noncommissural fusion Substantial fusion of all 3 commissures Bicommissural Left–right commissural fusion Right–noncommissural fusion Peak aortic stenosis gradient (mm Hg) Before valvuloplasty Acutely after valvuloplasty Aortic regurgitation severity acutely after valvuloplasty None or trivial Mild Moderate to severe Associated cardiovascular anomalies Previous cardiovascular interventions Surgical or balloon aortic valvuloplasty Aortic arch repair Ventricular septal defect closure Subaortic stenosis resection
Value 1.5 1 day to 16.4 years 49 (31%) 77 (49%) 54 (35%) 50 1 3 102 (65%) 60 42 66.6 ⫾ 2.0 29.3 ⫾ 14.4
78 (50%) 51 (33%) 27 (17%) 41 (26%) 32 (21%) 12 (8%) 20 (13%) 9 (6%) 7 (4%)
Data are presented as mean ⫾ SD, median (range), or n (% of total).
method, at peak flow during midsystole, from the parasternal long-axis, high left parasternal, or high right parasternal views. The AA was typically measured at the level of the right pulmonary artery, although in patients with atypical dilation, the maximum diameter of the AA was used regardless of location. The aortic annulus, aortic root, and AA Z scores were calculated on the basis of normative data obtained at our center. Valve morphology was characterized as unicommissural (unicuspid), bicommissural (bicuspid), or tricommissural (tricuspid) and by the commissures that were fused or underdeveloped. Valves with fusion or underdevelopment of 1 commissure and minor partial fusion of another were classified as bicommissural; those with complete fusion of 2 commissures or significant fusion of all 3 commissures were considered unicommissural. The degree of AR was measured on the first available echocardiogram within 1 year after balloon valvuloplasty according to standard methods, including vena contracta width in the orthogonal planes, the presence of left ventricular dilation, and the presence/degree of retrograde diastolic flow in the abdominal aortic Doppler pattern. AR severity was taken from the report of the interpreting noninvasive cardiologist and was collapsed into 2 categories thought to represent a clinically relevant delineation (less than moderate or moderate or greater) for the purposes of the analysis. Angiographic grading of AR was used for the analysis in 7 patients who did not have a postcatheterization echocardiogram within 1 year. The pre- and postdilation peak AS gradients, as measured in the catheterization laboratory, were used for analysis.
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The aortic Z scores were compared with normal (Z ⫽ 0) using 1-sample t test. A comparison of the baseline aortic dimensions using the demographic and diagnostic features was performed using an independent samples t test. The categorical variables were compared between groups using chi-square analysis. The changes in aortic dimensions over time were characterized using linear mixed effects models, which accounted for the correlation among repeated measurements of the same subject. Individual patients were treated as random effects, and additional clinical covariates were treated as fixed effects. If changes in the aortic dimensions over time were not linear, the quadratic and piecewise relations were explored. The rates of change in the aortic Z scores using this analytic approach reflect the average change across patients over time. When statistically significant relations between the aortic dimensions and clinical covariates were identified, interaction terms were used to determine whether the trends over time differed between the patient groups. The data are presented as the mean ⫾ SD, median (minimum to maximum), or frequencies. Results The study cohort included 156 patients, whose demographic, diagnostic, and procedural data are summarized in Table 1. The median duration from the precatheterization echocardiogram to balloon valvuloplasty was 1 day (range 0 days to 6 months). An average of 1.8 ⫾ 0.9 follow-up studies were evaluated per patient, with 112 patients studied in the 5-year window, 78 in the 10-year window, 47 in the 15-year window, and 16 in the 20-year window. Patients often had data in nonconsecutive follow-up windows; thus, a total of 95 patients had data at ⱖ10 years and 53 had data at ⱖ15 years. The AA Z scores were larger than normal before intervention and at all follow-up points (Table 2). Although not significantly different from normal before the intervention, the aortic annulus and root Z scores were larger than normal at all follow-up points, except the 20-year window (Table 2). Figure 1 depicts the aortic dimensions plotted against the body surface area, and Figure 2 shows the aortic Z scores in each of the evaluation windows. The AA was dilated (larger than normal, Z score ⬎2) before valvuloplasty in 49 patients (31%) and became dilated during follow-up in another 48 (total 62%). The aortic root was dilated before intervention in 10 patients (6%) and progressed to a dilated state during follow-up in 28 (total 24%). Before intervention, the patients with a unicommissural aortic valve had smaller aortic annulus Z scores than those with a bicommissural valve (⫺1.0 ⫾ 1.5 vs 0.1 ⫾ 1.3, p ⬍0.001), and a trend was seen toward smaller aortic root Z scores (⫺0.5 ⫾ 1.8 vs 0.0 ⫾ 1.2, p ⫽ 0.07). However, no difference was found in the AA Z scores (1.6 ⫾ 1.7 vs 1.4 ⫾ 1.6, p ⫽ 0.5). Patients who had undergone previous aortic coarctation repair had significantly smaller AA Z scores before valvuloplasty than those without arch obstruction (0.5 ⫾ 1.2 vs 1.6 ⫾ 1.6, p ⫽ 0.004). However, no differences were found in the annulus or root Z scores. Among patients with a bicommissural valve, no differences were found in the aortic Z scores according to the patterns of commissural fusion. None of the other demographic or diagnostic
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Table 2 Aortic annulus, root, and ascending aorta (AA) Z scores before intervention and at each follow-up interval Variable
Aortic annulus Z score Mean ⫾ SD Mean difference* Aortic root Z score Mean ⫾ SD Mean difference* Ascending aorta Z score Mean ⫾ SD Mean difference*
Before Balloon Valvuloplasty (n ⫽ 156)
Follow-up Interval (years) 5 (n ⫽ 112)
10 (n ⫽ 78)
15 (n ⫽ 47)
20 (n ⫽ 16)
⫺0.3 ⫾ 1.5
1.0 ⫾ 1.5 ⫹1.18
0.8 ⫾ 1.6 ⫹1.05
0.5 ⫾ 1.5 ⫹0.62
0.3 ⫾ 1.9 ⫹0.70
⫺0.2 ⫾ 1.5
0.8 ⫾ 1.4 ⫹0.93
0.8 ⫾ 1.6 ⫹0.89
0.9 ⫾ 1.3 ⫹0.98
0.7 ⫾ 1.5 ⫹1.01
1.5 ⫾ 1.6
2.6 ⫾ 2.2 ⫹1.20
2.6 ⫾ 2.7 ⫹1.21
3.1 ⫾ 2.5 ⫹1.73
2.6 ⫾ 2.1 ⫹2.11
Data are presented as mean ⫾ SD and median. All p ⬍0.001 versus normal, except aortic annulus and aortic root Z scores before balloon valvuloplasty (p ⫽ 0.06 and p ⫽ 0.09, respectively) and at 20 years (p ⫽ 0.6 and p ⫽ 0.11, respectively). * Compared with before balloon valvuloplasty.
variables assessed were associated with significant differences in the preintervention aortic annulus, aortic root, or AA Z scores. Using mixed modeling with time as a categorical variable (before intervention, 5-year window, and so forth), the mean AA Z score was greater at all postvalvuloplasty points than before intervention (all p ⬍0.001; Table 2). Quadratic and piecewise linear models fit the data better than a linear approach and showed a progressively increasing AA Z score over time. Using a piecewise model, the slope was steeper between the preintervention and 5-year window than later; however, the increase remained significant beyond 5 years (p ⫽ 0.017). The AA Z scores at all points tended to be greater in the patients with higher preintervention Z scores, but there was a significant interaction with time, such that the rate of increase was significantly greater for patients with lower preintervention Z scores. When the preintervention AA Z score was dichotomized, those with a Z score ⬍1 had significant increases over time, and there was a very modest and statistically insignificant increase among patients with a baseline Z score of ⱖ1 (Figure 3). Moderate or greater AR early after valvuloplasty was associated with greater AA Z scores than was mild or less AR, with a progressive difference over time (p ⫽ 0.04 for interaction with time; Figure 3). No difference was seen before valvuloplasty. In contrast, more significant residual AS early after valvuloplasty was associated with lower AA Z scores over time (for each 10-mm Hg increase in the gradient, the AA Z score was lower by ⫺0.20 on average; p ⫽ 0.05). The AA Z scores were also lower in patients with cardiovascular anomalies, in addition to AS (mean difference ⫺1.06, p ⫽ 0.001), and those who had undergone treatment of coarctation of the aorta (mean difference ⫺1.19, p ⫽ 0.004) or any cardiovascular intervention before valvuloplasty (mean difference ⫺1.34, p ⬍0.001), consistently across all points (i.e., no interaction with time). Valve morphology, age at intervention, preintervention AS gradient, and previous balloon aortic valvuloplasty were not significantly related to the AA Z score. Treating time as a categorical variable, the mean aortic root Z score was greater at all postvalvuloplasty points
than before intervention (all p ⬍0.001; Table 2). Piecewise linear modeling provided the best fit for the data, demonstrating a significant increase in the aortic root Z score from before intervention to the 5-year window (p ⬍0.001) but a flat slope from 5 to 20 years (p ⫽ 0.8). No statistically significant relation was found between the aortic root Z score and age at balloon dilation (p ⫽ 0.3), valve morphology (p ⫽ 0.9), or severity of postvalvuloplasty AR (p ⫽ 0.2). Treating time as a categorical variable, the mean aortic annulus diameter Z score was greater at all postvalvuloplasty evaluation windows than before intervention (p ⬍0.001 for 5 and 10 years, p ⫽ 0.005 for 15 years, and p ⫽ 0.04 for 20 years; Table 2). The best fit for the data were achieved with piecewise linear modeling, which demonstrated a significant increase in the aortic annulus Z score from before intervention to the 5-year window (p ⬍0.001) but a slightly negative slope from 5 to 20 years (p ⫽ 0.03). The mean aortic annulus Z scores were greater for patients with a bicommissural valve across all points (mean difference 0.57, p ⫽ 0.002), but no significant interaction was seen with time. The aortic annulus Z scores were also greater across time in patients with moderate or greater AR early after valvuloplasty (mean difference 0.95, p ⬍0.001), and patients who were older at the intervention (mean difference 0.07 for each additional year of age, p ⬍0.001). No significant interactions were found for either of these relations. Of the 156 patients in the present cohort, none were known to develop aortic dissection or rupture or to die from suspected complications related to AA dilation or disease. However, 7 underwent surgery for a dilated or aneurysmal AA a median of 11.8 years (range 9.9 to 22.4) after balloon aortic valvuloplasty. In 5 of these patients, the primary indication for surgery was aortic valve disease (mixed disease with predominant AR). The aortic valve was repaired at AA surgery in 3 of these patients and replaced in 2. The aortic valve had been repaired 6 years earlier in the patient who underwent aneurysmorrhaphy. The AA surgery consisted of supracoronary replacement with a 21- to 30-mm Dacron tube graft in 6 (median age 16.7 years, range 9.9 to 23.6) and a vertical plication aneurysmorrhaphy without
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Figure 2. Box plots demonstrating the Z scores of the aortic annulus, aortic root, and AA before aortic valvuloplasty and at 5-, 10-, 15-, and 20-year follow-up intervals. The colored boxes indicate the interquartile range for the patients with measurements at the indicated point, the line in the box indicates the median, error bars indicate the 10th and 90th percentiles, and circles indicate outliers.
able for the resected segment of the aorta in the 6 patients who had undergone replacement and revealed cystic medial degeneration in all cases. During a median follow-up of 4.1 years (range 0.7 to 6.9) after AA surgery, none of these patients had undergone reintervention on the aorta or valve. One patient had mild-to-moderate AR, and the others had mild or less. At a follow-up examination 6.9 years after surgery, the AA diameter was 4.1 cm (Z score 4.6) in the patient who had undergone aneurysmorrhaphy compared to 4.5 cm (Z score 11.5) before and 3.3 cm (Z score 5.4) 6 months after surgery. Discussion
Figure 1. Dimensions of the (A) aortic annulus, (B) aortic root, and (C) AA plotted against body surface area. The solid lines indicate the mean normal dimension (Z score 0) and 2 SDs above (Z score ⫹2) and below (Z score ⫺2) the normal mean. Open blue circles indicate preintervention values; measurements at the various follow-up points are represented by the symbols indicated.
cardiopulmonary bypass in 1 (age 12 years). The median preoperative AA diameter in these 7 patients was 4.5 cm (range 3.7 to 4.9 cm), and the median AA Z score was 7.3 (range 5.9 to 11.5). No operative deaths or major adverse events were recorded. Histopathologic findings were avail-
In pediatric patients with hemodynamically important valvar AS who underwent balloon aortic valvuloplasty, AA enlargement was common before intervention and became progressively more prominent and prevalent after valvuloplasty. For reasons that are not clear, increases in the AA Z score were greatest during the first 5 years but persisted at a more gradual rate across the entire 20-year follow-up period. Patients with smaller AA Z scores before intervention experienced greater increases over time, particularly during the first 5 years. Overall, 62% of the patients were documented to have an indexed AA diameter that was larger than normal during the study period. In contrast, the cumulative incidence of aortic root dilation was only 24%. Patients with moderate or severe AR early after valvuloplasty had larger AA Z scores during follow-up than those with mild or less AR, and the difference increased over time. In contrast, an inverse relation was found between residual AS early after valvuloplasty and AA Z scores, and no relation was found between valve morphology and AA dimension. These findings are limited because the analysis of postvalvuloplasty AS and AR, which can evolve over time, was limited to the early postintervention period; thus, the potential effect of later changes in aortic valve function on aortic dimensions could not be discerned.
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Figure 3. AA Z scores at baseline (Pre) and during follow-up after balloon aortic valvuloplasty (years after intervention) according to (A) preintervention AA Z score (Z score ⬍1 is indicated by solid circles and line; Z score ⱖ1 is indicated by open circles and dashed line), and (B) the severity of early postvalvuloplasty AR (less than moderate AR indicated by the open circles and solid line; moderate AR or greater is indicated by the closed circles and dashed line). No difference was seen in ascending aortic Z scores between the AR groups before intervention.
The contribution of hemodynamic aberrations to aortic dilation in patients with a congenitally abnormal aortic valve is unclear. Historically, aortic enlargement in patients with AS has often been considered a form of poststenotic dilation, which has been supported by the demonstration of post-stenotic vascular dilation in experimental settings and the occurrence of similar downstream arterial enlargement in patients with valvar pulmonary stenosis.13,14 However, degenerative changes are often found in the medial layer of the aorta in patients with a BAV, similar to those that occur in association with connective tissue disease, independent of the severity of aortic valve dysfunction, suggesting that aortic dilation might be related in part to an underlying aortopathy.15–17 This hypothesis, supported by the lack of a clear association between aortic dilation and aortic valve function or morphology in patients with BAV,3– 6,9,10 seems to suggest that flow disturbances are not primarily responsible for aortic dilation in this population, casting into doubt the concept of it being post-stenotic dilation. However,
more recently, studies using sophisticated imaging technologies and computational fluid dynamics have demonstrated abnormal flow patterns and wall stresses in the AA of patients with a BAV, even in the absence of AS.18 –21 Moreover, several studies found that aortic valve replacement without AA intervention prevented progressive aortic enlargement in patients with a BAV and degenerative disease of trileaflet valves, which might be interpreted as supporting evidence for the argument that AA dilation was exacerbated or caused by hemodynamic factors related to the aortic valve.22,23 Thus, the relative importance of hemodynamic factors in the etiology and prognosis of aortic dilation in this population is unclear. The risk of adverse outcomes related to AA dilation in children and adolescents with AS is unknown, and criteria for intervention have not been defined. Elucidation of these issues was beyond the scope of the present study. In adults with a BAV, the risk of aortic dissection ranges from 3 to 10/10,000 patient-years of follow-up.1,3 No studies of sufficient power to develop estimates in young patients have been performed6,7,9; however, given the lifelong presence of BAV as a congenital abnormality and the preponderance of older patients in studies of aortic dissection, the risk is almost certainly much lower during childhood and adolescence than later in life.11,24,25 Congenital AS is less common than a BAV, and it is unclear whether the natural history of aortic disease is similar in these populations. In our previous study of ⬎500 patients with congenital AS who were followed up for a median of 12 years after balloon valvuloplasty, 1 death occurred related to an aortic aneurysm in a patient with Turner syndrome, 22 years after balloon valvuloplasty had been performed during infancy.26 Turner syndrome is associated with aortic dilation and dissection, independent of other cardiovascular anomalies, which might have been pertinent.27 Also, the patient had an intimal flap in the AA after the initial valvuloplasty procedure that was still present at a follow-up catheterization 2 years later and might have been a contributing factor. No other known deaths related to, or surgery for, aortic dissection or rupture occurred in that series.26 Aortic rupture and dissection can occur in adult patients with a BAV or other congenital cardiovascular conditions at a relatively young age; however, they appear to be rare in children and young adults.6,11,14,24,28,29 Appropriate preventive management strategies in patients who have undergone therapy for congenital valvar AS and have a dilated AA or aortic root, whether exercise restriction or pharmacotherapy, are unknown, as are the appropriate timing and thresholds for surgical intervention. The same holds true for aortic dilation in the context of other congenital cardiovascular anomalies.30 Seven patients in the present cohort underwent surgery for AA aneurysm/ dilation, 5 of whom underwent concurrent aortic valve procedures, all with an AA diameter ⬍5 cm, a common consensus threshold for AA surgery. At a median of 4.1 years after surgery, all were alive and free of reintervention or aortic complications, with no deterioration in valve function. In our larger cohort of patients treated for valvar AS,12 8 additional patients underwent AA replacement concurrent with aortic valve replacement during follow-up, a median of 8.0 years after balloon valvuloplasty, with no deaths or
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major adverse events (unpublished data). No conclusions can be drawn from this small experience. The importance of monitoring aortic growth over time in this population is unknown, insofar as the clinical significance of aortic dilation has not been determined. To the extent that aortic dilation might be relevant, however, the present study has demonstrated that indexed AA growth is greatest during the first 5 years after aortic valvuloplasty and more modest, albeit ongoing, thereafter. The AA Z score increased an average of 1.2 during the first 5 years (0.24/year) and 2.1 from baseline to 20 years (0.105/year). From this gradual rate of growth, it seems unlikely that frequent monitoring is routinely necessary. A deeper understanding of how, and how often, to evaluate the aortic dimensions in this population requires additional investigation. One finding from the present study that might have implications for evaluation of patients with AS after balloon valvuloplasty is that significant postintervention AR was associated with progressively greater AA dilation over time. Thus, patients with moderate or greater AR might merit closer evaluation, both for AA dilation and because they have a greater risk of aortic valve replacement.12 The present study had several potentially important limitations. Because only patients with AS who underwent balloon valvuloplasty and had follow-up echocardiograms available at our center were included, a potential selection bias was present, and our findings might not be generalizable. Only patients with echocardiographic follow-up of ⱖ4 years were studied; thus, those who died before the first follow-up window were not represented, which might have introduced a survival bias. In a previous review of pediatric patients who underwent balloon valvuloplasty for AS at our center,26 no deaths occurred from AA or root-related causes within that period; however, we cannot be certain that aortic dimensions and growth were not subject to bias in this regard. Also, postvalvuloplasty AR and residual AS data were only included from the early postintervention period. These variables could change over time, and our study did not account for the potential time variance of these factors, significantly limiting our insight into the potential role of hemodynamics in aortic growth in this population. Given the modest rates of change beyond the initial 5-year evaluation interval, it is unlikely that accounting for the time variance of AR and AS would have substantially altered our findings. Similarly, the severity of AR was determined by a clinical reading of the echocardiogram early after intervention and was not determined by a separate core reader. Thus, our analyses might be confounded by an inconsistency in AR grading. Collapsing AR severity into 2 categories should have mitigated this confounder. Also, we did not assess the relations between the aortic dimensions and pharmacologic therapy, which is frequently prescribed in patients with aortic dilation in the current era, because an analysis of this factor would have been confounded by a variety of other factors.
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Incidence of aortic complications in patients with bicuspid aortic valves. Jama 2011;306:1104 –1112. Nkomo VT, Enriquez-Sarano M, Ammash NM, Melton LJ III, Bailey KR, Desjardins V, Horn RA, Tajik AJ. Bicuspid aortic valve associated with aortic dilatation: a community-based study. Arterioscler Thromb Vasc Biol 2003;23:351–356. Tzemos N, Therrien J, Yip J, Thanassoulis G, Tremblay S, Jamorski MT, Webb GD, Siu SC. Outcomes in adults with bicuspid aortic valves. Jama 2008;300:1317–1325. Thanassoulis G, Yip JW, Filion K, Jamorski M, Webb G, Siu SC, Therrien J. Retrospective study to identify predictors of the presence and rapid progression of aortic dilatation in patients with bicuspid aortic valves. Nat Clin Pract Cardiovasc Med 2008;5:821– 828. Della Corte A, Bancone C, Quarto C, Dialetto G, Covino FE, Scardone M, Caianiello G, Cotrufo M. Predictors of ascending aortic dilatation with bicuspid aortic valve: a wide spectrum of disease expression. Eur J Cardiothorac Surg 2007;31:397– 404. Mahle WT, Sutherland JL, Frias PA. Outcome of isolated bicuspid aortic valve in childhood. J Pediatr 2010;157:445– 449. Beroukhim RS, Roosevelt G, Yetman AT. Comparison of the pattern of aortic dilation in children with the Marfan’s syndrome versus children with a bicuspid aortic valve. Am J Cardiol 2006;98:1094 – 1095. Gurvitz M, Chang RK, Drant S, Allada V. Frequency of aortic root dilation in children with a bicuspid aortic valve. Am J Cardiol 2004; 94:1337–1340. Holmes KW, Lehmann CU, Dalal D, Nasir K, Dietz HC, Ravekes WJ, Thompson WR, Spevak PJ. Progressive dilation of the ascending aorta in children with isolated bicuspid aortic valve. Am J Cardiol 2007;99: 978 –983. Beaton AZ, Nguyen T, Lai WW, Chatterjee S, Ramaswamy P, Lytrivi ID, Parness IA, Srivastava S. Relation of coarctation of the aorta to the occurrence of ascending aortic dilation in children and young adults with bicuspid aortic valves. Am J Cardiol 2009;103:266 –270. Fikar CR, Koch S. Etiologic factors of acute aortic dissection in children and young adults. Clin Pediatr 2000;39:71– 80. Brown DW, Dipilato AE, Chong EC, Lock JE, McElhinney DB. Aortic valve reinterventions after balloon aortic valvuloplasty for congenital aortic stenosis: intermediate and late follow-up. J Am Coll Cardiol 2010;56:1740 –1749. Bruns DL, Connolly JE, Holman E, Stofer RC. Experimental observations on post-stenotic dilatation. J Thorac Cardiovasc Surg 1959; 38:662– 669. Guntheroth WG. A critical review of the American College of Cardiology/American Heart Association practice guidelines on bicuspid aortic valve with dilated ascending aorta. Am J Cardiol 2008;102:107– 110. Fedak PW, de Sa MP, Verma S, Nili N, Kazemian P, Butany J, Strauss BH, Weisel RD, David TE. Vascular matrix remodeling in patients with bicuspid aortic valve malformations: implications for aortic dilatation. J Thorac Cardiovasc Surg 2003;126:797– 806. Russo CF, Cannata A, Lanfranconi M, Vitali E, Garatti A, Bonacina E. Is aortic wall degeneration related to bicuspid aortic valve anatomy in patients with valvular disease? J Thorac Cardiovasc Surg 2008;136: 937–942. Jain D, Dietz HC, Oswald GL, Maleszewski JJ, Halushka MK. Causes and histopathology of ascending aortic disease in children and young adults. Cardiovasc Pathol 2011;20:15–25. Viscardi F, Vergara C, Antiga L, Merelli S, Veneziani A, Puppini G, Faggian G, Mazzucco A, Luciani GB. Comparative finite element model analysis of ascending aortic flow in bicuspid and tricuspid aortic valve. Artif Organs 2010;34:1114 –1120. Barker AJ, Lanning C, Shandas R. Quantification of hemodynamic wall shear stress in patients with bicuspid aortic valve using phasecontrast MRI. Ann Biomed Eng 2010;38:788 – 800. Hope MD, Hope TA, Meadows AK, Ordovas KG, Urbania TH, Alley MT, Higgins CB. Bicuspid aortic valve: four-dimensional MR evaluation of ascending aortic systolic flow patterns. Radiology 2010;255: 53– 61. Bauer M, Siniawski H, Pasic M, Schaumann B, Hetzer R. Different hemodynamic stress of the ascending aorta wall in patients with bicuspid and tricuspid aortic valve. J Card Surg 2006;21:218 –220.
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22. Andrus BW, O’Rourke DJ, Dacey LJ, Palac RT. Stability of ascending aortic dilatation following aortic valve replacement. Circulation 2003; 108:II295–II299. 23. Gaudino M, Anselmi A, Morelli M, Pragliola C, Tsiopoulos V, Glieca F, Possati G. Aortic expansion rate in patients with dilated poststenotic ascending aorta submitted only to aortic valve replacement long-term follow-up. J Am Coll Cardiol 2011;58:581–584. 24. Edwards WD, Leaf DS, Edwards JE. Dissecting aortic aneurysm associated with congenital bicuspid aortic valve. Circulation 1978;57: 1022–1025. 25. Homme JL, Aubry MC, Edwards WD, Bagniewski SM, Shane Pankratz V, Kral CA, Tazelaar HD. Surgical pathology of the ascending aorta: a clinicopathologic study of 513 cases. Am J Surg Pathol 2006;30:1159 –1168.
26. Brown DW, Dipilato AE, Chong EC, Gauvreau K, McElhinney DB, Colan SD, Lock JE. Sudden unexpected death after balloon valvuloplasty for congenital aortic stenosis. J Am Coll Cardiol 2010;56:1939 – 1946. 27. Bondy CA. Aortic dissection in Turner syndrome. Curr Opin Cardiol 2008;23:519 –526. 28. Maron BJ, Doerer JJ, Haas TS, Tierney DM, Mueller FO. Sudden deaths in young competitive athletes: analysis of 1866 deaths in the United States, 1980 –2006. Circulation 2009;119:1085–1092. 29. Hatzaras I, Tranquilli M, Coady M, Barrett PM, Bible J, Elefteriades JA. Weight lifting and aortic dissection: more evidence for a connection. Cardiology 2007;107:103–106. 30. Yetman AT, Graham T. The dilated aorta in patients with congenital cardiac defects. J Am Coll Cardiol 2009;53:461– 467.