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Original article
Bicuspid aortic valve and associated aortic dilation in the young
  1. Susan Fernandes1,2,
  2. Paul Khairy1,2,
  3. Dionne A Graham1,2,
  4. Steven D Colan1,2,
  5. Teresa C Galvin1,2,
  6. Stephen P Sanders1,2,
  7. Michael N Singh1,2,
  8. Ami Bhatt1,2,
  9. Ronald V Lacro1,2
  1. 1Departments of Cardiology and Pathology, Children's Hospital Boston, Boston, Massachusetts, USA
  2. 2Departments of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA
  1. Correspondence to Dr Ronald V Lacro, Department of Cardiology, Children's Hospital Boston, 300 Longwood Avenue, Boston, MA 02115, USA; ron.lacro{at}cardio.chboston.org

Abstract

Background The aorta in patients with bicuspid aortic valve (BAV) is larger and grows more rapidly than in patients with tricommissural aortic valve. Young patients with BAV can have significant aortic dilation that places them at risk for morbidity and mortality.

Objective The aims of this study were to determine the rate of growth of the aorta in young patients with BAV and to identify predictors of significant dilation and rapid aortic growth.

Methods 333 patients were randomly selected from an inception cohort of 1192 patients with BAV identified between 1986 and 1999.

Results Median age at the most recent study was 13.5 (0–30) years, 74% were male. Moderate/severe (Z>4) aortic root and ascending aortic dilation was present in 14/333 (5%) and 53/333 (16%) of patients, respectively. In longitudinal follow-up, only a minimal change in aortic Z-score was noted. Predictors of moderate/severe aortic root dilation included moderate/severe aortic regurgitation, absence of moderate/severe aortic stenosis and fusion of the right and left coronary leaflets. Predictors of moderate/severe ascending aortic dilation included moderate/severe aortic regurgitation and absence of aortic coarctation.

Conclusion Moderate/severe dilation of the ascending aorta is common in young patients with BAV, but moderate/severe dilation of the aortic root is less common. The Z-scores for both remained relatively constant over time even in patients with significant dilation, implying that young children with moderate/severe aortic dilation may be at the highest risk for dilation-related complications as adults.

  • Bicuspid aortic valve
  • aortic dilation
  • bicommissural aortic valve
  • congenital heart disease
  • Fallot's tetralogy
  • paediatric cardiology
  • transposition of the great arteries
  • quality of care and outcomes
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Introduction

Dilation of the aorta is a frequent complication in patients with bicuspid or bicommissural aortic valve (BAV)1–3 and the aorta in this population grows more rapidly than in the normal population.4 Although 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.5 Reported risk factors associated with progression of aortic dilation include older age, higher body surface area (BSA) and the presence of moderate to severe aortic regurgitation2; however, the rate of growth and the predictors associated with moderate or severe dilation and progressive dilation in a young cohort of patients with BAV are not well defined. The aims of this study were to determine the rate of growth of the aorta and to identify predictors of moderate or severe aortic dilation and predictors of more rapid growth in young patients with BAV.

Methods

From our inception cohort of 1192 patients with BAV identified between 1986 and 1999, 864 patients had either isolated BAV or BAV with aortic coarctation, 853 of whom had fusion of right and left (R-L) or right and non-coronary (R-N) leaflets. From this base population of 853, 333 patients were randomly selected for inclusion in the study cohort. This sample size provided 90% power to detect a difference in the prevalence of aortic dilation of 40% versus 60% for R-L versus R-N valve morphology, respectively, with the assumption that 70% of the sample would have R-L morphology. Characteristics of the inception cohort have been described previously.6 Given the potential for aortic dilation associated with Marfan syndrome and related disorders, Ehlers-Danlos syndrome, Loeys-Dietz syndrome, Turner syndrome and 22q11.2 deletion syndrome, patients with these diagnoses were excluded from this randomly selected cohort.7–10 Initial and most recent echocardiograms performed prior to any surgical or catheter intervention or diagnosis of endocarditis were reviewed. Aortic measurements were performed in parasternal long axis views using two-dimensional imaging, inner-edge to inner-edge, at maximum (mid-systolic) excursion. The aortic root diameter was measured at the maximum diameter of the sinuses of Valsalva and the ascending aortic diameter was measured at the largest diameter distal to the sinotubular junction. Aortic dimensions were compared with normative data and expressed as Z-scores (units = SD) relative to BSA calculated according to the formula of Haycock et al,11 based on normative data collected in 670 normal children and young adults varying in age from 0 to 30 years.12 For the purposes of this study, we defined mild aortic dilation as a Z-score >2 but ≤4, moderate or more dilation as a Z-score >4 but ≤6, and severe dilation as a Z-score >6 (>6 SD above the mean for BSA). Echocardiographic assessment of aortic stenosis was expressed as the maximum instantaneous Doppler gradient (mm Hg). Aortic stenosis was defined as moderate or more if the maximum instantaneous Doppler gradient was ≥50 mm Hg. Classification of the severity of aortic regurgitation was based on composite evaluation of proximal jet width, abdominal aortic Doppler and left ventricular end-diastolic volume or dimension. Patients were classified as having none, trivial, mild, moderate, or severe aortic regurgitation. The classification of moderate or severe regurgitation required pan-diastolic retrograde flow in the descending aorta and a left ventricular end-diastolic volume or dimension >2 SD above the mean, adjusted for BSA. Additional clinical data regarding catheter and surgical interventions and diagnosis of endocarditis were obtained from electronic and paper medical records and hospital databases. The study protocol was approved by the Institutional Review Board at Children's Hospital Boston.

Statistical analyses

Continuous variables are presented as mean ± SD or median and IQR, depending on the normality of their distribution. Nominal and ordinal variables are summarised as frequencies and percentages. Patient characteristics according to the morphological subtype of BAV were compared using χ2 tests, two sample t tests, or Mann–Whitney U tests, as appropriate. Linear mixed effects models were used to model the relationship between aortic root diameter and the square root of BSA in patients with BAV. To account for increasing variance with BSA, we modelled the SD as described previously.13 The estimated mean and SD were used to construct 95% prediction intervals as a function of BSA within the BAV population, which were then visually compared with the relationship observed in normal individuals.12 The relationship between ascending aorta diameter and the square root of BSA was modelled similarly. Univariate and multivariate linear regression were used to obtain unadjusted and adjusted estimates, respectively, of mean aortic root diameter Z-score at most recent echocardiogram as a function of BAV morphology, coarctation, aortic stenosis and aortic regurgitation. A χ2 test was used to compare the prevalence of moderate or severe aortic root dilation between patients with none or mild aortic regurgitation and patients with moderate or severe aortic regurgitation. A similar comparison was made for ascending aortic dilation. In the subset of patients with serial echocardiograms, the linear rates of change of aortic root and ascending aortic diameter Z-scores were modelled using generalised estimating equations to account for repeated measures within subjects. Effects of clinical variables on rates of change were assessed by including them as predictors, along with their interactions with time, in the models. A two-tailed p value <0.05 was considered statistically significant. Data analysis was performed with SAS software V.9.2 (SAS Institute).

Results

The 333 patients (74% male) randomly selected for inclusion had a median age of 13.5 years (range: 0–30 years) at most recent follow-up, with 228 (68%) having fusion of the R-L coronary leaflets and 105 (32%) fusion of R-N leaflets. Characteristics of the study population are provided in table 1. The randomly selected subcohort had similar characteristics with regard to BAV subtype, gender, age and valvular dysfunction as the full cohort with isolated BAV and BAV with associated aortic coarctation. A diagnosis of infective endocarditis was documented in 15/333 (4.5%) of patients.

Table 1

Characteristics of patients with BAV at most recent echocardiogram (before valve intervention or bacterial endocarditis)

Aortic root dilation

The aortic root was dilated (Z>2) in 74 (22%) patients. A comparison of the aortic root diameter in patients with BAV and the expected aortic root diameter for the normal population can be found in figure 1A. At the most recent echocardiogram, higher aortic root diameter Z-score was associated with moderate or more aortic regurgitation (2.19±1.68 vs 1.02±1.33, p=0.0002), absence of moderate or more aortic stenosis (1.19±1.35 vs 0.42±1.47, p=0.0008) and fusion of the R-L coronary leaflets compared with fusion of the R-N leaflets (1.21±1.38 vs 0.84±1.36, p=0.02). There was no statistical difference in the aortic root size between patients with and without aortic coarctation. In multivariate analysis, moderate or more aortic regurgitation (p<0.0001), absence of significant aortic stenosis (p=0.01) and fusion of R-L coronary leaflets (p=0.01) were independently associated with higher aortic root diameter Z-score (table 2).

Figure 1

Aortic root (A) and ascending aorta (B) diameter versus body surface area (BSA). The white line and shaded area represent the mean and 95% prediction interval, respectively, in the normal population. The solid line and dashed lines represent the mean and 95% prediction intervals, respectively, for the BAV patients.

Table 2

Relationship between aortic Z-scores and BAV and other risk factors for aortic dilation

The aortic root was moderately or severely dilated (Z>4) in 15 (5%) patients and was associated with the presence of moderate or more aortic regurgitation. Moderate or severe aortic root dilation was present in 4 (19.1%) patients with moderate or more aortic regurgitation compared with 11 (3.5%) patients with less than moderate aortic regurgitation (p=0.01).

Ascending aortic dilation

The ascending aorta was dilated (Z>2) in 163 (49%) patients. A comparison of the ascending aortic diameter in patients with BAV and the expected ascending aortic diameter for the normal population can be found in figure 1B. At the most recent echocardiogram, higher ascending aortic diameter Z-score was associated with moderate or more aortic regurgitation (4.27±1.80 vs 1.99±1.86, p<0.0001) and fusion of R-N leaflets compared with fusion of the R-L coronary leaflets (2.53±2.00 vs 1.95±1.88, p=0.01). The ascending aortic diameter Z-score was significantly lower in patients with BAV associated with aortic coarctation than those without (1.53±1.88 vs 2.34±1.91, p=0.0007). In multivariate analysis, moderate or more aortic regurgitation (p<0.0001) and absence of aortic coarctation (p=0.02) remained independently associated with higher ascending aortic diameter Z-score (table 2).

The ascending aorta was moderately or severely dilated (Z>4) in 53 (16%) patients and was associated with moderate or more aortic regurgitation. Moderate or severe ascending aortic dilation was present in 13 (61.9%) patients with moderate or more aortic regurgitation compared with 40 (12.8%) patients with less than moderate aortic regurgitation (p<0.0001).

Progression of aortic dilation

Of the 333 patients, 221 had serial echocardiographic studies prior to any valve intervention or bacterial endocarditis, permitting analysis of progression of aortic dilation. The group of patients with serial echocardiographic studies had similar characteristics as those with only one study except those with serial studies were older (14.8±4.9 vs 8.3±6.4, p<0.0001) and were more likely to have at least mild (Z>2) dilation of the ascending aorta than those that had only one study (53% vs 41%, p=0.01). The median follow-up for those patients who had serial echocardiographic studies was 6 years (range: 5 months to 15 years).

In a longitudinal analysis, the aortic root diameter Z-score changed by a mean of –0.009 (±0.010 SE) SD per year (table 3). BAV morphology, severity of aortic stenosis or aortic regurgitation and presence of aortic coarctation were not predictive of rate of change in Z-score over time. The rates of change in aortic root diameter Z-score in patients with (Z>2) and without (Z≤2) aortic root dilation at baseline were significantly different. Z-scores of patients without aortic root dilation remained relatively constant over time while patients with mild and moderate dilation at baseline tended to regress towards the mean (0.011±0.011 vs −0.068±0.026, p=0.005). No patient had severe aortic root dilation (Z≥6) at baseline or at last follow-up.

Table 3

BAV and associated risk factors for progression of aortic dilation

The ascending aortic diameter Z-score increased by 0.063 (±0.013 SE) SD per year and was more rapidly progressive in patients with fusion of the R-N leaflets compared with those with fusion of R-L coronary leaflets. Severity of aortic stenosis or aortic regurgitation and presence of aortic coarctation were not predictive of change in ascending aortic diameter Z-score over time. There was no significant difference in the rate of change in ascending aortic diameter Z-score between patients with (Z>2) and without (Z≤2) dilation at baseline. Patients with at least moderate dilation (Z>4) had no significant change in Z-score over time, while patients with less than moderate dilation (Z≤4) had a small increase in Z-score over time (−0.024±0.031 vs 0.076±0.015, p=0.004).

Only three of 333 patients had surgical intervention for aortic dilation. There was no documented aortic dissection or death. No patient had an aortic root diameter Z-score >6, while 12 patients had an ascending aortic diameter Z-score >6; seven of whom had an ascending aortic diameter Z-score ≥7. Three of these patients with an ascending aortic diameter Z-score ≥7 underwent surgical intervention. The first patient underwent surgical intervention at 25 years of age for severe dilation of the ascending aorta (5.5 cm, Z-score 8.77). This patient also had moderate dilation of the aortic root (4.45 cm, Z-score 4.56) and moderate aortic regurgitation. The second patient underwent surgical intervention at 13 years of age for severe dilation of the ascending aorta (5 cm, Z-score 9.38). This patient had a normal aortic root diameter and only mild aortic regurgitation. The third patient underwent surgical intervention at 27 years for severe aortic regurgitation and significant dilation of the ascending aorta (4.9 cm, Z-score 7.17). This patient also had moderate aortic root dilation (4.8 cm, Z-score 5.76). All three of these patients had Z-scores >6 at time of initial presentation. Four additional patients had an ascending aortic diameter Z-score ≥7 at most recent study but continued to be followed clinically. These included a 5-year-old with a Z-score of 7.4 (3.2 cm), a 16-year-old with a Z-score of 7.6 (4.8 cm); an 18-year-old with a Z-score of 7.0 (4.1 cm) and a 19-year-old with a Z-score of 7.0 (4.4 cm). All four of these patients had Z-scores >6 at time of initial presentation as well. No patient with less than moderate dilation (Z≤4) at initial presentation progressed to severe dilation (Z>6) at most recent study.

Discussion

The potential for progressive dilation of the aorta places patients with BAV at significant risk for morbidity and mortality from aortic aneurysm and dissection, which have been reported in adults but not in young children with BAV.2 14–17 The pathophysiology of these complications is not clear and appears not entirely dependent on the degree of valve dysfunction (stenosis and regurgitation).5 A recent study demonstrated dilation of the main pulmonary artery in patients with BAV in the absence of pulmonary valve pathology,18 indicating that the arteriopathy extends beyond the thoracic aorta. Possible pathogenic mechanisms for aortic dilation in patients with BAV have been proposed, including elastic fibre fragmentation, increased metalloproteinase expression, decreased expression of tissue inhibitors of metalloproteinases and smooth muscle cell apoptosis.19–25 Familial BAV has been reported and isolated aortic dilation without BAV has been noted in first-degree relatives of patients with BAV, suggesting underlying genetic influences.22 Cardiac screening of first-degree relatives of patients with left ventricular outflow tract obstruction has been recommended.26 Although the prevalence of dilation in patients with BAV is well established, the rate of progression during childhood and adolescence and risk factors for significant dilation were not previously well characterised.

In the current study, we report that aortic dilation is common in the young, but only a small subset have more than mild dilation. Predictors of moderate or more dilation are limited due, in part, to the relative infrequency of this finding.

BAV morphology has been suggested as a possible risk factor for aortic dilation. We previously reported that the subtype of BAV was strongly associated with valvular dysfunction, demonstrating that fusion of R-N leaflets was associated with at least a twofold higher odds of having moderate or severe aortic stenosis and moderate or more aortic regurgitation compared with other forms of BAV.6 In addition, R-N leaflet fusion was also associated with progressive valve dysfunction and was strongly predictive of valve intervention when compared with R-L coronary leaflet fusion.27 In our current study, R-L coronary leaflet fusion was associated with a higher prevalence of aortic root dilation and R-N leaflet fusion was associated with a more rapid growth of the ascending aorta as measured by change in Z-score over time. However, aortic valve morphology was not predictive of the presence of moderate or more aortic root or ascending aortic dilation.

The severity of aortic stenosis does not correlate with the degree of aortic dilation. Similar to other studies,5 28 we found that significant aortic stenosis was not a risk factor for the prevalence or progression of aortic dilation. In fact, patients with moderate or more aortic stenosis had less aortic root dilation than patients with less than moderate obstruction. However, this ‘protective’ effect was not seen for ascending aortic dilation or for progression of aortic dilation, either at the root or ascending aorta.

Moderate or more aortic regurgitation was associated with higher aortic root and ascending aortic diameter Z-scores; however, moderate or more aortic regurgitation was the only identifiable predictor of moderate or more ascending aortic dilation. This association has been noted in other studies in both children and adults with BAV,2 3 29 although it is unclear whether dilation begets regurgitation, regurgitation begets dilation, or both. Some authors have suggested haemodynamic reasons that could account for the aortic regurgitation causing aortic dilation such as increased wall stress due to increased stroke volume from aortic regurgitation.2 Other authors have suggested that aortic dilation likely precedes aortic regurgitation with the progression of aortic dilation causing poor coaptation of the aortic valve leaflets that leads to aortic regurgitation.30 Our results suggest that factors other than BAV morphology and valve dysfunction are likely influencing the degree and rate of aortic dilation.

BAV associated with aortic coarctation is associated with less valve dysfunction than isolated BAV, regardless of valve morphology.6 27 The current study complements these findings by demonstrating a lower prevalence of ascending aortic dilation in patients with aortic coarctation, consistent with a prior study by Thanassoulis and colleagues.2

In a longitudinal follow-up, only a minimal change in aortic root and ascending aortic diameter Z-score was noted (Z-score change of −0.009 and +0.063 per year, respectively), even in patients with dilation at presentation. Identification of associated factors is limited by the small magnitude of change. Patients with mild dilation tend to stay mild, whereas those with more significant dilation tend to maintain this pattern over time. That the aortic Z-scores remain relatively constant during childhood implies that the aorta continues to grow while the children grow, and that patients with moderate or severe dilation at a young age are most likely to have moderate to severe dilation as teenagers and young adults. Hence, patients with the highest Z-scores in early childhood will likely have the highest Z-scores in adulthood and, consequently, the highest risk for aortic complications including dissection. These data may help inform clinical decisions regarding the need and time course for echocardiographic surveillance and potential medical intervention.

It is currently recommended to repair the aorta when the aortic diameter approaches or exceeds 5 cm in older teenagers and adults,14 but guidelines for surgical intervention for younger and smaller individuals are not well established. Aortic dilation progressing to the point of surgical intervention was uncommon in our cohort; only three of our subjects underwent surgery, which was generally performed when the aortic diameter approached or exceeded 5 cm in teenagers and adults.

Given that BAV affects 1–2% of the general population,31–33 the financial impact of echocardiographic surveillance for aortic dilation in this population is potentially huge. Clinical management plans designed to improve patient care and decrease practice variability are becoming increasingly common in medicine and carry the potential to substantially impact costs, especially when they incorporate recommendations for frequency of testing. Our data suggest that, in patients with well-functioning BAV and no more than moderate aortic dilation, echocardiographic surveillance for aortic dilation need not be frequent (eg, every 5 years) unless they appear to be growing more rapidly than their BSA (ie, increasing Z-score). Until further data are available, it might be reasonable to recommend more frequent imaging surveillance for patients with severe dilation (eg, every 1 to 2 years). Patients with physical characteristics consistent with a connective tissue disorder and/or family history of aortic dilation or dissection might deserve more frequent surveillance. The overall financial impact of decreasing the number of routine echocardiograms performed on this population could potentially result in substantial savings in healthcare cost and resource utilisation.

Limitations

This study population is limited to patients with BAV referred for echocardiography. Patients without significant aortic stenosis or regurgitation were likely, therefore, to be under-sampled due to lack of physical findings.

Conclusion

Dilation of the aortic root and ascending aorta is common in young patients with BAV, though most have mild dilation and are unlikely to have significant progression or to undergo intervention for this indication during childhood and adolescence. In our cohort, there was minimal change in Z-score over time, irrespective of initial degree of dilation, valve morphology, or degree of valve dysfunction (aortic stenosis or aortic regurgitation). Given the minimal change in Z-score observed here, frequent (eg, annual) echocardiographic surveillance for aortic dilation during childhood does not appear warranted for patients with BAV who have good valve function and moderate or less aortic dilation. BAV morphological subtype and degree of aortic valve dysfunction appear to have limited effect on progression of aortic dilation. Further studies are needed to elucidate the risk factors and pathophysiological mechanisms that influence the occurrence and rate of progression of aortic dilation in patients with BAV.

References

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Footnotes

  • There are no relationships with industry.

  • Funding The research was funded in part by the Dunlevie Foundation.

  • Competing interests None.

  • Ethics approval The ethics approval was provided by Children's Hospital Boston Center for Clinical Investigation.

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Data sharing statement De-identified data can be provided upon request.

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