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a Department of Pediatric Cardiac Surgery, University Hospital of Ghent, Ghent, Belgium
b Department of Pediatric Cardiology, University Hospital of Ghent, Ghent, Belgium
Accepted for publication October 10, 2007.
* Address correspondence to Dr Bové, Department of Cardiac Surgery, University Hospital of Ghent, De Pintelaan 185, 5K12, Ghent, 9000, Belgium (Email: thierry.bove{at}ugent.be).
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Abstract |
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Methods: Ninety-three children were reviewed for functional and morphologic assessment of both reconstructed arteries after the arterial switch operation. Longitudinal analysis focused on neoaortic valve function, neoaortic obstruction, and neopulmonary stenosis as well as on the time-related size changes of both roots, with its clinical implications.
Results: Within a mean follow-up of 4.8 ± 3.9 years, aortic regurgitation of 2 or greater developed in 10% in TGA with intact ventricular septum (IVS) versus 23% in TGA with ventricular septal defect (VSD). A VSD and major pulmonary to aortic annulus size discrepancy were main precursors of early neoaortic valve dysfunction, whereas development of aortic regurgitation of 2 or greater was additionally promoted by the duration of follow-up. Presence of a VSD enhanced neoaortic root enlargement, resulting in a mean root z-score of 3.25 in TGA/VSD versus 1.96 in TGA/IVS. Root dilation was more severe in case of aortic regurgitation of 2 or greater (z = 3.38). Neoaortic obstruction occurred in 8%, mostly at the neosinotubular anastomosis, and correlated with prior pulmonary to aortic ratio greater than 1.5. Concerning the neopulmonary tract, increased flow velocity was observed in 24%, primarily at the supravalvular level. Two patients with pulmonary annulus hypoplasia (z < –2) required early reintervention. Regarding clinical outcome, freedom from reintervention at 1, 5, and 10 years was, respectively, 98%, 96%, and 96% for TGA/IVS, versus 65%, 63%, and 63% for TGA/VSD. A VSD and aortic arch obstruction were significant predictors for reintervention.
Conclusions: After arterial switch operation, the neoaortic root is usually enlarged, but with a growth pattern comparable to that of a normal population. The association of a VSD and major arterial root size discrepancy predisposes to both neoaortic valve dysfunction and root enlargement. Severe root dilation appears to be closely related to significant neoaortic valve regurgitation, mainly as a result of a time-depending and reciprocal process. Neopulmonary stenosis is a frequent finding, but rarely has clinical consequences. Because the factor "time" is the principal determinant of late neoaortic valve dysfunction and root dilation, strict serial surveillance after arterial switch operation is mandatory.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsCommentReferences |
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Over the last years, the focus has moved toward concerns of the ASO such as the fate of the neoaortic root and neoaortic valve function, the evolution of the neopulmonary trunk, and the occurrence of coronary artery stenosis. A few studies reported yet on the progressive dilation of the neoaortic root and the potential of late neoaortic valve dysfunction even after short-term surveillance [1–5]. Moreover, the late results of the pulmonary autograft as aortic valve substitute have raised some worrisome findings concerning the adaptability and durability of the pulmonary valve in the arterial system [6].
The purpose of this study was to assess both great arteries after ASO by serial echocardiographic analysis of the time-related interference between the neoarterial root dimensions and its functional components, in correlation with the clinical implications.
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Patients and Methods |
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Follow-Up Protocol
Routine clinical and echocardiographic evaluation was performed at 1 and 6 months after surgery, and yearly thereafter. The follow-up period ranged from 11 months to 13.7 years, averaging 4.8 ± 3.9 years. Total follow-up time was 442.2 patient-years. Follow-up duration reached 1 to 5 years for 39 patients (42%), 5 to 10 years for 35 patients (38%), and more than 10 years for 19 patients (20%), resulting in 100% completeness for the clinical and the functional echocardiographic data. The individual follow-up timespan for each patient was complete in 84% for measurements of the neoaortic root, and in 62% for the neopulmonary root.
Echocardiography focused on the neoaortic valve function with determination of gradient calculation by flow velocity acceleration and assessment of aortic regurgitation by using the quantitative grading as defined by Jenkins and coworkers [7]. Based on the width of the color jet, aortic regurgitation (AR) was estimated as none to trivial (grades 0 and 1), mild to moderate (grades 2 and 3), and severe (grade 4). The pulmonary valve was estimated in a similar way. Additionally, the pulmonary trunk was evaluated with color flow Doppler for measurement of flow accelerations at the valvular, supravalvular, and pulmonary branch level.
Serial postoperative measurement of the neoaortic root included the diameter of the valve at the level of the basal leaflet attachments, the diameter of the root at the widest midsinusal level, and the diameter of the neosinotubular junction, which corresponded to the distal anastomosis between neoaortic root and ascending aorta. Regarding the right ventricular outflow tract, only the diameter of the pulmonary valve could adequately be evaluated by retrospective analysis of the video records. All echocardiographic examinations were reviewed by one single observer masked for outcome.
Data Analysis
To obtain uniform data on morphologic and operative features, some variables were dichotomized. To simplify the variant coronary patterns, the coronary anatomy was identified as complex for single coronary ostium and intramural course, and simple for the other patterns. Concomitant aortic arch pathology was used as a single variable, independently whether it concerned coarctation or interrupted aortic arch.
Aortic to pulmonary annulus size discrepancy was objectified as the dichotomous pulmonary to aortic (P/A) ratio greater than 1.5 by preoperative short-axis echocardiogram and confirmed by the surgical report. The morphology of the aortic and pulmonary valve was classified as normal when tricuspid, and as abnormal when bicuspid or rarely quadricuspid. Regarding the operative variables, the technique of coronary artery transfer was categorized as direct versus trapdoor reimplantation.
The echocardiographic measurements of the neoaortic and neopulmonary root diameters were compared with the expected normal values as determined by the z-scores based on the body surface area of the patient at the time of the echocardiographic control [8]. The evolution of the measured diameters at the different levels was plotted against the upper and lower 95% confidence limits of the normal population [9]. As an index of growth or dilatation, the increase of z-score change per year has been calculated for each observed value. Significant enlargement of the measured diameter at any level was considered for a z-score greater than 3.
To rationalize the analysis of the aortic valve function, the study population was evaluated for the grade of AR at discharge, as well as for the progression or worsening of the AR during follow-up. Additionally, the analysis of potential risk factors for AR was performed by differentiating into significant AR (AR 
2) versus nonsignificant AR (AR <2).
Statistical Analysis
The statistical analysis was achieved with the SPSS 12.0 software (SPSS, Chicago, Illinois). Univariate analysis of continuous variables was performed by the Student t test. Comparison of categorical variables was done with the two-tailed 
2 test.
All variables reaching statistical significance by univariate analysis were entered into a multivariate logistic regression model for time-independent endpoints, and in a Cox regression model for time-variable factors. The Kaplan-Meier method was used for graphical comparison of time-depending outcome events, and statistical significance was calculated by the log-rank test. The Spearman rank test was employed for searching correlation between less frequent occurring events. Statistical significance was considered for p less than 0.05.
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Results |
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Further functional analysis revealed a small gradient of 20 mm Hg at valvular level in 1 patient (2%) of group 1. Otherwise, 6 patients (19%) in group 2 had a gradient in the left ventricular outflow tract (p = 0.002), located at subvalvular level by posterior septal malignment (n = 1), at valvular level (n = 1), and at the reconstructed sinotubular junction (n = 4). Although the low number of patients with a left-sided stenosis precluded major statistical analysis, important P/A size discrepancy (p = 0.0001) and a VSD (p = 0.002) strongly correlated with the later risk of left ventricular outflow tract obstruction.
The time-related evolution of the root dimensions plotted against the upper and lower 95% limits of the normal population is depicted in Figure 4. Using a linear regression model with time as random factor, the increase of diameter between groups 1 and 2 was, respectively, 1.83 mm/year versus 2.54 mm/year (p = 0.08) at the annulus level; 2.38 mm/year versus 3.27 mm/year (p = 0.07) at the midsinusal level, and 1.74 mm/year versus 2.19 mm/year (p = 0.43) at the sinotubular level.
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Systematic measurement of the neopulmonary root by retrospective analysis of echocardiograms was only representative for the pulmonary valve at its basal level. Evolution of the pulmonary valve annulus size during follow-up is shown in Figure 5, collecting the data of the two groups. This Figure illustrates the gradual growth of the pulmonary valve annulus mainly between the 5th and 50th percentile of a normal body surface area–matched population. The growth rate was comparable for both groups: 1.98 mm/year for group 1 and 1.76 mm/year for group 2 (p = 0.74). Moreover, there were no significant differences in mean z-score (–0.77 for group 1 and –0.41 for group 2, p = 0.28) nor in z-score change per year (0.07 for group 1 and –0.35 for group 2, p = 0.14). Statistical analysis could not reveal significant risk factors for development of post-ASO neopulmonary stenosis.
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Comment |
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The reasons for neoaortic root enlargement after the ASO are various. Although mechanical capability of the native pulmonary root to sustain systemic pressure stress has been proven, structural abnormalities of the arterial wall were observed [10]. Based on the finding of smooth muscle cell downregulation in the pulmonary artery of untreated TGA patients without VSD, Lalezari and colleagues [11] even suggested a genetic predisposition for late development of neoaortic root dilation.
Additionally, investigation of risk factors promoting dilation in this series revealed the major impact of the presence of a ventricular septal defect. Usually neonates with TGA and VSD have already a native pulmonary artery that is significantly larger than in a normal hearts, or than in neonates with TGA without VSD. This factor was even more determinant when the pulmonary to aortic annulus size discrepancy was pronounced [3, 12]. Pulmonary artery banding before ASO has also been associated with increased neoaortic root dilation [1, 13]. However, by adopting a policy of treating children with TGA as early as possible, independent of the association with VSD, this potentially confounding factor was lacking in this study.
On the other hand, we found that dilation of the neoaortic root at the three different levels of measurement occurred more extensively in these children presenting with a significant neoaortic valve regurgitation. Moderate aortic valve dysfunction even seemed to accelerate this process. Within the current length of follow-up of this study, it remains difficult to ascertain whether the neoaortic root dilation or the neoaortic valve dysfunction is the primary determinant. In this cohort, 3 patients with TGA and VSD already had mild to moderate AR at discharge, evolving toward a hemodynamically significant AR requiring reoperation in 1 case. All 3 patients finally ended with a severe neoaortic root dilation with a z-score greater than 6. In 2 of them, the VSD was closed through the pulmonary valve, which is known as a technique-related risk factor for neoaortic regurgitation. Losay and associates [12] suggested a similar conclusion when AR at discharge was retained as a significant risk factor for late AR development. However, in the majority of patients having AR grade 2 and significant root enlargement, the process appeared to be more progressive and time dependent, with the root dilation preceding the valve dysfunction, according to the results of McMahon and colleagues [4].
In half of our patients, some neoaortic valve dysfunction developed over time, as in the data published by Schwartz and coworkers [1] and Hwang and associates [3]. In contrast, Losay and colleagues [12] noted a lower number of late valve dysfunction, but they admitted that the lack of beforehand consensus on the quantification of aortic regurgitation might have underestimated the incidence of trivial AR. Such difference in the reported incidence of neoaortic valve dysfunction is relative, however, in view of the still subjective perception of echocardiographic findings, especially if they carry rather an observational than an imediate clinical value. Considering the development of more than trivial AR, the presence of a VSD and important pulmonary to aortic size discrepancy were observed as significant predictors. However, the principal risk factor of late neoaortic valve dysfunction was the duration of follow-up, used as a surrogate for the variable factor "time." These findings should underline the theory that the neoaortic root after the ASO is constantly mechanically challenged because of the combination of impaired distensibility [14] and inherent histologic dedifferentiation of the neoaortic root [11]. On top of that, this process might be enhanced by the destabilization of the junction between the enlarged native pulmonary root and the arterial trunk as favored by the often VSD-induced arterial root size discongruence. The increased stress on both leaflets and wall might subsequently facilitate the insidious and probably mutual morphologic and functional deterioration of the neoaortic root, with the factor time acting as the ultimate determinant.
More uncommon is the occurrence of left-sided obstruction after neoaortic root reconstruction at the time of ASO. Our data revealed 7 children in whom an obstructive gradient across the left ventricular outflow tract was noticed. Mostly the measured gradients were not hemodynamically significant, and carried functionally the same observational value as a trivial valve regurgitation. In a multi-institutional study, Williams and coparticipants [15] reported 6 patients of 514 neonates with TGA having neoaortic stenosis. The prevalence of post-ASO left-sided obstruction in their series is undoubtfully underestimated in comparison with our results by using reintervention rate as the substrate for outflow obstruction. Nevertheless, in accordance with their study, we also found left outflow obstruction mostly located at the new sinotubular junction, advanced by severe preoperative pulmonary to aortic root size discrepancy. That should eventually evocate the beneficial effect of surgically accommodating the discongruent neoaortic root to ascending aorta size ratio, to cope with the risk of both neoaortic valve dysfunction and supravalvular neoaortic stenosis, as proposed by Siamak and colleagues [16].
The fate of the right ventricular outflow tract after the ASO has been described extensively, but mainly from a functional point of view. Owing to specific technical issues, pulmonary stenosis is commonly located at the supravalvular and branch level. The reported incidence varies from 7% to 50% [17, 18]. Our series noted a 52% occurrence of neopulmonary stenosis, but the incidence decreased to 24% when only gradients above 20 mm Hg were accounted for, according to the number reported by Nogi and coworkers [18]. Univariate analysis showed a significant predominance in TGA with VSD. That can be explained by the often marked size mismatch between both neoarterial roots, resulting in forward stretching of the neopulmonary artery by a posterior large neoaortic root [15]. These gradients on the supravalvular pulmonary outflow tract remained stable over time, without major clinical consequences. The potential risk factors for developing neopulmonary artery stenosis are primarily surgery related [15, 18]. By using a uniform technique based on a single, large, pantaloon-sized patch of autologous pericardium and extensive mobilization of the pulmonary bifurcation before the Lecompte maneuver, we were able to minimize the effect of this factor.
Another concern is the size and the growth of the neopulmonary annulus, eventually leading to pulmonary valve stenosis. Nakanishi and colleagues [19] observed a small annulus or even growth failure of the neopulmonary annulus after ASO in 18% of their series, being more frequent in patients with prior pulmonary artery banding and in patients with VSD. Nogi and coworkers [18] demonstrated that the neopulmonary valve size remains currently small if the native aortic valve was small, and might be susceptible to growth retardation. Unlike Williams and coworkers [15], they were not able to identify promoting factors like coarctation, side-by-side position of the great arteries or associated ventricular septal defect. Our data confirm the overall small size of the neopulmonary valve annulus, corresponding to the small size of the original aortic valve annulus before the ASO, given by an average negative z-score. As graphically illustrated, the neopulmonary valve seems to grow within the lower limits of the normal range, commensurate to the somatic growth of the normal pulmonary valve. Only 5 children ended with a pulmonary annulus that could be defined as hypoplastic by a z-score less than –2. Critical pulmonary valve stenosis occurred twice in TGA with VSD patients, respectively treated by operative transannular patching and pulmonary valve dilation early after ASO.
Despite these concerns, the clinical impact of neoaortic root dilation, neoaortic valve dysfunction, as well as residual right-sided lesions of the outflow tract remains limited at midterm follow-up, when reintervention rate is used as study endpoint. The cumulative freedom from all kind of reinterventions in our cohort shows that 82% stay free from apparent functional sequelae at 5 to 10 years after ASO. This percentage dropped significantly to 63% in children with TGA with VSD, emphasizing the association of a ventricular septal defect and, less pronounced, aortic arch pathology as important predictors of the risk for later reintervention. These findings corresponded well with other studies reporting on the midterm outcome of the ASO, and equally in low- and high-volume centers [20, 21]. Since the factor "time" appears to be the main determinant of neoaortic valve dysfunction and concomitant neoaortic root enlargement, a longer follow-up will actually better define the clinical significance of this issue.
The limitations of our study are obviously related to its retrospective character. Subsequently, the echocardiographic results are dependent on the possibility of operator-related measurement variability, which was countered as much as possible by reassessment of echocardiograms by one observer, blinded for the study outcome. Secondarily, the morphologic measurements of the full neopulmonary trunk are incomplete as most observers focused the follow-up examination on the functional behavior of the right ventricular outflow tract after ASO. Therefore, only the pulmonary annulus diameter could be reliably included. Although the application of a prospective method on the study design is undoubtedly superior, we feel confident that the major conclusions drawn from our results would probably not be altered but only more refined.
In conclusion, after ASO for TGA, the reconstructed neoaortic root is commonly larger, but shows a growth pattern in pace with the normal population. The presence of more than trivial neoaortic valve regurgitation appears to accelerate the root size increase, probably based on the reciprocal stress effect between leaflet function and root adaptation to late neoaortic root remodeling. The association of a VSD, resulting in major pulmonary to aortic root size discrepancy, is identified as the most important promotor of neoaortic valve dysfunction. However, the factor "time" appears to be the main determinant of the functional and anatomical fate of the neoaorta at midterm follow-up. For the right-sided outflow tract after the ASO, proper surgical technique allows reducing the occurrence of supravalvular neopulmonary stenosis. Growth deficiency of the neopulmonary valve annulus will perhaps be more concerning in the long term. Although the morphologic and functional sequelae at the level of the reconstructed neoarterial trunks are not frequently contributing to the clinical outcome of the arterial switch procedure at midterm assessment, further serial surveillance is warranted for determination of its real impact.
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  T. Bottio, G. Thiene, V. Tarzia, G. Rizzoli, and G. Gerosa Arterial Switch Operation, Aortic Root Dilation, and Long-Term Aortic Valve Competence Ann. Thorac. Surg., December 1, 2008; 86(6): 2025 - 2026. [Full Text] [PDF]
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