Ann Thorac Surg 2005;79:1366-1371
© 2005 The Society of Thoracic Surgeons
Original articles: Cardiovascular
Aortic Valve Prolapse Associated With Outlet-Type Ventricular Septal Defect
Shuenn-Nan Chiu, MDa,
Jou-Kou Wang, MD, PhDa,
Ming-Tai Lin, MDa,
En-Ting Wu, MDa,
Frank L. Lu, MDa,
Chung-I Chang, MDb,
Yih-Sharng Chen, MD, PhDb,
Ing-Sh Chiu, MD, PhDb,
Hung-Chi Lue, MDa,
Mei-Hwan Wu, MD, PhDa,*
a Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan,
b Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan, and College of Medicine, National Taiwan University, Taipei, Taiwan
Accepted for publication October 12, 2004.
* Address reprint requests to Dr Mei-Hwan Wu, Department of Pediatrics, National Taiwan University Hospital, No. 7, Chung-Shan S. Rd, Taipei 100, Taiwan (E-mail: mhwu{at}ha.mc.ntu.edu.tw).
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Abstract
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BACKGROUND: Aortic valve prolapse is frequently associated with juxta-arterial ventricular septal defect. The significance of its association with other outlet types of ventricular septal defect, however, remains unclear.
METHODS: From 1987 to 2002, 677 patients (male:female ratio, 424:253) who received surgical repair for ventricular septal defect extending to the outlet septum were reviewed. Based on surgical findings, ventricular septal defects were classified as juxta-arterial, perimembranous outlet, or muscular outlet type.
RESULTS: Aortic valve prolapse occurred in 373 of 677 patients (57.2%) with 209 juxta-arterial, 103 perimembranous outlet, and 61 muscular outlet type. Significant aortic regurgitation developed in 51 of 373 (14%). Among 252 patients with regular follow-up, the mean onset ages of aortic valve prolapse in juxta-arterial, perimembranous outlet, and muscular outlet type were 4.9, 5.0, and 5.1 years, respectively (no statistical difference). The presence of larger shunt and probably anterior malalignment predicted an earlier onset of aortic valve prolapse. Perimembranous outlet and muscular outlet type ventricular septal defect were frequently associated with infundibular hypertrophy and subaortic ridge, and perimembranous outlet type was associated with anterior septal malalignment. In juxta-arterial ventricular septal defect and ventricular septal defect with anterior malalignment, prolapsed cusp was always the right coronary cusp, but noncoronary cusp involvement was also common in perimembranous outlet type (17 of 103, 16.5%).
CONCLUSIONS: The association with anterior septal malalignment, infundibular stenosis and subaortic ridge is related to the location of the outlet ventricular septal defect. The age of onset of aortic valve prolapse in each type was quite similar, and a larger shunt may predict an earlier onset.
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Introduction
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According to the classification by Soto and associates [1], Tynan and Anderson [2], and Gatzoulis and colleagues [3], outlet type ventricular septal defects (VSD) include doubly committed juxta-arterial, perimembranous outlet type, and muscular outlet type. With a relative high incidence in Asian countries [4, 5], the association of juxta-arterial type VSD with aortic valve prolapse (AVP), mainly right coronary cusp prolapse, and aortic regurgitation (AR) has been defined. According to previous reports, the incidence of AVP in juxta-arterial VSD was 36% to 79% [6–8]. The peak age for AVP was around 7 years, and that for AR was between 5 and 10 years [6, 7, 9]. To avoid irreversibility of AVP and AR after operation, early surgical intervention in juxta-arterial type VSD is suggested at most centers as long as significant AVP is detected either by echocardiography or by angiography [10–13]. In contrast, study about AVP and AR in perimembranous outlet and muscular outlet VSD is limited. This study based on a large cohort of patients was to compare the clinical manifestations of AVP and AR in the three types of outlet VSD.
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Patients and Methods
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Patients
From September 1987 to December 2002, 717 patients who had undergone surgical repair of VSD that extended to the outlet septum were retrospectively studied. Patients associated with complex cardiac lesions such as double outlet ventricle, tetralogy of Fallot, transposition of great artery, arch anomaly, and mitral valve anomaly were excluded. Forty patients were also excluded due to inadequate surgical information as type categorization. For the 677 remaining patients (male:female ratio, 424:253), AVP developed in 373 (57.2%). The medical records, echocardiographic recordings, and angiographic and surgical findings of these patients were reviewed.
Methods
The classification of VSD was according to the Soto and Anderson classification as illustrated in Figure 1 [1, 2]. For juxta-arterial type, the defect is immediately beneath both aortic and pulmonary valve, with aortic valve and pulmonary valve in fibrous continuity. Both the outlet septum and septal component of subpulmonary infundibulum are absent. For muscular outlet VSD, the defect is in muscular septum opening into outlet septum, with intact subpulmonary infundibulum between the pulmonary valve and defect. For perimembranous outlet VSD, the defect is in the membranous septum and extending toward the outlet. Classification of VSD was based on the surgical findings, as there may be controversial between echocardiography and cardiac catheterization diagnosis. The size of VSD was defined as the largest anatomical diameter measured during surgery to avoid underestimation at echocardiography or angiography due to AVP.
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Fig 1. Schematic presentation of the location of three outlet types of ventricular septal defect from the right ventricular aspect. (JA = doubly committed juxta-arterial; PO = perimembranous outlet; MO = muscular outlet.)
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The diagnosis of AVP was made according to the echocardiographic findings that were confirmed by angiographic or surgical findings. The grading of AR by echocardiograms was based on the Omoto scale system as trivial (slight under aortic valve), mild (not reaching tip of mitral valve leaflet), moderate (reaching tip of mitral valve leaflet), and severe (beyond tip of mitral valve leaflet) [14, 15]. Only AR greater than mild degree will be considered as significant AR and used in statistical analysis.
The associated anomalies were defined either by echocardiography or during surgery. The anterior malaligument was defined as anterior deviation of the outlet septum relative to the muscular interventricular septum. The subaortic ridge was a fibrous subaortic ridge that may cause left ventricular outlet narrowing. The infundibular hypertrophy was either due to hypertrophy of anomalous muscle bundles of right ventricle or secondary to long-term jet effect of VSD over the infundibulum. For those defined as syndromic, it means patients have other associated syndromes in addition to ventricular septal defect, with most of them being Down syndrome. For the 446 patients receiving cardiac catheterization (all receiving catheterization within 1 month before surgery), Qp/Qs and mean pulmonary artery pressure were measured. The Qp/Qs was the ratio between flow of pulmonary circulation and systemic circulation. When the value was greater than 1.5, it indicated a significant left to right shunt.
Statistics
The statistics used in our study include 
2 study, likelihood ratio, or Fisher's exact test for the comparisons of mean and frequency. One-way analysis of variance (ANOVA) was applied for numeric comparison. Linear multiple regression was used for multivariate analysis. The log-rank test was used for comparisons in Kaplan-Meier curves. Statistical significance was defined as a p value less than 0.05.
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Results
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The clinical characteristics of 677 patients with outlet VSD are summarized in Table 1. The surgical indications differed between the two groups as most of the patients with AVP underwent operation owing to valve prolapse and some because of heart failure symptoms. For those without AVP, most received an operation because of heart failure, and some because of associated lesions. So we can see more heart failure symptoms, younger age at operation, larger Qp/Qs, and higher pulmonary artery pressure in patients without AVP as compared with patients with AVP.
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Table 1. Comparisons of Clinical Characteristics in 677 Patients With Outlet Ventricular Septal Defect According to Presence of Aortic Valve Prolapse
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The data of the 373 patients with AVP associated with various types VSD are further studied and summarized in Table 2. The age at operation ranged from 0.1 to 64.4 years (median, 7.2). Aortic regurgitation was found in 51 patients (14%), with 29 (56.9%) of them presenting as mild degree AR. The symptoms of heart failure and the Qp/Qs ratio showed no significant difference among these three types of VSD, only the mean pulmonary artery pressure was higher in perimembranous outlet VSD. The size of VSD was, however, smallest in muscular outlet VSD, and almost the same in juxta-arterial and perimembranous outlet VSD. Infundibular hypertrophy was found in only about one tenth of the VSD patients but was present in one third of the patients with perimembranous outlet or muscular outlet type. Similarly, the anterior malalignment of outlet septum and the presence of subaortic ridge were most frequently found in perimembranous outlet type.
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Table 2. Comparisons of Variables in Different Types of Ventricular Septal Defect and Aortic Valve Prolapse Patients
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Rupture of sinus Valsalva was noted in 20 VSD patients with AVP (5.4%), and most commonly in juxta-arterial VSD (8.1%). Necessity of aortic valvuloplasty or aortic valve replacement during or soon after VSD repair (less than 1 month after VSD repair) was higher in the juxta-arterial and perimembranous outlet type than in the muscular outlet type. Also, we found both the incidence and severity of AR were lowest in the muscular outlet type (Table 2). To clarify the effects of possible confounding factors such as patient age, size of VSD, or shunt flow, we performed multiregression analysis and found that muscular outlet type VSD was still associated with the lowest chance with severe AVP (defined as necessity for aortic valvuloplasty or aortic valve replacement during or soon after repair of VSD; Table 3).
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Table 3. Risk Factors of Severe Aortic Valve Prolapse as Defined by Necessity of Aortic Valvuloplasty or Aortic Valve Plasty During or Soon After Surgery by Linear Multiregression Analysis
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In all juxta-arterial type cases and most muscular outlet VSD, the right coronary cusp was the major prolapsed cusp. But in the perimembranous outlet type, the involvement of noncoronary cusp prolapse was also common (16.5%; Table 2). However, we found that all patients with anterior malalignment VSD (17 perimembranous outlet type and 4 muscular outlet type) had a trend for AVP involving only the right coronary cusp (21/21, p = 0.06).
Onset of AVP and AR
Among the 373 patients with AVP, 252 patients had received regular follow-up since birth. Among them, the onset age of AVP ranged from 0.2 to 18.8 years, (mean, 5.0 ± 4.1; median, 4.0). The mean onset ages of AVP in juxta-arterial, perimembranous outlet, and muscular outlet VSD were 4.9 ± 3.9, 5.0 ± 4.7, and 5.1 ± 3.8 years, respectively (p = 0.89, by log-rank test). By Kaplan-Meier analysis, the probability of freedome from AVP in each type of VSD in our study population is shown in Figure 2. The onset age of AR ranged from 0.7 to 14.9 years (mean, 5.8 ± 4.7; median, 3.9). As only 10 of the 252 patients had AR during follow-up, no further analysis of AR onset in each type of VSD was done. Using the multiregression analysis, we found that patients with larger Qp/Qs had an earlier onset of AVP, and those with anterior malalignment also tended to have earlier onset of AVP (Table 4). Further risk stratification in three types VSD is shown in Table 5. Larger shunt was the only significant risk factor for earlier onset of AVP in juxta-arterial type. For perimembranous and muscular outlet type, no significant risk factor for earlier onset AVP could be found.
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Fig 2. Kaplan-Meier curve of the onset age of aortic valve prolapse in ventricular septal defect patients with regular follow-up. Log-rank analysis showed no statistical difference in the onset age of these three types of ventricular septal defect, with p value 0.89. Dotted line = perimembranous outlet; heavy line = doubly committed juxta-arterial; light line = muscular outlet.
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Table 5. Risk Factors of Earlier Onset of Aortic Valve Prolapse in Three Types of Ventricular Septal Defect by Linear Multiregression Analysis
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Comment
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Aortic valve prolapse and aortic regurgitation can occur in outlet type VSD, but the occurrence may vary in VSD with different outlet extension, and such data are still far from clear. The main findings of this study on patients with outlet type VSD and AVP were these: (1) the onset age of AVP and AR was not different among different outlet type VSD; (2) the presence of a large shunt and possibly anterior malalignment might predict an earlier onset of AVP; (3) the perimembranous outlet and muscular outlet VSD when complicated with AVP were also frequently associated with infundibular hypertrophy (stenosis), anterior malalignment of interventricular septum, and subaortic ridge; (4) AVP in juxta-arterial VSD was always isolated right coronary cusp prolapse, whereas noncoronary cusp or combined noncoronary cusp and right coronary cusp prolapse could be found in perimembranous outlet VSD and rarely in the muscular outlet type; and (5) the severity of AVP defined as necessity of aortic valve repair was lowest in muscular outlet type VSD.
Previous studies of VSD and AVP have only defined the onset age of AVP and AR in juxta-arterial VSD [6–9]. Our data of a large patient cohort revealed that the onset age of AVP was similar among the different outlet types of VSD, including juxta-arterial, perimembranous outlet, and muscular outlet VSD. The mechanism of AVP in juxta-arterial VSD may include lack of infundibular septal support, intrinsic discontinuity of aortic valve annulus and aortic media, and Venturi effect of the VSD jet [8, 16]. For perimembranous outlet VSD, although abnormal development of sinus Valsalva was proposed as a possible reason, the most acceptable mechanism of AVP is still the Venturi effect [17]. The mechanism of AVP in muscular outlet VSD may be less complicated and mainly related to the Venturi effect. Because of the different underlying mechanisms for AVP in various types of outlet VSD, the incidence of AVP was reported to be highest in juxta-arterial VSD and lower in perimembranous outlet and muscular outlet VSD [16, 18]. However, we nonetheless observed that the onset age of the three outlet types VSD was similar. Although patients without AVP may receive operation early owing to large shunt and heart failure and therefore the onset age of AVP in each type of VSD obtained from this study may be skewed, our observation may still have an important clinical implication. It may be suggested that in outlet type VSD, regardless of its extension, the same discipline should be followed to detect AVP early.
As to the risk factors for an early onset of AVP in outlet VSD, we found a larger shunt and possibly anterior malalignment would predict an earlier onset of AVP. The importance of larger shunt in AVP was especially true in juxta-arterial VSD. The reasons why a large shunt may predispose to the development of AVP are still unclear, but it may be partially explained by the Venturi effect, as larger shunt may increase flow velocity, which makes greater pressure drop. Larger pressure difference through VSD then makes aortic valve prolapse easier [10, 12, 19].
As for the associated lesions, we found less subaortic ridge, infundibular hypertrophy, or anterior malalignment in juxta-arterial type VSD, which could be due to the deficiency of outlet septum in juxta-arterial type VSD. In perimembranous or muscular outlet VSD, the subaortic ridge was frequently present with anterior malalignment. However, the mechanism was still unclear [20, 21]. On the other hand, the incidence of infundibular hypertrophy in perimembranous outlet and muscular outlet VSD was relatively high (around 30%), so this pathology should be carefully evaluated before surgery. Surgical resection of the hypertrophic muscle is commonly indicated to prevent residual infundibular stenosis [22].
Because our study population was surgical patients, the true incidence of AVP or AR in the three types of VSD could not be estimated. However, we found more rupture of sinus Valsalva in juxta-arterial type VSD. The rupture of sinus Valsalva and necessity of aortic valvuloplasty were lowest for muscular outlet type VSD, which may indicate that the progression of AVP may be relatively slow in muscular outlet type VSD. We suspect that more support beneath the aortic valve is present in muscular outlet type than in juxta-arterial VSD. However, whether AVP in muscular outlet type VSD carries a better prognosis or not needs further investigation.
In concordance with our previous study, isolated right coronary cusp prolapse was found in all juxta-arterial VSD, and noncoronary cusp prolapse was found in 15.6% of perimembranous outlet and 2.3% of muscular outlet VSD patients [7]. The lack of infundibular septum in juxta-arterial VSD makes right coronary cusp lack support beneath [17]. In perimembranous outlet VSD, because the VSD is located below both right coronary cusp and noncoronary cusp, the Venturi effect that affects both cusps may result in either right coronary cusp or noncoronary cusp prolapse or both. However, we also found that AVP in those with anterior malalignment always involves the right coronary cusp. We suspect that anterior malalignment with aorta overriding makes the aortic cusp lack support beneath, which may mimic the situation in juxta-arterial VSD. So the pattern of aortic cusp involved is similar to that in juxta-arterial VSD.
Conclusion
Although the clinical characteristics were distinct among the three outlet types of VSD (less subaortic ridge and infundibular hypertrophy in juxta-arterial type and more anterior malalignment in perimembranous outlet type), the onset age of AVP and AR was similar among the patients with juxta-arterial, perimembranous outlet, and muscular outlet VSD. In juxta-arterial VSD and that with anterior malalignment, the prolapsed cusp was always the right coronary cusp, but noncoronary cusp involvement was also common in perimembranous outlet type. In VSD with larger shunt, AVP tended to have an earlier onset, which was especially true in juxta-arterial VSD.
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Abstract
Introduction
