Prognostic Implications of Initial Echocardiographic Findings in Adolescents and Adults with Supracristal Ventricular Septal Defects

Prognostic Implications of Initial Echocardiographic Findings in Adolescents and Adults with Supracristal Ventricular Septal Defects Min Soo Cho, MD, Sun-Joo Jang, MD, Byung Joo Sun, MD, Jeong Yoon Jang, MD, Jung-Min Ahn, MD, Dae-Hee Kim, MD, Jong-Min Song, MD, Duk-Hyun Kang, MD, and Jae-Kwan Song, MD, Seoul, South Korea

Background: Although surgery is recommended for pediatric patients with supracristal ventricular septal defects (sVSDs) to prevent progression of aortic regurgitation (AR), outcomes in adolescents and adults with sVSDs are not known. Methods: In this retrospective observational study, clinical data without surgery were obtained in 60 patients with sVSDs (group 1; mean age, 36 6 13 years), 120 age- and defect size–matched patients with perimembranous ventricular septal defects (group 2), and 52 patients with sVSDs who underwent surgery (group 3; mean age, 32 6 11 years). Results: Aortic sinus wall prolapse (38% vs 3%, P < .0001) and moderate to severe AR (7% vs 0%, P = .012) were more frequently observed in group 1 than in group 2. Five, three, and two patients in group 1 had surgery during follow-up because of rupture of the aneurysm of the sinus of Valsalva, endocarditis, and heart failure, respectively. Group 1 had a lower 12-year clinical event-free (surgery and endocarditis) rate (76 6 9% vs 94 6 4%, P = .031) but an equivalent overall survival rate (100% vs 94 6 3%, P = .143) compared with group 2. Patients with maximal prolapsing aortic sinus wall length > 7 mm showed a higher frequency of aneurysm of the sinus of Valsalva rupture than those with no prolapse or maximal prolapsing length # 7 mm (80% [four of five] vs 2% [one of 55], P < .001). The event-free and overall survival rates were comparable between groups 1 and 3, with equivalent 10-year AR progression–free survival rates (94 6 5% vs 91 6 5%, P = .301). Conclusions: Aneurysm of the sinus of Valsalva rupture, rather than AR progression, was the main clinical event. Watchful monitoring of patients with high-risk echocardiographic features may be a rational option. (J Am Soc Echocardiogr 2014;27:965-71.) Keywords: Subarterial ventricular septal defect, Aortic regurgitation, Aneurysm of sinus of Valsalva, Echocardiography

The association between ventricular septal defect (VSD) and aortic regurgitation (AR) was recognized as an important disease entity many years ago. Supracristal VSD (sVSD) is strongly associated with this disease entity, which is characterized by a totally deficient infundibular septum1 and a lack of continuity between the aortic media, annulus, and ventricular septum.2 Aortic valve prolapse that results in AR and aneurysm of the sinus of Valsalva (ASV) are common aortic complications of sVSD and are reported to progress once they develop.3-6 Therefore, it has been recommended to repair the defect surgically as soon as these aortic complications are From the Cardiac Imaging Center, Asan Medical Center Heart Institute, University of Ulsan College of Medicine, Seoul, South Korea. Reprint requests: Jae-Kwan Song, MD, Cardiac Imaging Center, Asan Medical Center Heart Institute, University of Ulsan College of Medicine, 388-1 Poongnap-dong Songpa-gu, Seoul, 138-736, South Korea (E-mail: jksong@amc. seoul.kr). 0894-7317/$36.00 Copyright 2014 by the American Society of Echocardiography. http://dx.doi.org/10.1016/j.echo.2014.05.016

detected.2,7-9 However, this recommendation is based on observational studies of young pediatric patients (mean age < 10 years),5,8,9 and the natural history of patients with sVSDs who have reached adolescence or adulthood is poorly understood. Given that the aorta and cardiac chambers grow only during childhood and stop expanding significantly after 15 years of age,10 it is possible that the progression or pattern of these aortic complications in adult patients with sVSDs may differ from those in children, and even in young pediatric patients, the role of prophylactic surgery for patients without aortic complications remains controversial.11,12 We aimed to evaluate the natural histories of adolescents and adults with sVSDs and to determine factors associated with the development of aortic complications, including AR progression and ASV rupture. The clinical outcomes of those adolescent or adult patients with sVSDs, who were followed conservatively and treated surgically only when necessary, were compared with those of adult patients with perimembranous VSDs (pmVSDs), for whom the same watchful monitoring strategy has been accepted as the standard approach, and those of patients with sVSDs who underwent initial surgery. 965

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Abbreviations

AR = Aortic regurgitation

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METHODS Study Population

Between January 1990 and November 2009, 134 patients >16 years of age were confirmed pmVSD = Perimembranous to have isolated sVSDs without ventricular septal defect complex congenital lesions in our institution. The routine evalusVSD = Supracristal ation included transthoracic ventricular septal defect echocardiography and a singleVSD = Ventricular septal pass heart scan using 99mTc-diethdefect ylenetriamene penta-acetate to measure Qp/Qs. Patients were excluded if they had Eisenmenger syndrome (n = 2) or were not followed up after the initial visit (n = 20). The subjects thus consisted of the remaining 60 patients with sVSDs who were followed conservatively and whose follow-up data were available (group 1) and 52 who underwent initial surgery (group 3). In group 3, the development of complications (ASV rupture [n = 11] and infective endocarditis [n = 6]) or heart failure (n = 5) was main indication for surgery, and the remaining 30 stable patients without symptoms underwent surgery under attending physicians’ discretion. As a control group, 120 age- and defect size–matched patients with pmVSDs who were also followed conservatively for the development of symptoms or complications before surgical intervention were selected from the database of our echocardiography laboratory (group 2). This retrospective study conformed to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a priori approval by our institutional review board. The requirement for informed consent was waived by the board for this study. ASV = Aneurysm of the sinus of Valsalva

Echocardiography The diagnoses of sVSD and pmVSD were based on the echocardiographic observations,13,14 and transesophageal echocardiography was generally recommended for detailed evaluation of sVSDs and associated anatomic abnormalities, which was performed in >70% of patients. The echocardiographic images were reviewed to determine whether significant aortic sinus wall prolapse was present because of herniation of the aortic wall through the VSD (Figures 1A–1D). The size of the remnant VSD showing flow communication through the defect was measured at mid-systole in the magnified view (Figure 1). In patients with aortic sinus wall prolapse, the maximal length of the prolapsed wall was measured at diastole; the maximal distance between the crest of interventricular septum and beginning of the aortic sinus wall prolapse at systole was defined as presumptive true VSD size (Figures 1E–1H). Parasternal long-axis images on transthoracic echocardiography were used for VSD size measurement; in patients with poor resolution, the long-axis image on transesophageal echocardiography was used. The degree of AR was assessed by comprehensive Doppler echocardiographic measurements using jet width, jet cross-sectional area in the left ventricular outflow tract, and Doppler tracing of the aortic flow and classified as mild, moderate, or severe.15 Cardiac chamber dimensions and left ventricular ejection fraction were measured according to the recommendations of the American Society of Echocardiography.16 Data Collection and Analysis A chart review was performed, and the data were collected by using a standardized form that recorded the information regarding

patient demographics, medical history, clinical presentation, result of imaging studies, and adverse clinical events. Adverse clinical events included a composite of open-heart surgery for any cause, including reoperation after the initial surgery in group 3, cardiac death, and the development of infective endocarditis.9 Followup data were collected by a direct telephone interview and a detailed review of all medical records. The causes and dates of any deaths were confirmed by information gathered from the National Population Registry of the Korean National Statistical Office, together with a review of all available clinical records at the time of death. The median follow-up durations were 78 months in the sVSD group (interquartile range, 37–137 months) and 71 months in the pmVSD group (interquartile range, 39–115 months). Statistical Analysis All statistical analyses were performed by using SPSS version 18.0 (SPSS, Inc, Chicago, IL). Summary statistics are presented as frequencies and percentages or as mean 6 SD. Differences between two groups in terms of continuous variables were tested by using unpaired Student t tests and the Mann-Whitney U test and differences among three groups by using analysis of variance and the Tukey method for post hoc analysis. The c2 test or Fisher exact test was used to compare the frequencies of categorical variables between groups. Bonferroni correction was used for multiple comparisons. The Spearman rank correlation test was performed to evaluate an association between AR severity and the maximal length of the prolapsing aortic wall. To determine the cutoff value of the maximal length of the prolapsing aortic wall for predicting the development of ASV rupture, a receiver operating characteristic curve was used. To identify factors that were associated with the development of clinical events in groups 1 and 2, univariate and multivariate Cox proportional-hazard models were used. In multivariate analysis, VSD type, left atrial size, and left ventricular size were used in the backward linear regression method. Cumulative survival and eventfree survival rate curves were generated with the Kaplan-Meier method and compared by using the log-rank test. All P values were two sided, and P values < .05 were considered significant. Intraobserver and interobserver variability for the measurement of VSD size were assessed by Bland-Altman analysis, with interobserver variability by intraclass correlation coefficients between two independent observers for 20 randomly selected patients. The two independent observers achieved interobserver variability of 0.92 to 0.98 and intraobserver variability of 0.94 to 0.98.

RESULTS The baseline characteristics of the patients are summarized in Table 1. Groups 1 and 2 did not differ with regard to age at initial diagnosis, mean size of the remnant VSD, left ventricular size, or Qp/Qs. Compared with group 2, group 1 had a significantly higher prevalence of aortic sinus wall prolapse (P < .0001) and moderate to severe AR (P = .012). Moderate to severe AR was observed only in the sVSD group. There was no significant association between AR severity and the maximal length of the prolapsing aortic sinus wall in the group 1 (r = –0.115, P = .603). The presumptive true VSD size (6.1 6 4.1 vs 8.7 6 5.6 mm, P = .010) and remnant VSD size (3.5 6 0.9 vs 5.1 6 3.3 mm, P < .001) were larger in group 3 compared with group 1. This trend was also observed in patients

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Figure 1 Representative transthoracic echocardiographic images (A–D) of sVSDs (arrow) with (A,B) and without (C,D) a prolapsing aortic sinus wall (dotted line). In the magnified images (B,D), the sizes of the remnant VSDs are measured (double-headed arrows). Transesophageal echocardiographic images (E–H) shows how the maximal length of a prolapsing aortic sinus wall (white arrow) and the presumptive true VSD size (dotted arrow) are measured. Ao, aorta; LA, left atrium; LV, left ventricle; RV, right ventricle.

Table 1 Baseline characteristics of the subjects Variable

Group 1 (n = 60)

Group 2 (n = 120)

Group 3 (n = 52)

P

Age (y) Men Diabetes Hypertension Qp/Qs on heart scan Echocardiographic data Remnant defect size (mm) LV diastolic dimension (mm) LA dimension (mm) Trans-VSD PG (mm Hg) RV-RA PG (mm Hg) LV ejection fraction (%) AR Mild Moderate Severe Prolapse of aortic sinus wall

36.3 6 12.6 29 (48.3%) 3 (5.0%) 9 (15.0%) 1.35 6 0.15

36.5 6 14.2 56 (46.7%) 5 (4.2%) 20 (16.7%) 1.32 6 0.18

32.2 6 10.9 33 (63.5%) 0 (0%) 2 (3.8%) 1.79 6 0.76*

.127 .116 .290 .069 .353

3.5 6 0.9 52.2 6 5.9 37.3 6 5.7 117.0 6 32.6 22.0 6 5.4 62.3 6 5.8 24 (40.0%) 20 3 1 23 (38.3%)

3.6 6 1.3 51.3 6 6.3 37.7 6 5.9 109.5 6 31.2 24.3 6 8.5 61.7 6 7.2 10 (8.3%)* 10 0 0 3 (2.5%)*

5.1 6 3.3 56.7 6 8.5* 41.4 6 7.5* 102.5 6 26.5 36.4 6 17.6* 61.5 6 7.7 39 (75.0%)* 28 7 4 28 (53.8%)

<.001 <.001 <.001 .076 <.001 <.001 <.001

<.001

LA, Left atrial; LV, left ventricular; PG, pressure gradient; RA, right atrium; RV, right ventricular. Data are expressed as mean 6 SD or number (percentage). *P < .05 versus group 1.

with sVSDs and aortic wall prolapse (10.3 6 4.0 and 12.8 6 4.8 mm in groups 1 and 3, respectively, P = .052). Compared with group 1, group 3 showed larger left ventricles and left atria and a higher

prevalence of AR. Sixteen patients underwent additional aortic valve procedures during initial surgery for sVSDs, with valve repair in nine and replacement in seven patients.

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Figure 2 Representative echocardiographic images of a patient with a sVSD before (A–D) and after (E–H) the ASV ruptured. At the time of the initial diagnosis in 1999, prolapse of the aortic sinus (dotted line in A) wall was present, but there was no evidence of AR or aorta–right ventricular shunt (D). Eleven years later, the patient reported the sudden onset of dyspnea, and echocardiography showed a prominent aneurysmal change (E). Color Doppler flow mapping revealed continuous shunt flow from the aorta to the right ventricle (H) in addition to the shunt through the VSD (G).

During follow-up, ASV rupture into the right ventricle occurred in five patients in group 1 (Figure 2), and urgent surgical correction was required. Three patients in group 1 developed infective endocarditis, which also required open-heart surgery. One patient developed ASV rupture and infective endocarditis simultaneously. Vegetations developed in the right ventricular side of the sVSD in two patients and in the aortic valve in one patient. The other indication for open-heart surgery during follow-up was the development of heart failure symptoms, which occurred in two patients. One of these patients refused surgical intervention for severe AR at the time of the initial diagnosis, developed progressive dyspnea, and underwent open-heart surgery. The other patient exhibited a progressive increase in Qp/Qs (from 1.4 to 1.6) and a decrease in left ventricular ejection fraction (from 66% to 53%) 10 years after diagnosis, and surgery was recommended because of the development of symptoms. None of the patients underwent surgery because of progression to severe AR. In group 2, two patients underwent open-heart surgery because of infective endocarditis and the development of heart failure symptoms. Another two patients with pmVSDs also developed infective endocarditis and recovered without surgical intervention. None of the patients in the sVSD group died, whereas four patients in the pmVSD group had noncardiac deaths. Adverse clinical events occurred more frequently in group 1 (15.0% [nine of 60] vs 3.3% [four of 120], P = .011). Univariate analysis revealed that VSD type, left atrial size, left ventricular end-diastolic dimension, aortic sinus wall prolapse, and AR were significantly associated with the development of adverse clinical events. A multivariate Cox proportional-hazard model revealed that sVSD (hazard ratio,

4.55; 95% confidence interval, 1.17–17.74; P = .029) and left atrial size (hazard ratio per millimeter, 1.18; 95% confidence interval, 1.07–1.30; P = .001) were independent risk factors for the development of adverse clinical events. The 12-year adverse event-free survival rate was lower in the sVSD group (76 6 9% vs 94 6 4%, P = .031), but the two groups did not differ in 12-year overall survival rate (100% vs 94 6 3%, P = .143; Figure 3). ASV rupture in the sVSD group developed suddenly, without any preceding symptoms or signs. Except for one patient, all patients showed prominent prolapse of the aortic sinus wall at the time of the initial diagnosis, and the duration from the diagnosis of sVSD to ASV rupture was longer than the durations from diagnosis to all other clinical events (median, 142 months [range, 85–165 months] vs 48 months [range, 9–120 months]; P = .014). Of 23 patients with aortic sinus wall prolapse at the initial diagnosis, four (17%) developed ASV rupture, whereas only one of 37 patients (3%) without aortic sinus wall prolapse developed ASV rupture (P = .066). ASV rupture was critically dependent on the maximal length of the prolapsing aortic sinus wall: patients with maximal prolapsing aortic sinus wall length > 7 mm showed a higher frequency of ASV rupture than those with no prolapse or maximal prolapsing length # 7 mm (80% [four of five] vs 1.8% [one of 55], P < .001). The positive and negative predictive values were 80% and 98%, respectively. During follow-up period, two patients in group 3 died of sudden cardiac death and infective endocarditis. The 12-year event-free and overall survival rates were comparable between groups 1 and 3 (Figure 3). Of the nine patients in group 1 who developed adverse clinical events, initial evaluation showed mild, moderate, and severe

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Figure 3 Comparison of event-free and overall survival rates between the groups. AR in two, two, and one patient, respectively. Two patients who underwent open-heart surgery because of progressive dyspnea and did not show any change in AR severity during follow-up. Among five patients who developed ASV rupture, AR progression was observed in two (from mild to moderate AR in one patient and from no AR to moderate AR in the other). AR progression from no AR to severe AR happened in one patient who developed infective endocarditis involving the aortic valve, whereas the other patients who developed endocarditis not involving the valve did not show any AR progression. Of the 51 patients with sVSDs who did not develop events, followup echocardiographic data showing whether the severity of AR had changed over time were available for 38 patients (74.5%) during follow-up (median follow-up, 86 months; interquartile range, 31–140 months). Only two of the patients showed changes in the severity of AR (Figure 4A). None of the 38 patients developed severe AR during follow-up. Long-term echocardiographic follow-up data (median follow-up, 62 months; interquartile range, 23–106 months) were available in 41 patients (78.8%) in group 3, and three patients showed AR progression (Figure 4B), but none underwent the repeat surgery to control AR. Interestingly, these three patients all underwent aortic valve repair procedures at the time of initial sVSD closure surgery. The 10-year AR progression-free survival rate was not different between groups 1 and 3 (94 6 5% vs 91 6 5%, P = .301). DISCUSSION This retrospective analysis of clinical outcomes of sVSD and pmVSD revealed that open-heart surgery was more frequently performed during the watchful monitoring of adult patients with sVSDs than during the watchful monitoring of adult patients with pmVSDs. However, as discussed in more detail below, these events did not develop as frequently in adolescent or adult patients with sVSDs as in pediatric patients with sVSDs. Moreover, these events did not translate directly into excess mortality; indeed, the overall survival rates were excellent.

Figure 4 Diagrams showing the severity of AR in patients with sVSDs during follow-up with (lower panel, B) and without (upper panel, A) initial surgery. AR progression was rare, and ASV rupture and infective endocarditis were the main causes that necessitated surgical intervention. Rupture of the ASV was the most frequent clinical event and was associated with prolapse of the aortic sinus wall through the sVSD. It was found to be critically dependent on the maximal length of the prolapsing wall. Thus, watchful waiting and close monitoring of patients with these high-risk echocardiographic features can be a rational management option for adult patients with sVSDs. Natural History of sVSD: Age, Defect Size, and Other Echocardiographic Findings Supporting the idea of early or prophylactic surgery in patients with sVSDs is that longer durations from the onset of AR to surgical

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intervention are associated with persistent AR after repair surgery.8 However, other investigators have not found that surgery performed before the onset of AR is beneficial.17,18 Moreover, the clinical factors that determine the development of these serious aortic complications have not been investigated fully. The currently available data regarding the natural history of sVSD are based on retrospective analyses of pediatric patients. These analyses show that the prevalence rates of aortic wall prolapse and AR increase gradually in a linear fashion as the age of the patient increases5 and that >80% of pediatric patients with sVSDs needed surgical intervention, with a high rate of AR progression during follow-up.5,9 These findings differ markedly from our finding that adolescent or adults with sVSD who were followed conservatively had a frequency of surgical intervention of 15% (nine of 60) and negligible AR progression. Two possible answers may explain this large difference. VSD size could be an important factor determining the prognosis: the defects observed in our group 1 were <5 mm in size (3.5 6 0.9 mm), whereas the largest series of pediatric patients with sVSDs to date has shown that 82% (176 of 214) had sVSDs defect that were $5 mm in size, with significantly larger Qp/Qs values.9 Because the amount of shunt during systole is believed to be an important hemodynamic factor that contributes to the progression of the syndrome of sVSD and AR,2 it is conceivable that the small defects seen in adults are more likely to be associated with a lower incidence of aortic complications. Supporting the prognostic value of defect size is that some investigators have recommended that even young asymptomatic patients with small defects (<5 mm) can be managed conservatively.9 However, it is also well known that sVSD should be restrictive with regard to the development of prolapse of the adjacent aortic sinus wall and AR. The Venturi effect is believed to be the predominant mechanism behind aortic valve cusp deformity and subsequent AR,19,20 a notion that is supported by the finding that pediatric patients with sVSDs and AR syndrome are nearly always older and seldom have congestive heart failure episodes in infancy, which are characteristic of large VSD. The average Qp/Qs of patients with this syndrome is <2, and pulmonary artery pressures are at most only mildly elevated.20 Thus, the VSD must be restrictive but of sufficient size to produce aortic valve cusp distortion. The other explanation for the difference between adult and pediatric patients with sVSDs in terms of surgery and AR progression rates relates to the normal growth pattern of the aorta. The aorta and cardiac chambers grow in unison and at a predictable rate after birth: their dimensions at birth are 50% of those in adulthood, and this rises to 75% at 5 years of age and 90% at 12 years of age. After puberty, the growth rate slows even further, with significant increases no longer seen after 15 years of age.10 Several studies also show that the cumulative development of aortic complications in pediatric patients with sVSDs is age dependent.4,6,9 Notably, a follow-up echocardiographic study revealed that 65% (17 of 26) of neonates or young infants with sVSDs who did not exhibit AR subsequently developed AR,5 which suggests that AR in association with sVSD is an acquired lesion.20 Moreover, several studies suggest that the peak age for aortic wall prolapse is about 7 years, while the peak age for AR is between 5 and 10 years.6,21-23 All of these findings suggest strongly that the normal rapid growth of the aorta and cardiac chambers in the childhood or infancy plays a critical role in the development of aortic complications in sVSD. Because progressive aortic enlargement is expected to occur mainly during childhood, this could explain why patients with sVSDs tend to develop aortic complications in childhood. Thus, our findings

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support the notion that not only VSD size but also age is an important clinical variable that determines the development of aortic complications and the prognosis of patients with sVSDs. ASV Rupture versus AR Progression ASV rupture is another well-known aortic complication of sVSD, and sVSD is the most common underlying disease associated with the development of ASV rupture.24-26 According to one large-scale study, the incidence of ASV in pediatric patients with sVSDs was less than half that of aortic valve prolapse and AR in patients with sVSDs (9.1% [36 of 395] vs 24.1% [95 of 395]).4 Thus, ASV rupture has not been described as an important complication in pediatric patients with sVSDs. However, in the present study, it was the most common cause of late surgery, and none of our patients underwent surgery for AR progression alone. This apparent discrepancy can again be explained by the different peak age of these complications: prolapse and regurgitation of the aortic valve develop most frequently between 5 and 8 years of age, whereas ASV is not found before the age of 10 years, only begins to develop during the teenage years, and is most frequently diagnosed in patients aged >20 years.4 Thus, the development of adverse clinical events associated with aortic complications in patients with sVSDs is highly dependent on patient age. Our finding showing a close relationship between ASV rupture and the maximal prolapsing aortic sinus wall length at the initial diagnosis reinforces the prognostic implication of echocardiographic findings. However, because of its retrospective study setting and relatively small number of patients with ASV rupture, we could not conclude that prophylactic surgery would be beneficial for selected patients with aortic sinus wall prolapse. Further study is necessary to determine the indication for surgery for patients with sVSDs and aortic sinus wall prolapse to prevent ASV rupture. Limitations This was an observational study at a single center, which lends itself to potential bias. Lack of established guidelines for the management of adolescent and adult patients with sVSDs contributed to inhomogeneity of surgical indications for patients with sVSD and baseline differences between groups in our study, which might affect the long-term outcomes. This, together with the fact that Asians and Caucasians differ in the relative incidence of sVSD, means that the findings of the present study should be generalized with caution. The patients who did not visit our institution after the first visit were excluded from analysis, and follow-up echocardiographic data were not available in all of the patients who did not show clinical events. Thus, the frequency with which significant AR developed may have been underestimated. However, because events such as hospital admission, mortality, and surgery could be assessed in all study subjects, we believe our main findings are valid despite these limitations. Because those excluded from analysis had comparable age, Qp/Qs, prevalence of AR, and sinus wall prolapse, we may expect a similar favorable prognosis. CONCLUSIONS Clinical outcomes of adolescent and adult patients with sVSDs are characterized by low complication rates and different patterns of complication development. Older patients with sVSDs are at risk for ASV rupture, which is higher than the risk for AR progression. A strong association is present between ASV rupture and aortic sinus wall prolapse.

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The role of prophylactic surgery for patients at high risk (maximal prolapsing aortic sinus wall length > 7 mm) needs to be clarified.

REFERENCES 1. Soto B, Becker AE, Moulaert AJ, Lie JT, Anderson RH. Classification of ventricular septal defects. Br Heart J 1980;43:332-43. 2. Yacoub MH, Khan H, Stavri G, Shinebourne E, Radley-Smith R. Anatomic correction of the syndrome of prolapsing right coronary aortic cusp, dilatation of the sinus of Valsalva, and ventricular septal defect. J Thorac Cardiovasc Surg 1997;113:253-61. 3. Plauth WH, Braunwald E, Rockoff SD, Mason DT, Morrow AG. Ventricular septal defect and aortic regurgitation. Am J Med 1965;39:552-67. 4. Momma K, Toyama K, Atsuyoshi T, Ando M, Nakazawa M, Hirosawa K, et al. Natural history of subarterial infundibular ventricular septal defect. Am Heart J 1984;108:1312-7. 5. Schmidt KG, Cassidy SC, Silverman NH, Stanger P. Doubly committed subarterial ventricular septal defect: echocardiographic features and surgical implications. J Am Coll Cardiol 1988;12:1538-46. 6. Tohyama K, Satomi G, Momma K. Aortic valve prolapse and aortic regurgitation associated with subpulmonic ventricular septal defect. Am J Cardiol 1997;79:1285-9. 7. Hitchcock JF, Suijker WJL, Ksiezycka E, Harinck E, van Mill GJ, Ruzyllo W, et al. Management of ventricular septal defect with associated aortic regurgitation. Ann Thorac Surg 1991;52:70-3. 8. Komai H, Naito Y, Fujiwara K, Noguchi Y, Nishimura Y, Uemura S. Surgical strategy for doubly committed subarterial ventricular septal defect with aortic cusp prolapse. Ann Thorac Surg 1997;64:1146-9. 9. Lun KS, Li H, Leung MP, Yung TC, Chiu CSW, Cheung YF. Analysis of indications for surgical closure of subarterial ventricular septal defect without associated aortic cusp prolapse and aortic regurgitation. Am J Cardiol 2001;87:1266-70. 10. Nidorf SM, Picard MH, Triulzi MO, Thomas JD, Newell J, King ME, et al. New perspectives in the assessment of cardiac chamber dimensions during development and adulthood. J Am Coll Cardiol 1992;19:983-8. 11. Backer CL, Winters RC, Zales VR, Takami H, Muster AJ, Benson W Jr, et al. Restrictive ventricular septal defect: how small is too small to closure? Ann Thorac Surg 1993;56:1014-9. 12. Santini F, Mazzucco A. Timing of surgical closure of subpulmonary ventricular septal defect in infancy. Am J Cardiol 1997;80:976-7. 13. Griffin ML, Sullivan ID, Anderson RH, Macartney FJ. Doubly committed subarterial ventricular septal defect: new morphological criteria with echocardiographic and angiocardiographic correlation. Br Heart J 1988;59:474-9.

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14. Van Praagh R, Geva T, Kreutzer J. Ventricular septal defect: how shall we describe, name and classify them? J Am Coll Cardiol 1989;14: 1298-9. 15. Zoghbi WA, Enriquez-Sarano M, Foster E, Grayburn PA, Kraft CD, Levine RA, et al. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003;16:777-802. 16. Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, et al. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18: 1440-63. 17. Keane JF, Plauth WH, Nadas AS. Ventricular septal defect with aortic regurgitation. Circulation 1977;56(Suppl I):I-72-7. 18. Karpawich PP, Duff DF, Mullins CE, Cooley DA, McNamara DG. Ventricular septal defect with associated aortic valve insufficiency: progression of insufficiency and operative results in young children. J Thorac Cardiovasc Surg 1981;82:182-9. 19. Tatsuno K, Konno S, Ando M, Sakakibara S. Pathogenetic mechanisms of prolapsing aortic valve and aortic regurgitation associated with ventricular septal defect: anatomical, angiographic, and surgical considerations. Circulation 1973;48:1028-37. 20. Tweddel JS, Pelech AN, Frommelt PC. Ventricular septal defect and aortic valve regurgitation: pathophysiology and indications for surgery. Semin Thorac Cardiovasc Surg Pediatr Card Surg Ann 2006;9:147-52. 21. Lue HC, Sung TC, Hou SH, Wu MH, Cheng SJ, Chu SH, et al. Ventricular septal defect in Chinese with aortic valve prolapse and aortic regurgitation. Heart Vessels 1986;2:111-6. 22. Mori K, Matsuoka S, Tatara K, Hayabuchi Y, Nii M, Kuroda Y. Echocardiographic evaluation of the development of aortic valve prolapse in supracristal ventricular septal defect. Eur J Pediatr 1995;154:176-81. 23. Chiu SN, Wang JK, Lin MT, Wu ET, Lu FL, Chang CI, et al. Aortic valve prolapse associated with outlet-type ventricular septal defect. Ann Thorac Surg 2005;79:1366-71. 24. Chu SH, Hung CR, How SS, Chang H, Wang SS, Tsai CH, et al. Ruptured aneurysms of the sinus of Valsalva in Oriental patients. J Thorac Cardiovasc Surg 1990;99:288-98. 25. Choudhary SK, Bhan A, Sharma R, Airan B, Kumar AS, Venugopal P. Sinus of Valsalva aneurysms: 20 years’ experience. J Card Surg 1997;12: 300-8. 26. Jung SH, Yun TJ, Im YM, Park JJ, Song H, Lee JW, et al. Ruptured sinus of Valsalva aneurysm: transaortic repair may cause sinus of Valsalva distortion and aortic regurgitation. J Thorac Cardiovasc Surg 2008;135:153-8.