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Address for reprints: Can Yerebakan, MD, Children's National Heart Institute, Children's National Hospital, The George Washington University School of Medicine and Health Sciences, 111 Michigan Ave NW, Washington, DC 20010.
The aim of the study was to evaluate the course of aortic valve regurgitation in patients with preoperative aortic valve regurgitation and ventricular septal defect who underwent repair of the ventricular septal defect without aortic valve repair.
Methods
A total of 37 consecutive patients with a ventricular septal defect and aortic regurgitation who underwent surgery between April 2007 and March 2016 were included in the study. Demographic, echocardiographic, operative, and clinical data were reviewed. Early and late mortality and morbidity were analyzed. Aortic regurgitation grade, left ventricular function, and dimensions were compared between the preoperative transesophageal echocardiography and postoperative transthoracic echocardiogram at last follow-up. Multivariate logistic regression analysis was performed to determine factors associated with improvement of aortic valve function.
Results
There was no early or late mortality. No reoperations or reinterventions were required. A total of 17 patients had mild or greater aortic regurgitation preoperatively. Only 5 patients had mild or greater aortic regurgitation at follow-up of 4.3 years (0.5-10.1). Twenty-eight (76%) of the 37 patients showed an improvement in their aortic regurgitation grade. Left ventricular end-systolic and end-diastolic diameter z-scores were significantly lower at follow-up (P = .007 and P = .001, respectively). Multivariable logistic regression identified low preoperative left ventricular ejection fraction as the only predictor of nonimprovement of aortic regurgitation (95% confidence interval, 0.732-0.999, P = .002).
Conclusions
Repair of a ventricular septal defect with accompanying aortic regurgitation can be performed with excellent results without surgical intervention on the aortic valve. Accompanying aortic regurgitation, especially trivial to mild, at the time of ventricular septal defect repair improves in the majority of cases. Low preoperative left ventricular ejection fraction is predictive of nonimprovement of aortic regurgitation grade.
Aortic valve intervention can be avoided at the time of VSD closure in patients with trivial to mild AR. An early VSD closure alone improves aortic valve disease.
The intervention on the aortic valve in patients with a VSD with AR remains controversial. Our midterm results showed the closure of VSD at the stage of trivial or mild AR can not only stop the progression of AR but also result in improvement. Early closure of VSD may prevent any intervention on aortic valve.
Ventricular septal defects (VSDs) are known to be associated with aortic regurgitation (AR) due to prolapse of the right and noncoronary aortic cusps.
The prolapse of the aortic valve cusp due to the Venturi effect (Laubri-Pezzi syndrome) may reduce the left to right shunt, but it can also lead to distortion of the aortic valve leaflets, loss of coaptation, and progressive AR.
Pathogenetic mechanisms of prolapsing aortic valve and aortic regurgitation associated with ventricular septal defect: anatomical, angiographic, and surgical considerations.
Development of new or worsening AR is often considered an indication for intervention on the VSD even if it is not leading to a hemodynamically significant shunting. The natural history of AR after repair of these defects has been extensively studied in Asian countries.
The aim of this study is to evaluate the fate of AR after isolated repair of the VSD and to identify predictors of continued or progressive aortic insufficiency (AI).
Materials and Methods
A retrospective review of all patients with subarterial or perimembranous VSDs with AR who underwent isolated repair of VSD without surgical aortic valve intervention at Children's National Hospital, Washington, DC, between April 2007 and March 2016 was undertaken.
Patients with VSDs other than juxta-arterial and perimembranous VSDs, patients with VSD without AR, and patients with follow-up less than 6 months were excluded. Demographic, operative, postoperative, and follow-up data were collected. Intraoperative transesophageal echocardiography was performed for each patient to assess the location and size of VSD, degree of aortic cusp prolapse, and AR before and after the surgical intervention. The quantity of AR was graded as trivial, mild, moderate, and severe according to standards published by the American Society of Echocardiography.
European Association of Echocardiography recommendations for the assessment of valvular regurgitation. Part 1: aortic and pulmonary regurgitation (native valve disease).
The restriction through the VSD was graded according to peak velocity (1 ≥ 4 m/s, 2 = 3-4 m/s, 3 = 2.5-3 m/s). AR grade, left ventricular function, and left ventricular dimensions were compared between the preoperative and follow-up transthoracic echocardiograms. Surgery was performed using standard bicaval venous cannulation at moderate hypothermia at 28 °C to 32 °C. All patients underwent VSD closure through a transatrial or transpulmonary approach using a Dacron or a glutaraldehyde-treated autologous pericardial patch and interrupted pledgeted sutures. Cusp prolapse was graded on a 3-point scale by echocardiographic imaging: mild (buckling of aortic cusp with minimal herniation, aortic cusp protrudes slightly into defect only during early systole), moderate (prolapse of cusp with obvious herniation into the septal defect), and severe (prolapse of cusp and its sinus through the defect into the right ventricular outflow tract during both systole and diastole).
VSD size (according to categories of mean peak velocity), change in AR grade, percent fractional shortening, percent left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume index, left ventricular end-systolic volume index, Z-scores for left ventricular end-diastolic diameter, left ventricular end-systolic dimension, left ventricular posterior wall in diastole, and left ventricular posterior wall in systole are reported as median and interquartile range (IQR) and compared with the nonparametric Wilcoxon signed-rank test. Patients with mild or more AI at follow-up were considered to have “persistent AR.” This was based on a clinical need to observe these patients in the future for progression of AR. Multivariable logistic regression analysis with a backward selection was applied to identify factors associated with persistent AR at follow-up and the Wald test used to assess significance and the odds ratio and 95% confidence interval (CI) as measures of risk. Because the outcome was binary, the rule of thumb has been relaxed to 1 variable per 5 outcomes or 4 events per variable (as opposed to 1 in 10 events per variable for continuous outcomes).
The Fisher exact test was used to determine the significance of association between degree of preoperative cusp prolapse and residual VSD with persistent AR. The probability of persistent AR based on preoperative LVEF was determined by maximum likelihood estimation. Statistical analysis was performed using Stata version 16 (StataCorp LLC).
Results
A total of 37 patients were enrolled in the study (54% were male). Median age at surgery was 2.7 years (IQR, 0.2-16.6), and median weight at surgery was 13.4 kg (IQR, 6.9-20.8 kg) (Table 1). Preoperative AR grade was less than mild in 20 patients (54%), mild in 14 patients (38%), moderate in 2 patients (5%), and severe in 1 patient (3%). Thus, 17 patients had mild or greater AR preoperatively. All patients underwent VSD repair alone. The VSD was closed via a transatrial approach in 86% of patients and transpulmonary in 14% of patients. Perimembranous VSD was the most common type of VSD (n = 28; 75.6%) (Table 1). There were no operative or long-term mortalities, and no reinterventions were performed during the follow-up. All patients underwent echocardiography at their clinical visits including the latest one. The median duration of clinical and echocardiographic follow-up was 4.3 years (IQR, 2.6-5.5). The follow-up was 100% at the end of the study period.
Table 1Demographics and ventricular septal defect closure approach
At a median follow-up of 4.3 years, 28 of the 37 patients with restrictive VSD (76%) showed an improvement in AR (95% CI, 60-87) and 5% (14%; 95% CI, 6-28) had greater than or equal to mild AR (Figures 1 and 2). None of the patients with mild or more AR had a worsening in the AR grade, whereas 10% of patients (2/20) with trivial AR progressed to mild AR. Of the 2 patients with moderate AR, 1 improved to no AR and the other continued to have moderate AR at follow-up. One patient with severe AR continued to have severe AR at follow-up. Preoperatively, the left ventricular end-systolic dimension and left ventricular end-diastolic diameter z-scores were (median value with IQR) 1.0 (0.3-2.1) and 1.4 (0.5-2.8), respectively. Postoperatively, they were 0.7 (0.2-1.3) and 0.4 (−0.3 to 0.7), respectively (P = .007 and P = .001, respectively) (Table 2). A corresponding reduction in LVEF and fractional shortening was noted (Table 2). Median values (IQR) for preoperative and postoperative left ventricular end-diastolic volume index were 50.9 (36.9-71.2) and 46 (37.5-54.3) with a P value of .046 (Table 2 and Figure 3. Although median values (IQR) for preoperative and postoperative left ventricular end-systolic volume index were 19 (11.9-22.9) and 17.6 (14.6-23.8) mL/m2 (21-40) with a P value of .367 (Table 2 and Figure 3), a comparison of various preoperative echocardiographic parameters revealed preoperative ejection fraction (EF) to be significantly lower in the persistent AR group (58.8%; 56.7%-59.6% vs 66.6%; 62.7%-69%; P = .003) (Table 3). Logistic regression analysis identified low preoperative LVEF as the only predictor of persistent AR (odds ratio, 1.35; CI, 1.05-1.82; P = .009) (Table 4). The preoperative degree of aortic cusp prolapse was compared with last follow-up AI grade (Tables 4 and 5) that showed no association between these 2 parameters. We also looked into the association of trivial residual VSDs. For the 5 patients with persistent AI, 3 (60%) had residual VSD as discharge, and among the 32 patients without persistent AI, 12 (37.5%) had residual VSD at discharge (Fisher exact test P = .377).
Figure 1Sankey diagram depicting change in AR at follow-up after isolated closure repair of VSD in patients with VSD with concomitant AR.
Figure 2Graphical Abstract summarizing the study. Of 37 patients with VSD and AR included in the study, 76% had improvement in grade of AR. VSD, Ventricular septal defect; AR, aortic regurgitation.
N = 37. Data show median values (IQR) with changes assessed by the Wilcoxon signed-rank test. AR, Aortic regurgitation; VSD, ventricular septal defect; LVEDd, left ventricular end-diastolic external diameter; LVESd, left ventricular external diameter systolic; LVPWd, left ventricular posterior wall in diastole; LVPWs, left ventricular posterior wall thickness at end systole; FS, fractional shortening; LVEF, left ventricular ejection fraction; LVEDVi, left ventricular end-diastolic volume index; LVEDV, left ventricular end-diastolic volume; LVESVi, left ventricular end-systolic volume index; LVESV, left ventricular end-systolic volume.
Figure 3Box and whisker diagram comparing preoperative and postoperative (A) left ventricular end-diastolic volume index, (B) left ventricular end-systolic volume index, (C) left ventricular end-diastolic volume z-score, and (D) left ventricular end-systolic volume z-score. The lower and upper borders of the box represent the 25th and 75th percentiles, respectively. The middle horizontal line represents the median. The lower and upper whiskers represent the minimum and maximum values of nonoutliers. LVEDVi, Left ventricular end-diastolic volume index; LVESVi, left ventricular end-diastolic volume index; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume.
Data are presented as median (IQR). P values were calculated using the Wilcoxon rank-sum test. AR, Aortic regurgitation; LVIDs, left ventricular internal diameter systolic; LVIDd, left ventricular internal diameter diastolic; FS, fractional shortening; EF, ejection fraction; EDVi, end-diastolic volume index; ESVi, end-systolic volume index.
AR may be associated with VSDs with an incidence from 6.9% to 44% in various studies depending on the age, location of VSD, and geographic origin of the cohort.
The mechanism commonly accepted is prolapse of the aortic valve leaflet resulting from the Venturi effect of the blood flowing from the left ventricle to the right ventricle through the VSD during systole.
Pathogenetic mechanisms of prolapsing aortic valve and aortic regurgitation associated with ventricular septal defect: anatomical, angiographic, and surgical considerations.
Although several studies delineated the natural history of AR with a VSD, others have focused on the progression of AR after VSD repair and aortic valve repair.
Surgical aortic valvuloplasty in children and adolescents with aortic regurgitation: acute and intermediate effects on aortic valve function and left ventricular dimensions.
However, there is a paucity of studies looking at perimembranous and juxtarterial VSD with AR as a cohort to follow up the progression of AR after isolated VSD repair particularly from the Western hemisphere.
At our center, worsening AR or appearance of new AR in association with cusp prolapse is considered as an indication for an early surgical intervention in these patients. The general advantages of early primary repair and low risk of cardiopulmonary bypass procedure have been described.
The rationale of early repair of VSDs with aortic valve regurgitation are (1) the potential advantage of halting progression of cusp prolapse and AI; (2) the VSD might close only with further prolapse of the aortic valve leaflet, thus at a risk of AR higher if one chooses to wait for symptoms of VSD to develop; and (3) although the results of concomitant aortic valve repair with VSD closure are good, there is a continued risk of reintervention over a period of time.
Surgical aortic valvuloplasty in children and adolescents with aortic regurgitation: acute and intermediate effects on aortic valve function and left ventricular dimensions.
Early repair of VSD aims to eliminate that risk of re-repairing or replacing the aortic valve. In their analysis of 154 patients of VSD with AR, Giridhara and colleagues
have shown 30% of patients with subaortic VSD and preoperative moderate to severe AR required aortic valve replacement in the postoperative period, thus supporting earlier VSD repair. Thus, most centers would operate on VSD associated with aortic valve prolapse before the AR progresses to a moderate level.
Our results indicate that the closure of VSD alone can prevent progression of aortic valve disease. In grades up to moderate AR, one could expect an improvement in the degree of AR. AR progression from trivial to mild in 10% of patients may point out the need for continued close follow-up of this cohort of patients over time. A potential myocardial reverse remodeling can be expected after VSD repair, as shown by the reduction in z-scores of left ventricular end-systolic and end-diastolic dimensions in our cohort (Figure 2).
found progression of AR in only 1 patient at a median follow-up of 13.1 years. They also concluded that aortic valve abnormalities and delayed operation were associated with AR progression or persistent AR (mild or more).
The natural history of AR in an asymptomatic adult population described by Bonow and colleagues
showed that EF first increases and over a period of returns to normal before decreasing as the disease progresses. Logistic regression analysis in our study has revealed that lower preoperative EF is associated with nonimprovement in AR grade. However, the median preoperative EF in our cohort was high normal with the lower limit of the IQR being normal. Thus, EF lower than expected in the presence of AR (high normal) could be a surrogate for the chronicity of AR and thus predict nonimprovement in AR grade at follow-up. We also noticed no association between the degree of preoperative aortic cusp prolapse and the last follow-up AI grade. Of note, Cheung and colleagues
did notice the impact of preoperative aortic cusp prolapse on long-term outcomes.
Different parameters have been proposed by using 2-dimensional echocardiography to assess preoperative risk factors that can determine operative and postoperative outcomes,
but this is the first study to show that lower preoperative LVEF is an independent predictor of persistent AR. The pathophysiology behind this finding is unclear but may be related to the lower LVEF being a surrogate for chronicity and degree of AR. However, this finding prompts careful evaluation of the aortic valve and ventricular function at the time of VSD repair.
Study Limitations
The limitations of study are its retrospective nature, limited number of patients, and short follow-up period.
Conclusions
Our results suggest primary closure of perimembranous or subarterial VSD with or without aortic valve prolapse with trivial to mild AR without surgical intervention on the native aortic valve can be done with good postoperative clinical outcomes (Figure 2). A lower preoperative LVEF may be a predictor for nonimprovement of the AR grade. The degree of preoperative aortic cusp prolapse was not associated with persistent AR.
Conflict of Interest Statement
The authors reported no conflicts of interest.
The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.
The authors thank Sofia Hanabergh for designing the Figures 2 and 4.
Pathogenetic mechanisms of prolapsing aortic valve and aortic regurgitation associated with ventricular septal defect: anatomical, angiographic, and surgical considerations.
European Association of Echocardiography recommendations for the assessment of valvular regurgitation. Part 1: aortic and pulmonary regurgitation (native valve disease).
Surgical aortic valvuloplasty in children and adolescents with aortic regurgitation: acute and intermediate effects on aortic valve function and left ventricular dimensions.
The Institutional Review Board approved the study and waived documentation of informed consent for this study (Institutional Review Board No. 00010646 approved on May 23, 2019).
Drs Bukhari and Desair contributed equally to this article.
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