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Whether Pulmonary Valve Replacement in Asymptomatic Patients With Moderate or Severe Regurgitation After Tetralogy of Fallot Repair Is Appropriate: A Case‐Control Study

Background Although right ventricular (RV) volume was significantly decreased in symptomatic patients with repaired tetralogy of Fallot (rTOF) after pulmonary valve replacement (PVR), RV size was still enlarged along with RV dysfunction. Methods and Results A prospective case‐control study was conducted in a tertiary hospital; 81 asymptomatic repaired tetralogy of Fallot patients with moderate or severe pulmonary regurgitation were enrolled. The enrolled cohort was divided into 2 groups: PVR group (n=41) and medication group (n=40). Cardiac magnetic resonance, transthoracic echocardiography, and electrocardiography were scheduled after recruitment and 6 months after PVR or recruitment. Adverse events were recorded during follow‐up. Three deaths, 1 heart transplantation, 3 PVRs, and 2 symptomatic heart failures in medication group and 1 redo PVR in the PVR group were observed during follow‐up. Compared with the medication group, the PVR group had significantly lower adverse events rate (P=0.023; odds ratio, 0.086; 95% CI, 0.010–0.716), and RV function was significantly improved (P<0.05). Binary logistic regression analysis identified preoperative RV end‐systolic volume index (10‐mL/m2 increment, P=0.009; odds ratio, 0.64; 95% CI, 0.457–0.893) was an independent predictor of normalization of RV size after PVR. A preoperative RV end‐systolic volume index cut‐off value of 120 mL/m2 (area under curve, 0.819; sensitivity, 90.3%; specificity, 70%) was analyzed by receiver operating characteristic curves for normalized RV size after PVR. Conclusions PVR in asymptomatic repaired tetralogy of Fallot patients is appropriate and effective in reducing right ventricular size and preserving right ventricular function. The recommended criterion of RV end‐systolic volume index for PVR is 120 mL/m2.

A favorable 30-year survival rate of repaired tetralogy of Fallot (rTOF) is achieved following successful improvement in surgical techniques and perioperative care. Consequently, a growing population of adolescents and adult patients with rTOF is emerging. 1 Classic surgical methods, especially transannular patches, may cause severe pulmonary regurgitation (PR) and significant right ventricular (RV) outflow tract (ROVT) hemodynamic dysfunction. 2 Although PR is initially well tolerated in most patients, the long-standing valve insufficiency may cause RV enlargement, tricuspid regurgitation, arrhythmia, RV failure, and eventually left ventricular (LV) failure. Approximately 40% of individuals with rTOF die of heart failure, and %10% suffer from sudden deaths, probably attributed to arrhythmias. 3 Pulmonary valve replacement (PVR) is the gold-standard treatment for PR. However, for patients with rTOF and PR, the optimal timing of PVR remains debatable. Currently, the recommended timing of PVR depends mainly on symptoms and specific biological/physiological variables. 4,5 Nevertheless, because of the discouraging outcomes in these patients, some surgeons advocated for early intervention for PR in asymptomatic patients. Therrien et al [6][7][8] reported that RV enlargement and dysfunction might be prevented by early PVR. However, the optimal timing and indications of PVR for those asymptomatic rTOF patients are still sparking debate, which has catalyzed increasing research efforts over the past decade. [6][7][8][9] In this study, our hypothesis was that PVR in asymptomatic rTOF patients could decrease the adverse events rate, reduce the RV size to normal volume, and improve RV function. We aimed to evaluate the outcomes of PVR and attempted to detect a parameter that could be used to determine the best timing of PVR intervention.

Materials and Methods
The data, analytical methods, and study materials will not be made available to other researchers for purposes of reproducing the results or replicating the procedure.

Study Design
This study was a prospective case-control study undertaken at the Fuwai Hospital. The Ethics Committee of the Fuwai Hospital approved the study protocol. All patients were provided written informed consent before enrollment.

Population
From June 2014 to April 2018, asymptomatic rTOF patients with moderate or severe PR examined by transthoracic echocardiography (TTE) during routine follow-up at the Fuwai Hospital were recruited. Eighty-one patients met the inclusion criteria and were enrolled in this study. Medical history and individual data were collected from medical records. Cardiac magnetic resonance (CMR), TTE, and ECG were examined at enrollment and reexamined 6-months later after surgery (PVR group) or enrollment (medication group). Parameters were indexed to body surface area, if appropriate. Clinical status was obtained through outpatient follow-up or phone conversation with patients or family members every 3 months after enrollment.

Data Definitions
According to Khaled Alfakih's study, 10 regardless of sex, normal RV size and RV function were defined as RV enddiastolic volume index (EDVI) ≤114 mL/m 2 and RV EDVI ≤114 mL/m 2 plus RV ejection fraction (EF) ≥48%, respectively, by steady-state free precession imaging sequences. Asymptomatic patients were defined as those who maintained a functional status in the New York Heart Association class I or II, without occurrence of syncope caused by arrhythmia or symptoms/signs of heart failure. Adverse events included death, cardiac transplantation, syncope caused by arrhythmias, PVR, or symptomatic heart failure during follow-up. Echocardiographic criterion for the assessment of tricuspid and pulmonary regurgitation severity was graded as follows: Grade 0 (absent), Grade 1 (trivial+), Grade 2 (mild+), Grade 3 (moderate+), and Grade 4 (severe+).

Inclusion and Exclusion Criteria
According to the indications for PVR in asymptomatic patients with moderate or severe PR after TOF repair recommended by Boston Children's Hospital in 2013, 11 our center established the following criteria.

PVR group
PVRs were performed on a cardiopulmonary bypass with mild hypothermia or on a beating heart (in the absence of

Clinical Perspective
What Is New?
• Pulmonary valve replacement in asymptomatic patients with moderate or great regurgitation after repaired tetralogy of Fallot repair is appropriate. • The recommended criterion of right ventricular end-systolic volume index for pulmonary valve replacement in asymptomatic patients with moderate or great regurgitation after repaired tetralogy of Fallot repair is 120 mL/m 2 .
What Are the Clinical Implications?
• Pulmonary valve replacement in asymptomatic patients with moderate or great regurgitation after repaired tetralogy of Fallot repair should be considered as a routine strategy following the recommended criteria.
right-to-left shunt). A longitudinal incision was performed in the pulmonary trunk or a previously placed patch. Either bioprosthetic valve (bovine pericardial; Edwards Lifesciences, Irvine, CA) or homograft valve was inserted in an orthotropic position. The concomitant procedures are summarized in Table 1.

Medication group
Digoxin and diuretics were taken in the medication group.
Determination of dose was based on body weight of children, whereas digoxin 0.25 mg Qd, furosemide 20 mg Qd, and spironolactone 25 mg Qd were given at the conventional dose in adults. Electrolytes and serum digoxin levels were measured routinely.

Cardiac magnetic resonance
CMR was performed on a 1.5 Tesla magnetic resonance scanner (Magnetom Avanto; Siemens Medical Solutions, Erlangen, Germany). All imaging acquisitions were captured under breath control with the steady-stage precession sequence technique. Late gadolinium enhancement images were acquired 15 minutes after intravenous administration of 0.2 mmol/kg of gadolinium-DTPA (Magnevist; Schering, Berlin, Germany) using a phase-sensitive inversion recovery/spoiled gradient echo sequence. Late gadolinium enhancement was performed only when patients were enrolled. RVOT aneurysm was defined as outward movement during systole of part of the ventricular wall or its reconstructed outflow tract. Images were reviewed and

Results
Demographic data and operative characteristics are summarized in Table 1, and the aforementioned examination variables are summarized in Tables 2 and 3. Baseline characteristics were well balanced between groups. After a mean 33.1AE10.0 months' follow-up, 3 deaths, 1 heart transplantation, 3 PVRs, and 2 symptomatic heart failures were recorded in the medication group during follow-up, whereas only 1 redo PVR was recorded attributed to deterioration of the pulmonary valve in the PVR group. Tricuspid regurgitation improvement in the PVR group was significantly better than that in the medication group after treatment (1.08AE0.89 to 2.74AE1.87; P=0.000) at latest TTE follow-up. Freedom from adverse events between the groups analyzed by the Kaplan-Meier method was significantly different between groups (P=0.006; Figure 1).  Examinations were performed when participants were enrolled and reperformed after a mean duration of 28.36AE10.09 months. Thirty-two of 40 patients had severe PR, and the remaining 8 patients had moderate PR, preoperatively. Myocardial fibrosis, severe or absent left pulmonary artery stenosis, and RVOT aneurysm were found in 5, 5, and 6 patients by CMR, respectively. Two patients with normal RV size were observed; 1 returned to normal with pre-RV EDVI 126 mL/m 2 , whereas the other developed a larger RV size within its normal range. Causes of death in 3 cases included 2 sudden deaths and 1 heart failure. Heart transplantation was performed in another hospital 18 months after enrollment. According to the criteria of PVR for symptomatic rTOF patients in our institution (moderate or severe pulmonary regurgitation with ≥1 of the following: [1] New York Heart Association class III/IV, [2] sustained tachyarrhythmia related to right-sided heart volume load, [3] syncope caused by arrhythmias, and [4] significant hemodynamic abnormalities, such as severe aortic valve regurgitation, severe tricuspid valve regurgitation, large RVOT aneurysm, etc), 3 patients developed into symptomatic and underwent PVR 20, 26, and 40 months after enrollment, separately. Two patients developed symptomatic heart failure 14 and 21 months after enrollment without PVR, separately.
The analysis revealed that there was no significant difference in examination results between enrollment and follow-up period. Cox regression analysis identified that arrhythmia and preoperative RV ESVI were the independent risk factors of adverse events (Table 4).

PVR Group
Examinations were performed with a mean duration of 3.68AE4.50 months preoperatively and repeated at a mean duration of 17  In CMR, LV EF and corrected RV EF were significantly increased after PVR (P<0.05). Pulmonary regurgitation fraction, RV EDVI, RV ESVI, and RV EDD were significantly decreased after PVR (P<0.05), whereas LV EDVI and LV ESVI did not change significantly after operation. LV EF, RV EDD, and tricuspid regurgitation detected by TTE improved significantly after PVR (P<0.05). Postoperative cardiothoracic ratio was significantly decreased. QRS duration was not significantly changed postoperatively.

Predictors of Normalization of RV Size and Cut-Off Value Predicting Normalization of RV Size
Results of the binary logistics regression analysis for predictors of normalization of RV size are shown in Table 5. Preoperative RV ESVI (10-mL/m 2 increment, P=0.009; odds ratio, 0.64; 95% CI, 0.457-0.893) was the independent predictor of normalization of RV size after PVR in multivariate analysis.

Discussion
Our study demonstrated a beneficial effect of PVR in asymptomatic rTOF patients with moderate or great pulmonary regurgitation on RV size and function, and normalization of RV size after PVR had a correlation with preoperative RV ESVI.
Optimal timing of PVR has sparked debate, which has catalyzed increasing research efforts over the past decade. Several studies 6,12,13 revealed that minimal benefit was achieved in some of the sickest patients after PVR, indicating   17 which implies that PVR should be performed within 20 years after TOF repair to prevent occurrence of adverse outcomes. In the current study, PVR was underwent after a duration of 17 (6.30) years after TOF repair, which indicates that the timing for PVR was acceptable. Compared with the PVR group, incidence of adverse events was higher in the medication group after a duration of 13.83 (9.34) years after TOF repair, although in the face of younger enrollment age. Furthermore, compared with symptomatic rTOF patients, RV function in asymptomatic rTOF patients was maintained in the compensatory stage, indicating an increased likelihood of restoration of RV function after PVR. Although RV size decreases after PVR, RV normalization does not occur very often. 4 Several studies 8,18,19 found that RV size does not return to normal after PVR unless preoperative RV EDVI was <160 to 170 mL/m 2 or RV ESVI was <85 to 90 mL/m 2 . However, normalization of RV size did occur in 3 patients with the preoperative RV EDVI >200 mL/m 2 , suggesting that normalization was possible even in patients with a massive RV volume. According to our results, it appears that there is no determined upper threshold for normalization, which agrees with previous studies. 20 However, it should be pointed out that these 3 patients in our study did not present arrhythmia, RVOT aneurysm, or myocardial fibrosis, which have been confirmed as risk factors of RV dysfunction by previous studies. 21,22 In this study, logistics regression analysis found that preoperative RV ESVI was the independent predictor of normalization of RV size. ROC curve analysis calculated preoperative RV EDVI and RV ESVI cut-off values of 155 and 120 mL/m 2 for normalization of RV size, respectively. It is worthwhile to emphasize that the cut-off value was calculated by an ROC curve with a maximum value of the Youden index, and sensitivity and specificity levels should be carefully selected during clinical decision making.
Some studies 23,24 found that RV EF did not improve significantly after PVR. We assumed that the reasonfor this phenomenon was that the noncorrected preoperative RV EF was over-rated. In our study, the corrected RV EF, which only calculated the net pulmonary flow, was used to evaluate RV function instead of the conventional RV EF. A dramatic increase from 20.71% to 37.94% in the corrected RV EF was found, suggesting that the surgery was beneficial for recovery of RV function.
Several studies [25][26][27][28] identified QRS duration as an important predictor of RV remodeling and noted that QRS duration shortens after an operation. However, QRS duration did not change significantly in the current study, and the reason might be that all these patients were preoperatively asymptomatic. The preoperative QRS duration cut-off value calculated by the ROC curve is hardly of practical significance because of the low sensitivity.
The study has a number of important limitations; no rigid protocol or guideline for PVR in these asymptomatic rTOF patients was followed. Inclusion and exclusion criteria were derived from the Consensus, which was mainly based on former retrospective studies. The small study population was another important limitation. Cardiac function in our study lacked of objective evaluation. Hence, the cardiopulmonary exercise testing or 6-minute walk test was arranged for the subsequent patients. An extended follow-up time span should be adopted.

Conclusion
In the current study, we confirmed a beneficial effect of PVR in asymptomatic rTOF patients with moderate or great pulmonary regurgitation on RV size and function. Our findings indicated that the criterion for ESVI should be updated because the RV ESVI >120 mL/m 2 is related to less RV normalization. were analyzed by receiver operating characteristic curves for normalized RV size after pulmonary valve replacement. EDVI indicates end-diastolic volume index; ESVI, end-systolic volume index; MRI, magnetic resonance imaging; RV, right ventricular.