Echocardiographic parameters of severe pulmonary regurgitation after surgical repair of tetralogy of Fallot

Abstract Aims Reliable evaluation of the severity and consequences of pulmonary regurgitation (PR) in patients with repaired tetralogy of Fallot (TOF) is crucial to timely identify the need for pulmonary valve intervention. We aimed to identify the accuracy of echocardiographic parameters to differentiate between moderate and severe PR, using phase contrast cardiac magnetic resonance imaging (CMR) as gold standard. Methods and results In this cross‐sectional study, 45 TOF patients with both echocardiographic and CMR measurements of PR were enrolled. All quantitative and semiquantitative echocardiographic measurements such as pressure half time (PHT), Color flow jet width (CFJW), ratio CFJW/right ventricle outflow tract (RVOT) diameter, PR index and the presence of early termination of the PR jet, end‐diastolic antegrade flow and diastolic backflow in main pulmonary artery (MPA), and PA branches correlated significantly with PR fraction on CMR. Qualitative assessment with color flow on echocardiography overestimated PR Multivariate linear regression analysis identified the ratio of CFJW/RVOT diameter and PHT as independent predictors of PR fraction. Accuracy of echo parameters was tested to differentiate between mild‐to‐moderate and severe PR Combining different echocardiographic parameters increased sensitivity and specificity. The addition of diastolic flow reversal in the PA branches to PHT below 167 milliseconds increased the NPV from 87% to 89% and PPV from 62% to 76%. Conclusions Comparison with CMR confirms that echocardiographic parameters are reliable in predicting PR severity. Combined measurement of diastolic flow reversal in the pulmonary artery branches and PHT is reliable in the detection of severe PR in the follow‐up of TOF patients.


| INTRODUC TI ON
Pulmonary regurgitation (PR) is common after surgical repair of tetralogy of Fallot (TOF) and pulmonary valve replacement (PVR) is advised before the onset of irreversible right ventricular dysfunction. 1,2 The optimal timing of PVR, especially in the absence of symptoms or signs of hemodynamic or electrical instability, remains subject of debate. The desired restoration of RV size and function must be put against the risk of multiple interventions over the course of a patient's lifetime, keeping in mind that the long-term outcome of PVR has yet to be shown. 1 However, with the introduction of percutaneous treatment options, such as placing a "Melodyvalve," a lower threshold for intervention might arise. Determining the severity of PR and evaluating the consequences of this PR on the right ventricle (RV) is crucial in the follow-up of patients with TOF.
Phase contrast cardiac magnetic resonance imaging (CMR) is considered the gold standard for the assessment of PR severity, RV dilatation, and function. [3][4][5] However, since CMR is time-consuming, expensive, and not accessible to patients with claustrophobia and/ or implanted cardiac devices, echocardiography is considered the first-line screening modality for the assessment of PR in routine daily practice. 6,7 Although echocardiography is widely available and used, interpretation of PR is largely qualitative 1 or semiquantitative and contradictory results have been published regarding the predictive value and accuracy of these measurements compared to CMR. 5,[8][9][10][11][12][13][14][15][16][17] In our experience, not all cardiologists are familiar with the different possibilities and opportunities of echocardiography, and knowledge on adequate PR assessment is lacking. Furthermore, the optimal threshold of the different measurements is not uniformly defined. 14,18 Finally, Doppler signals can be influenced by a restrictive RV physiology, mimicking severe PR in the presence of only mild pulmonary insufficiency.
The aim of this study is (1) to describe all echocardiographic parameters of PR and evaluate their accuracy to differentiate between mild-to-moderate and severe PR compared with the gold standard CMR and (2) to identify the (combination of the) most simple, accurate, and ready to use echocardiographic parameter(s) for reliable estimation of PR in the follow-up of operated TOF patients in daily clinical practice.

| Study population
All consecutive patients who underwent surgical repair of TOF in the Erasmus MC, Rotterdam, The Netherlands between 1968 and 2000 at age <15 years and who participated in the "quality-of-life" study, 19 and had echocardiography and CMR were recruited for this cross-sectional study. The methods and results of this long-term longitudinal follow-up study have been previously described. 19 The in-hospital cardiac examination included medical history, physical examination, standard 12-lead ECG, echocardiography, and CMR. All investigations were aimed to be performed on the same day. In the current study, we have focused on the CMR and echocardiographic findings at last follow-up. Patients were excluded from this substudy if no CMR imaging was performed (due to ICD/pacemaker, claustrophobia, rejected, or no show). The institutional Medical Ethical Committee approved the study (METC nr 2010-015). Written informed consent was obtained from all patients.

| Echocardiography
A comprehensive 2-dimensional transthoracic echocardiogram in harmonic imaging was performed using an iE33 ultrasound system (Philips Medical Systems, Best, The Netherlands) equipped with a transthoracic broad-band S5-1 or a broad-band X5-1 matrix transducer.
Chamber measurements, including left ventricular ejection fraction (EF) (Simpson's method), RV fractional area change (FAC), and tricuspid annular plane systolic excursion (TAPSE) were performed conform guidelines of the American Society of Echocardiography. 20 Valvular regurgitation and stenosis were evaluated according to the European Association of Echocardiography recommendations. 16,17 In addition, the following parameters were assessed for PR severity ( Figure 1

| Statistical analysis
Continuous data are presented as mean ± standard deviation (SD) or median with interquartile ranges when appropriate. Categorical variables are presented as frequencies and percentages. To quantify correlations, we used the Pearson correlation test for continuous variables or Spearman rank correlation test when appropriate.

| Study population
The baseline characteristics of the 45 patients with repaired TOF included in this study are summarized in   Table 3.

| Evaluation of the accuracy of echocardiographic PR analysis
Both the ratio CFJW/RVOT diameter and PHT were significantly associated with the PR fraction on CMR. The cutoff points for, respectively, ratio CFJW/RVOT diameter and PHT at 20% and 40% PR were derived from linear regression analysis ( Figure 2).
Accuracy of echocardiographic parameters was tested to differentiate between mild-to-moderate and severe PR (dichotomized at 40%). An overview of the differentiate capacity and the predictive values of all echocardiographic parameters are listed in Table 4.
The presence of diastolic flow reversal in the main PA and in the PA branches, had excellent sensitivity and NPV to identify severe PR However, specificity values are rather low. PHT on the contrary shows excellent specificity of 100% and a PPV of 100%. Based on the linear regression analysis, the optimal cutoff value to detect severe PR at 40% in our study population is a PHT of less than 167 milliseconds (Figure 2). Using this cutoff value, the sensitivity for detection of severe PR significantly increased to 81% with both good PPV and NPV ( Table 4).
The ratio of the CFJW over RVOT diameter showed good correlation with PR fraction (   PHT appeared to be a good predictor of severe PR, both as a continuous and dichotomous variable. 8,9,14 The more severe the PR, the more rapid equalization of right ventricular and PA

| CLINIC AL RECOMMENDATIONS
Echocardiography is recommended as first-line diagnostic method for initial and longitudinal assessment of PR in TOF patients. 6,7 Grading of PR severity, however, remains difficult as standards for PR quantification are less robust than those for aortic regurgitation. 16,17 Recently combined measurements PHT, slope, jet-to-RVOT ratio have been suggested in the follow-up of TOF TA B L E 4 Sensitivity and specificity of echocardiographic variables in differentiating between mild to moderate (0%-40%) and severe (>40%) PR on CMR patients. 9,14,15 Measuring CFJW is, however, affected by a large interobserver variation. We investigated all available echocardiographic parameters for PR severity and found that the combination of backflow in the PA branches and a short PHT is as accurate as the more complex measurements. We, therefore, recommend this ready to use and easier approach to assess PR severity in TOF patients: 1. Evaluation with color flow over PV, PA, and PA branches from the parasternal short-axis view at the level of the aortic valve.

2.
If no backflow from the PA branches is present, we can exclude severe PR.

3.
If diastolic flow reversal from the PA branches is present, we can further differentiate between moderate and severe PR using continuous wave Doppler analysis. If both backflow in PA branches is visualized and PHT is short, severe PR is present.
Careful follow-up should be organized in patients with severe PR However, the prognostic value and implications on clinical follow-up (timing of referral for PVR) and frequency of follow-up visits need to be evaluated in a prospective follow-up study and larger patient population.

| LI M ITATI O N S
The following limitations need to be acknowledged. Firstly, the sample size is limited and secondly, this is a cross-sectional study which implies that clinical implications of the described findings need to be evaluated in a large, prospective follow-up study.
Thirdly, the median interval between the echocardiogram and CMR exam was 1.5 months. The study population included 2 outliers with, respectively, 353 and 368 days between both exams.
Both patients, however, had an echocardiogram one year before and one year after the CMR. As the severity of the PR on echocardiogram had not changed through these 2 years (PHT was, respectively, 220 milliseconds and 223 milliseconds for the first patient and 153 milliseconds and 158 milliseconds for the second patient) F I G U R E 3 Suggestion for clinical decision tree. Flowchart to visualize decision rule for severe PR based on specificity and sensitivity analysis described in Table 4. Percentages represent probabilities that severe PR (>40% PR on CMR) will be detected by echocardiography using the combination of diastolic flow reversal in pulmonary artery branches and pressure half time