Predicting Regurgitant Fraction in Pediatric Patients with Repaired Fallot Using Right Ventricular Strain

Abstract

Background:

The major cause of re-intervention in Fallot patients (tetralogy of Fallot [TOF]) is pulmonary regurgitation. Current cutoffs for pulmonary valve replacement (PVR) are all cardiac magnetic resonance (CMR) derived, based on the regurgitant fraction (RF) and/or right ventricular end-diastolic volume index. In this study, we aimed at determining if three-dimensional (3D)-derived right ventricular indices, notably RV global longitudinal strain (GLS), can act as a predictor for RF and hence facilitate the decision-making and timely referral of such patients.

Methodology:

For this purpose, 3D volumetry and speckle tracking echocardiography has been performed on Fallot patients, with recent CMR in the past 6 months, 42 controls were included to benchmark echocardiographic results. Echocardiography-derived left ventricle (LV) and right ventricle (RV) volumes as well as longitudinal strain were calculated and tested for diagnostic accuracy to predict RF.

Results:

Bland–Altmann analyses showed a good correlation between volumes obtained by CMR and those obtained by echocardiography, differences in volumes between CMR and echocardiography derived volumes were less evident in the LV compared to the RV, RV GLS <11% was sensitive and specific in predicting severe pulmonary regurge.

Conclusion:

The study of strains, particularly RV strains in repaired TOF patients, is not new to the literature. However, to our knowledge, previous studies did not attempt to determine a cutoff of RV GLS in predicting severe PR and subsequent need for PVR, the findings of this study are limited by a small sample size, but they open new horizons in the diagnostics of repaired TOF patients.

INTRODUCTION

Tetralogy of Fallot (TOF) is a congenital heart condition that cannot be outgrown. Patient transits from a pressure-loaded to a volume-loaded right ventricle (RV) because of pulmonary insufficiency. The surgical management of TOF frequently includes procedures such as pulmonary valvotomy, transannular patch placement, or incision in the right ventricular infundibulum. These interventions can potentially lead to long-term regurgitation of the pulmonary valve.[1,2]

Despite being the first-line imaging for the right ventricle, two-dimensional echocardiography remains very flawed in the visualization of RV due to the complex and peculiar anatomy of this chamber and the long distance between the inflow and outflow portion. For the latter reason, cardiac magnetic resonance imaging (CMRI) is the standard assessment tool, for decision-making regarding pulmonary valve replacement (PVR) needs. CMRI cutoffs include a right ventricular volume index >150, a regurgitant fraction (RF) >40% in asymptomatic patients, and a lower cutoff of <28% if symptoms or tachyarrhythmia develop.[3,4]

Three-dimensional (3D) echocardiographic reconstruction has offered itself recently as a promising bed-side tool that can gradually replace the need for a costly and lengthy CMRI, in this study we aimed to determine if RV 3D RV ejection fraction (EF), 3D RV end-diastolic volume index (EDVI), and RV global longitudinal strain (RV GLS) are the good predictors of RF in repaired Fallot patients.

METHODOLOGY

Study subjects

This study was designed as a cross-sectional and case–control study, it was conducted in the postoperative clinic of Cairo University Children’s Hospital (CUCH). It included two groups:

• Group 1: pediatric patients between 5 and 18 years with repaired TOF

Inclusion criteria:

Fallot patients repaired with transannular patch technique.

Exclusion criteria:

1. Patients with RV to pulmonary artery conduit, status poststent implantation in the main pulmonary artery

2. More than mild discrete right ventricular outflow tract or branch pulmonary artery narrowing defined by gradient >20 mmHg estimated via Doppler echocardiography

3. Valve sparing Fallot repair

4. Lack of cardiac magnetic resonance (CMR) examination in the last 6 months

5. Any arrythmia documented by electrocardiography in the last clinic visit.

   • Group 2: Thirty age- and sex-matched controls were recruited from the well-child clinic in CUCH for benchmarking advanced echocardiographic parameters.

Study methods

• Anthropometric measurements including weight and body surface area calculation

• Demographic characteristics including age and sex of patients and controls

• Patients’ files: Were examined for the results of the last CMRI examination, notably, for the right ventricular volume index (RV EDVI), left ventricular volume index (LV EDVI), RF

• Echocardiographic examination has been performed according to the American Heart Association guidelines.[5]

Three-dimensional volumetry and speckle-tracking echocardiography

image acquisition has been performed using a single machine Philips Epiq7 (Philips Medical Systems, Andover, Massachu setts), and analyzed using the associated Tomtec software.

• For the left ventricle: 3D LV dataset was derived from the apical view, the boundaries of the LV were determined by determining the apex and the mitral annulus, and the software automatically reconstructed the LV cavity shape at end-diastole and end-systole; with subsequent calculation of LV volumes and strains

• For the right ventricle: An apical four chamber was obtained visualizing the RV apex and tricuspid annulus. The software automatically tracked the RV contours throughout the entire cardiac cycle, and calculated the RV volume curve, RV end-diastolic volume, and RV global longitudinal strain (GLS).

Tissue Doppler imaging for the calculation of

• RV E/E’ ratio which is the ratio of peak early trans-tricuspid velocity to early tricuspid annular diastolic velocity

• LV E/E’ ratio is the ratio of peak early transmitral velocity to the average of early mitral annular and basal septal diastolic velocities.

Statistical analysis

Data were analyzed using the IBM SPSS (Statistics for Windows, Version 29.0.2.0 Armonk, NY: USA; IBM Corp); numerical data were presented as either mean and standard deviation when normally distributed and as median and interquartile range when skewed. The categorical variables were displayed as frequencies and percentages. Inter-method agreement was expressed using the Bland–Altmann plot and the diagnostic accuracy of right ventricular GLS to predict severe PR (RF > 40%) was determined using receiver operating characteristic (ROC) analysis, with the calculation of the predictive cutoff, this was illustrated by both an interactive dot diagram and a ROC curve. Interobserver variability for RV GLS was expressed using Kappa index.

RESULTS

Cases and controls were matched for age and body surface area, as planned in the methodology to allow comparison of advanced echocardiographic parameters between them, the age range for cases was 1–13 years, and in controls, age ranged from 1 to 10 years [Table 1].

Table 1.

Demographic and anthropometric characteristics of the study subjects

	Controls (n=21)	TOF (n=21)	P
Age (years)
Median (range)	5 (1–10)	7 (1–13)	0.124
Weight (kg), mean±SD	17.4±2.4	19±3.8	0.107
BSA (m2), mean±SD	0.71±0.07	0.79±0.11	0.119

SD=Standard deviation, BSA=Body surface area, TOF=Tetralogy of Fallot

Regarding advanced echocardiographic parameters [Table 2], LV EDVI was lower in cases compared to controls, which is the reverse of what is seen for the RV EDVI, which was significantly higher in cases (73 ± 5 vs. 49 ± 4). Coming to functional parameters, LV and RV GLS were significantly reduced in cases, reflecting biventricular dysfunction in cases compared to controls, CMR data retrieved from patients’ files were the LV EDVI, RV EDVI, and RF of the pulmonary valve [Table 3], the first two were compared to values obtained by 3D echocardiography using Bland-Altmann analysis [Figure 1a and b]. There was a greater difference, between the CMR and Echocardiographic assessment of the RV volume (limits of agreement = −14.55–−11.42 mL/m²), while the gap between CMRI and echocardiography-derived LV volumes was narrower (limits of agreement: −10.25–−8.12 mL/m²).

Table 2.

Echocardiographic characteristics of the study subjects

Variable	TOF (n=21), mean±SD	Control (n=21), mean±SD	P
LV EDVI (mL/m2)	60.3±2.4	63.6±3.1	0.06
3D EF (%)	65.0±2.2	68.1±2.3	0.04
LV GLS (%)	14.5±2.3	22.3±1.9	<0.001
LV E/E’	10.9±1.4	6.8±0.8	<0.001
RV EDVI (mL/m2)	73.2±5.3	49.0±4.6	<0.001
RV GLS (%)	11.2±2.8	22.4±1.6	<0.001
RV E/E’	11.4±2.0	6.2±1.0	<0.001

EF=Ejection fraction, GLS=Global longitudinal strain, LV=Left ventricle, RV=Right ventricle, TOF=Tetralogy of fallot, EDVI=End-diastolic volume index, LV E/E’ ratio=Ratio of early transmitral flow to average early diastolic mitral annular and basal septal velocities, SD=Standard deviation, RV E/E’=Ratio of early trans-tricuspid velocity to early diastolic tricuspid annular velocity, 3D=Three-dimensional

Table 3.

Cardiac magnetic resonance measures in tetralogy of fallot cases

Variable	Mean±SD
RF by CMR (%)	39.7±7.9
RV EDVI by CMR (mL/m2)	86.2±6.1
LV EDVI by CMR (mL/m2)	72.8±3.5

SD=Standard deviation, CMR=Cardiac magnetic resonance, EDVI=End diastolic volume index, LV=Left ventricle, RV=Right ventricle, RF=Regurgitant fraction

Figure 1.

(a) Bland–Altman plot to compare right ventricle end-diastolic volume index (EDVI) by echocardiography versus cardiac magnetic resonance (CMR). (b) Bland–Altman plot to compare left ventricle EDVI by echocardiography versus CMR. CMR: Cardiac magnetic resonance imaging, EDVI: End-diastolic volume index, RV: Right ventricle, LV: Left ventricle

The RV GLS could predict severe PR, with a sensitivity of 100% and specificity of 81% [Figure 2a and b and with a cut-off <− 11%].

Figure 2.

(a) Interactive dot diagram reflecting the diagnostic accuracy and cutoff right ventricle (RV) global longitudinal strain (GLS) in prediction of severe pulmonary regurgitation (PR). (b) Receiver operating characteristic analysis reflecting the diagnostic accuracy and cutoff RV GLS in prediction of severe PR. GLS: Global longitudinal strain, PR: Pulmonary regurgitation, RV: Right ventricle. AUC: Area under the curve

A Kappa index was calculated at 0.9 to reflect inter-observer variability for RV GLS.

DISCUSSION

Patients with TOF following surgical repair represent a growing population with congenital heart disease as they now survive into adulthood. Residual pulmonary regurgitation (PR) is an important determinant of outcome as it may contribute to right ventricle (RV) enlargement and dysfunction and result in exercise intolerance, propensity for arrhythmias, and an increased risk for sudden cardiac death.[6]

Right ventricle (RV) dysfunction is a major prognostic factor and is strongly associated with impaired clinical status after TOF repair. Multiple studies have demonstrated that adequate timing of PVR, based on CMR-derived measurements of RV end-diastolic and end-systolic threshold volumes can result in normalization of RV size and function and improvement in functional status. Although echocardiography is the primary imaging modality in congenital heart disease secondary to its ease and proven clinical utility, this has not been held for evaluation of the RV, especially in the presence of RV dilation.[7]

Measuring pulmonary RF is mandatory in the follow-up of patients with repaired TOF. The measurement of RF is currently only possible using CMRI. Compared to CMRI, the use of echocardiography as a diagnostic cardiac modality is in many respects unparalleled.[8]

In our study, we used several updated functional echocardiographic parameters such as 3D speckle-tracking data to check if such parameters are correlated with RF by CMRI and if they hold a predictive value for RF. A finding as such can alleviate the need for CMRI and replace it with echocardiographic parameters that are easier to implement in developing countries.

Our study included 21 cases of TOF and 21 control and the mean age was 5.9 for patients and 4.4 for controls. Controls were matched for age and sex for no significant difference.

Left ventricular systolic and diastolic functions were impaired in patients with repaired Fallot tetralogy. This is of a great agreement with previous results, Davlouros et al.[9] (2002) found a significant correlation between RV and LVEF. They pointed out the importance of ventricular–ventricular interaction in repaired TOF. A previous report of 29 patients with repaired TOF studied by radionuclide ventriculography, reported a subclinical LV dysfunction during exercise. The mechanism of RV–LV interaction is incompletely understood. The shared myocardial fibers between the LV and RV and the adverse impact of septal shift may contribute to LV dysfunction.

RV strain in repaired TOF was reduced compared to controls. In cases of right ventricle (RV) dysfunction, the geometrical and temporal interaction between the RV and left ventricle (LV) occurs, at least partially, at the regions around the septal hinge points, where there is heightened shear stress and localized injury. Specifically, the shortening of the LV circumferentially and the RV longitudinally at these septal insertion areas contributes to increased stress and shear forces, as well as fibrosis. These heightened mechanical stresses initiate mechanical transduction and molecular signaling through integrins, leading to the upregulation of transforming growth factor beta signaling, which is ultimately linked to the remodeling of the extracellular matrix and fibrosis. This mechanical transduction signaling is particularly prominent in the hypertensive RV and the septal hinge point areas. In addition, the histological and functional alterations in the left ventricle (LV), along with fibrosis, were marked by a rise in major histocompatibility complex (β-MHC) expression and a reduction in the levels of Ca²⁺-handling proteins. These shifts in α- and β-MHC expression were related to the modifications observed in LV mechanics.[10]

RV strain and its clinical implications have been previously investigated by several studies. For instance, RV strain has shown correlations to clinical outcomes in heart failure, pulmonary embolism, and pulmonary hypertension.[11,12]

An excellent sensitivity has been achieved regarding severe pulmonary regurgitation (PR) prediction. RV GLS was 100% sensitive in predicting severe PR as shown by CMRI with a cut-off of <−1%. In contrast, Oliveira et al. found that that RV GLS is an effective and reproducible tool for the assessment of RV systolic function in pediatric patients with repaired TOF. He demonstrated that an RV GLS of − 18% can be used as a cutoff value to identify RV systolic dysfunction.[13] Our study also showed an excellent reproducibility of the data, with a Kappa index of 0.9 in the analysis of the RV GLS, however our cut-off seems more realistic than the one suggested by Oliveira et al. It is also worth noting that the cut-off suggested by Oliveira et al. is not a cut-off to predict PR but to reflect RV dysfunction; this might explain why it is a relatively elevated cut-off and reflects the peculiarity of this study; which remains the first to explore the predictive value of RV GLS in diagnosing sever PR.

The repeatability of RV strain calculation by echocardiography in our study (0.9) was satisfactory as previously reported in Tunthong et al. study (0.83). The new available software allows reduction of human error and standardizes relatively the examination, which explains the low inter-observer variability and the possible reproducibility of these results.[14]

Toro et al.[15] reported decreased RV GLS in patients operated on for TOF compared to normal controls in both Pediatric and adult patients. Scherptong et al.[16] found a good correlation (r = 0.61) between RV GLS and CMRI RV EF in a small group of adults operated on for TOF.[15]

They also reported that RV GLS continued to deteriorate in serial assessments despite preserved RV EF suggesting that regional wall-motion evaluations may detect early findings of subtle RV dysfunction.[13,15] A study by Bernard et al. reported decent correlation (r = 0.46) between RV GLS and CMRI RV EF in adolescents and adults with enlarged RVs and decreased RV EF operated on for TOF in infancy.[17]

We have demonstrated a similar good association of RV GLS and CMRI-derived RF in pediatric patients with repaired TOF. We suggest that speckle-tracking echocardiography (STE) could be routinely used in the evaluation and follow-up of patients with repaired Fallot tetralogy owing to its ease in operability and in light of the findings of this study, which showed the sensitivity of RV GLS in prediction of severe PR.

CONCLUSION

We demonstrated that STE is a valuable tool in the assessment of patients post-Fallot repair, where 3D RV GLS was associated with severe PR and thus could be considered as a parameter in decision-making for PVR analogous to CMRI, with less tedious examination, it is also worth mentioning that in spite of an easier examination, extensive training for using strain software and the availability of equipped machines remains a barrier in developing countries that needs to be tackled. This study also might be the first to suggest a predictive cutoff for RV GLS to predict RF (−11%).

Limitations

The study has several limitations that may affect its findings. First, it involves a small sample size of only 21 cases and 21 controls, which can reduce the statistical power and limit the generalizability of the outcomes. In addition, the research was conducted solely at CUCH, raising concerns about selection bias and external validity due to its single-center design. The exclusion of patients who underwent various tetralogy of fallot (TOF) repair techniques, such as valve-sparing procedures, narrows the study’s focus and may not accurately represent the broader TOF patient population. Furthermore, the requirement for participants to have recent CMRI could have inadvertently excluded individuals with poorer follow-up, introducing potential bias. Finally, the cross-sectional design employed does not facilitate a longitudinal analysis of right ventricle GLS (RV GLS) over time, which would provide more comprehensive data on its predictive value regarding progressive right ventricle dysfunction. It is also worth noting that there is still a wide discrepancy between RV volumes by CMR and 3D echocardiography reaching up to 14 mL/m²; however, the main focus of the study was to check this discrepancy and to determine if RV GLS is a good predictor of RF.

Ethical statement

The authors assert that all procedures contributing to this work comply with the ethical standards of the relevant Egyptian guidelines on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008, and has been approved by the institutional committee of the Pediatrics’ department, Faculty of Medicine, Cairo University.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.