Characteristics of altered biventricular hemodynamics after arterial switch operation for patients with d-transposition of the great arteries with preserved ejection fraction: a four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) study

Introduction

Dextro-transposition of the great arteries (D-TGA) is a cyanotic heart defect accounting for 5–7% of all congenital heart defects (CHDs) (1). Newborns with D-TGA can undergo corrective surgical repair early and survive to adulthood. In typical corrective surgery, called the arterial switch operation (ASO), the aorta and the pulmonary artery are translocated, and the coronary arteries are reimplanted into the neo-aorta (2). In the long term, the main complications of D-TGA treated by ASO are neo-aortic root dilatation and pulmonary artery obstruction (3-5). The continuous strict follow-up and monitoring of postoperative patients is essential to ensure the maintenance of ventricular function.

Echocardiography is the first-line imaging modality used for presurgical planning in children with D-TGA. Cardiovascular magnetic resonance (CMR) imaging provides comprehensive morphologic and ventricular functional information for CHD patients (6,7). Four-dimensional (4D) flow has been introduced as a novel tool for the visualization and quantification of flow in the heart and major blood vessels (8). 4D flow magnetic resonance imaging (MRI) with a time-dependent velocity vector field is able to depict hemodynamic characteristics, such as viscous energy loss (EL) and kinetic energy (KE), in individuals with tetralogy of Fallot (TOF) or Fontan palliation (9-12). It also has potential for use in comprehensive intraventricular fluid dynamic assessments of D-TGA patients.

D-TGA patients have excellent long-term overall survival after ASO. However, life-long monitoring of biventricular function by CMR imaging is required to detect potential functional deterioration long after ASO (13). Previous research has reported that the specific geometry of the ascending neo-aorta after ASO, including the Lecompte maneuver, is related to altered ascending aortic flow hemodynamics (14). However, the pathophysiological mechanisms for altered biventricular hemodynamics in ASO patients remain unknown. We hypothesized that biventricular hemodynamic parameters derived from 4D flow would be associated with postoperative adverse events in D-TGA patients with preserved ejection fraction (EF). In this study, we aimed to: (I) compare the biventricular KE and vorticity of ASO patients and age- and sex-matched controls; (II) investigate the associations of 4D flow biventricular hemodynamics parameters and neo-aortic root dilation, supravalvular pulmonary stenosis, and pulmonary artery transvalvular pressure difference. We present this article in accordance with the STROBE reporting checklist (available at https://qims.amegroups.com/article/view/10.21037/qims-24-840/rc).

Methods

Study subjects

In total, 104 D-TGA patients who underwent operation and 62 healthy controls were prospectively recruited for this study between July 2017 and August 2023. The patients underwent routine CMR examinations. The study flow chart is shown in Figure 1. To be eligible for inclusion in this study, the patients had to meet the following inclusion criteria: (I) be aged ≥3 or ≤18 years; (II) not have undergone any previous interventional management, such as re-intervention procedures, in the last three years; (III) have undergone assessment of neo-aortic root dilation, supravalvular pulmonary stenosis, and pulmonary artery transvalvular pressure difference by echocardiography in the two weeks before the CMR examination; and (IV) have preserved left ventricular ejection fraction (LVEF) >50% or right ventricular ejection fraction (RVEF) >45% by echocardiography. D-TGA patients were excluded from the study if they met any of the following exclusion criteria: (I) had a medical history of prior cardiovascular disease, pulmonary disease, or pulmonary hypertension; (II) had poor-quality CMR images or no 4D flow scans; and/or (III) had serious liver or kidney dysfunction. Additionally, 17 age- and sex-matched healthy control subjects were also recruited through our institutional website.

Figure 1 Flow chart showing recruitment of study subjects. D-TGA, dextro-transposition of the great arteries; ASO, arterial switch operation; LVEF, left ventricle ejection fraction; RVEF, right ventricle ejection fraction; CMR, cardiovascular magnetic resonance; 4D, four dimensional.

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). All the patients or their legal guardians and the healthy control subjects provided written informed consent. The study was approved by the Institutional Medical Ethics Committee of Shanghai Children’s Medical Center (No. SCMCIRB-K2022.49-1).

Echocardiography acquisition

The echocardiographic examination was performed using the Philips EPIQ 7C ultrasound machine (Philips, Andover, MA, USA) with a matrix array transducer (S5-1, S8-3). Previous research defined aortic dilatation as a Z-score >2.0 (15). The pulmonary supravalvar area and valve were imaged from the apical, parasternal, and subxiphoid windows. The diameter of the main pulmonary artery (MPA) was measured by echocardiography, and the stenosis of the MPA was graded based on its maximal velocity (Vmax) as follows: mild (2–3 m/s), moderate (3–4 m/s), or severe (>4 m/s) (16). Obstruction of the pulmonary artery was defined as the gradient of pressure of the MPA, and was calculated using the Bernoulli equation. Echocardiography was used to assess the transvalvular pressure difference according to the criteria described. This gradient was classified as mild (10–36 mmHg), moderate (36–64 mmHg), or severe (>64 mmHg) (Figure 2) (17).

Figure 2 Evaluation of D-TGA vascular abnormalities using ultrasound color Doppler and blood flow. (A) Dilation of aortic sinus (blue arrow); (B) mild pulmonary artery stenosis (red arrow); (C) moderate obstruction of the pulmonary artery (41 mmHg). D-TGA, dextro-transposition of the great arteries.

CMR acquisition

All the subjects were scanned using a 3.0 Telsa system (Discovery MR750, GE, Chicago, IL, USA) using an 8- or 32-channel cardiac coil. The two-dimensional balanced steady state-free precession cine was used to evaluate biventricular function, and the parameters were as follows: repetition time (TR)/echo time (TE): 3.1/1.5 ms; acquisition matrix: (288–320)×(288–320); flip angle: 60°; slice thickness (no gap): 6–7 mm; and reconstructed cardiac phases: 30. Intravenous bolus injection of 0.2 mmol/kg gadopentetate dimeglumine for the contrast enhanced-magnetic resonance angiography (CE-MRA) was administered.

4D flow CMR datasets were acquired with retrospective electrocardiographic-gating during free-breathing. Three-dimensional cardiac cine with k-adaptive-t auto calibrating reconstruction for cartesian (kat ARC) was the prototype for the 4D flow imaging sequence based on the DV24 version. Full volumetric coverage of the two ventricles was provided from the transverse plane. The 4D flow CMR sequence parameters were as follows: TR/TE: 4.3/2.1 ms; volumetric element (voxel) size: (1.6–2.2)×(1.6–2.2)×(1.6–2.2) mm³; flip angle: 15°; temporal resolution: 30 frames/cycle; acquired temporal resolution: 43–75 ms; reconstructed temporal resolution: 26–45 ms; velocity encoding: 120–160 cm/s (in accordance with the 4D flow consensus statement (18), the pulmonary artery obstruction cases used echocardiographic velocity to avoid aliasing artifacts); and parallel imaging reduction factor: R=8. The late gadolinium enhancement (LGE) parameters were as follows: TR/TE: 3.4/1.5 ms; field of view: 260–350 mm × 260–350 mm; flip angle: 35°; and slice thickness: 5–8 mm. LGE was assessed by late post-contrast imaging acquired 7–15 min (depending on heart rate) following contrast administration in the D-TGA group. The patients aged under eight years underwent the CMR examination with sedation, while the patients aged older than eight years, who were cooperative and could complete the CMR scan, as well as all the other subjects, underwent the CMR examination without sedation.

Cardiac function, valve regurgitation and LGE assessment

The epi- and endo-contours were drawn at the end-diastolic and end-systolic phase on the short-axis images for the left ventricle (LV) and right ventricle (RV). The mass, end-diastolic volume (EDV), stroke volume (SV), end-systolic volume (ESV), and EF were calculated using MASS (Leiden, The Netherlands). Mass, EDV, ESV, and SV were indexed by the body surface area (BSA). The indexed volumetric and mass variables were EDVi, ESVi, SVi, and massi. Aortic and pulmonary regurgitation were measured by 4D flow valve tracking in the D-TGA group with reference to those previously reported (8).

Intracardiac 4D flow CMR assessment

The contours of the endocardium and epicardium of the LV and RV underwent semi-automatic segmentation in all the short-axis heart phases. According to the contours, the pathline emission of the flow components, KE, and vorticity were analyzed using commercial software (MASS, Leiden, The Netherlands) (19). The hemodynamic parameters were obtained by averaging the KE value over the diastolic and systolic phases. The following definitions were adopted: (I) direct flow: blood that enters and exits the ventricle in the analyzed cardiac cycle; (II) retained inflow: blood that enters the ventricle but does not exit during the analyzed cycle; (III) delayed ejection flow: blood that starts and resides in the ventricle and exits during the analyzed cycle; and (IV) residual volume: blood that remains in the ventricle for at least two cardiac cycles.

For each voxel, the KE was calculated using the following formula:

KE=1/2ρ_blood·V_voxel·v_voxel2[1]

where ρblood was the density of the blood (1.06 g/cm³), Vvoxel was the voxel volume, and vvoxel was the velocity magnitude of the corresponding voxel. For each phase, the total KE of the ventricle was obtained by adding the KE of every voxel. All the parameters were normalized to the KE ventricular end-diastolic volume (KEi_EDV) and reported accordingly in µJ/mL (20).

The components of the flow rotation were computed in each voxel of the segmented ventricular volumes. Since vorticity magnitude describes the local spinning motion of a fluid near a point, vorticity was expressed by the following formula:

ω=∇×V[2]

where ∇ is the curl of its velocity field V, and was calculated using a compact derivative algorithm (21).

Time-resolved KE and vorticity curves were generated to derive physiologically relevant parameters (Figure 3).

Figure 3 Four-chamber view with LV/RV particle tracing overlayed at the peak systole, peak early, and late diastolic filling phase in a 13-year-old male D-TGA patient. The corresponding LV/RV KEi_EDV. The LV/RV vorticity curve was described at one cardiac cycle. Red color: residual volume; blue color: delayed ejection flow; yellow color: retained inflow; green color: direct flow. The red arrow indicates the LV vortex ring on the short axis. The yellow arrow indicates the RV vortex ring on the short axis. LV, left ventricle; KE, kinetic energy; RV, right ventricle; D-TGA, dextro-transposition of the great arteries; KEi_EDV, kinetic energy normalized to end-diastolic volume; Peak systolic KEi_EDV, peak KEi_EDV of blood flow during systole; Systolic KEi_EDV, average KEi_EDV of blood flow during systole; Peak E-wave KEi_EDV, peak KEi_EDV of blood flow during early filling; Peak A-wave KEi_EDV peak KEi_EDV of blood flow during late filling.

Statistical analysis

The data were presented as the median (interquartile range) or number (%). The t-test was used to compare the normally distributed variables, and the Mann-Whitney U-test was used to compare the non-normally distributed variables between the D-TGA patients and controls. Based on the previously described adverse outcomes of the D-TGA patients, a univariate analysis was conducted using a prior selection of explanatory variables. The stepwise regression algorithm was introduced, and Akaike information criterion was used as the screening quantitative index. Based on multicollinearity, the parameters were incorporated into the multivariable model. The association between the variables was expressed as the 95% confidence interval (CI). The intraclass correlation coefficient (ICC) and coefficient of variation (COV) were used to assess the intra- and inter-observer agreements in all the 4D flow parameters using five random patients and five random subjects. A P value <0.05 was considered statistically significant.

Results

Participant characteristics and myocardial function

The demographic, morphological, and functional characteristics of the subjects are set out in Table 1. There was no significant difference between the D-TGA patients and controls in this study in terms of age. The median CMR postoperative follow-up time was 8.3 years. The study included D-TGA patients with intact ventricular septum (14 cases), and D-TGA patients with ventricular septal defects (VSDs) (20 cases). Five patients underwent valvuloplasty or balloon pulmonary angioplasty after ASO. Of the patients, 25 had neo-aortic root dilation, and 25 had obstruction of the pulmonary artery, including 16 cases of supravalvular pulmonary stenosis. The D-TGA patients were significantly smaller than the controls in terms of height, weight, and BSA, and had a significantly lower heart rate (all P<0.05, Table 1). There were no statistically significant differences between the two groups in terms of EDVi, ESVi, SVi, and EF in the LV and RV (Table 1). LV massi, RV massi, and the RVEDV/LVEDV ratio did not differ significantly between the two groups. Among the patients, 24 had aortic valve regurgitation (6%), 32 had pulmonary valve regurgitation (10%), and 2 (6%) had positive myocardial LGE.

Changes in the flow components, KE, and vorticity profiles

All the included subjects had good quality 4D flow CMR data, as confirmed by a valid count of 80–99%.

In relation to the LV, the D-TGA patients had significantly lower values than the controls in terms of the retained inflow, average KEi_EDV, peak systolic KEi_EDV, systolic KEi_EDV, peak E-wave KEi_EDV, and peak A-wave KEi_EDV (all P<0.05, Table 2 and Figures 4,5). The D-TGA patients had significantly decreased average vorticity, peak systolic vorticity, systolic vorticity, peak A-wave vorticity, and diastolic vorticity than the controls (all P<0.01, Table 3 and Figure 6).

Figure 4 Comparison of the blood flow components of both ventricles between the D-TGA group and control group. LV, left ventricle; RV, right ventricle; D-TGA, dextro-transposition of the great arteries.

Figure 5 Comparison of the kinetic energy of both ventricles between the D-TGA group and the control group. *, P<0.05 compared with healthy controls; ***, P<0.001 compared with healthy controls. LV, left ventricle; RV, right ventricle; D-TGA, dextro-transposition of the great arteries; KEi_EDV, kinetic energy normalized to end-diastolic volume.

Figure 6 Comparison of the vorticity of both ventricles between the D-TGA group and the control group. *, P<0.05 compared with healthy controls; ***, P<0.001 compared with healthy controls. LV, left ventricle; RV, right ventricle; D-TGA, dextro-transposition of the great arteries.

In relation to the RV, the D-TGA patients differed significantly in all the flow component parameters and KE parameters compared to the controls (all P<0.001, Table 2), except diastolic KEi_EDV (P=0.452; Figures 4,5). In terms of the vorticity parameters, the D-TGA patients did not differ significantly from the controls (all P>0.05, Table 3 and Figure 6). A significant increase was observed in the peak E-wave KEi_EDV of the D-TGA patients with supravalvular pulmonary stenosis (P=0.042, Table 4). There was also a significant increase in the average vorticity, peak systolic vorticity, and systolic vorticity between the supravalvular and non-supravalvular pulmonary stenosis patient subgroups (all P<0.05, Table 4).

Association between the RV 4D flow parameters and pulmonary artery obstruction

In the univariate analysis, all the KEi_EDV parameters were associated with a transvalvular pressure difference (r=12.64, P<0.001 for the average KEi_EDV; r=8.45, P=0.021 for the systolic KEi_EDV; r=10.54, P=0.003 for the systolic KEi_EDV; r=10.81, P=0.002 for the peak E-wave KEi_EDV; r=10.29, P=0.004 for the peak E-wave KEi_EDV; and r=9.32, P=0.010 for the peak A-wave KEi_EDV; Table 5).

In the multivariate analysis, the diastolic KEi_EDV, peak E-wave KEi_EDV peak A-wave KEi_EDV, and average vorticity were associated with a transvalvular pressure difference (β=13.54, P<0.001 for the diastolic KEi_EDV; β=105.26, P<0.001 for the peak E-wave KEi_EDV; β=−49.36, P=0.027 for the peak A-wave KEi_EDV; β=−56.37, P<0.001 for average vorticity; Table 5).

Reproducibility

Additionally, 10 randomly selected subjects were used to assess the reproducibility of the blood flow components, KE, and vorticity parameters. The respective ICC for intra-observer variability was 89.1–99.8% and that for inter-observer variability was 84.9–96.8%. The respective COV for intra-observer variability was 2.6–11.5 and that for inter-observer variability was 4.4–13.5 (Table 6).

Discussion

Main findings

Currently, 4D flow CMR imaging allows for the visualization and quantification of abnormal hemodynamics, which has led to better knowledge of cardiovascular hemodynamics and disease progression in CHD patients (22,23). Previous studies have assessed hemodynamic vorticity in Fontan patients and volunteers (24-26). This was the first 4D flow CMR study to investigate biventricular vorticity for D-TGA patients. The main findings of the study are as follows: (I) some LV and RV flow components and the KEi_EDV parameters differed significantly between two groups; (II) LV systolic vorticity, diastolic vorticity, and peak A-wave vorticity differed significantly between the two groups. (III) The supravalvular pulmonary stenosis subgroup had significantly higher RV systolic vorticity and peak E-wave KEi_EDV than non-supravalvular pulmonary stenosis group; and (IV) all the RV diastolic KEi_EDV parameters and RV average vorticity were risk factors for pulmonary artery obstruction.

LV and RV hemodynamics are more sensitive markers than EF

In our study, the LV and RV of the D-TGA patients exhibited normal cardiac function and did not differ significantly compared to the control group during aortic and pulmonary mild valve regurgitation. Previous studies (17) have shown that patients with D-TGA generally maintain biventricular function similar to that of controls in a medium-term follow-up period of less than 20 years after ASO. Our study included younger subjects than previous studies; the median age of the patients in the D-TGA group was 9.5 years, and that of the control group was 10.0 years. These findings align with the results of previous research (17).

In total, 64% of the patients had aortic valve regurgitation in our study. The presence of aortic valve regurgitation and neo-aortic root dilation altered the proportion of the flow component. Significant differences were observed in the retained inflow of the LV between the two groups, with percentages of 12.3% and 19.8%, respectively. Previous research has shown that the retained inflow needs to decelerate at the end of diastole, so that additional KE can subsequently be acquired before ejection during a subsequent systole in a normal LV (27). It may be that the decreased proportion of the LV retained inflow decreases its ability of accelerate blood compared to a normal LV. Grotenhuis et al. (28) examined biventricular systolic and diastolic dysfunction in patients with D-TGA patients, and found that parts of the biventricular flow components, especially the RV, differed significantly between the two groups Thus, the hemodynamics parameters are more sensitive markers than EF in evaluating systolic and diastolic dysfunction (see also the previous review (29).

The value of LV hemodynamics in myocardial remodeling

The LV average KEi_EDV, peak systolic KEi_EDV, systolic KEi_EDV, peak E-wave KEi_EDV, and peak A-wave KEi_EDV of the D-TGA patients were found to be significantly lower than those of the controls. This could be attributed to two main factors. First, the altered aortic geometry may result in increased LV afterload, leading to decreased LV hemodynamic efficiency (26). Second, it is possible that the myocardial tissue in D-TGA patients has experienced early damage due to perinatal cyanosis and cardioplegia. It should be noted that the potential influence of other factors could not be excluded in our study.

Grotenhuis et al. examined diffuse myocardial fibrosis of the LV in D-TGA patients using T1 relaxometry CMR imaging, and reported that it was correlated with the LV mass/volume ratio (R=0.60, P<0.001) (28). In D-TGA patients, subclinical signs of ventricular and myocardial remodeling are present, including increased LV dimensions and signs of LV fibrosis. There were no significant differences in the LV mass index and RVEDV/LVEDV ratio in D-TGA patients and controls. It may be that LV remodeling needs to be assessed over a longer period in the future.

The characteristics of KE and vorticity in D-TGA

KE is a crucial component of the heart’s external work, and is responsible for accelerating blood from a resting state to its current velocity (30). Callaghan et al. (31) conducted a study using 4D-flow MRI to examine the biventricular hemodynamics in patients with arterial and atrial switch D-TGA and normal subjects, and observed that increased EL leads to alterations in decreased KE. In our study, we observed significant differences in the RV KEi_EDV parameters with normal cardiac function, except diastolic KEi_EDV. Compared to the LV, the RV is more susceptible to disruption and disorder, primarily because morphologically, it is characterized by a fused inflow and a highly spherical ventricle.

Vorticity is commonly defined as the curl of a fluid velocity vector. Our previous research showed that the presence of vortices in the ventricular blood volume may serve as an indicator of enhanced cardiac efficiency (32). In this study, we observed significantly reduced levels of LV systolic vorticity and peak A-wave vorticity in the patient group compared to the control group. These findings suggest that myocardial fibrosis and abnormal preload might have contributed to inefficient blood flow transmission in our study cohort (33). Further research needs to be conducted to explore the potential relationship between 4D flow hemodynamic parameters and fibrosis, which could help elucidate the underlying mechanisms of myocardial fibrosis.

This study did not find any significant differences in the RV vorticity parameters between the D-TGA patients and controls. The formation of the physiologic vortex has been hypothesized to create efficient flow pathways, minimizing turbulence and EL, and potentially reflecting the heart’s adaptability to changing conditions. The formation of the RV diastolic vortex ring could not be accurately quantified using 4D flow CMR imaging. The mechanism of RV vortex ring transmission requires further research.

The relationship between RV hemodynamics and pulmonary artery abnormalities

Santens et al. (17) reported that pulmonary artery stenosis was frequently found in 234 of 289 patients, the stenosis was severe (15 patients, 6.4%). The obstruction was usually located at the bifurcation of the pulmonary artery (158 patients, 68%) in a 35-year follow-up study. Delaney et al. (34) reported that inefficient pulmonary artery flow might be an important predictor of RV afterload in D-TGA patients. Conversely, with an RV mass and a contractile reserve of approximately one-third of the LV, the RV output is highly sensitive to increases in afterload. Thus, the assessment of RV hemodynamics is particularly important in D-TGA patients. Our previous research also found that RV systolic and diastolic dysfunction highly prevalent in pediatric TOF patients during preserved RVEF (35). In our study, the RV systolic vorticity and peak E-wave KEi_EDV of the pulmonary stenosis group were significantly higher than those of the non-pulmonary stenosis group. The evidence from this study showed that this efficient hemodynamics are sensitive makers and might contribute to the adaptive remodeling of the RV.

Progressive obstruction in pulmonary circulation can lead to pressure loading in the RV, resulting in varying degrees of chronic pressure overload. As a result, multiple interventions may be necessary to reduce the pressure load on the RV, including balloon dilatation and stenting (16). In our study, all parameters related to the RV KE_iEDV were identified as independent predictors of pulmonary artery obstruction through the univariate analysis. Further, the RV diastolic KE_iEDV parameters and RV average vorticity were found to be risk factors for pulmonary artery obstruction in the multivariable model. Our research established a non-invasive RV hemodynamic model that can be used to optimize management strategies for the best long-term outcomes in D-TGA patients. We found acceptable inter- and intra-observer reproducibility in the biventricular hemodynamics measurements of the flow components, KE, and vorticity. This study has shown that the reproducibility of biventricular hemodynamics measurements is feasible, which is consistent with findings from previous large cohort studies on normal biventricular hemodynamics (29,32).

Limitations

This study had a number of limitations. This was a single-center prospective study; thus, further research needs to be conducted at multiple centers and with multiple vendors. The use of sedation for children aged under 8 years old (which occurred in 6 cases) was indicated by our institution protocol. However, the sedative effect might have altered the flow hemodynamics in these D-TGA patients. We cannot exclude the possibility of referral bias, although all the patients were asymptomatic. Several patients were removed from the study due to inadequate image quality, resulting from the long scan of the 4D flow sequence. Sotelo et al. (35) analyzed hemodynamic parameters in the aortas of healthy volunteers and patients with D-TGA, and found a relationship between the velocity angle and aortic root dilatation in the patients with D-TGA. In our study, 25 (73%) patients had neo-aortic root dilation. Unfortunately, we did not use 4D flow to evaluate the progress of the aortic root dilatation. We will compare the hemodynamics of aortic root dilatation and arterial-ventricular interaction in a further study (36). We normalized KE to EDV, as we did in our previous study (20). However, some studies have normalized KE to SV (31). The Bernoulli equation for pressure gradient quantification provides an estimate of the flow inside the ventricular outflow tract by echocardiography and can be used as a method for non-invasive evaluation in the next stage of research. In summary, we view this as a relatively preliminary study and note that multi-center, larger patient population studies need to be conducted.

Conclusions

We found that 4D flow biventricular hemodynamics were more sensitive markers than EF in postoperative D-TGA patients. The RV KEi_EDV parameters and RV average vorticity were risk factors for pulmonary artery obstruction.

Acknowledgments

Funding: This study was supported by grants from the National Key Clinical Specialties Construction Program, Innovative Research Team of High-Level Local Universities in Shanghai, National Natural Science Foundation of China (No. 82171902), the Shanghai Committee of Science and Technology (Nos.17411965400 and 22TS1400800), and the SJTU Trans-Med Awards Research (No. 20220101).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://qims.amegroups.com/article/view/10.21037/qims-24-840/rc

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-24-840/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work, including ensuring that any questions related to the accuracy or integrity of any part of the work have been appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study was approved by the Institutional Medical Ethics Committee of Shanghai Children’s Medical Center (No. SCMCIRB-K2022.49-1). All the patients or their legal guardians and the healthy subjects provided written informed consent.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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