Background
Cardiovascular magnetic resonance (CMR) is crucial for initial diagnosis, pre- and postoperative evaluation, and follow-up in children and adults with congenital heart disease (CHD) [
1‐
3]. Cardiovascular magnetic resonance angiography (CMRA) provides radiation-free assessment of vascular structures and anomalies in children with CHD [
4]. Contrast-enhanced CMRA techniques can generally be based on multiphase/time-resolved approaches and single-phase approaches with high spatial resolution using electrocardiogram (ECG) triggering and respiratory navigator gating [
5,
6].
Although macrocyclic gadolinium-based contrast agents have an excellent safety profile, there are controversies regarding its retention in tissues after successive examinations [
7]. However, the clinical significance is still unknown and there is currently no evidence of an associated toxicity [
8,
9]. Nonetheless, strategies to reduce the gadolinium exposure are desirable, particularly in young children with CHD who undergo numerous CMR follow-up examinations during their lifetime. Gadolinium-free examinations also eliminate the risks of rare complications such as tissue necrosis after extravasation, allergic reactions, and nephrogenic systemic fibrosis. In addition, non-contrast examinations reduce examination costs and facilitate a faster and more time efficient clinical workflow.
Current non-contrast CMRA techniques for assessing the great vessels are typically based on balanced steady-state free precession (bSSFP) [
10,
11]. Although they have shown promise in high-resolution imaging, the major drawback to off-resonance artifacts has limited their application, particularly at higher field strength like 3T or when covering a large field-of-view [
12,
13]. Recently introduced flow-independent relaxation-enhanced angiography without contrast (REACT) technique employed a magnetization-prepared non-balanced dual-echo approach with 3D isotropic readout for native high-resolution CMRA [
14,
15]. First studies in CHD using this technique has shown promising results in adults with predominantly corrected CHD at 1.5 T and other vascular territories [
16‐
18]. Therefore, it may be a potential contrast-free alternative to visualize even more complex cardiovascular anatomies and much smaller vascular structures in a challenging cohort of young children with CHD at 3 T.
This study aimed to evaluate non-contrast REACT CMRA for assessment of the great vessels in young children with complex CHD in comparison to contrast-enhanced cardiac-gated steady-state CMRA as reference standard.
Methods
Study cohort
This retrospective study was approved by the local institutional review board that waived informed consent. From April to July 2021, consecutive young children with complex CHD, who had undergone CMR were identified. Patients aged < 10 years who had undergone both contrast-enhanced CMRA and non-contrast CMRA (for comparability in upcoming non-contrast follow-up examinations) under deep sedation were included for analysis. No exclusion criteria were applied regarding the type of CHD or previously performed surgical or interventional procedures.
Cardiovascular magnetic resonance
All examinations were performed on a clinical whole-body 3T system (Ingenia Elition X, Philips Healthcare, Best, the Netherlands). For signal reception, a 16-channel body array coil (35 patients) or a 12-channel array coil (1 patient) with digital interface were used. The CMR protocol for CHD evaluation consisted of ECG gated bSSFP cine imaging in standard orientations, phase contrast velocity-encoded flow imaging of vessels of interest, and late gadolinium enhancement (LGE) in standard orientations. The CMR protocol was individually extended according to the type of CHD or specific cardiovascular abnormalities.
Non-contrast REACT CMRA
The imaging sequence applied was a 3D, magnetization-prepared, non-balanced, dual-echo acquisition with generalized Dixon for water and fat separation [
14,
19]. For magnetization-preparation non-volume-selective T2-prep pulse and inversion recovery pulse with short inversion time were applied to suppress tissues with short to intermediate T1 and T2 relaxation times such as muscles, nerves, and internal organs. Signal of the native blood was enhanced due to its long T1 and T2 relaxation times, while residual fat signal was further removed with the help of Dixon in the obtained water images [
20]. To minimize cardiac and respiratory motions, data acquisition was applied with prospective ECG (end-diastole) and respiratory gating (end-expiration). For imaging acceleration, a standard vendor implementation of the compressed sensing technology combined with parallel imaging, termed compressed SENSE (Philips Healthcare) [
21,
22], was used with a factor of 5. In short, variable density sampling is used for data acquisition, while wavelet sparsifying transformation and L1-regularization are employed for online iterative reconstruction. REACT CMRA was acquired at the beginning of the scan protocol (before contrast injection) in all patients.
Contrast-enhanced CMRA
The high-resolution single-phase steady-state CMRA was acquired during a slow infusion (flow rate: 0.1–0.3 ml/s) of a gadolinium-based contrast agent at a dose of 0.1 mmol per kg of body weight (Gadobutrol, Gadovist, Bayer Healthcare, Berlin, Germany). Dual-echo Dixon readout was used to achieve fat removal in water images [
20,
23]. Respiratory navigator gating for end-expiration and ECG triggering for end-diastole was applied for data acquisition. A compressed SENSE factor of 6 was used for imaging acceleration.
Both CMRA methods were applied in the coronal plane covering the chest. Imaging parameters are given in Table
1. Dixon-based water-only, fat-only, in-phase, and out-of-phase images were reconstructed and transferred for image analysis.
Table 1
Cardiovascular imaging parameters of native relaxation-enhanced angiography without contrast (REACT) and contrast-enhanced steady-state magnetic resonance angiography (CMRA) used in the present study
Time of echo (ms) | 1.42/2.8 | 1.93/3.4 |
Time of repetition (ms) | 4.7 | 5.1 |
Orientation | Coronal | Coronal |
Voxel size (mm³), acquired | 1.39 × 1.40 × 1.40 | 1.19 × 1.20 × 2.40 |
Voxel size (mm³), reconstructed | 0.45 × 0.45 × 0.70 | 0.69 × 0.69 × 1.20 |
Acquisition matrix (mm³) | 216 × 214 × 125 | 252 × 249 × 80 |
Field of view (mm³) | 300 × 300 × 88 | 300 × 300 × 96 |
Sampling of k-space | Cartesian | Cartesian |
T2 prep/inversion delay time (ms) | 50/10.8 | No/320 |
Turbo field echo factor | 31 | 19 |
Flip angle (°) | 15 | 20 |
Compressed SENSE | Yes, factor 5 | Yes, factor 6 |
Electrocardiogram gating | Yes | Yes |
Number of heart phases | 1 (single phase) | 1 (single phase) |
Respiratory gating | Yes, gating window (7 mm) | Yes, gating window (7 mm) |
Image analysis
Image quality assessment and vessel diameter measurements were performed independently by two radiologists in a blinded fashion for both CMRA methods (first reader: AI, 5 years of CMR experience; second reader: NM, 4 years of CMR experience) using a commercially available software (DeepUnity R20 XX, Dedalus HealthCare GmbH). Water-only images were primarily used for image analysis of both CMRA techniques (in-phase-images were additionally used if fat-water swapping artifacts were present).
Image quality
The following great vessels of the heart were defined as vessels of interest: ascending aorta, main pulmonary artery, left pulmonary artery, right pulmonary artery, left superior pulmonary vein, right superior pulmonary vein, superior vena cava, inferior vena cava. The origin of the right and left coronary artery were also evaluated. Image quality assessment was performed visually. Qualitative ratings were based on a five-point Likert scale defined as follows: (5) excellent = no artifacts, good vessel border delineation, (4) good = minimal artifacts, minimal vessel blurring, (3) intermediate = some artifacts, some vessel blurring, (2) poor = severe artifacts, severe vessel blurring, (1) non-diagnostic = vessels are not identifiable. The overall image quality score included ratings for all predefined vessels.
Vessel diameter measurements
For quantitative analysis, following vessels were analyzed: ascending aorta and descending aorta (at pulmonary bifurcation level), main pulmonary artery or conduit (midline between pulmonary valve and bifurcation), left and right pulmonary artery (or distal to the anastomotic area of Glenn shunt), left and right inferior, as well as superior pulmonary veins (1 cm distal to the atrial ostium or common trunk, respectively). Measurements were performed independently by both readers at the same predefined landmarks according to recent CMR guidelines for adults and children [
24]. For each plane, the inner diameter was measured perpendicularly on multiplanar reconstructed images. Vessels with non-diagnostic quality were excluded from quantitative analysis.
Artifacts
The presence of artifacts compromising the great vessels was reviewed by both readers in consensus agreement. The evaluation included susceptibility artifacts (e.g., due to surgical or interventional material), flow artifacts (e.g., due to high and turbulent flow or valve insufficiency), and fat-water swap artifacts (Dixon method-specific signal swapping in calculated fat and water images) [
16].
Vascular findings
Most patients referred for CMR had complex cardiovascular anomalies, most of which were already known based on medical history and previous examinations (e.g., echocardiography, cardiac catheterization, or CMR). Final diagnosis of all vascular abnormalities and all accompanying clinically relevant findings based on CMRA was made in consensus by experienced, board-certified CMR readers (JAL with 10 years of CMR experience and CH with 17 years of CMR experience).
Statistical analysis
Commercially available software (Prism, version 9.2, Graph-Pad Software, San Diego, California, USA) was used for statistical analysis. Data are presented as mean ± standard deviation or as absolute frequency. The Shapiro–Wilk test was applied to check for normal distribution of continuous data. Quantitative measurements between both CMRA methods were compared using the paired
t-test, Pearson correlation, and Bland–Altman analysis. Differences in image quality ratings were tested using the Wilcoxon signed-rank test. The McNemar test was used to compare the frequency of occurring artifacts between both CMRA techniques. Intraclass correlation coefficients (ICC) were applied to analyze interobserver reproducibility [
25].
Discussion
This intraindividual comparison study presents a non-contrast high-resolution 3D isotropic CMRA that demonstrated high overall image quality and equivalent diagnostic findings in young children (median age: 4 years) with complex CHD, compared to contrast-enhanced steady-state CMRA. Improved image quality at the ascending aorta including the proximal coronary arteries and at the inferior vena cava underline that native REACT CMRA can be implemented for clinical use in CHD.
Due to the ongoing debate on CMR contrast deposit in the human body, efforts to reduce the use of gadolinium contrast media have been intensified over the recent years. So far there is no standard approach for gadolinium-free CMRA in children with complex CHD. To accurately assess vessel diameter and clearly visualize even small vessels and vascular connections in CHD, high spatial resolution cardiac and respiratory gated CMRA is often complementary performed to time resolved multiphase CMRA [
23]. However, its acquisition requires additional contrast agent administration. Considering the young age of CHD patients, high-resolution non-contrast-enhanced techniques are strongly desirable in clinical practice but are often not applied owing to a lack of validation. Acquisition of the proposed REACT CMRA was successful in all patients with free breathing. Non-contrast REACT CMRA could be acquired early during the CMR examination, providing a three-dimensional overview of the entire cardiovascular anatomy and facilitating cine and flow imaging planning. The mean acquisition time for REACT CMRA was longer than contrast-enhanced CMRA. Considering the total scan duration of a typical CMR protocol for CHD, this was still within an acceptable range. Previous studies on native CMRA imaging in a pediatric CHD cohort reported longer mean scan times of approximately 7–10 min (max. 18 min) using a bSSFP whole-heart technique and conventional navigator [
26,
27]. However, the majority of non-contrast-enhanced CMRA studies focused on coronary vessels rather than the great vessels and were not based on young pediatric CHD.
REACT-CMRA provided accurate and reliable measurements of vessel diameter comparable to contrast-enhanced CMRA. Although there was a small difference between both methods in the vessel diameter of the inferior pulmonary veins (probably related to impaired image quality due to flow artifacts on REACT CMRA), the difference was still within an acceptable range. The overall image quality score of REACT CMRA was comparable to contrast-enhanced CMRA. Major benefits in image quality were achieved at the ascending aorta including the proximal coronary arteries and at the inferior vena cava.
Excellent diagnostic quality of the ascending aorta on non-contrast REACT CMRA allowed for accurate detection of aortic ectasia at pre- or postsurgical follow-up (two patients). Because of the high prevalence in CHD, concomitant assessment of aberrant coronary anatomy is of particular value [
28]. In clinical routine, acquisition of coronary whole heart imaging is often necessary in addition to thoracic contrast-enhanced CMRA [
28], which extends examination time. Here, REACT CMRA could reduce examination time by combined assessment of the great vessels and coronary arteries. Furthermore, visualization and accurate measurements of the superior and inferior vena cava are important in patients with Glenn or Fontan circulation for pre- or postsurgical follow-up [
29,
30]. REACT CMRA partially showed moderate image quality of the superior vena cava and pulmonary arteries due to Glenn or Fontan circulation (50% of patients) with lower venous blood signal and flow turbulences, but still reached adequate diagnostic quality.
The slightly impaired image quality for the pulmonary arteries and the intermediate image quality for the pulmonary veins were mainly contributed to artifacts caused by high and turbulent pulmonary flow (especially in patients with severe pulmonary insufficiency or high and turbulent vein flow during diastole). However, clinically relevant abnormalities such as dilatation or stenosis of the pulmonary arteries were adequately assessed compared to contrast-enhanced CMRA. Turbulent flow effects occurred particularly in highly pulsatile circulations like in patients with repaired tetralogy of Fallot. It is known from previous whole heart imaging studies that these effects can be reduced or even compensated by data acquisition in different cardiac phases [
27]. Our results indicate that the unique and complex cardiovascular hemodynamics in young children with CHD are not generally comparable with an adolescent or adult cohort [
16,
31,
32] and might require dedicated technical adjustments for non-contrast imaging due to pronounced flow-related effects.
As most patients in our cohort were referred for pre- or postsurgical follow-up with known CHD, most findings of vascular abnormalities were stable. However, all additional vascular findings diagnosed with contrast-enhanced CMRA could also be visualized with REACT-CMRA (e.g., progressive dilatation of the great vessels or graft/shunt stenosis). There was no difference in the detection of aorto-pulmonary collateral arteries or signs of venous collateralization between both CMRA techniques. In two patients (6%) the use of REACT CMRA was beneficial compared to contrast-enhanced CMRA (evaluation of graft stenosis and detection of a coronary anomaly). However, in three patients (8%) with severe pulmonary insufficiency, the main pulmonary arteries could not be adequately assessed on REACT CMRA because of distinct flow artifacts. In one patient (3%) a partial anomalous pulmonary venous connection was better depicted on contrast-enhanced CMRA.
CMR is particularly well suited for contrast reduction because it is usually based on double dose contrast administration owing to LGE imaging. The assessment of disease- or surgery-related myocardial fibrosis by LGE imaging may improve risk stratification, especially in grown-up patients with CHD [
33‐
35]. As the concrete prognostic value of repeated LGE imaging in children is poorly studied, its acquisition on regular follow-up is not essential and currently depends on individual clinical decision making. In young patients with known and clinically stable CHD and no clinical indication for time-resolved CMRA or LGE imaging, a contrast-free protocol is reasonable, and could be complemented by the use of non-contrast REACT CMRA.
Limitations
Our study has several limitations. The number of patients in the current study is relatively small. However, a wide range of complex CHD types with postoperative conditions were included, suggesting applicability in pre- and postoperative follow-up. Nevertheless, studies with larger patient cohorts are needed to provide subgroup analyses of different age groups and CHD types to further standardize the approach in different clinical settings. There might be an observer bias, as readers could not be blinded to the CMRA techniques for qualitative and quantitative analyses. In this study, only morphological vascular findings could be assessed with REACT and single-phase contrast-enhanced CMRA, but not functional findings detectable with cine and flow imaging or time-resolved CMRA. Signal and contrast to noise analysis were not performed due to different acceleration factors. Furthermore, comparison of REACT CMRA to other non-contrast techniques such as bSSFP-based or Quiescent-Interval Single Shot (QISS) CMRA was beyond the scope of this study. However, bSSFP CMRA is generally limited at 3T due to predominant off-resonance artifacts caused by field inhomogeneity.
Conclusion
In conclusion, non-contrast REACT CMRA provides high image quality, accurate vascular measurements, and equivalent diagnostic certainty compared to high-resolution contrast-enhanced steady-state CMRA in a challenging cohort of young children with complex CHD. As part of a standard CMR protocol, REACT CMRA can enable gadolinium-free examinations without compromises in diagnostic quality for children with CHD undergoing pre- or postsurgical follow-up.
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