We performed a retrospective study designed to compare the accuracy and reliability of directly measuring AVVR in pediatric CHD with 4DF CMR compared to the standard indirect methods. There were three major findings of our study. (1) Our data demonstrate that assessment of AVVR by JET was overall the most precise measurement, particularly in subjects with tricuspid regurgitation. Though all four methods performed well, the JET correlated with VOL better than AIM and JET correlated with AIM better than VOL. Unlike AIM, the JET method was found to be accurate compared to VOL -- the clinical standard. Further, the JET method showed excellent inter- and intra-observer reliability in a diverse population of pediatric CHD, unaffected by the presence of aliasing or laterality of AVVR. (2) VOL had weaker correlations and larger measurement variability compared with the JET and AIM methods than JET vs. VOL and AIM methods. Though intra- and inter-observer reliability of VOL by ICC were excellent, inter-observer reliability measurements showed a small but statistically significant difference between observers. (3) Despite strong correlations, the AIM using static and valve-tracking techniques underestimated AVVR relative to the JET and VOL methods. Though the degree of this underestimation was small in most subjects, these findings support JET as an alternative measure of internal validation in measuring AVVR.
Measurement of AVVR
This is the first study demonstrating validity of the JET method to accurately and reliably measure AVVR compared to multiple indirect methods in a diverse pediatric cohort with CHD. Our findings support the results of prior work on the JET method in other patient populations. A retrospective study of 21 adults without CHD found that RF directly measured by 4DF CMR was highly reliable and accurate compared to the VOL method [
40]. The correlation and measurement variability noted between the JET and VOL methods in our cohort are similar to prior data from pediatric and adult cohorts [
24,
29].
Although this is the first such report in children, the JET method by 4DF CMR has been previously found in adults to have high accuracy and reliability relative to the VOL method, particularly in measuring tricuspid regurgitation [
40]. 4DF CMR post-processing allows for visualization of flow to aid in the positioning of measurement planes through the use of velocity vectors [
37]. Prior work has demonstrated improved accuracy for the AIM method when the atrioventricular plane is placed at the peak inflow velocity as opposed to the valvular plane [
37,
50]. The importance of a measurement plane perpendicular to flow likely extends to JET planes and may explain the relatively worse correlation between measurements of mitral RF between the JET and the VOL and AIM methods. Tricuspid regurgitant jets tend to be more central and laminar in orientation as opposed to mitral jets which are more commonly eccentric with a large angle change during systole [
40]. In a cohort of 32 children and adults with repaired atrioventricular septal defect (AVSD) and left-sided regurgitation, the regurgitant jets were found to be non-circular, dynamic, and eccentric with a median angulation change of 30–36° during systole [
24]. These features increase the technical difficulty of maintaining an orthogonal plane to the mitral regurgitant jet through systole. As can be seen in a subject with repaired AVSD and resultant mitral cleft (Fig.
2b), the large eccentric regurgitant jet which projects along the inferior mural aspect of the left atrium throughout systole complicates creating a true cross-sectional plane. Five of the 18 (28%) subjects in our cohort with mitral regurgitation had a history of AVSD which may have affected accuracy of our JET measurements despite excellent reliability. Our data highlight the clinical applicability of the JET method in pediatric CHD requiring evaluation of tricuspid regurgitation. Although the results were also promising in cases of mitral regurgitation, considerably eccentric or dynamic jets may affect the accuracy of the JET method.
Our initial intent was to use VOL as the clinical standard to which to compare JET and AIM methods. Upon analysis of the data we found that all four methods were fairly consistent, but that VOL was not the most precise measurement -- which raises the question of its role as the clinical standard. The accuracy of VOL is affected by measurement errors inherent in planimetry, particularly given the practice variation in basal slice inclusion and contour selection, which may have contributed to lower measurement precision [
16,
51]. However, our planimetry reliability analyses found excellent intra- and inter-observer reliability for both LV and RV measurements. Similarly, our results demonstrated excellent reliability for the VOL method, supporting the results from multiple prior works [
9,
17,
29,
40]. Two additional practical concerns with the VOL method arose from our data. In our cohort, VOL classified more subjects with moderate or severe regurgitation than the JET and AIM methods. This may result in greater consideration for surgery when VOL is used to measure regurgitation. Furthermore, a limitation to the use of VOL as the clinical standard are cases in which the indirect calculation results in a negative RF (Table
2). Negative RFs were found in 5/44 (11%) subjects by the VOL method as well as in a separate 6/44 (14%) and 7/44 (16%) by AIM
stat and AIM
track, respectively.
The AIM methods systematically underestimated RF compared to VOL and JET methods. Though these differences may be clinically insignificant in certain patients, for subjects with mild regurgitation (~ 60% of our cohort), these differences represented up to 25% of their total RF. AIM
stat measured slightly but consistently larger than AIM
track, consistent with prior studies demonstrating that static AV planes overestimate RVol and RF relative to tracking planes [
23,
37,
52]. The differences found in our study were smaller than prior reports and may be due to our methodology; determination of a “static plane” by 4DF CMR has significantly more flexibility than a standard 2D CMR scan and may have increased accuracy of the measurements. This is supported by our sub-group analysis demonstrating that AIM
stat calculated using 2D PC AVFF measurements correlated worse with and had a larger median difference from VOL than AIM
stat calculated using 4DF CMR static AVFF. Prior work using 4DF CMR and retrospective valve tracking annular inflow methods do not report their calculated AVVR as outcomes, instead comparing net inlet and outlet flows for internal validation, which limits direct comparison to our results as well as general clinical applicability [
22,
25]. Recent work has demonstrated feasibility of an automatic valve-tracking 4DF CMR technique with improved reliability and internal consistency in measuring net valve flow across all four cardiac valves compared to manual valve-tracking technique in a large cohort of subjects with CHD [
36]. However, their RF measurements were not compared to a clinical standard (such as VOL) or outcome measures. Future work assessing the accuracy of the automatic valve-tracking AIM method may demonstrate improved accuracy than found in our study with manual valve-tracking.
Logistical advantages of 4DF CMR
2D CMR requires technical expertise from technologists and physicians to prescribe AV planes during the acquisition in patients with complex CHD anatomy, resulting in scan durations of 1–1.5 h [
41,
53]. This has important implications on anesthetic requirements in pediatrics and on clinical efficiency. 4DF CMR, as a single acquisition with all planes created during post-processing, takes ~ 10 min after an initial localizer sequence. Acquisition of standard 2D PC requires multiple localizing sequences to achieve optimal orthogonal planes. Children are more likely to move in-between sequences, requiring repeat localizer sequences and longer exam times. This has resulted in the adoption of 4DF CMR for acquisition of all flow measurements at our institution, though 2D cine acquisitions are still necessary for planimetry.
Our post-processing analysis times for the AIM and JET methods were short and represent an opportunity to improve clinical flow and resource utilization in the MRI workflow. Our analysis time for the AIM
track method was significantly shorter than prior reports of 15–35 min per patient, likely due to the use of semi-automated software that adjusted to through plane motion [
23,
25]. The JET method analysis time was relatively short (3.1 ± 2.1 min) irrespective of number and morphology of regurgitant jets.
Limitations
Several limitations were present in our study. VOL in this study utilized 2D planimetry measurements and 4DF PC semilunar flow measurements, which precludes comparison of a true 2D VOL measurement to the 4DF JET. However, 4DF PC measurements of semilunar flow have been previously validated with excellent internal consistency and accuracy compared to 2D PC CMR [
22,
30,
31,
35,
39], thus we do not believe this negatively impacted the validity of our results. We excluded subjects with significant semilunar regurgitation and our data may not be generalizable to those populations. Arterial encoding speeds were utilized in our cohort as part of our institution’s clinical practice based off prior published findings demonstrating reliable quantification of venous blood flow at arterial VENCs with the use of IV contrast, although this may have contributed to underestimation of the AIM method [
41,
54]. It is not our clinical practice to perform multiple 4DF sequences at different VENC settings, though this may allow for more accurate data. Future application of phase unwrapping software may allow for a single, low-VENC 4DF sequence. Despite arterial VENCs, aliasing of regurgitant jets was common. However, tracing the jets distal to the aliasing segment allowed for accurate and reproducible data. We employ contrast agents for all our 4DF acquisitions. Recent research has found dose-dependent retention of gadolinium-based contrast in the brains of patients despite normal renal function, though long-term effects from chronic exposure remain unknown [
55]. Although ferumoxytol is used clinically at an increasing number of centers for cardiac imaging, there remains a black box warning in pediatric imaging due to the small risk of adverse reactions, most notably hypotension [
56]. Further study is necessary to clarify the risk:benefit ratio of contrast administration for these studies. Although our methodology for calculating AVVR differed slightly from published recommendations we accounted for even a small amount of semilunar regurgitation in order to optimize accuracy when comparing methodologies [
13,
16,
53,
57]. Lastly, this study did not validate direct AVVR quantification against clinical outcome measures, as this was beyond the scope of the study.