Validation of aortic valve 4D flow analysis and myocardial deformation by cardiovascular magnetic resonance in patients after the arterial switch operation

Patients were scanned according to a predefined imaging protocol with gadolinium contrast, without anaesthesia or sedation on a 1.5-T CMR system (Ingenia R4.1.2, Philips Healthcare, Best, The Netherlands).

Routine balanced steady-state free precession cine images were acquired in various orientations (short axis multi-plane, 4-chamber and 2-chamber long axis, right and LV outflow tract views in 2 planes) during repeated end-expiratory breath holds using a balanced turbo field echo sequence (voxel size 1.25 × 1.25 × 8 mm, reconstructed temporal resolution 30 frames/ cycle) to provide anatomical information for post-processing. Multi-plane short axis images were also used for planimetric analysis of stroke volume.

4D flow through the AV and mitral valve (MV) was measured with a retrospectively electrocardiography gated, velocity encoded phase-contrast sequence, during free breathing, without correction for breathing movement, without parallel imaging, with a field of view covering the basal volume, voxel size 3.5 × 3.5 × 3.5 mm, temporal resolution 30 frames/ cycle, velocity encoding 1.8 m/s, flip angle 10^o, TR: 7.3 ms, TE: 3.9 ms [14]. The scan time was 3.42 min at a heart rate of 75 bpm. Significant degree of AR was defined as more than 5% regurgitation fraction [15]. Quantitative 2D flow across the AV was measured with a retrospectively electrocardiography gated, velocity encoded phase-contrast sequence during end-respiratory breath hold, voxel size 2.5 × 2.5 × 8 mm, temporal resolution 20 frames/ cycle, velocity encoding 2.5 ms, TR: 4.7 ms, TE 2.8 ms [16].

LV planimetric analysis was performed by manual tracing of endocardial contours on short axis images, using Qmass MR Research edition (version 7.4, Medis, Leiden, The Netherlands) to quantify LV end diastolic volume (LVEDV, corrected for body surface area (BSA)), end systolic volume (LVESV, corrected for BSA), mass and ejection fraction (LVEF).

4D velocity-encoded CMR data over the AV and MV were analysed using CMR 4D flow (version 2.0, Pie Medical Imaging, Maastricht, The Netherlands) with valve tracking, to quantify flow volume and degree of AR. MV flow assessment was used as internal validation of AV flow volume. For external validation of 4D flow volumes, 2D velocity-encoded CMR data over the AV were analysed using QFlow (version 5.6, Medis). Contours were manually traced in all phases of the 4D and 2D measurements. 4D AR was measured at peak velocity of the jet perpendicular to maximum flow velocity (Fig. 1).

Feature tracking was performed using the 2D Cardiac Performance Analysis MR module of Imaging Arena (version 1.2, TomTec Imaging Systems GmbH, Unterschleissheim, Germany). LV GLS was determined from analysis of the four chamber CMR views, as an average of the six individual segments of the LV [17]. Segments were excluded if non-capturing by the software was observed by eye-balling. If two or more LV segments showed non-capturing, the patient was excluded from analysis.

All CMR analyses were performed by one researcher and subsequently re-analyzed by a second observer to test for inter-observer agreement. Both researchers had 4 years of experience with CMR imaging.

Doppler transthoracic echocardiography was performed on a Toshiba Artida (Toshiba, Tokyo, Japan) with a 5-MHz transducer. Longitudinal strain analysis was performed with TomTec Image Suite (Version 6.0, TomTec Imaging Systems GmbH). After assessment of full view of all parts of LV myocardium for at least one cardiac cycle, a six-segment analysis was performed. Segments were excluded if eye-balling of the analysis confirmed non-capturing by the software. If two or more segments showed non-capturing, the patient was excluded from analysis. GLS was calculated as an average of the available segments.

All echocardiography analyses were performed by one researcher (4 years of experience), and subsequently re-analyzed by a second observer to test for inter-observer agreement (12 years of experience).

Normality of distribution was checked using the Shapiro Wilk test. Normally distributed continuous data were reported as mean ± standard deviation. Alternatively distributed data were expressed as median (interquartile range). For comparison of groups, independent samples t-test or ANOVA were used as appropriate. For agreement, the difference (between tests and within tests as inter- and intra-observer agreement, respectively) was first checked for significance through one-sample t-test. Agreement was then expressed as two-way, random-effects intra-class correlation (ICC) and checked visually through Bland-Altman plot. ICC was interpreted according to Koo and Li [18]. The coefficient of variance (CoV) was defined as the standard deviation of the differences between the two measurements divided by the mean of these measurements. For all tests a p-value of < 0.05 was accepted as statistically significant.

4D flow assessment of the AV demonstrated degree of AR of 4.1 ± 4.1% (Table 2), while 11 ASO patients (13.6%) had significant AR exceeding 5%. 2D flow showed comparable regurgitation at 3.2 ± 7.1% (p = 0.33), which agreed well with 4D flow (ICC = 0.85, CoV = 9.1%). In patients with significant AR, 4D flow had a tendency for a higher regurgitation fraction than 2D flow (8.6% ± 4.9% vs. 6.3 ± 7.2%, p = 0.09). When we dichotomized our ASO patients for 4D flow derived AR below or more than 5%, only indexed LVEDV differed significantly between groups (p = 0.014).

For external validation of aortic 4D flow assessment, 4D flow derived stroke volume was compared to 2D flow derived stroke volume, demonstrating good agreement (ICC = 0.77, CoV = 11.0%, p = 0.20). The Bland-Altman plot is shown in Fig. 2. The outliers in this plot demonstrated good agreement between stroke volumes on 4D aortic, 4D mitral and planimetric measurements (within 5 ml of one another). 2D stroke volume mostly underestimated aortic flow compared to these other methods, despite good imaging quality of the 2D flow measurements in these patients. As a second external validation, 4D flow derived stroke volume was compared to planimetric stroke volume derived from the multi-plane short axis images. Agreement was also excellent (ICC = 0.95, CoV = 6.3%, p = 0.26) with the Bland-Altman plot in Fig. 3.

For internal validation of 4D flow, the 4D stroke volume across the MV (85.9 ± 25 ml) was compared to aortic 4D stroke volume, demonstrating excellent agreement (ICC = 0.94, CoV = 8.2%, p = 0.13) (Fig. 4). Inter-observer agreement was excellent for 4D flow stroke volume (ICC = 0.93, CoV = 4.8%, p = 0.32), similar to intra-observer agreement (ICC = 0.97, CoV = 2.3%, p = 0.58). Compared to 4D flow, the agreement between aortic 2D flow stroke volume and planimetric stroke volume (ICC = 0.87, CoV = 12.7%) was slightly less (p = 0.18) (Fig. 5).

To validate GLS by CMR feature tracking, a comparison was made to GLS by echocardiographic speckle tracking (Table 3). Agreement between CMR and echocardiography was good (ICC = 0.80, CoV = 9.6%, p = 0.67) as also shown in the Bland-Altman plot (Fig. 6). Inter-observer agreement for GLS assessment by feature tracking was excellent (ICC = 0.94, CoV = 4.2%, p = 0.70). Individual LV segmental analysis also showed good agreement between the different segments on feature tracking and speckle tracking (Table 4).

AR is a well-known complication mid- to long-term after ASO [4]. Although only a minority of ASO patients suffer from significant AR, it may result in reintervention for up to 5% of patients [19]. This AR after ASO is most likely related to aortic root dilation in combination with histological differences in neo-aortic root and valve compositions compared to the native aortic root tissue [20]. Different studies have published conflicting results on the progression rate of AR in ASO patients. However, most recently published reports indicate a slow progression rate of AR over time [3, 19, 21, 22]. Our ASO patients with significant AR demonstrated increased indexed LVEDV when compared to ASO patients with AR less than 5%, as a reflection of increased volume load of the LV.

Agreement between 4D and 2D flow CMR assessment of AR was good in our study. Stroke volume across the AV by 4D flow agreed better with MV flow assessment and planimetric short axis stroke volume measurements than 2D aortic flow, suggesting that 4D flow is a more reliable tool than 2D flow CMR for AV flow assessment. Our findings are in line with Roes et al. [23], who compared 4D flow and 2D flow volumes over the AV and the other intracardiac valves in both healthy volunteers and in patients with AR. 4D flow CMR showed excellent agreement over all intracardiac valves in both groups in their study. 2D flow in healthy subjects demonstrated only average correlation between valves in a study by Kilner et al. [24].

Interestingly, 4D flow gave slightly larger stroke volumes of the LV than 2D flow assessment in our study. In line with this, aortic flow was underestimated by 2D stroke volume in several study participants despite good imaging quality of the 2D flow measurements. In the same patients, all other stroke volume measurements showed good agreement with 4D stroke volume. We were unable to identify common denominators for the cases in which 2D analysis might have underestimated the stroke volume in ASO patients. Jarvis et al. validated 4D flow CMR for quantification of peak velocity across the AV in ASO patients [25]. This study reported higher peak velocities with 4D flow compared to 2D flow CMR, which may explain why 2D flow CMR underestimates flow volumes. This is in agreement with the hypothesis postulated by Roes et al. that eccentric ejection and/or regurgitation jets – which are commonly present in ASO patients – are measured more accurately with 4D flow CMR than with 2D flow CMR [23]. Since 2D flow CMR is measured in a fixed plane, correction for eccentricity of flow and adequate correction for through-plane motion of the aortic root during the cardiac cycle are not possible. With 4D flow CMR the measurement plane is adjusted throughout each phase of the cardiac cycle, as flow is recorded in three orthogonal imaging planes, thereby correcting for both flow eccentricity and through-plane motion of the aortic root [26, 27]. Given the excellent agreement between 4D flow CMR with planimetric flow volumes and the availability of semi-automated analysis of acquisitions with acceptable analysis time, 4D flow CMR appears to be ready for clinical use. Furthermore, despite the significant time expenditure for a 4D flow sequence acquisition (10 to 15 min scan time), the ability to scan both ventricles and great vessels with one sequence provides an important advantage over several individual 2D sequences.

Global LV function is generally preserved in ASO patients [4, 28]. Despite this, concerns about long-term preservation of LV function remain, since the myocardial tissue in ASO patients has possibly suffered early damage related to perinatal cyanosis and cardioplegia. Also, altered aortic geometry may increase LV afterload [29]. Impaired deformation expressed by GLS and torsion of the LV has been reported in ASO patients in studies by Pettersen et al. and Di Salvo et al., despite normal LVEF in these studies [6, 7]. GLS has been demonstrated to represent subclinical cardiac dysfunction when abnormal, and is an established precursor of overt ventricular systolic dysfunction [30]. Furthermore, Grotenhuis et al. recently reported diffuse myocardial fibrosis of the LV in ASO patients by use of T1 relaxometry CMR. [Grotenhuis, Eur Heart J 2018] Overt LV failure has not been reported frequently, but follow-up beyond the third decennium after ASO is very limited. Whether the impaired deformation and global myocardial fibrosis will progress into LV failure, remains to be elucidated. Evaluation of systolic LV function should therefore include EF and GLS assessment, as part of long-term follow-up assessment in ASO patients. Although infrequently reported, segmental strain analysis could be used for detection of regional wall motion abnormalities related to prior complications from coronary artery reimplantation [31, 32].

Our study shows good agreement between GLS assessed by CMR and echocardiography, as well as good agreement between the different LV segments, which implies that feature tracking is a valid alternative for speckle tracking. As the acoustic window for echocardiographic analysis can become limited during mid- to long-term follow-up of ASO patients [33, 34] GLS analysis by CMR provides a suitable alternative in this population.

For maximum adherence to clinical practice, the 2D flow CMR data was acquired at 20 frames/ cycle, while 4D and cine images were acquired at 30 frames/ cycle. This may have resulted in lower peak velocity and lower stroke volumes. 2D flow was also acquired on breath hold, where 4D flow was performed with free breathing.

Furthermore, for flow measurements as well as feature tracking, no golden standard was readily available. Therefore, we used consistency in net forward flow volume between consecutive valves as internal reference and multi-slice short-axis planimetric CMR flow volume as best available external reference. Feature tracking on 2D cine images, as used in this study, also has inherent limitations. The temporal resolution is lower than with echocardiography feature tracking and through-plane motion may cause inadequate tracking, both leading to an underestimation of peak deformation [35].