Quantification of regurgitation in mitral valve prolapse with four-dimensional flow cardiovascular magnetic resonance

In past years, considerable advances in surgical treatment options of mitral regurgitation (MR) resulted in improved life expectancy, but prognosis and clinical decision making with regard to timing of surgery strongly depend on the accurate quantification of MR using cardiac imaging techniques [1].

Transthoracic multiparametric echocardiography (TTE) is at the forefront and widely recognized as the non-invasive standard of reference for assessment of MR [2] including proximal isovelocity surface area (PISA) determination with its typical methodological limitations (i.e. the reliance on geometric assumptions of a hemispheric flow convergence region (FCR), and Doppler measurement angle dependency). Hence, and particularly in borderline cases [3], a multimodality approach employing standard volumetric cardiovascular magnetic resonance (CMR) has been incorporated [4, 5].

In addition, time-resolved, three-dimensional (3D) full anatomic coverage with three-directional velocity-encoded phase contrast CMR, referred to as four-dimensional (4D) flow CMR has further broadened the diagnostic armamentarium [6] and has been proposed for quantification of blood flow volumes across the mitral valve. The potential benefit of 4D flow CMR in relation to the 2D CMR phase contrast (PC) technique, is the acquisition in one single examination of a “three-directional” velocity-encoding data-set. Permitting to place in a retrospective manner an analysis plane in any location perpendicular to blood flow, which may be critically important for quantify peak velocity and visualization of blood flow in cases of complex valve flow jets.

Previous 4D flow CMR studies using retrospective valve tracking or direct jet analysis, have been carried out in functional MR [7, 8], congenital heart disease [9], small patient groups [10], or in mixed patient populations [11, 12]. However, it can be speculated that these data cannot be generalized to patients with mitral valve prolapse (MVP) because concomitant MR may be challenging to assess due to geometrical asymmetry of the orifice area ("slit-like") and highly dynamic and eccentric MR jets. Thus, data on the clinical utility of 4D flow CMR in patients with MVP are still scarce. Therefore, we aimed to evaluate the value of cine-guided valve segmentation of 4D flow CMR in assessment of regurgitation in MVP when compared to standardized routine CMR and TTE.

4D flow CMR analysis was successfully performed in 97% of subjects. 4DF_indirect quantification could be performed in all patients and controls (n = 60), while a 4DF_direct assessment in only 46 patients of the MR group (n = 54). A 2D-TTE derived PISA method could be obtained in all patients with MVP. There were no differences in blood pressure or heart rate values between CMR and TTE studies (132 ± 18 / 73 ± 11 vs. 133 ± 17 / 75 ± 11 mmHg, and 67 ± 11 vs. 68 ± 11 beats per minutes, p > 0.164). Post-processing times were shorter with 4DF_indirect method (indirect: 4.2 ± 0.7 min vs. direct: 6.4 ± 1.4 min; mean difference: 2.2 ± 1.3 min, p < 0.001).

Demographic and baseline patient characteristics are presented in Table 1. MR patients were older and more prone to have comorbidities than the control group. CMR and TTE characteristics are shown in Table 2. Patients with severe MR had higher TTE and CMR derived LVEDV and LV SV compared with MR grade 1 + /2 + and 3 + , but similar LVOT SV or forward SV values reflecting progressively higher RVol and RF values through the groups.

The present prospective study aimed to evaluate the clinical utility of cine-guided valve segmentation of 4D flow CMR for the assessment of MR in MVP in direct comparison to standard CMR and TTE. The main findings can be summarized as follows: (1) in patients with MVP, quantification of RVol and RF by 4D flow CMR was feasible and reproducible; (2) strong correlation was observed between standard CMR and 4DF_indirect methods, with no significant bias; conversely, 4DF_direct significantly underestimated RVol as compared with all other methods; (3) 4DF_indirect showed better intra- and inter-technique agreement and reliability than 4DF_direct method; and (4) despite moderate to strong correlation between methods, PISA method systematically showed higher RVol and RF as compared with CMR techniques.

Recently 4D flow CMR was introduced and validated in vitro with phantom models [11], and first clinical experiences with healthy subjects and patients with MR demonstrated its feasibility. However, previous studies have been performed in functional MR [7, 8], congenital heart disease [8, 15], small study groups [10, 16], or in rather mixed patient populations [9, 11, 12, 16]. In the present study we investigated the clinical utility of 4D flow CMR in a homogeneous group of MVP patients. Quantification of regurgitation in MVP is particularly challenging since extensive changes in valve geometry often lead to adherent or eccentric jets. Thus, volumetric measurement techniques may be preferable in MVP since regurgitant volume and fraction can be derived without any assumptions about hemodynamic or shape and are generally not or only minimally affected by the direction of the MR jet or geometry of the mitral orifice. First clinical studies using 4D flow CMR for direct assessment of both atrioventricular valves demonstrated excellent agreement between SV through the valve of interest and ascending aorta [11], or between all four valves [12]. The present study data demonstrated that 4DF_indirect is highly reproducible with higher concordance to standard CMR than 4DF_direct. Recently, Fidock and colleagues [16] reported similar findings for primary MR. Nevertheless, they analyzed a small subgroup (n = 12), provided no direct comparison with TTE, and reported a rather low RVol (mean 28.6 ± 2.5 ml). In the present study the higher mean RVol of 57 ± 34 ml indicates that a substantial number of patients with high grade MR were included which will facilitate generalizability and applicability of our results in a clinical routine setting.

In the present study, 4DF_direct quantification could not be performed in 8 patients of the MVP group (n = 54) due to difficulties to delineate the cross-sectional area of the MR jet due to poor visualization (n = 4), excessive aliasing (n = 1), or poor contrast between blood pool and the regurgitant Jet (n = 3). Similarly, in a cohort of 44 children with congenital heart disease and atrioventricular valve regurgitation, Jacobs and colleagues reported that six patients (9%) were excluded due to concerns related to image quality including excessive aliasing on 4D flow (n = 1), movement during 4D flow acquisitions (n = 2), and poor visualization of the regurgitant jets (n = 3). Nevertheless, they reported a better concordance between standard CMR and 4D flow direct measurement of the regurgitant jet, as compared with an annular inflow indirect method, but with slightly superior performance in subjects with tricuspid regurgitation compared to those with MR [15]. Moreover and in accordance with our results, Feneis et al., in a cohort of 21 adults with tricuspid regurgitation (TR) and MR, showed that direct method was better for the assessment of TR, and the indirect method had a better diagnostic performance for the MR [10]. As mentioned by the authors, this could be explained because TR jets tend to be more central and laminar as compared to MR jets, which are more prone to be multiple, eccentric, and dynamic with systolic angulation change [14]. Which makes it challenging even with the use of retrospective valve tracking. This might explain the systematically lower values of RVol by 4DF_direct method observed in our study. Moreover, as previously showed [17], in patients with prominent bileaflet MVP, the volumetric CMR method may underestimate the LVESV as it only considers the volume located between the apex and the mitral annulus, and neglects the volume that is contained within the prolapsed mitral leaflets at end systole (prolapsed volume). Which may lead to an overestimation of the RVol. In our cohort we identified 14 patients with bileaflet MVP. In this subgroup, the mean prolapsed volume was 8.7 ± 4.8 ml. The corrected RVol tacking into account this prolapsed volume, as proposed from Vincenti et al., was accordingly significantly lower than the uncorrected RVol (30.4 ± 20.4 ml vs 39 ± 21.2 ml, p < 0.001). Notwithstanding, in this subgroup of patients, we observed no significant differences between uncorrected RVol by CMR and RVol by 4D flow (CMR: 39 ± 21 ml, 4DF_indirect: 42 ± 32 ml, and 4DF_direct: 37 ± 17 ml, p > 0.68). It might be speculated that measuring the anterograde mitral blood flow (MV-SV_4D-flow) slightly above (ventricular side) or at the level of the mitral valve annulus may not discriminate between prolapsed volume and RVol. Nevertheless, retrograde mitral blood flow (RVol_direct) was measured positioning the plane on the atrial side of the MV, and still the RVol by 4DF_direct was significantly higher than the corrected RVol (n = 12; 37 ± 17 ml vs 28 ± 18 ml, p = 0.008). Difficulties in identifying the contour of the cross-sectional regurgitant jet area using the 4D flow PC images may have contributed to overestimation of the RVol by 4DF_direct compared to corrected RVol, possibly due to applying slightly bigger ROI´s areas. However, the lack of a subgroup of patients with no MR and bileaflet MVP made the evaluation of this hypothesis not possible. Therefore, future studies will have to appraise this issue.

In addition, cine-guided valve segmentation provided better contrast of the borders of the mitral valve as compared with the contouring of the regurgitant jet in the 4D flow PC images. Aforementioned technical difficulties may also explain the observed longer post-processing time and higher inter-observer variability of the 4DF_direct method (CV: 32% vs. 12%). Kamphuis et al. [9] demonstrated a shorter analysis time to quantify the flow over all 4 valves for automated versus manual tracking (14 min vs. 25 min) and reported an excellent reproducibility for the measurement of mitral valve flow (intra-observer, CV 5.2%; inter-observer, 5.6%). Additionally, Jacobs et al. [15], reported excellent post-processing times for assessment of atrioventricular valve regurgitation, using a semi-automated 4D flow CMR algorithm (indirect method 3.7 ± 1.9 min vs. direct method 3.1 ± 2.1 min, p = 0.114).

Even though, we still observed broad limits of agreement between standard CMR and 4DF_indirect methods, the Lin´s coefficient showed moderate to substantial agreement and there were no systematic bias. These widespread limits of agreement may be expected to be more pronounced in the groups with MR 3 + /4 + , where the impact in grading of regurgitation should be less decisive. Indeed, consistency in grading MR severity between standard CMR and 4DF_indirect was clinically acceptable (kappa = 0.542; p < 0.001); with 75% of subjects having the same MR grade and 22% with only one scale misclassification. Only 2 of 60 subjects with MR 4 + by standard CMR were reclassified as MR 2 + by 4DF_indirect. Importantly, all controls were classified as none/trace MR with both methods and no MR 1 + was reclassified as severe. Which, is a real scenario in the daily clinical practice. Other studies have showed similar limits of agreement when comparing two different methods of MR quantification [15, 18]. Calkoen et al. [14] found narrower limits of agreement between standard CMR and 4D flow (− 12 to 20 ml), but they included a cohort with a mean RVol of 11 ± 6 ml (vs. 57 ± 34 ml in our study).

Finally, we observed higher values of RVol and RF by TTE PISA method as compared with CMR techniques. There is some data suggesting that PISA method might overestimate the RVol in organic MR when compared with CMR [18, 19]. In accordance with our study, Uretsky et al. [18] observed similar bias between TTE and CMR (mean difference of 16 ml with wide limits of agreement: -38 to 70 ml). This might be in part secondary to difficulties in contouring the dynamic FCR. Thavendiranathan et al. [20] compared the diagnostic accuracy of 3D-PISA method in assessing functional MR using the peak 3D-PISA and the integrated 3D-PISA derived RVol (calculated for each systolic frame) taking into account the dynamic of the MR. They showed that compared with CMR derived RVol (33 ± 22 ml), the integrated 3D-PISA derived RVol (34 ± 26 ml) was not significantly different; however, the peak 3D-PISA derived RVol was higher (48 ± 27 ml).

In the present study, 4DF_indirect method performed comparably to standard 2D CMR, but with the need of additional acquisition and post-processing time. Nonetheless, 4D flow CMR may exhibit some potential translational outlooks and advantages. It permits to map out retrospectively the velocities and flow patterns throughout the whole heart, which may give a much more complete picture of the heart valve pathology, not only due to a 3D visualization of the regurgitant jet, but also because it could permit to derive advanced hemodynamic metrics (i.e. shear stress, turbulent kinetic energy, flow vorticity and helicity) which may help to better understand the pathophysiology and its relationship with clinical outcomes. Moreover, development of acceleration techniques, improved automated methods, and emerging machine learning algorithms, may improve 4D flow CMR techniques, allowing analysis of the entire cardiac hemodynamics in a retrospective manner for cross-checking quantification in case of uncertainty.

Future studies will have to validate our findings, and appraise the potential correlation of 4D flow CMR and of its derived advanced hemodynamic parameters with clinical outcomes in different scenarios, which could be of value in understanding the pathophysiology and progression to symptoms and adverse events in MVP patients.

Present study demonstrated that cine-guided valve segmentation 4D flow CMR for the assessment of MR in MVP is feasible and may enable comparable evaluation to standard volumetric calculation CMR, but with lower RVol when TTE is used as reference. 4DF_indirect method has higher intra- and inter-technique agreement than 4DF_direct method and might be used as an adjunctive technique for cross-checking MR quantification in MVP.