As a practical approach to effective regurgitant orifice area (EROA), which corresponds hemodynamically to the cross-sectional area of the vena contracta (VC) as the narrowest portion of the proximal regurgitant jet [8‐10], the VC width (VCW) of a color Doppler jet has become an accepted quantitative parameter for estimating MR severity [4‐6, 11‐14]. However, this simplified assumption of the VCW only holds when the EROA is nearly circular, and recent studies have indicated that the EROA is non-circular in most patients [14‐17, 18••], particularly when the VCW at the same time appears narrow in the 4-chamber view and broad in the 2-chamber view as in most cases of functional MR due to incomplete mitral leaflet closure [19]. Nonetheless, the VCW is still an accepted and recommended parameter for the estimation of severity of mitral regurgitation [4‐6, 11, 20] and part of an integrative approach of different semiquantitative and quantitative 2D and color Doppler parameters for the estimation of MR severity [3‐6]. This integrative approach can be practically applied in clinical routine for grading MR severity by using a standardized scoring system (Fig. 1) [21]. In 2004, color Doppler RT3DE was demonstrated to provide a three-dimensional volume dataset that contains the full anatomic information of the color Doppler flow jet in comparison to two-dimensional color Doppler imaging presenting the flow jet only incompletely in a cross-sectional image plane [16]. Using special analysis software, a color Doppler RT3DE dataset can be cropped to provide a direct en face view to the VCA of a flow jet or image planes in any orientation (“anyplane mode”) can be reconstructed from the dataset providing best presentation of the VCA and VCW (Fig. 2) [22]. Alternatively, the 3D dataset can also be tomographically sliced for accurate identification of the level of the VCA [23]. Khanna et al. initially demonstrated color Doppler RT3DE as a feasible method to provide direct visualization and planimetry of the VCA of a regurgitant jet [16]. Kahlert et al. first proved that RT3DE overcomes the limitations of 2D measurements of VCW by direct assessment of the size and shape of the VCA and demonstrated the differences in VCA asymmetry among different etiologies of MR [18••]. In the majority of patients with functional MR, RT3DE showed typical elongation of the VCA along the semilunar-shaped line of coaptation particularly in cases of incomplete mitral leaflet closure due to leaflet tethering. The variability of shape, size, and number of VCAs in a spectrum of patients with both functional and organic MR is demonstrated in Fig. 3 [23]. Several recent studies compared 3D VCA measurements with other methods particularly for the quantification of mitral regurgitation and demonstrated an increasing superior accuracy of 3D measurements compared to 2D measurements the more asymmetric the VCA was. Subsequent studies provided further validation of RT3DE assessment of the asymmetric VCA by comparison against independent methods [24, 25] and the proof of superiority of 3D VCA measurements compared to 2D VCA measurement in both central and eccentric jets [26] as well as in multiple jets [27]. An overview of recent clinical studies in which 3D VCA measurement has been compared with other methods of MR quantification is provided in Table 1. In all studies, the correlation between direct 3D measurement of VCA and 2D methods was good, but 2D methods, particularly 2D VCW and hemispherical PISA, systematically underestimated the true EROA the more elliptic or asymmetric it was [18••, 24‐30].

As a consequence, RT3DE assessment of the VCA has significantly changed the understanding of the anatomy of the VCA, which indeed led to a change of paradigm in the assessment of mitral regurgitation severity [31]. Based on the VCA measurements obtained by RT3DE, Kahlert et al. proposed a larger cut-off value of 0.6 cm² for the VCA compared to 0.4 cm² for 2D-derived EROA by the PISA method and accordingly 0.8 cm for mean VCW (mean of 4- and 2-chamber views) instead of 0.7 cm for 4-chamber-based VCW for severe MR for all etiologies, including functional MR [18••], thus overcoming the practical limitation of having a proposed cut-off value of 0.2 cm² for severe functional MR [32] and 0.4 cm² for severe organic MR [5]. This concept of the asymmetric VCA with new cut-off values particularly the 0.8 cm for mean VCW to define severe MR was recently adopted by the guidelines of the European Society of Cardiology [4, 6, 20]. However, as the direct measurement of the VCA using RT3DE is currently still performed manually and only few studies exist investigating VCA cut-off values of MR severity, no cut-off values for VCA have been recommended yet. Zeng et al. proposed a lower cut-off value of the VCA of 0.41 cm² for differentiation of moderate from severe MR that can be applied in all etiologies and orifice shapes [30]. As a potential explanation for the difference between the two cut-off values, Kahlert et al. [18••] derived their 3D cut-off value of 0.6 cm² by correcting the prior 2D-based cut-off value for the underestimation of the true asymmetric VCA by 2D methods, whereas Zeng et al. [30] derived their 3D VCA cut-off value of 0.41 cm² from MR grading based on an integration of conventional 2D methods including 2D PISA, 2D VCW, and 2D jet area. As these two first studies come to significantly different cut-off values for VCA to define severe MR, further studies ideally evaluating the clinical and prognostic value of VCA cut-off values in longitudinal observations are vitally needed.

Accurate measurement of VCA by RT3DE also provides increased accuracy of the estimation of MR flow volume as calculated from the VCA by RT3DE times the velocity-time integral of regurgitant flow by continuous wave Doppler [25, 29]. Marsan et al. validated this as a practical approach and found excellent correlation with regurgitant volume measured by velocity-encoded cardiac magnetic resonance (CMR) (r = 0.94) without significant difference between the two techniques (mean difference = −0.08 ml/beat) [29]. Compared to this, 2D echocardiographic assessment of MR volume using VCW in the 4-chamber view significantly underestimated regurgitant volume (p = 0.006) as compared with CMR. As for the 3D VCA measurement itself, further validation of 3D VCA-based MR volume calculation is needed.

While RT3DE has overcome fundamental limitations of 2D echocardiographic measurements of VC dimensions, other limitations still remain. In order to measure regurgitant flow rate or flow volume, it would be ultimately desired to measure the different velocities across the VCA accurately in order to determine the products of individual small areas of flow times the individual flow velocity through this area integrated over the entire VCA. Instead of measuring the true spectrum of velocities, current approaches to flow rate only measure the highest velocity across the VCA by means of continuous wave spectral Doppler or calculate the velocity-time integral (VTI) of the highest velocities times VCA to estimate flow volume [29]. As a promising solution of this limitation and a view towards new future technical approaches to measure MR flow, Plicht et al. recently demonstrated that multiple color Doppler aliasing of regurgitant flow at the VCA from a RT3DE color Doppler dataset can be unmasked by dealiasing to accurately calculate absolute regurgitant flow [33]. Alternatively, Skaug et al. described a method based on multiple-beam high pulse repetition frequency (HPRF) color Doppler analysis using 3D color Doppler for accurate automated identification of the VCA and calculation of regurgitant flow [34]. Other limitations that still remain to the representation of the VCA using RT3DE color Doppler belong to a limited temporal and spatial resolution of 3D color Doppler datasets, translation artifacts, and complex dynamic changes of VCA size and shape.

Compared to VCA, the proximal isovelocity surface area (PISA) method is hemodynamically more complex. Nonetheless, limitations that pertain to the 2D color Doppler application of the VCA method are similar to the PISA method, which is because of the hemodynamic assumption of a hemispheric shape of isovelocities in the proximal flow field that only holds for a circular regurgitant lesion in unconfined flow [35, 36]. However, as implicated by the asymmetric nature of the VCA, asymmetry should be evident also for the shape of PISA. Early studies using 3D color Doppler datasets already demonstrated that the shape of PISA is not hemispheric but elongated towards a more hemielliptic shape in most cases causing systematic underestimation of EROA and regurgitant flow measured by the hemispheric PISA method [17, 28, 37, 38]. Based on early reports on using a hemielliptic PISA formula [37, 39], more recently, several investigators applied this hemielliptic PISA formula to three orthogonal image planes reformatted from RT3DE datasets and confirmed significant underestimation of MR flow and EROA by 2D hemispheric PISA in patients with non-hemispheric PISA as visualized by RT3DE (Fig. 4) [17, 18••, 33]. Beside the significant underestimation of EROA (p < 0.001), Yosefy et al. found clinical important underestimation of the grade of MR severity in 45 % of patients [17]. Kahlert et al. found only small underestimation of 3D-VCA by EROA from 3D-based hemielliptic PISA (mean error −0.09 ± 0.14 cm², p <0.001) and described underestimation of EROA by 2D hemispheric PISA to be strongly dependent on the asymmetry of PISA and etiology of MR [18••]. In principle, hemielliptic PISA can be obtained from RT3DE datasets using PISA width, length, and radius for the calculation of the hemielliptic PISA surface by a hemielliptic formula (Fig. 5). The EROA from hemielliptic PISA can then be calculated as EROA = PISA(HE) times Nyquist velocity divided by MR flow velocity as measured by continuous wave Doppler echocardiography. Although the hemielliptic PISA method based on three PISA dimensions is a practical approach to an asymmetric PISA shape, the hemielliptic formula behind is complex and not routinely implemented in current 3D echocardiography systems. A more practical approximation of a hemielliptic surface area is provided by the following formula proposed by Knut Thomsen where r is the PISA radius, D1 and D2 are the PISA width and length, and p = 1.6075.

To overcome the limitations of 2D analysis of PISA shape and size, several research groups either validated in vitro or in vivo estimates of the 3D PISA shape by manual measurements of either three perpendicular PISA diameters [17, 18••, 33] or more diameters [40] or PISA surface [41‐43, 44•] or investigated computer simulations for semi-automated 3D reconstruction of PISA [45] and found significantly improved accuracy of 3D PISA estimates of EROA and regurgitant flow. An overview of recent clinical studies in which 3D PISA measurements have been compared with other methods of MR quantification is provided in Table 2. Importantly, in a recent study, Ashikhmina et al. demonstrated that direct manual 3D surface reconstruction of asymmetric PISA without geometric assumptions provides significantly larger PISA and EROA (mean 0.44 cm²) not only compared to conventional hemispheric PISA (mean EROA 0.19 cm²), but also compared to 3D-derived hemielliptic PISA (mean EROA 0.26 cm²), suggesting that even the hemielliptic PISA shape is a suboptimal geometric assumption of the asymmetric PISA in functional MR [44•]. All these approaches, however, have not yet found their way into clinical routine application. As a consequence, increasing effort has recently been spent on the development of automated analysis software providing 3D detection of the true PISA surface in the proximal flow convergence zone. Early studies already validated special custom-made computer software for automated detection of the 3D surface of a defined Nyquist velocity in the proximal flow field in 3D echocardiographic patient datasets [37]. Recently, a commercially available method for 3D quantification of PISA without geometric assumptions using single-beat RT3DE color Doppler datasets has been validated in vitro and also described to be feasible in a clinical setting [46•, 47, 48••]. After initial description and validation of this new automated method for quantification of 3D PISA-derived EROA and MR volume [46•, 47], Thavendiranathan et al. recently conducted thorough in vitro validation and clinical validation using RT3D TTE datasets against independent reference methods and found increased accuracy and reproducibility compared to 2DE methods as well as independency from regurgitant orifice geometry [48••]. Using the same automated 3D PISA method, Choi et al. calculated MR volume as EROA times velocity-time integral and found in a differentiated subgroup analysis in 211 patients that MR severity, asymmetrical regurgitant orifice, and eccentric jet were predictors of significant higher accuracy of 3D PISA-derived MR volume compared to 2D PISA using phase-contrast cardiac MRI for reference [49]. The importance of eccentric pattern of the regurgitant jet as a source of significant inaccuracy of 2D PISA measurement compared to 3D-methods was also implicated in the studies by Chandra et al. and de Agustin et al. [47, 50]. However, there is reason for concern that current transthoracic color Doppler RT3DE image quality might not be sufficient enough for valid application of this automated analysis in an acceptable proportion of patients in routine clinical practice. Based on the concept of measuring MR flow volume by integrating the dynamically changing PISA over systolic time as described by our group [51], Thavendiranathan et al. recently applied this automated 3D PISA analysis to a series of color Doppler frames throughout systole [48••]. While presently integration of 3D PISA flow over time has to be performed manually, however, automated integration of 3D PISA flow over systole with appropriately high-color Doppler frame rate would be desired. Using receiver operating characteristic (ROC) curves, Thavendiranathan et al. found a cut-off value of 0.51 cm² for 3D PISA EROA to best differentiate severe from non-severe MR (area under the curve (AUC) 0.91) [48••]. As a notable clinical approach, Schmidt et al. [52•] recently evaluated the same automated 3D PISA method against grading of MR severity based on a weighted integration of routine grading according to current guidelines [6], the MR severity score proposed by our group [21], and the MR index introduced by Thomas et al. [53]. In a receiver operator characteristics curve analysis (ROC) using this integrated metascore, mean EROA determined with automated 3D PISA performed best (AUC = 0.907) compared to peak EROA (AUC 0.840) and EROA calculated from 2D PISA (AUC 0.747). In addition, based on ROC analysis, they found a mean EROA of 0.15 cm² and a cut-off of 0.36 cm² for peak EROA to distinguish severe from non-severe MR.

Potential limitations of the existing automated 3D methods being subject of future research include underestimation of convergent flow velocities near the base of the PISA where velocity vectors are almost perpendicular to the vector of the ultrasound beam, dynamic changes of regurgitant flow rate and PISA size during systole combined with dynamic axial and transverse translation of the center of the regurgitant orifice.