Usefulness of Vena Contracta for Identifying Severe Secondary Mitral Regurgitation: A Three-Dimensional Transesophageal Echocardiography Study

Background: In secondary mitral regurgitation (SMR), effective regurgitant orifice area by the proximal isovelocity surface area method (EROAPISA) evaluation might cause an underestimation of regurgitant orifice area because of its ellipticity compared with vena contracta area (VCA). We aimed to reassess the SMR severity using VCA-related parameters and EROAPISA. Methods: The three-dimensional transesophageal echocardiography data of 128 patients with SMR were retrospectively analyzed; the following parameters were evaluated: EROAPISA, anteroposterior and mediolateral vena contracta widths (VCWs) of VCA (i.e., VCWAP and VCWML), VCWAverage calculated as (VCWAP + VCWML)/2, and VCAEllipse calculated as π × (VCWAP/2) × (VCWML/2). Severe SMR was defined as ≥0.39 cm2. Results: The mean age of the patients was 77.0 ± 8.9 years, and 78 (60.9%) were males. Compared with EROAPISA (r = 0.801), VCWAverage (r = 0.940) and VCAEllipse (r = 0.980) were strongly correlated with VCA. On receiver-operating characteristic curve analysis, VCWAverage and VCAEllipse had C-statistics of 0.981 (95% confidence interval [CI], 0.963–1.000) and 0.985 (95% CI, 0.970–1.000), respectively; these were significantly higher than 0.910 (95% CI, 0.859–0.961) in EROAPISA (p = 0.007 and p = 0.003, respectively). The best cutoff values for severe SMR of VCWAverage and VCAEllipse were 0.78 cm and 0.42 cm2, respectively. The prevalence of severe SMR significantly increased with an increase in EROAPISA (38 of 88 [43.2%] patients with EROAPISA <0.30 cm2, 21 of 24 [87.5%] patients with EROAPISA = 0.30–0.40 cm2, and 16 of 16 [100%] patients with EROAPISA ≥0.40 cm2 [Cochran–Armitage test; p < 0.001]). Among patients with EROAPISA <0.30 cm2, SMR severity based on VCA was accurately reclassified using VCWAverage (McNemar’s test; p = 0.505) and VCAEllipse (p = 0.182). Conclusions: Among patients who had SMR with EROAPISA of <0.30 cm2, suggestive of moderate or less SMR according to current guidelines, >40% had discordantly severe SMR based on VCA. VCWAverage and VCAEllipse values were useful for identifying severe SMR based on VCA in these patients.


Introduction
Secondary mitral regurgitation (SMR) is a common valvular heart disease that affects heart failure symptoms and clinical outcomes [1][2][3]. According to the current guidelines, two-dimensional (2D) echocardiographic parameters, including vena contracta width (VCW) and effective regurgitant orifice area by the proximal isovelocity surface area method (EROA PISA ), are recommended to determine SMR severity; however, the severity may be underestimated using VCW and EROA PISA if regurgitant orifice area is elliptical [4][5][6].
Vena contracta area (VCA) hydrodynamically corresponds to the regurgitant orifice area [7]. Kahlert et al. [8] primarily reported direct planimetry of VCA (VCA 3D ) based on three-dimensional transesophageal echocardiography (3D-TEE), and VCA 3D was subsequently validated using an in vitro model and cardiac magnetic resonance imaging [9,10]. Furthermore, Goebel et al. [11] re-ported that compared with EROA PISA , VCA 3D is a robust parameter for discriminating severe SMR. Moreover, previous studies have suggested that VCA 3D is elliptical in cases of SMR based on several vena contracta (VC) parameters, including anteroposterior VCW (VCW AP ), mediolateral VCW (VCW ML ), average of VCW AP and VCW ML (VCW Average ), and VCA calculated as an ellipse (VCA Ellipse ). These studies have also reported that the ellipticity consequently limited the ability of VCW AP and EROA PISA to accurately classify SMR severity [8,12]. However, these were relatively small-scale studies, and there is little information available regarding the best cutoff values of VC parameters for severe SMR.
Thus, we hypothesized that parameters that considered the elliptical shape of the mitral regurgitant orifice, including VCA Average and VCA Ellipse , are better surrogate markers for severe SMR based on VCA 3D than EROA PISA . This study also investigated the best cutoff values of these VC parameters for severe SMR. Furthermore, we reassessed the true SMR severity using the cutoff values of VC parameters to avoid underestimating SMR based on EROA PISA .

Patient Population
Patient characteristics and echocardiographic data were collected from the medical records and echocardiography reports. The study protocol was approved by the Institutional Review Board of New Tokyo Hospital and was in accordance with the guidelines of the Declaration of Helsinki. The requirement for informed consent was waived because of the retrospective nature of this study. Based on integrative methods using qualitative, semiquantitative, and quantitative approaches, 154 patients with at least mild SMR were identified via a review of echocardiography databases at New Tokyo Hospital between January 2018 and March 2021. These patients underwent 3D-TEE based on clinical indications and transthoracic echocardiography (TTE) within 1 month of 3D-TEE at our center [4]. SMR was defined as incomplete mitral leaflet closure because of regional myocardial dysfunction, global left ventricular remodeling, apical tethering of the mitral valve (MV), or annular dilation in the presence of an anatomically normal valve apparatus [4,13]. Of 172 patients, those with multiple or nonholosystolic SMR jet (6 patients), previous MV intervention (7 patients), concomitant mitral stenosis (2 patients) [14], and mitral annular calcification (3 patients) were excluded from this study.
Overall, 19 of 154 patients were excluded because the quality of 3D imaging was inadequate for VCA 3D analysis, and 7 patients were excluded because of incomplete data for the quantitative assessment of SMR; hence, 128 patients were included in the final analysis.
Regarding two-dimensional TTE (2D-TTE) parameters, left ventricular end-diastolic and -systolic volumes, left ventricular ejection fraction (LVEF), and left atrial volume were estimated using the biplane Simpson disk method via transthoracic echocardiography.
Regarding TEE parameters, EROA PISA and regurgitant volume (RV PISA ) were estimated using the proximal isovelocity surface area method [4]. A continuous wave Doppler cursor was aligned parallel to the SMR jet for obtaining peak velocity and velocity-time integral at a Nyquist limit of 50-70 cm/s, with the gain set to a level immediately below the threshold for noise. EROA PISA was derived using a color Doppler in a four-chamber view at an aliasing velocity of 30-40 cm/s. Moreover, during systole, proximal isovelocity surface area (PISA) radius and flow velocity parameters were obtained at similar time points for calculating EROA PISA . To determine VC parameters, 3D color Doppler datasets were acquired from an intercommissural view using full volume for each patient. The quantification of VCA 3D was performed via multiplanar reconstruction using dedicated software (Philips QLAB Versions 9.0, Philips Healthcare, Andover, MA, USA) ( Fig. 1) [4]. The cropping plane was moved along the direction of the jet until the smallest jet cross-sectional area became visible at the level of VC. Subsequently, VCA 3D was measured using manual planimetry of the color Doppler flow signal. VCW AP and VCW ML were also measured as anteroposterior and mediolateral VCWs, respectively, in reconstructed 2D planes from the 3D-TEE dataset; VCW AP and VCW ML were obtained in the left ventricular outflow tract and intercommissural views (or views that were close to intercommissural views), respectively [8]. VCW Average was calculated as (VCW AP + VCW ML )/2, VCA Ellipse was calculated as π × (VCW AP /2) × (VCW ML /2) [8], and VCA 3D shape index was calculated as VCW ML /VCW AP . In patients with irregular rhythm (i.e., atrial fibrillation or flutter not requiring constant ventricular pacing for bradycardia), these parameters were calculated as the mean of 3-5 parameters performed by avoiding remarkable irregular RR intervals. EROA PISA and VC parameters were performed by one observer (H.O.).
VCA 3D of ≥0.39 cm 2 was used as a reference standard of severe SMR in the current study, considering that the severity of SMR may be underestimated using EROA PISA and that VCA 3D is a more robust parameter for distinguishing severe SMR than EROA PISA [4,11].

Statistical Analysis
Categorical variables were presented as frequencies and analyzed using chi-square, Fisher's exact, or Cochran-Armitage test, as appropriate. Continuous variables were presented as mean ± standard deviation or median with interquartile range and were compared using Mann-Whitney U or Jonckheere-Terpstra test, as appropriate. The overall rates of correct SMR severity classifications based on VCA 3D were statistically compared using McNemar's test in 2 × 2 tables. Correlations between different parameters were determined using Pearson's test and linear regression analysis. Receiver operating characteristic (ROC) curve analyses were performed to assess the ability of each parameter to identify severe SMR based on VCA 3D . The Youden index was used to determine the best cutoff value for severe SMR based on VCA 3D considering optimal sensitivity and specificity. Discrimination of severe SMR based Continuous data are presented as means ± standard deviations, except brain natriuretic peptide (median and interquartile range); categorical data are given as the counts (percentages). eGFR, estimated glomerular filtration rate; NYHA, New York Heart Association.
on VCA 3D was assessed using the C-statistic. All statistical tests were two-tailed, and a two-sided p-value of <0.05 was considered to indicate statistical significance. Data analysis was performed using EZR software version 1.50 (Saitama Medical Center, Jichi Medical University, Saitama, Japan) [19].
In addition, patients with nonsevere SMR, according to VCW Average of <0.78 cm and VCA Ellipse of <0.42 cm 2 , showed significantly lower VCA 3D (p < 0.001 for both) and SMR incidence based on VCA 3D (p < 0.001 for both) than those with severe SMR based on VCW Average and VCA Ellipse (Fig. 3C,D and Fig. 4C,D). Notably, SMR severity based on VCA 3D was correctly reclassified as severe SMR based on VCW Average (p = 0.505) and VCA Ellipse (p = 0.182).

SMR Severity Based on EROA PISA Considering VCW Average and VCA Ellipse
Our patients were classified into the following three subgroups based on EROA PISA according to the current guidelines [4]: 88 patients with EROA PISA of <0.30 cm 2 , 24 patients with EROA PISA of 0.30-0.40 cm 2 , and 16 patients with EROA PISA of ≥0.40 cm 2 . According to the incremental EROA PISA , VCA 3D (p < 0.001) and SMR incidence based on VCA 3D (p < 0.001) significantly increased (Fig. 5A,B). Notably, in patients with EROA PISA of <0.30 cm 2 , which is suggestive of moderate SMR according to the current guidelines, 38 of 88 (43.2%) patients had severe MR based on VCA 3D . However, SMR severity based on VCA 3D in patients with EROA PISA of <0.30 cm 2 was correctly reclassified as severe MR based on VCW Average (p = 0.505) and VCA Ellipse (p = 0.182) (Fig. 6A,B).

Discussion
The current study revealed the following findings: (1) VCW Average and VCA Ellipse had a fairly strong correlation with VCA 3D , with the best cutoff values of 0.78 cm and 0.42 cm 2 , respectively, and (2) VCW Average of ≥0.78 cm and VCA Ellipse of ≥0.42 cm 2 might be useful in identifying severe SMR based on VCA 3D , particularly in patients with EROA PISA of <0.30 cm 2 , corresponding to moderate SMR according to the current guidelines, who are at potential risk of underestimation of SMR severity because of the ellipticity of regurgitant orifice area [4].

Usefulness of VCW Average and VCA Ellipse in Identifying Severe SMR
Although VCW AP was shown to be a reliable semiquantitative parameter for evaluating SMR severity according to the current guidelines, VCW ML evaluation is not routinely used as a stand-alone parameter [4]. However, according to a previous study by Kahlert et al. [8], VCW ML was more strongly correlated with VCA 3D than with VCW AP . Furthermore, VCW Average is strongly correlated with VCA 3D [8]. To accurately identify severe SMR, the current guidelines recommend calculating VCW Average with a cutoff value of 0.80 cm for severe SMR if the regurgitant orifice area is elliptical [4]. However, there is little information on the discrimination and best cutoff value of VCW Average for severe SMR. Our study indicated that VCW Average had a fairly strong correlation with VCA 3D and showed adequately good discrimination of severe SMR. Notably, the best cutoff value of VCW Average was 0.78 cmwhich is close to the value of 0.80 cm according to the current guidelines-with adequately high sensitivity and specificity for severe SMR based on VCA 3D [4]. Further, VCA Ellipse had a strong correlation with VCA 3D and showed good discrimination of severe SMR. Moreover, the best cutoff value of VCA Ellipse was 0.42 cm 2 , with high sensitivity and specificity for severe SMR based on VCA 3D .
The current study and previous studies have demonstrated that the regurgitant orifice area in SMR may be elliptical [8,12], indicating that SMR severity based on VCW AP and EROA PISA is underestimated [4][5][6]. Furthermore, there was a weak correlation between the VCA 3D shape index and difference between VCA 3D and EROA PISA ; this finding conforms to that reported by Goebel et al. [11], suggesting that the ellipticity of the regurgitant orifice area rather than the extent of ellipticity is related to the underestimation of SMR severity based on EROA PISA .

Assessment of SMR Severity to Avoid its Underestimation
Patients with SMR having EROA PISA of <0.30 cm 2 , corresponding to moderate SMR according to the current guidelines, have a potential risk of underestimation of SMR severity because of the elliptical regurgitant orifice area [4]. Of the 88 patients with EROA PISA of <0.30 cm 2 in the current study, 38 (43.2%) had severe MR based on VCA 3D . In such cases, VCW Average of ≥0.78 cm and/or VCA Ellipse of ≥0.42 cm 2 might be useful in identifying discordantly severe SMR based on VCA 3D . If EROA PISA is ≥0.30 cm 2 , SMR severity is expected to be truly severe based on VCA 3D ; however, EROA PISA of <0.30 cm 2 does not necessarily indicate nonsevere SMR based on VCA 3D .
If VCW Average of ≥0.78 cm and/or VCA Ellipse of ≥0.42 cm 2 are calculated using VCW AP and VCW ML , SMR severity might be considered discordantly severe despite the EROA PISA of <0.30 cm 2 . After the exclusion of severe SMR according to the abovementioned assessment, symptomatic patients may be evaluated using exercise-stress echocardiography to confirm significantly worsening SMR, if applicable.

Clinical Implications
Although severe SMR is associated with adverse clinical outcomes [1][2][3], it may be underestimated using conventional echocardiographic parameters, including VCW AP and EROA PISA . Moreover, an inaccurate assessment of SMR severity can lead to misleading indications for optimal MV interventions, including MV transcatheter edgeto-edge repair, which is known to be effective and is recommended in patients with SMR with reduced LVEF [5,20,21]. Karam et al. [22] reported that MV transcatheter edge-to-edge repair for SMR is equally effective in patients with EROA PISA of <0.30 cm 2 and those with EROA PISA of ≥0.30 cm 2 in terms of clinical outcomes, suggesting that patients with EROA PISA of <0.30 cm 2 may have a higher severity of SMR than expected based on EROA PISA . To obtain an accurate evaluation of SMR severity, VCA 3D is useful as a substantially reliable echocardiographic parameter [11]. However, the assessment of VCA 3D is relatively time-consuming and requires good quality of 3D-echocardiographic data [4]. VCW Average and VCA Ellipse , which were calculated via simple equations using VCW AP and VCW ML , showed fairly strong correlations with VCA 3D and good discrimination of severe SMR based on VCA 3D . Therefore, instead of VCA 3D , VCW Average and VCA Ellipse , with best cutoff values of 0.78 cm and 0.42 cm 2 , respectively, might be helpful in identifying true severe SMR.

Study Limitations
This study has several important limitations. First, this was a small-scale retrospective analysis of patients with SMR who underwent TEE, with a considerable bias in data accumulation (i.e., selection bias). Second, our study defined severe SMR as VCA 3D of ≥0.39 cm 2 based on the findings of a previous study [11]. However, our results may not be accurate when using other definitions of severe SMR based on modalities other than echocardiography, including cardiac magnetic resonance imaging. Third, TEE and TTE were not performed on the same day. Hence, there might have been differences in the hemodynamic status at the time of TEE and TTE. Finally, we measured VCW AP and VCW ML using 3D-TEE data, which may not be similar to VCW AP and VCW ML determined using 2D-TEE. However, there were no significant differences between VCW AP and VCW ML measured using 3D-TEE and 2D-echocardiography according to a previous study [8].

Conclusions
VCW Average and VCA Ellipse based on 3D-TEE were strongly associated with VCA 3D . Therefore, in general, the regurgitant orifice area of SMR may be elliptical, and SMR severity might be underestimated if determined using only VCW AP and EROA PISA . Hence, VCW Average and VCA Ellipse , with best cutoff values of 0.78 cm and 0.42 cm 2 , respectively, were useful in identifying severe SMR.

Availability of Data and Materials
Data will be shared on request to the corresponding author with the permission of New Tokyo Hospital and St. Marianna University Hospital.

Author Contributions
HO and MI designed the study. HO acquired and analyzed the data. HO, MI, TN, YJA and SA interpreted the results. HO and MI prepared the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Ethics Approval and Consent to Participate
The study protocol was approved by the Institutional Review Board of New Tokyo Hospital (0267) and was in accordance with the guidelines of the Declaration of Helsinki. The requirement for informed consent was waived because of the retrospective nature of this study.