Measurement of mitral valve area by direct three dimensional planimetry compared to multiplanar reconstruction in patients with rheumatic mitral stenosis

Mitral valve area (MVA) measurement by three-dimensional transesophageal echocardiography (3D-TEE) has a crucial role in the evaluation of mitral stenosis (MS) severity. Three-dimensional direct (3D-direct) planimetry has been proposed as a new technique to measure mitral valve area. This study aimed to compare the 3D-direct mitral valve planimetry to conventional three-dimensional multiplanar reconstruction (3D-MPR) in severe MS using 3D-TEE. In this cross-sectional, prospective study; 149 patients with severe MS who were referred for transesophageal echocardiography in Shahid Madani Hospital (Tabriz Iran), just before percutaneous transmitral commissurotomy (PTMC), recruited consecutively. All patients underwent 2D transthoracic echocardiography (2D-TTE) and 3D-TEE in a single session before PTMC. During 2D-TTE planimetry, pressure half time (PHT), and proximal isovelocity surface area (PISA) were applied to measure the MVA. Transmitral mean pressure gradient (MPG) was measured. During 3D-TEE, MVA planimetry was carried out with both 3D-direct and 3D-MPR methods. 3D-direct was applied from both atrial and ventricular views. The consistency of MVA measurements with 3D-direct, 3D-MPR, and 2D-TTE methods was statistically investigated. Our sample consisted of 109 (73.2%) women and 40 (26.8%) men. The mean age was 51.75 ± 9.81 years. The agreement between 3D-direct and 3D-MPR planimetry was significant and moderate (0.99 ± 0.29 cm2 vs. 1.12 ± 0.26 cm2, intraclass correlation = 0.716, p value = 0.001).The accuracy of the 3D-direct method reduced significantly compared to the MPR method at MVA > 1.5 cm2. The maximum difference between two methods was observed in cases with MVAs larger than 1.5 cm2. MVA measured with the 3D-MPR method was significantly correlated with a 2D-TTE method, with a moderate agreement (intraclass correlation = 0.644, p value = 0.001). Also, 2D-TTE and 3D-direct TEE techniques yielded significantly consistent measurements of the MVA (1.06 ± 0.026 cm2 vs. 0.99 ± 0.29 cm2, intraclass correlation = 0.787, p value = 0.001); however, with a slight overestimation of the MVA by the former with a net difference of 0.06 ± 0.013 cm2. Mitral valve pressure gradient (MPG) had no significant correlation with planimetry results. A significant inverse correlation was seen between the MVA and pulmonary arterial systolic pressure. 3D-direct planimetry has an acceptable agreement with 3D-MPR planimetry at MVA less than 1.5 cm2, but their correlation decreases significantly at MVA above 1.5 cm2. 3D-direct planimetry underestimates MVA compared to 3D-MPR, especially at MVA above 1.5 cm2. It seems that the saddle shape of mitral valve, interferes with 3D-direct measurement of commissures at moderate MS. The 2D-TTE planimetry has generally acceptable accuracy, but its correlation to the 3D-TEE methods is significantly reduced in cases with moderate to severe MS (i.e. MVA > 1.0 cm2).


Introduction
Rheumatic heart disease (RHD) remains the most common reason for mitral stenosis (MS), although its prevalence has decreased drastically in the developed countries [1,2]. In the developing countries, RHD is still the major cause of MS (e.g. 97% of cases in India) [3]. Mitral valve area (MVA) planimetry using two-dimensional transthoracic echocardiography (2D-TTE) is a common accurate method for evaluating the severity of rheumatic mitral stenosis (MS) and planning for management [4,5]. Although the 2D-TTE measurement of MVA is considered a sophisticated method [6], expertise and proper echocardiographic windows are required to perform it precisely on the tip of the mitral valve leaflets (MV) in a well-oriented plane [7]. In recent years, technological advances in 3D echocardiography have made possible more realistic visualization and investigation of MVA measurement. This technique improved the accuracy of the planimetry in non-experienced operators significantly [7,8]. 3D-TEE has an impressive diagnostic value in the evaluation of mitral valve commissures [9]. Real-time threedimensional transesophageal echocardiography (3D-TEE) produced excellent images with high resolutions of the MVA [8,10]. 3D-direct planimetry has been proposed as a new planimetry method of MVA. Recent small studies showed acceptable agreement between 3D-direct and 3D-MPR planimetry methods with some discrepancies which are attributed to the differences in measurement of major diameter of mitral valve [11,12]. At the study by Zhong X and et al. this difference mostly attributed to non-parallel orientation of mitral valve during planimetry by 3D-direct method [12]. They came to conclusion that 3D-direct method underestimates mitral valve area compared to MPR method. Moreover, a new study performed on a small number of patients showed a moderate to good correlation between 3D-direct and 3D-MPR methods, but similar to Zhongs study, this study didn't evaluated the results difference between diverse severity of mitral stenosis, and also in this study, the cause of the results difference between two method didn't investigated [13]. Considering the saddle-like shape of the mitral valve and it's possible effect on planimetry, we compared the results of 3D-direct and 3D-MPR planimetry methods to evaluate the role of mitral valve shape on measurement results difference and also to evaluate the impact of stenosis severity on the two method results difference. We assessed the absolute difference between results of these two methods. Furthermore, we compared the results of these two methods at different stenosis severity including, below 1 cm 2 , 1-1.5 cm 2 and above 1.5 cm 2 in large numbers of patients. We evaluated the association between 2D-TTE and 3D-TEE planimetry results, with a consideration of their moderate to good agreement which is addressed at some previously published studies [13].

Subjects and the design of the study
This is a cross-sectional, prospective, observational study. All adult patients (18-80 years old) with severe MS who were initially candidates for percutaneous transmitral commissurotomy (PTMC), were recruited consecutively. The inclusion period was from April 2017 to March 2019. The study took place at Shahid Madani Heart Hospital, which is the tertiary heart center in Tabriz, Iran. All patients underwent 2D-TTE and 3D-TEE for measurement of the MVA in a single inpatient session on the same day before PTMC. The exclusion criteria were the history of PTMC during last month and contraindication of TEE (e.g. esophageal disorders). Patients with left atrium (LA), left atrium appendage (LAA) clot or progressive MS (i.e. MVA > 1.5 cm 2 ) based on 3D planimetry results were excluded from subsequent PTMC.

2D -TTE
2D-TTE images were obtained using a Philips EPIQ 7C ultrasound machine with an X5-1 matrix probe (Philips Co., Netherlands). In direct planimetry, the MVA was measured by the operator after adjusting the setting to an optimized view. The smallest optimal mitral valve orifice was captured on leaflet tips through the parasternal short-axis view in mid-diastole during the maximal opening at smallest orifice dimension [5]. Furthermore, MVA was estimated through pressure half time (PHT) and proximal isovelocity surface area (PISA) models. Transmitral mean pressure gradient (MPG), and peak mitral flow velocity were measured, and MR severity was assessed based on American Society of Echocardiography guideline recommendations [14]. LV ejection fraction (LVEF), LA volume index (LAVI), pulmonary artery systolic pressure (based on tricuspid regurgitation peak pressure gradient) were measured. Concomitant aortic, tricuspid, and pulmonary valve regurgitation and/or stenosis were evaluated.

3D -TEE
A 2-7 MHz, real-time 3D-TEE X matrix-array transducer (Philips EPIQ 7C ultrasound machine) was used to obtain the 3D images. After optimizing the gain (generally at midrange, 50 units), compression controls, and time gain compensation over four consecutive heartbeats at sinus rhythm, a 3D Zoom data set was acquired at 0, 45, 75, and 120 degrees. At atrial fibrillation, single beat acquisition was applied and images with stitch artifacts were discarded. At the 3D-MPR method, one 2D-cut plane was place on MV leaflets tips, and other planes were placed perpendicularly. Multiple slice mode (islice method) was applied parallel to MV leaflets tips to determine the narrowest MV orifice. At the 3D-direct method, all 3D data sets were cropped. In this method, planimetry was applied at en face MV orientation from both left atrial and left ventricular sides. Planimetry at both 3D-direct and 3D-MPR methods was performed on MV leaflets tips in mid diastole during the maximal opening, at the smallest orifice dimension [11][12][13]. All measurements were done with an expert echocardiographist and were subsequently reviewed by a second echocardiographist. In cases with suboptimal quality of the 3D images, multiple attempts were made to achieve the optimal measurement.

Statistical analysis
Statistical analysis was performed using the IBM SPSS Statistics for Windows, Version 22.0. Continuous variables were expressed as the mean ± SD. Categorical variables were presented in frequencies and percentages. The normality of data distribution was assessed by Kolmogrov-Smirnov test. P values < 0.05 were considered statistically significant. For further analysis, MVA was categorized into 3 subgroups including MVA < 1.0 cm 2 , 1.0-1.5 cm 2 , and > 1.5 cm 2 . The agreement of measured MVA by 2D-TTE and 3D-TEE was evaluated by the two-way mixed intra-class correlation coefficient (ICC), Pearson correlation coefficient (R), and the Bland-Altman method.

Ethics
The research protocol was approved by the institutional review board of research ethics at Tabriz University of Medical Sciences, Iran (IR.TBZMED.REC.1398.1166). The procedure and patient rights were explained to the subjects verbally, and written informed consent was obtained from all participants.

Results
One hundred forty-nine subjects were enrolled in this study. Clinical characteristics of patients are summarized in Table 1. The sample population was composed of 109 (73.2%) female and 40 (26.8%) male patients with an average age of 51.75 ± 9.81 years. More than half of the patients (55.0%) had sinus rhythm, while the remainder of them had atrial fibrillation. Most of the included patients were symptomatic, with dyspnea being the most common complaint (89.9%). Tricuspid insufficiency was present in 96.6% of patients, which was followed by mitral regurgitation in 89.3%, and aortic regurgitation in 74.5%.
The echocardiographic results of all patients with different 2D-TTE and 3D-TEE methods are summarized in Table 2. The mean MVA measured by 3D-direct method was 0.99 ± 0.29 cm 2 , while MVA by 3D-MPR method was 1.12 ± 0.26 cm 2 . MVA measurement in the 3D-direct method overally was in significant concordance with 3D-MPR method with a good agreement (intraclass correlation = 0.716, p value = 0.001). MVA measured by 3D-direct through LA and LV views was statistically in concordance with an excellent agreement (intraclass correlation = 0.964, p value = 0.001). The average MVA in 2D-TTE was 1.06 ± 0.026 cm 2 . MVA measurement in the 2D-TTE had a significant correlation with 3D-MPR method with a moderate agreement (intraclass correlation = 0.644, p value = 0.001), while MVA measurement in the 2D-TTE had significant consistency with 3D-direct method with a good  1). Comparing the different measurement methods, it was found out that, on average, MVA measured by 3D-direct was 0.12 ± 0.003 cm 2 less than that of 3D-MPR and 0.06 ± 0.013 cm 2 less than that of 2D-TTE. The MVA measured by 3D-MPR method was 0.06 ± 0.019 larger than that of 2D-TTE (Fig. 2). The left atrium was enlarged severely in most cases and the mean LAVI was 82.39 ± 1.34 ml/m 2 . Pulmonary artery systolic pressure increased modestly in most patients and mean SPAP was 44.6 ± 14.56 mmHg. The mean LVEF was 52% ± 4%. The echocardiographic findings of all the patients were analyzed in three subgroups of MVA (i.e. < 1 cm 2 , 1-1.5 cm 2 , > 1.5 cm 2 ) ( Table 3). The analysis of the subgroups of MVA between 3D-direct and 3D-MPR TEE methods showed significant correlation with a moderate agreement at MVA less than 1 cm 2 , weak agreement at MVA between 1 and 1.5 cm 2 and no significant agreement at MVA above 1.5 cm 2 . Further analysis of the three categories of MVA between 2 and 3D-direct methods showed good agreement at MVAs below 1 cm 2 , moderate agreement between 1 and 1.5 cm 2 , and less agreement in MVA more than 1.5 cm 2 . The analysis of MVA between 2D-TTE and 3D-MPR methods showed significant correlation with a moderate agreement at MVA less than 1 cm 2 , weak agreement at MVA between 1 and  The inter-observer agreement in the measurement of MVA by 3-MPR between two expert echocardiogeaphists was 0.745 with p value = 0.001. AF rhythm was found in 44.3% of the patients which warrants anticoagulation.

Discussion
The results of our study with a relatively large sample size indicated that MVA measurement by two different 3D-direct and 3D-MPR planimetry methods had consistent results, with moderate to excellent agreement (intraclass correlation = 0.716, p value = 0.001). Overlay MVA measured by the 3D-direct method is less than 3D-MPR, and mitral stenosis severity is overestimated by 3D-direct dominantly at MVA above 1.5 cm 2 . Our subgroup analysis revealed that although there was a significant correlation between 3D-direct and 3D-MPR in very severe MS (i.e. MVA < 1 cm 2 ),but no significant correlation was observed in cases with progressive (moderate) MS (i.e. MVA > 1.5 cm 2 ). 3D-MPR is the most accurate method for planimetry and can theoretically produce reliable measurements by delineating the mitral valve orifice. Our results showed that the  (Fig. 3). We observed that when we use 3D-direct method, we had to frequently tilt the 3D volume image to allow measurement of entire MVA at progressive MS. So using a single en face plane during 3D-direct planimetry will underestimate MVA significantly. 3D-MPR is a 3D data set processing that combines image reconstruction and multiplanar cropping to identify the narrowest orifice of the valve (Fig. 3). Considering the higher accuracy of the MPR technique it seems that in the case of progressive (moderate) MS, it is better to measure the MVA by 3D-MPR method instead of 3D-direct. Recently, Zhong et al., by comparing 3D-direct and 3D-MPR methods in the case of patients with MS demonstrated that while MVA measured by 3D-direct was significantly lower than that obtained by 3D-MPR (12). The underestimation of MVA by 3D-direct was also reported by other studies [13,15]. Our study confirms and extends the findings of previous studies as we compared 3D-direct and MPR techniques in different severities of MS (Fig. 4).
MVA measured by 2D-TTE and various 3D-TEE methods had consistent results with moderate to excellent agreement. The MVA measured by 2D method was on average lower than that measured by 3D-MPR method and, in general, 2D method overestimated MS severity. Comparing the three subgroups of MVA (MVA < 1 cm 2 , MVA between 1 and 1.5 cm 2 and MVA > 1.5 cm 2 ) measured by 3D-direct, 3D-MPR and 2D methods, showed that there is a good agreement between 2D and different 3D methods at MVAs below 1 cm 2 , moderate agreement at MVA between 1 and 1.5 cm 2 , and no agreement at MVA more than 1.5 cm 2 . Traditionally, 2D-TTE is a well-established routine method for MVA measurement in the patients with MS, which is believed to be unaffected by hemodynamic changes. However, considering that obtaining an optimal perpendicular short-axis plane that crosses the tip of the mitral leaflets is sometimes difficult, the 2D-TTE method is less accurate than the 3D-TEE. Our results demonstrated that there was a significant correlation between MVA measured by 2D-TTE and 3D-TEE methods at MVA less than 1.5 cm 2 , but at MVA above 1.5 cm 2 the correlation is non-significant. This results showed that 2D-TTE has acceptable and consistent results and could be used confidently for planning patients with severe MS for PTMC but in the patients with discrepancy between clinical and echocardiographic findings, 3D-MPR or 3D-direct could be used for decision making. According to the current guidelines, an accurate determination of MVA is essential for choosing the best therapeutic strategy for MS patients [16].
During the study after initial evaluation and determining MVA by 3D methods, we excluded patients with MVA > 1.5 cm 2 from planned PTMC.
Our results were supported by the findings of some recently published studies (12, 13, and 14). But they are not consistent with the results of older studies. Min et al. compared the MVA measured by 2D-TTE and 3D-TEE in 87 patients with MS. They reported more overestimation in the measurement of the MVA by 0.19 ± 0.2 cm 2 with 2D-TEE in comparison to 3D-MPR. On the other hand, our study showed that 2D-TTE underestimates MVA compared to 3D-MPR, but overestimates when it is compared to 3D-direct. [17,18]. It seems that the difference between the our results and older studies is related to the sample size and the increase in experience in using 3D planimetry. Mean MV gradient had no significant correlation with MVA measured by both 2D-TTE and 3D-TEE methods in our study. Likewise, in the study of Najih et al. 42% of patients with severe MS (MVA < 1 cm 2 ) had a mean MV gradient < 10 mmHg, which suggests the absence of a direct correlation between an MVA < 1 cm 2 or < 1.5 cm 2 and a mean MV gradient > 10 mmHg [19]. It was notable that even severe MS exists with a mean MV gradient < 10 mmHg [19]. The 2020 European Society of Cardiology guideline defined the severe MS as an MVA of < 1.5 cm 2 and a mean MV gradient of > 5 mmHg, under a condition in which this gradient is interpreted as a product of the heart rate and the patient having sinus rhythm [20]. Consequently, although the mean MV gradient is an important indicator of MS tolerance, it is not a reliable marker of MS severity. This is mostly because of its dependence on several hemodynamic parameters including rhythm, heart rate, cardiac output, and the coexistence of mitral insufficiency [5,20,21]. Thus, it is suggested that the value of the mean MV gradient should never be interpreted as a single value.
The systolic PAP estimated through echocardiography had a significant inverse correlation with MVA in all measurement methods; therefore, it seems to be better than MG in assessing the severity of mitral valve stenosis.

Conclusion
MVA measurement by 3D-direct method showed generally significant consistency and agreement with 3D-MPR method especially at MVA less than 1.5 cm 2 . In practice, 3D-direct could be an acceptable and relatively less time-consuming method for measuring MVA. 2D-TTE planimetry yields an acceptable accuracy in measurement of MVA, comparable to that of 3D-MPR and 3D-direct planimetry, but its correlation with 3D-TEE methods is significantly reduced in cases where the valve stenosis is moderate (i.e. MVA > 1.5 cm 2 ). 2D-TTE and 3D-direct TEE methods slightly underestimated MVA compared to 3D-MPR, especially at MVA above 1.5 cm 2 . It's better to Carefully interpret the results of the latter two methods in conjunction with 3D-MPR. Incomplete evaluation of mitral valve commissures area due to saddle-like shape of MV at progressive (moderate) MS is probably a cause of 3D-direct underestimation. Finally, MPG failed to show a significant correlation with MVA measured by both 2D-TTE and 3D-TEE methods. Pulmonary artery systolic pressure had a significant inverse relation with measured MVA.

Limitations of the study
Our study had some limitations that should be addressed. It could be preferable to assess the 3D-TTE results and compare them with the results of 3D-TEE and 2D-TTE. However, the main aim of this study was to evaluate the accuracy of the results of different methods of 3D-TEE planimetry in patients with severe MS. Another limitation is the lack of invasive hemodynamic results related to MG and SPAP, which could have been helpful in assessing the true gradient and pulmonary pressure.