Reproducibility of Proximal Isovelocity Surface Area, Vena Contracta, and Regurgitant Jet Area for Assessment of Mitral Regurgitation Severity

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1 JACC: CARDIOVASCULAR IMAGING VOL. 3, NO. 3, BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN X/10/$36.00 PUBLISHED BY ELSEVIER INC. DOI: /j.jcmg Reproducibility of Proximal Isovelocity Surface Area, Vena Contracta, and Regurgitant Jet Area for Simon Biner, MD,* Asim Rafique, MD, Farhad Rafii, MD, Kirsten Tolstrup, MD, Omid Noorani, MS, Takahiro Shiota, MD, Swaminatha Gurudevan, MD, Robert J. Siegel, MD Tel Aviv, Israel; and Los Angeles, California OBJECTIVES The aim of this study was to evaluate the interobserver agreement of proximal isovelocity surface area (PISA) and vena contracta (VC) for differentiating severe from nonsevere mitral regurgitation (MR). BACKGROUND Recommendation for MR evaluation stresses the importance of VC width and effective regurgitant orifice area by PISA measurements. Reliable and accurate assessment of MR is important for clinical decision making regarding corrective surgery. We hypothesize that color Doppler-based quantitative measurements for classifying MR as severe versus nonsevere may be particularly susceptible to interobserver agreement. METHODS The PISA and VC measurements of 16 patients with MR were interpreted by 18 echocardiologists from 11 academic institutions. In addition, we obtained quantitative assessment of MR based on color flow Doppler jet area. RESULTS The overall interobserver agreement for grading MR as severe or nonsevere using qualitative and quantitative parameters was similar and suboptimal: 0.32 (95% confidence interval [CI]: 0.1 to 0.52) for jet area based MR grade, 0.28 (95% CI: 0.11 to 0.45) for VC measurements, and 0.37 (95% CI: 0.16 to 0.58) for PISA measurements. Significant univariate predictors of substantial interobserver agreement for: 1) jet area based MR grade was functional etiology (p 0.039); 2) VC was central MR (p 0.013) and identifiable effective regurgitant orifice (p 0.049); and 3) PISA was presence of a central MR jet (p 0.003), fixed proximal flow convergence (p 0.025), and functional etiology (p 0.049). Significant multivariate predictors of raw interobserver agreement 80% included: 1) for VC, identifiable effective regurgitant orifice (p 0.035); and 2) for PISA, central regurgitant jet (p 0.02). CONCLUSIONS The VC and PISA measurements for distinction of severe versus nonsevere MR are only modestly reliable and associated with suboptimal interobserver agreement. The presence of an identifiable effective regurgitant orifice improves reproducibility of VC and a central regurgitant jet predicts substantial agreement among multiple observers of PISA assessment. (J Am Coll Cardiol Img 2010;3:235 43) 2010 by the American College of Cardiology Foundation From the *Division of Cardiology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Division of Cardiology, Cedars-Sinai Medical Center; Department of Internal Medicine, Kaiser Permanente; and Department of Biomathematics, University of California, Los Angeles, Los Angeles, California. Manuscript received May 14, 2009; revised manuscript received September 22, 2009, accepted September 28, 2009.

2 236 JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 3, 2010 American Society of Echocardiography guideline recommendations for the evaluation of mitral regurgitation (MR) severity include assessment of color flow Doppler (CFD) regurgitant jet area and quantification of MR by vena contracta (VC) and by effective regurgitant orifice area (EROA) using proximal isovelocity surface area (PISA) (1,2). A reproducible method for assessment of MR severity is important for the management of patients with MR. Visualization of the regurgitant jet area in the left atrium provides a fast assessment of the shape, size, and direction of the regurgitant jet and a qualitative See page 244 ABBREVIATIONS AND ACRONYMS CFD color flow Doppler EROA effective regurgitant orifice area MR mitral regurgitation PISA proximal isovelocity surface area VC vena contracta evaluation of its severity, whereas assessment of VC and PISA requires meticulous attention to technical details both at image acquisition and during actual measurements (Figs. 1A and 1B) (2 5). Echocardiographic research laboratories have demonstrated that PISA and VC are accurate for MR assessment and have good interobserver agreement (3,6 11). However, the etiology of MR, the mitral valve morphology, and the regurgitant jet characteristics further complicate the assessment of MR (2,5,6). In addition, the dynamic nature of MR and pansystolic changes in VC and proximal flow convergence rate may also lead to a considerable temporal variation of both the VC width and the 2-dimensional PISA radius throughout systole, causing uncertainty among echocardiogram readers about which particular frame to choose for measurement (7). Therefore, we hypothesized that quantitative measurements of PISA and VC for classifying MR as severe versus nonsevere will have considerable interobserver agreement among clinical echocardiologists. The primary aim of this study was to evaluate the interobserver agreement of quantitative MR assessment by PISA and VC for differentiating severe from nonsevere MR. In addition, we also evaluated the reproducibility of qualitative CFD-based MR jet area as it is frequently used in clinical settings to help identify severity of MR. METHODS Patients. Interobserver agreement of jet area based assessment of MR severity, PISA, and VC was evaluated using transthoracic echocardiograms of Figure 1. Measurement of MR PISA Radius and VC Width (A) A magnified 4-chamber view was used to measure proximal isovelocity surface area (PISA) radius. The Nyquist limit was adjusted in each case to provide optimal visualization of the mitral regurgitation (MR) proximal flow convergence. The PISA radius is measured between the aliasing line of the isovelocity surface and the level of mitral regurgitant orifice. (B) A magnified parasternal long axis view was used to measure vena contracta (VC) width. To obtain an optimal VC, the transducer was sometimes angulated out of the standard imaging plane so as to identify simultaneously the 3 components including: the area of proximal flow acceleration, the VC, and the downstream expansion of the mitral regurgitation jet. The VC width (effective regurgitant orifice) is the dimension of the neck between proximal flow convergence and flow expansion in receiving chamber. 16 consecutive patients referred to Cedars Sinai Medical Center for possible surgical correction of MR. All patients had a history of effort intolerance or were asymptomatic with left ventricular systolic dysfunction. The focus of the assessment was the classification of MR into severe versus nonsevere categories to identify appropriate candidates for mitral valve surgery. The Cedars Sinai Medical Center Institutional Review Board approved this study. Interpreters. Eighteen cardiologists with mean 16 (range 2 to 40) years of post-cardiology fellowship experience as echocardiographic specialists (echocardiologists), practicing at 11 different universitybased institutions in the U.S., Japan, and Israel were provided secure Web-based access to relevant echo-

3 JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 3, cardiographic images. The influence of institutional standards on interobserver agreement was evaluated by comparing the agreement of the 6 echocardiologists practicing in a single institution to the agreement of the echocardiologists from multiple institutions. Echocardiography. A single trained sonographer with clinical trial research experience performed all studies. A narrow color flow sector width and the least depth were chosen to maximize image resolution. The CFD images of the mitral valve regurgitant jet were acquired in the parasternal long axis, apical 4- and 2-chamber views at a Nyquist limit of 50 to 60 cm/s (2). In addition, proximal flow convergence was recorded using a magnified 4-chamber view, with baseline shift of the Nyquist limit to optimize visualization of flow convergence (2) (Figs. 2A and 2B). All echocardiogram clips (moving images) were available on the Website. There were no still frame images. The reader, however, was able to play the images, stop frame them, magnify them, perform frame-by-frame analysis, as well as take measurements using calibration markings and caliper. All imaging were performed with the ie33 ultrasound system (Phillips Medical Systems, Andover, Massachusetts). As shown in Figures 3A and 3B, VC was acquired on a magnified parasternal long axis view. To image the VC, the transducer was angulated out of the standard imaging planes in an attempt to visualize the area of proximal flow acceleration, the VC, and the downstream expansion of the jet (2). Study parameters. Participants were provided CFD images and were asked to rate the following parameters: 1) MR grade from 1 to 4 based on visual qualitative assessment of the jet area; 2) manual quantitative measurement of VC; and 3) quantitative measurement of PISA radius. If the echocardiologist found a parameter to be uninterpretable, it was noted. According to reported values of PISA radius, the EROA was calculated using the following formula: 2 EROA 2 R PISA V aliasing V max where R PISA is PISA radius (cm), V aliasing is aliasing velocity of the proximal flow convergence (cm/s), and V max is maximal velocity of continuous wave Doppler MR signal (cm/s). Definitions. The MR was graded as severe or nonsevere for each echocardiogram-doppler parameter. MR was considered severe if VC was 7 mm, if EROA was 40 mm 2, or the jet size based grade Figure 2. Limitation of PISA Radius for Assessment of MR Severity (A) Clear definition of the aliasing line of the proximal isovelocity surface area (PISA) is critical for accurate assessment of mitral regurgitation (MR) severity. As shown in this apical 4-chamber view, the aliasing line of the isovelocity surface and the regurgitant orifice are well visualized, therefore reducing the potential overall interobserver variability in the assessment of MR severity. (B) In this apical 4-chamber view, the MR isovelocity surface is readily identifiable; however, precise location of the regurgitant orifice is difficult to judge. This makes the assessment of proximal isovelocity surface area radius less reliable and increases the interobserver variability in the assessment of MR severity. was 3 or 4; MR was considered nonsevere if VC was 6.9 mm, EROA was 39 mm 2, or jet size based assessment graded it as 1 or 2. The MR jet was considered eccentric if it was in close contact with the mitral leaflet behind the regurgitant orifice, and impinged to the medial or lateral wall of the left atrium, whereas central jets were initially directed into the center of the left atrium (2,3). For each patient, temporal variability of PISA radius and VC width were assessed by measuring these parameters frame by frame throughout sys-

4 238 JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 3, 2010 Figure 3. Limitation of VC Width for Assessment of MR Severity (A) As shown in this parasternal long axis view, the transition from proximal flow conversion (arrow) to the vena contracta (VC) of mitral regurgitant (MR) jet is visualized facilitating identification of the effective regurgitant orifice. A clearly defined VC neck is essential for reliable assessment of MR severity. (B) In this parasternal long axis view, the transition from the proximal flow conversion to the VC is not well visualized. Consequently, the identification of the effective MR orifice is challenging. No clear VC neck is seen; therefore, this introduces more potential interobserver variability in the assessment of MR severity. tole. We classified PISA and VC as having substantial pansystolic variation if there was greater than a 30% difference between the greatest and smallest values of any 2 different frames of the same cardiac cycle. We classified PISA as nonspherical if the maximal and minimal radius of the proximal flow convergence demonstrated a greater than 30% variation within 1 cardiac cycle. We used a cutoff of 30% to define substantial temporal variability of PISA radius and VC width as well as PISA sphericity to account for a 7% to 8% intraobserver variability of the small-scale measurements in our laboratory. In addition, a 30% difference in these parameters was readily detectable by visual assessment. Figure 3 demonstrates identification of the effective regurgitant orifice, which was defined as visible if the transition of proximal flow convergence to the VC was clearly identifiable. Overall, raw interobserver agreement (percent agreement) of 80% was classified as substantial agreement as this agreement rate was considered clinically adequate by all investigators. Values between 60% and 79% were classified as fair agreement and values below 60% as poor agreement (notably least possible interobserver agreement is 50%, which practically is equivalent to maximal disagreement). Statistical analysis. Statistical analysis was performed with the SPSS 13.0 software (SPSS Inc., Chicago, Illinois). Continuous data are presented as mean SD. Categorical data are presented as absolute number or percentages. The significance level was set at p Interobserver agreement was assessed using the overall raw agreement (percent agreement) and the Fleiss kappa statistic (12). Fleiss multirater kappa coefficient is an agreement rate adjusted for chance rate of agreement, and it was calculated using the Online Kappa Calculator developed by Randolph (13). For this purpose, we used Randolph s multirater variation of Brennan and Prediger s (14) freemarginal kappa. Raw agreement and multirater kappa were calculated for 3 methods (VC, PISA, and jet area based MR severity) in 16 patients by 18 observers and were calculated for each of the individual patients to determine the range of agreement within each method across all participants. Subsequently, cumulative raw agreement and multirate kappa were calculated for 3 study methods in patients with substantial raw agreement ( 80%) and those with suboptimal raw agreement ( 80%). Mean and 95% confidence intervals of multirater kappa were derived for 3 study methods and t test was used for comparison of multirater kappa among various study methods. The MR characteristics thought to be clinically significant were dichotomized. Fisher exact test was used to compare the significance of these predictive parameters on raw agreement of 80% versus 80%. Significant variables were included in the multivariate logistic regression analysis to predict raw agreement 80%. A p value 0.05 was considered significant for all analyses.

5 JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 3, Table 1. Baseline Clinical and Echocardiographic Characteristics Patient, n 16 Age, yrs Sex, M/F 9/7 Etiology, degenerative/functional 8/8 MR jet, eccentric/central 10/6 PISA spherical, yes/no 10/6 30% variation of PISA radius, yes/no 7/9 30% variation of VC width, yes/no 7/9 Effective MR orifice identifiable, yes/no 7/9 MR mitral regurgitation; PISA proximal isovelocity surface area; VC vena contracta. RESULTS Baseline characteristics. Clinical and echocardiographic characteristics of 16 patients studied are summarized in Table 1: mean age was years and 56% were men. Eight (50%) had functional MR (6 with ischemic and 2 with dilated cardiomyopathy); 8 cases were degenerative (5 with mitral valve prolapse and 3 with flail leaflet). In 6 patients with functional MR, the jet was central. In all 8 degenerative MR patients and 2 functional MR cases, the jet was eccentric. For both the PISA radius as well as for VC width 7 (5 degenerative and 2 functional MR) cases demonstrated 30% frameby-frame variability, whereas in the rest of the cases, the variability in these parameters was not substantial. The effective regurgitant orifice in the parasternal long axis view was visualized in 7 other cases (Fig. 2A). Prevalence of severe MR. MR severity based on jet area was deemed interpretable by readers in 273 of 288 (95%) instances, whereas VC and PISA were interpreted in 206 of 288 (72%) and 207 of 288 (72%), respectively (p 0.001). Table 2 shows the proportion of observers who rated MR as severe according to various assessment methods in each patient. Using the parameter of jet area, echocardiologists graded MR as severe in 169 of 273 (62%) instances: using VC, MR was graded as severe in 74 of 206 (36%); and using PISA, measurements were consistent with severe MR in 85 of 207 (41%) times (p 0.001). Interobserver agreement. Overall interobserver agreement on the classification of MR as severe or nonsevere was only fair for each of the study parameters. Raw agreement and kappa coefficient were: 75 16% and 0.32 (95% confidence interval [CI]: 0.12 to 0.52), respectively, for jet area based MR grade, 0.28 (95% CI: 0.11 to 0.45) and 75 Table 2. The Rate of Classification of MR as Severe by 18 Observers on 3 Study Parameters 15% for VC measurements, and 78 15% and 0.37 (95% CI: 0.16 to 0.58) for PISA measurements. Figure 4 shows the absolute and percentage distribution of substantial (raw agreement 80%), 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% 4 (25%) 5 (31%) VC (%) PISA (%) Jet Size (%) Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Patient Overall Abbreviations as in Table 1. 7 (44%) 5 (31%) 4 (25%) 7 (44%) 2 (12%) 8 (50%) Jet Area Vena Contracta EROA Poor Fair Substantial 6 (38%) Figure 4. Distribution of Overall Raw Interobserver Agreement for Assessment of MR Severity Substantial (raw agreement 80%), fair (raw agreement 60% to 79%), and poor (raw agreement 60%) interobserver agreements are shown for 3 study parameters for 18 observers. Out of 16 patients, substantial agreement was achieved in 44% of cases for mitral regurgitation (MR) jet area, 44% of patients for vena contracta method, and only 38% for effective regurgitant orifice area (EROA) based on proximal isovelocity surface area radius.

6 240 JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 3, % 50% 40% 30% 20% 10% 0% 44% 56% Jet Area 44% 44% Vena Contracta Multi Center Single Center 56% 50% EROA Figure 5. Distribution of Substantial Interobserver Agreement Among Echocardiologists Practicing in a Single Center and Multiple Centers Eighteen cardiologists practicing at 11 different institutions in the U.S., Japan, and Israel assessed mitral regurgitation (MR) severity using 3 methods in 16 patients. In addition, interobserver agreement for assessment of MR severity was compared among the 6 echocardiologists practicing within a single institution to the agreement of the echocardiologists from multiple institutions. There was a similar, suboptimal rate of substantial interobserver agreement (raw agreement 80%) for all 3 color flow Doppler parameters among interpreters from both single center and multicenter interpreters. fair (raw agreement 60% to 79%), and poor (raw agreement 60%) agreement for 3 study parameters. Raw agreement 80% was observed only in 7 (44%) patients for jet area based assessment. In this subgroup, cumulative kappa coefficient was 0.72 (95% CI: 0.68 to 0.76). Substantial agreement for VC was achieved also in 7 (44%) cases, whereas kappa in this subgroup was 0.61 (95% CI: 0.58 to 0.64). For PISA measurement, substantial agreement was present in 6 (38%) patients, kappa 0.85 (95% CI: 0.84 to 0.86). The difference was not significant among the 3 study parameters. In the rest of the cases, the agreement was fair or poor. As shown in Figure 5, separate analysis of interobserver agreement among interpreters practicing in a single institution and those from multiple centers demonstrated that the proportion of raw agreement 80% was insignificantly different for all 3 study parameters, including jet area: 56% for single institution versus 44% for multiple institutions (p 0.72). For VC, raw agreement 80% was same for physicians practicing in single center versus multiple centers at 44% (p 1.0), and for EROA measurement by PISA, raw agreement 80% between the 2 groups of observers was 56% versus 50% of the patients (p 0.99). Similarly there was no significant difference in the proportion of fair or poor agreements for all 3 study methods. Predictors of substantial interobserver agreement. To define the source of heterogeneous agreement on MR severity, etiologic and echocardiographic variables that may limit the accuracy of assessment for each study method were included in univariate and multivariate analysis. Table 3 shows the list of the variables evaluated for each study method as well as their value to predict raw agreement 80%. The only significant univariate predictor of raw agreement 80% for the jet area based method was functional etiology (p 0.039). An eccentric jet had an insignificant influence on interobserver agreement. Multivariate analysis did not identify Table 3. Univariate and Multivariate Analysis of Morphological and Etiologic Predictors of Substantial Interobserver Agreement for Jet Area, VC, and PISA Suboptimal Agreement (Raw Agreement <80%) Substantial Agreement (Raw Agreement >80%) Univariate p Value Multivariate p Value Jet Area MR jet, eccentric/central 50/50 17/ NS Etiology, degenerative/functional 67/33 0/ NS VC MR jet, eccentric/central 89/11 29/ NS Effective MR orifice identifiable, yes/no 22/78 71/ Etiology, degenerative/functional 67/33 29/71 NS NS 30% pansystolic variation of VC width, yes/no 78/22 33/67 NS NS EROA by PISA MR jet, eccentric/central 90/10 17/ PISA spherical, yes/no 70/30 50/ NS Etiology, degenerative/functional 70/30 17/ NS 30% pansystolic variation of PISA radius, yes/no 80/20 20/ NS EROA effective regurgitant orifice area; other abbreviations as in Table 1.

7 JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 3, any significant predictor of raw agreement 80% (Table 3). In univariate analysis, the statistically significant predictors for raw agreement 80% for VC were central MR (p 0.013) as well as an identifiable effective regurgitant orifice (p 0.049). Whereas in the multivariate analysis, only the measure of an identifiable effective regurgitant orifice showed a significant predictive power of raw agreement 80% (p 0.035) (Table 3). For the PISA radius measurement, the presence of a central MR jet (p 0.003), fixed proximal flow convergence (p 0.025), and functional etiology (p 0.049) were statistically significant univariate variables for prediction of raw agreement 80%. By multivariate analysis, central regurgitant jet morphology was the only significant predictor of raw interobserver agreement 80% (p 0.02) (Table 3). DISCUSSION This is the first multicenter study to evaluate the interobserver agreement of the quantitative parameters of VC width and PISA to differentiate severe from nonsevere MR. We found that classification of MR as severe as opposed to nonsevere using the quantitative CFD parameters of VC and PISA yielded only fair interobserver agreement (kappa: 0.28 to 0.37). The interobserver agreement for qualitative assessment for identifying severe from nonsevere MR was similar to the quantitative methods (kappa: 0.32). Our study group was composed of clinically experienced, practicing echocardiologists from 11 different academic institutions. Furthermore, we found that the interobserver agreement among echocardiologists practicing and instructing within the same institution was similar to the multicenter interobserver agreement and inferior to previously reported studies from single institutions validating the use of PISA and VC (3,6 11). The VC width and EROA calculated by PISA are both affected by valve morphology and color flow jet characteristics. Incorporation of echocardiographic and etiologic variables in univariate and multivariate analysis revealed some of the sources of disagreement in our study. Various echocardiographic parameters were found to be significant in predicting good agreement for each study method in the univariate analysis. However, the presence of a central regurgitant jet was the only independent discriminator between suboptimal (raw agreement 80%) and substantial reproducibility (raw agreement 80%) for PISA radius measurement. In addition, the identification of an effective regurgitant orifice was the single multivariate predictor of raw agreement 80% for VC measurement. Depending on whether observers use standardized measurements in an echocardiographic core laboratory, in a rigorously controlled research setting, or whether the MR grade is assessed by multiple enrolling sites with multiple echocardiologists, the rate of agreement is markedly different. Reliability of MR classification was reported in the EVEREST I (Endovascular Valve Edge-to-Edge Repair Study) trial. Two qualitative parameters CFD jet characteristics and pulmonary vein flow and 4 quantitative parameters VC width, regurgitant volume, regurgitant fraction, and EROA were evaluated. Parameters were integrated to form composite MR grade. Individual parameters and composite MR severity were found to be reproducible (15). However, considerable disagreement was reported in MR severity grading among echocardiogram readers in the Acorn Clinical Trial (16). All studies were interpreted to show significant MR at enrolling sites, but the core laboratory found that 41% of patients did not have significant MR: 7.4 % of patients had no detectable MR, 10.6% had mild MR, and 23.3% had moderate MR. Thomas et al. (17) proposed an MR index of 6 different indicators of MR: jet penetration into the left atrium, PISA radius, continuous wave jet intensity, pulmonary artery pressure, pulmonary venous flow pattern, and left atrial size. However, there was still a considerable overlap between moderate and severe MR (17). There are several potential explanations for the limited reproducibility for the assessment of MR severity. Qualitative assessment of mitral regurgitation based on jet area varies on any given still frame and may thus be mischaracterized due to the frameby-frame change in jet size. Whereas the eye rapidly integrates the change in jet area over time, this type of visual estimation can be highly subjective and varies among observers assessment. The etiology of MR, the mitral valve morphology, and the regurgitant jet characteristics can further compound the MR assessment (4,5). Sources of error in the measurement of PISA include the presence of an eccentric jet, nonhemispheric geometry of proximal flow convergence, imprecise identification of regurgitant orifice (Fig. 2), and dynamic changes of PISA radius throughout systole (6,7). As with PISA, inherent characteristics of MR can influence

8 242 JACC: CARDIOVASCULAR IMAGING, VOL. 3, NO. 3, 2010 the ability to accurately determine the VC width. The limitations of VC include an eccentric MR jet, dynamic VC, and inadequate visualization of any of the 3 components of VC (Fig. 3): proximal flow acceleration, the VC, and the downstream expansion of the jet (3,4). The American Society of Echocardiography 2003 guidelines for the evaluation of valvular regurgitation emphasize an integrated approach for the classification of MR severity (2). However, in a subsequent large retrospective study in which severity of MR was quantified by Doppler echocardiography, 198 patients with an EROA greater than 0.40 cm 2 had a 4% per year risk of cardiac death during a mean follow-up period of 2.7 years (18). These findings largely contributed to the recent American College of Cardiology/American Heart Association 2008 guideline (1) recommendation to consider mitral valve surgery for asymptomatic patients with severe MR. Given the current recommendations for surgery on asymptomatic patients with severe MR, it is crucial to accurately differentiate severe from nonsevere MR. However, our study demonstrates that not only qualitative CFD but also quantitative CFD parameters have limited reproducibility and thus may be suboptimal in the clinical setting. We believe that the findings of our study, which identifies the potential difficulties in reliability to differentiate severe from nonsevere MR, support the concept of Gaasch and Meyer (19), namely to question the diagnosis of severe chronic MR when little or no left ventricular or left atrial enlargement is found. Study limitations. The relatively small number of patients studied (n 16) is a limitation. However, there were 18 observers and consequently each study parameter was assessed over 200 times. Small sample size may result in overfitted models. However, it will be practically difficult to have 18 cardiologists evaluate MR in a bigger sample size by 3 different methods, although we do realize that it would be ideal to have a bigger sample size. We were attempting to differentiate severe from nonsevere MR, and we have not assessed entire spectrum of MR severity. Had patients with mild MR been included in this study, the interobserver agreement may have been better. The absence of a true gold standard for MR assessment is a potential limitation for any study as it precludes the evaluation of the accuracy of the interpretations. In the absence of such a gold standard, substantial variation exists in the classification of MR as severe in the same patient depending on the method used. These differences limit raw agreement rate maximums to an extent that readers may not appreciate. Clinical implications. As color Doppler flow methods have limited interobserver agreement, the classification of MR as severe and clinical decision making in patients with MR should incorporate the use of additional less equivocal and more reproducible parameters such as mitral inflow pattern, MR jet continuous Doppler profile, mitral inflow pattern, pulmonary venous flow, and mitral valve morphology, as well as left ventricular and left atrial dimensions and left ventricular systolic function and pulmonary artery systolic pressure as recommended by the American Society of Echocardiography (2). CONCLUSIONS The presence of a central MR jet improves the reproducibility of EROA assessment by PISA and the ability to identify the effective regurgitant orifice significantly enhances interobserver agreement of VC assessment. The VC, PISA, and CFD regurgitant jet based assessments of MR grade have substantial interobserver agreement. Use of the VC and PISA method in routine clinical practice, and for clinical decision making based solely on EROA calculation in asymptomatic MR patients may be problematic. Reprint requests and correspondence: Dr. Robert J. Siegel, 8700 Beverly Boulevard, Room 5623, Los Angeles, California siegel@cshs.org. REFERENCES 1. Bonow RO, Carabello BA, Chatterjee K, et al focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to develop guidelines for the management of patients with valvular heart disease). J Am Coll Cardiol 2008;52: e Zoghbi WA, Enriquez-Sarano M, Foster E, et al., on behalf of American Society of Echocardiography. Recommendations for evaluation of the severity of native valvular regurgitation with two-dimensional and Doppler echocardiography. J Am Soc Echocardiogr 2003;16: Hall SA, Brickner ME, Willett DL, Irani WN, Afridi I, Grayburn PA. Assessment of mitral regurgitation severity by Doppler color flow mapping of the vena contracta. Circulation 1997;95: Roberts BJ, Grayburn PA. Color flow imaging of vena contracta in mitral regurgitation: technical considerations. J Am Soc Echocardiogr 2003; 16:

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